Primary_Ciliary_Dyskinesia

Genetic MONDO:0016575 Pathograph 122 Show in embeddings browser Ciliopathy Respiratory Disease

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous motile ciliopathy in which defective axonemal motors, regulatory structures or multiciliogenesis impair transport by respiratory cilia. Most forms are autosomal recessive; FOXJ1 and TUBB4B can cause dominant disease, and DNAAF6, OFD1 and RPGR can cause X-linked disease. Chronic wet cough, sino-otologic disease, recurrent infection and bronchiectasis follow impaired airway clearance. Nodal-cilia involvement causes genotype-dependent situs abnormalities, while reproductive cilia and sperm flagella contribute to subfertility. Normal ciliary ultrastructure, beat frequency or nasal nitric oxide do not individually exclude PCD. Clinical trajectories vary within and between genotypes; genotype associations and experimental epithelial mechanisms do not constitute validated individual severity tiers.

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Classifications

Harrison's Part

Mechanistic Nosology

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Subtypes

Primary ciliary dyskinesia 1 (DNAI1-related) MONDO:0009484

DNAI1 hgnc:2954 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic DNAI1 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DNAI1 / primary ciliary dyskinesia 1 relationship as Definitive with autosomal recessive inheritance. DNAI1 encodes dynein axonemal intermediate chain 1. The founding human report identified compound heterozygous DNAI1 defects in unrelated families, including patients whose internal organs were normally positioned.

Show evidence (2 references)

CGGV:assertion_396be572-5b2c-4859-90dd-434a91c1ce96-2022-06-30T160000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAI1 to primary ciliary dyskinesia 1 (MONDO:0009484) with classification Definitive.

PMID:11231901 SUPPORT Human clinical

"We identified compound heterozygous DNAI1 gene defects in three independent patients and in two of their siblings who presented with PCD and situs solitus (i.e., normal position of inner organs)."

The founding DNAI1 report, establishing biallelic DNAI1 defects in unrelated families with primary ciliary dyskinesia.

Primary ciliary dyskinesia 2 (DNAAF3-related) MONDO:0011718

DNAAF3 hgnc:30492 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic DNAAF3 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DNAAF3 / primary ciliary dyskinesia 2 relationship as Definitive with autosomal recessive inheritance.

Show evidence (2 references)

CGGV:assertion_40329b6f-2d65-49dd-863b-f79dcd1b5a23-2022-05-09T155600.823Z SUPPORT Other

ClinGen gene-disease validity row binding DNAAF3 to primary ciliary dyskinesia 2 (MONDO:0011718) with classification Definitive.

PMID:22387996 SUPPORT Human clinical

"We identified loss-of-function mutations in the human DNAAF3 gene in individuals from families with situs inversus and defects in the assembly of inner and outer dynein arms."

Reports the DNAAF3 loss-of-function families with dynein-arm assembly defects and situs inversus.

Primary ciliary dyskinesia 3 (DNAH5-related) MONDO:0012085

DNAH5 hgnc:2950 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic DNAH5 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DNAH5 / primary ciliary dyskinesia 3 relationship as Definitive with autosomal recessive inheritance. This stratum is curated in full as its own entry; the row is a pointer so the stratum stays discoverable from the umbrella.

Show evidence (1 reference)

CGGV:assertion_4390dba1-012d-4e08-a841-ffc08ebdc737-2022-01-07T190607.723Z SUPPORT Other

ClinGen gene-disease validity row binding DNAH5 to primary ciliary dyskinesia 3 (MONDO:0012085) with classification Definitive.

Primary ciliary dyskinesia 5 (HYDIN-related) MONDO:0012088

HYDIN hgnc:19368 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic HYDIN variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the HYDIN / primary ciliary dyskinesia 5 relationship as Definitive with autosomal recessive inheritance.

Show evidence (2 references)

CGGV:assertion_6c491ab7-496f-43b9-9bca-500901cb686d-2022-02-22T183411.247Z SUPPORT Other

ClinGen gene-disease validity row binding HYDIN to primary ciliary dyskinesia 5 (MONDO:0012088) with classification Definitive.

PMID:31545650 SUPPORT Human clinical

"which revealed one novel loss-of-function mutation in SPEF2 and three reported and 13 novel HYDIN mutations in 15 individuals"

Reports HYDIN mutations in 15 individuals from a cohort screened for central-pair defects.

Primary ciliary dyskinesia 6 (NME8-related) MONDO:0012571

NME8 hgnc:16473 Autosomal recessive inheritance

Primary ciliary dyskinesia attributed to biallelic NME8 variants on the strength of a single proband. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classified the NME8 / primary ciliary dyskinesia relationship as Limited in 2023 and reclassified it as Disputed in 2026, citing the single incompletely investigated report and the absence of NME8 expression in human airway ciliated cells. ClinGen curated NME8 against primary ciliary dyskinesia (MONDO:0016575) rather than against this numbered entity. MONDO:0012571 carries 'NME8 primary ciliary dyskinesia' and 'CILD6' among the synonyms EBI OLS4 returns for it, and HGNC lists CILD6 as an alias symbol of NME8.

Show evidence (1 reference)

CGGV:assertion_57ca8383-55b6-4edd-9be2-67b1c5142ed1-2026-03-12T000000.000Z REFUTE Other

"NME8 | HGNC:16473 | primary ciliary dyskinesia | MONDO:0016575 | AR | Disputed | SOP12 | Motile Ciliopathy Gene Curation Expert Panel | 2026-03-12T00:00:00.000Z"

ClinGen gene-disease validity row now classifying the NME8 relationship to primary ciliary dyskinesia (MONDO:0016575) as Disputed, which weighs against NME8 as an established cause of this subtype.

Primary ciliary dyskinesia 7 (DNAH11-related) MONDO:0012748

DNAH11 hgnc:2942 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic DNAH11 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DNAH11 / primary ciliary dyskinesia 7 relationship as Definitive with autosomal recessive inheritance.

Show evidence (1 reference)

CGGV:assertion_84088c46-0763-4ed6-9352-530d846e8b24-2021-10-25T190427.941Z SUPPORT Other

ClinGen gene-disease validity row binding DNAH11 to primary ciliary dyskinesia 7 (MONDO:0012748) with classification Definitive.

Primary ciliary dyskinesia 10 (DNAAF2-related) MONDO:0012918

DNAAF2 hgnc:20188 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic DNAAF2 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DNAAF2 / primary ciliary dyskinesia 10 relationship as Definitive with autosomal recessive inheritance.

Show evidence (1 reference)

CGGV:assertion_39e5de96-3f16-4dde-a7bc-b3e27364b7f8-2024-02-08T170000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAAF2 to primary ciliary dyskinesia 10 (MONDO:0012918) with classification Definitive.

Primary ciliary dyskinesia 11 (RSPH4A-related) MONDO:0012978

RSPH4A hgnc:21558 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic RSPH4A variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the RSPH4A / primary ciliary dyskinesia 11 relationship as Definitive with autosomal recessive inheritance. RSPH4A encodes a component of the axonemal radial spoke head. In the founding linkage study RSPH4A was the 6q22.1 locus, found in the five families with complete absence of the central pair, and laterality was not disturbed in the human or zebrafish data.

Show evidence (4 references)

CGGV:assertion_6f876804-e14a-4c7e-a826-232c7f445c7f-2022-04-05T150444.668Z SUPPORT Other

ClinGen gene-disease validity row binding RSPH4A to primary ciliary dyskinesia 11 (MONDO:0012978) with classification Definitive.

PMID:19200523 SUPPORT Human clinical

"Mutations were subsequently identified in two positional candidate genes, RSPH9 on chromosome 6p21.1 and RSPH4A on chromosome 6q22.1. Haplotype analysis identified a common ancestral founder effect RSPH4A mutation present in UK-Pakistani pedigrees. Both RSPH9 and RSPH4A encode protein components..."

The founding report binding RSPH4A to primary ciliary dyskinesia and naming the radial spoke head as the affected structure.

PMID:19200523 SUPPORT INDIRECT Human clinical

"Disturbance in function of these genes was not associated with defects in left-right axis determination in humans or zebrafish."

Records that laterality was not disturbed, which is why this stratum is not expected to show situs abnormalities.

+ 1 more reference

Primary ciliary dyskinesia 12 (RSPH9-related) MONDO:0012979

RSPH9 hgnc:21057 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic RSPH9 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the RSPH9 / primary ciliary dyskinesia 12 relationship as Definitive with autosomal recessive inheritance. RSPH9 encodes a second component of the axonemal radial spoke head. In the founding linkage study RSPH9 was the 6p21.1 locus, found in the two families with intermittent absence of the central-pair structure.

Show evidence (3 references)

CGGV:assertion_25b8ea38-8de2-45b7-95a1-51b33affb747-2023-10-12T160000.000Z SUPPORT Other

ClinGen gene-disease validity row binding RSPH9 to primary ciliary dyskinesia 12 (MONDO:0012979) with classification Definitive.

PMID:19200523 SUPPORT Human clinical

"This identified two loci, in two families with intermittent absence of the central-pair structure (chromosome 6p21.1, Zmax 6.7) and in five families with complete absence of the central pair (chromosome 6q22.1, Zmax 7.0)."

Records the ultrastructural split between the two radial spoke head loci.

PMID:19200523 SUPPORT Human clinical

"Mutations were subsequently identified in two positional candidate genes, RSPH9 on chromosome 6p21.1 and RSPH4A on chromosome 6q22.1."

Assigns RSPH9 to the 6p21.1 locus and RSPH4A to the 6q22.1 locus.

Primary ciliary dyskinesia 13 (DNAAF1-related) MONDO:0013174

DNAAF1 hgnc:30539 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic DNAAF1 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DNAAF1 / primary ciliary dyskinesia 13 relationship as Definitive with autosomal recessive inheritance.

Show evidence (1 reference)

CGGV:assertion_41e4b8cd-35bd-4e99-ba2d-606f191a13cf-2023-03-09T170000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAAF1 to primary ciliary dyskinesia 13 (MONDO:0013174) with classification Definitive.

Primary ciliary dyskinesia 14 (CCDC39-related) MONDO:0013434

CCDC39 hgnc:25244 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic CCDC39 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the CCDC39 / primary ciliary dyskinesia 14 relationship as Definitive with autosomal recessive inheritance.

Show evidence (1 reference)

CGGV:assertion_79c47f13-dd33-45e4-a170-6ff26aa2732c-2021-11-02T204310.116Z SUPPORT Other

ClinGen gene-disease validity row binding CCDC39 to primary ciliary dyskinesia 14 (MONDO:0013434) with classification Definitive.

Primary ciliary dyskinesia 15 (CCDC40-related) MONDO:0013435

CCDC40 hgnc:26090 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic CCDC40 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the CCDC40 / primary ciliary dyskinesia 15 relationship as Definitive with autosomal recessive inheritance. CCDC40 is required for axonemal recruitment of CCDC39, and disruption of either underlies a similar form of the disease. The founding report describes misplacement of the central pair with defective assembly of inner dynein arms and dynein regulatory complexes.

Show evidence (3 references)

CGGV:assertion_e9c192c6-9f74-4beb-85ba-a42199e9794a-2021-12-10T031508.185Z SUPPORT Other

ClinGen gene-disease validity row binding CCDC40 to primary ciliary dyskinesia 15 (MONDO:0013435) with classification Definitive.

PMID:21131974 SUPPORT Human clinical

"We further show that CCDC40 mutations in humans result in a variant of PCD characterized by misplacement of the central pair of microtubules and defective assembly of inner dynein arms and dynein regulatory complexes."

The founding report binding CCDC40 to primary ciliary dyskinesia and stating the axonemal lesion.

PMID:21131974 SUPPORT Human clinical

"CCDC40 localizes to motile cilia and the apical cytoplasm and is required for axonemal recruitment of CCDC39, disruption of which underlies a similar variant of PCD."

Records the CCDC39 dependency that makes this stratum mechanistically paired with CILD14.

Primary ciliary dyskinesia 16 (DNAL1-related) MONDO:0013525

DNAL1 hgnc:23247 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic DNAL1 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DNAL1 / primary ciliary dyskinesia 16 relationship as Definitive with autosomal recessive inheritance. DNAL1 encodes dynein axonemal light chain 1. The founding report describes absent or markedly shortened outer dynein arms, with the variant reducing light-chain stability and its interactions with the dynein heavy chain and with tubulin.

Show evidence (3 references)

CGGV:assertion_54088550-2704-4c1b-ac1b-51b62353a223-2024-04-11T160000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAL1 to primary ciliary dyskinesia 16 (MONDO:0013525) with classification Definitive.

PMID:21496787 SUPPORT Human clinical

"We demonstrate here that a homozygous point mutation in this gene is associated with PCD with absent or markedly shortened ODA."

The founding report binding DNAL1 to primary ciliary dyskinesia and stating the outer-dynein-arm lesion.

PMID:21496787 SUPPORT In vitro / ex vivo

"The mutation reduces the stability of the axonemal dynein light chain 1 and damages its interactions with dynein heavy chain and with tubulin."

Biochemical basis of the outer-dynein-arm defect in this stratum.

Primary ciliary dyskinesia 17 (DNAAF19-related) MONDO:0013854

DNAAF19 hgnc:32700 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic DNAAF19 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DNAAF19 / primary ciliary dyskinesia 17 relationship as Definitive with autosomal recessive inheritance.

Show evidence (2 references)

CGGV:assertion_9974aaef-9082-4bcd-b05a-28869447b5de-2022-12-08T170000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAAF19 to primary ciliary dyskinesia 17 (MONDO:0013854) with classification Definitive.

PMID:22581229 SUPPORT Human clinical

"Screening 146 unrelated PCD families identified individuals in six families with reduced outer dynein arms who carried mutations in CCDC103."

Reports CCDC103 (now DNAAF19) mutations in six PCD families with reduced outer dynein arms.

Primary ciliary dyskinesia 18 (DNAAF5-related) MONDO:0013940

DNAAF5 hgnc:26013 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic DNAAF5 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DNAAF5 / primary ciliary dyskinesia 18 relationship as Definitive with autosomal recessive inheritance.

Show evidence (2 references)

CGGV:assertion_9b47c717-e0a5-43ce-865b-0b14289216d7-2024-06-19T110000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAAF5 to primary ciliary dyskinesia 18 (MONDO:0013940) with classification Definitive.

PMID:23040496 SUPPORT Human clinical

"A single autosomal-recessive nonsynonymous missense mutation was identified in HEATR2, an uncharacterized gene that belongs to a family not previously associated with ciliary assembly or function."

Reports the founding HEATR2 (now DNAAF5) mutation in nine related PCD-affected subjects.

Primary ciliary dyskinesia 19 (DNAAF11-related) MONDO:0013979

DNAAF11 hgnc:16725 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic DNAAF11 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DNAAF11 / primary ciliary dyskinesia 19 relationship as Definitive with autosomal recessive inheritance.

Show evidence (2 references)

CGGV:assertion_7063ef1e-8ce2-4f35-a765-f08efc2e541a-2023-06-08T160000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAAF11 to primary ciliary dyskinesia 19 (MONDO:0013979) with classification Definitive.

PMID:23122589 SUPPORT Human clinical

"We identified, via homozygosity mapping, an early frameshift in LRRC6, a gene that encodes a leucine-rich-repeat (LRR)-containing protein."

Reports the founding LRRC6 (now DNAAF11) frameshift in PCD with absent dynein arms.

Primary ciliary dyskinesia 20 (ODAD1-related) MONDO:0014030

ODAD1 hgnc:26560 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic ODAD1 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the ODAD1 / primary ciliary dyskinesia 20 relationship as Definitive with autosomal recessive inheritance.

Show evidence (1 reference)

CGGV:assertion_999e752a-e549-447f-b142-265be7dd5935-2022-08-17T110000.000Z SUPPORT Other

ClinGen gene-disease validity row binding ODAD1 to primary ciliary dyskinesia 20 (MONDO:0014030) with classification Definitive.

Primary ciliary dyskinesia 21 (DRC1-related) MONDO:0014123

DRC1 hgnc:24245 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic DRC1 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DRC1 / primary ciliary dyskinesia 21 relationship as Definitive with autosomal recessive inheritance.

Show evidence (2 references)

CGGV:assertion_ef37e7a5-e14e-4c71-8231-b01bd636b2b9-2025-03-13T160000.000Z SUPPORT Other

"DRC1 | HGNC:24245 | primary ciliary dyskinesia 21 | MONDO:0014123 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-03-13T16:00:00.000Z"

ClinGen gene-disease validity row binding DRC1 to primary ciliary dyskinesia 21 (MONDO:0014123) with classification Definitive.

PMID:36747106 SUPPORT Human clinical

"three of 20 (15%) patients were positive for DRC1 exon 1-4 deletion"

Reports the DRC1 exon 1-4 deletion share of a Korean PCD cohort.

Primary ciliary dyskinesia 22 (ZMYND10-related) MONDO:0014192

ZMYND10 hgnc:19412 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic ZMYND10 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the ZMYND10 / primary ciliary dyskinesia 22 relationship as Definitive with autosomal recessive inheritance. ZMYND10 (HGNC alias DNAAF7) interacts with LRRC6, and the founding report proposes that a cytoplasmic complex containing the two is necessary for motile ciliary function. Loss removes the axonemal dynein components DNAH5 and DNALI1 from respiratory cilia, placing the lesion before axonemal delivery rather than in the axoneme itself.

Show evidence (4 references)

CGGV:assertion_9549c727-fece-494c-9892-83c0ac05f3b4-2023-02-07T170000.000Z SUPPORT Other

ClinGen gene-disease validity row binding ZMYND10 to primary ciliary dyskinesia 22 (MONDO:0014192) with classification Definitive.

PMID:23891469 SUPPORT Human clinical

"Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families."

The founding report binding biallelic ZMYND10 variants to primary ciliary dyskinesia in 14 families.

PMID:23891469 SUPPORT In vitro / ex vivo

"Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia."

Places the ZMYND10 lesion in cytoplasmic dynein-arm preassembly: axonemal dynein components fail to reach the axoneme.

+ 1 more reference

Primary ciliary dyskinesia 23 (ODAD2-related) MONDO:0014193

ODAD2 hgnc:25583 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic ODAD2 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the ODAD2 / primary ciliary dyskinesia 23 relationship as Definitive with autosomal recessive inheritance. ODAD2 (previous symbol ARMC4) is an axonemal protein required for the proper targeting and anchoring of the outer dynein arms. The founding report describes reduced numbers of outer dynein arms with severely impaired beating, and randomization of left-right asymmetry.

Show evidence (3 references)

CGGV:assertion_4ac46902-bffa-46f9-bc0d-081e6461d5e2-2022-12-14T170000.000Z SUPPORT Other

ClinGen gene-disease validity row binding ODAD2 to primary ciliary dyskinesia 23 (MONDO:0014193) with classification Definitive.

PMID:23849778 SUPPORT Human clinical

"By using combined high resolution copy-number variant and mutation analysis, we identified ARMC4 mutations in twelve PCD individuals whose cells showed reduced numbers of ODAs and severely impaired ciliary beating."

Founding report binding ODAD2/ARMC4 to primary ciliary dyskinesia with an outer-dynein-arm deficit.

PMID:23849778 SUPPORT In vitro / ex vivo

"We demonstrate that ARMC4 is an axonemal protein that is necessary for proper targeting and anchoring of ODAs."

States the docking-and-anchoring role that places this gene on the outer-dynein-arm docking node.

Primary ciliary dyskinesia 24 (RSPH1-related) MONDO:0014202

RSPH1 hgnc:12371 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic RSPH1 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the RSPH1 / primary ciliary dyskinesia 24 relationship as Definitive with autosomal recessive inheritance.

Show evidence (1 reference)

CGGV:assertion_f2bdb2e5-9659-46af-b306-e01207f31174-2022-06-07T110000.000Z SUPPORT Other

ClinGen gene-disease validity row binding RSPH1 to primary ciliary dyskinesia 24 (MONDO:0014202) with classification Definitive.

Primary ciliary dyskinesia 25 (DNAAF4-related) MONDO:0014203

DNAAF4 hgnc:21493 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic DNAAF4 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DNAAF4 / primary ciliary dyskinesia 25 relationship as Definitive with autosomal recessive inheritance.

Show evidence (1 reference)

CGGV:assertion_79950f5d-fd90-4765-9f8a-489c3f862fcd-2024-04-11T160000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAAF4 to primary ciliary dyskinesia 25 (MONDO:0014203) with classification Definitive.

Primary ciliary dyskinesia 26 (CFAP298-related) MONDO:0014211

CFAP298 hgnc:1301 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic CFAP298 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the CFAP298 / primary ciliary dyskinesia 26 relationship as Moderate with autosomal recessive inheritance.

Show evidence (2 references)

CGGV:assertion_f29143ae-869e-4e4c-8464-8c61f2c2663c-2023-08-10T160000.000Z SUPPORT Other

ClinGen gene-disease validity row binding CFAP298 to primary ciliary dyskinesia 26 (MONDO:0014211) with classification Moderate.

PMID:24094744 SUPPORT Human clinical

"Analysis of 295 individuals with PCD identified recessive truncating mutations of C21orf59 in four families and CCDC65 in two families."

Reports recessive truncating C21orf59 (now CFAP298) mutations in four PCD families.

Primary ciliary dyskinesia 27 (DRC2-related) MONDO:0014215

DRC2 hgnc:29937 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic DRC2 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DRC2 / primary ciliary dyskinesia 27 relationship as Definitive with autosomal recessive inheritance. DRC2 (previous symbol CCDC65) is a nexin-dynein regulatory complex subunit. Affected cilia beat abnormally with no ultrastructural defect detectable by transmission electron microscopy, so ultrastructure-led diagnosis can miss it.

Show evidence (3 references)

CGGV:assertion_662ab516-ba5f-46aa-97b2-ef4c8f3201a5-2024-08-08T160000.000Z SUPPORT Other

"DRC2 | HGNC:29937 | primary ciliary dyskinesia 27 | MONDO:0014215 | AR | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-08-08T16:00:00.000Z"

ClinGen gene-disease validity row binding DRC2 to primary ciliary dyskinesia 27 (MONDO:0014215) with classification Definitive.

PMID:23991085 SUPPORT Human clinical

"A single novel mutation in CCDC65, which created a termination codon at position 293, was identified in a subject with typical clinical features of PCD."

Founding report binding DRC2/CCDC65 to primary ciliary dyskinesia.

PMID:23991085 SUPPORT Human clinical

"The affected individual had altered cilia beating patterns, and no detectable ultrastructural defects of the ciliary axoneme, emphasizing the role of the nexin-dynein regulatory complex and the limitations of certain methods for PCD diagnosis."

Records that ultrastructure is normal in this stratum, which is the diagnostic consequence of a nexin-dynein regulatory complex defect.

Primary ciliary dyskinesia 28 (SPAG1-related) MONDO:0014216

SPAG1 hgnc:11212 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic SPAG1 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the SPAG1 / primary ciliary dyskinesia 28 relationship as Definitive with autosomal recessive inheritance. SPAG1 (HGNC alias DNAAF13) is present in airway cell lysates but not in isolated axonemes, placing it in cytoplasmic assembly or trafficking of the axonemal dynein arms. Affected individuals show combined outer and inner dynein arm defects.

Show evidence (3 references)

CGGV:assertion_c0d43e40-0aa3-41cf-9e3a-8311e685c7be-2022-06-22T190000.000Z SUPPORT Other

ClinGen gene-disease validity row binding SPAG1 to primary ciliary dyskinesia 28 (MONDO:0014216) with classification Definitive.

PMID:24055112 SUPPORT Human clinical

"All 14 affected individuals with SPAG1 mutations had a characteristic PCD phenotype, including 8 with situs abnormalities."

Founding report binding biallelic SPAG1 variants to primary ciliary dyskinesia, with laterality defects in 8 of 14.

PMID:24055112 SUPPORT In vitro / ex vivo

"SPAG1 was present in human airway epithelial cell lysates but was not present in isolated axonemes, and immunofluorescence staining showed an absence of ODA and IDA proteins in cilia from an affected individual, thus indicating that SPAG1 probably plays a role in the cytoplasmic assembly and/or..."

States the cytoplasmic preassembly role that places SPAG1 on the preassembly node rather than in the axoneme.

Primary ciliary dyskinesia 29 (CCNO-related) MONDO:0014378

CCNO hgnc:18576 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic CCNO variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the CCNO / primary ciliary dyskinesia 29 relationship as Definitive with autosomal recessive inheritance.

Show evidence (1 reference)

CGGV:assertion_20a78ac7-91a7-44a6-b42e-22611de2d170-2022-08-19T160000.000Z SUPPORT Other

ClinGen gene-disease validity row binding CCNO to primary ciliary dyskinesia 29 (MONDO:0014378) with classification Definitive.

Primary ciliary dyskinesia 32 (RSPH3-related) MONDO:0014657

RSPH3 hgnc:21054 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic RSPH3 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the RSPH3 / primary ciliary dyskinesia 32 relationship as Definitive with autosomal recessive inheritance. The Chlamydomonas ortholog of RSPH3 encodes a radial spoke stalk protein. Patient cilia show a near absence of detectable radial spokes with a variable proportion of central-complex defects, while the radial spoke head proteins RSPH1 and RSPH4A and the neck protein RSPH23 remain present.

Show evidence (5 references)

CGGV:assertion_988a074a-14e9-41e3-a1a6-fff72dda3936-2024-08-08T160000.000Z SUPPORT Other

ClinGen gene-disease validity row binding RSPH3 to primary ciliary dyskinesia 32 (MONDO:0014657) with classification Definitive.

PMID:26073779 SUPPORT Human clinical

"We identified non-ambiguous RSPH3 mutations in 5 of 48 independent families affected by CC/RS defects."

Founding report binding biallelic RSPH3 variants to primary ciliary dyskinesia in five families.

PMID:26073779 SUPPORT Human clinical

"A striking feature of the ultrastructural phenotype associated with RSPH3 mutations is the near absence of detectable RSs in all cilia in combination with a variable proportion of cilia with CC defects."

States the radial spoke lesion that places RSPH3 on the radial spoke node.

+ 2 more references

Primary ciliary dyskinesia 33 (DRC4-related) MONDO:0014750

DRC4 hgnc:4166 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic DRC4 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DRC4 / primary ciliary dyskinesia 33 relationship as Definitive with autosomal recessive inheritance. DRC4 (previous symbol GAS8) is a nexin-dynein regulatory complex subunit. As with DRC2 the axonemal architecture is preserved, so the defect is not regularly discernible by transmission electron microscopy; it was found by immunofluorescence instead.

Show evidence (5 references)

CGGV:assertion_d34bf201-5f6d-41c0-842d-5c029823ef60-2025-12-10T200000.000Z SUPPORT Other

"DRC4 | HGNC:4166 | primary ciliary dyskinesia 33 | MONDO:0014750 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-12-10T20:00:00.000Z"

ClinGen gene-disease validity row binding DRC4 to primary ciliary dyskinesia 33 (MONDO:0014750) with classification Definitive.

PMID:26387594 SUPPORT Human clinical

"Genome-wide exome sequence analyses identified recessive loss-of-function mutations in GAS8 encoding DRC4 in three independent PCD-affected families."

Founding report binding biallelic DRC4/GAS8 variants to primary ciliary dyskinesia in three families.

PMID:26387594 SUPPORT Human clinical

"This applies in particular to isolated defects of the nexin links, also known as the nexin-dynein regulatory complex (N-DRC), connecting the peripheral outer microtubular doublets."

States why a nexin-dynein regulatory complex defect is not reliably visible on transmission electron microscopy.

+ 2 more references

Primary ciliary dyskinesia 34 (DNAJB13-related) MONDO:0014909

DNAJB13 hgnc:30718 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic DNAJB13 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DNAJB13 / primary ciliary dyskinesia 34 relationship as Moderate with autosomal recessive inheritance. DNAJB13 encodes an HSP40 co-chaperone whose Chlamydomonas ortholog localizes to the radial spokes. The reported individuals had central-complex defects with normal dynein arm structure; the missense change found in the first family destabilizes the protein and triggers proteasomal degradation.

Show evidence (3 references)

CGGV:assertion_fd64a9ab-9f83-43c8-a23d-2617da493010-2025-06-12T090000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAJB13 to primary ciliary dyskinesia 34 (MONDO:0014909) with classification Moderate.

PMID:27486783 SUPPORT Human clinical

"To identify the molecular basis of a PCD phenotype characterized by central complex (CC) defects but normal DA structure, a phenotype found in ~15% of cases, we performed whole-exome sequencing in a male individual with PCD and unexplained CC defects."

States the ultrastructural phenotype this stratum presents with: central-complex defects without a dynein arm defect.

PMID:27486783 SUPPORT In vitro / ex vivo

"In vitro studies showed that this missense substitution (p.Met278Arg), which involves a highly conserved residue of several HSP40 family members, leads to protein instability and triggers proteasomal degradation, a result confirmed by the absence of endogenous DNAJB13 in cilia and sperm from..."

Functional basis of the DNAJB13 defect in the founding family.

Primary ciliary dyskinesia 35 (ODAD4-related) MONDO:0014910

ODAD4 hgnc:25280 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic ODAD4 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the ODAD4 / primary ciliary dyskinesia 35 relationship as Definitive with autosomal recessive inheritance.

Show evidence (2 references)

CGGV:assertion_547fed6e-47df-44b5-bf4a-e31f7b045862-2022-12-08T170000.000Z SUPPORT Other

ClinGen gene-disease validity row binding ODAD4 to primary ciliary dyskinesia 35 (MONDO:0014910) with classification Definitive.

PMID:27486780 SUPPORT Human clinical

"we identified recessive loss-of-function mutations within TTC25 in three individuals from two unrelated families affected by PCD"

Reports the founding TTC25 (now ODAD4) loss-of-function mutations in two PCD families.

Ciliary dyskinesia, primary, 36, X-linked (DNAAF6-related) MONDO:0010517

DNAAF6 hgnc:28570 X-linked inheritance

Primary ciliary dyskinesia caused by pathogenic DNAAF6 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DNAAF6 / ciliary dyskinesia, primary, 36, X-linked relationship as Definitive with X-linked inheritance.

Show evidence (2 references)

CGGV:assertion_5de9de15-2c09-48f5-bcaf-08c42b97700e-2024-08-17T190000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAAF6 to ciliary dyskinesia, primary, 36, X-linked (MONDO:0010517) with classification Definitive.

PMID:28176794 SUPPORT Human clinical

"we demonstrate that large genomic deletions as well as point mutations involving PIH1D3 are responsible for an X-linked form of PCD causing disruption of early axonemal dynein assembly."

Establishes PIH1D3 (now DNAAF6) as the cause of an X-linked form of PCD.

Ciliary dyskinesia, primary, 37 (DNAH1-related) MONDO:0033204

DNAH1 hgnc:2940 Autosomal recessive inheritance

MONDO and OMIM place biallelic DNAH1 variants in the numbered series as CILD37 (OMIM:617577), and ClinGen grades the gene Limited for primary ciliary dyskinesia. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DNAH1 / primary ciliary dyskinesia relationship as Limited with autosomal recessive inheritance. ClinGen curated DNAH1 against primary ciliary dyskinesia (MONDO:0016575) rather than against this numbered entity. This stratum is curated in full as its own entry; the row is a pointer so the stratum stays discoverable from the umbrella.

Show evidence (1 reference)

CGGV:assertion_a07c8b6e-a558-498b-975c-b12e96878a44-2025-10-16T160000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAH1 to primary ciliary dyskinesia (MONDO:0016575) with classification Limited.

Ciliary dyskinesia, primary, 38 (CFAP300-related) MONDO:0054843

CFAP300 hgnc:28188 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic CFAP300 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the CFAP300 / ciliary dyskinesia, primary, 38 relationship as Definitive with autosomal recessive inheritance. CFAP300 (previous symbol C11orf70) is required for the intraflagellar-transport-dependent assembly of axonemal dyneins. Affected children have immotile respiratory cilia with combined inner and outer dynein arm loss, and laterality defects.

Show evidence (3 references)

CGGV:assertion_6bcfa4e4-37a3-43a7-9b4d-60554bc7600c-2022-09-08T110000.000Z SUPPORT Other

ClinGen gene-disease validity row binding CFAP300 to ciliary dyskinesia, primary, 38 (MONDO:0054843) with classification Definitive.

PMID:29727692 SUPPORT Human clinical

"The affected children share a consistent PCD phenotype from early life with laterality defects and immotile respiratory cilia displaying combined loss of inner and outer dynein arms (IDA+ODA)."

Founding report binding biallelic CFAP300 variants to primary ciliary dyskinesia and stating the combined dynein arm lesion.

PMID:29727692 SUPPORT In vitro / ex vivo

"In summary, C11orf70 is essential for assembly of dynein arms and C11orf70 mutations cause defective cilia motility and PCD."

States the dynein-arm assembly role that places CFAP300 on the preassembly node.

Ciliary dyskinesia, primary, 39 (LRRC56-related) MONDO:0032637

LRRC56 hgnc:25430 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic LRRC56 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the LRRC56 / ciliary dyskinesia, primary, 39 relationship as Moderate with autosomal recessive inheritance.

Show evidence (2 references)

CGGV:assertion_ceef14a8-34d2-41ac-8c03-47c5eaff8986-2024-11-19T200000.000Z SUPPORT Other

ClinGen gene-disease validity row binding LRRC56 to ciliary dyskinesia, primary, 39 (MONDO:0032637) with classification Moderate.

PMID:36176820 SUPPORT Human clinical

"Next-generation sequencing of known or potential ciliopathy genes revealed him homozygous for a novel mutation c.494T>C of the LRRC56 gene, thus defining PCD as a potential cause of his features."

Case report of homozygous LRRC56 variant in a child with situs inversus totalis and recurrent respiratory infection.

Ciliary dyskinesia, primary, 40 (DNAH9-related) MONDO:0032664

DNAH9 hgnc:2953 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic DNAH9 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DNAH9 / ciliary dyskinesia, primary, 40 relationship as Definitive with autosomal recessive inheritance. This stratum is curated in full as its own entry; the row is a pointer so the stratum stays discoverable from the umbrella.

Show evidence (1 reference)

CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAH9 to ciliary dyskinesia, primary, 40 (MONDO:0032664) with classification Definitive.

Ciliary dyskinesia, primary, 42 (MCIDAS-related) MONDO:0032872

MCIDAS hgnc:40050 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic MCIDAS variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the MCIDAS / ciliary dyskinesia, primary, 42 relationship as Definitive with autosomal recessive inheritance. MCIDAS encodes multicilin, a regulator of multiciliated cell differentiation upstream of CCNO and FOXJ1. The lesion is primarily a shortage of cilia: mutant respiratory cells carry only one or two cilia each, and those few cilia also lack ciliary motility-related proteins.

Show evidence (3 references)

CGGV:assertion_866c87d2-9c7d-4f5e-bd7f-358d8e44fa54-2022-12-29T200000.000Z SUPPORT Other

ClinGen gene-disease validity row binding MCIDAS to ciliary dyskinesia, primary, 42 (MONDO:0032872) with classification Definitive.

PMID:25048963 SUPPORT Human clinical

"MCIDAS mutant respiratory epithelial cells carry only one or two cilia per cell, which lack ciliary motility-related proteins (DNAH5; CCDC39) as seen in primary ciliary dyskinesia."

Founding report binding biallelic MCIDAS variants to reduced generation of multiple motile cilia with absent motility proteins.

PMID:25048963 SUPPORT In vitro / ex vivo

"Thus, our findings identify Multicilin as a key regulator of CCNO/FOXJ1 for human multiciliated cell differentiation"

Places MCIDAS upstream of CCNO and FOXJ1 in multiciliogenesis, which is the node this stratum acts at.

Ciliary dyskinesia, primary, 43 (FOXJ1-related) MONDO:0032874

FOXJ1 hgnc:3816 Autosomal dominant inheritance

Primary ciliary dyskinesia caused by pathogenic FOXJ1 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the FOXJ1 / ciliary dyskinesia, primary, 43 relationship as Definitive with autosomal dominant inheritance. FOXJ1 encodes a forkhead transcription factor required for motile ciliogenesis. This stratum is autosomal dominant, unlike the predominantly autosomal recessive series around it: the founding report describes heterozygous de novo variants. Hydrocephalus internus accompanies the airway disease and laterality randomization, and mutant respiratory cells have reduced cilia numbers and mislocalized basal bodies.

Show evidence (4 references)

CGGV:assertion_53a48f3c-42fc-4c60-becb-149019b1e4bf-2025-10-17T190000.000Z SUPPORT Other

ClinGen gene-disease validity row binding FOXJ1 to ciliary dyskinesia, primary, 43 (MONDO:0032874) with classification Definitive.

PMID:31630787 SUPPORT Human clinical

"Heterozygous de novo mutations in FOXJ1, which encodes a well-known member of the forkhead transcription factors important for ciliogenesis of motile cilia, cause a motile ciliopathy that is characterized by hydrocephalus internus, chronic destructive airway disease, and randomization of..."

Founding report establishing the dominant, de novo mode of inheritance and the phenotype of this stratum.

PMID:31630787 SUPPORT In vitro / ex vivo

"Mutant respiratory epithelial cells are unable to generate a fluid flow and exhibit a reduced number of cilia per cell, as documented by high-speed video microscopy (HVMA), transmission electron microscopy (TEM), and immunofluorescence analysis (IF)."

States the reduced-ciliogenesis lesion that places FOXJ1 on the multiciliogenesis node.

+ 1 more reference

Ciliary dyskinesia, primary, 44 (NEK10-related) MONDO:0032914

NEK10 hgnc:18592 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic NEK10 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the NEK10 / ciliary dyskinesia, primary, 44 relationship as Definitive with autosomal recessive inheritance.

Show evidence (2 references)

CGGV:assertion_72a2f8fa-ee83-48cc-93fa-22a8990c8d13-2025-10-17T190000.000Z SUPPORT Other

"NEK10 | HGNC:18592 | ciliary dyskinesia, primary, 44 | MONDO:0032914 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-10-17T19:00:00.000Z"

ClinGen gene-disease validity row binding NEK10 to ciliary dyskinesia, primary, 44 (MONDO:0032914) with classification Definitive.

PMID:32414360 SUPPORT Human clinical

"Using whole exome sequencing we identified a homozygous truncating variant (c.3402 T > A); p.(Tyr1134*) in the NEK10 gene."

Reports a homozygous truncating NEK10 variant in two siblings with a classical PCD presentation.

Ciliary dyskinesia, primary, 45 (TTC12-related) MONDO:0032924

TTC12 hgnc:23700 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic TTC12 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the TTC12 / ciliary dyskinesia, primary, 45 relationship as Definitive with autosomal recessive inheritance.

Show evidence (2 references)

CGGV:assertion_1ff366d1-58ff-44dd-b7c3-799d1fe250c6-2025-05-08T160000.000Z SUPPORT Other

"TTC12 | HGNC:23700 | ciliary dyskinesia, primary, 45 | MONDO:0032924 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-05-08T16:00:00.000Z"

ClinGen gene-disease validity row binding TTC12 to ciliary dyskinesia, primary, 45 (MONDO:0032924) with classification Definitive.

PMID:31978331 SUPPORT Human clinical

"We identified four loss-of-function mutations in TTC12, which encodes a cytoplasmic protein, in four independent families in which affected individuals displayed a peculiar PCD phenotype characterized by the absence of ODAs and IDAs in sperm flagella, contrasting with the absence of only IDAs in..."

Establishes TTC12 as a PCD gene and records the cilia-versus-flagella difference in dynein-arm loss.

Ciliary dyskinesia, primary, 48, without situs inversus (NME5-related) MONDO:0031054

NME5 hgnc:7853 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic NME5 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the NME5 / ciliary dyskinesia, primary, 48, without situs inversus relationship as Moderate with autosomal recessive inheritance. The MONDO label records absence of situs inversus; the founding report describes a patient with situs solitus and radial-spoke/central-pair defects.

Show evidence (2 references)

CGGV:assertion_00efe110-5916-4da0-92ac-cee8c8b18140-2024-02-08T170000.000Z SUPPORT Other

"NME5 | HGNC:7853 | ciliary dyskinesia, primary, 48, without situs inversus | MONDO:0031054 | AR | Moderate | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-02-08T17:00:00.000Z"

ClinGen gene-disease validity row binding NME5 to ciliary dyskinesia, primary, 48, without situs inversus (MONDO:0031054) with classification Moderate.

PMID:32185794 SUPPORT Human clinical

"We identified a homozygous nonsense variant (c.572G>A; p.Trp191*) in NME5, which encodes a protein component of the RS neck, in one PCD patient with situs solitus."

Reports the founding NME5 nonsense variant in a PCD patient with radial-spoke defects and situs solitus.

Ciliary dyskinesia, primary, 49, without situs inversus (CFAP74-related) MONDO:0859353

CFAP74 hgnc:29368 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic CFAP74 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the CFAP74 / ciliary dyskinesia, primary, 49, without situs inversus relationship as Moderate with autosomal recessive inheritance. CFAP74 is the mammalian homolog of FAP74, which Chlamydomonas work identifies as a subunit of the C1d projection of the central apparatus. Ciliary ultrastructure is normal and beat changes are subtle, and affected individuals present no situs abnormalities, which is what the MONDO label for this stratum records.

Show evidence (4 references)

CGGV:assertion_e5a065a6-73b9-46ba-89a2-afadedb4b82c-2025-06-18T160000.000Z SUPPORT Other

ClinGen gene-disease validity row binding CFAP74 to ciliary dyskinesia, primary, 49, without situs inversus (MONDO:0859353) with classification Moderate.

PMID:36047773 SUPPORT Human clinical

"Here, we report three affected individuals from two families with compound heterozygous mutations in CFAP74 and demonstrate abnormal ciliary beating and reduced mucociliary clearance responsible for the PCD phenotype."

Founding report binding biallelic CFAP74 variants to primary ciliary dyskinesia with normal ultrastructure.

PMID:36047773 SUPPORT Human clinical

"CP complex associated defects are difficult to identify because affected individuals present no situs abnormalities and show subtle changes in high-speed video microscopy analysis (HSVMA)"

Explains why this stratum presents without situs abnormalities, which the MONDO label records.

+ 1 more reference

Ciliary dyskinesia, primary, 50 (DNAH7-related) MONDO:0957252

DNAH7 hgnc:18661 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic DNAH7 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DNAH7 / primary ciliary dyskinesia relationship as Limited with autosomal recessive inheritance. ClinGen curated DNAH7 against primary ciliary dyskinesia (MONDO:0016575) rather than against this numbered entity, and graded it Limited. The founding human report describes asthenozoospermia with losses of the inner dynein arms in spermatozoa rather than a respiratory phenotype.

Show evidence (3 references)

CGGV:assertion_90a097d6-5127-4466-8c81-00e99dab2696-2025-02-13T170000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAH7 to primary ciliary dyskinesia (MONDO:0016575) with classification Limited.

PMID:34476482 SUPPORT Human clinical

"Our study is the first to demonstrate that bi-allelic mutations in DNAH7 may impair the integrality of axoneme structure, affect sperm motility, and cause asthenozoospermia in humans."

The founding DNAH7 report describes asthenozoospermia with inner-dynein-arm loss in spermatozoa, not respiratory PCD.

PMID:34476482 SUPPORT Human clinical

"The spermatozoa from the patients with DNAH7 bi-allelic mutations showed specific losses in the inner dynein arms."

Records the axonemal lesion the founding report found, which is confined to the sperm flagellum.

Ciliary dyskinesia, primary, 52 (DAW1-related) MONDO:0957922

DAW1 hgnc:26383 Autosomal recessive inheritance

MONDO and OMIM place biallelic DAW1 variants in the numbered series as CILD52 (OMIM:620570), but the evidence for a primary ciliary dyskinesia phenotype is thin. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the DAW1 / primary ciliary dyskinesia relationship as Limited with autosomal recessive inheritance. ClinGen curated DAW1 against primary ciliary dyskinesia (MONDO:0016575) rather than against this numbered entity. ClinGen separately classifies DAW1 / visceral heterotaxy (MONDO:0018677) as Moderate, a higher grade than it gives DAW1 for primary ciliary dyskinesia. The founding report describes laterality defects with respiratory symptoms, and its own conclusion names the entity a human motile ciliopathy rather than primary ciliary dyskinesia; a later study reports heterotaxy and congenital heart disease with no evidence of primary ciliary dyskinesia. The weight of the evidence read here is a laterality-dominant motile ciliopathy, so DAW1 is deliberately not wired into this entry's pathograph.

Show evidence (5 references)

CGGV:assertion_8610990f-63cf-466a-8cd7-fbf7ae58d0f2-2024-06-13T160000.000Z SUPPORT Other

"DAW1 | HGNC:26383 | primary ciliary dyskinesia | MONDO:0016575 | AR | Limited | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-06-13T16:00:00.000Z"

ClinGen gene-disease validity row binding DAW1 to primary ciliary dyskinesia (MONDO:0016575) with classification Limited.

CGGV:assertion_999c6072-d9c6-4339-aea7-8247941748a6-2024-07-11T160000.000Z SUPPORT Other

"DAW1 | HGNC:26383 | visceral heterotaxy | MONDO:0018677 | AR | Moderate | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-07-11T16:00:00.000Z"

ClinGen grades DAW1 higher for visceral heterotaxy than for primary ciliary dyskinesia.

PMID:36074124 SUPPORT Human clinical

"In this study, we identified biallelic DAW1 variants associated with laterality defects and respiratory symptoms compatible with motile cilia dysfunction."

The founding report states the phenotype as laterality defects with respiratory symptoms.

+ 2 more references

Ciliary dyskinesia, primary, 53 (CLXN-related) MONDO:0957991

CLXN hgnc:25678 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic CLXN variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the CLXN / ciliary dyskinesia, primary, 53 relationship as Strong with autosomal recessive inheritance. CLXN (previous symbol EFCAB1) encodes the calcium-binding protein calaxin, which the founding report proposes be called outer dynein arm docking complex associated protein ODAD5. Transmission electron microscopy shows outer dynein arm defects confined to the distal ciliary axoneme.

Show evidence (3 references)

CGGV:assertion_18721467-867b-4687-b4f2-5af09951ada5-2025-04-10T160000.000Z SUPPORT Other

ClinGen gene-disease validity row binding CLXN to ciliary dyskinesia, primary, 53 (MONDO:0957991) with classification Strong.

PMID:36727596 SUPPORT Human clinical

"In this study, we identified homozygous pathogenic variants in CLXN (EFCAB1/ODAD5) in 3 individuals with laterality defects and respiratory symptoms."

Founding report binding biallelic CLXN variants to primary ciliary dyskinesia in three individuals.

PMID:36727596 SUPPORT In vitro / ex vivo

"Our results revealed that pathogenic variants in CLXN cause PCD with defects in the assembly of distal ODAs in the respiratory cilia. CLXN should be referred to as ODA-docking complex-associated protein ODAD5."

States the outer-dynein-arm docking role that places CLXN on the docking node.

Ciliary dyskinesia, primary, 54 (CFAP54-related) MONDO:0100607

CFAP54 hgnc:26456 Autosomal recessive inheritance

Primary ciliary dyskinesia caused by pathogenic CFAP54 variants. The ClinGen Motile Ciliopathy Gene Curation Expert Panel classifies the CFAP54 / ciliary dyskinesia, primary, 54 relationship as Strong with autosomal recessive inheritance. CFAP54 is one of the C1d central-apparatus genes identified together with CFAP46, CFAP74 and CFAP221. Affected individuals show insufficient ciliary clearance on in vitro transport assays.

Show evidence (2 references)

CGGV:assertion_f16ea0ce-7d5d-4bdc-92fe-52d111913161-2025-07-16T070000.000Z SUPPORT Other

ClinGen gene-disease validity row binding CFAP54 to ciliary dyskinesia, primary, 54 (MONDO:0100607) with classification Strong.

PMID:39362668 SUPPORT In vitro / ex vivo

"However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance."

C1d-defective patient cells show transport failure despite normal routine diagnostics.

◈

Mechanistic Hypotheses

Canonical Axonemal Motile-Cilia Beat-Failure / Mucociliary Clearance Model

canonical_motile_cilia_beat_failure CANONICAL

Evidence balance 5 support

Inherited defects in axonemal motors, assembly and regulation impair effective respiratory ciliary beating. Reduced multiciliogenesis and C1d-associated transport dysfunction are parallel upstream routes to impaired mucociliary clearance. Retained secretions favor recurrent infection, neutrophilic inflammation, airway remodeling and heterogeneous obstructive decline. This convergent model does not require complete immotility, abnormal routine TEM, or complete absence of clearance in every patient.

The complete June OpenScientist report and citation manifest were reassessed in September 2026; the canonical core remains supported. The provider-reported 135-paper corpus is not reconstructable from the 50-PMID sidecar. Valid cilia-number, genotype, reproductive, inflammatory and species qualifications are represented. CCNO residual cilia can retain normal motor proteins, whereas MCIDAS residual cilia lack DNAH5/CCDC39. The report omitted existing genotype-stratified longitudinal work and overstated absence of PCD randomized trials. BESTCILIA reduces exacerbations without separating antimicrobial from immunomodulatory effects; CLEAN-PCD has comparator-specific short-term results. DNAI1 mouse-cell rescue establishes proximal function, while separate 2026 human RCT1100-101/102 conference data did not demonstrate post-treatment ciliary restoration. NOS, sputum-induced M2-like macrophage responses, IFT88 mouse remodeling and infection-induced YTHDF1/DNAH5 regulation remain scoped leads, not universal mutation-intrinsic human pathways. Early-treated infant morbidity does not show early care is ineffective. Full claim and artifact judgments are in the adjacent codex assessment.

Pathograph links

Ciliary Dysfunction -> Impaired Mucociliary Clearance INDIRECT KNOWN INTERMEDIATES This ciliary defect impairs effective respiratory surface transport.

Reduced Multiciliogenesis -> Impaired Mucociliary Clearance INDIRECT KNOWN INTERMEDIATES This ciliary defect impairs effective respiratory surface transport.

Ciliary Disorientation -> Impaired Mucociliary Clearance INDIRECT KNOWN INTERMEDIATES Loss of common ciliary orientation can reduce effective directional transport; the GAS2L2 deletion model supports a clearance consequence but does not isolate orientation as the only mediator.

Central-Apparatus Transport Dysfunction -> Impaired Mucociliary Clearance INDIRECT KNOWN INTERMEDIATES This ciliary defect impairs effective respiratory surface transport.

CCDC39-CCDC40 Axonemal Scaffold Loss -> Ciliary Dysfunction DIRECT Loss of the scaffold-dependent axonemal network disrupts motor/regulatory organization.

Impaired Mucociliary Clearance -> Chronic Airway Infection and Neutrophilic Inflammation INDIRECT KNOWN INTERMEDIATES Retained secretions and microorganisms permit persistent infection and inflammatory responses.

Chronic Airway Infection and Neutrophilic Inflammation -> Bronchiectasis and Airway Wall Remodeling INDIRECT KNOWN INTERMEDIATES Persistent infection and inflammatory injury damage airway walls and alter mucus production.

Bronchiectasis and Airway Wall Remodeling -> Progressive Obstructive Lung Function Decline INDIRECT KNOWN INTERMEDIATES Chronic airway structural injury contributes to heterogeneous airflow limitation.

Cytoplasmic Dynein Arm Preassembly Failure -> Ciliary Dysfunction DIRECT Dynein arms that are never assembled in the cytoplasm cannot be imported into the axoneme, so the cilium lacks the motors that generate its beat.

Outer Dynein Arm Docking and Attachment Failure -> Ciliary Dysfunction DIRECT Outer dynein arms are the principal source of the force that drives the ciliary beat, so an axoneme that cannot retain them loses that force.

Central Pair Apparatus Defect -> Ciliary Dysfunction DIRECT Loss of central pair components alters the beat rather than abolishing it, which is why routine beat, ultrastructure and situs assessment can all read as normal in this group.

Radial Spoke Defect -> Ciliary Dysfunction DIRECT A radial spoke lesion changes the waveform rather than abolishing motility, so beat frequency can be preserved while transport is not.

Nexin-Dynein Regulatory Complex Defect -> Ciliary Dysfunction DIRECT Without the regulatory complex the doublets are no longer coordinated, and the beat becomes stiff and dyskinetic rather than absent.

Deep research

OpenScientist citations 48 citations 2026-06-19T18:07:27.584850

Show evidence (5 references)

PMID:31772028 SUPPORT Human clinical

"Combined outer/inner dynein arms (ODA/IDA) defect induces total ciliary immotility, regardless of the gene involved."

In the studied ultrastructural classes, combined dynein-arm loss produced immotility. Other genotypes show dyskinetic, hyperkinetic or apparently normal beating; this is not a universal immotility rule.

PMID:24747639 SUPPORT Human clinical

"marked reduction in the number of multiple motile cilia"

CCNO patient studies distinguish reduced cilia number from abnormal beating of residual cilia.

PMID:39362668 SUPPORT In vitro / ex vivo

"However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance."

C1d-defective patient cells show transport failure despite normal routine TEM, nasal NO and high-speed beat assessment. The selected situs-solitus cohort does not independently estimate population laterality risk.

+ 2 more references

Embryonic Nodal-Cilia Laterality-Determination Arm

embryonic_nodal_cilia_laterality CANONICAL

Evidence balance 5 support

For PCD genotypes affecting embryonic motile monocilia, defective nodal motion disrupts directional flow and asymmetric flow-sensing signals. Mouse experiments connect mechanical bending of immotile crown-cell cilia to PKD2-dependent calcium signaling and Dand5 RNA decay, enabling asymmetric NODAL/PITX2 patterning. Failure of this developmental system permits situs solitus, mirror-image situs or discordant laterality. Laterality involvement depends on tissue-specific machinery: radial-spoke/central-apparatus and CCNO/MCIDAS defects generally spare nodal monocilia, whereas CCDC39/CCDC40 as well as ODA genes can affect laterality.

The OpenScientist core is supported, but its claim of complete human mechanistic resolution and ODA-only genotype rule is too broad. The report omitted pre-existing direct mouse and zebrafish optical-tweezer evidence (PMIDs 36603091/36603098) and Dand5 post-transcriptional regulation (34210974); its blanket lack of a mammalian mechanosensing test is incorrect. Human node function remains inferred from conserved experiments and clinical genetics. Artificial-flow rescue does not rule out intracellular chirality upstream of flow. Heterotaxy is not explained by an evidence-backed turbulent-flow mechanism, and its frequency depends on definition, cohort and ascertainment. The 559-person cohort had 51.2% situs solitus, 38.5% complete inversion and 10.4% ambiguus, with 2.5% meeting its narrower complex-cardiovascular heterotaxy definition. Older North American cohorts can overlap. DRC1 single-case evidence is not equivalent to RSPH1 negative-control cohorts, and normal-TEM DNAH11 can still affect situs. The provider 100-paper search corpus and figure placeholders cannot be independently reconstructed from the 37-PMID citation sidecar.

Pathograph links

CCDC39-CCDC40 Axonemal Scaffold Loss -> Nodal Ciliary Motility Defect INDIRECT KNOWN INTERMEDIATES CCDC39/CCDC40-associated defects can disrupt nodal function as well as airway cilia; not all IDA/central-apparatus classes share this effect.

Nodal Ciliary Motility Defect -> Disrupted Directional Nodal Flow INDIRECT KNOWN INTERMEDIATES Disruption propagates through the experimentally supported vertebrate left-right patterning pathway; the direct perturbation evidence is from model embryos.

Disrupted Directional Nodal Flow -> Loss of Asymmetric Flow-Sensing and Nodal Signaling INDIRECT KNOWN INTERMEDIATES Disruption propagates through the experimentally supported vertebrate left-right patterning pathway; the direct perturbation evidence is from model embryos.

Loss of Asymmetric Flow-Sensing and Nodal Signaling -> Randomized Organ Laterality INDIRECT KNOWN INTERMEDIATES Disruption propagates through the experimentally supported vertebrate left-right patterning pathway; the direct perturbation evidence is from model embryos.

Randomized Organ Laterality -> Heterotaxy INDIRECT KNOWN INTERMEDIATES Discordant laterality can produce situs ambiguus with or without complex cardiovascular involvement.

Deep research

OpenScientist citations 36 citations 2026-06-19T18:49:22.715981

Show evidence (5 references)

PMID:27486780 SUPPORT Model organism

"we observed immotile nodal cilia and missing leftward flow via particle image velocimetry."

Ttc25 mutant mice directly connect a PCD-associated dynein-docking defect to nodal immotility and absent directional flow.

PMID:27486780 SUPPORT Model organism

"we observed immotile nodal cilia and missing leftward flow via particle image velocimetry."

Ttc25 mutant mice directly connect a PCD-associated dynein-docking defect to nodal immotility and absent directional flow.

PMID:36603091 SUPPORT Model organism

"Application of mechanical stimuli to immotile cilia by optical tweezers induced calcium ion transients and degradation of Dand5 messenger RNA (mRNA) in the targeted cells."

The 2023 mouse study directly tests mechanical sensing and downstream Dand5 responses, predating but omitted from the OpenScientist report.

+ 2 more references

Genotype / Ultrastructure-Defect Severity Stratification

genotype_ultrastructure_severity EMERGING

Evidence balance 5 support 1 refute

Genotype and ultrastructural classes associate with group-level clinical outcomes, but do not define validated severe, standard and mild tiers for an individual. CCDC39/CCDC40-associated IDA/MTD and CCNO groups show worse lung function in several cohorts; RSPH1, DNAH11 and ODAD1 can have milder group outcomes. Age, specific alleles, diagnostic ascertainment, infection, care and modifiers contribute to within-gene variation. CCDC39/CCDC40 scaffold loss causes motility-independent cellular stress, fate switching and barrier defects, a plausible additional mechanism whose mediation of patient decline remains unproven. Residual transport and cough compensation require direct physiological measurement.

The June OpenScientist report remains partially supported and the hypothesis EMERGING. The 137-person, 732-visit five-year study is mislabeled n=118 in its evidence matrix. A significant slope within IDA/MTD but not another group is not itself a between-group interaction test. Registry cross-sectional differences, nNO trends, neonatal distress and ENT intervention timing measure distinct outcomes. A small nonsignificant DNAH5/DNAH11 comparison does not prove equivalence. The 2026 functional study compared RSPH1 with DNAH5, not ODA with IDA: seven, eight and eight participants including controls; whole-lung MCC was not significantly different between genotypes, while cough clearance was higher in RSPH1 in small unadjusted comparisons. Neither universal absent MCC nor a validated cough-mediated explanation follows. CCDC39/40 cellular rescue supports cellular causality, not clinical severity mediation; its preprint and final paper are one study. CCNO hydrocephalus/infertility percentages pool new and previously reported cases. DNAH5 loss-of-function risk concerns neonatal distress; TAS2R38 modifier/ceiling effects remain observational. The claimed absence of cross-genotype omics is incorrect: 2024 mouse Cfap221/Cfap54/Spef2 scRNA-seq exists, alongside DNAH5 patient-cell redox work and CCDC39/40 proteomics. Robust multi-genotype human clinical mediation remains an open question. The 59-paper provider corpus exceeds the auditable 26-PMID sidecar; no raw computation or figure files were supplied.

Pathograph links

CCDC39-CCDC40 Axonemal Scaffold Loss -> Ciliary Dysfunction DIRECT Loss of the scaffold-dependent axonemal network disrupts motor/regulatory organization.

CCDC39-CCDC40 Axonemal Scaffold Loss -> Proteostasis Stress and Secretory Cell-Fate Switching DIRECT Scaffold loss triggers motility-independent cellular quality-control and fate effects in patient cultures.

Proteostasis Stress and Secretory Cell-Fate Switching -> Periciliary Barrier Dysfunction INDIRECT KNOWN INTERMEDIATES Altered cell fate and ciliary architecture accompany loss of the protective periciliary barrier; rescue supports a common scaffold-dependent cellular pathway.

Periciliary Barrier Dysfunction -> Impaired Mucociliary Clearance INDIRECT UNKNOWN INTERMEDIATES Periciliary barrier defects may compound transport impairment in CCDC39/CCDC40 cultures; the additional contribution to human whole-lung clearance remains unresolved.

Deep research

OpenScientist citations 26 citations 2026-06-19T19:27:20.619805

Show evidence (6 references)

PMID:38871375 SUPPORT Human clinical

"Median FEV1 z-scores were significantly lower in CCNO (-3.26), CCDC39 (-2.49) and CCDC40 (-2.96) variant groups"

The 1236-person multinational registry supports group associations in cross-sectional measurements, not longitudinal trajectories or fixed severity tiers.

PMID:30067075 SUPPORT Human clinical

"For the entire cohort, percent predicted FEV1 decline was heterogeneous with a mean (SE) decline of 0.57 (0.25) percent predicted/yr."

Five-year multicenter observational study supports heterogeneous decline. A slope differing from zero only in one subgroup does not establish that all other genotypes cannot decline.

PMID:39879322 SUPPORT In vitro / ex vivo

"the absence of the axonemal CCDC39/CCDC40 heterodimer resulted in the loss of a network of more than 90 ciliary structural proteins"

Patient-cilia proteomics and cross-species structural work establish a broad scaffold-dependent protein network. The preprint PMID:38562900 is the same study, not an independent replication.

+ 3 more references

Discussions and Knowledge Gaps

Which ciliary features explain deficient transport in C1d-associated PCD when routine beat assessment is inconspicuous?

KNOWLEDGE GAP OPEN PCD-GAP-001

Attached to

pathophysiology#Central-Apparatus Transport Dysfunction experimental_models#C1d-defective patient airway transport model

Patient cultures establish a transport defect, but do not isolate phase coordination, stroke geometry, orientation, ciliated coverage or mucus loading as its cause. A direct transport endpoint is needed to adjudicate additional imaging features.

Proposed experiments

Paired ciliary kinematics and transport in C1d patient cultures

PCD-EXP-001

Measure beat frequency, waveform, effective-stroke direction, pairwise phase relationships, ciliated and motile fractions and particle transport in matched fields across independent donors and differentiation batches. Standardize temperature, mucus load, maturation and recording duration; retain immotile and sparse fields.

Model systems

C1d patient-derived nasal ALI cultures

PRIMARY CELL CULTURE namo:TwoDCellCulture link

Readouts

Ciliary phase coordination and stroke geometry

pathophysiology#Central-Apparatus Transport Dysfunction

Quantify phase coherence separately from common beat direction and beat frequency.

cilium movement GO:0003341

Particle transport speed and directionality

pathophysiology#Central-Apparatus Transport Dysfunction

Measure transport independently of the imaging-derived feature set.

mucociliary clearance GO:0120197

Controls

Healthy donor cultures under matched conditions

Isogenic correction where technically feasible

Use correction to distinguish genotype effects from donor background; molecular correction must be followed by functional testing.

Decision criterion

Pre-specify a donor-held-out comparison of transport prediction with and without coordination and waveform features, adjusting for coverage, frequency and mucus conditions. Define a meaningful effect and uncertainty bound before analysis.

Supporting outcome

Reproducible donor-held-out improvement would support added mechanistic information from the new features.

Refuting outcome

No improvement with sufficiently narrow uncertainty would argue against useful incremental information under the tested conditions; wide uncertainty would remain inconclusive.

Show evidence (1 reference)

PMID:39362668 SUPPORT In vitro / ex vivo

"However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance."

Patient-derived C1d cultures show deficient transport despite inconspicuous routine ciliary diagnostics; the mechanism of transport inefficiency remains unresolved.

How faithfully do expanded or reprogrammed airway models preserve subtle patient ciliary phenotypes across passage and differentiation?

HUMAN MODEL MISMATCH OPEN PCD-GAP-002

Attached to

pathophysiology#Ciliary Dysfunction experimental_models#BMI1-expanded DNAH5 patient airway epithelial cell model experimental_models#Patient-derived airway organoid model experimental_models#Patient-specific hiPSC-derived airway epithelium model

Retention of immotility and outer-dynein-arm loss in DNAH5 models is evidence for those endpoints. It does not establish preservation of subtle waveform or coordination defects across genotypes, culture systems and passage, or correspondence to the fresh patient sample.

Proposed experiments

Within-donor comparison of fresh and expanded ciliary phenotypes

PCD-EXP-002

Compare fresh nasal samples with early and late ALI passage, BMI1-expanded derivatives and organoids from the same donors; add independently differentiated iPSC clones where available. Include DNAH5 immotility and motile normal-TEM genotypes. Repeat fresh sampling after recovery from acute infection to assess secondary dysfunction.

Model systems

Matched fresh nasal epithelial samples and derived airway cultures

PRIMARY CELL CULTURE namo:TwoDCellCulture link

Readouts

Within-donor ciliary phenotype concordance

pathophysiology#Ciliary Dysfunction

Compare motile fraction, beat frequency, waveform and spatial coordination; analyze donors independently of fields and technical replicates.

cilium movement GO:0003341

Controls

Matched healthy donors and culture batches

Repeated fresh sample

Separate sampling and inflammatory-state variability from changes introduced during culture.

Decision criterion

Define endpoint-specific equivalence margins from repeat-sampling variability before testing platform and passage effects; assess concordance within genotype rather than pooling all PCD.

Supporting outcome

Concordance within the pre-specified margins would support model use for that genotype and endpoint.

Refuting outcome

Reproducible passage- or platform-dependent shifts exceeding margins would limit that context of use, even if gross immotility remains stable.

Show evidence (2 references)

PMID:41064994 SUPPORT In vitro / ex vivo

"We report that the cells retain their proliferation and differentiation capacity for at least 19 passages and recapitulate the disease phenotype with immotile cilia lacking DNAH5 and other outer dynein arm proteins."

Supports prolonged expansion and retention of the DNAH5 outer-dynein-arm defect; it does not establish fidelity for motile, normal-TEM PCD genotypes.

PMID:34693619 SUPPORT In vitro / ex vivo

"Patient-specific differences in ciliary beating are observed and are in agreement with the patients' genetic mutations."

Supports the organoid model as a genotype-resolved readout of the ciliary dysfunction central to PCD.

Are partial-correction requirements determined by genotype, spatial arrangement and the behavior of uncorrected cells?

KNOWLEDGE GAP OPEN PCD-GAP-003

Attached to

pathophysiology#Impaired Mucociliary Clearance experimental_models#Mixed wild-type and CCDC40-deficient airway epithelial cultures experimental_models#CCDC40 mRNA replacement in patient airway cultures

CCDC40 mixing experiments and mRNA rescue both support functional testing beyond protein expression. The preprint estimate near 75% wild-type ciliated cells is conditional on its donor mixture and ex vivo benchmark; the 10%-74% expression range in the mRNA study measures a different quantity and cannot be treated as a conflicting correction threshold.

Proposed experiments

Genotype-resolved mosaic rescue and transport curves

PCD-EXP-003

Generate graded isogenic correction or replacement in CCDC40, DNAH5 and a motile normal-TEM genotype. Measure expression-positive and functionally corrected fractions separately among all epithelial cells and among ciliated cells. Compare clustered and dispersed correction while controlling total ciliation and mucus load.

Model systems

Patient-derived airway ALI cultures with graded correction

PRIMARY CELL CULTURE namo:TwoDCellCulture link

Readouts

Transport response to functional correction fraction

pathophysiology#Impaired Mucociliary Clearance

Estimate transport velocity, directional persistence and clearance per beat against measured functional correction and spatial coverage.

mucociliary clearance GO:0120197

Controls

Uncorrected, mock-treated and fully corrected isogenic cultures

Wild-type and mutant mixing benchmark

Compare mixing with actual correction without assuming they are equivalent interventions.

Decision criterion

Fit donor-aware transport curves and compare genotype and spatial-arrangement effects against a common-curve model with pre-specified meaningful differences; validate against held-out cultures.

Supporting outcome

Distinct reproducible curves would support genotype- or topology-specific correction requirements.

Refuting outcome

Equivalent curves within pre-specified margins would weaken genotype or spatial dependence over the tested range; neither result establishes a clinical threshold.

Show evidence (3 references)

PMID:41757021 SUPPORT In vitro / ex vivo

"Mucociliary transport declined nonlinearly, with speeds dropping from ~56 μm/s (100% WT) to ~9 μm/s in 100% mutant cultures."

The preprint reports a nonlinear transport response to mixing wild-type and CCDC40-mutant cells; this is not a clinical efficacy threshold.

PMID:41757021 SUPPORT Computational

"Modeling revealed that transport efficiency was equivalent to that recorded in ex vivo human tissues and plateaued when ~75% of the ciliated population was WT."

Preprint estimate uses the ciliated-cell population as denominator and an ex vivo tissue benchmark; transfer to other genotypes, delivery methods or patients remains untested.

PMID:42089334 SUPPORT In vitro / ex vivo

"Further, we showed improved ciliary transport of fluorescent particles."

Patient-cell rescue goes beyond beat frequency to an in vitro transport readout; it remains distinct from clinical whole-lung clearance or outcomes.

How much of measured epithelial coordination is intrinsic to the PCD genotype versus imposed by culture flow and geometry?

HUMAN MODEL MISMATCH OPEN PCD-GAP-004

Attached to

pathophysiology#Ciliary Dysfunction experimental_models#iPSC-derived microfluidic airway-on-a-chip model

The airway-on-a-chip study shows that fluid shear regulates planar polarity and ciliogenesis. Thus an organized flow field is partly a product of the model conditions. Planar alignment, temporal phase synchrony and net transport must be measured separately before a coordination metric is interpreted as patient-intrinsic dysfunction.

Proposed experiments

Genotype by mechanical-context comparison

PCD-EXP-004

Compare patient and isogenic corrected airway sheets under matched static and controlled-shear conditions. Measure before conditioning, during conditioning and after withdrawal; quantify ciliated coverage and mucus loading alongside flow.

Model systems

Patient and corrected iPSC-derived airway-on-a-chip

ORGAN ON CHIP namo:OrganOnChip link

Readouts

Planar alignment and phase coordination

pathophysiology#Ciliary Dysfunction

Separate directional alignment from temporal phase relationships and account for ciliated coverage.

cilium movement GO:0003341

Directional transport after conditioning

pathophysiology#Impaired Mucociliary Clearance

Assess endogenous transport after external flow stops, distinguishing imposed advection from cilia-driven movement.

mucociliary clearance GO:0120197

Controls

Isogenic corrected epithelium under each flow condition

Static cultures at matched differentiation stage

Decision criterion

Pre-specify genotype, shear and interaction contrasts with donor or clone as the independent unit; test whether the disease-associated signal persists after removal of imposed flow.

Supporting outcome

A persistent genotype effect across mechanical conditions would support an intrinsic defect in the measured feature.

Refuting outcome

A signal abolished or reversed by conditioning would limit interpretation as a platform-independent disease readout.

Show evidence (2 references)

PMID:34233948 SUPPORT In vitro / ex vivo

"Here, we combine human iPSCs and airway-on-a-chip technology, to demonstrate the effectiveness of fluid shear stress (FSS) for regulating the global axis of multicellular planar cell polarity (PCP), as well as inducing ciliogenesis, thereby contributing to quantifiable unidirectional mucociliary flow."

Shows that the platform imposes a mechanical context that affects polarity and flow; it is relevant to interpreting coordination measurements.

PMID:34233948 SUPPORT In vitro / ex vivo

"The application of an airway cell sheet derived from patient-derived iPSCs and their gene-edited counterparts, as well as genetic knockout iPSCs of PCD causative genes, made it possible to recapitulate the abnormal ciliary functions in organized PCP using the airway-on-a-chip."

Establishes PCD ciliary phenotyping in an engineered, planar-polarized human airway epithelium.

Does loss of motile cilia drive airway wall remodeling in human PCD through a direct epithelial-homeostasis route, independently of the infection-inflammation cycle?

HUMAN MODEL MISMATCH OPEN PCD-GAP-005

Attached to

pathophysiology#Bronchiectasis and Airway Wall Remodeling pathophysiology#Periciliary Barrier Dysfunction

Conditional IFT88 deletion in adult mice removed airway cilia and produced bronchial remodeling, epithelial hypertrophy and hyperplasia, increased club-cell numbers and airway hyperreactivity without detectable inflammation or an apparent mucus-clearance defect. IFT88 is an intraflagellar-transport gene that also affects non-motile cilia and epithelial differentiation, so the model is not equivalent to a human axonemal PCD genotype. Two node descriptions in this entry already qualify the experiment on those grounds and keep remodeling downstream of chronic infection and inflammation; whether a cilia-autonomous route contributes in human PCD has not been tested.

Proposed experiments

Remodeling-versus-inflammation dissociation in early human PCD airway

PCD-EXP-005

In genotype-defined children diagnosed before chronic infection is established, pair bronchial biopsy or brushing histomorphometry (basal and club-cell composition, epithelial hypertrophy, basement-membrane thickening) with airway inflammatory markers and a regional clearance measurement, and test whether structural remodeling is present in airway segments whose inflammatory and clearance measures are unremarkable.

Decision criterion

Pre-specify the remodeling indices, the inflammatory and clearance ranges that count as unaffected, and a meaningful effect size, with the participant as the independent unit and adjustment for age, genotype and treatment history.

Would support

pathophysiology#Bronchiectasis and Airway Wall Remodeling

Supporting outcome

Elevated remodeling indices in segments whose inflammatory markers and clearance sit within the non-PCD range would support a cilia-autonomous contribution in humans.

Refuting outcome

Remodeling that tracks inflammatory burden and clearance failure with no residual component would leave the infection-driven cascade sufficient over the sampled age range.

Show evidence (2 references)

PMID:24213915 SUPPORT Model organism

"In IFT88(-) mice there was a substantial loss of airway cilia on respiratory epithelium. Three months after the deletion of cilia, there was clear evidence for bronchial remodeling that was not associated with inflammation or apparent defects in mucus clearance."

Establishes the inflammation-independent remodeling phenotype in the IFT88-deletion mouse that this entry discusses in three node and hypothesis descriptions. It is a mouse result and does not demonstrate the route in human PCD, which is the open question this discussion records.

PMID:24213915 SUPPORT Model organism

"Club cells may be prevented from differentiating into respiratory epithelial cells because of a lack of IFT88 protein that is necessary to form a single nonmotile cilium."

The authors attribute part of the phenotype to loss of a nonmotile cilium needed for club-cell differentiation, which is why the IFT88 model is not equivalent to a human axonemal PCD genotype.

⚙

Pathophysiology

Ciliary Dysfunction

Defects in dynein motors, their cytoplasmic assembly or docking, and axonemal regulatory structures impair coordinated ciliary movement. Combined outer/inner dynein-arm loss can cause immotility, whereas DNAH11-related disease can retain hyperkinetic but ineffective beating and RSPH1-related disease can retain frequency with an abnormal circular waveform. This beat-dysfunction route is distinct from reduced multiciliogenesis and transport failure despite apparently normal routine beat measurements. Radial spoke and nexin-dynein regulatory complex lesions are modeled as separate upstream nodes, because each is a distinct structure whose loss reaches the beat by its own route; the genes for those two complexes are wired there rather than here.

Canonical Axonemal Motile-Cilia Beat-Failure / Mucociliary Clearance Model

respiratory tract multiciliated cell CL:4030034

DNAI1 hgnc:2954 DNAH5 hgnc:2950 DNAH11 hgnc:2942 DNAH9 hgnc:2953 ODAD1 hgnc:26560 SPEF2 hgnc:26293 NEK10 hgnc:18592 NME8 hgnc:16473 LRRC56 hgnc:25430 DNAL1 hgnc:23247

cilium movement GO:0003341 ⚠ ABNORMAL

Cilia GO:0005929 axoneme GO:0005930 outer dynein arm GO:0036157

respiratory tract epithelium UBERON:0004802 nasal cavity epithelium UBERON:0005384 trachea UBERON:0003126 bronchus UBERON:0002185

Experimental models

Patient-derived nasal epithelial air-liquid interface model PRIMARY CELL CULTURE Retains a range of patient ciliary beat and ultrastructural defects after basal-cell expansion.

Patient-derived airway organoid model ORGANOID Differentiated patient airway organoids retain mutation-associated ciliary beating abnormalities.

Patient-specific hiPSC-derived airway epithelium model IPSC DERIVED MODEL DNAH5 and NME5 patient-derived hiPSC airway epithelia reproduce their respective structural and functional ciliary defects.

DNAH5 patient redox profiling and separate GSTA2 airway-cell perturbation PRIMARY CELL CULTURE Separate GSTA2 knockdown slows ciliary beating in primary human airway cells, with partial catalase rescue of transport.

BMI1-expanded DNAH5 patient airway epithelial cell model CELL LINE Retains DNAH5-associated ciliary immotility and missing outer-dynein-arm proteins after expansion.

iPSC-derived microfluidic airway-on-a-chip model ORGAN ON CHIP Recapitulates abnormal PCD ciliary function in an organized planar-polarity context.

BCi-NS1.1 dyskinetic airway epithelial cell line CELL LINE Reproduces dyskinetic circular ciliary beating in the reported cell-line culture.

Animal models

Mdnah5 (Dnah5) loss-of-function (insertional mutation) Mouse Mouse recapitulates Models immotility and outer-dynein-arm loss in Dnah5-deficient mice.

Xenopus lrrc56-knockdown multiciliated cells Xenopus laevis recapitulates Reproduces the outer-dynein-arm assembly failure that underlies the ODA-defect class of PCD, and places Lrrc56 upstream of the ODA docking complex through Odad3.

Xenopus embryonic epidermis foxi1e ionocyte-depletion model Xenopus laevis perturbs Produces fewer cilia per multiciliated cell and abnormal ciliary beating by depleting a neighboring epidermal cell type.

Downstream

Impaired Mucociliary Clearance This ciliary defect impairs effective respiratory surface transport.

Show evidence (2 references)

PMID:31772028 SUPPORT Human clinical

"Combined outer/inner dynein arms (ODA/IDA) defect induces total ciliary immotility, regardless of the gene involved."

PMID:24568568 SUPPORT Human clinical

"Cilia from individuals with RSPH1 mutations had normal beat frequency"

RSPH1 patient cilia retained frequency but had an abnormal circular waveform, showing why frequency alone is insufficient.

Reduced Multiciliogenesis

CCNO and MCIDAS defects impair the generation of numerous motile cilia. CCNO affects centriole amplification and maturation; MCIDAS acts upstream in multiciliated-cell differentiation and motor-protein expression. FOXJ1 and dominant-negative TUBB4B variants can also reduce cilia generation through distinct transcriptional or microtubule mechanisms. Cilia number and the structure/function of residual cilia must be assessed separately. Nodal monocilia are generally spared by CCNO/MCIDAS defects; that negative prediction does not extend to every ciliogenesis gene.

Canonical Axonemal Motile-Cilia Beat-Failure / Mucociliary Clearance Model

respiratory tract multiciliated cell CL:4030034

CCNO hgnc:18576 MCIDAS hgnc:40050 FOXJ1 hgnc:3816 TUBB4B hgnc:20771

cilium assembly GO:0060271 ↓ DECREASED

respiratory tract epithelium UBERON:0004802

Downstream

Impaired Mucociliary Clearance This ciliary defect impairs effective respiratory surface transport.

Show evidence (4 references)

PMID:24747639 SUPPORT Human clinical

"marked reduction in the number of multiple motile cilia"

CCNO patient studies distinguish reduced cilia number from abnormal beating of residual cilia.

PMID:25048963 SUPPORT Human clinical

"MCIDAS mutant respiratory epithelial cells carry only one or two cilia per cell, which lack ciliary motility-related proteins (DNAH5; CCDC39) as seen in primary ciliary dyskinesia."

MCIDAS disrupts the multiciliogenesis program; remaining cilia need not share CCNO residual-cilium normality.

PMID:38662826 SUPPORT In vitro / ex vivo

"Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner."

Human genetics and functional models support a separate dominant-negative ciliogenesis route.

+ 1 more reference

Ciliary Disorientation

GAS2L2 deficiency disrupts orientation of airway motile cilia despite preserved axonemal ultrastructure. Patient-derived nasal cells show asynchronous, hyperkinetic beating. Directional alignment is distinct from beat frequency and temporal phase coordination; these properties should be quantified separately. Conditional Gas2l2 deletion impairs clearance in mice, supporting a transport consequence without establishing that every normal-TEM PCD genotype shares this mechanism.

Canonical Axonemal Motile-Cilia Beat-Failure / Mucociliary Clearance Model

respiratory tract multiciliated cell CL:4030034

GAS2L2 hgnc:24846

cilium movement GO:0003341 ⚠ ABNORMAL

nasal cavity epithelium UBERON:0005384

Experimental models

GAS2L2-deficient patient nasal epithelial orientation model PRIMARY CELL CULTURE Measures patient-associated ciliary disorientation together with asynchronous, increased-frequency beating.

Downstream

Impaired Mucociliary Clearance Loss of common ciliary orientation can reduce effective directional transport; the GAS2L2 deletion model supports a clearance consequence but does not isolate orientation as the only mediator.

Show evidence (1 reference)

PMID:30665704 SUPPORT In vitro / ex vivo

"Cultured GAS2L2-deficient nasal epithelial cells from one of the affected individuals showed defects in ciliary orientation and had an asynchronous and hyperkinetic (GAS2L2-deficient = 19.8 Hz versus control = 15.8 Hz) ciliary-beat pattern."

Patient-derived nasal cells demonstrate an orientation defect with asynchronous hyperkinetic beating; this does not establish the cause of transport failure in C1d-associated disease.

Central-Apparatus Transport Dysfunction

Mechanism confidence: Provisional

Loss of C1d projection components can impair collective ciliary transport despite apparently normal beat frequency, waveform, routine TEM and nasal nitric oxide. The nine-person characterization included CFAP46, CFAP54, CFAP74 and CFAP221 variants, with transport experiments on available patient cultures. The physiological transport endpoint therefore complements routine single-cilium observations. Clinical gene-validity grades differ and should not be inferred from inclusion in one functional study.

Canonical Axonemal Motile-Cilia Beat-Failure / Mucociliary Clearance Model

respiratory tract multiciliated cell CL:4030034

CFAP46 hgnc:25247 CFAP54 hgnc:26456 CFAP74 hgnc:29368 CFAP221 hgnc:33720

mucociliary clearance GO:0120197 ↓ DECREASED

respiratory tract epithelium UBERON:0004802

Experimental models

C1d-defective patient airway transport model PRIMARY CELL CULTURE Directly measures ineffective transport in C1d-defective patient cultures.

Downstream

Impaired Mucociliary Clearance This ciliary defect impairs effective respiratory surface transport.

Show evidence (1 reference)

PMID:39362668 SUPPORT In vitro / ex vivo

"However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance."

CCDC39-CCDC40 Axonemal Scaffold Loss

Mechanism confidence: Provisional

The CCDC39/CCDC40 heterodimer organizes inner dynein arms, nexin-dynein regulatory and other axonemal structures. Its absence removes a network of over 90 structural proteins, including ciliary address-recognition proteins. This disrupts motility and triggers cellular effects beyond beating; these experiments support a candidate explanation for excess clinical severity without establishing longitudinal clinical mediation.

Canonical Axonemal Motile-Cilia Beat-Failure / Mucociliary Clearance Model Embryonic Nodal-Cilia Laterality-Determination Arm Genotype / Ultrastructure-Defect Severity Stratification

respiratory tract multiciliated cell CL:4030034

CCDC39 hgnc:25244 CCDC40 hgnc:26090

axoneme assembly GO:0035082 ⚠ ABNORMAL

respiratory tract epithelium UBERON:0004802

Experimental models

CCDC40 mRNA replacement in patient airway cultures PRIMARY CELL CULTURE mRNA replacement restores CCDC40 and integration of associated axonemal proteins.

Animal models

ccdc40 mutant / morphant Zebrafish Zebrafish recapitulates Ccdc40 loss disrupts ciliary axonemal organization and motility.

Downstream

Ciliary Dysfunction Loss of the scaffold-dependent axonemal network disrupts motor/regulatory organization.

Proteostasis Stress and Secretory Cell-Fate Switching Scaffold loss triggers motility-independent cellular quality-control and fate effects in patient cultures.

Nodal Ciliary Motility Defect CCDC39/CCDC40-associated defects can disrupt nodal function as well as airway cilia; not all IDA/central-apparatus classes share this effect.

Show evidence (1 reference)

PMID:39879322 SUPPORT In vitro / ex vivo

"the absence of the axonemal CCDC39/CCDC40 heterodimer resulted in the loss of a network of more than 90 ciliary structural proteins"

Patient-cilia proteomics and cross-species structural work establish a broad scaffold-dependent protein network. The preprint PMID:38562900 is the same study, not an independent replication.

Proteostasis Stress and Secretory Cell-Fate Switching

Mechanism confidence: Provisional

In CCDC39/CCDC40-deficient airway cells, destabilization of the axonemal network activates quality-control pathways and shifts multiciliated cells toward mucus-producing cells. Normal CCDC39 transgene expression reversed the measured phenotypes in CCDC39-variant cells. This is a demonstrated cellular phenotype, while its quantitative contribution to patient lung-function decline remains unresolved.

Genotype / Ultrastructure-Defect Severity Stratification

respiratory tract multiciliated cell CL:4030034

CCDC39 hgnc:25244 CCDC40 hgnc:26090

respiratory tract epithelium UBERON:0004802

Downstream

Periciliary Barrier Dysfunction Altered cell fate and ciliary architecture accompany loss of the protective periciliary barrier; rescue supports a common scaffold-dependent cellular pathway.

Show evidence (2 references)

PMID:39879322 SUPPORT In vitro / ex vivo

"The absence of the network impaired microtubule architecture, activated cell quality control pathways, switched multiciliated cell fate to mucus-producing cells and resulted in a defective periciliary barrier."

Patient-cell experiments identify proteostasis, cell-fate and barrier abnormalities downstream of scaffold loss.

PMID:39879322 SUPPORT In vitro / ex vivo

"In CCDC39 variant cells, these phenotypes were reversed through expression of a normal CCDC39 transgene."

Genetic rescue supports causality for cellular phenotypes, not yet clinical rescue.

Periciliary Barrier Dysfunction

Mechanism confidence: Provisional

CCDC39/CCDC40-deficient cell cultures have altered epithelial composition and a defective periciliary barrier, providing a potential additional impediment to airway surface transport. This route is mechanistically distinct from complete motile-cilium loss after conditional IFT88 deletion in mice, and neither model proves that infection-independent bronchiectasis is universal in human PCD.

Genotype / Ultrastructure-Defect Severity Stratification

respiratory tract multiciliated cell CL:4030034

respiratory tract epithelium UBERON:0004802

Downstream

Impaired Mucociliary Clearance Periciliary barrier defects may compound transport impairment in CCDC39/CCDC40 cultures; the additional contribution to human whole-lung clearance remains unresolved.

Show evidence (1 reference)

PMID:39879322 SUPPORT In vitro / ex vivo

Patient-cell experiments identify proteostasis, cell-fate and barrier abnormalities downstream of scaffold loss.

Impaired Mucociliary Clearance

Ineffective propulsion by airway cilia, insufficient cilia number and impaired epithelial transport retain mucus and inhaled material. Radioaerosol clearance was absent in most of 69 measured patients spanning 26 genotypes, with a residual-clearance exception in CCDC103-related disease. Voluntary cough improved clearance and represents a partly compensating mechanism; regional deposition and cough complicate interpretation of whole-lung tracer measurements.

Canonical Axonemal Motile-Cilia Beat-Failure / Mucociliary Clearance Model

respiratory tract multiciliated cell CL:4030034

mucociliary clearance GO:0120197 ↓ DECREASED

respiratory system UBERON:0001004 paranasal sinus UBERON:0001825

Experimental models

Patient-specific hiPSC-derived airway epithelium model IPSC DERIVED MODEL Patient-specific hiPSC airway epithelia reproduce impaired culture-surface transport.

CCDC40 mRNA replacement in patient airway cultures PRIMARY CELL CULTURE Treatment improves fluorescent-particle transport in patient cultures.

Mixed wild-type and CCDC40-deficient airway epithelial cultures PRIMARY CELL CULTURE Perturbs the fraction of functional cells to measure emergent epithelial transport.

Computational models

CFD model of mucociliary clearance under ciliary abnormalities PHYSIOLOGICAL Simulates how cilia beat/coordination abnormalities reduce net mucus transport, recapitulating impaired mucociliary clearance.

Downstream

Chronic Airway Infection and Neutrophilic Inflammation Retained secretions and microorganisms permit persistent infection and inflammatory responses.

Chronic Cough Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional inflammatory/structural intermediates affect expression.

Recurrent Respiratory Infections Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional inflammatory/structural intermediates affect expression.

Chronic Otitis Media Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional inflammatory/structural intermediates affect expression.

Nasal Polyposis Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional inflammatory/structural intermediates affect expression.

Chronic Rhinosinusitis Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional inflammatory/structural intermediates affect expression.

Productive Cough Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional inflammatory/structural intermediates affect expression.

Recurrent Sinopulmonary Infections Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional inflammatory/structural intermediates affect expression.

Nasal Congestion Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional inflammatory/structural intermediates affect expression.

Chronic Rhinitis Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional inflammatory/structural intermediates affect expression.

Abnormal Sputum Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional inflammatory/structural intermediates affect expression.

Recurrent Otitis Media Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional inflammatory/structural intermediates affect expression.

Wheezing Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional inflammatory/structural intermediates affect expression.

Atelectasis Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional inflammatory/structural intermediates affect expression.

Conductive Hearing Impairment Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional inflammatory/structural intermediates affect expression.

Hearing Loss Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional inflammatory/structural intermediates affect expression.

Neonatal Respiratory Distress Impaired perinatal airway fluid/secretory transport is a plausible contributor to neonatal distress, alongside early obstruction and atelectasis. The human phenotype and model-organism fluid-clearance experiments do not fully establish this intermediary mechanism in infants.

Sinusitis Impaired epithelial clearance predisposes to recurrent infection and mucosal inflammation.

Otitis Media Impaired epithelial clearance predisposes to recurrent infection and mucosal inflammation.

Show evidence (3 references)

PMID:38076675 SUPPORT Human clinical

"Mucociliary clearance by PRMC was consistently absent in most PCD patients, regardless of genotype."

Retrospective radioaerosol assessment included 69 patients and 26 genotypes. One CCDC103 participant retained measurable clearance; the 24-year collection window is not 24-year longitudinal follow-up of every participant.

PMID:38076675 SUPPORT Human clinical

"Voluntary cough significantly improved clearance, with a median improvement of 11%"

Human functional testing supports compensatory cough clearance without establishing a genotype-specific mechanism of milder disease.

PMID:41561107 SUPPORT Human clinical

"the results suggest cough clearance may differ between these two genotypes"

The genotypes are RSPH1 and DNAH5, not ODA and IDA. Small unadjusted comparisons support a cough-compensation lead without proving clinical severity mediation.

Chronic Airway Infection and Neutrophilic Inflammation

Retained secretions favor persistent airway infection, neutrophil recruitment and protease/oxidative injury. Haemophilus influenzae is prominent in pediatric cohorts; Pseudomonas aeruginosa isolation associates with worse structural and functional disease, but observational associations do not determine whether it independently drives progression. Antibiotic-responsive sputum elastase and ex vivo macrophage responses demonstrate inflammatory complexity without replacing the neutrophil-dominant clinical phenotype.

Canonical Axonemal Motile-Cilia Beat-Failure / Mucociliary Clearance Model

neutrophil CL:0000775

inflammatory response GO:0006954 ⚠ ABNORMAL response to bacterium GO:0009617 ⚠ ABNORMAL

bronchus UBERON:0002185

Downstream

Bronchiectasis and Airway Wall Remodeling Persistent infection and inflammatory injury damage airway walls and alter mucus production.

Show evidence (3 references)

PMID:15806596 SUPPORT Human clinical

"Stable PCD children have increased cough frequency and neutrophilic airway inflammation."

Stable pediatric PCD sputum shows neutrophilic inflammation; association with cough does not independently establish every remodeling step.

PMID:11376511 SUPPORT Other

"Failure to keep the airways sterile by MCC results in a host inflammatory response to the persistent microorganisms which, if it becomes chronic, causes damage to the airway wall and upregulation of mucus production manifest clinically as bronchiectasis, sinusitis and otitis."

Mechanistic review supports the established clearance-infection-injury sequence; the human evidence is not a single longitudinal mediation experiment.

PMID:41582098 SUPPORT In vitro / ex vivo

"PCD sputum induced a phagocytosis prone, M2-like phenotype in healthy macrophages."

Sputum from 27 PCD subjects versus seven controls was applied to healthy monocyte-derived macrophages. This in vitro conditioning response is not an established in vivo PCD macrophage endotype.

Bronchiectasis and Airway Wall Remodeling

Persistent infection, inflammatory injury and altered mucus handling damage airway walls and produce bronchial dilation. Structural disease varies by age, genotype and treatment history; bronchiectasis is not present in every newly diagnosed infant. The IFT88-deletion mouse remodeling experiment is an adjacent cilia-homeostasis model, not direct proof of an inflammation-independent route in all human PCD.

Canonical Axonemal Motile-Cilia Beat-Failure / Mucociliary Clearance Model Genotype / Ultrastructure-Defect Severity Stratification

bronchial epithelial cell CL:0002328

tissue remodeling GO:0048771 ⚠ ABNORMAL

bronchus UBERON:0002185 lung UBERON:0002048

Downstream

Progressive Obstructive Lung Function Decline Chronic airway structural injury contributes to heterogeneous airflow limitation.

Bronchiectasis A recognized organ-specific consequence, with occurrence restricted by genotype, disease extent and clinical context.

Airway Obstruction A recognized organ-specific consequence, with occurrence restricted by genotype, disease extent and clinical context.

Digital Clubbing Clubbing can accompany established chronic suppurative lung disease.

Show evidence (1 reference)

PMID:11376511 SUPPORT Other

Mechanistic review supports the established clearance-infection-injury sequence; the human evidence is not a single longitudinal mediation experiment.

Progressive Obstructive Lung Function Decline

Chronic airway obstruction and structural injury can reduce FEV1 over time. In the five-year pediatric cohort, decline varied substantially and the IDA/MTD/CA subgroup had the clearest negative slope. Normal or improved trajectories occur; FEV1 is an airflow measure and is not interchangeable with gas exchange, nasal NO, or a deterministic genotype severity tier.

lung UBERON:0002048

Downstream

Respiratory Failure A recognized organ-specific consequence, with occurrence restricted by genotype, disease extent and clinical context.

Show evidence (1 reference)

PMID:30067075 SUPPORT Human clinical

"For the entire cohort, percent predicted FEV1 decline was heterogeneous with a mean (SE) decline of 0.57 (0.25) percent predicted/yr."

Five-year multicenter observational study supports heterogeneous decline. A slope differing from zero only in one subgroup does not establish that all other genotypes cannot decline.

Nodal Ciliary Motility Defect

PCD variants affecting machinery required by embryonic motile monocilia impair symmetry-breaking flow. Outer dynein-arm genes and CCDC39/CCDC40-related axonemal organization can be involved; an ODA-only rule is false. Central-apparatus/radial-spoke and CCNO/MCIDAS multiciliogenesis defects generally spare this arm because nodal 9+0 monocilia lack those respective requirements.

Embryonic Nodal-Cilia Laterality-Determination Arm

DNAH5 hgnc:2950 DNAH11 hgnc:2942 DNAH9 hgnc:2953 DNAI1 hgnc:2954 CCDC39 hgnc:25244 CCDC40 hgnc:26090

epithelial cilium movement involved in determination of left/right asymmetry GO:0060287 ⚠ ABNORMAL

embryo UBERON:0000922

Animal models

Mdnah5 (Dnah5) loss-of-function (insertional mutation) Mouse Mouse recapitulates Randomized mouse laterality supports the nodal arm; it is not direct human embryonic imaging.

ccdc40 mutant / morphant Zebrafish Zebrafish recapitulates Vertebrate embryonic laterality phenotypes support an effect beyond ODA-only genotypes.

Downstream

Disrupted Directional Nodal Flow Disruption propagates through the experimentally supported vertebrate left-right patterning pathway; the direct perturbation evidence is from model embryos.

Show evidence (3 references)

PMID:27486780 SUPPORT Model organism

"we observed immotile nodal cilia and missing leftward flow via particle image velocimetry."

Ttc25 mutant mice directly connect a PCD-associated dynein-docking defect to nodal immotility and absent directional flow.

PMID:21131974 SUPPORT Human clinical

"Consistent with a conserved functional role of CCDC40 for nodal cilia function, five patients displayed situs solitus (32%) and 11 patients situs inversus (68%)."

Human CCDC40 cases include both normal and reversed situs; nodal protein localization is not established by the clinical phenotype.

PMID:21131974 SUPPORT Model organism

"Both laterality and curly-tail down phenotypes could be rescued by co-injection of ccdc40 mRNA (Fig. 2h,j)."

Zebrafish ccdc40 knockdown and mRNA rescue directly test developmental laterality function.

Disrupted Directional Nodal Flow

Normally, rotation of posteriorly tilted nodal motile cilia generates directional extracellular flow. Loss or disorganization of this flow disrupts the instructive left-right signal. Artificial flow can direct situs in immotile-cilia mouse mutants; human embryonic flow is inferred from conserved biology and genotype-phenotype evidence.

Embryonic Nodal-Cilia Laterality-Determination Arm

determination of left/right symmetry GO:0007368 ⚠ ABNORMAL

embryo UBERON:0000922

Downstream

Loss of Asymmetric Flow-Sensing and Nodal Signaling Disruption propagates through the experimentally supported vertebrate left-right patterning pathway; the direct perturbation evidence is from model embryos.

Show evidence (2 references)

PMID:27486780 SUPPORT Model organism

"we observed immotile nodal cilia and missing leftward flow via particle image velocimetry."

Ttc25 mutant mice directly connect a PCD-associated dynein-docking defect to nodal immotility and absent directional flow.

PMID:12097914 SUPPORT Model organism

"The artificial flow was also able to direct the situs of mutant mouse embryos with immotile cilia."

External flow manipulation establishes causal sufficiency downstream of ciliary motion in mouse embryos. It does not exclude intracellular chirality upstream of flow.

Loss of Asymmetric Flow-Sensing and Nodal Signaling

Directional flow mechanically bends immotile crown-cell cilia. Polarized PKD2-dependent calcium responses promote left-sided DAND5 mRNA decay, relieving NODAL antagonism and enabling the asymmetric developmental program. BICC1 and the CCR4-NOT complex participate in Dand5 RNA decay in mice. When instructive flow is absent, this asymmetry is lost or randomized. PKD2/PKD1L1 are sensing machinery, not asserted here as general causes of respiratory PCD.

Embryonic Nodal-Cilia Laterality-Determination Arm

PKD2 hgnc:9009 PKD1L1 hgnc:18053 DAND5 hgnc:26780 NODAL hgnc:7865 BICC1 hgnc:19351 CNOT3 hgnc:7879 PITX2 hgnc:9005

determination of left/right symmetry GO:0007368 ⚠ ABNORMAL

embryo UBERON:0000922

Downstream

Randomized Organ Laterality Disruption propagates through the experimentally supported vertebrate left-right patterning pathway; the direct perturbation evidence is from model embryos.

Show evidence (2 references)

PMID:36603091 SUPPORT Model organism

"Application of mechanical stimuli to immotile cilia by optical tweezers induced calcium ion transients and degradation of Dand5 messenger RNA (mRNA) in the targeted cells."

The 2023 mouse study directly tests mechanical sensing and downstream Dand5 responses, predating but omitted from the OpenScientist report.

PMID:34210974 SUPPORT Model organism

"The Cnot3 component of the Ccr4-Not deadenylase complex interacts with Bicc1 and is also required for Dand5 mRNA decay at the node."

Genetic and RNA-regulatory experiments specify the flow-to-asymmetric-RNA step in the mouse organizer.

Randomized Organ Laterality

Disrupted asymmetric developmental signaling permits normal situs, complete mirror-image situs or discordant situs across organs. Human cohort distributions are not a strict binary 50:50 coin flip, and genotype composition and diagnostic ascertainment affect estimates. Situs inversus totalis itself should not be encoded as the cause of heterotaxy-associated heart defects or intestinal malrotation. The precise flow/signaling basis for discordant organ outcomes remains unresolved.

Embryonic Nodal-Cilia Laterality-Determination Arm

embryo UBERON:0000922

Downstream

Situs Inversus Totalis A recognized organ-specific consequence, with occurrence restricted by genotype, disease extent and clinical context.

Abnormal Heart Morphology Discordant laterality can include congenital cardiac or vascular malformations; these are not an obligatory consequence of complete mirror-image situs.

Intestinal Malrotation Intestinal malrotation is a recognized PCD-associated organ-position defect. Its placement in the developmental laterality branch is a clinical mechanistic interpretation, not evidence that situs inversus totalis causes malrotation.

Heterotaxy Discordant laterality can produce situs ambiguus with or without complex cardiovascular involvement.

Show evidence (2 references)

PMID:36342963 SUPPORT Human clinical

"Of 559 participants, 286 (51.2%), 215 (38.5%), and 58 (10.4%) were identified as having situs solitus, situs inversustotalis, and situs ambiguus, respectively"

Human laterality distributions distinguish total inversion from situs ambiguus. Heterotaxy definitions vary; this study restricted heterotaxy to ambiguus with complex cardiovascular defects (14/559).

PMID:12097914 SUPPORT Model organism

"The artificial flow was also able to direct the situs of mutant mouse embryos with immotile cilia."

External flow manipulation establishes causal sufficiency downstream of ciliary motion in mouse embryos. It does not exclude intracellular chirality upstream of flow.

Sperm Flagellar and Reproductive Tract Dysfunction

Variants affecting sperm flagella can reduce sperm motility and contribute to male infertility. Some motile-cilia genes also affect cilia of the male reproductive tract. Tissue-specific axonemal composition means respiratory disease does not imply uniformly immotile sperm or infertility in every male.

DNAH7 hgnc:18661 TTC12 hgnc:23700

cilium movement GO:0003341 ⚠ ABNORMAL

Downstream

Male Infertility A recognized organ-specific consequence, with occurrence restricted by genotype, disease extent and clinical context.

Abnormal Sperm Motility A recognized organ-specific consequence, with occurrence restricted by genotype, disease extent and clinical context.

Show evidence (4 references)

PMID:38962571 SUPPORT Human clinical

"Among 168 adults who had tried to conceive, 39 of 50 men (78%) and 72 of 118 women (61%) were infertile."

The international self-report study supports sex-specific fertility impairment, with denominators restricted to participants who had tried to conceive; it does not establish obligatory infertility or a universal shared molecular lesion.

PMID:41005984 SUPPORT Other

"Male PCD subjects are often infertile due to dysfunction of the sperm tail and cilia in the efferent duct"

The joint guideline summarizes both flagellar and efferent-duct contributions.

PMID:34476482 SUPPORT Human clinical

"The spermatozoa from the patients with DNAH7 bi-allelic mutations showed specific losses in the inner dynein arms."

Records an axonemal lesion confined to the sperm flagellum in DNAH7-mutant men, which is why DNAH7 is wired to this node rather than to the respiratory beat-failure chain.

+ 1 more reference

Oviduct Ciliary Transport Dysfunction

Abnormal motile cilia in the oviduct can impair gamete or embryo transport and contribute to female subfertility and ectopic pregnancy risk. Fertility remains possible and varies by genotype; clinical self-report associations do not isolate ciliary transport from every other determinant of reproductive outcome.

cilium movement GO:0003341 ⚠ ABNORMAL

Downstream

Female Infertility A recognized organ-specific consequence, with occurrence restricted by genotype, disease extent and clinical context.

Ectopic Pregnancy Impaired oviduct transport is a plausible contributor to the observed reproductive risk; patient-specific mediation is not established.

Show evidence (2 references)

PMID:38962571 SUPPORT Human clinical

"Among 168 adults who had tried to conceive, 39 of 50 men (78%) and 72 of 118 women (61%) were infertile."

PMID:41005984 SUPPORT Other

"female individuals are often subfertile due to the involvement of cilia in the oviducts"

The guideline supports the organ-specific ciliary mechanism.

Ependymal Ciliary Dysfunction

Motile ependymal cilia participate in ventricular fluid handling. Hydrocephalus is uncommon across human PCD but enriched in selected ciliogenesis disorders such as FOXJ1-associated disease. Mouse PCD models often show much more severe hydrocephalus, and species, tissue and modifier effects limit a simple ciliary-beat-to-CSF-obstruction inference.

ependymal cell CL:0000065

FOXJ1 hgnc:3816

cilium movement GO:0003341 ⚠ ABNORMAL

Animal models

Mdnah5 (Dnah5) loss-of-function (insertional mutation) Mouse Mouse recapitulates Severe mouse hydrocephalus models ciliary-fluid effects but overstates typical human penetrance.

Downstream

Hydrocephalus A recognized organ-specific consequence, with occurrence restricted by genotype, disease extent and clinical context.

Show evidence (1 reference)

PMID:34132502 SUPPORT Human clinical

"FOXJ1 pathogenic variants cause PCD in a de novo, autosomal dominant inheritance pattern, and are associated with hydrocephalus."

Human FOXJ1 cases support a restricted association with hydrocephalus; severe hydrocephalus in mouse PCD models should not set a pan-PCD human frequency.

Ciliary Oxidative Stress and Glutathione Response

Mechanism confidence: Provisional

DNAH5-deficient patient airway cultures and patient-derived iPSC airway cells show increased ROS and NRF2-regulated glutathione-transferase expression. GSTA2 localizes to motile cilia, and loss-of-function experiments slow ciliary motility. These data identify a ciliary redox-maintenance pathway and genotype-associated cellular response; they do not establish that antioxidant treatment improves PCD outcomes or that every PCD genotype shares the response.

respiratory tract multiciliated cell CL:4030034

DNAH5 hgnc:2950 GSTA2 hgnc:4627 NFE2L2 hgnc:7782

respiratory tract epithelium UBERON:0004802

Experimental models

DNAH5 patient redox profiling and separate GSTA2 airway-cell perturbation PRIMARY CELL CULTURE Measures genotype-associated ROS and GSTA/NRF2 expression in patient-derived epithelial cultures.

Show evidence (2 references)

PMID:39042459 SUPPORT In vitro / ex vivo

"Primary and iPS-derived PCD multiciliated cells had increased expression of glutathione-S-transferases GSTA2 and GSTA1, as well as NRF2 target genes, accompanied by elevated levels of reactive oxygen species (ROS)."

DNAH5 patient cultures and iPSC-derived cells show an intrinsic oxidative-stress response; increased GSTA expression is not a GSTA deficiency.

PMID:39042459 SUPPORT In vitro / ex vivo

"Loss of human GSTA2 and C. reinhardtii GSTA resulted in slowed cilia motility"

Functional experiments establish a role for GSTA in motility, while increased expression in DNAH5 PCD may be compensatory.

Cytoplasmic Dynein Arm Preassembly Failure

Axonemal dynein arms are multi-subunit motors assembled in the cytoplasm before import into the cilium, so a defect in a cytoplasmic assembly factor leaves the axoneme without outer and inner dynein arms. This is the mechanism shared by the DNAAF-class genes and by TTC12 and CFAP298, and it is upstream of, and distinct from, the axoneme-resident docking, scaffold and central-apparatus defects modeled separately in this entry.

Canonical Axonemal Motile-Cilia Beat-Failure / Mucociliary Clearance Model

respiratory tract multiciliated cell CL:4030034

DNAAF1 hgnc:30539 DNAAF2 hgnc:20188 DNAAF3 hgnc:30492 DNAAF4 hgnc:21493 DNAAF5 hgnc:26013 DNAAF6 hgnc:28570 DNAAF11 hgnc:16725 CFAP298 hgnc:1301 TTC12 hgnc:23700 CFAP300 hgnc:28188 ZMYND10 hgnc:19412 SPAG1 hgnc:11212

axonemal dynein complex assembly GO:0070286 ↓ DECREASED

respiratory tract epithelium UBERON:0004802

Downstream

Ciliary Dysfunction Dynein arms that are never assembled in the cytoplasm cannot be imported into the axoneme, so the cilium lacks the motors that generate its beat.

Show evidence (3 references)

PMID:22154137 SUPPORT REVIEW SYNTHESIS Other

"The dyneins are composed of multiple subunits, which are thought to be preassembled in the cytoplasm before they are transported into cilia and flagella."

States the cytoplasmic-preassembly step this node models, as the review's synthesis of the field rather than as its own result.

PMID:22387996 SUPPORT Other

"Altered abundance of dynein subunits in mutant cytoplasm suggests that DNAAF3 (PF22) acts at a similar stage as other preassembly proteins, for example, DNAAF2 (also known as PF13 or KTU) and DNAAF1 (also known as ODA7 or LRRC50), in the dynein preassembly pathway."

Places DNAAF1, DNAAF2 and DNAAF3 at the same step of the cytoplasmic preassembly pathway, which is what groups these genes on one node.

PMID:23040496 SUPPORT In vitro / ex vivo

"HEATR2 was localized to the cytoplasm and not in cilia, which suggests a role in either dynein arm transport or assembly"

Localizes the DNAAF5 product to the cytoplasm rather than to the cilium, supporting a pre-import rather than axonemal site of action.

Outer Dynein Arm Docking and Attachment Failure

Assembled outer dynein arms still have to be docked onto and held on the axoneme. Loss of a docking-complex subunit or of an axoneme-resident attachment factor therefore removes outer dynein arms at a step after cytoplasmic assembly, which is a different lesion from the preassembly failure modeled upstream. DNAAF19 carries a DNAAF symbol but its product is axoneme-associated and acts at this step.

Canonical Axonemal Motile-Cilia Beat-Failure / Mucociliary Clearance Model

respiratory tract multiciliated cell CL:4030034

ODAD1 hgnc:26560 ODAD4 hgnc:25280 DNAAF19 hgnc:32700 ODAD2 hgnc:25583 CLXN hgnc:25678

outer dynein arm assembly GO:0036158 ↓ DECREASED

outer dynein arm GO:0036157

respiratory tract epithelium UBERON:0004802

Downstream

Ciliary Dysfunction Outer dynein arms are the principal source of the force that drives the ciliary beat, so an axoneme that cannot retain them loses that force.

Show evidence (3 references)

PMID:27486780 SUPPORT Other

"here we report TTC25 as a new member of the ODA-DC machinery in humans and mice."

Places the ODAD4 product in the outer dynein arm docking complex alongside ODAD1.

PMID:22581229 SUPPORT Other

"These results identify Ccdc103 as a dynein arm attachment factor that causes primary ciliary dyskinesia when mutated."

Assigns the DNAAF19 product an axonemal dynein-arm attachment role rather than a cytoplasmic preassembly role.

PMID:22581229 SUPPORT Other

"Chlamydomonas Ccdc103/Pr46b functions as a tightly bound, axoneme-associated protein."

Locates the orthologous product in the axoneme rather than in the cytoplasm, which is why DNAAF19 sits on this node despite its DNAAF symbol.

Central Pair Apparatus Defect

Mechanism confidence: Provisional

HYDIN and SPEF2 losses remove components of the axonemal central pair apparatus. The resulting disease is diagnostically distinctive rather than ultrastructurally obvious: beating abnormalities are subtle, routine ciliary ultrastructure and situs composition are normal, and HYDIN variant calling is confounded by the near-identical pseudogene HYDIN2. This is a central-pair lesion, separate from the C1d projection defect modeled for the CFAP46/CFAP54/CFAP74/CFAP221 group.

Canonical Axonemal Motile-Cilia Beat-Failure / Mucociliary Clearance Model

respiratory tract multiciliated cell CL:4030034

HYDIN hgnc:19368 SPEF2 hgnc:26293

axonemal central apparatus assembly GO:1904158 ↓ DECREASED

axonemal central apparatus GO:1990716

respiratory tract epithelium UBERON:0004802

Downstream

Ciliary Dysfunction Loss of central pair components alters the beat rather than abolishing it, which is why routine beat, ultrastructure and situs assessment can all read as normal in this group.

Show evidence (3 references)

PMID:31545650 SUPPORT BACKGROUND Other

"Mutations in HYDIN are known to cause CP defects"

Assigns HYDIN-related disease to the central-pair defect class, as established background in the citing study rather than as its own result.

PMID:31545650 SUPPORT Human clinical

"We identified a mutation of SPEF2 that is causative for PCD with a CP defect."

Adds SPEF2 to the central-pair defect class on this study's own genetic and immunofluorescence result.

PMID:31545650 SUPPORT BACKGROUND Other

"the genetic analysis of HYDIN variants is confounded by the pseudogene HYDIN2, which is almost identical in terms of intron/exon structure"

Records the HYDIN2 pseudogene as the reason HYDIN variant calling is unreliable.

Radial Spoke Defect

The radial spokes link each outer microtubule doublet to the sheath that surrounds the central pair of microtubules, and the knockdown data below show the spoke head is needed for normal ciliary movement. RSPH1, RSPH4A and RSPH9 are radial spoke head components and NME5 a component of the spoke neck; the Chlamydomonas orthologs of RSPH3 and DNAJB13 are a spoke stalk protein and a spoke-localised HSP40 co-chaperone. Loss of any of them disturbs the beat. Patient ultrastructure in this group ranges from a near absence of radial spokes to central-complex changes with intact dynein arms, so it is a different lesion from the dynein-arm and multiciliogenesis routes.

Canonical Axonemal Motile-Cilia Beat-Failure / Mucociliary Clearance Model

respiratory tract multiciliated cell CL:4030034

RSPH1 hgnc:12371 RSPH3 hgnc:21054 RSPH4A hgnc:21558 RSPH9 hgnc:21057 DNAJB13 hgnc:30718 NME5 hgnc:7853

radial spoke assembly GO:0062177 ↓ DECREASED

radial spoke GO:0001534

respiratory tract epithelium UBERON:0004802

Downstream

Ciliary Dysfunction A radial spoke lesion changes the waveform rather than abolishing motility, so beat frequency can be preserved while transport is not.

Show evidence (6 references)

PMID:19200523 SUPPORT Human clinical

"Both RSPH9 and RSPH4A encode protein components of the axonemal radial spoke head."

Assigns RSPH9 and RSPH4A to the radial spoke head, the structure this node is about.

PMID:19200523 SUPPORT Model organism

"Investigation of the effect of knockdown or mutations of RSPH9 orthologs in zebrafish and Chlamydomonas indicate that radial spoke head proteins are important in maintaining normal movement in motile"

Zebrafish and Chlamydomonas knockdown of RSPH9 orthologs establishes that the radial spoke head is required for normal movement, which is the functional content of this node. The model systems are inside the quote, which is what the MODEL_ORGANISM grading rests on.

PMID:26073779 SUPPORT Human clinical

"It also unveils the key role of RSPH3 in the proper building of RSs and the CC in humans."

Places RSPH3 in radial spoke assembly in human cilia, alongside the head components.

+ 3 more references

Nexin-Dynein Regulatory Complex Defect

The nexin-dynein regulatory complex (N-DRC) links adjacent outer microtubule doublets and regulates dynein activity across them. DRC1, DRC2 and DRC4 are subunits 1, 2 and 4 of that complex. Because the complex is a connector rather than a visible arm or spoke, loss of a subunit leaves the axonemal architecture looking intact on routine transmission electron microscopy while the beat becomes stiff and dyskinetic, so this group is identified by immunofluorescence rather than by ultrastructure. The subunits are interdependent: DRC4 is absent from DRC2-deficient airway cells.

Canonical Axonemal Motile-Cilia Beat-Failure / Mucociliary Clearance Model

respiratory tract multiciliated cell CL:4030034

DRC1 hgnc:24245 DRC2 hgnc:29937 DRC4 hgnc:4166

regulation of cilium beat frequency GO:0003356 ⚠ ABNORMAL

axonemal nexin link GO:0005931

respiratory tract epithelium UBERON:0004802

Downstream

Ciliary Dysfunction Without the regulatory complex the doublets are no longer coordinated, and the beat becomes stiff and dyskinetic rather than absent.

Show evidence (4 references)

PMID:26387594 SUPPORT Human clinical

"Immunofluorescence analyses of respiratory cells from PCD-affected individuals detected a N-DRC defect."

Establishes the N-DRC defect as a detectable lesion class in affected individuals.

PMID:23991085 SUPPORT In vitro / ex vivo

"CCDC65, an orthologue of the Chlamydomonas nexin-dynein regulatory complex protein DRC2, was localized to the cilia of normal nasal epithelial cells but was absent in those from the proband."

Places DRC2 in the N-DRC and shows it is absent from the cilia of an affected individual.

PMID:23991085 SUPPORT In vitro / ex vivo

"Moreover, Gas8, a nexin-dynein regulatory complex component previously identified to associate with CCDC65, was absent in airway cells from the PCD subject and CCDC65-silenced cells."

Shows the two subunits are interdependent, which is why they are modeled as one node rather than two.

+ 1 more reference

⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Cardiovascular 2

Situs Inversus Totalis FREQUENT HP:0001696

Situs inversus totalis occurred in 215/559 (38.5%) in the cited multicenter cohort; the approximately half with any laterality defect also includes situs ambiguus. Rates depend on genotype and ascertainment.

Show evidence (1 reference)

PMID:36342963 SUPPORT Human clinical

"Of 559 participants, 286 (51.2%), 215 (38.5%), and 58 (10.4%) were identified as having situs solitus, situs inversustotalis, and situs ambiguus, respectively"

Human laterality distributions distinguish total inversion from situs ambiguus. Heterotaxy definitions vary; this study restricted heterotaxy to ambiguus with complex cardiovascular defects (14/559).

Abnormal Heart Morphology OCCASIONAL HP:0001627

Congenital cardiac defects are particularly relevant to heterotaxy/situs ambiguus, not an obligatory consequence of complete mirror-image situs.

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"HP:0001627 | Abnormal heart morphology | Occasional (29-5%)"

Orphanet phenotype data classifies abnormal heart morphology as occasional (29-5%) in primary ciliary dyskinesia.

Digestive 1

Intestinal Malrotation VERY_RARE HP:0002566

Associated with situs abnormalities

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"HP:0002566 | Intestinal malrotation | Very rare (<4-1%)"

Orphanet phenotype data classifies intestinal malrotation as very rare (<4-1%) in primary ciliary dyskinesia.

Ear 5

Chronic Otitis Media FREQUENT HP:0000389

Show evidence (3 references)

ORPHA:244 SUPPORT Other

"HP:0000389 | Chronic otitis media | Frequent (79-30%)"

Orphanet phenotype data classifies chronic otitis media as frequent (79-30%) in primary ciliary dyskinesia.

PMID:29135867 SUPPORT

"All 15 patients showed ciliary ultrastructural abnormalities on electron microscopy and/or biallelic mutations in genes associated with ciliary function or structure. All 30 eardrums examined showed certain abnormalities. Fourteen patients had otitis media with effusion or its sequelae. The..."

The study found that patients with primary ciliary dyskinesia (PCD) frequently exhibited otologic issues, including chronic otitis media.

PMID:19796826 SUPPORT

"Primary ciliary dyskinesia is an autosomal recessively inherited group of disorders of ciliary ultrastructure. Otolaryngologists are frequently involved in the management of some of the most common symptoms of primary ciliary dyskinesia including chronic rhinitis, sinusitis and otitis media with..."

This reference supports that chronic otitis media and other otologic issues are common in patients with primary ciliary dyskinesia.

Hearing Loss Hearing impairment HP:0000365

Show evidence (1 reference)

PMID:41005984 SUPPORT Other

"Individuals with PCD frequently suffer from chronic middle ear disease and can have conductive and sensorineural hearing loss"

PCD-specific guideline supports hearing impairment; severity, age and mechanism vary.

Otitis Media FREQUENT HP:0000388

Show evidence (1 reference)

PMID:11376511 SUPPORT Other

Mechanistic review supports the established clearance-infection-injury sequence; the human evidence is not a single longitudinal mediation experiment.

Recurrent Otitis Media FREQUENT HP:0000403

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"HP:0000403 | Recurrent otitis media | Frequent (79-30%)"

Orphanet phenotype data classifies recurrent otitis media as frequent (79-30%) in primary ciliary dyskinesia.

Conductive Hearing Impairment OCCASIONAL HP:0000405

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"HP:0000405 | Conductive hearing impairment | Occasional (29-5%)"

Orphanet phenotype data classifies conductive hearing impairment as occasional (29-5%) in primary ciliary dyskinesia.

Genitourinary 3

Male Infertility HP:0003251

Risk depends on gene and reproductive history. The 2024 self-report survey classified 78% of 50 men and 61% of 118 women who had tried to conceive as infertile, including those using assisted reproduction. Selection, recall and referral bias limit population estimates; conception remains possible.

Show evidence (1 reference)

PMID:38962571 SUPPORT Human clinical

"Among 168 adults who had tried to conceive, 39 of 50 men (78%) and 72 of 118 women (61%) were infertile."

Abnormal Sperm Motility FREQUENT HP:0012206

Frequency is applicable to the relevant reproductive population, not all patients. Fertility is genotype-dependent and some affected individuals conceive naturally; semen testing or fertility assessment is needed for individual counseling.

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"HP:0012206 | Abnormal sperm motility | Frequent (79-30%)"

Orphanet phenotype data classifies abnormal sperm motility as frequent (79-30%) in primary ciliary dyskinesia.

Female Infertility HP:0008222

Show evidence (1 reference)

PMID:38962571 SUPPORT Human clinical

"Among 168 adults who had tried to conceive, 39 of 50 men (78%) and 72 of 118 women (61%) were infertile."

Head and Neck 5

Nasal Polyposis HP:0100582

Reported in a subset, with ascertainment and age affecting frequency. Older PCD consensus reports up to 15%, so a frequent 30–79% category is not justified by the broad disease annotation alone.

Show evidence (1 reference)

PMID:26418604 SUPPORT Other

"Nasal polyposis has been observed in up to 15% of PCD patients."

Guideline literature summary supplies a bounded clinical estimate, not a population-independent frequency.

Sinusitis FREQUENT HP:0000246

Show evidence (1 reference)

PMID:11376511 SUPPORT Other

Mechanistic review supports the established clearance-infection-injury sequence; the human evidence is not a single longitudinal mediation experiment.

Chronic Rhinosinusitis FREQUENT Chronic sinusitis HP:0011109

Chronic inflammation of nasal passages and sinuses

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"HP:0011109 | Chronic sinusitis | Frequent (79-30%)"

Orphanet phenotype data classifies chronic sinusitis as frequent (79-30%) in primary ciliary dyskinesia.

Nasal Congestion FREQUENT HP:0001742

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"HP:0001742 | Nasal congestion | Frequent (79-30%)"

Orphanet phenotype data classifies nasal congestion as frequent (79-30%) in primary ciliary dyskinesia.

Chronic Rhinitis FREQUENT HP:0002257

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"HP:0002257 | Chronic rhinitis | Frequent (79-30%)"

Orphanet phenotype data classifies chronic rhinitis as frequent (79-30%) in primary ciliary dyskinesia.

Immune 2

Recurrent Respiratory Infections HP:0002205

Show evidence (1 reference)

PMID:41005984 SUPPORT Other

"Individuals with PCD often have persistent wet cough, chronic rhinosinusitis, recurrent otitis media, and recurrent respiratory infections beginning early in life and continuing throughout adulthood"

Guideline supports early and persistent respiratory infections.

Recurrent Sinopulmonary Infections FREQUENT HP:0005425

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"HP:0005425 | Recurrent sinopulmonary infections | Frequent (79-30%)"

Orphanet phenotype data classifies recurrent sinopulmonary infections as frequent (79-30%) in primary ciliary dyskinesia.

Limbs 1

Digital Clubbing OCCASIONAL HP:0001217

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"HP:0001217 | Clubbing | Occasional (29-5%)"

Orphanet phenotype data classifies digital clubbing as occasional (29-5%) in primary ciliary dyskinesia.

Nervous System 1

Hydrocephalus VERY_RARE HP:0000238

Uncommon across human PCD but enriched in selected genotypes, including FOXJ1. Severe or lethal hydrocephalus in mouse mutants must not be generalized to humans.

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"HP:0000238 | Hydrocephalus | Very rare (<4-1%)"

Orphanet phenotype data classifies hydrocephalus as very rare (<4-1%) in primary ciliary dyskinesia.

Respiratory 9

Chronic Cough HP:0034315

Show evidence (1 reference)

PMID:41005984 SUPPORT Other

"PCD is associated with early-onset chronic wet cough and rhinosinusitis, laterality defects, middle ear disease and reduced fertility."

Joint ERS/ATS guideline supports the characteristic symptom spectrum; this sentence does not provide quantitative frequency estimates.

Bronchiectasis HP:0002110

Occurrence depends strongly on age and ascertainment. A cumulative complication should not be assigned the Orphanet cross-sectional 5–29% band without an age denominator.

Show evidence (1 reference)

PMID:41005984 SUPPORT Other

"The disease course can be heterogeneous, but most people develop bronchiectasis and progressive lung disease that can lead to respiratory failure"

PCD-specific guideline supports cumulative structural disease while recognizing heterogeneous trajectories.

Neonatal Respiratory Distress FREQUENT HP:0002643

Often delayed/persistent distress in term newborns with oxygen requirement and atelectasis. The exact human contribution of retained fetal lung fluid is unresolved; mouse neonatal lethality is not a human outcome estimate.

Show evidence (3 references)

ORPHA:244 SUPPORT Other

"HP:0002643 | Neonatal respiratory distress | Frequent (79-30%)"

Orphanet phenotype data classifies neonatal respiratory distress as frequent (79-30%) in primary ciliary dyskinesia.

PMID:19720631 SUPPORT

"73% had a history of neonatal respiratory distress."

In a consanguineous British Asian PCD cohort, 73% of patients had neonatal respiratory distress.

PMID:40344341 SUPPORT Human clinical

"Of the 455 participants analyzed, 305 (67.0%) reported NRD."

Term-born participants with known neonatal history in a multicenter PCD study; prematurity and complex congenital heart disease were excluded.

Productive Cough HP:0031245

Show evidence (1 reference)

PMID:41005984 SUPPORT Other

"PCD is associated with early-onset chronic wet cough and rhinosinusitis, laterality defects, middle ear disease and reduced fertility."

Joint ERS/ATS guideline supports the characteristic symptom spectrum; this sentence does not provide quantitative frequency estimates.

Abnormal Sputum FREQUENT HP:0032016

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"HP:0032016 | Abnormal sputum | Frequent (79-30%)"

Orphanet phenotype data classifies abnormal sputum as frequent (79-30%) in primary ciliary dyskinesia.

Wheezing OCCASIONAL HP:0030828

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"HP:0030828 | Wheezing | Occasional (29-5%)"

Orphanet phenotype data classifies wheezing as occasional (29-5%) in primary ciliary dyskinesia.

Atelectasis OCCASIONAL HP:0100750

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"HP:0100750 | Atelectasis | Occasional (29-5%)"

Orphanet phenotype data classifies atelectasis as occasional (29-5%) in primary ciliary dyskinesia.

Airway Obstruction OCCASIONAL HP:0006536

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"HP:0006536 | Airway obstruction | Occasional (29-5%)"

Orphanet phenotype data classifies airway obstruction as occasional (29-5%) in primary ciliary dyskinesia.

Respiratory Failure VERY_RARE HP:0002878

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"HP:0002878 | Respiratory failure | Very rare (<4-1%)"

Orphanet phenotype data classifies respiratory failure as very rare (<4-1%) in primary ciliary dyskinesia.

Growth 1

Heterotaxy HP:0030853

Show evidence (1 reference)

PMID:36342963 SUPPORT Human clinical

"Of 559 participants, 286 (51.2%), 215 (38.5%), and 58 (10.4%) were identified as having situs solitus, situs inversustotalis, and situs ambiguus, respectively"

Human laterality distributions distinguish total inversion from situs ambiguus. Heterotaxy definitions vary; this study restricted heterotaxy to ambiguus with complex cardiovascular defects (14/559).

Other 1

Ectopic Pregnancy

Show evidence (1 reference)

PMID:41561099 SUPPORT Other

"women might be at higher risk of ectopic pregnancies"

PCD reproductive-care consensus recognizes this risk while recommending individualized fertility counseling.

🧬

Genetic Associations

DNAI1 (Pathogenic Variants)

Gene: DNAI1 hgnc:2954

Show evidence (4 references)

ORPHA:244 SUPPORT Other

"DNAI1 | dynein axonemal intermediate chain 1 | hgnc:2954 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association data confirms DNAI1 as a disease-causing gene for primary ciliary dyskinesia.

PMID:35869935 SUPPORT

"13 rare variants were identified in patients with PCD, among which were three homozygous causative variants (including one splicing variant) in the PCD-associated genes CCDC40 and DNAI1."

The study identifies causative variants in DNAI1 associated with primary ciliary dyskinesia.

PMID:15750039 SUPPORT

"The most frequent genetic defects comprise recessive mutations of DNAH5 and DNAI1, which encode outer dynein arm (ODA) components."

This study mentions DNAI1 mutations as frequent genetic defects causing primary ciliary dyskinesia.

+ 1 more reference

DNAH5 (Pathogenic Variants)

Gene: DNAH5 hgnc:2950 gene page

Show evidence (2 references)

ORPHA:244 SUPPORT Other

"DNAH5 | dynein axonemal heavy chain 5 | hgnc:2950 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association data confirms DNAH5 as a disease-causing gene for primary ciliary dyskinesia.

PMID:31118369 SUPPORT

"A genetic examination detected compound heterozygous mutations of DNAH5 that encode ODA components."

The study reports a case of primary ciliary dyskinesia (PCD) with DNAH5 mutations, confirming the association between PCD and pathogenic variants in DNAH5.

DNAH11 (Pathogenic Variants)

Gene: DNAH11 hgnc:2942 gene page

Show evidence (2 references)

ORPHA:244 SUPPORT Other

"DNAH11 | dynein axonemal heavy chain 11 | hgnc:2942 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association data confirms DNAH11 as a disease-causing gene for primary ciliary dyskinesia.

PMID:40344341 SUPPORT Human clinical

"The odds ratio for NRD in the DNAH11 group was significantly lower (OR: 0.35, 95% CI: 0.16-0.76) compared to NRD in the ODA group."

Phenotype-specific association with neonatal distress, not a universal lung-function prognosis.

CCDC39 (Pathogenic Variants)

Gene: CCDC39 hgnc:25244

Show evidence (2 references)

ORPHA:244 SUPPORT Other

"CCDC39 | coiled-coil domain 39 molecular ruler complex subunit | hgnc:25244 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association data confirms CCDC39 as a disease-causing gene for primary ciliary dyskinesia.

PMID:39879322 SUPPORT In vitro / ex vivo

"the absence of the axonemal CCDC39/CCDC40 heterodimer resulted in the loss of a network of more than 90 ciliary structural proteins"

Patient-cilia proteomics and cross-species structural work establish a broad scaffold-dependent protein network. The preprint PMID:38562900 is the same study, not an independent replication.

CCDC40 (Pathogenic Variants)

Gene: CCDC40 hgnc:26090

Show evidence (2 references)

ORPHA:244 SUPPORT Other

"CCDC40 | coiled-coil domain 40 molecular ruler complex subunit | hgnc:26090 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association data confirms CCDC40 as a disease-causing gene for primary ciliary dyskinesia.

PMID:39879322 SUPPORT In vitro / ex vivo

"the absence of the axonemal CCDC39/CCDC40 heterodimer resulted in the loss of a network of more than 90 ciliary structural proteins"

Patient-cilia proteomics and cross-species structural work establish a broad scaffold-dependent protein network. The preprint PMID:38562900 is the same study, not an independent replication.

RSPH1 (Pathogenic Variants)

Gene: RSPH1 hgnc:12371

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"RSPH1 | radial spoke head component 1 | hgnc:12371 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet gene-disease association data confirms RSPH1 as a disease-causing gene for primary ciliary dyskinesia.

RSPH4A (Pathogenic Variants)

Gene: RSPH4A hgnc:21558

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"RSPH4A | radial spoke head component 4A | hgnc:21558 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association data confirms RSPH4A as a disease-causing gene for primary ciliary dyskinesia.

RSPH9 (Pathogenic Variants)

Gene: RSPH9 hgnc:21057

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"RSPH9 | radial spoke head component 9 | hgnc:21057 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association data confirms RSPH9 as a disease-causing gene for primary ciliary dyskinesia.

CCNO (Pathogenic Variants)

Gene: CCNO hgnc:18576

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"CCNO | cyclin O | hgnc:18576 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet gene-disease association data confirms CCNO as a disease-causing gene for primary ciliary dyskinesia.

FOXJ1 (Pathogenic Variants)

Gene: FOXJ1 hgnc:3816 gene page

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"FOXJ1 | forkhead box J1 | hgnc:3816 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet gene-disease association data confirms FOXJ1 as a disease-causing gene for primary ciliary dyskinesia.

MCIDAS (Pathogenic Variants)

Gene: MCIDAS hgnc:40050

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"MCIDAS | multiciliate differentiation and DNA synthesis associated cell cycle protein | hgnc:40050 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet gene-disease association data confirms MCIDAS as a disease-causing gene for primary ciliary dyskinesia.

ODAD1 (Pathogenic Variants)

Gene: ODAD1 hgnc:26560

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

"ODAD1 | outer dynein arm docking complex subunit 1 | hgnc:26560 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet gene-disease association data confirms ODAD1 as a disease-causing gene for primary ciliary dyskinesia.

CFAP221 (Pathogenic Variants)

Gene: CFAP221 hgnc:33720 gene page

Show evidence (1 reference)

CGGV:assertion_c7c841e5-2973-4f23-8603-970e9e2cbc92-2025-12-16T120000.000Z SUPPORT Other

ClinGen classifies the CFAP221-primary ciliary dyskinesia gene-disease relationship as definitive with autosomal recessive inheritance.

CFAP46 (Limited evidence for PCD association)

Gene: CFAP46 hgnc:25247

Show evidence (1 reference)

CGGV:assertion_eabe809a-1203-4d42-9052-21f39717754f-2025-10-17T160000.000Z SUPPORT Other

ClinGen classifies the CFAP46-primary ciliary dyskinesia gene-disease relationship as limited with autosomal recessive inheritance.

CFAP54 (Pathogenic Variants)

Gene: CFAP54 hgnc:26456 gene page

Show evidence (3 references)

CGGV:assertion_f16ea0ce-7d5d-4bdc-92fe-52d111913161-2025-07-16T070000.000Z SUPPORT Other

ClinGen's Motile Ciliopathy Gene Curation Expert Panel classifies the CFAP54-primary ciliary dyskinesia relationship as Strong with autosomal recessive inheritance.

CGGV:assertion_f16ea0ce-7d5d-4bdc-92fe-52d111913161-2025-07-16T070000.000Z SUPPORT Other

"Nodal cilia lack a central pair apparatus, so mouse models as well as humans with CFAP54 -PCD would not be expected to develop the laterality defects often associated with PCD."

Explains mechanistically why situs is normal in this PCD type, rather than leaving it as an unexplained observation.

PMID:39362668 SUPPORT In vitro / ex vivo

"However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance."

CFAP57 (Limited evidence for PCD association)

Gene: CFAP57 hgnc:26485 gene page

Show evidence (1 reference)

CGGV:assertion_50ed292f-0044-4c82-9419-a040cbcaf205-2022-06-23T160000.000Z SUPPORT Other

ClinGen classifies the CFAP57-primary ciliary dyskinesia gene-disease relationship as limited with autosomal recessive inheritance.

DAW1 (Limited evidence for PCD association)

Gene: DAW1 hgnc:26383 gene page

Show evidence (1 reference)

CGGV:assertion_8610990f-63cf-466a-8cd7-fbf7ae58d0f2-2024-06-13T160000.000Z SUPPORT Other

ClinGen classifies the DAW1-primary ciliary dyskinesia gene-disease relationship as limited with autosomal recessive inheritance.

DNAH1 (Limited evidence for PCD association)

Gene: DNAH1 hgnc:2940 gene page

Show evidence (1 reference)

CGGV:assertion_a07c8b6e-a558-498b-975c-b12e96878a44-2025-10-16T160000.000Z SUPPORT Other

ClinGen classifies the DNAH1-primary ciliary dyskinesia gene-disease relationship as limited with autosomal recessive inheritance.

DNAH10 (Limited evidence for PCD association)

Gene: DNAH10 hgnc:2941 gene page

Show evidence (1 reference)

CGGV:assertion_698c6b23-a6fb-4b56-a38e-b29d5f8bbd86-2025-02-13T170000.000Z SUPPORT Other

ClinGen classifies the DNAH10-primary ciliary dyskinesia gene-disease relationship as limited with autosomal recessive inheritance.

DNAH7 (Limited evidence for PCD association)

Gene: DNAH7 hgnc:18661 gene page

Show evidence (1 reference)

CGGV:assertion_90a097d6-5127-4466-8c81-00e99dab2696-2025-02-13T170000.000Z SUPPORT Other

ClinGen classifies the DNAH7-primary ciliary dyskinesia gene-disease relationship as limited with autosomal recessive inheritance.

NME8 (Disputed ClinGen gene-disease validity for PCD)

Gene: NME8 hgnc:16473 relationship_type: DISPUTED

Show evidence (3 references)

ORPHA:244 SUPPORT Other

"NME8 | NME/NM23 family member 8 | hgnc:16473 | Disease-causing germline mutation(s) in"

Orphanet still lists NME8 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_57ca8383-55b6-4edd-9be2-67b1c5142ed1-2026-03-12T000000.000Z REFUTE Other

"the genetic evidence is limited to a single report with incomplete genomic investigation, and subsequent expression studies have not demonstrated NME8 expression in human airway ciliated cells"

ClinGen's evidence summary gives the two grounds for disputing NME8 as a primary ciliary dyskinesia gene: a single proband identified by gene-targeted methods, and no detectable NME8 expression in human airway ciliated cells.

CGGV:assertion_57ca8383-55b6-4edd-9be2-67b1c5142ed1-2026-03-12T000000.000Z REFUTE Other

"While most PCD genes were strongly upregulated during differentiation, NME8 was the only gene that showed no detectable expression throughout the experiment."

Of 26 PCD genes followed through airway epithelial ciliogenesis, NME8 was the only one never expressed, which argues against a role in motile airway cilia.

SPEF2 (Pathogenic Variants)

Gene: SPEF2 hgnc:26293 gene page

Show evidence (1 reference)

CGGV:assertion_e137eed5-fcd8-4497-a6dc-6651062d1cf3-2025-01-09T170000.000Z SUPPORT Other

ClinGen classifies the SPEF2-primary ciliary dyskinesia gene-disease relationship as definitive with autosomal recessive inheritance.

DNAH9 (Pathogenic variants)

Gene: DNAH9 hgnc:2953 gene page

Autosomal recessive

Show evidence (1 reference)

PMID:30471718 SUPPORT Human clinical

"Here we report loss-of-function mutations in DNAH9 in five independent families causing situs abnormalities associated with subtle respiratory ciliary dysfunction."

Human families and functional localization studies support this tissue-dependent genotype.

TUBB4B (Pathogenic variants)

Gene: TUBB4B hgnc:20771 gene page

Autosomal dominant

Show evidence (1 reference)

PMID:38662826 SUPPORT In vitro / ex vivo

"Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner."

Twelve-patient PCD cohort with model and structure-function studies supports an additional dominant mechanism beyond FOXJ1.

CFAP74 (Pathogenic variants)

Gene: CFAP74 hgnc:29368

Autosomal recessive

Show evidence (1 reference)

PMID:39362668 SUPPORT In vitro / ex vivo

"However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance."

GAS2L2 (Biallelic variants associated with ciliary disorientation and PCD)

Gene: GAS2L2 hgnc:24846

Show evidence (1 reference)

PMID:30665704 SUPPORT Human clinical

"Further genetic screening of unrelated PCD subjects identified a second proband with a compound heterozygous variant carrying the identical frameshift variant and a large deletion (c.867_∗343+1207del; p.?) starting in exon 5."

A second unrelated proband carries biallelic GAS2L2 variants. The original cohort is small and does not establish variant-specific natural history.

DNAAF1 (Pathogenic Variants)

Gene: DNAAF1 hgnc:30539 relationship_type: CAUSATIVE

Show evidence (3 references)

ORPHA:244 SUPPORT Other

"DNAAF1 | dynein axonemal assembly factor 1 | hgnc:30539 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association row listing DNAAF1 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_41e4b8cd-35bd-4e99-ba2d-606f191a13cf-2023-03-09T170000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAAF1 to primary ciliary dyskinesia 13 (MONDO:0013174) with classification Definitive.

PMID:22387996 SUPPORT Other

Names DNAAF1 as ODA7 or LRRC50 and places it in the cytoplasmic dynein preassembly pathway.

DNAAF2 (Pathogenic Variants)

Gene: DNAAF2 hgnc:20188 relationship_type: CAUSATIVE

Show evidence (4 references)

ORPHA:244 SUPPORT Other

"DNAAF2 | dynein axonemal assembly factor 2 | hgnc:20188 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association row listing DNAAF2 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_39e5de96-3f16-4dde-a7bc-b3e27364b7f8-2024-02-08T170000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAAF2 to primary ciliary dyskinesia 10 (MONDO:0012918) with classification Definitive.

PMID:28176794 SUPPORT BACKGROUND Other

"multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2-DNAAF4-HSP90 complex"

Places DNAAF2 in the cytoplasmic dynein preassembly complex.

+ 1 more reference

DNAAF3 (Pathogenic Variants)

Gene: DNAAF3 hgnc:30492 relationship_type: CAUSATIVE

Show evidence (3 references)

ORPHA:244 SUPPORT Other

"DNAAF3 | dynein axonemal assembly factor 3 | hgnc:30492 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association row listing DNAAF3 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_40329b6f-2d65-49dd-863b-f79dcd1b5a23-2022-05-09T155600.823Z SUPPORT Other

ClinGen gene-disease validity row binding DNAAF3 to primary ciliary dyskinesia 2 (MONDO:0011718) with classification Definitive.

PMID:22387996 SUPPORT Other

Places DNAAF3 alongside DNAAF1 and DNAAF2 in the cytoplasmic dynein preassembly pathway.

DNAAF4 (Pathogenic Variants)

Gene: DNAAF4 hgnc:21493 gene page relationship_type: CAUSATIVE

Show evidence (3 references)

ORPHA:244 SUPPORT Other

"DNAAF4 | dynein axonemal assembly factor 4 | hgnc:21493 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet gene-disease association row listing DNAAF4 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_79950f5d-fd90-4765-9f8a-489c3f862fcd-2024-04-11T160000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAAF4 to primary ciliary dyskinesia 25 (MONDO:0014203) with classification Definitive.

PMID:28176794 SUPPORT BACKGROUND Other

"multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2-DNAAF4-HSP90 complex"

Places DNAAF4 in the cytoplasmic dynein preassembly complex.

DNAAF5 (Pathogenic Variants)

Gene: DNAAF5 hgnc:26013 relationship_type: CAUSATIVE

Show evidence (3 references)

ORPHA:244 SUPPORT Other

"DNAAF5 | dynein axonemal assembly factor 5 | hgnc:26013 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association row listing DNAAF5 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_9b47c717-e0a5-43ce-865b-0b14289216d7-2024-06-19T110000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAAF5 to primary ciliary dyskinesia 18 (MONDO:0013940) with classification Definitive.

PMID:23040496 SUPPORT In vitro / ex vivo

"HEATR2 was localized to the cytoplasm and not in cilia, which suggests a role in either dynein arm transport or assembly"

Cytoplasmic rather than ciliary localisation of the DNAAF5 product in human airway epithelial cells.

DNAAF6 (Pathogenic Variants)

Gene: DNAAF6 hgnc:28570 relationship_type: CAUSATIVE

Show evidence (3 references)

ORPHA:244 SUPPORT Other

"DNAAF6 | PIH1 domain containing 3 | hgnc:28570 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet gene-disease association row listing DNAAF6 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_5de9de15-2c09-48f5-bcaf-08c42b97700e-2024-08-17T190000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAAF6 to ciliary dyskinesia, primary, 36, X-linked (MONDO:0010517) with classification Definitive.

PMID:28176794 SUPPORT Human clinical

"we demonstrate that large genomic deletions as well as point mutations involving PIH1D3 are responsible for an X-linked form of PCD causing disruption of early axonemal dynein assembly."

Establishes PIH1D3, now DNAAF6, as the cause of an X-linked form of PCD acting through early axonemal dynein assembly.

DNAAF11 (Pathogenic Variants)

Gene: DNAAF11 hgnc:16725 relationship_type: CAUSATIVE

Show evidence (5 references)

ORPHA:244 SUPPORT Other

"DNAAF11 | dynein axonemal assembly factor 11 | hgnc:16725 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet gene-disease association row listing DNAAF11 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_7063ef1e-8ce2-4f35-a765-f08efc2e541a-2023-06-08T160000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAAF11 to primary ciliary dyskinesia 19 (MONDO:0013979) with classification Definitive.

PMID:23122589 SUPPORT Other

"The evolutionarily conserved LRRC6, therefore, emerges as an additional player in DA assembly"

Assigns the DNAAF11 product a role in dynein-arm assembly.

+ 2 more references

DNAAF19 (Pathogenic Variants)

Gene: DNAAF19 hgnc:32700 relationship_type: CAUSATIVE

Show evidence (3 references)

ORPHA:244 SUPPORT Other

"DNAAF19 | dynein axonemal assembly factor 19 | hgnc:32700 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association row listing DNAAF19 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_9974aaef-9082-4bcd-b05a-28869447b5de-2022-12-08T170000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAAF19 to primary ciliary dyskinesia 17 (MONDO:0013854) with classification Definitive.

PMID:22581229 SUPPORT Other

"These results identify Ccdc103 as a dynein arm attachment factor that causes primary ciliary dyskinesia when mutated."

Assigns the DNAAF19 product a dynein-arm attachment role.

CFAP298 (Moderate ClinGen gene-disease validity for PCD 26)

Gene: CFAP298 hgnc:1301

Show evidence (3 references)

ORPHA:244 SUPPORT Other

"CFAP298 | cilia and flagella associated protein 298 | hgnc:1301 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association row listing CFAP298 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_f29143ae-869e-4e4c-8464-8c61f2c2663c-2023-08-10T160000.000Z SUPPORT Other

ClinGen gene-disease validity row binding CFAP298 to primary ciliary dyskinesia 26 (MONDO:0014211) with classification Moderate.

PMID:24094744 SUPPORT Human clinical

"mutations in C21orf59 caused loss of both outer and inner dynein arm components"

Combined outer and inner dynein-arm loss in CFAP298-mutant cilia.

TTC12 (Pathogenic Variants)

Gene: TTC12 hgnc:23700 relationship_type: CAUSATIVE

Show evidence (3 references)

ORPHA:244 SUPPORT Other

"TTC12 | tetratricopeptide repeat domain 12 | hgnc:23700 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet gene-disease association row listing TTC12 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_1ff366d1-58ff-44dd-b7c3-799d1fe250c6-2025-05-08T160000.000Z SUPPORT Other

"TTC12 | HGNC:23700 | ciliary dyskinesia, primary, 45 | MONDO:0032924 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-05-08T16:00:00.000Z"

ClinGen gene-disease validity row binding TTC12 to ciliary dyskinesia, primary, 45 (MONDO:0032924) with classification Definitive.

PMID:31978331 SUPPORT Human clinical

Records the cytoplasmic localisation of the TTC12 product and the cilia-versus-flagella difference in dynein-arm loss.

LRRC56 (Moderate ClinGen gene-disease validity for CILD 39)

Gene: LRRC56 hgnc:25430

Show evidence (2 references)

ORPHA:244 SUPPORT Other

"LRRC56 | leucine rich repeat containing 56 | hgnc:25430 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association row listing LRRC56 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_ceef14a8-34d2-41ac-8c03-47c5eaff8986-2024-11-19T200000.000Z SUPPORT Other

ClinGen gene-disease validity row binding LRRC56 to ciliary dyskinesia, primary, 39 (MONDO:0032637) with classification Moderate.

NEK10 (Pathogenic Variants)

Gene: NEK10 hgnc:18592 relationship_type: CAUSATIVE

Show evidence (2 references)

ORPHA:244 SUPPORT Other

"NEK10 | NIMA related kinase 10 | hgnc:18592 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association row listing NEK10 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_72a2f8fa-ee83-48cc-93fa-22a8990c8d13-2025-10-17T190000.000Z SUPPORT Other

"NEK10 | HGNC:18592 | ciliary dyskinesia, primary, 44 | MONDO:0032914 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-10-17T19:00:00.000Z"

ClinGen gene-disease validity row binding NEK10 to ciliary dyskinesia, primary, 44 (MONDO:0032914) with classification Definitive.

NME5 (Moderate ClinGen gene-disease validity for CILD 48)

Gene: NME5 hgnc:7853

Show evidence (3 references)

ORPHA:244 SUPPORT Other

"NME5 | NME/NM23 family member 5 | hgnc:7853 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association row listing NME5 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_00efe110-5916-4da0-92ac-cee8c8b18140-2024-02-08T170000.000Z SUPPORT Other

"NME5 | HGNC:7853 | ciliary dyskinesia, primary, 48, without situs inversus | MONDO:0031054 | AR | Moderate | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-02-08T17:00:00.000Z"

ClinGen gene-disease validity row binding NME5 to ciliary dyskinesia, primary, 48, without situs inversus (MONDO:0031054) with classification Moderate.

PMID:32185794 SUPPORT Human clinical

"We identified a homozygous nonsense variant (c.572G>A; p.Trp191*) in NME5, which encodes a protein component of the RS neck, in one PCD patient with situs solitus."

Identifies the NME5 product as a radial-spoke neck component and records situs solitus in the reported patient.

DRC1 (Pathogenic Variants)

Gene: DRC1 hgnc:24245 relationship_type: CAUSATIVE

Show evidence (3 references)

ORPHA:244 SUPPORT Other

"DRC1 | dynein regulatory complex subunit 1 | hgnc:24245 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet gene-disease association row listing DRC1 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_ef37e7a5-e14e-4c71-8231-b01bd636b2b9-2025-03-13T160000.000Z SUPPORT Other

"DRC1 | HGNC:24245 | primary ciliary dyskinesia 21 | MONDO:0014123 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-03-13T16:00:00.000Z"

ClinGen gene-disease validity row binding DRC1 to primary ciliary dyskinesia 21 (MONDO:0014123) with classification Definitive.

PMID:36747106 SUPPORT Human clinical

"This study demonstrated that the DRC1 exon 1-4 deletion is a founder mutation based on haplotype analysis."

Establishes the DRC1 exon 1-4 deletion as a founder allele.

ODAD4 (Pathogenic Variants)

Gene: ODAD4 hgnc:25280 relationship_type: CAUSATIVE

Show evidence (4 references)

ORPHA:244 SUPPORT Other

"ODAD4 | outer dynein arm docking complex subunit 4 | hgnc:25280 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet gene-disease association row listing ODAD4 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_547fed6e-47df-44b5-bf4a-e31f7b045862-2022-12-08T170000.000Z SUPPORT Other

ClinGen gene-disease validity row binding ODAD4 to primary ciliary dyskinesia 35 (MONDO:0014910) with classification Definitive.

PMID:27486780 SUPPORT Other

"here we report TTC25 as a new member of the ODA-DC machinery in humans and mice."

Places the ODAD4 product in the outer dynein arm docking complex.

+ 1 more reference

HYDIN (Pathogenic Variants)

Gene: HYDIN hgnc:19368 relationship_type: CAUSATIVE

Show evidence (5 references)

ORPHA:244 SUPPORT Other

"HYDIN | HYDIN axonemal central pair apparatus protein | hgnc:19368 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet gene-disease association row listing HYDIN as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_6c491ab7-496f-43b9-9bca-500901cb686d-2022-02-22T183411.247Z SUPPORT Other

ClinGen gene-disease validity row binding HYDIN to primary ciliary dyskinesia 5 (MONDO:0012088) with classification Definitive.

PMID:31545650 SUPPORT BACKGROUND Other

"Mutations in HYDIN are known to cause CP defects"

Assigns HYDIN-related disease to the central-pair defect class.

+ 2 more references

BRWD1 (Disputed ClinGen gene-disease validity for PCD)

Gene: BRWD1 hgnc:12760 relationship_type: DISPUTED

Show evidence (3 references)

ORPHA:244 SUPPORT Other

"BRWD1 | bromodomain and WD repeat domain containing 1 | hgnc:12760 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association row listing BRWD1 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_9f74ee87-e640-4604-9bb7-e7617907f92c-2022-11-10T110000.000Z SUPPORT Other

ClinGen gene-disease validity row binding BRWD1 to primary ciliary dyskinesia (MONDO:0016575) with classification Disputed.

PMID:33389130 SUPPORT Human clinical

"To our knowledge, this is the first report of a BRWD1-variant-related disease in humans, manifesting as an autosomal recessive form of MMAF and PCD/PCD-like symptoms."

The founding BRWD1 report characterises the respiratory component as PCD or PCD-like rather than established PCD.

DNAL1 (Pathogenic Variants)

Gene: DNAL1 hgnc:23247 relationship_type: CAUSATIVE

Show evidence (4 references)

ORPHA:244 SUPPORT Other

"DNAL1 | dynein axonemal light chain 1 | hgnc:23247 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association row listing DNAL1 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_54088550-2704-4c1b-ac1b-51b62353a223-2024-04-11T160000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAL1 to primary ciliary dyskinesia 16 (MONDO:0013525) with classification Definitive.

PMID:21496787 SUPPORT Human clinical

"We demonstrate here that a homozygous point mutation in this gene is associated with PCD with absent or markedly shortened ODA."

The founding report binding DNAL1 to primary ciliary dyskinesia and stating the outer-dynein-arm lesion.

+ 1 more reference

ZMYND10 (Pathogenic Variants)

Gene: ZMYND10 hgnc:19412 relationship_type: CAUSATIVE

Show evidence (5 references)

ORPHA:244 SUPPORT Other

"ZMYND10 | zinc finger MYND-type containing 10 | hgnc:19412 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet gene-disease association row listing ZMYND10 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_9549c727-fece-494c-9892-83c0ac05f3b4-2023-02-07T170000.000Z SUPPORT Other

ClinGen gene-disease validity row binding ZMYND10 to primary ciliary dyskinesia 22 (MONDO:0014192) with classification Definitive.

PMID:23891469 SUPPORT Human clinical

The founding report binding biallelic ZMYND10 variants to primary ciliary dyskinesia in 14 families.

+ 2 more references

ODAD2 (Pathogenic Variants)

Gene: ODAD2 hgnc:25583 relationship_type: CAUSATIVE

Show evidence (4 references)

ORPHA:244 SUPPORT Other

"ODAD2 | outer dynein arm docking complex subunit 2 | hgnc:25583 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet gene-disease association row listing ODAD2 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_4ac46902-bffa-46f9-bc0d-081e6461d5e2-2022-12-14T170000.000Z SUPPORT Other

ClinGen gene-disease validity row binding ODAD2 to primary ciliary dyskinesia 23 (MONDO:0014193) with classification Definitive.

PMID:23849778 SUPPORT Human clinical

Founding report binding ODAD2/ARMC4 to primary ciliary dyskinesia with an outer-dynein-arm deficit.

+ 1 more reference

DRC2 (Pathogenic Variants)

Gene: DRC2 hgnc:29937 relationship_type: CAUSATIVE

Show evidence (4 references)

ORPHA:244 SUPPORT Other

"DRC2 | dynein regulatory complex subunit 2 | hgnc:29937 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association row listing DRC2 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_662ab516-ba5f-46aa-97b2-ef4c8f3201a5-2024-08-08T160000.000Z SUPPORT Other

"DRC2 | HGNC:29937 | primary ciliary dyskinesia 27 | MONDO:0014215 | AR | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-08-08T16:00:00.000Z"

ClinGen gene-disease validity row binding DRC2 to primary ciliary dyskinesia 27 (MONDO:0014215) with classification Definitive.

PMID:23991085 SUPPORT Human clinical

"A single novel mutation in CCDC65, which created a termination codon at position 293, was identified in a subject with typical clinical features of PCD."

Founding report binding DRC2/CCDC65 to primary ciliary dyskinesia.

+ 1 more reference

SPAG1 (Pathogenic Variants)

Gene: SPAG1 hgnc:11212 relationship_type: CAUSATIVE

Show evidence (4 references)

ORPHA:244 SUPPORT Other

"SPAG1 | sperm associated antigen 1 | hgnc:11212 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association row listing SPAG1 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_c0d43e40-0aa3-41cf-9e3a-8311e685c7be-2022-06-22T190000.000Z SUPPORT Other

ClinGen gene-disease validity row binding SPAG1 to primary ciliary dyskinesia 28 (MONDO:0014216) with classification Definitive.

PMID:24055112 SUPPORT Human clinical

"All 14 affected individuals with SPAG1 mutations had a characteristic PCD phenotype, including 8 with situs abnormalities."

Founding report binding biallelic SPAG1 variants to primary ciliary dyskinesia, with laterality defects in 8 of 14.

+ 1 more reference

RSPH3 (Pathogenic Variants)

Gene: RSPH3 hgnc:21054 relationship_type: CAUSATIVE

Show evidence (6 references)

ORPHA:244 SUPPORT Other

"RSPH3 | radial spoke head 3 | hgnc:21054 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association row listing RSPH3 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_988a074a-14e9-41e3-a1a6-fff72dda3936-2024-08-08T160000.000Z SUPPORT Other

ClinGen gene-disease validity row binding RSPH3 to primary ciliary dyskinesia 32 (MONDO:0014657) with classification Definitive.

PMID:26073779 SUPPORT Human clinical

"We identified non-ambiguous RSPH3 mutations in 5 of 48 independent families affected by CC/RS defects."

Founding report binding biallelic RSPH3 variants to primary ciliary dyskinesia in five families.

+ 3 more references

DRC4 (Pathogenic Variants)

Gene: DRC4 hgnc:4166 relationship_type: CAUSATIVE

Show evidence (6 references)

ORPHA:244 SUPPORT Other

"DRC4 | dynein regulatory complex subunit 4 | hgnc:4166 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet gene-disease association row listing DRC4 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_d34bf201-5f6d-41c0-842d-5c029823ef60-2025-12-10T200000.000Z SUPPORT Other

"DRC4 | HGNC:4166 | primary ciliary dyskinesia 33 | MONDO:0014750 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-12-10T20:00:00.000Z"

ClinGen gene-disease validity row binding DRC4 to primary ciliary dyskinesia 33 (MONDO:0014750) with classification Definitive.

PMID:26387594 SUPPORT Human clinical

"Genome-wide exome sequence analyses identified recessive loss-of-function mutations in GAS8 encoding DRC4 in three independent PCD-affected families."

Founding report binding biallelic DRC4/GAS8 variants to primary ciliary dyskinesia in three families.

+ 3 more references

DNAJB13 (Moderate ClinGen gene-disease validity for primary ciliary dyskinesia 34)

Gene: DNAJB13 hgnc:30718

Show evidence (4 references)

ORPHA:244 SUPPORT Other

"DNAJB13 | DnaJ heat shock protein family (Hsp40) member B13 | hgnc:30718 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet gene-disease association row listing DNAJB13 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_fd64a9ab-9f83-43c8-a23d-2617da493010-2025-06-12T090000.000Z SUPPORT Other

ClinGen gene-disease validity row binding DNAJB13 to primary ciliary dyskinesia 34 (MONDO:0014909) with classification Moderate.

PMID:27486783 SUPPORT Human clinical

States the ultrastructural phenotype this stratum presents with: central-complex defects without a dynein arm defect.

+ 1 more reference

CFAP300 (Pathogenic Variants)

Gene: CFAP300 hgnc:28188 relationship_type: CAUSATIVE

Show evidence (4 references)

ORPHA:244 SUPPORT Other

"CFAP300 | cilia and flagella associated protein 300 | hgnc:28188 | Disease-causing germline mutation(s) (loss of function) in"

Orphanet gene-disease association row listing CFAP300 as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_6bcfa4e4-37a3-43a7-9b4d-60554bc7600c-2022-09-08T110000.000Z SUPPORT Other

ClinGen gene-disease validity row binding CFAP300 to ciliary dyskinesia, primary, 38 (MONDO:0054843) with classification Definitive.

PMID:29727692 SUPPORT Human clinical

"The affected children share a consistent PCD phenotype from early life with laterality defects and immotile respiratory cilia displaying combined loss of inner and outer dynein arms (IDA+ODA)."

Founding report binding biallelic CFAP300 variants to primary ciliary dyskinesia and stating the combined dynein arm lesion.

+ 1 more reference

CLXN (Pathogenic Variants)

Gene: CLXN hgnc:25678 relationship_type: CAUSATIVE

Show evidence (4 references)

ORPHA:244 SUPPORT Other

"CLXN | calaxin | hgnc:25678 | Disease-causing germline mutation(s) in"

Orphanet gene-disease association row listing CLXN as a disease-causing gene for primary ciliary dyskinesia.

CGGV:assertion_18721467-867b-4687-b4f2-5af09951ada5-2025-04-10T160000.000Z SUPPORT Other

ClinGen gene-disease validity row binding CLXN to ciliary dyskinesia, primary, 53 (MONDO:0957991) with classification Strong.

PMID:36727596 SUPPORT Human clinical

"In this study, we identified homozygous pathogenic variants in CLXN (EFCAB1/ODAD5) in 3 individuals with laterality defects and respiratory symptoms."

Founding report binding biallelic CLXN variants to primary ciliary dyskinesia in three individuals.

+ 1 more reference

💊

Medical Actions

Airway Clearance Techniques

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Regular individualized airway clearance, exercise and specialist physiotherapy help mobilize retained secretions. Evidence does not identify one superior technique; the small PCD randomized literature has low certainty. Hypertonic saline can be considered individually for mucus management.

Mechanism Target:

BYPASSES Impaired Mucociliary Clearance — Mechanical airway clearance helps compensate for ineffective ciliary transport.

Show evidence (1 reference)

PMID:41561099 SUPPORT Other

"a personalised and tailored treatment plan for airway clearance, which could include mucolytics such as hypertonic saline as required"

Current specialist-care consensus supports tailored clearance rather than a proven universally superior technique.

Antibiotic Therapy

Action: antibiotic therapy Ontology label: Antibiotic Therapy NCIT:C15620

Agent: azithromycin CHEBI:2955

Treat pulmonary exacerbations promptly with culture-informed antibiotics and an individualized clinical plan. This is distinct from long-term azithromycin maintenance; organism, prior microbiology, severity and response determine the regimen.

Mechanism Target:

INHIBITS Chronic Airway Infection and Neutrophilic Inflammation — Antimicrobial treatment reduces susceptible airway pathogens.

Target Phenotypes: Recurrent Respiratory Infections HP:0002205

Show evidence (1 reference)

PMID:26586601 SUPPORT Other

"regular airway clearance, routine microbiological surveillance, antibiotic treatment for pulmonary exacerbation, and health vaccinations."

PCD treatment review supports acute infection management and surveillance, not blanket prophylaxis.

Bronchodilators

Action: bronchodilator therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: bronchodilator NCIT:C319

Consider bronchodilators case by case for demonstrable reversible airflow obstruction or coexisting asthma. They are not established routine disease-modifying treatment for all PCD; inhaled corticosteroids require a separate indication.

Show evidence (1 reference)

PMID:26418604 SUPPORT Other

"inhaled bronchodilators can be used on a case‐by‐case basis in PCD."

PCD Foundation consensus supports individualized use and describes mixed study results.

Nasal Steroids

Action: Pharmacotherapy NCIT:C15986

Agent: corticosteroid CHEBI:50858

Intranasal corticosteroids may be used for associated nasal polyposis or chronic rhinosinusitis; evidence for PCD-specific benefit is limited and this is not treatment of the ciliary defect.

Show evidence (1 reference)

PMID:26418604 SUPPORT Other

"Antibiotics and nasal steroids may be used in acute on chronic exacerbations of rhinosinusitis"

Consensus addresses symptom-directed sinonasal treatment with limited disease-specific evidence.

Hearing Aids

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Specialist ENT and audiology assessment guides hearing aids and other management for persistent hearing impairment; middle-ear disease and tympanostomy decisions require PCD-specific considerations.

Show evidence (1 reference)

PMID:26418604 SUPPORT Other

"Complications of ROM may include multiple sets of pressure equalization tubes, conductive hearing loss, speech/language delay, or need for hearing aids."

The PCD-specific consensus discusses hearing support for chronic otitis-related impairment; benefit should not be inferred from unrelated hearing-loss diseases.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Provide gene-specific inheritance and reproductive counseling, testing of appropriate relatives and access to fertility services. Autosomal recessive, dominant and X-linked forms have different recurrence implications; infertility is not obligatory.

Show evidence (1 reference)

PMID:41561099 SUPPORT Other

"adults with PCD should have local access to genetic counselling and fertility services."

Contemporary PCD care consensus explicitly recommends both services.

Azithromycin Maintenance

Action: Pharmacotherapy NCIT:C15986

Agent: azithromycin CHEBI:2955

Platform: Small molecule

For selected patients with frequent exacerbations, six months of maintenance azithromycin reduced exacerbations in BESTCILIA. Participants were aged 7–50 with FEV1 above 40% predicted. The trial does not establish lifelong benefit or separate antimicrobial from immunomodulatory mechanisms; microbial surveillance, including nontuberculous mycobacteria, informs selection.

Mechanism Target:

MODULATES Chronic Airway Infection and Neutrophilic Inflammation — Reduces exacerbations through antimicrobial and/or immunomodulatory actions not separated by the trial.

Show evidence (1 reference)

PMID:32380069 SUPPORT Human clinical

"rate ratio 0·45 [95% CI 0·26-0·78]; p=0·004"

Randomized 90-person phase III trial demonstrated fewer exacerbations over six months; prevention of irreversible damage was a proposed downstream implication, not the primary proven endpoint.

Multidisciplinary Support and Preventive Care

Action: Supportive Care NCIT:C15747

Specialist follow-up includes vaccination, nutrition, ENT/hearing care, sinonasal irrigation, psychological support when needed, fertility care and planned transition to adult services. Advanced lung disease warrants specialist consideration of oxygen, ventilatory support or transplantation according to clinical status.

Show evidence (2 references)

PMID:41561099 SUPPORT Other

"We present a consensus statement on 15 standards covering provision of pulmonary, ear, nose and throat, and fertility care, screening for situs abnormalities and transition from paediatric to adult care services."

England consensus describes broad specialist-care standards; individual interventions retain different levels of evidence.

PMID:26586601 SUPPORT Other

"regular airway clearance, routine microbiological surveillance, antibiotic treatment for pulmonary exacerbation, and health vaccinations."

PCD-specific review includes vaccination among routine care measures.

Brensocatib for Non-CF Bronchiectasis

Action: Pharmacotherapy NCIT:C15986

Platform: Small molecule

The DPP-1 inhibitor brensocatib targets neutrophil serine-protease activation. Its 2025 US indication covers non-cystic fibrosis bronchiectasis in patients aged at least 12, which can include PCD-associated bronchiectasis. ASPEN demonstrated fewer exacerbations in the broader bronchiectasis population, not a separately powered PCD trial. PCD-specific benefit and individual selection require specialist interpretation; this treatment does not repair the ciliary genetic defect.

Mechanism Target:

INHIBITS Chronic Airway Infection and Neutrophilic Inflammation — DPP-1 inhibition targets the neutrophil-serine-protease component of airway inflammation. It does not directly correct the motile-cilia genetic defect, and clinical efficacy specifically within PCD remains uncertain.

Show evidence (1 reference)

PMID:40267423 SUPPORT Other

"Brensocatib, an oral, reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), targets neutrophil serine proteases, key mediators of neutrophilic inflammation."

This background pharmacology statement identifies the neutrophil-protease target; it is separate from the randomized clinical outcome and does not establish a PCD-specific treatment effect.

Show evidence (1 reference)

PMID:40267423 SUPPORT Human clinical

"Among patients with bronchiectasis, once-daily treatment with brensocatib (10 mg or 25 mg) led to a lower annualized rate of pulmonary exacerbations than placebo, and the decline in FEV1 was less with the 25-mg dose of brensocatib than with placebo."

The randomized result concerns the broader non-CF bronchiectasis trial population, not a separately demonstrated PCD subgroup benefit.

🌍

Environmental Factors

Air Pollution

Air pollution may aggravate airway disease through general epithelial injury and inflammation. The cited airway literature is indirect background, not PCD-specific causal or exposure-response evidence.

Show evidence (1 reference)

PMID:34574829 SUPPORT Other

"In general, air pollution decreases quality of life and life expectancy. It exacerbates acute and chronic respiratory symptoms in patients with chronic airway diseases"

General airway review supplies indirect biological plausibility; it does not establish a PCD-specific causal exposure-response effect.

🔬

Biochemical Markers

Nasal Nitric Oxide (Decreased)

Context: Often reduced nasal NO production rate; assay protocol, age and genotype affect interpretation

Reference Ranges

≥ 77 nL/min (individuals aged 5 years and older; standardized chemiluminescence measurement during velum-closure breath-hold)

Suggestive of primary ciliary dyskinesia (< 77 nL/min) Above the low-nNO diagnostic threshold (≥ 77 nL/min)

Suggestive of primary ciliary dyskinesia: Below 77 nL/min is supportive in an appropriate clinical context using the specified protocol. Repeat testing and genetics/TEM or other adjunct testing are needed; low values also occur in CF and viral infection.

Above the low-nNO diagnostic threshold: A result at or above 77 nL/min does not exclude PCD. RSPH1 and C1d-related disease can have normal or higher production rates despite clinically important transport defects.

This is a diagnostic decision threshold, not a physiological reference interval or acute severity marker. The original 77 nL/min cutoff applies to standardized velum-closure measurements in cooperative subjects aged at least five; tidal-breathing measurements in younger children require separate protocols. CF and intercurrent viral infection can lower nNO. Normal nNO occurs in RSPH1, C1d and other genotypes and cannot exclude PCD. Nasal production rate is not interchangeable with exhaled concentration or FeNO.

Show evidence (2 references)

PMID:24024753 SUPPORT Human clinical

"The disease-specific nNO cutoff value was defined at 77 nl/minute (sensitivity, 0.98; specificity, >0.999)."

Establishes the standardized 77 nL/min nasal NO diagnostic cutoff for PCD.

PMID:24024753 SUPPORT Human clinical

"nNO values in PCD (mean ± standard deviation, 20.7 ± 24.1 nl/min; range, 1.5-207.3 nl/min) only rarely overlapped with the nNO values of healthy control subjects (304.6 ± 118.8; 125.5-867.0 nl/min)"

Documents the markedly low PCD nNO distribution versus the much higher healthy-control values that underpin the bands.

Show evidence (6 references)

PMID:41005984 SUPPORT Other

"Low nNO levels are described in most individuals with PCD compared to healthy and disease controls, although reasons for the low nNO remain uncertain."

The joint guideline states that nasal NO is low in most, not all, people with PCD relative to both healthy and disease controls, and that the cause of the low level is unknown.

PMID:41005984 SUPPORT Other

"Some patients with PCD have nNO levels above the recommended threshold for diagnosis, and other tests should be considered if the clinical suspicion of PCD remains."

Supports the band stating that a value at or above the threshold does not exclude PCD.

PMID:24024753 SUPPORT Human clinical

"The disease-specific nNO cutoff value was defined at 77 nl/minute (sensitivity, 0.98; specificity, >0.999)."

Original standardized cutoff study. The quoted specificity primarily reflects comparison with healthy controls; it should not be applied to every symptomatic referral population.

+ 3 more references

🔬

Diagnosis

Clinical Suspicion and Specialist Multimodal Assessment

Early persistent wet cough and rhinosinusitis, unexplained term neonatal respiratory distress, chronic middle-ear disease or laterality defects warrant specialist evaluation. No single normal test excludes PCD. The 2025 joint ERS/ATS guideline combines genetics/TEM with high-speed video microscopy, immunofluorescence and nasal nitric oxide as adjuncts, interpreted with pre-test probability.

Show evidence (1 reference)

PMID:41005984 SUPPORT Other

"The panel gives a strong recommendation for use of high-speed video microscopy, immunofluorescence and nasal nitric oxide as adjunct tests to transmission electron microscopy and/or genetics for PCD diagnosis."

Defines the updated integrated diagnostic strategy.

Molecular Genetic Diagnosis

Pathogenic or likely pathogenic variants in a sufficiently validated gene must match its inheritance pattern: biallelic for recessive, hemizygous for relevant X-linked, or monoallelic for dominant disease. Gene panels, copy-number analysis and selected exome/genome sequencing improve yield. A VUS or a variant in a gene with limited validity alone does not confirm PCD.

Show evidence (2 references)

PMID:41005984 SUPPORT Other

"any genetic test that provided a pathogenic or likely pathogenic variant (using ACMG criteria) found in a known PCD-associated gene consistent with the known inheritance pattern for that gene"

The guideline requires pathogenicity, gene validity and inheritance consistency.

PMID:39115449 SUPPORT Human clinical

"Three identified variants were deletions, ranging from 3 to 13 kb"

Small selected WGS cohort illustrates structural variants missed by narrower testing; its high yield is not an all-referral sensitivity estimate.

Ciliary Ultrastructure and Function

TEM hallmark class 1 defects can confirm PCD; class 2 findings require additional evidence. Normal TEM occurs in a substantial minority. Expert high-speed assessment evaluates waveform as well as frequency, with repeat or ALI-culture assessment when secondary injury confounds native samples. C1d defects may retain normal routine TEM and beating while failing transport assays.

Show evidence (2 references)

PMID:41005984 SUPPORT Other

"Class 1 defects confirm a diagnosis of PCD, while Class 2 defects are suggestive of PCD and require supporting evidence from other diagnostic modalities."

Distinguishes diagnostic and suggestive ultrastructural classes.

PMID:39362668 SUPPORT In vitro / ex vivo

"However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance."

Nasal Nitric Oxide

Standardized nasal NO is a useful adjunct. Interpret the 77 nL/min velum-closure threshold with age, method, CF exclusion and intercurrent infection. Tidal-breathing measurements in younger children are protocol-specific. Normal results in some genotypes do not exclude PCD.

No LOINC measurement is bound, because the release has no nasal nitric oxide code at all and the two exhaled nitric oxide codes it does carry are a different quantity from a different airway compartment. The enumeration, across both the LOINC release table and the Monarch KG, is recorded once on the matching biochemical marker rather than repeated here. Note what that absence costs: this disease owns a standardized numeric threshold, 77 nL/min at velum closure, and the marker record already carries it as reference-range bands, so the bands exist with no code to key them to. That makes the measurement a candidate for a LOINC term request.

Show evidence (1 reference)

PMID:41005984 SUPPORT Other

"no adjunct test is suitable as a standalone test to diagnose PCD and no single adjunct or reference test is suitable to exclude PCD."

A low or normal nasal-NO result cannot independently settle diagnosis.

Organ and Longitudinal Assessment

Assess lung function, cultures, nutritional status, hearing and sinonasal disease; clarify situs/cardiac anatomy when the genotype can affect laterality. Fertility and transition to adult care require dedicated discussion. Repeated CT imaging is individualized to clinical need.

Show evidence (2 references)

PMID:41561099 SUPPORT Other

"individuals with PCD should have at least one abdominal ultrasound and echocardiogram in their records, unless a patient's PCD was known to be caused by a gene that does not cause laterality defects"

England specialist-care consensus scopes situs screening by genotype.

PMID:41561099 SUPPORT Other

"At annual review, patients should have appropriate assessment of their recent clinical history with a focus on number of exacerbations, lung function, respiratory sample culture, blood tests, observations and physical examination, assessment of nutritional status as well as physiotherapy review"

Consensus identifies practical multidimensional follow-up.

📊

Prevalence

Europe

Prevalence at birth 1.0–9.0 per 100,000 1–9 per 100,000 (births)

Show evidence (2 references)

ORPHA:244 SUPPORT Other

"1-9 / 100 000 | Europe | Prevalence at birth | PMID:23871404"

Orphanet epidemiology data reports prevalence at birth in Europe of 1-9 per 100,000.

PMID:23871404 SUPPORT Other

"Prevalence, about 1/15,000 to 1/30,000, is probably underestimated, as diagnosis might not be evocated in absence of Kartagener syndrome."

French review estimates prevalence at 1/15,000 to 1/30,000, consistent with the Orphanet range of 1-9 per 100,000.

British Asian population of Bradford, United Kingdom

Point prevalence 44.150110375275936–44.150110375275936 per 100,000 1–9 per 10,000

The primary source supersedes the incorrect Pakistan geography in the secondary Orphanet table. Fifty-two percent of parents were first cousins; ascertainment and ancestry limit generalization.

Show evidence (1 reference)

PMID:19720631 SUPPORT Human clinical

"The prevalence of PCD in the population studied was one in 2265."

Fifteen-year ascertainment in the highly consanguineous British Asian population of Bradford, UK. This is not a Pakistan national prevalence estimate.

Global modeled genetic prevalence

Point prevalence

Variant-frequency modeling estimated a minimum of one in 7554 using 29 autosomal-recessive PCD genes and 182681 individuals. This is a Hardy-Weinberg-based estimate from variant databases, not observed case ascertainment or a measured birth-prevalence series; inclusion of uncertain variants changes the estimates markedly.

Show evidence (1 reference)

PMID:35051411 SUPPORT Computational

"Primary ciliary dyskinesia (PCD) is a motile ciliopathy characterised by otosinopulmonary infections. ... The aim of the study was to estimate the worldwide prevalence and ethnic heterogeneity of PCD. METHODS: We calculated the allele frequency of disease-causing variants in 29 PCD genes..."

The minimum global estimate of 1 in 7,554 is modeled from PCD-variant allele frequencies using Hardy-Weinberg assumptions. It is not a count of clinically diagnosed patients; including uncertain variants changes the estimate.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Primary_Ciliary_Dyskinesia:

Cystic Fibrosis

Overlapping Features CF also causes chronic suppurative respiratory disease, bronchiectasis and sometimes low nasal NO. Sweat chloride and CFTR evaluation distinguish CF; laterality defects and hallmark motile-cilia findings favor PCD.

Show evidence (2 references)

PMID:41005984 SUPPORT Other

"More extensive testing for alternative diagnoses (e.g. cystic fibrosis and primary immunodeficiency) should be considered during the evaluation of subjects for PCD."

The guideline names cystic fibrosis as an alternative diagnosis to exclude during PCD evaluation.

PMID:24024753 SUPPORT Human clinical

"however, there was overlap with cystic fibrosis (134.0 ± 73.5; 15.6-386.1 nl/min)."

Nasal NO in PCD rarely overlapped with healthy, asthma or COPD controls but did overlap with cystic fibrosis, so a low nasal NO does not by itself separate the two diseases.

Secondary Ciliary Dysfunction and Other Causes of Bronchiectasis

Overlapping Features Acute infection, acquired epithelial injury, immunodeficiency and aspiration can produce overlapping respiratory manifestations or secondary beat abnormalities. Clinical context, repeat/culture ciliary assessment and molecular or hallmark ultrastructural evidence help distinguish inherited PCD. Isolated laterality syndromes and sensory ciliopathies need separate genetic interpretation.

Show evidence (1 reference)

PMID:41005984 SUPPORT Other

"Class 1 defects confirm a diagnosis of PCD, while Class 2 defects are suggestive of PCD and require supporting evidence from other diagnostic modalities."

The guideline distinguishes diagnostic evidence from suggestive or potentially confounded findings.

📊

Related Datasets

Gene expression profile at single cell level of human nasal primary airway cells from DNAH5 subjects geo:GSE272189

Public human nasal ALI-culture scRNA-seq series linked to PMID:39042459. GEO lists 15 samples; the primary discovery comparison includes four DNAH5 PCD donors, their four heterozygous mothers and five unrelated controls, with additional samples represented in the accession. Sample count is not an independent patient count. Cultured and iPSC validation identified oxidative stress and ciliary GSTA2 responses; no independent raw-data reanalysis was performed in this curation.

human SINGLE CELL RNA SEQ

PMID:39042459

Show evidence (1 reference)

PMID:39042459 SUPPORT In vitro / ex vivo

"We used single-cell RNA-Seq, proteomics, and advanced microscopy to compare primary culture epithelial cells from patients with PCD, their heterozygous mothers, and healthy individuals"

Single-cell transcriptomic dataset of human PCD airway epithelial cells (DNAH5 patients) versus heterozygous mothers and controls.

Cellular responses in the airway ciliary microenvironment from mouse models of primary ciliary dyskinesia with central pair apparatus defects geo:GSE254100

Public mouse tracheal scRNA-seq with four GEO sample records: wild type and Cfap221/Pcdp1 nm1054, Spef2 bgh and Cfap54 gene-trap mutant preparations on the 129S6/SvEvTac background. Published cell-type-specific differential expression includes shared and distinct responses across genotypes. Human HGNC bindings identify the orthologous disease genes; the samples are mouse, not human. No raw-data reanalysis was performed in this curation.

house mouse SINGLE CELL RNA SEQ

PMID:39558053

Show evidence (1 reference)

PMID:39558053 SUPPORT Model organism

"we have used single-cell RNA sequencing to investigate responses in tracheal epithelial cells from mice with mutations in CPA genes"

Single-cell transcriptomic dataset of tracheal epithelium from central-pair-apparatus PCD mouse models (Cfap221, Cfap54, Spef2).

🔬

Clinical Trials

BESTCILIA PHASE_III COMPLETED

Multicentre, double-blind, randomised, placebo-controlled phase 3 trial of azithromycin maintenance therapy (three times weekly for 6 months) in patients with PCD aged 7-50 years; the first multinational pharmacotherapy RCT in PCD. Registered as EudraCT 2013-004664-58.

Target Phenotypes: Recurrent respiratory infections HP:0002205

Show evidence (1 reference)

PMID:32380069 SUPPORT Human clinical

"azithromycin maintenance therapy for 6 months was well tolerated and halved the rate of respiratory exacerbations."

The BESTCILIA RCT showed azithromycin maintenance halved respiratory exacerbations over 6 months in PCD.

NCT02871778 PHASE_II COMPLETED

CLEAN-PCD randomized 123 participants aged at least 12 with ppFEV1 40 to below 90 to idrevloride (VX-371) with or without 4.2% hypertonic saline, with 28-day treatment and washout periods. The published combination-versus-saline comparison improved ppFEV1 by 1.5 percentage points (95% CI below 0.1 to 3.0; p=0.044). Combination versus placebo and idrevloride alone versus placebo were nonsignificant. The registry retains an ivacaftor-containing protocol description, but ivacaftor is not an intervention in these published results. ENaC-inhibition rationale does not establish primary ENaC hyperabsorption in PCD.

Target Phenotypes: Airway obstruction HP:0006536 Recurrent respiratory infections HP:0002205

Show evidence (3 references)

clinicaltrials:NCT02871778 SUPPORT Human clinical

"To evaluate the safety and efficacy of treatment with VX-371 with and without ivacaftor, and the effect of VX-371 with and without ivacaftor on quality of life (QOL) in subjects with primary ciliary dyskinesia (PCD)."

Registry describes the registered protocol including ivacaftor; the primary publication reports the idrevloride/hypertonic-saline results. Protocol text should not replace the actual published intervention comparison.

PMID:37660715 SUPPORT Human clinical

"There was no significant difference in ppFEV1 for the parallel comparison of idrevloride in hypertonic saline compared with placebo or the crossover comparison of idrevloride with placebo."

Comparator-specific negative results temper the small combination-versus-saline signal in this short phase II trial.

PMID:37660715 SUPPORT Human clinical

"than with hypertonic saline alone (least-squares mean absolute change from baseline of -0·5 percentage points, -2·0 to 0·9; difference 1·5 percentage points, 95% CI <0·1 to 3·0; p=0·044)."

The published primary comparison behind the 1.5-percentage-point ppFEV1 difference stated in the trial description, for idrevloride in hypertonic saline versus hypertonic saline alone.

NCT06633757 PHASE_I COMPLETED

RCT1100-103 is a phase 1b open-label DNAI1 mRNA study in adults with DNAI1-associated PCD; the registry is completed as checked September 2026. Separate RCT1100-101/102 conference results (nine and seven participants) reported no grade 3 or greater or serious adverse events, but no improvement in post-treatment outer dynein arms, ciliary movement or DNAI1 immunofluorescence. These early results do not establish clinical efficacy and should not be attributed to RCT1100-103.

Target Phenotypes: Recurrent respiratory infections HP:0002205

Show evidence (2 references)

clinicaltrials:NCT06633757 SUPPORT Human clinical

"This is a multi-dose study with RCT1100 and is designed to provide safety, tolerability and preliminary efficacy data for future clinical studies."

ClinicalTrials.gov confirms a multi-dose study of the inhaled DNAI1 mRNA therapy RCT1100 in DNAI1-mutation PCD assessing safety, tolerability, and preliminary efficacy.

DOI:10.1093/ajrccm/aamag286.098 SUPPORT Human clinical

"No difference was seen in the average number of outer dynein arms present per cross section, ciliary movement, or DNAI1 measured by immunofluorescence in post-treatment bronchial samples."

Primary 2026 conference abstract of separate -101/-102 studies supplies limited human pharmacodynamic evidence; it is not a full peer-reviewed randomized efficacy trial.

🧫

Experimental Models

Patient-derived nasal epithelial air-liquid interface model PRIMARY_CELL_CULTURE namo:TwoDCellCulture

Expanded basal epithelial cells from nasal brush biopsies re-differentiated in miniaturized air-liquid interface cultures to preserve genotype-linked ciliary ultrastructural and motility defects in primary ciliary dyskinesia. These cultures support experimental screens rather than proof that every readthrough or replacement strategy restores clinical clearance.

Organism

human NCBITaxon:9606

Tissue

nasal cavity epithelium UBERON:0005384

Cell source

Patient-derived nasal basal epithelial cells expanded from nasal brush biopsies

Culture

Miniaturized 96-well Transwell air-liquid interface culture

Publication

PMID:33795320

Pathograph links

Ciliary Dysfunction recapitulates fidelity: moderate observes: cellular Retains a range of patient ciliary beat and ultrastructural defects after basal-cell expansion.

Limitations: The measured culture phenotype does not establish prediction of individual clinical severity or whole-lung clearance.

Readouts

Ciliary beat pattern and frequency

Video analysis identifies genotype-associated motility abnormalities; different defects need not change frequency in the same direction.

cilium movement GO:0003341

Direction: ALTERED

Show evidence (1 reference)

PMID:33795320 SUPPORT In vitro / ex vivo

"Initial analyses of ciliary ultrastructure, beat pattern and beat frequency in the 96-well transwell format ALI cultures indicate that a range of different PCD defects can be retained in these cultures."

Supports use of expanded nasal ALI cultures as a disease-relevant PCD model that preserves mutation-associated ciliary defects.

Show evidence (1 reference)

PMID:33795320 SUPPORT In vitro / ex vivo

Supports use of expanded nasal ALI cultures as a disease-relevant PCD model that preserves mutation-associated ciliary defects.

Findings

Patient-derived nasal ALI cultures retain genotype-linked ciliary ultrastructural and motility defects and can be used to test rescue strategies for reduced multiciliogenesis

Show evidence (2 references)

PMID:33795320 SUPPORT In vitro / ex vivo

Supports use of expanded nasal ALI cultures as a disease-relevant PCD model that preserves mutation-associated ciliary defects.

PMID:33795320 SUPPORT In vitro / ex vivo

"As proof-of-principle, we performed a personalised investigation in a patient with a rare and severe form of PCD (reduced generation of motile cilia), in this case caused by a homozygous nonsense mutation in the MCIDAS gene."

Links the ALI model to a mechanistically relevant multiciliogenesis defect within a defined PCD genotype.

Show evidence (1 reference)

PMID:33795320 SUPPORT In vitro / ex vivo

"Primary cell culture of basal epithelial cells from nasal brush biopsies followed by ciliated differentiation at the air-liquid interface (ALI) has proven to be a useful tool in PCD diagnostics but the technique's broader utility, including in pre-clinical PCD research, has been restricted by..."

Establishes patient-derived nasal ALI culture as an existing PCD modeling system and motivates the expanded higher-throughput format.

Patient-derived airway organoid model ORGANOID namo:Organoid

Airway organoids established from nasal inferior turbinate brush samples and differentiated toward ciliated cells to capture patient-specific ciliary beating abnormalities in primary ciliary dyskinesia.

Organism

human NCBITaxon:9606

Tissue

nasal cavity epithelium UBERON:0005384

Cell source

Patient-derived nasal inferior turbinate epithelial cells expanded as airway organoids

Culture

Long-term expandable airway organoid culture with ciliated differentiation

Publication

PMID:34693619

Pathograph links

Ciliary Dysfunction recapitulates fidelity: moderate observes: cellular Differentiated patient airway organoids retain mutation-associated ciliary beating abnormalities.

Limitations: Expansion and ciliated differentiation were demonstrated in a small genotype panel. Closed organoid geometry and culture composition limit extrapolation to airway transport; molecular editing alone is not evidence of functional rescue.

Readouts

Patient-specific ciliary beating

Ciliary beating differs between patient organoids in agreement with their mutations.

cilium movement GO:0003341

Direction: ALTERED

Show evidence (1 reference)

PMID:34693619 SUPPORT In vitro / ex vivo

"Patient-specific differences in ciliary beating are observed and are in agreement with the patients' genetic mutations."

Supports the organoid model as a genotype-resolved readout of the ciliary dysfunction central to PCD.

Show evidence (1 reference)

PMID:34693619 SUPPORT In vitro / ex vivo

"Patient-specific differences in ciliary beating are observed and are in agreement with the patients' genetic mutations."

Supports the organoid model as a genotype-resolved readout of the ciliary dysfunction central to PCD.

Findings

Patient-derived airway organoids reproduce mutation-linked differences in ciliary beating and support genotype-specific functional interrogation

Show evidence (2 references)

PMID:34693619 SUPPORT In vitro / ex vivo

"Patient-specific differences in ciliary beating are observed and are in agreement with the patients' genetic mutations."

Supports the organoid model as a genotype-resolved readout of the ciliary dysfunction central to PCD.

PMID:34693619 SUPPORT In vitro / ex vivo

"More detailed organoid ciliary phenotypes can thus be documented in addition to the standard diagnostic procedure."

Supports use of organoids for mechanistically richer ciliary phenotyping in PCD.

Show evidence (1 reference)

PMID:34693619 SUPPORT In vitro / ex vivo

"We apply this condition to AOs established from nasal inferior turbinate brush samples of patients suffering from primary ciliary dyskinesia (PCD), a pulmonary disease caused by dysfunction of the motile cilia in the airways."

Establishes patient-derived airway organoids as a directly disease-relevant non-animal model for PCD.

Patient-specific hiPSC-derived airway epithelium model IPSC_DERIVED_MODEL namo:TwoDCellCulture

Human induced pluripotent stem cell-derived airway epithelium differentiated at air-liquid interface to model structural ciliary defects and impaired mucociliary transport in genetically defined primary ciliary dyskinesia.

Organism

human NCBITaxon:9606

Tissue

respiratory airway UBERON:0001005

Cell source

Patient-specific induced pluripotent stem cell lines differentiated into ciliated airway epithelium

Culture

Air-liquid interface differentiation of hiPSC-derived airway epithelium

Publication

PMID:37296588

Pathograph links

Ciliary Dysfunction recapitulates fidelity: moderate observes: cellular DNAH5 and NME5 patient-derived hiPSC airway epithelia reproduce their respective structural and functional ciliary defects.

Limitations: Two patient-specific lines do not establish fidelity across PCD genotypes, reprogramming clones or differentiation batches.

Readouts

Ciliary motility and ultrastructure

Electron microscopy, immunofluorescence and beat-frequency measurements assess two patient-specific hiPSC lines.

cilium movement GO:0003341

Direction: ALTERED

Show evidence (1 reference)

PMID:37296588 SUPPORT In vitro / ex vivo

"Applying transmission electron microscopy, immunofluorescence staining, ciliary beat frequency, and mucociliary transport measurements, we could demonstrate that ciliated respiratory epithelia cells derived from two PCD patient-specific hiPSC lines carrying mutations in DNAH5 and NME5,..."

Shows that hiPSC-derived airway epithelium reproduces the molecular and functional consequences of PCD mutations, including impaired transport.

Show evidence (1 reference)

PMID:37296588 SUPPORT In vitro / ex vivo

Shows that hiPSC-derived airway epithelium reproduces the molecular and functional consequences of PCD mutations, including impaired transport.

Impaired Mucociliary Clearance recapitulates fidelity: moderate observes: tissue Patient-specific hiPSC airway epithelia reproduce impaired culture-surface transport.

Limitations: The measured culture phenotype does not establish prediction of individual clinical severity or whole-lung clearance.

Readouts

Mucociliary transport

Transport measurements complement structural and beat-frequency phenotyping of DNAH5 and NME5 cultures.

mucociliary clearance GO:0120197

Direction: DECREASED

Show evidence (1 reference)

PMID:37296588 SUPPORT In vitro / ex vivo

Shows that hiPSC-derived airway epithelium reproduces the molecular and functional consequences of PCD mutations, including impaired transport.

Show evidence (1 reference)

PMID:37296588 SUPPORT In vitro / ex vivo

Shows that hiPSC-derived airway epithelium reproduces the molecular and functional consequences of PCD mutations, including impaired transport.

Findings

Patient-specific hiPSC-derived airway epithelium reproduces molecular, ultrastructural, and functional ciliary defects, including impaired mucociliary transport

Show evidence (1 reference)

PMID:37296588 SUPPORT In vitro / ex vivo

Shows that hiPSC-derived airway epithelium reproduces the molecular and functional consequences of PCD mutations, including impaired transport.

Show evidence (2 references)

PMID:37296588 SUPPORT In vitro / ex vivo

"Here, we developed an in vitro model for PCD based on human induced pluripotent stem cell (hiPSC)-derived airway epithelium in Air-Liquid-Interface cultures."

Establishes hiPSC-derived airway epithelium as a PCD-specific in vitro model.

PMID:37296588 SUPPORT In vitro / ex vivo

"Motile cilia dysfunction results in diminished mucociliary clearance (MCC) of pathogens in the respiratory tract and chronic airway inflammation and infections successively causing progressive lung damage."

Connects the model's mucociliary transport readouts to the central airway pathophysiology of PCD.

CCDC40 mRNA replacement in patient airway cultures PRIMARY_CELL_CULTURE namo:TwoDCellCulture

Lipid nanoparticle CCDC40 mRNA was tested in nasal ALI cultures from five CCDC40-deficient individuals, restoring expression in 10–74% of ciliated cells, associated axonemal proteins, beating and particle transport. Parallel zebrafish olfactory-pit flow rescue is preclinical vertebrate evidence. The study proposes a human phase I trial; it does not report clinical efficacy.

Organism

human NCBITaxon:9606

Tissue

nasal cavity epithelium UBERON:0005384

Cell source

Nasal respiratory epithelial cells from five CCDC40-deficient individuals

Culture

Air-liquid interface culture treated with lipid nanoparticle-formulated CCDC40 mRNA

Publication

PMID:42089334

Pathograph links

CCDC39-CCDC40 Axonemal Scaffold Loss rescues fidelity: moderate observes: cellular mRNA replacement restores CCDC40 and integration of associated axonemal proteins.

Limitations: The measured culture phenotype does not establish prediction of individual clinical severity or whole-lung clearance.

Readouts

Axonemal protein reconstitution

CCDC40 expression in 10%-74% of ciliated cells permits associated-protein integration; this is not a fraction of clinically corrected lung tissue.

Direction: RESTORED

Show evidence (1 reference)

PMID:42089334 SUPPORT In vitro / ex vivo

"Topical application of exogenous LNP-CCDC40-mRNA to CCDC40-deficient cells results in endogenous CCDC40 expression (10%-74% of ciliated cells), enabling axonemal integration of CCDC40-associated proteins (CCDC39, GAS8/DRC4, DNALI1)."

Documents partial cellular expression and reassembly of associated proteins in treated patient airway cultures.

Show evidence (1 reference)

PMID:42089334 SUPPORT In vitro / ex vivo

Documents partial cellular expression and reassembly of associated proteins in treated patient airway cultures.

Impaired Mucociliary Clearance rescues fidelity: moderate observes: tissue Treatment improves fluorescent-particle transport in patient cultures.

Limitations: The measured culture phenotype does not establish prediction of individual clinical severity or whole-lung clearance.

Readouts

Fluorescent-particle transport after mRNA delivery

Improved transport relative to untreated CCDC40-deficient cultures; complete normalization is not established by this endpoint statement.

mucociliary clearance GO:0120197

Direction: INCREASED

Show evidence (1 reference)

PMID:42089334 SUPPORT In vitro / ex vivo

"Further, we showed improved ciliary transport of fluorescent particles."

Patient-cell rescue goes beyond beat frequency to an in vitro transport readout; it remains distinct from clinical whole-lung clearance or outcomes.

Show evidence (1 reference)

PMID:42089334 SUPPORT In vitro / ex vivo

"Further, we showed improved ciliary transport of fluorescent particles."

Patient-cell rescue goes beyond beat frequency to an in vitro transport readout; it remains distinct from clinical whole-lung clearance or outcomes.

Show evidence (1 reference)

PMID:42089334 SUPPORT In vitro / ex vivo

"Further, we showed improved ciliary transport of fluorescent particles."

Patient-cell rescue goes beyond beat frequency to an in vitro transport readout; it remains distinct from clinical whole-lung clearance or outcomes.

DNAH5 patient redox profiling and separate GSTA2 airway-cell perturbation PRIMARY_CELL_CULTURE namo:TwoDCellCulture

The study compared DNAH5 PCD cultures with maternal/healthy controls and confirmed increased GSTA/NRF2 expression in patient-derived iPSC airway cells. Separate GSTA2 knockdown in primary human airway cultures reduced beat frequency and microbead transport, with partial catalase rescue. These assay contexts must remain distinct; the knockdown is not a model of the increased GSTA2 state in DNAH5 PCD.

Organism

human NCBITaxon:9606

Cell source

Patient-derived nasal epithelial cells, patient-derived iPSC airway cells and normal primary human airway cells

Culture

Air-liquid interface epithelial culture with transcriptomics, ROS measurements and separate GSTA2 shRNA experiments

Publication

PMID:39042459

Pathograph links

Ciliary Oxidative Stress and Glutathione Response measures fidelity: moderate observes: cellular Measures genotype-associated ROS and GSTA/NRF2 expression in patient-derived epithelial cultures.

Limitations: Observed upregulation does not isolate its causal contribution to patient ciliary dysfunction or clinical severity.

Readouts

ROS and antioxidant-response expression

Patient-derived cultures show increased ROS and GSTA/NRF2 expression.

Direction: INCREASED

Show evidence (1 reference)

PMID:39042459 SUPPORT In vitro / ex vivo

DNAH5 patient cultures and iPSC-derived cells show an intrinsic oxidative-stress response; increased GSTA expression is not a GSTA deficiency.

Show evidence (1 reference)

PMID:39042459 SUPPORT In vitro / ex vivo

DNAH5 patient cultures and iPSC-derived cells show an intrinsic oxidative-stress response; increased GSTA expression is not a GSTA deficiency.

Ciliary Dysfunction perturbs fidelity: low observes: cellular Separate GSTA2 knockdown slows ciliary beating in primary human airway cells, with partial catalase rescue of transport.

Limitations: Loss of GSTA2 is an experimental perturbation, not the increased GSTA2 expression state measured in DNAH5 PCD.

Readouts

Ciliary beat frequency after GSTA2 knockdown

Separate GSTA2 depletion in primary human airway cultures reduces beat frequency; it is not the patient-associated increased GSTA2 state.

cilium movement GO:0003341

Direction: DECREASED

Show evidence (1 reference)

PMID:39042459 SUPPORT In vitro / ex vivo

"GSTA2 knockdown (KD) resulted in a significant decrease in cilia beat frequency (CBF) and ciliary transport of microbeads on the surface of ciliated cells compared with a nontargeted control sequence (Figure 7, H and I)."

GSTA2 depletion perturbed motility and transport in primary human airway cultures; this intervention is different from the increased GSTA2 state observed in DNAH5 PCD.

Show evidence (2 references)

PMID:39042459 SUPPORT In vitro / ex vivo

GSTA2 depletion perturbed motility and transport in primary human airway cultures; this intervention is different from the increased GSTA2 state observed in DNAH5 PCD.

+ 1 more reference

Show evidence (3 references)

PMID:39042459 SUPPORT In vitro / ex vivo

DNAH5 patient cultures and iPSC-derived cells show an intrinsic oxidative-stress response; increased GSTA expression is not a GSTA deficiency.

PMID:39042459 SUPPORT In vitro / ex vivo

GSTA2 depletion perturbed motility and transport in primary human airway cultures; this intervention is different from the increased GSTA2 state observed in DNAH5 PCD.

PMID:39042459 SUPPORT In vitro / ex vivo

"Moreover, cilia function partially recovers in GSTA2 knockdown after treatment with catalase, which neutralizes reactive oxygen species."

Catalase partially rescued transport after experimental GSTA2 knockdown, not established genetic-motor restoration in DNAH5 patient cilia.

C1d-defective patient airway transport model PRIMARY_CELL_CULTURE namo:TwoDCellCulture

Transport assays in a subset of the C1d study cohort reveal functional deficits that routine ultrastructure and beat assessment can miss. Transport experiments do not independently validate all four genes reported in the clinical cohort.

Organism

human NCBITaxon:9606

Tissue

respiratory tract epithelium UBERON:0004802

Cell source

Nasal epithelial cells from individuals with CFAP46 or CFAP54 variants

Culture

Expanded and differentiated air-liquid interface cultures with particle transport assays

Publication

PMID:39362668

Pathograph links

Central-Apparatus Transport Dysfunction recapitulates fidelity: moderate observes: tissue Directly measures ineffective transport in C1d-defective patient cultures.

Limitations: The measured culture phenotype does not establish prediction of individual clinical severity or whole-lung clearance.

Readouts

Ciliary particle transport

Particle movement across patient-derived ciliated epithelia is reduced relative to control cultures; reduced synchrony is a candidate explanation, not established by this measurement.

mucociliary clearance GO:0120197

Direction: DECREASED

Show evidence (1 reference)

PMID:39362668 SUPPORT In vitro / ex vivo

"However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance."

Patient-derived C1d cultures show deficient transport despite inconspicuous routine ciliary diagnostics; the mechanism of transport inefficiency remains unresolved.

Show evidence (1 reference)

PMID:39362668 SUPPORT In vitro / ex vivo

"However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance."

Patient-derived C1d cultures show deficient transport despite inconspicuous routine ciliary diagnostics; the mechanism of transport inefficiency remains unresolved.

Show evidence (1 reference)

PMID:39362668 SUPPORT In vitro / ex vivo

"However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance."

Patient-derived C1d cultures show deficient transport despite inconspicuous routine ciliary diagnostics; the mechanism of transport inefficiency remains unresolved.

BMI1-expanded DNAH5 patient airway epithelial cell model CELL_LINE namo:CellLineModel

A renewable patient-derived airway model retains ciliated differentiation and the DNAH5-associated immotile phenotype across extended passage. Demonstrated expansion is finite; indefinite immortalization and cross-genotype fidelity are not established.

Organism

human NCBITaxon:9606

Tissue

respiratory tract epithelium UBERON:0004802

Cell source

BMI1-transduced bronchial and nasal basal epithelial cells from two donors with biallelic DNAH5 variants

Culture

Lentiviral BMI1 expansion followed by air-liquid interface differentiation

Publication

PMID:41064994

Pathograph links

Ciliary Dysfunction recapitulates fidelity: moderate observes: cellular Retains DNAH5-associated ciliary immotility and missing outer-dynein-arm proteins after expansion.

Limitations: Validation is confined to two DNAH5 donors and an immotile phenotype. BMI1 transduction, passage and differentiation conditions may affect other endpoints; coordination fidelity in beating-cilia PCD is unestablished.

Readouts

Ciliary motility

Differentiated patient-derived cultures bear immotile cilia.

cilium movement GO:0003341

Direction: ABOLISHED

Show evidence (1 reference)

PMID:41064994 SUPPORT In vitro / ex vivo

Supports prolonged expansion and retention of the DNAH5 outer-dynein-arm defect; it does not establish fidelity for motile, normal-TEM PCD genotypes.

Axonemal DNAH5 and outer-dynein-arm proteins

Patient-derived cilia lack DNAH5 and other outer-dynein-arm proteins.

Direction: ABOLISHED

Show evidence (1 reference)

PMID:41064994 SUPPORT In vitro / ex vivo

Supports prolonged expansion and retention of the DNAH5 outer-dynein-arm defect; it does not establish fidelity for motile, normal-TEM PCD genotypes.

Show evidence (1 reference)

PMID:41064994 SUPPORT In vitro / ex vivo

Supports prolonged expansion and retention of the DNAH5 outer-dynein-arm defect; it does not establish fidelity for motile, normal-TEM PCD genotypes.

Findings

BMI1-expanded DNAH5 cultures show altered ion-channel activity relative to non-PCD cultures; its relationship to immotility remains exploratory.

Show evidence (1 reference)

PMID:41064994 SUPPORT In vitro / ex vivo

"Characterisation of the ion transport properties of these PCD cells grown at an air-liquid interface showed lower activity of the Na+ channel ENaC and enhanced CFTR activity compared to non-PCD cells, which might be linked to ciliary immotility."

The two-donor model study reports lower ENaC and higher CFTR activity. It does not establish that these changes cause ciliary dysfunction or characterize all PCD genotypes.

Show evidence (1 reference)

PMID:41064994 SUPPORT In vitro / ex vivo

Supports prolonged expansion and retention of the DNAH5 outer-dynein-arm defect; it does not establish fidelity for motile, normal-TEM PCD genotypes.

iPSC-derived microfluidic airway-on-a-chip model ORGAN_ON_CHIP namo:OrganOnChip

Combines iPSC airway differentiation with fluid shear to organize multicellular planar polarity and quantify directional flow. Patient and edited cells support genetic comparison in this engineered context.

Organism

human NCBITaxon:9606

Tissue

respiratory tract epithelium UBERON:0004802

Cell source

Human patient-derived, gene-edited and knockout iPSC airway cell sheets

Culture

Microfluidic airway-on-a-chip with fluid-shear regulation of planar cell polarity

Publication

PMID:34233948

Pathograph links

Ciliary Dysfunction recapitulates fidelity: moderate observes: tissue Recapitulates abnormal PCD ciliary function in an organized planar-polarity context.

Limitations: Shear-induced polarity and ciliogenesis are active experimental conditions. Platform organization must be separated from genotype effects before interpreting synchrony as an intrinsic patient defect.

Readouts

Ciliary function in polarized airway sheets

PCD-associated abnormal ciliary function persists when the chip organizes multicellular planar polarity.

cilium movement GO:0003341

Direction: ALTERED

Show evidence (1 reference)

PMID:34233948 SUPPORT In vitro / ex vivo

Establishes PCD ciliary phenotyping in an engineered, planar-polarized human airway epithelium.

Show evidence (1 reference)

PMID:34233948 SUPPORT In vitro / ex vivo

Establishes PCD ciliary phenotyping in an engineered, planar-polarized human airway epithelium.

Show evidence (1 reference)

PMID:34233948 SUPPORT In vitro / ex vivo

Establishes PCD ciliary phenotyping in an engineered, planar-polarized human airway epithelium.

BCi-NS1.1 dyskinetic airway epithelial cell line CELL_LINE namo:CellLineModel

The reported BCi-NS1.1 culture had slow circular ciliary beating and a central-microtubule defect confirmed by electron microscopy. This is a phenotypic model for ciliary modulation, not a genotype-defined patient model or an automatically normal airway control.

Organism

human NCBITaxon:9606

Tissue

respiratory tract epithelium UBERON:0004802

Cell source

Immortalized human bronchial epithelial BCi-NS1.1 cell line

Culture

Air-liquid interface differentiation

Publication

PMID:29481304

Pathograph links

Ciliary Dysfunction partially recapitulates fidelity: low observes: cellular Reproduces dyskinetic circular ciliary beating in the reported cell-line culture.

Limitations: No causal patient PCD genotype is established. The report concerns the tested stock and culture conditions; it does not establish identical behavior in all BCi-NS1.1 stocks or prove that immortalization caused the defect.

Readouts

Circular ciliary beat pattern

High-speed video detects circular dyskinetic motion, with a corresponding ultrastructural defect.

cilium movement GO:0003341

Direction: ALTERED

Show evidence (1 reference)

PMID:29481304 SUPPORT In vitro / ex vivo

"Although changes in CBF induced by known modulators were as expected, the cilia displayed a dyskinetic, circular beat pattern characteristic of central microtubular agenesis with outer doublet transposition."

Supports a dyskinetic ciliary phenotype in BCi-NS1.1, without establishing a PCD patient genotype.

Show evidence (1 reference)

PMID:29481304 SUPPORT In vitro / ex vivo

Supports a dyskinetic ciliary phenotype in BCi-NS1.1, without establishing a PCD patient genotype.

Show evidence (1 reference)

PMID:29481304 SUPPORT In vitro / ex vivo

Supports a dyskinetic ciliary phenotype in BCi-NS1.1, without establishing a PCD patient genotype.

Mixed wild-type and CCDC40-deficient airway epithelial cultures PRIMARY_CELL_CULTURE namo:TwoDCellCulture

A 2026 preprint tests mixtures of healthy and mutant cells, rather than therapeutic correction of mutant cells. Transport depends nonlinearly on composition, with a modeled ex vivo transport benchmark near 75% wild-type representation among ciliated cells. This culture-specific estimate is not a universal therapeutic target.

Organism

human NCBITaxon:9606

Tissue

respiratory tract epithelium UBERON:0004802

Cell source

Human bronchial epithelial cells mixed at defined wild-type and CCDC40-deficient ratios

Culture

Differentiated mosaic airway epithelia with high-speed imaging and particle tracking

Publication

PMID:41757021

Pathograph links

Impaired Mucociliary Clearance perturbs fidelity: moderate observes: tissue Perturbs the fraction of functional cells to measure emergent epithelial transport.

Limitations: Preprint; mixing distinct donor cells is not isogenic therapeutic rescue. Cell composition, mutant-neighbor effects, spatial arrangement and the ex vivo calibration limit extrapolation to in vivo clearance or other PCD genotypes.

Readouts

Transport velocity across wild-type fractions

Velocity falls from approximately 56 to 9 micrometres per second between entirely wild-type and entirely mutant cultures; mixing ratios also affect epithelial composition.

mucociliary clearance GO:0120197

Direction: DECREASED

Show evidence (1 reference)

PMID:41757021 SUPPORT In vitro / ex vivo

"Mucociliary transport declined nonlinearly, with speeds dropping from ~56 μm/s (100% WT) to ~9 μm/s in 100% mutant cultures."

The preprint reports a nonlinear transport response to mixing wild-type and CCDC40-mutant cells; this is not a clinical efficacy threshold.

Show evidence (1 reference)

PMID:41757021 SUPPORT In vitro / ex vivo

"Mucociliary transport declined nonlinearly, with speeds dropping from ~56 μm/s (100% WT) to ~9 μm/s in 100% mutant cultures."

The preprint reports a nonlinear transport response to mixing wild-type and CCDC40-mutant cells; this is not a clinical efficacy threshold.

Show evidence (1 reference)

PMID:41757021 SUPPORT In vitro / ex vivo

"Mucociliary transport declined nonlinearly, with speeds dropping from ~56 μm/s (100% WT) to ~9 μm/s in 100% mutant cultures."

The preprint reports a nonlinear transport response to mixing wild-type and CCDC40-mutant cells; this is not a clinical efficacy threshold.

GAS2L2-deficient patient nasal epithelial orientation model PRIMARY_CELL_CULTURE namo:TwoDCellCulture

Nasal epithelial cultures from one affected individual reproduce ciliary disorientation and asynchronous hyperkinetic beating despite normal patient axonemal structure. Separate mouse and Xenopus experiments in the paper provide cross-species evidence.

Organism

human NCBITaxon:9606

Tissue

nasal cavity epithelium UBERON:0005384

Cell source

Cultured nasal epithelial cells from one GAS2L2-deficient individual

Culture

Differentiated nasal epithelial culture with ciliary orientation and beat analysis

Publication

PMID:30665704

Pathograph links

Ciliary Disorientation recapitulates fidelity: moderate observes: cellular Measures patient-associated ciliary disorientation together with asynchronous, increased-frequency beating.

Limitations: One patient-derived culture background; the measured frequency difference is not a diagnostic threshold or estimate across GAS2L2 genotypes. Clinical clearance was not measured by this culture readout.

Readouts

Ciliary orientation and beat coordination

Cultured patient cilia show disorientation and asynchronous beating; temporal coordination and directional alignment are separate endpoints.

Direction: ALTERED

Show evidence (1 reference)

PMID:30665704 SUPPORT In vitro / ex vivo

Patient-derived nasal cells demonstrate an orientation defect with asynchronous hyperkinetic beating; this does not establish the cause of transport failure in C1d-associated disease.

Ciliary beat frequency

Reported frequency was 19.8 Hz in GAS2L2-deficient cells versus 15.8 Hz in controls under the study conditions.

cilium movement GO:0003341

Direction: INCREASED

Show evidence (1 reference)

PMID:30665704 SUPPORT In vitro / ex vivo

Patient-derived nasal cells demonstrate an orientation defect with asynchronous hyperkinetic beating; this does not establish the cause of transport failure in C1d-associated disease.

Show evidence (1 reference)

PMID:30665704 SUPPORT In vitro / ex vivo

Patient-derived nasal cells demonstrate an orientation defect with asynchronous hyperkinetic beating; this does not establish the cause of transport failure in C1d-associated disease.

Show evidence (1 reference)

PMID:30665704 SUPPORT In vitro / ex vivo

Patient-derived nasal cells demonstrate an orientation defect with asynchronous hyperkinetic beating; this does not establish the cause of transport failure in C1d-associated disease.

🐁

Animal Models

Mdnah5 (Dnah5) loss-of-function (insertional mutation) Mouse Spontaneous/engineered axonemal dynein mutant

Insertional loss-of-function mutation in the axonemal outer-dynein-arm heavy chain gene Mdnah5 (the mouse ortholog of human DNAH5) reproduces the core PCD phenotype — recurrent respiratory infection, randomized laterality (situs inversus), ciliary immotility with absent outer dynein arms — and additionally causes lethal hydrocephalus, supporting the motile-cilia beat-failure model. Animal hydrocephalus severity and neonatal lethality do not define the usual human PCD course.

Species

Mouse

Genotype

Mdnah5 (Dnah5) loss-of-function (insertional mutation)

Genes

DNAH5 hgnc:2950

Pathograph links

Ciliary Dysfunction recapitulates fidelity: moderate Models immotility and outer-dynein-arm loss in Dnah5-deficient mice.

Limitations: Model-organism phenotypes do not establish human frequency or quantitative disease progression.

Nodal Ciliary Motility Defect recapitulates fidelity: moderate Randomized mouse laterality supports the nodal arm; it is not direct human embryonic imaging.

Limitations: Model-organism phenotypes do not establish human frequency or quantitative disease progression.

Ependymal Ciliary Dysfunction recapitulates fidelity: moderate Severe mouse hydrocephalus models ciliary-fluid effects but overstates typical human penetrance.

Limitations: Model-organism phenotypes do not establish human frequency or quantitative disease progression.

Show evidence (1 reference)

PMID:11912187 SUPPORT Model organism

"We have characterized an insertional mutation in a mouse axonemal dynein heavy chain gene (Mdnah5) that reproduces most of the classical features of PCD, including recurrent respiratory infections, situs inversus and ciliary immotility."

The Mdnah5 mutant mouse recapitulates the cardinal PCD features and models the DNAH5 outer-dynein-arm defect.

ccdc40 mutant / morphant Zebrafish Motile-cilia / left-right patterning mutant

ccdc40 zebrafish (alongside mouse Ccdc40 mutants) model the CCDC39/CCDC40 inner-dynein-arm/microtubular-disorganization class of PCD: loss of Ccdc40 impairs motile-cilia beating and randomizes left-right axis formation, paralleling the laterality defects and severe ciliary dysmotility seen in CCDC40-mutant patients. Animal hydrocephalus severity and neonatal lethality do not define the usual human PCD course.

Species

Zebrafish

Genotype

ccdc40 mutant / morphant

Genes

CCDC40 hgnc:26090

Pathograph links

CCDC39-CCDC40 Axonemal Scaffold Loss recapitulates fidelity: moderate Ccdc40 loss disrupts ciliary axonemal organization and motility.

Limitations: Model-organism phenotypes do not establish human frequency or quantitative disease progression.

Nodal Ciliary Motility Defect recapitulates fidelity: moderate Vertebrate embryonic laterality phenotypes support an effect beyond ODA-only genotypes.

Limitations: Model-organism phenotypes do not establish human frequency or quantitative disease progression.

Show evidence (1 reference)

PMID:21131974 SUPPORT Model organism

"In mouse and zebrafish, Ccdc40 is expressed in tissues that contain motile cilia, and mutations in Ccdc40 result in cilia with reduced ranges of motility."

Mouse and zebrafish Ccdc40 mutants model the motile-cilia dysfunction and laterality defects of CCDC40-associated PCD.

Xenopus lrrc56-knockdown multiciliated cells Targeted knockdown / in vivo interactome model of a motile ciliopathy

Xenopus epidermal multiciliated cells provide a live-imaging surrogate for the human airway multiciliated epithelium. Knockdown of lrrc56 strips outer dynein arms from the distal axoneme and displaces the outer-dynein-arm docking-complex subunit Odad3, and PCD-associated LRRC56 and ODAD3 variants disrupt the same localization and interaction. The model therefore captures the axonemal-assembly step that fails in outer-dynein-arm PCD, but it is a transient knockdown in embryonic epidermis and reports on cilia ultrastructure and protein localization rather than on airway infection, bronchiectasis, or any organ-level PCD outcome.

Species

Xenopus laevis

Genotype

Morpholino knockdown of lrrc56 in epidermal multiciliated cells, with rescue by wild-type Flag-Lrrc56 and by PCD-associated LRRC56 and ODAD3 variants

Genes

LRRC56 hgnc:25430 ODAD3 hgnc:28303

Publication

PMID:41229303

Pathograph links

Ciliary Dysfunction recapitulates fidelity: moderate Reproduces the outer-dynein-arm assembly failure that underlies the ODA-defect class of PCD, and places Lrrc56 upstream of the ODA docking complex through Odad3.

Limitations: Morpholino knockdown in embryonic epidermal multiciliated cells, not a germline null in airway epithelium; the readouts are axonemal protein localization rather than ciliary beat pattern or mucociliary transport, so the link to beat failure is inferred from ODA loss rather than measured here.

Readouts

Axonemal Dnal4 (ODA light chain) distribution

Direction: DECREASED

Interpretation: Loss of an outer-dynein-arm subunit from the axoneme is the structural signature of ODA-defect PCD; rescue by wild-type Lrrc56 establishes specificity.

Show evidence (1 reference)

PMID:41229303 SUPPORT Model organism

"Lrrc56 knockdown disrupted the normal axonemal distribution of the ODA light chain subunit Dnal4 (GFP-Dnal4), which is typically enriched along the length of the axoneme"

States the measured reduction in axonemal ODA subunit signal on lrrc56 knockdown.

Axonemal Odad3 (ODA docking complex) signal

Direction: DECREASED

Interpretation: Places the docking complex downstream of Lrrc56, so an LRRC56 defect and an ODAD3 defect converge on the same axonemal step.

Show evidence (1 reference)

PMID:41229303 SUPPORT Model organism

"following Lrrc56 knockdown, the Odad3-GFP signal was significantly reduced along the axoneme compared to that in controls"

Quantified loss of the docking-complex subunit from the axoneme after lrrc56 knockdown.

Show evidence (2 references)

PMID:41229303 SUPPORT Model organism

"loss of lrrc56 causes specific depletion of outer dynein arms (ODAs) from the distal axoneme"

Establishes that the Xenopus knockdown reproduces the outer-dynein-arm defect that defines this PCD class.

+ 1 more reference

Xenopus embryonic epidermis foxi1e ionocyte-depletion model Non-cell-autonomous perturbation of multiciliated cell development

Frog embryonic skin contains multiciliated, mucus-secreting and foxi1e-dependent ionocyte-like cells. Depleting ionocytes leaves multiciliated cells with fewer and aberrantly beating cilia. The reduced count concerns cilia per cell, not disappearance of the multiciliated cell population. This non-cell-autonomous epithelial perturbation is a surrogate-system finding, not a model of a human PCD genotype.

Species

Xenopus laevis

Genotype

Morpholino knockdown of foxi1e, depleting ionocytes from the embryonic epidermis

Publication

PMID:21183475

Pathograph links

Ciliary Dysfunction perturbs fidelity: low Produces fewer cilia per multiciliated cell and abnormal ciliary beating by depleting a neighboring epidermal cell type.

Limitations: No PCD gene is involved and no PCD genotype is modelled — the perturbation is of ionocyte development, and the ciliary phenotype is a secondary consequence. Frog embryonic epidermis is a surrogate for airway epithelium rather than the tissue itself, and FOXI1 has not been implicated in human PCD. Treat this as evidence about the cellular architecture that mucociliary function depends on, not as a disease model.

Readouts

Cilia per multiciliated cell after foxi1e knockdown

Direction: DECREASED

Interpretation: Cilia per cell decrease after ionocyte depletion; abnormal beating is also observed. This is not evidence for a reduced number of multiciliated cells.

Show evidence (1 reference)

PMID:21183475 SUPPORT Model organism

"Depletion of ionocytes by foxi1e knockdown has detrimental effects on the development of multiciliated cells, which show fewer and aberrantly beating cilia."

Reports the measured effect on multiciliated cell development and ciliary beating.

Show evidence (1 reference)

PMID:21183475 SUPPORT Model organism

"Depletion of ionocytes by foxi1e knockdown has detrimental effects on the development of multiciliated cells, which show fewer and aberrantly beating cilia. These results reveal a newly identified role for ionocytes and suggest that the frog embryonic skin is a model system that is particularly..."

The knockdown result is the perturbation of ciliary function this link records, and the authors present the system as suited to studying cell-cell interactions in mucociliary epithelia, which is the level at which this link is informative for PCD.

Show evidence (1 reference)

PMID:21183475 SUPPORT Model organism

"We show that frog ionocytes express the transcription factor foxi1e, which is required for the development of these cells. Depletion of ionocytes by foxi1e knockdown has detrimental effects on the development of multiciliated cells, which show fewer and aberrantly beating cilia."

Establishes the model as described, foxi1e knockdown depleting epidermal ionocytes, with the resulting multiciliated-cell phenotype of fewer and abnormally beating cilia.

🧮

Computational Models

CFD model of mucociliary clearance under ciliary abnormalities PHYSIOLOGICAL

Three-dimensional computational study of mucus transport under varied ciliary density, beat pattern, frequency, coordination and missing-cilia regions. The institutional abstract reports stronger effects for density, pattern and frequency and weaker effects for some spatial arrangements. This general physiological model is not calibrated to PCD patient genotypes or proven clinical trajectories.

DOI:10.1016/j.jnnfm.2023.105029

Pathograph links

Impaired Mucociliary Clearance Simulates how cilia beat/coordination abnormalities reduce net mucus transport, recapitulating impaired mucociliary clearance.

Findings

Published computational results identify cilia density, waveform and frequency as important determinants of transport in the modeled system; clinical PCD effect sizes are not established.

DOI metadata and the author institutional record (https://kth.diva-portal.org/smash/record.jsf?pid=diva2:1779672) identify the study. The sanctioned DOI cache lacks full text; solver implementation and quantitative validation were not independently verified, and no simulation was rerun.

{ }

Source YAML

click to show

name: Primary_Ciliary_Dyskinesia
creation_date: '2025-12-04T16:57:31Z'
description: >-
  Primary ciliary dyskinesia (PCD) is a genetically heterogeneous motile ciliopathy in which defective
  axonemal motors, regulatory structures or multiciliogenesis impair transport by respiratory cilia.
  Most forms are autosomal recessive; FOXJ1 and TUBB4B can cause dominant disease, and DNAAF6, OFD1
  and RPGR can cause X-linked disease. Chronic wet cough, sino-otologic disease, recurrent infection
  and bronchiectasis follow impaired airway clearance. Nodal-cilia involvement causes genotype-dependent
  situs abnormalities, while reproductive cilia and sperm flagella contribute to subfertility. Normal
  ciliary ultrastructure, beat frequency or nasal nitric oxide do not individually exclude PCD. Clinical
  trajectories vary within and between genotypes; genotype associations and experimental epithelial
  mechanisms do not constitute validated individual severity tiers.
category: Genetic
parents:
- Ciliopathy
- Respiratory Disease
has_subtypes:
- name: CILD1
  display_name: Primary ciliary dyskinesia 1 (DNAI1-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic DNAI1 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the DNAI1 / primary ciliary dyskinesia 1 relationship as Definitive with
    autosomal recessive inheritance. DNAI1 encodes dynein axonemal intermediate chain 1. The founding human
    report identified compound heterozygous DNAI1 defects in unrelated families, including patients whose
    internal organs were normally positioned.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 1
    term:
      id: MONDO:0009484
      label: primary ciliary dyskinesia 1
  genes:
  - preferred_term: DNAI1
    term:
      id: hgnc:2954
      label: DNAI1
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_396be572-5b2c-4859-90dd-434a91c1ce96-2022-06-30T160000.000Z
      reference_title: DNAI1 / primary ciliary dyskinesia 1 (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: DNAI1 | HGNC:2954 | primary ciliary dyskinesia 1 | MONDO:0009484 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-06-30T16:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_396be572-5b2c-4859-90dd-434a91c1ce96-2022-06-30T160000.000Z
    reference_title: DNAI1 / primary ciliary dyskinesia 1 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DNAI1 | HGNC:2954 | primary ciliary dyskinesia 1 | MONDO:0009484 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-06-30T16:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding DNAI1 to primary ciliary dyskinesia 1 (MONDO:0009484) with
      classification Definitive.
  - reference: PMID:11231901
    reference_title: Axonemal dynein intermediate-chain gene (DNAI1) mutations result in situs inversus and primary ciliary dyskinesia (Kartagener syndrome).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified compound heterozygous DNAI1 gene defects in three independent patients and in two of their siblings who presented with PCD and situs solitus (i.e., normal position of inner organs).
    explanation: >-
      The founding DNAI1 report, establishing biallelic DNAI1 defects in unrelated families with primary
      ciliary dyskinesia.
- name: CILD2
  display_name: Primary ciliary dyskinesia 2 (DNAAF3-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic DNAAF3 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the DNAAF3 / primary ciliary dyskinesia 2 relationship as Definitive
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 2
    term:
      id: MONDO:0011718
      label: primary ciliary dyskinesia 2
  genes:
  - preferred_term: DNAAF3
    term:
      id: hgnc:30492
      label: DNAAF3
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_40329b6f-2d65-49dd-863b-f79dcd1b5a23-2022-05-09T155600.823Z
      reference_title: 'DNAAF3 / primary ciliary dyskinesia 2 (Definitive)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'DNAAF3 | HGNC:30492 | primary ciliary dyskinesia 2 | MONDO:0011718 | AR | Definitive | SOP8 | Motile Ciliopathy Gene Curation Expert Panel | 2022-05-09T15:56:00.823Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_40329b6f-2d65-49dd-863b-f79dcd1b5a23-2022-05-09T155600.823Z
    reference_title: 'DNAAF3 / primary ciliary dyskinesia 2 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF3 | HGNC:30492 | primary ciliary dyskinesia 2 | MONDO:0011718 | AR | Definitive | SOP8 | Motile Ciliopathy Gene Curation Expert Panel | 2022-05-09T15:56:00.823Z'
    explanation: >-
      ClinGen gene-disease validity row binding DNAAF3 to primary ciliary dyskinesia 2 (MONDO:0011718) with
      classification Definitive.
  - reference: PMID:22387996
    reference_title: 'Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We identified loss-of-function mutations in the human DNAAF3 gene in individuals from families with situs inversus and defects in the assembly of inner and outer dynein arms.'
    explanation: >-
      Reports the DNAAF3 loss-of-function families with dynein-arm assembly defects and situs inversus.
- name: CILD3
  display_name: Primary ciliary dyskinesia 3 (DNAH5-related)
  classification: gene
  curated_in: Primary_Ciliary_Dyskinesia_3
  description: >-
    Primary ciliary dyskinesia caused by pathogenic DNAH5 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the DNAH5 / primary ciliary dyskinesia 3 relationship as Definitive with
    autosomal recessive inheritance. This stratum is curated in full as its own entry; the row is a pointer so
    the stratum stays discoverable from the umbrella.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 3
    term:
      id: MONDO:0012085
      label: primary ciliary dyskinesia 3
  genes:
  - preferred_term: DNAH5
    term:
      id: hgnc:2950
      label: DNAH5
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_4390dba1-012d-4e08-a841-ffc08ebdc737-2022-01-07T190607.723Z
      reference_title: DNAH5 / primary ciliary dyskinesia 3 (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: DNAH5 | HGNC:2950 | primary ciliary dyskinesia 3 | MONDO:0012085 | AR | Definitive | SOP8 | Motile Ciliopathy Gene Curation Expert Panel | 2022-01-07T19:06:07.723Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_4390dba1-012d-4e08-a841-ffc08ebdc737-2022-01-07T190607.723Z
    reference_title: DNAH5 / primary ciliary dyskinesia 3 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DNAH5 | HGNC:2950 | primary ciliary dyskinesia 3 | MONDO:0012085 | AR | Definitive | SOP8 | Motile Ciliopathy Gene Curation Expert Panel | 2022-01-07T19:06:07.723Z
    explanation: >-
      ClinGen gene-disease validity row binding DNAH5 to primary ciliary dyskinesia 3 (MONDO:0012085) with
      classification Definitive.
- name: CILD5
  display_name: Primary ciliary dyskinesia 5 (HYDIN-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic HYDIN variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the HYDIN / primary ciliary dyskinesia 5 relationship as Definitive
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 5
    term:
      id: MONDO:0012088
      label: primary ciliary dyskinesia 5
  genes:
  - preferred_term: HYDIN
    term:
      id: hgnc:19368
      label: HYDIN
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_6c491ab7-496f-43b9-9bca-500901cb686d-2022-02-22T183411.247Z
      reference_title: 'HYDIN / primary ciliary dyskinesia 5 (Definitive)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'HYDIN | HGNC:19368 | primary ciliary dyskinesia 5 | MONDO:0012088 | AR | Definitive | SOP8 | Motile Ciliopathy Gene Curation Expert Panel | 2022-02-22T18:34:11.247Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_6c491ab7-496f-43b9-9bca-500901cb686d-2022-02-22T183411.247Z
    reference_title: 'HYDIN / primary ciliary dyskinesia 5 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'HYDIN | HGNC:19368 | primary ciliary dyskinesia 5 | MONDO:0012088 | AR | Definitive | SOP8 | Motile Ciliopathy Gene Curation Expert Panel | 2022-02-22T18:34:11.247Z'
    explanation: >-
      ClinGen gene-disease validity row binding HYDIN to primary ciliary dyskinesia 5 (MONDO:0012088) with
      classification Definitive.
  - reference: PMID:31545650
    reference_title: 'SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'which revealed one novel loss-of-function mutation in SPEF2 and three reported and 13 novel HYDIN mutations in 15 individuals'
    explanation: >-
      Reports HYDIN mutations in 15 individuals from a cohort screened for central-pair defects.
- name: CILD6
  display_name: Primary ciliary dyskinesia 6 (NME8-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia attributed to biallelic NME8 variants on the strength of a single proband.
    The ClinGen Motile Ciliopathy Gene Curation Expert Panel classified the NME8 / primary ciliary
    dyskinesia relationship as Limited in 2023 and reclassified it as Disputed in 2026, citing the single
    incompletely investigated report and the absence of NME8 expression in human airway ciliated cells.
    ClinGen curated NME8 against primary ciliary dyskinesia (MONDO:0016575) rather than against this
    numbered entity. MONDO:0012571 carries 'NME8 primary ciliary dyskinesia' and 'CILD6' among the synonyms EBI OLS4 returns
    for it, and HGNC lists CILD6 as an alias symbol of NME8.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 6
    term:
      id: MONDO:0012571
      label: primary ciliary dyskinesia 6
  genes:
  - preferred_term: NME8
    term:
      id: hgnc:16473
      label: NME8
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_57ca8383-55b6-4edd-9be2-67b1c5142ed1-2026-03-12T000000.000Z
      reference_title: 'NME8 / primary ciliary dyskinesia (Disputed)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'NME8 | HGNC:16473 | primary ciliary dyskinesia | MONDO:0016575 | AR | Disputed | SOP12 | Motile Ciliopathy Gene Curation Expert Panel | 2026-03-12T00:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship,
        while classifying the relationship itself as Disputed.
  evidence:
  - reference: CGGV:assertion_57ca8383-55b6-4edd-9be2-67b1c5142ed1-2026-03-12T000000.000Z
    reference_title: 'NME8 / primary ciliary dyskinesia (Disputed)'
    supports: REFUTE
    evidence_source: OTHER
    snippet: 'NME8 | HGNC:16473 | primary ciliary dyskinesia | MONDO:0016575 | AR | Disputed | SOP12 | Motile Ciliopathy Gene Curation Expert Panel | 2026-03-12T00:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row now classifying the NME8 relationship to primary ciliary
      dyskinesia (MONDO:0016575) as Disputed, which weighs against NME8 as an established cause of this
      subtype.
- name: CILD7
  display_name: Primary ciliary dyskinesia 7 (DNAH11-related)
  classification: gene
  curated_in: Primary_Ciliary_Dyskinesia_7
  description: >-
    Primary ciliary dyskinesia caused by pathogenic DNAH11 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the DNAH11 / primary ciliary dyskinesia 7 relationship as Definitive
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 7
    term:
      id: MONDO:0012748
      label: primary ciliary dyskinesia 7
  genes:
  - preferred_term: DNAH11
    term:
      id: hgnc:2942
      label: DNAH11
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_84088c46-0763-4ed6-9352-530d846e8b24-2021-10-25T190427.941Z
      reference_title: 'DNAH11 / primary ciliary dyskinesia 7 (Definitive)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'DNAH11 | HGNC:2942 | primary ciliary dyskinesia 7 | MONDO:0012748 | AR | Definitive | SOP8 | Motile Ciliopathy Gene Curation Expert Panel | 2021-10-25T19:04:27.941Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_84088c46-0763-4ed6-9352-530d846e8b24-2021-10-25T190427.941Z
    reference_title: 'DNAH11 / primary ciliary dyskinesia 7 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAH11 | HGNC:2942 | primary ciliary dyskinesia 7 | MONDO:0012748 | AR | Definitive | SOP8 | Motile Ciliopathy Gene Curation Expert Panel | 2021-10-25T19:04:27.941Z'
    explanation: >-
      ClinGen gene-disease validity row binding DNAH11 to primary ciliary dyskinesia 7 (MONDO:0012748) with
      classification Definitive.
- name: CILD10
  display_name: Primary ciliary dyskinesia 10 (DNAAF2-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic DNAAF2 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the DNAAF2 / primary ciliary dyskinesia 10 relationship as Definitive
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 10
    term:
      id: MONDO:0012918
      label: primary ciliary dyskinesia 10
  genes:
  - preferred_term: DNAAF2
    term:
      id: hgnc:20188
      label: DNAAF2
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_39e5de96-3f16-4dde-a7bc-b3e27364b7f8-2024-02-08T170000.000Z
      reference_title: 'DNAAF2 / primary ciliary dyskinesia 10 (Definitive)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'DNAAF2 | HGNC:20188 | primary ciliary dyskinesia 10 | MONDO:0012918 | AR | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-02-08T17:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_39e5de96-3f16-4dde-a7bc-b3e27364b7f8-2024-02-08T170000.000Z
    reference_title: 'DNAAF2 / primary ciliary dyskinesia 10 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF2 | HGNC:20188 | primary ciliary dyskinesia 10 | MONDO:0012918 | AR | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-02-08T17:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding DNAAF2 to primary ciliary dyskinesia 10 (MONDO:0012918)
      with classification Definitive.
- name: CILD11
  display_name: Primary ciliary dyskinesia 11 (RSPH4A-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic RSPH4A variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the RSPH4A / primary ciliary dyskinesia 11 relationship as Definitive
    with autosomal recessive inheritance. RSPH4A encodes a component of the axonemal radial spoke head. In the
    founding linkage study RSPH4A was the 6q22.1 locus, found in the five families with complete absence of
    the central pair, and laterality was not disturbed in the human or zebrafish data.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 11
    term:
      id: MONDO:0012978
      label: primary ciliary dyskinesia 11
  genes:
  - preferred_term: RSPH4A
    term:
      id: hgnc:21558
      label: RSPH4A
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_6f876804-e14a-4c7e-a826-232c7f445c7f-2022-04-05T150444.668Z
      reference_title: RSPH4A / primary ciliary dyskinesia 11 (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: RSPH4A | HGNC:21558 | primary ciliary dyskinesia 11 | MONDO:0012978 | AR | Definitive | SOP8 | Motile Ciliopathy Gene Curation Expert Panel | 2022-04-05T15:04:44.668Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_6f876804-e14a-4c7e-a826-232c7f445c7f-2022-04-05T150444.668Z
    reference_title: RSPH4A / primary ciliary dyskinesia 11 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: RSPH4A | HGNC:21558 | primary ciliary dyskinesia 11 | MONDO:0012978 | AR | Definitive | SOP8 | Motile Ciliopathy Gene Curation Expert Panel | 2022-04-05T15:04:44.668Z
    explanation: >-
      ClinGen gene-disease validity row binding RSPH4A to primary ciliary dyskinesia 11 (MONDO:0012978) with
      classification Definitive.
  - reference: PMID:19200523
    reference_title: Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mutations were subsequently identified in two positional candidate genes, RSPH9 on chromosome 6p21.1 and RSPH4A on chromosome 6q22.1. Haplotype analysis identified a common ancestral founder effect RSPH4A mutation present in UK-Pakistani pedigrees. Both RSPH9 and RSPH4A encode protein components of the axonemal radial spoke head.
    explanation: >-
      The founding report binding RSPH4A to primary ciliary dyskinesia and naming the radial spoke head as the
      affected structure.
  - reference: PMID:19200523
    reference_title: Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: Disturbance in function of these genes was not associated with defects in left-right axis determination in humans or zebrafish.
    explanation: >-
      Records that laterality was not disturbed, which is why this stratum is not expected to show situs
      abnormalities.
  - reference: PMID:19200523
    reference_title: Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This identified two loci, in two families with intermittent absence of the central-pair structure (chromosome 6p21.1, Zmax 6.7) and in five families with complete absence of the central pair (chromosome 6q22.1, Zmax 7.0).
    explanation: >-
      Records the ultrastructural split between the two radial spoke head loci.
- name: CILD12
  display_name: Primary ciliary dyskinesia 12 (RSPH9-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic RSPH9 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the RSPH9 / primary ciliary dyskinesia 12 relationship as Definitive with
    autosomal recessive inheritance. RSPH9 encodes a second component of the axonemal radial spoke head. In
    the founding linkage study RSPH9 was the 6p21.1 locus, found in the two families with intermittent absence
    of the central-pair structure.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 12
    term:
      id: MONDO:0012979
      label: primary ciliary dyskinesia 12
  genes:
  - preferred_term: RSPH9
    term:
      id: hgnc:21057
      label: RSPH9
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_25b8ea38-8de2-45b7-95a1-51b33affb747-2023-10-12T160000.000Z
      reference_title: RSPH9 / primary ciliary dyskinesia 12 (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: RSPH9 | HGNC:21057 | primary ciliary dyskinesia 12 | MONDO:0012979 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2023-10-12T16:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_25b8ea38-8de2-45b7-95a1-51b33affb747-2023-10-12T160000.000Z
    reference_title: RSPH9 / primary ciliary dyskinesia 12 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: RSPH9 | HGNC:21057 | primary ciliary dyskinesia 12 | MONDO:0012979 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2023-10-12T16:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding RSPH9 to primary ciliary dyskinesia 12 (MONDO:0012979) with
      classification Definitive.
  - reference: PMID:19200523
    reference_title: Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This identified two loci, in two families with intermittent absence of the central-pair structure (chromosome 6p21.1, Zmax 6.7) and in five families with complete absence of the central pair (chromosome 6q22.1, Zmax 7.0).
    explanation: >-
      Records the ultrastructural split between the two radial spoke head loci.
  - reference: PMID:19200523
    reference_title: Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mutations were subsequently identified in two positional candidate genes, RSPH9 on chromosome 6p21.1 and RSPH4A on chromosome 6q22.1.
    explanation: >-
      Assigns RSPH9 to the 6p21.1 locus and RSPH4A to the 6q22.1 locus.
- name: CILD13
  display_name: Primary ciliary dyskinesia 13 (DNAAF1-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic DNAAF1 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the DNAAF1 / primary ciliary dyskinesia 13 relationship as Definitive
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 13
    term:
      id: MONDO:0013174
      label: primary ciliary dyskinesia 13
  genes:
  - preferred_term: DNAAF1
    term:
      id: hgnc:30539
      label: DNAAF1
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_41e4b8cd-35bd-4e99-ba2d-606f191a13cf-2023-03-09T170000.000Z
      reference_title: 'DNAAF1 / primary ciliary dyskinesia 13 (Definitive)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'DNAAF1 | HGNC:30539 | primary ciliary dyskinesia 13 | MONDO:0013174 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2023-03-09T17:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_41e4b8cd-35bd-4e99-ba2d-606f191a13cf-2023-03-09T170000.000Z
    reference_title: 'DNAAF1 / primary ciliary dyskinesia 13 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF1 | HGNC:30539 | primary ciliary dyskinesia 13 | MONDO:0013174 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2023-03-09T17:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding DNAAF1 to primary ciliary dyskinesia 13 (MONDO:0013174)
      with classification Definitive.
- name: CILD14
  display_name: Primary ciliary dyskinesia 14 (CCDC39-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic CCDC39 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the CCDC39 / primary ciliary dyskinesia 14 relationship as Definitive
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 14
    term:
      id: MONDO:0013434
      label: primary ciliary dyskinesia 14
  genes:
  - preferred_term: CCDC39
    term:
      id: hgnc:25244
      label: CCDC39
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_79c47f13-dd33-45e4-a170-6ff26aa2732c-2021-11-02T204310.116Z
      reference_title: 'CCDC39 / primary ciliary dyskinesia 14 (Definitive)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'CCDC39 | HGNC:25244 | primary ciliary dyskinesia 14 | MONDO:0013434 | AR | Definitive | SOP8 | Motile Ciliopathy Gene Curation Expert Panel | 2021-11-02T20:43:10.116Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_79c47f13-dd33-45e4-a170-6ff26aa2732c-2021-11-02T204310.116Z
    reference_title: 'CCDC39 / primary ciliary dyskinesia 14 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'CCDC39 | HGNC:25244 | primary ciliary dyskinesia 14 | MONDO:0013434 | AR | Definitive | SOP8 | Motile Ciliopathy Gene Curation Expert Panel | 2021-11-02T20:43:10.116Z'
    explanation: >-
      ClinGen gene-disease validity row binding CCDC39 to primary ciliary dyskinesia 14 (MONDO:0013434)
      with classification Definitive.
- name: CILD15
  display_name: Primary ciliary dyskinesia 15 (CCDC40-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic CCDC40 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the CCDC40 / primary ciliary dyskinesia 15 relationship as Definitive
    with autosomal recessive inheritance. CCDC40 is required for axonemal recruitment of CCDC39, and
    disruption of either underlies a similar form of the disease. The founding report describes misplacement
    of the central pair with defective assembly of inner dynein arms and dynein regulatory complexes.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 15
    term:
      id: MONDO:0013435
      label: primary ciliary dyskinesia 15
  genes:
  - preferred_term: CCDC40
    term:
      id: hgnc:26090
      label: CCDC40
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_e9c192c6-9f74-4beb-85ba-a42199e9794a-2021-12-10T031508.185Z
      reference_title: CCDC40 / primary ciliary dyskinesia 15 (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: CCDC40 | HGNC:26090 | primary ciliary dyskinesia 15 | MONDO:0013435 | AR | Definitive | SOP8 | Motile Ciliopathy Gene Curation Expert Panel | 2021-12-10T03:15:08.185Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_e9c192c6-9f74-4beb-85ba-a42199e9794a-2021-12-10T031508.185Z
    reference_title: CCDC40 / primary ciliary dyskinesia 15 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CCDC40 | HGNC:26090 | primary ciliary dyskinesia 15 | MONDO:0013435 | AR | Definitive | SOP8 | Motile Ciliopathy Gene Curation Expert Panel | 2021-12-10T03:15:08.185Z
    explanation: >-
      ClinGen gene-disease validity row binding CCDC40 to primary ciliary dyskinesia 15 (MONDO:0013435) with
      classification Definitive.
  - reference: PMID:21131974
    reference_title: The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We further show that CCDC40 mutations in humans result in a variant of PCD characterized by misplacement of the central pair of microtubules and defective assembly of inner dynein arms and dynein regulatory complexes.
    explanation: >-
      The founding report binding CCDC40 to primary ciliary dyskinesia and stating the axonemal lesion.
  - reference: PMID:21131974
    reference_title: The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CCDC40 localizes to motile cilia and the apical cytoplasm and is required for axonemal recruitment of CCDC39, disruption of which underlies a similar variant of PCD.
    explanation: >-
      Records the CCDC39 dependency that makes this stratum mechanistically paired with CILD14.
- name: CILD16
  display_name: Primary ciliary dyskinesia 16 (DNAL1-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic DNAL1 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the DNAL1 / primary ciliary dyskinesia 16 relationship as Definitive with
    autosomal recessive inheritance. DNAL1 encodes dynein axonemal light chain 1. The founding report
    describes absent or markedly shortened outer dynein arms, with the variant reducing light-chain stability
    and its interactions with the dynein heavy chain and with tubulin.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 16
    term:
      id: MONDO:0013525
      label: primary ciliary dyskinesia 16
  genes:
  - preferred_term: DNAL1
    term:
      id: hgnc:23247
      label: DNAL1
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_54088550-2704-4c1b-ac1b-51b62353a223-2024-04-11T160000.000Z
      reference_title: DNAL1 / primary ciliary dyskinesia 16 (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: DNAL1 | HGNC:23247 | primary ciliary dyskinesia 16 | MONDO:0013525 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2024-04-11T16:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_54088550-2704-4c1b-ac1b-51b62353a223-2024-04-11T160000.000Z
    reference_title: DNAL1 / primary ciliary dyskinesia 16 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DNAL1 | HGNC:23247 | primary ciliary dyskinesia 16 | MONDO:0013525 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2024-04-11T16:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding DNAL1 to primary ciliary dyskinesia 16 (MONDO:0013525) with
      classification Definitive.
  - reference: PMID:21496787
    reference_title: Primary ciliary dyskinesia caused by homozygous mutation in DNAL1, encoding dynein light chain 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We demonstrate here that a homozygous point mutation in this gene is associated with PCD with absent or markedly shortened ODA.
    explanation: >-
      The founding report binding DNAL1 to primary ciliary dyskinesia and stating the outer-dynein-arm lesion.
  - reference: PMID:21496787
    reference_title: Primary ciliary dyskinesia caused by homozygous mutation in DNAL1, encoding dynein light chain 1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The mutation reduces the stability of the axonemal dynein light chain 1 and damages its interactions with dynein heavy chain and with tubulin.
    explanation: >-
      Biochemical basis of the outer-dynein-arm defect in this stratum.
- name: CILD17
  display_name: Primary ciliary dyskinesia 17 (DNAAF19-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic DNAAF19 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the DNAAF19 / primary ciliary dyskinesia 17 relationship as Definitive
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 17
    term:
      id: MONDO:0013854
      label: primary ciliary dyskinesia 17
  genes:
  - preferred_term: DNAAF19
    term:
      id: hgnc:32700
      label: CCDC103
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_9974aaef-9082-4bcd-b05a-28869447b5de-2022-12-08T170000.000Z
      reference_title: 'DNAAF19 / primary ciliary dyskinesia 17 (Definitive)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'DNAAF19 | HGNC:32700 | primary ciliary dyskinesia 17 | MONDO:0013854 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-12-08T17:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_9974aaef-9082-4bcd-b05a-28869447b5de-2022-12-08T170000.000Z
    reference_title: 'DNAAF19 / primary ciliary dyskinesia 17 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF19 | HGNC:32700 | primary ciliary dyskinesia 17 | MONDO:0013854 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-12-08T17:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding DNAAF19 to primary ciliary dyskinesia 17 (MONDO:0013854)
      with classification Definitive.
  - reference: PMID:22581229
    reference_title: 'CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Screening 146 unrelated PCD families identified individuals in six families with reduced outer dynein arms who carried mutations in CCDC103.'
    explanation: >-
      Reports CCDC103 (now DNAAF19) mutations in six PCD families with reduced outer dynein arms.
- name: CILD18
  display_name: Primary ciliary dyskinesia 18 (DNAAF5-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic DNAAF5 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the DNAAF5 / primary ciliary dyskinesia 18 relationship as Definitive
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 18
    term:
      id: MONDO:0013940
      label: primary ciliary dyskinesia 18
  genes:
  - preferred_term: DNAAF5
    term:
      id: hgnc:26013
      label: DNAAF5
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_9b47c717-e0a5-43ce-865b-0b14289216d7-2024-06-19T110000.000Z
      reference_title: 'DNAAF5 / primary ciliary dyskinesia 18 (Definitive)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'DNAAF5 | HGNC:26013 | primary ciliary dyskinesia 18 | MONDO:0013940 | AR | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-06-19T11:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_9b47c717-e0a5-43ce-865b-0b14289216d7-2024-06-19T110000.000Z
    reference_title: 'DNAAF5 / primary ciliary dyskinesia 18 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF5 | HGNC:26013 | primary ciliary dyskinesia 18 | MONDO:0013940 | AR | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-06-19T11:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding DNAAF5 to primary ciliary dyskinesia 18 (MONDO:0013940)
      with classification Definitive.
  - reference: PMID:23040496
    reference_title: 'Whole-exome capture and sequencing identifies HEATR2 mutation as a cause of primary ciliary dyskinesia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'A single autosomal-recessive nonsynonymous missense mutation was identified in HEATR2, an uncharacterized gene that belongs to a family not previously associated with ciliary assembly or function.'
    explanation: >-
      Reports the founding HEATR2 (now DNAAF5) mutation in nine related PCD-affected subjects.
- name: CILD19
  display_name: Primary ciliary dyskinesia 19 (DNAAF11-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic DNAAF11 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the DNAAF11 / primary ciliary dyskinesia 19 relationship as Definitive
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 19
    term:
      id: MONDO:0013979
      label: primary ciliary dyskinesia 19
  genes:
  - preferred_term: DNAAF11
    term:
      id: hgnc:16725
      label: DNAAF11
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_7063ef1e-8ce2-4f35-a765-f08efc2e541a-2023-06-08T160000.000Z
      reference_title: 'DNAAF11 / primary ciliary dyskinesia 19 (Definitive)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'DNAAF11 | HGNC:16725 | primary ciliary dyskinesia 19 | MONDO:0013979 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2023-06-08T16:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_7063ef1e-8ce2-4f35-a765-f08efc2e541a-2023-06-08T160000.000Z
    reference_title: 'DNAAF11 / primary ciliary dyskinesia 19 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF11 | HGNC:16725 | primary ciliary dyskinesia 19 | MONDO:0013979 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2023-06-08T16:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding DNAAF11 to primary ciliary dyskinesia 19 (MONDO:0013979)
      with classification Definitive.
  - reference: PMID:23122589
    reference_title: 'Loss-of-function mutations in LRRC6, a gene essential for proper axonemal assembly of inner and outer dynein arms, cause primary ciliary dyskinesia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We identified, via homozygosity mapping, an early frameshift in LRRC6, a gene that encodes a leucine-rich-repeat (LRR)-containing protein.'
    explanation: >-
      Reports the founding LRRC6 (now DNAAF11) frameshift in PCD with absent dynein arms.
- name: CILD20
  display_name: Primary ciliary dyskinesia 20 (ODAD1-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic ODAD1 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the ODAD1 / primary ciliary dyskinesia 20 relationship as Definitive
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 20
    term:
      id: MONDO:0014030
      label: primary ciliary dyskinesia 20
  genes:
  - preferred_term: ODAD1
    term:
      id: hgnc:26560
      label: ODAD1
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_999e752a-e549-447f-b142-265be7dd5935-2022-08-17T110000.000Z
      reference_title: 'ODAD1 / primary ciliary dyskinesia 20 (Definitive)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'ODAD1 | HGNC:26560 | primary ciliary dyskinesia 20 | MONDO:0014030 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-08-17T11:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_999e752a-e549-447f-b142-265be7dd5935-2022-08-17T110000.000Z
    reference_title: 'ODAD1 / primary ciliary dyskinesia 20 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'ODAD1 | HGNC:26560 | primary ciliary dyskinesia 20 | MONDO:0014030 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-08-17T11:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding ODAD1 to primary ciliary dyskinesia 20 (MONDO:0014030) with
      classification Definitive.
- name: CILD21
  display_name: Primary ciliary dyskinesia 21 (DRC1-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic DRC1 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the DRC1 / primary ciliary dyskinesia 21 relationship as Definitive
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 21
    term:
      id: MONDO:0014123
      label: primary ciliary dyskinesia 21
  genes:
  - preferred_term: DRC1
    term:
      id: hgnc:24245
      label: DRC1
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_ef37e7a5-e14e-4c71-8231-b01bd636b2b9-2025-03-13T160000.000Z
      reference_title: 'DRC1 / primary ciliary dyskinesia 21 (Definitive)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'DRC1 | HGNC:24245 | primary ciliary dyskinesia 21 | MONDO:0014123 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-03-13T16:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_ef37e7a5-e14e-4c71-8231-b01bd636b2b9-2025-03-13T160000.000Z
    reference_title: 'DRC1 / primary ciliary dyskinesia 21 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DRC1 | HGNC:24245 | primary ciliary dyskinesia 21 | MONDO:0014123 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-03-13T16:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding DRC1 to primary ciliary dyskinesia 21 (MONDO:0014123) with
      classification Definitive.
  - reference: PMID:36747106
    reference_title: 'Prevalence and founder effect of DRC1 exon 1-4 deletion in Korean patients with primary ciliary dyskinesia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'three of 20 (15%) patients were positive for DRC1 exon 1-4 deletion'
    explanation: >-
      Reports the DRC1 exon 1-4 deletion share of a Korean PCD cohort.
- name: CILD22
  display_name: Primary ciliary dyskinesia 22 (ZMYND10-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic ZMYND10 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the ZMYND10 / primary ciliary dyskinesia 22 relationship as Definitive
    with autosomal recessive inheritance. ZMYND10 (HGNC alias DNAAF7) interacts with LRRC6, and the founding
    report proposes that a cytoplasmic complex containing the two is necessary for motile ciliary function.
    Loss removes the axonemal dynein components DNAH5 and DNALI1 from respiratory cilia, placing the lesion
    before axonemal delivery rather than in the axoneme itself.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 22
    term:
      id: MONDO:0014192
      label: primary ciliary dyskinesia 22
  genes:
  - preferred_term: ZMYND10
    term:
      id: hgnc:19412
      label: ZMYND10
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_9549c727-fece-494c-9892-83c0ac05f3b4-2023-02-07T170000.000Z
      reference_title: ZMYND10 / primary ciliary dyskinesia 22 (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: ZMYND10 | HGNC:19412 | primary ciliary dyskinesia 22 | MONDO:0014192 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2023-02-07T17:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_9549c727-fece-494c-9892-83c0ac05f3b4-2023-02-07T170000.000Z
    reference_title: ZMYND10 / primary ciliary dyskinesia 22 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: ZMYND10 | HGNC:19412 | primary ciliary dyskinesia 22 | MONDO:0014192 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2023-02-07T17:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding ZMYND10 to primary ciliary dyskinesia 22 (MONDO:0014192) with
      classification Definitive.
  - reference: PMID:23891469
    reference_title: ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families.
    explanation: >-
      The founding report binding biallelic ZMYND10 variants to primary ciliary dyskinesia in 14 families.
  - reference: PMID:23891469
    reference_title: ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia.
    explanation: >-
      Places the ZMYND10 lesion in cytoplasmic dynein-arm preassembly: axonemal dynein components fail to
      reach the axoneme.
  - reference: PMID:23891469
    reference_title: ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function.
    explanation: >-
      The founding report's own proposal, stated as a suggestion rather than a demonstrated complex.
- name: CILD23
  display_name: Primary ciliary dyskinesia 23 (ODAD2-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic ODAD2 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the ODAD2 / primary ciliary dyskinesia 23 relationship as Definitive with
    autosomal recessive inheritance. ODAD2 (previous symbol ARMC4) is an axonemal protein required for the
    proper targeting and anchoring of the outer dynein arms. The founding report describes reduced numbers of
    outer dynein arms with severely impaired beating, and randomization of left-right asymmetry.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 23
    term:
      id: MONDO:0014193
      label: primary ciliary dyskinesia 23
  genes:
  - preferred_term: ODAD2
    term:
      id: hgnc:25583
      label: ODAD2
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_4ac46902-bffa-46f9-bc0d-081e6461d5e2-2022-12-14T170000.000Z
      reference_title: ODAD2 / primary ciliary dyskinesia 23 (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: ODAD2 | HGNC:25583 | primary ciliary dyskinesia 23 | MONDO:0014193 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-12-14T17:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_4ac46902-bffa-46f9-bc0d-081e6461d5e2-2022-12-14T170000.000Z
    reference_title: ODAD2 / primary ciliary dyskinesia 23 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: ODAD2 | HGNC:25583 | primary ciliary dyskinesia 23 | MONDO:0014193 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-12-14T17:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding ODAD2 to primary ciliary dyskinesia 23 (MONDO:0014193) with
      classification Definitive.
  - reference: PMID:23849778
    reference_title: ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: By using combined high resolution copy-number variant and mutation analysis, we identified ARMC4 mutations in twelve PCD individuals whose cells showed reduced numbers of ODAs and severely impaired ciliary beating.
    explanation: >-
      Founding report binding ODAD2/ARMC4 to primary ciliary dyskinesia with an outer-dynein-arm deficit.
  - reference: PMID:23849778
    reference_title: ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We demonstrate that ARMC4 is an axonemal protein that is necessary for proper targeting and anchoring of ODAs.
    explanation: >-
      States the docking-and-anchoring role that places this gene on the outer-dynein-arm docking node.
- name: CILD24
  display_name: Primary ciliary dyskinesia 24 (RSPH1-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic RSPH1 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the RSPH1 / primary ciliary dyskinesia 24 relationship as Definitive
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 24
    term:
      id: MONDO:0014202
      label: primary ciliary dyskinesia 24
  genes:
  - preferred_term: RSPH1
    term:
      id: hgnc:12371
      label: RSPH1
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_f2bdb2e5-9659-46af-b306-e01207f31174-2022-06-07T110000.000Z
      reference_title: 'RSPH1 / primary ciliary dyskinesia 24 (Definitive)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'RSPH1 | HGNC:12371 | primary ciliary dyskinesia 24 | MONDO:0014202 | AR | Definitive | SOP8 | Motile Ciliopathy Gene Curation Expert Panel | 2022-06-07T11:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_f2bdb2e5-9659-46af-b306-e01207f31174-2022-06-07T110000.000Z
    reference_title: 'RSPH1 / primary ciliary dyskinesia 24 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'RSPH1 | HGNC:12371 | primary ciliary dyskinesia 24 | MONDO:0014202 | AR | Definitive | SOP8 | Motile Ciliopathy Gene Curation Expert Panel | 2022-06-07T11:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding RSPH1 to primary ciliary dyskinesia 24 (MONDO:0014202) with
      classification Definitive.
- name: CILD25
  display_name: Primary ciliary dyskinesia 25 (DNAAF4-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic DNAAF4 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the DNAAF4 / primary ciliary dyskinesia 25 relationship as Definitive
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 25
    term:
      id: MONDO:0014203
      label: primary ciliary dyskinesia 25
  genes:
  - preferred_term: DNAAF4
    term:
      id: hgnc:21493
      label: DNAAF4
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_79950f5d-fd90-4765-9f8a-489c3f862fcd-2024-04-11T160000.000Z
      reference_title: 'DNAAF4 / primary ciliary dyskinesia 25 (Definitive)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'DNAAF4 | HGNC:21493 | primary ciliary dyskinesia 25 | MONDO:0014203 | AR | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-04-11T16:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_79950f5d-fd90-4765-9f8a-489c3f862fcd-2024-04-11T160000.000Z
    reference_title: 'DNAAF4 / primary ciliary dyskinesia 25 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF4 | HGNC:21493 | primary ciliary dyskinesia 25 | MONDO:0014203 | AR | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-04-11T16:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding DNAAF4 to primary ciliary dyskinesia 25 (MONDO:0014203)
      with classification Definitive.
- name: CILD26
  display_name: Primary ciliary dyskinesia 26 (CFAP298-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic CFAP298 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the CFAP298 / primary ciliary dyskinesia 26 relationship as Moderate
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 26
    term:
      id: MONDO:0014211
      label: primary ciliary dyskinesia 26
  genes:
  - preferred_term: CFAP298
    term:
      id: hgnc:1301
      label: CFAP298
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_f29143ae-869e-4e4c-8464-8c61f2c2663c-2023-08-10T160000.000Z
      reference_title: 'CFAP298 / primary ciliary dyskinesia 26 (Moderate)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'CFAP298 | HGNC:1301 | primary ciliary dyskinesia 26 | MONDO:0014211 | AR | Moderate | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2023-08-10T16:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_f29143ae-869e-4e4c-8464-8c61f2c2663c-2023-08-10T160000.000Z
    reference_title: 'CFAP298 / primary ciliary dyskinesia 26 (Moderate)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'CFAP298 | HGNC:1301 | primary ciliary dyskinesia 26 | MONDO:0014211 | AR | Moderate | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2023-08-10T16:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding CFAP298 to primary ciliary dyskinesia 26 (MONDO:0014211)
      with classification Moderate.
  - reference: PMID:24094744
    reference_title: 'Zebrafish Ciliopathy Screen Plus Human Mutational Analysis Identifies C21orf59 and CCDC65 Defects as Causing Primary Ciliary Dyskinesia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Analysis of 295 individuals with PCD identified recessive truncating mutations of C21orf59 in four families and CCDC65 in two families.'
    explanation: >-
      Reports recessive truncating C21orf59 (now CFAP298) mutations in four PCD families.
- name: CILD27
  display_name: Primary ciliary dyskinesia 27 (DRC2-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic DRC2 variants. The ClinGen Motile Ciliopathy Gene Curation
    Expert Panel classifies the DRC2 / primary ciliary dyskinesia 27 relationship as Definitive with autosomal
    recessive inheritance. DRC2 (previous symbol CCDC65) is a nexin-dynein regulatory complex subunit.
    Affected cilia beat abnormally with no ultrastructural defect detectable by transmission electron
    microscopy, so ultrastructure-led diagnosis can miss it.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 27
    term:
      id: MONDO:0014215
      label: primary ciliary dyskinesia 27
  genes:
  - preferred_term: DRC2
    term:
      id: hgnc:29937
      label: CCDC65
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_662ab516-ba5f-46aa-97b2-ef4c8f3201a5-2024-08-08T160000.000Z
      reference_title: DRC2 / primary ciliary dyskinesia 27 (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: DRC2 | HGNC:29937 | primary ciliary dyskinesia 27 | MONDO:0014215 | AR | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-08-08T16:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_662ab516-ba5f-46aa-97b2-ef4c8f3201a5-2024-08-08T160000.000Z
    reference_title: DRC2 / primary ciliary dyskinesia 27 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DRC2 | HGNC:29937 | primary ciliary dyskinesia 27 | MONDO:0014215 | AR | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-08-08T16:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding DRC2 to primary ciliary dyskinesia 27 (MONDO:0014215) with
      classification Definitive.
  - reference: PMID:23991085
    reference_title: CCDC65 mutation causes primary ciliary dyskinesia with normal ultrastructure and hyperkinetic cilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A single novel mutation in CCDC65, which created a termination codon at position 293, was identified in a subject with typical clinical features of PCD.
    explanation: >-
      Founding report binding DRC2/CCDC65 to primary ciliary dyskinesia.
  - reference: PMID:23991085
    reference_title: CCDC65 mutation causes primary ciliary dyskinesia with normal ultrastructure and hyperkinetic cilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The affected individual had altered cilia beating patterns, and no detectable ultrastructural defects of the ciliary axoneme, emphasizing the role of the nexin-dynein regulatory complex and the limitations of certain methods for PCD diagnosis.
    explanation: >-
      Records that ultrastructure is normal in this stratum, which is the diagnostic consequence of a
      nexin-dynein regulatory complex defect.
- name: CILD28
  display_name: Primary ciliary dyskinesia 28 (SPAG1-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic SPAG1 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the SPAG1 / primary ciliary dyskinesia 28 relationship as Definitive with
    autosomal recessive inheritance. SPAG1 (HGNC alias DNAAF13) is present in airway cell lysates but not in
    isolated axonemes, placing it in cytoplasmic assembly or trafficking of the axonemal dynein arms. Affected
    individuals show combined outer and inner dynein arm defects.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 28
    term:
      id: MONDO:0014216
      label: primary ciliary dyskinesia 28
  genes:
  - preferred_term: SPAG1
    term:
      id: hgnc:11212
      label: SPAG1
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_c0d43e40-0aa3-41cf-9e3a-8311e685c7be-2022-06-22T190000.000Z
      reference_title: SPAG1 / primary ciliary dyskinesia 28 (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: SPAG1 | HGNC:11212 | primary ciliary dyskinesia 28 | MONDO:0014216 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-06-22T19:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_c0d43e40-0aa3-41cf-9e3a-8311e685c7be-2022-06-22T190000.000Z
    reference_title: SPAG1 / primary ciliary dyskinesia 28 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: SPAG1 | HGNC:11212 | primary ciliary dyskinesia 28 | MONDO:0014216 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-06-22T19:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding SPAG1 to primary ciliary dyskinesia 28 (MONDO:0014216) with
      classification Definitive.
  - reference: PMID:24055112
    reference_title: Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All 14 affected individuals with SPAG1 mutations had a characteristic PCD phenotype, including 8 with situs abnormalities.
    explanation: >-
      Founding report binding biallelic SPAG1 variants to primary ciliary dyskinesia, with laterality defects
      in 8 of 14.
  - reference: PMID:24055112
    reference_title: Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: SPAG1 was present in human airway epithelial cell lysates but was not present in isolated axonemes, and immunofluorescence staining showed an absence of ODA and IDA proteins in cilia from an affected individual, thus indicating that SPAG1 probably plays a role in the cytoplasmic assembly and/or trafficking of the axonemal dynein arms.
    explanation: >-
      States the cytoplasmic preassembly role that places SPAG1 on the preassembly node rather than in the
      axoneme.
- name: CILD29
  display_name: Primary ciliary dyskinesia 29 (CCNO-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic CCNO variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the CCNO / primary ciliary dyskinesia 29 relationship as Definitive
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 29
    term:
      id: MONDO:0014378
      label: primary ciliary dyskinesia 29
  genes:
  - preferred_term: CCNO
    term:
      id: hgnc:18576
      label: CCNO
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_20a78ac7-91a7-44a6-b42e-22611de2d170-2022-08-19T160000.000Z
      reference_title: 'CCNO / primary ciliary dyskinesia 29 (Definitive)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'CCNO | HGNC:18576 | primary ciliary dyskinesia 29 | MONDO:0014378 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-08-19T16:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_20a78ac7-91a7-44a6-b42e-22611de2d170-2022-08-19T160000.000Z
    reference_title: 'CCNO / primary ciliary dyskinesia 29 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'CCNO | HGNC:18576 | primary ciliary dyskinesia 29 | MONDO:0014378 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-08-19T16:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding CCNO to primary ciliary dyskinesia 29 (MONDO:0014378) with
      classification Definitive.
- name: CILD32
  display_name: Primary ciliary dyskinesia 32 (RSPH3-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic RSPH3 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the RSPH3 / primary ciliary dyskinesia 32 relationship as Definitive with
    autosomal recessive inheritance. The Chlamydomonas ortholog of RSPH3 encodes a radial spoke stalk protein.
    Patient cilia show a near absence of detectable radial spokes with a variable proportion of
    central-complex defects, while the radial spoke head proteins RSPH1 and RSPH4A and the neck protein RSPH23
    remain present.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 32
    term:
      id: MONDO:0014657
      label: primary ciliary dyskinesia 32
  genes:
  - preferred_term: RSPH3
    term:
      id: hgnc:21054
      label: RSPH3
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_988a074a-14e9-41e3-a1a6-fff72dda3936-2024-08-08T160000.000Z
      reference_title: RSPH3 / primary ciliary dyskinesia 32 (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: RSPH3 | HGNC:21054 | primary ciliary dyskinesia 32 | MONDO:0014657 | AR | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-08-08T16:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_988a074a-14e9-41e3-a1a6-fff72dda3936-2024-08-08T160000.000Z
    reference_title: RSPH3 / primary ciliary dyskinesia 32 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: RSPH3 | HGNC:21054 | primary ciliary dyskinesia 32 | MONDO:0014657 | AR | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-08-08T16:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding RSPH3 to primary ciliary dyskinesia 32 (MONDO:0014657) with
      classification Definitive.
  - reference: PMID:26073779
    reference_title: RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified non-ambiguous RSPH3 mutations in 5 of 48 independent families affected by CC/RS defects.
    explanation: >-
      Founding report binding biallelic RSPH3 variants to primary ciliary dyskinesia in five families.
  - reference: PMID:26073779
    reference_title: RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A striking feature of the ultrastructural phenotype associated with RSPH3 mutations is the near absence of detectable RSs in all cilia in combination with a variable proportion of cilia with CC defects.
    explanation: >-
      States the radial spoke lesion that places RSPH3 on the radial spoke node.
  - reference: PMID:26073779
    reference_title: RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: in whom RSPH23 (a RS-neck protein) and RSPH1 and RSPH4A (RS-head proteins) were found to be still present within cilia
    explanation: >-
      Distinguishes the RSPH3 lesion from the radial spoke head genes, whose products remain present.
  - reference: PMID:26073779
    reference_title: RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: RSPH3, whose ortholog in the flagellated alga Chlamydomonas reinhardtii encodes a RS-stalk protein, is mainly expressed in respiratory and testicular cells.
    explanation: >-
      The stalk assignment is made through the Chlamydomonas ortholog, not directly in human.
- name: CILD33
  display_name: Primary ciliary dyskinesia 33 (DRC4-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic DRC4 variants. The ClinGen Motile Ciliopathy Gene Curation
    Expert Panel classifies the DRC4 / primary ciliary dyskinesia 33 relationship as Definitive with autosomal
    recessive inheritance. DRC4 (previous symbol GAS8) is a nexin-dynein regulatory complex subunit. As with
    DRC2 the axonemal architecture is preserved, so the defect is not regularly discernible by transmission
    electron microscopy; it was found by immunofluorescence instead.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 33
    term:
      id: MONDO:0014750
      label: primary ciliary dyskinesia 33
  genes:
  - preferred_term: DRC4
    term:
      id: hgnc:4166
      label: GAS8
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_d34bf201-5f6d-41c0-842d-5c029823ef60-2025-12-10T200000.000Z
      reference_title: DRC4 / primary ciliary dyskinesia 33 (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: DRC4 | HGNC:4166 | primary ciliary dyskinesia 33 | MONDO:0014750 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-12-10T20:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_d34bf201-5f6d-41c0-842d-5c029823ef60-2025-12-10T200000.000Z
    reference_title: DRC4 / primary ciliary dyskinesia 33 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DRC4 | HGNC:4166 | primary ciliary dyskinesia 33 | MONDO:0014750 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-12-10T20:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding DRC4 to primary ciliary dyskinesia 33 (MONDO:0014750) with
      classification Definitive.
  - reference: PMID:26387594
    reference_title: Loss-of-Function GAS8 Mutations Cause Primary Ciliary Dyskinesia and Disrupt the Nexin-Dynein Regulatory Complex.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genome-wide exome sequence analyses identified recessive loss-of-function mutations in GAS8 encoding DRC4 in three independent PCD-affected families.
    explanation: >-
      Founding report binding biallelic DRC4/GAS8 variants to primary ciliary dyskinesia in three families.
  - reference: PMID:26387594
    reference_title: Loss-of-Function GAS8 Mutations Cause Primary Ciliary Dyskinesia and Disrupt the Nexin-Dynein Regulatory Complex.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This applies in particular to isolated defects of the nexin links, also known as the nexin-dynein regulatory complex (N-DRC), connecting the peripheral outer microtubular doublets.
    explanation: >-
      States why a nexin-dynein regulatory complex defect is not reliably visible on transmission electron
      microscopy.
  - reference: PMID:26387594
    reference_title: Loss-of-Function GAS8 Mutations Cause Primary Ciliary Dyskinesia and Disrupt the Nexin-Dynein Regulatory Complex.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, some defects are not regularly discernable by TEM because the ciliary architecture of the axoneme remains preserved.
    explanation: >-
      States that the architecture is preserved, which is why ultrastructure reads as normal here.
  - reference: PMID:26387594
    reference_title: Loss-of-Function GAS8 Mutations Cause Primary Ciliary Dyskinesia and Disrupt the Nexin-Dynein Regulatory Complex.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Immunofluorescence analyses of respiratory cells from PCD-affected individuals detected a N-DRC defect.
    explanation: >-
      Records the method by which this lesion class was found.
- name: CILD34
  display_name: Primary ciliary dyskinesia 34 (DNAJB13-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic DNAJB13 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the DNAJB13 / primary ciliary dyskinesia 34 relationship as Moderate with
    autosomal recessive inheritance. DNAJB13 encodes an HSP40 co-chaperone whose Chlamydomonas ortholog
    localizes to the radial spokes. The reported individuals had central-complex defects with normal dynein
    arm structure; the missense change found in the first family destabilizes the protein and triggers
    proteasomal degradation.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 34
    term:
      id: MONDO:0014909
      label: primary ciliary dyskinesia 34
  genes:
  - preferred_term: DNAJB13
    term:
      id: hgnc:30718
      label: DNAJB13
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_fd64a9ab-9f83-43c8-a23d-2617da493010-2025-06-12T090000.000Z
      reference_title: DNAJB13 / primary ciliary dyskinesia 34 (Moderate)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: DNAJB13 | HGNC:30718 | primary ciliary dyskinesia 34 | MONDO:0014909 | AR | Moderate | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-06-12T09:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_fd64a9ab-9f83-43c8-a23d-2617da493010-2025-06-12T090000.000Z
    reference_title: DNAJB13 / primary ciliary dyskinesia 34 (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DNAJB13 | HGNC:30718 | primary ciliary dyskinesia 34 | MONDO:0014909 | AR | Moderate | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-06-12T09:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding DNAJB13 to primary ciliary dyskinesia 34 (MONDO:0014909) with
      classification Moderate.
  - reference: PMID:27486783
    reference_title: Mutations in DNAJB13, Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: To identify the molecular basis of a PCD phenotype characterized by central complex (CC) defects but normal DA structure, a phenotype found in ~15% of cases, we performed whole-exome sequencing in a male individual with PCD and unexplained CC defects.
    explanation: >-
      States the ultrastructural phenotype this stratum presents with: central-complex defects without a
      dynein arm defect.
  - reference: PMID:27486783
    reference_title: Mutations in DNAJB13, Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In vitro studies showed that this missense substitution (p.Met278Arg), which involves a highly conserved residue of several HSP40 family members, leads to protein instability and triggers proteasomal degradation, a result confirmed by the absence of endogenous DNAJB13 in cilia and sperm from this individual.
    explanation: >-
      Functional basis of the DNAJB13 defect in the founding family.
- name: CILD35
  display_name: Primary ciliary dyskinesia 35 (ODAD4-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic ODAD4 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the ODAD4 / primary ciliary dyskinesia 35 relationship as Definitive
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: primary ciliary dyskinesia 35
    term:
      id: MONDO:0014910
      label: primary ciliary dyskinesia 35
  genes:
  - preferred_term: ODAD4
    term:
      id: hgnc:25280
      label: ODAD4
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_547fed6e-47df-44b5-bf4a-e31f7b045862-2022-12-08T170000.000Z
      reference_title: 'ODAD4 / primary ciliary dyskinesia 35 (Definitive)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'ODAD4 | HGNC:25280 | primary ciliary dyskinesia 35 | MONDO:0014910 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-12-08T17:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_547fed6e-47df-44b5-bf4a-e31f7b045862-2022-12-08T170000.000Z
    reference_title: 'ODAD4 / primary ciliary dyskinesia 35 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'ODAD4 | HGNC:25280 | primary ciliary dyskinesia 35 | MONDO:0014910 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-12-08T17:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding ODAD4 to primary ciliary dyskinesia 35 (MONDO:0014910) with
      classification Definitive.
  - reference: PMID:27486780
    reference_title: 'TTC25 Deficiency Results in Defects of the Outer Dynein Arm Docking Machinery and Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'we identified recessive loss-of-function mutations within TTC25 in three individuals from two unrelated families affected by PCD'
    explanation: >-
      Reports the founding TTC25 (now ODAD4) loss-of-function mutations in two PCD families.
- name: CILD36
  display_name: Ciliary dyskinesia, primary, 36, X-linked (DNAAF6-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic DNAAF6 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the DNAAF6 / ciliary dyskinesia, primary, 36, X-linked relationship as
    Definitive with X-linked inheritance.
  subtype_term:
    preferred_term: 'ciliary dyskinesia, primary, 36, X-linked'
    term:
      id: MONDO:0010517
      label: 'ciliary dyskinesia, primary, 36, X-linked'
  genes:
  - preferred_term: DNAAF6
    term:
      id: hgnc:28570
      label: DNAAF6
  inheritance:
  - name: X-linked inheritance
    inheritance_term:
      preferred_term: X-linked inheritance
      term:
        id: HP:0001417
        label: X-linked inheritance
    evidence:
    - reference: CGGV:assertion_5de9de15-2c09-48f5-bcaf-08c42b97700e-2024-08-17T190000.000Z
      reference_title: 'DNAAF6 / ciliary dyskinesia, primary, 36, X-linked (Definitive)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'DNAAF6 | HGNC:28570 | ciliary dyskinesia, primary, 36, X-linked | MONDO:0010517 | XL | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-08-17T19:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance XL (X-linked) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_5de9de15-2c09-48f5-bcaf-08c42b97700e-2024-08-17T190000.000Z
    reference_title: 'DNAAF6 / ciliary dyskinesia, primary, 36, X-linked (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF6 | HGNC:28570 | ciliary dyskinesia, primary, 36, X-linked | MONDO:0010517 | XL | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-08-17T19:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding DNAAF6 to ciliary dyskinesia, primary, 36, X-linked
      (MONDO:0010517) with classification Definitive.
  - reference: PMID:28176794
    reference_title: 'X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'we demonstrate that large genomic deletions as well as point mutations involving PIH1D3 are responsible for an X-linked form of PCD causing disruption of early axonemal dynein assembly.'
    explanation: >-
      Establishes PIH1D3 (now DNAAF6) as the cause of an X-linked form of PCD.
- name: CILD37
  display_name: Ciliary dyskinesia, primary, 37 (DNAH1-related)
  classification: gene
  curated_in: Primary_Ciliary_Dyskinesia_37
  description: >-
    MONDO and OMIM place biallelic DNAH1 variants in the numbered series as CILD37 (OMIM:617577), and ClinGen
    grades the gene Limited for primary ciliary dyskinesia. The ClinGen Motile Ciliopathy Gene Curation Expert
    Panel classifies the DNAH1 / primary ciliary dyskinesia relationship as Limited with autosomal recessive
    inheritance. ClinGen curated DNAH1 against primary ciliary dyskinesia (MONDO:0016575) rather than against
    this numbered entity. This stratum is curated in full as its own entry; the row is a pointer so the
    stratum stays discoverable from the umbrella.
  subtype_term:
    preferred_term: ciliary dyskinesia, primary, 37
    term:
      id: MONDO:0033204
      label: ciliary dyskinesia, primary, 37
  genes:
  - preferred_term: DNAH1
    term:
      id: hgnc:2940
      label: DNAH1
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_a07c8b6e-a558-498b-975c-b12e96878a44-2025-10-16T160000.000Z
      reference_title: DNAH1 / primary ciliary dyskinesia (Limited)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: DNAH1 | HGNC:2940 | primary ciliary dyskinesia | MONDO:0016575 | AR | Limited | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-10-16T16:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_a07c8b6e-a558-498b-975c-b12e96878a44-2025-10-16T160000.000Z
    reference_title: DNAH1 / primary ciliary dyskinesia (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DNAH1 | HGNC:2940 | primary ciliary dyskinesia | MONDO:0016575 | AR | Limited | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-10-16T16:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding DNAH1 to primary ciliary dyskinesia (MONDO:0016575) with
      classification Limited.
- name: CILD38
  display_name: Ciliary dyskinesia, primary, 38 (CFAP300-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic CFAP300 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the CFAP300 / ciliary dyskinesia, primary, 38 relationship as Definitive
    with autosomal recessive inheritance. CFAP300 (previous symbol C11orf70) is required for the
    intraflagellar-transport-dependent assembly of axonemal dyneins. Affected children have immotile
    respiratory cilia with combined inner and outer dynein arm loss, and laterality defects.
  subtype_term:
    preferred_term: ciliary dyskinesia, primary, 38
    term:
      id: MONDO:0054843
      label: ciliary dyskinesia, primary, 38
  genes:
  - preferred_term: CFAP300
    term:
      id: hgnc:28188
      label: CFAP300
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_6bcfa4e4-37a3-43a7-9b4d-60554bc7600c-2022-09-08T110000.000Z
      reference_title: CFAP300 / ciliary dyskinesia, primary, 38 (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: CFAP300 | HGNC:28188 | ciliary dyskinesia, primary, 38 | MONDO:0054843 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-09-08T11:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_6bcfa4e4-37a3-43a7-9b4d-60554bc7600c-2022-09-08T110000.000Z
    reference_title: CFAP300 / ciliary dyskinesia, primary, 38 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CFAP300 | HGNC:28188 | ciliary dyskinesia, primary, 38 | MONDO:0054843 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-09-08T11:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding CFAP300 to ciliary dyskinesia, primary, 38 (MONDO:0054843)
      with classification Definitive.
  - reference: PMID:29727692
    reference_title: C11orf70 Mutations Disrupting the Intraflagellar Transport-Dependent Assembly of Multiple Axonemal Dyneins Cause Primary Ciliary Dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The affected children share a consistent PCD phenotype from early life with laterality defects and immotile respiratory cilia displaying combined loss of inner and outer dynein arms (IDA+ODA).
    explanation: >-
      Founding report binding biallelic CFAP300 variants to primary ciliary dyskinesia and stating the
      combined dynein arm lesion.
  - reference: PMID:29727692
    reference_title: C11orf70 Mutations Disrupting the Intraflagellar Transport-Dependent Assembly of Multiple Axonemal Dyneins Cause Primary Ciliary Dyskinesia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In summary, C11orf70 is essential for assembly of dynein arms and C11orf70 mutations cause defective cilia motility and PCD.
    explanation: >-
      States the dynein-arm assembly role that places CFAP300 on the preassembly node.
- name: CILD39
  display_name: Ciliary dyskinesia, primary, 39 (LRRC56-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic LRRC56 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the LRRC56 / ciliary dyskinesia, primary, 39 relationship as Moderate
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: 'ciliary dyskinesia, primary, 39'
    term:
      id: MONDO:0032637
      label: 'ciliary dyskinesia, primary, 39'
  genes:
  - preferred_term: LRRC56
    term:
      id: hgnc:25430
      label: LRRC56
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_ceef14a8-34d2-41ac-8c03-47c5eaff8986-2024-11-19T200000.000Z
      reference_title: 'LRRC56 / ciliary dyskinesia, primary, 39 (Moderate)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'LRRC56 | HGNC:25430 | ciliary dyskinesia, primary, 39 | MONDO:0032637 | AR | Moderate | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2024-11-19T20:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_ceef14a8-34d2-41ac-8c03-47c5eaff8986-2024-11-19T200000.000Z
    reference_title: 'LRRC56 / ciliary dyskinesia, primary, 39 (Moderate)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'LRRC56 | HGNC:25430 | ciliary dyskinesia, primary, 39 | MONDO:0032637 | AR | Moderate | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2024-11-19T20:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding LRRC56 to ciliary dyskinesia, primary, 39 (MONDO:0032637)
      with classification Moderate.
  - reference: PMID:36176820
    reference_title: 'Primary Ciliary Dyskinesia: Phenotype Resulting From a Novel Variant of LRRC56 Gene.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Next-generation sequencing of known or potential ciliopathy genes revealed him homozygous for a novel mutation c.494T>C of the LRRC56 gene, thus defining PCD as a potential cause of his features.'
    explanation: >-
      Case report of homozygous LRRC56 variant in a child with situs inversus totalis and recurrent
      respiratory infection.
- name: CILD40
  display_name: Ciliary dyskinesia, primary, 40 (DNAH9-related)
  classification: gene
  curated_in: Primary_Ciliary_Dyskinesia_40
  description: >-
    Primary ciliary dyskinesia caused by pathogenic DNAH9 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the DNAH9 / ciliary dyskinesia, primary, 40 relationship as Definitive
    with autosomal recessive inheritance. This stratum is curated in full as its own entry; the row is a
    pointer so the stratum stays discoverable from the umbrella.
  subtype_term:
    preferred_term: ciliary dyskinesia, primary, 40
    term:
      id: MONDO:0032664
      label: ciliary dyskinesia, primary, 40
  genes:
  - preferred_term: DNAH9
    term:
      id: hgnc:2953
      label: DNAH9
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
      reference_title: DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: DNAH9 | HGNC:2953 | ciliary dyskinesia, primary, 40 | MONDO:0032664 | AR | Definitive | SOP12 | Motile Ciliopathy Gene Curation Expert Panel | 2026-06-11T10:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
    reference_title: DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DNAH9 | HGNC:2953 | ciliary dyskinesia, primary, 40 | MONDO:0032664 | AR | Definitive | SOP12 | Motile Ciliopathy Gene Curation Expert Panel | 2026-06-11T10:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding DNAH9 to ciliary dyskinesia, primary, 40 (MONDO:0032664) with
      classification Definitive.
- name: CILD42
  display_name: Ciliary dyskinesia, primary, 42 (MCIDAS-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic MCIDAS variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the MCIDAS / ciliary dyskinesia, primary, 42 relationship as Definitive
    with autosomal recessive inheritance. MCIDAS encodes multicilin, a regulator of multiciliated cell
    differentiation upstream of CCNO and FOXJ1. The lesion is primarily a shortage of cilia: mutant
    respiratory cells carry only one or two cilia each, and those few cilia also lack ciliary motility-related
    proteins.
  subtype_term:
    preferred_term: ciliary dyskinesia, primary, 42
    term:
      id: MONDO:0032872
      label: ciliary dyskinesia, primary, 42
  genes:
  - preferred_term: MCIDAS
    term:
      id: hgnc:40050
      label: MCIDAS
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_866c87d2-9c7d-4f5e-bd7f-358d8e44fa54-2022-12-29T200000.000Z
      reference_title: MCIDAS / ciliary dyskinesia, primary, 42 (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: MCIDAS | HGNC:40050 | ciliary dyskinesia, primary, 42 | MONDO:0032872 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-12-29T20:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_866c87d2-9c7d-4f5e-bd7f-358d8e44fa54-2022-12-29T200000.000Z
    reference_title: MCIDAS / ciliary dyskinesia, primary, 42 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: MCIDAS | HGNC:40050 | ciliary dyskinesia, primary, 42 | MONDO:0032872 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-12-29T20:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding MCIDAS to ciliary dyskinesia, primary, 42 (MONDO:0032872) with
      classification Definitive.
  - reference: PMID:25048963
    reference_title: MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MCIDAS mutant respiratory epithelial cells carry only one or two cilia per cell, which lack ciliary motility-related proteins (DNAH5; CCDC39) as seen in primary ciliary dyskinesia.
    explanation: >-
      Founding report binding biallelic MCIDAS variants to reduced generation of multiple motile cilia with
      absent motility proteins.
  - reference: PMID:25048963
    reference_title: MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Thus, our findings identify Multicilin as a key regulator of CCNO/FOXJ1 for human multiciliated cell differentiation
    explanation: >-
      Places MCIDAS upstream of CCNO and FOXJ1 in multiciliogenesis, which is the node this stratum acts at.
- name: CILD43
  display_name: Ciliary dyskinesia, primary, 43 (FOXJ1-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic FOXJ1 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the FOXJ1 / ciliary dyskinesia, primary, 43 relationship as Definitive
    with autosomal dominant inheritance. FOXJ1 encodes a forkhead transcription factor required for motile
    ciliogenesis. This stratum is autosomal dominant, unlike the predominantly autosomal recessive series
    around it: the founding report describes heterozygous de novo variants. Hydrocephalus internus accompanies
    the airway disease and laterality randomization, and mutant respiratory cells have reduced cilia numbers
    and mislocalized basal bodies.
  subtype_term:
    preferred_term: ciliary dyskinesia, primary, 43
    term:
      id: MONDO:0032874
      label: ciliary dyskinesia, primary, 43
  genes:
  - preferred_term: FOXJ1
    term:
      id: hgnc:3816
      label: FOXJ1
  inheritance:
  - name: Autosomal dominant inheritance
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: CGGV:assertion_53a48f3c-42fc-4c60-becb-149019b1e4bf-2025-10-17T190000.000Z
      reference_title: FOXJ1 / ciliary dyskinesia, primary, 43 (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: FOXJ1 | HGNC:3816 | ciliary dyskinesia, primary, 43 | MONDO:0032874 | AD | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-10-17T19:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AD (autosomal dominant) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_53a48f3c-42fc-4c60-becb-149019b1e4bf-2025-10-17T190000.000Z
    reference_title: FOXJ1 / ciliary dyskinesia, primary, 43 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: FOXJ1 | HGNC:3816 | ciliary dyskinesia, primary, 43 | MONDO:0032874 | AD | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-10-17T19:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding FOXJ1 to ciliary dyskinesia, primary, 43 (MONDO:0032874) with
      classification Definitive.
  - reference: PMID:31630787
    reference_title: De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Heterozygous de novo mutations in FOXJ1, which encodes a well-known member of the forkhead transcription factors important for ciliogenesis of motile cilia, cause a motile ciliopathy that is characterized by hydrocephalus internus, chronic destructive airway disease, and randomization of left/right body asymmetry.
    explanation: >-
      Founding report establishing the dominant, de novo mode of inheritance and the phenotype of this
      stratum.
  - reference: PMID:31630787
    reference_title: De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Mutant respiratory epithelial cells are unable to generate a fluid flow and exhibit a reduced number of cilia per cell, as documented by high-speed video microscopy (HVMA), transmission electron microscopy (TEM), and immunofluorescence analysis (IF).
    explanation: >-
      States the reduced-ciliogenesis lesion that places FOXJ1 on the multiciliogenesis node.
  - reference: PMID:31630787
    reference_title: De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: TEM and IF demonstrate mislocalized basal bodies.
    explanation: >-
      Records the basal-body mislocalization in mutant respiratory epithelial cells.
- name: CILD44
  display_name: Ciliary dyskinesia, primary, 44 (NEK10-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic NEK10 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the NEK10 / ciliary dyskinesia, primary, 44 relationship as Definitive
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: 'ciliary dyskinesia, primary, 44'
    term:
      id: MONDO:0032914
      label: 'ciliary dyskinesia, primary, 44'
  genes:
  - preferred_term: NEK10
    term:
      id: hgnc:18592
      label: NEK10
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_72a2f8fa-ee83-48cc-93fa-22a8990c8d13-2025-10-17T190000.000Z
      reference_title: 'NEK10 / ciliary dyskinesia, primary, 44 (Definitive)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'NEK10 | HGNC:18592 | ciliary dyskinesia, primary, 44 | MONDO:0032914 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-10-17T19:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_72a2f8fa-ee83-48cc-93fa-22a8990c8d13-2025-10-17T190000.000Z
    reference_title: 'NEK10 / ciliary dyskinesia, primary, 44 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'NEK10 | HGNC:18592 | ciliary dyskinesia, primary, 44 | MONDO:0032914 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-10-17T19:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding NEK10 to ciliary dyskinesia, primary, 44 (MONDO:0032914)
      with classification Definitive.
  - reference: PMID:32414360
    reference_title: 'Homozygous truncating NEK10 mutation, associated with primary ciliary dyskinesia: a case report.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Using whole exome sequencing we identified a homozygous truncating variant (c.3402 T > A); p.(Tyr1134*) in the NEK10 gene.'
    explanation: >-
      Reports a homozygous truncating NEK10 variant in two siblings with a classical PCD presentation.
- name: CILD45
  display_name: Ciliary dyskinesia, primary, 45 (TTC12-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic TTC12 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the TTC12 / ciliary dyskinesia, primary, 45 relationship as Definitive
    with autosomal recessive inheritance.
  subtype_term:
    preferred_term: 'ciliary dyskinesia, primary, 45'
    term:
      id: MONDO:0032924
      label: 'ciliary dyskinesia, primary, 45'
  genes:
  - preferred_term: TTC12
    term:
      id: hgnc:23700
      label: TTC12
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_1ff366d1-58ff-44dd-b7c3-799d1fe250c6-2025-05-08T160000.000Z
      reference_title: 'TTC12 / ciliary dyskinesia, primary, 45 (Definitive)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'TTC12 | HGNC:23700 | ciliary dyskinesia, primary, 45 | MONDO:0032924 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-05-08T16:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_1ff366d1-58ff-44dd-b7c3-799d1fe250c6-2025-05-08T160000.000Z
    reference_title: 'TTC12 / ciliary dyskinesia, primary, 45 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'TTC12 | HGNC:23700 | ciliary dyskinesia, primary, 45 | MONDO:0032924 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-05-08T16:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding TTC12 to ciliary dyskinesia, primary, 45 (MONDO:0032924)
      with classification Definitive.
  - reference: PMID:31978331
    reference_title: 'TTC12 Loss-of-Function Mutations Cause Primary Ciliary Dyskinesia and Unveil Distinct Dynein Assembly Mechanisms in Motile Cilia Versus Flagella.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We identified four loss-of-function mutations in TTC12, which encodes a cytoplasmic protein, in four independent families in which affected individuals displayed a peculiar PCD phenotype characterized by the absence of ODAs and IDAs in sperm flagella, contrasting with the absence of only IDAs in respiratory cilia.'
    explanation: >-
      Establishes TTC12 as a PCD gene and records the cilia-versus-flagella difference in dynein-arm loss.
- name: CILD48
  display_name: Ciliary dyskinesia, primary, 48, without situs inversus (NME5-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic NME5 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the NME5 / ciliary dyskinesia, primary, 48, without situs inversus
    relationship as Moderate with autosomal recessive inheritance. The MONDO label records absence of situs
    inversus; the founding report describes a patient with situs solitus and radial-spoke/central-pair
    defects.
  subtype_term:
    preferred_term: 'ciliary dyskinesia, primary, 48, without situs inversus'
    term:
      id: MONDO:0031054
      label: 'ciliary dyskinesia, primary, 48, without situs inversus'
  genes:
  - preferred_term: NME5
    term:
      id: hgnc:7853
      label: NME5
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_00efe110-5916-4da0-92ac-cee8c8b18140-2024-02-08T170000.000Z
      reference_title: 'NME5 / ciliary dyskinesia, primary, 48, without situs inversus (Moderate)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'NME5 | HGNC:7853 | ciliary dyskinesia, primary, 48, without situs inversus | MONDO:0031054 | AR | Moderate | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-02-08T17:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_00efe110-5916-4da0-92ac-cee8c8b18140-2024-02-08T170000.000Z
    reference_title: 'NME5 / ciliary dyskinesia, primary, 48, without situs inversus (Moderate)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'NME5 | HGNC:7853 | ciliary dyskinesia, primary, 48, without situs inversus | MONDO:0031054 | AR | Moderate | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-02-08T17:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding NME5 to ciliary dyskinesia, primary, 48, without situs
      inversus (MONDO:0031054) with classification Moderate.
  - reference: PMID:32185794
    reference_title: 'A nonsense variant in NME5 causes human primary ciliary dyskinesia with radial spoke defects.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We identified a homozygous nonsense variant (c.572G>A; p.Trp191*) in NME5, which encodes a protein component of the RS neck, in one PCD patient with situs solitus.'
    explanation: >-
      Reports the founding NME5 nonsense variant in a PCD patient with radial-spoke defects and situs
      solitus.
- name: CILD49
  display_name: Ciliary dyskinesia, primary, 49, without situs inversus (CFAP74-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic CFAP74 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the CFAP74 / ciliary dyskinesia, primary, 49, without situs inversus
    relationship as Moderate with autosomal recessive inheritance. CFAP74 is the mammalian homolog of FAP74,
    which Chlamydomonas work identifies as a subunit of the C1d projection of the central apparatus. Ciliary
    ultrastructure is normal and beat changes are subtle, and affected individuals present no situs
    abnormalities, which is what the MONDO label for this stratum records.
  subtype_term:
    preferred_term: ciliary dyskinesia, primary, 49, without situs inversus
    term:
      id: MONDO:0859353
      label: ciliary dyskinesia, primary, 49, without situs inversus
  genes:
  - preferred_term: CFAP74
    term:
      id: hgnc:29368
      label: CFAP74
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_e5a065a6-73b9-46ba-89a2-afadedb4b82c-2025-06-18T160000.000Z
      reference_title: CFAP74 / ciliary dyskinesia, primary, 49, without situs inversus (Moderate)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: CFAP74 | HGNC:29368 | ciliary dyskinesia, primary, 49, without situs inversus | MONDO:0859353 | AR | Moderate | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-06-18T16:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_e5a065a6-73b9-46ba-89a2-afadedb4b82c-2025-06-18T160000.000Z
    reference_title: CFAP74 / ciliary dyskinesia, primary, 49, without situs inversus (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CFAP74 | HGNC:29368 | ciliary dyskinesia, primary, 49, without situs inversus | MONDO:0859353 | AR | Moderate | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-06-18T16:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding CFAP74 to ciliary dyskinesia, primary, 49, without situs
      inversus (MONDO:0859353) with classification Moderate.
  - reference: PMID:36047773
    reference_title: Recessive Mutations in CFAP74 Cause Primary Ciliary Dyskinesia with Normal Ciliary Ultrastructure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we report three affected individuals from two families with compound heterozygous mutations in CFAP74 and demonstrate abnormal ciliary beating and reduced mucociliary clearance responsible for the PCD phenotype.
    explanation: >-
      Founding report binding biallelic CFAP74 variants to primary ciliary dyskinesia with normal
      ultrastructure.
  - reference: PMID:36047773
    reference_title: Recessive Mutations in CFAP74 Cause Primary Ciliary Dyskinesia with Normal Ciliary Ultrastructure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CP complex associated defects are difficult to identify because affected individuals present no situs abnormalities and show subtle changes in high-speed video microscopy analysis (HSVMA)
    explanation: >-
      Explains why this stratum presents without situs abnormalities, which the MONDO label records.
  - reference: PMID:36047773
    reference_title: Recessive Mutations in CFAP74 Cause Primary Ciliary Dyskinesia with Normal Ciliary Ultrastructure.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CFAP74 (cilia and flagella associated protein 74) is the mammalian homolog of FAP74, a subunit of the C1d projection of the central apparatus
    explanation: >-
      Assigns CFAP74 to the C1d projection through its Chlamydomonas homolog, as background in the citing
      report.
- name: CILD50
  display_name: Ciliary dyskinesia, primary, 50 (DNAH7-related)
  classification: gene
  curated_in: Primary_Ciliary_Dyskinesia_50
  description: >-
    Primary ciliary dyskinesia caused by pathogenic DNAH7 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the DNAH7 / primary ciliary dyskinesia relationship as Limited with
    autosomal recessive inheritance. ClinGen curated DNAH7 against primary ciliary dyskinesia
    (MONDO:0016575) rather than against this numbered entity, and graded it Limited. The founding human report describes asthenozoospermia with losses of the inner dynein arms in
    spermatozoa rather than a respiratory phenotype.
  subtype_term:
    preferred_term: 'ciliary dyskinesia, primary, 50'
    term:
      id: MONDO:0957252
      label: 'ciliary dyskinesia, primary, 50'
  genes:
  - preferred_term: DNAH7
    term:
      id: hgnc:18661
      label: DNAH7
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_90a097d6-5127-4466-8c81-00e99dab2696-2025-02-13T170000.000Z
      reference_title: 'DNAH7 / primary ciliary dyskinesia (Limited)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'DNAH7 | HGNC:18661 | primary ciliary dyskinesia | MONDO:0016575 | AR | Limited | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2025-02-13T17:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_90a097d6-5127-4466-8c81-00e99dab2696-2025-02-13T170000.000Z
    reference_title: 'DNAH7 / primary ciliary dyskinesia (Limited)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAH7 | HGNC:18661 | primary ciliary dyskinesia | MONDO:0016575 | AR | Limited | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2025-02-13T17:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding DNAH7 to primary ciliary dyskinesia (MONDO:0016575) with
      classification Limited.
  - reference: PMID:34476482
    reference_title: 'Bi-allelic mutations in DNAH7 cause asthenozoospermia by impairing the integrality of axoneme structure.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'Our study is the first to demonstrate that bi-allelic mutations in DNAH7 may impair the integrality of axoneme structure, affect sperm motility, and cause asthenozoospermia in humans.'
    explanation: >-
      The founding DNAH7 report describes asthenozoospermia with inner-dynein-arm loss in spermatozoa, not
      respiratory PCD.
  - reference: PMID:34476482
    reference_title: Bi-allelic mutations in DNAH7 cause asthenozoospermia by impairing the integrality of axoneme structure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The spermatozoa from the patients with DNAH7 bi-allelic mutations showed specific losses in the inner dynein arms.
    explanation: >-
      Records the axonemal lesion the founding report found, which is confined to the sperm flagellum.
- name: CILD52
  display_name: Ciliary dyskinesia, primary, 52 (DAW1-related)
  classification: gene
  description: >-
    MONDO and OMIM place biallelic DAW1 variants in the numbered series as CILD52 (OMIM:620570), but the
    evidence for a primary ciliary dyskinesia phenotype is thin. The ClinGen Motile Ciliopathy Gene Curation
    Expert Panel classifies the DAW1 / primary ciliary dyskinesia relationship as Limited with autosomal
    recessive inheritance. ClinGen curated DAW1 against primary ciliary dyskinesia (MONDO:0016575) rather than
    against this numbered entity. ClinGen separately classifies DAW1 / visceral heterotaxy (MONDO:0018677) as
    Moderate, a higher grade than it gives DAW1 for primary ciliary dyskinesia. The founding report describes
    laterality defects with respiratory symptoms, and its own conclusion names the entity a human motile
    ciliopathy rather than primary ciliary dyskinesia; a later study reports heterotaxy and congenital heart
    disease with no evidence of primary ciliary dyskinesia. The weight of the evidence read here is a
    laterality-dominant motile ciliopathy, so DAW1 is deliberately not wired into this entry's pathograph.
  subtype_term:
    preferred_term: ciliary dyskinesia, primary, 52
    term:
      id: MONDO:0957922
      label: ciliary dyskinesia, primary, 52
  genes:
  - preferred_term: DAW1
    term:
      id: hgnc:26383
      label: DAW1
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_8610990f-63cf-466a-8cd7-fbf7ae58d0f2-2024-06-13T160000.000Z
      reference_title: DAW1 / primary ciliary dyskinesia (Limited)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: DAW1 | HGNC:26383 | primary ciliary dyskinesia | MONDO:0016575 | AR | Limited | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-06-13T16:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_8610990f-63cf-466a-8cd7-fbf7ae58d0f2-2024-06-13T160000.000Z
    reference_title: DAW1 / primary ciliary dyskinesia (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DAW1 | HGNC:26383 | primary ciliary dyskinesia | MONDO:0016575 | AR | Limited | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-06-13T16:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding DAW1 to primary ciliary dyskinesia (MONDO:0016575) with
      classification Limited.
  - reference: CGGV:assertion_999c6072-d9c6-4339-aea7-8247941748a6-2024-07-11T160000.000Z
    reference_title: DAW1 / visceral heterotaxy (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DAW1 | HGNC:26383 | visceral heterotaxy | MONDO:0018677 | AR | Moderate | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-07-11T16:00:00.000Z
    explanation: >-
      ClinGen grades DAW1 higher for visceral heterotaxy than for primary ciliary dyskinesia.
  - reference: PMID:36074124
    reference_title: Biallelic DAW1 variants cause a motile ciliopathy characterized by laterality defects and subtle ciliary beating abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In this study, we identified biallelic DAW1 variants associated with laterality defects and respiratory symptoms compatible with motile cilia dysfunction.
    explanation: >-
      The founding report states the phenotype as laterality defects with respiratory symptoms.
  - reference: PMID:36074124
    reference_title: Biallelic DAW1 variants cause a motile ciliopathy characterized by laterality defects and subtle ciliary beating abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Our data define biallelic DAW1 variants as a cause of human motile ciliopathy and determine that the disease mechanism involves motile cilia dysfunction
    explanation: >-
      The founding report's own conclusion names the entity a motile ciliopathy, not primary ciliary
      dyskinesia.
  - reference: PMID:42773161
    reference_title: Biallelic DAW1 variants reveal a tissue-specific role in heterotaxy without primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we identify compound heterozygous variants in DAW1, a dynein arm assembly factor, in a proband with an HTX/laterality defect spectrum, presenting with complex CHD without extracardiac organ malposition and no evidence of PCD.
    explanation: >-
      A later report describes biallelic DAW1 variants with heterotaxy and congenital heart disease and no
      evidence of primary ciliary dyskinesia, which weighs against the numbered CILD placement.
- name: CILD53
  display_name: Ciliary dyskinesia, primary, 53 (CLXN-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic CLXN variants. The ClinGen Motile Ciliopathy Gene Curation
    Expert Panel classifies the CLXN / ciliary dyskinesia, primary, 53 relationship as Strong with autosomal
    recessive inheritance. CLXN (previous symbol EFCAB1) encodes the calcium-binding protein calaxin, which
    the founding report proposes be called outer dynein arm docking complex associated protein ODAD5.
    Transmission electron microscopy shows outer dynein arm defects confined to the distal ciliary axoneme.
  subtype_term:
    preferred_term: ciliary dyskinesia, primary, 53
    term:
      id: MONDO:0957991
      label: ciliary dyskinesia, primary, 53
  genes:
  - preferred_term: CLXN
    term:
      id: hgnc:25678
      label: CLXN
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_18721467-867b-4687-b4f2-5af09951ada5-2025-04-10T160000.000Z
      reference_title: CLXN / ciliary dyskinesia, primary, 53 (Strong)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: CLXN | HGNC:25678 | ciliary dyskinesia, primary, 53 | MONDO:0957991 | AR | Strong | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-04-10T16:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_18721467-867b-4687-b4f2-5af09951ada5-2025-04-10T160000.000Z
    reference_title: CLXN / ciliary dyskinesia, primary, 53 (Strong)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CLXN | HGNC:25678 | ciliary dyskinesia, primary, 53 | MONDO:0957991 | AR | Strong | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-04-10T16:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding CLXN to ciliary dyskinesia, primary, 53 (MONDO:0957991) with
      classification Strong.
  - reference: PMID:36727596
    reference_title: Pathogenic variants in CLXN encoding the outer dynein arm docking-associated calcium-binding protein calaxin cause primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In this study, we identified homozygous pathogenic variants in CLXN (EFCAB1/ODAD5) in 3 individuals with laterality defects and respiratory symptoms.
    explanation: >-
      Founding report binding biallelic CLXN variants to primary ciliary dyskinesia in three individuals.
  - reference: PMID:36727596
    reference_title: Pathogenic variants in CLXN encoding the outer dynein arm docking-associated calcium-binding protein calaxin cause primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Our results revealed that pathogenic variants in CLXN cause PCD with defects in the assembly of distal ODAs in the respiratory cilia. CLXN should be referred to as ODA-docking complex-associated protein ODAD5.
    explanation: >-
      States the outer-dynein-arm docking role that places CLXN on the docking node.
- name: CILD54
  display_name: Ciliary dyskinesia, primary, 54 (CFAP54-related)
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic CFAP54 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the CFAP54 / ciliary dyskinesia, primary, 54 relationship as Strong with
    autosomal recessive inheritance. CFAP54 is one of the C1d central-apparatus genes identified together with
    CFAP46, CFAP74 and CFAP221. Affected individuals show insufficient ciliary clearance on in vitro transport
    assays.
  subtype_term:
    preferred_term: ciliary dyskinesia, primary, 54
    term:
      id: MONDO:0100607
      label: ciliary dyskinesia, primary, 54
  genes:
  - preferred_term: CFAP54
    term:
      id: hgnc:26456
      label: CFAP54
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_f16ea0ce-7d5d-4bdc-92fe-52d111913161-2025-07-16T070000.000Z
      reference_title: CFAP54 / ciliary dyskinesia, primary, 54 (Strong)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: CFAP54 | HGNC:26456 | ciliary dyskinesia, primary, 54 | MONDO:0100607 | AR | Strong | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-07-16T07:00:00.000Z
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_f16ea0ce-7d5d-4bdc-92fe-52d111913161-2025-07-16T070000.000Z
    reference_title: CFAP54 / ciliary dyskinesia, primary, 54 (Strong)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CFAP54 | HGNC:26456 | ciliary dyskinesia, primary, 54 | MONDO:0100607 | AR | Strong | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-07-16T07:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding CFAP54 to ciliary dyskinesia, primary, 54 (MONDO:0100607) with
      classification Strong.
  - reference: PMID:39362668
    reference_title: Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance.
    explanation: >-
      C1d-defective patient cells show transport failure despite normal routine diagnostics.
- name: CFAP46-related
  display_name: CFAP46-related primary ciliary dyskinesia
  classification: gene
  description: >-
    Primary ciliary dyskinesia caused by pathogenic CFAP46 variants. The ClinGen Motile Ciliopathy Gene
    Curation Expert Panel classifies the CFAP46 / primary ciliary dyskinesia relationship as Limited with
    autosomal recessive inheritance. ClinGen curated CFAP46 against primary ciliary dyskinesia
    (MONDO:0016575) rather than against this MONDO gene-named class, and graded it Limited. The MONDO class
    has no OMIM cross-reference and carries only a GARD xref (read from EBI OLS4).
  subtype_term:
    preferred_term: CFAP46-related primary ciliary dyskinesia
    term:
      id: MONDO:1010146
      label: CFAP46-related primary ciliary dyskinesia
  genes:
  - preferred_term: CFAP46
    term:
      id: hgnc:25247
      label: CFAP46
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: CGGV:assertion_eabe809a-1203-4d42-9052-21f39717754f-2025-10-17T160000.000Z
      reference_title: 'CFAP46 / primary ciliary dyskinesia (Limited)'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: 'CFAP46 | HGNC:25247 | primary ciliary dyskinesia | MONDO:0016575 | AR | Limited | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-10-17T16:00:00.000Z'
      explanation: >-
        ClinGen records mode of inheritance AR (autosomal recessive) for this gene-disease relationship.
  evidence:
  - reference: CGGV:assertion_eabe809a-1203-4d42-9052-21f39717754f-2025-10-17T160000.000Z
    reference_title: 'CFAP46 / primary ciliary dyskinesia (Limited)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'CFAP46 | HGNC:25247 | primary ciliary dyskinesia | MONDO:0016575 | AR | Limited | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-10-17T16:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding CFAP46 to primary ciliary dyskinesia (MONDO:0016575) with
      classification Limited.
  - reference: PMID:39362668
    reference_title: 'Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'we identified pathogenic variants in the novel primary ciliary dyskinesia genes CFAP46 and CFAP54, and the known primary ciliary dyskinesia gene CFAP221.'
    explanation: >-
      Reports pathogenic CFAP46 variants in individuals with a defective C1d central-apparatus projection.
prevalence:
- population: Europe
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_low: 1.0
  rate_high: 9.0
  percentage: 0.001-0.009
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: 1-9 / 100 000 | Europe | Prevalence at birth | PMID:23871404
    explanation: Orphanet epidemiology data reports prevalence at birth in Europe of 1-9 per 100,000.
    evidence_source: OTHER
  - reference: PMID:23871404
    reference_title: '[Congenital ciliary dyskinesia. Focus].'
    supports: SUPPORT
    snippet: Prevalence, about 1/15,000 to 1/30,000, is probably underestimated, as diagnosis might not be evocated in absence of Kartagener syndrome.
    explanation: French review estimates prevalence at 1/15,000 to 1/30,000, consistent with the Orphanet range of 1-9 per 100,000.
    evidence_source: OTHER
- population: British Asian population of Bradford, United Kingdom
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_low: 44.150110375275936
  rate_high: 44.150110375275936
  percentage: '0.0442'
  evidence:
  - reference: PMID:19720631
    reference_title: High prevalence of primary ciliary dyskinesia in a British Asian population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The prevalence of PCD in the population studied was one in 2265.
    explanation: >-
      Fifteen-year ascertainment in the highly consanguineous British Asian population of Bradford,
      UK. This is not a Pakistan national prevalence estimate.
  notes: >-
    The primary source supersedes the incorrect Pakistan geography in the secondary Orphanet table.
    Fifty-two percent of parents were first cousins; ascertainment and ancestry limit generalization.
- population: Global modeled genetic prevalence
  measure_type: POINT_PREVALENCE
  notes: >-
    Variant-frequency modeling estimated a minimum of one in 7554 using 29 autosomal-recessive PCD
    genes and 182681 individuals. This is a Hardy-Weinberg-based estimate from variant databases,
    not observed case ascertainment or a measured birth-prevalence series; inclusion of uncertain
    variants changes the estimates markedly.
  evidence:
  - reference: PMID:35051411
    reference_title: 'The global prevalence and ethnic heterogeneity of primary ciliary dyskinesia gene variants: a genetic database analysis.'
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Primary ciliary dyskinesia (PCD) is a motile ciliopathy characterised by otosinopulmonary
      infections. ... The aim of the study was to estimate the worldwide prevalence and ethnic
      heterogeneity of PCD. METHODS: We calculated the allele frequency of disease-causing variants
      in 29 PCD genes associated with autosomal recessive inheritance in 182 681 unique individuals
      to estimate the global prevalence of PCD in seven ethnicities (African or African American,
      Latino, Ashkenazi Jewish, Finnish, non-Finnish European, east Asian, and south Asian). ...
      Using the Hardy-Weinberg equilibrium equation, we were able to calculate a lower-end
      prevalence of PCD for each ethnicity by including only pathogenic and likely pathogenic
      variants; and upper-end prevalence by also including VUS. This approach was similar to
      previous work on Li-Fraumeni (TP53 variants) prevalence. We were not diagnosing PCD, but
      rather estimating prevalence based on known variants. FINDINGS: The overall minimum global
      prevalence of PCD is calculated to be at least one in 7554 individuals, although this is
      likely to be an underestimate because some variants currently classified as VUS might be
      disease-causing and some pathogenic variants might not be detected by our methods.
    explanation: >-
      The minimum global estimate of 1 in 7,554 is modeled from PCD-variant allele frequencies using
      Hardy-Weinberg assumptions. It is not a count of clinically diagnosed patients; including
      uncertain variants changes the estimate.
pathophysiology:
- name: Ciliary Dysfunction
  description: >-
    Defects in dynein motors, their cytoplasmic assembly or docking, and axonemal regulatory structures
    impair coordinated ciliary movement. Combined outer/inner dynein-arm loss can cause immotility,
    whereas DNAH11-related disease can retain hyperkinetic but ineffective beating and RSPH1-related
    disease can retain frequency with an abnormal circular waveform. This beat-dysfunction route
    is distinct from reduced multiciliogenesis and transport failure despite apparently normal routine
    beat measurements. Radial spoke and nexin-dynein regulatory complex lesions are modeled as
    separate upstream nodes, because each is a distinct structure whose loss reaches the beat by its
    own route; the genes for those two complexes are wired there rather than here.
  evidence:
  - reference: PMID:31772028
    reference_title: Deep phenotyping, including quantitative ciliary beating parameters, and extensive genotyping in primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Combined outer/inner dynein arms (ODA/IDA) defect induces total ciliary immotility, regardless of the gene involved.
    explanation: >-
      In the studied ultrastructural classes, combined dynein-arm loss produced immotility. Other
      genotypes show dyskinetic, hyperkinetic or apparently normal beating; this is not a universal
      immotility rule.
  - reference: PMID:24568568
    reference_title: Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cilia from individuals with RSPH1 mutations had normal beat frequency
    explanation: >-
      RSPH1 patient cilia retained frequency but had an abnormal circular waveform, showing why frequency
      alone is insufficient.
  genes:
  - preferred_term: DNAI1
    term:
      id: hgnc:2954
      label: DNAI1
  - preferred_term: DNAH5
    term:
      id: hgnc:2950
      label: DNAH5
  - preferred_term: DNAH11
    term:
      id: hgnc:2942
      label: DNAH11
  - preferred_term: DNAH9
    term:
      id: hgnc:2953
      label: DNAH9
  - preferred_term: ODAD1
    term:
      id: hgnc:26560
      label: ODAD1
  - preferred_term: SPEF2
    term:
      id: hgnc:26293
      label: SPEF2
  - preferred_term: NEK10
    term:
      id: hgnc:18592
      label: NEK10
  - preferred_term: NME8
    term:
      id: hgnc:16473
      label: NME8
  - preferred_term: LRRC56
    term:
      id: hgnc:25430
      label: LRRC56
  - preferred_term: DNAL1
    term:
      id: hgnc:23247
      label: DNAL1
  biological_processes:
  - preferred_term: cilium movement
    modifier: ABNORMAL
    term:
      id: GO:0003341
      label: cilium movement
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  conforms_to: ciliopathy_dysfunction#Motile Cilia Beat Dysfunction
  downstream:
  - target: Impaired Mucociliary Clearance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      This ciliary defect impairs effective respiratory surface transport.
    evidence:
    - reference: PMID:38076675
      reference_title: 'Pulmonary radioaerosol mucociliary clearance assessment: searching for genotype-specific differences and potential as an outcome measure in primary ciliary dyskinesia.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Mucociliary clearance by PRMC was consistently absent in most PCD patients, regardless of genotype.
      explanation: >-
        Retrospective radioaerosol assessment included 69 patients and 26 genotypes. One CCDC103
        participant retained measurable clearance; the 24-year collection window is not 24-year longitudinal
        follow-up of every participant.
    hypothesis_groups:
    - canonical_motile_cilia_beat_failure
  locations:
  - preferred_term: respiratory tract epithelium
    term:
      id: UBERON:0004802
      label: respiratory tract epithelium
  - preferred_term: nasal cavity epithelium
    term:
      id: UBERON:0005384
      label: nasal cavity epithelium
  - preferred_term: trachea
    term:
      id: UBERON:0003126
      label: trachea
  - preferred_term: bronchus
    term:
      id: UBERON:0002185
      label: bronchus
  cellular_components:
  - preferred_term: Cilia
    term:
      id: GO:0005929
      label: cilium
  - preferred_term: axoneme
    term:
      id: GO:0005930
      label: axoneme
  - preferred_term: outer dynein arm
    term:
      id: GO:0036157
      label: outer dynein arm
  biological_scale: CELLULAR
- name: Reduced Multiciliogenesis
  description: >-
    CCNO and MCIDAS defects impair the generation of numerous motile cilia. CCNO affects centriole
    amplification and maturation; MCIDAS acts upstream in multiciliated-cell differentiation and
    motor-protein expression. FOXJ1 and dominant-negative TUBB4B variants can also reduce cilia generation
    through distinct transcriptional or microtubule mechanisms. Cilia number and the structure/function
    of residual cilia must be assessed separately. Nodal monocilia are generally spared by CCNO/MCIDAS
    defects; that negative prediction does not extend to every ciliogenesis gene.
  evidence:
  - reference: PMID:24747639
    reference_title: Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: marked reduction in the number of multiple motile cilia
    explanation: >-
      CCNO patient studies distinguish reduced cilia number from abnormal beating of residual cilia.
  - reference: PMID:25048963
    reference_title: MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MCIDAS mutant respiratory epithelial cells carry only one or two cilia per cell, which lack ciliary motility-related proteins (DNAH5; CCDC39) as seen in primary ciliary dyskinesia.
    explanation: >-
      MCIDAS disrupts the multiciliogenesis program; remaining cilia need not share CCNO residual-cilium
      normality.
  - reference: PMID:38662826
    reference_title: Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner.
    explanation: >-
      Human genetics and functional models support a separate dominant-negative ciliogenesis route.
  - reference: PMID:34132502
    reference_title: Autosomal dominant variants in FOXJ1 causing primary ciliary dyskinesia in two patients with obstructive hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: FOXJ1 pathogenic variants cause PCD in a de novo, autosomal dominant inheritance pattern, and are associated with hydrocephalus.
    explanation: >-
      Human FOXJ1 cases support a restricted association with hydrocephalus; severe hydrocephalus
      in mouse PCD models should not set a pan-PCD human frequency.
  genes:
  - preferred_term: CCNO
    term:
      id: hgnc:18576
      label: CCNO
  - preferred_term: MCIDAS
    term:
      id: hgnc:40050
      label: MCIDAS
  - preferred_term: FOXJ1
    term:
      id: hgnc:3816
      label: FOXJ1
  - preferred_term: TUBB4B
    term:
      id: hgnc:20771
      label: TUBB4B
  biological_processes:
  - preferred_term: cilium assembly
    modifier: DECREASED
    term:
      id: GO:0060271
      label: cilium assembly
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  downstream:
  - target: Impaired Mucociliary Clearance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      This ciliary defect impairs effective respiratory surface transport.
    evidence:
    - reference: PMID:24747639
      reference_title: Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: marked reduction in the number of multiple motile cilia
      explanation: >-
        CCNO patient studies distinguish reduced cilia number from abnormal beating of residual cilia.
    - reference: PMID:25048963
      reference_title: MCIDAS mutations result in a mucociliary clearance disorder with reduced generation of multiple motile cilia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: MCIDAS mutant respiratory epithelial cells carry only one or two cilia per cell, which lack ciliary motility-related proteins (DNAH5; CCDC39) as seen in primary ciliary dyskinesia.
      explanation: >-
        MCIDAS disrupts the multiciliogenesis program; remaining cilia need not share CCNO residual-cilium
        normality.
    hypothesis_groups:
    - canonical_motile_cilia_beat_failure
  locations:
  - preferred_term: respiratory tract epithelium
    term:
      id: UBERON:0004802
      label: respiratory tract epithelium
  biological_scale: CELLULAR
- name: Ciliary Disorientation
  description: GAS2L2 deficiency disrupts orientation of airway motile cilia despite preserved axonemal ultrastructure. Patient-derived nasal cells show asynchronous, hyperkinetic beating. Directional alignment is distinct from beat frequency and temporal phase coordination; these properties should be quantified separately. Conditional Gas2l2 deletion impairs clearance in mice, supporting a transport consequence without establishing that every normal-TEM PCD genotype shares this mechanism.
  genes:
  - preferred_term: GAS2L2
    term:
      id: hgnc:24846
      label: GAS2L2
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  locations:
  - preferred_term: nasal cavity epithelium
    term:
      id: UBERON:0005384
      label: nasal cavity epithelium
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: cilium movement
    modifier: ABNORMAL
    term:
      id: GO:0003341
      label: cilium movement
  evidence:
  - reference: PMID:30665704
    reference_title: Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Cultured GAS2L2-deficient nasal epithelial cells from one of the affected individuals showed defects in ciliary orientation and had an asynchronous and hyperkinetic (GAS2L2-deficient = 19.8 Hz versus control = 15.8 Hz) ciliary-beat pattern.
    explanation: Patient-derived nasal cells demonstrate an orientation defect with asynchronous hyperkinetic beating; this does not establish the cause of transport failure in C1d-associated disease.
  downstream:
  - target: Impaired Mucociliary Clearance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Loss of common ciliary orientation can reduce effective directional transport; the GAS2L2 deletion model supports a clearance consequence but does not isolate orientation as the only mediator.
    evidence:
    - reference: PMID:30665704
      reference_title: Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: In mice, the absence of Gas2l2 caused neonatal death, and the conditional deletion of Gas2l2 impaired mucociliary clearance (MCC) and led to mucus accumulation.
      explanation: Conditional mouse deletion supports impaired airway clearance downstream of GAS2L2 loss; it does not measure human whole-lung transport or isolate orientation from other effects of the deletion.
    hypothesis_groups:
    - canonical_motile_cilia_beat_failure
- name: Central-Apparatus Transport Dysfunction
  mechanism_confidence: PROVISIONAL
  description: >-
    Loss of C1d projection components can impair collective ciliary transport despite apparently
    normal beat frequency, waveform, routine TEM and nasal nitric oxide. The nine-person characterization
    included CFAP46, CFAP54, CFAP74 and CFAP221 variants, with transport experiments on available
    patient cultures. The physiological transport endpoint therefore complements routine single-cilium
    observations. Clinical gene-validity grades differ and should not be inferred from inclusion
    in one functional study.
  evidence:
  - reference: PMID:39362668
    reference_title: Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance.
    explanation: >-
      C1d-defective patient cells show transport failure despite normal routine TEM, nasal NO and
      high-speed beat assessment. The selected situs-solitus cohort does not independently estimate
      population laterality risk.
  genes:
  - preferred_term: CFAP46
    term:
      id: hgnc:25247
      label: CFAP46
  - preferred_term: CFAP54
    term:
      id: hgnc:26456
      label: CFAP54
  - preferred_term: CFAP74
    term:
      id: hgnc:29368
      label: CFAP74
  - preferred_term: CFAP221
    term:
      id: hgnc:33720
      label: CFAP221
  biological_processes:
  - preferred_term: mucociliary clearance
    modifier: DECREASED
    term:
      id: GO:0120197
      label: mucociliary clearance
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  downstream:
  - target: Impaired Mucociliary Clearance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      This ciliary defect impairs effective respiratory surface transport.
    evidence:
    - reference: PMID:39362668
      reference_title: Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance.
      explanation: >-
        C1d-defective patient cells show transport failure despite normal routine TEM, nasal NO and
        high-speed beat assessment. The selected situs-solitus cohort does not independently estimate
        population laterality risk.
    hypothesis_groups:
    - canonical_motile_cilia_beat_failure
  locations:
  - preferred_term: respiratory tract epithelium
    term:
      id: UBERON:0004802
      label: respiratory tract epithelium
  biological_scale: CELLULAR
- name: CCDC39-CCDC40 Axonemal Scaffold Loss
  mechanism_confidence: PROVISIONAL
  description: >-
    The CCDC39/CCDC40 heterodimer organizes inner dynein arms, nexin-dynein regulatory and other
    axonemal structures. Its absence removes a network of over 90 structural proteins, including
    ciliary address-recognition proteins. This disrupts motility and triggers cellular effects beyond
    beating; these experiments support a candidate explanation for excess clinical severity without
    establishing longitudinal clinical mediation.
  evidence:
  - reference: PMID:39879322
    reference_title: Undocking of an extensive ciliary network induces proteostasis and cell fate switching resulting in severe primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the absence of the axonemal CCDC39/CCDC40 heterodimer resulted in the loss of a network of more than 90 ciliary structural proteins
    explanation: >-
      Patient-cilia proteomics and cross-species structural work establish a broad scaffold-dependent
      protein network. The preprint PMID:38562900 is the same study, not an independent replication.
  genes:
  - preferred_term: CCDC39
    term:
      id: hgnc:25244
      label: CCDC39
  - preferred_term: CCDC40
    term:
      id: hgnc:26090
      label: CCDC40
  biological_processes:
  - preferred_term: axoneme assembly
    modifier: ABNORMAL
    term:
      id: GO:0035082
      label: axoneme assembly
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  downstream:
  - target: Ciliary Dysfunction
    causal_link_type: DIRECT
    description: >-
      Loss of the scaffold-dependent axonemal network disrupts motor/regulatory organization.
    evidence:
    - reference: PMID:39879322
      reference_title: Undocking of an extensive ciliary network induces proteostasis and cell fate switching resulting in severe primary ciliary dyskinesia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: the absence of the axonemal CCDC39/CCDC40 heterodimer resulted in the loss of a network of more than 90 ciliary structural proteins
      explanation: >-
        Patient-cilia proteomics and cross-species structural work establish a broad scaffold-dependent
        protein network. The preprint PMID:38562900 is the same study, not an independent replication.
    hypothesis_groups:
    - canonical_motile_cilia_beat_failure
    - genotype_ultrastructure_severity
  - target: Proteostasis Stress and Secretory Cell-Fate Switching
    causal_link_type: DIRECT
    description: >-
      Scaffold loss triggers motility-independent cellular quality-control and fate effects in patient
      cultures.
    evidence:
    - reference: PMID:39879322
      reference_title: Undocking of an extensive ciliary network induces proteostasis and cell fate switching resulting in severe primary ciliary dyskinesia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The absence of the network impaired microtubule architecture, activated cell quality control pathways, switched multiciliated cell fate to mucus-producing cells and resulted in a defective periciliary barrier.
      explanation: >-
        Patient-cell experiments identify proteostasis, cell-fate and barrier abnormalities downstream
        of scaffold loss.
    hypothesis_groups:
    - genotype_ultrastructure_severity
  - target: Nodal Ciliary Motility Defect
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      CCDC39/CCDC40-associated defects can disrupt nodal function as well as airway cilia; not all
      IDA/central-apparatus classes share this effect.
    evidence:
    - reference: PMID:21131974
      reference_title: The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Consistent with a conserved functional role of CCDC40 for nodal cilia function, five patients displayed situs solitus (32%) and 11 patients situs inversus (68%).
      explanation: >-
        Human CCDC40 cases include both normal and reversed situs; nodal protein localization is not
        established by the clinical phenotype.
    - reference: PMID:21131974
      reference_title: The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Both laterality and curly-tail down phenotypes could be rescued by co-injection of ccdc40 mRNA (Fig. 2h,j).
      explanation: >-
        Zebrafish ccdc40 knockdown and mRNA rescue directly test developmental laterality function.
    hypothesis_groups:
    - embryonic_nodal_cilia_laterality
  locations:
  - preferred_term: respiratory tract epithelium
    term:
      id: UBERON:0004802
      label: respiratory tract epithelium
  biological_scale: MOLECULAR
- name: Proteostasis Stress and Secretory Cell-Fate Switching
  mechanism_confidence: PROVISIONAL
  description: >-
    In CCDC39/CCDC40-deficient airway cells, destabilization of the axonemal network activates quality-control
    pathways and shifts multiciliated cells toward mucus-producing cells. Normal CCDC39 transgene
    expression reversed the measured phenotypes in CCDC39-variant cells. This is a demonstrated cellular
    phenotype, while its quantitative contribution to patient lung-function decline remains unresolved.
  evidence:
  - reference: PMID:39879322
    reference_title: Undocking of an extensive ciliary network induces proteostasis and cell fate switching resulting in severe primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The absence of the network impaired microtubule architecture, activated cell quality control pathways, switched multiciliated cell fate to mucus-producing cells and resulted in a defective periciliary barrier.
    explanation: >-
      Patient-cell experiments identify proteostasis, cell-fate and barrier abnormalities downstream
      of scaffold loss.
  - reference: PMID:39879322
    reference_title: Undocking of an extensive ciliary network induces proteostasis and cell fate switching resulting in severe primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In CCDC39 variant cells, these phenotypes were reversed through expression of a normal CCDC39 transgene.
    explanation: >-
      Genetic rescue supports causality for cellular phenotypes, not yet clinical rescue.
  genes:
  - preferred_term: CCDC39
    term:
      id: hgnc:25244
      label: CCDC39
  - preferred_term: CCDC40
    term:
      id: hgnc:26090
      label: CCDC40
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  downstream:
  - target: Periciliary Barrier Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Altered cell fate and ciliary architecture accompany loss of the protective periciliary barrier;
      rescue supports a common scaffold-dependent cellular pathway.
    evidence:
    - reference: PMID:39879322
      reference_title: Undocking of an extensive ciliary network induces proteostasis and cell fate switching resulting in severe primary ciliary dyskinesia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The absence of the network impaired microtubule architecture, activated cell quality control pathways, switched multiciliated cell fate to mucus-producing cells and resulted in a defective periciliary barrier.
      explanation: >-
        Patient-cell experiments identify proteostasis, cell-fate and barrier abnormalities downstream
        of scaffold loss.
    hypothesis_groups:
    - genotype_ultrastructure_severity
  locations:
  - preferred_term: respiratory tract epithelium
    term:
      id: UBERON:0004802
      label: respiratory tract epithelium
  biological_scale: CELLULAR
- name: Periciliary Barrier Dysfunction
  mechanism_confidence: PROVISIONAL
  description: >-
    CCDC39/CCDC40-deficient cell cultures have altered epithelial composition and a defective periciliary
    barrier, providing a potential additional impediment to airway surface transport. This route
    is mechanistically distinct from complete motile-cilium loss after conditional IFT88 deletion
    in mice, and neither model proves that infection-independent bronchiectasis is universal in human
    PCD.
  evidence:
  - reference: PMID:39879322
    reference_title: Undocking of an extensive ciliary network induces proteostasis and cell fate switching resulting in severe primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The absence of the network impaired microtubule architecture, activated cell quality control pathways, switched multiciliated cell fate to mucus-producing cells and resulted in a defective periciliary barrier.
    explanation: >-
      Patient-cell experiments identify proteostasis, cell-fate and barrier abnormalities downstream
      of scaffold loss.
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  downstream:
  - target: Impaired Mucociliary Clearance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Periciliary barrier defects may compound transport impairment in CCDC39/CCDC40 cultures; the
      additional contribution to human whole-lung clearance remains unresolved.
    evidence:
    - reference: PMID:39879322
      reference_title: Undocking of an extensive ciliary network induces proteostasis and cell fate switching resulting in severe primary ciliary dyskinesia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The absence of the network impaired microtubule architecture, activated cell quality control pathways, switched multiciliated cell fate to mucus-producing cells and resulted in a defective periciliary barrier.
      explanation: >-
        Patient-cell experiments identify proteostasis, cell-fate and barrier abnormalities downstream
        of scaffold loss.
    hypothesis_groups:
    - genotype_ultrastructure_severity
  locations:
  - preferred_term: respiratory tract epithelium
    term:
      id: UBERON:0004802
      label: respiratory tract epithelium
  biological_scale: TISSUE
- name: Impaired Mucociliary Clearance
  description: >-
    Ineffective propulsion by airway cilia, insufficient cilia number and impaired epithelial transport
    retain mucus and inhaled material. Radioaerosol clearance was absent in most of 69 measured patients
    spanning 26 genotypes, with a residual-clearance exception in CCDC103-related disease. Voluntary
    cough improved clearance and represents a partly compensating mechanism; regional deposition
    and cough complicate interpretation of whole-lung tracer measurements.
  evidence:
  - reference: PMID:38076675
    reference_title: 'Pulmonary radioaerosol mucociliary clearance assessment: searching for genotype-specific differences and potential as an outcome measure in primary ciliary dyskinesia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mucociliary clearance by PRMC was consistently absent in most PCD patients, regardless of genotype.
    explanation: >-
      Retrospective radioaerosol assessment included 69 patients and 26 genotypes. One CCDC103 participant
      retained measurable clearance; the 24-year collection window is not 24-year longitudinal follow-up
      of every participant.
  - reference: PMID:38076675
    reference_title: 'Pulmonary radioaerosol mucociliary clearance assessment: searching for genotype-specific differences and potential as an outcome measure in primary ciliary dyskinesia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Voluntary cough significantly improved clearance, with a median improvement of 11%
    explanation: >-
      Human functional testing supports compensatory cough clearance without establishing a genotype-specific
      mechanism of milder disease.
  - reference: PMID:41561107
    reference_title: Mucociliary and cough clearance in primary ciliary dyskinesia as affected by mutations in RSPH1 or DNAH5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the results suggest cough clearance may differ between these two genotypes
    explanation: >-
      The genotypes are RSPH1 and DNAH5, not ODA and IDA. Small unadjusted comparisons support a
      cough-compensation lead without proving clinical severity mediation.
  biological_processes:
  - preferred_term: mucociliary clearance
    modifier: DECREASED
    term:
      id: GO:0120197
      label: mucociliary clearance
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  downstream:
  - target: Chronic Airway Infection and Neutrophilic Inflammation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Retained secretions and microorganisms permit persistent infection and inflammatory responses.
    evidence:
    - reference: PMID:11376511
      reference_title: Pathophysiology and treatment of airway mucociliary clearance. A moving tale.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Failure to keep the airways sterile by MCC results in a host inflammatory response to the persistent microorganisms which, if it becomes chronic, causes damage to the airway wall and upregulation of mucus production manifest clinically as bronchiectasis, sinusitis and otitis.
      explanation: >-
        Mechanistic review supports the established clearance-infection-injury sequence; the human
        evidence is not a single longitudinal mediation experiment.
    hypothesis_groups:
    - canonical_motile_cilia_beat_failure
  - target: Chronic Cough
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional
      inflammatory/structural intermediates affect expression.
    evidence:
    - reference: PMID:41005984
      reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: PCD is associated with early-onset chronic wet cough and rhinosinusitis, laterality defects, middle ear disease and reduced fertility.
      explanation: >-
        Joint ERS/ATS guideline supports the characteristic symptom spectrum; this sentence does
        not provide quantitative frequency estimates.
  - target: Recurrent Respiratory Infections
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional
      inflammatory/structural intermediates affect expression.
    evidence:
    - reference: PMID:41005984
      reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Individuals with PCD often have persistent wet cough, chronic rhinosinusitis, recurrent otitis media, and recurrent respiratory infections beginning early in life and continuing throughout adulthood
      explanation: >-
        Guideline supports early and persistent respiratory infections.
  - target: Chronic Otitis Media
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional
      inflammatory/structural intermediates affect expression.
    evidence:
    - reference: ORPHA:244
      reference_title: Primary ciliary dyskinesia
      supports: SUPPORT
      snippet: HP:0000389 | Chronic otitis media | Frequent (79-30%)
      explanation: Orphanet phenotype data classifies chronic otitis media as frequent (79-30%) in primary ciliary dyskinesia.
      evidence_source: OTHER
    - reference: PMID:29135867
      reference_title: Analysis of Otologic Features of Patients With Primary Ciliary Dyskinesia.
      supports: SUPPORT
      snippet: All 15 patients showed ciliary ultrastructural abnormalities on electron microscopy and/or biallelic mutations in genes associated with ciliary function or structure. All 30 eardrums examined showed certain abnormalities. Fourteen patients had otitis media with effusion or its sequelae. The remaining patient had chronic otitis media.
      explanation: The study found that patients with primary ciliary dyskinesia (PCD) frequently exhibited otologic issues, including chronic otitis media.
    - reference: PMID:19796826
      reference_title: 'Management of otitis media with effusion in children with primary ciliary dyskinesia: a literature review.'
      supports: SUPPORT
      snippet: Primary ciliary dyskinesia is an autosomal recessively inherited group of disorders of ciliary ultrastructure. Otolaryngologists are frequently involved in the management of some of the most common symptoms of primary ciliary dyskinesia including chronic rhinitis, sinusitis and otitis media with effusion.
      explanation: This reference supports that chronic otitis media and other otologic issues are common in patients with primary ciliary dyskinesia.
  - target: Nasal Polyposis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional
      inflammatory/structural intermediates affect expression.
    evidence:
    - reference: ORPHA:244
      reference_title: Primary ciliary dyskinesia
      supports: SUPPORT
      snippet: HP:0100582 | Nasal polyposis | Frequent (79-30%)
      explanation: Orphanet phenotype data classifies nasal polyposis as frequent (79-30%) in primary ciliary dyskinesia.
      evidence_source: OTHER
  - target: Chronic Rhinosinusitis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional
      inflammatory/structural intermediates affect expression.
    evidence:
    - reference: ORPHA:244
      reference_title: Primary ciliary dyskinesia
      supports: SUPPORT
      snippet: HP:0011109 | Chronic sinusitis | Frequent (79-30%)
      explanation: Orphanet phenotype data classifies chronic sinusitis as frequent (79-30%) in primary ciliary dyskinesia.
      evidence_source: OTHER
  - target: Productive Cough
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional
      inflammatory/structural intermediates affect expression.
    evidence:
    - reference: PMID:41005984
      reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: PCD is associated with early-onset chronic wet cough and rhinosinusitis, laterality defects, middle ear disease and reduced fertility.
      explanation: >-
        Joint ERS/ATS guideline supports the characteristic symptom spectrum; this sentence does
        not provide quantitative frequency estimates.
  - target: Recurrent Sinopulmonary Infections
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional
      inflammatory/structural intermediates affect expression.
    evidence:
    - reference: ORPHA:244
      reference_title: Primary ciliary dyskinesia
      supports: SUPPORT
      snippet: HP:0005425 | Recurrent sinopulmonary infections | Frequent (79-30%)
      explanation: Orphanet phenotype data classifies recurrent sinopulmonary infections as frequent (79-30%) in primary ciliary dyskinesia.
      evidence_source: OTHER
  - target: Nasal Congestion
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional
      inflammatory/structural intermediates affect expression.
    evidence:
    - reference: ORPHA:244
      reference_title: Primary ciliary dyskinesia
      supports: SUPPORT
      snippet: HP:0001742 | Nasal congestion | Frequent (79-30%)
      explanation: Orphanet phenotype data classifies nasal congestion as frequent (79-30%) in primary ciliary dyskinesia.
      evidence_source: OTHER
  - target: Chronic Rhinitis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional
      inflammatory/structural intermediates affect expression.
    evidence:
    - reference: ORPHA:244
      reference_title: Primary ciliary dyskinesia
      supports: SUPPORT
      snippet: HP:0002257 | Chronic rhinitis | Frequent (79-30%)
      explanation: Orphanet phenotype data classifies chronic rhinitis as frequent (79-30%) in primary ciliary dyskinesia.
      evidence_source: OTHER
  - target: Abnormal Sputum
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional
      inflammatory/structural intermediates affect expression.
    evidence:
    - reference: ORPHA:244
      reference_title: Primary ciliary dyskinesia
      supports: SUPPORT
      snippet: HP:0032016 | Abnormal sputum | Frequent (79-30%)
      explanation: Orphanet phenotype data classifies abnormal sputum as frequent (79-30%) in primary ciliary dyskinesia.
      evidence_source: OTHER
  - target: Recurrent Otitis Media
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional
      inflammatory/structural intermediates affect expression.
    evidence:
    - reference: ORPHA:244
      reference_title: Primary ciliary dyskinesia
      supports: SUPPORT
      snippet: HP:0000403 | Recurrent otitis media | Frequent (79-30%)
      explanation: Orphanet phenotype data classifies recurrent otitis media as frequent (79-30%) in primary ciliary dyskinesia.
      evidence_source: OTHER
  - target: Wheezing
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional
      inflammatory/structural intermediates affect expression.
    evidence:
    - reference: ORPHA:244
      reference_title: Primary ciliary dyskinesia
      supports: SUPPORT
      snippet: HP:0030828 | Wheezing | Occasional (29-5%)
      explanation: Orphanet phenotype data classifies wheezing as occasional (29-5%) in primary ciliary dyskinesia.
      evidence_source: OTHER
  - target: Atelectasis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional
      inflammatory/structural intermediates affect expression.
    evidence:
    - reference: ORPHA:244
      reference_title: Primary ciliary dyskinesia
      supports: SUPPORT
      snippet: HP:0100750 | Atelectasis | Occasional (29-5%)
      explanation: Orphanet phenotype data classifies atelectasis as occasional (29-5%) in primary ciliary dyskinesia.
      evidence_source: OTHER
  - target: Conductive Hearing Impairment
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional
      inflammatory/structural intermediates affect expression.
    evidence:
    - reference: ORPHA:244
      reference_title: Primary ciliary dyskinesia
      supports: SUPPORT
      snippet: HP:0000405 | Conductive hearing impairment | Occasional (29-5%)
      explanation: Orphanet phenotype data classifies conductive hearing impairment as occasional (29-5%) in primary ciliary dyskinesia.
      evidence_source: OTHER
  - target: Hearing Loss
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired respiratory or middle-ear clearance contributes to this manifestation; age and additional
      inflammatory/structural intermediates affect expression.
    evidence:
    - reference: PMID:41005984
      reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Individuals with PCD frequently suffer from chronic middle ear disease and can have conductive and sensorineural hearing loss
      explanation: >-
        PCD-specific guideline supports hearing impairment; severity, age and mechanism vary.
  - target: Neonatal Respiratory Distress
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired perinatal airway fluid/secretory transport is a plausible contributor to neonatal
      distress, alongside early obstruction and atelectasis. The human phenotype and model-organism
      fluid-clearance experiments do not fully establish this intermediary mechanism in infants.
    evidence:
    - reference: ORPHA:244
      reference_title: Primary ciliary dyskinesia
      supports: SUPPORT
      snippet: HP:0002643 | Neonatal respiratory distress | Frequent (79-30%)
      explanation: Orphanet phenotype data classifies neonatal respiratory distress as frequent (79-30%) in primary ciliary dyskinesia.
      evidence_source: OTHER
    - reference: PMID:19720631
      reference_title: High prevalence of primary ciliary dyskinesia in a British Asian population.
      supports: SUPPORT
      snippet: 73% had a history of neonatal respiratory distress.
      explanation: In a consanguineous British Asian PCD cohort, 73% of patients had neonatal respiratory distress.
    - reference: PMID:40344341
      reference_title: The Association of Neonatal Respiratory Distress With Ciliary Ultrastructure and Genotype in Primary Ciliary Dyskinesia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Of the 455 participants analyzed, 305 (67.0%) reported NRD.
      explanation: >-
        Term-born participants with known neonatal history in a multicenter PCD study; prematurity
        and complex congenital heart disease were excluded.
  - target: Sinusitis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired epithelial clearance predisposes to recurrent infection and mucosal inflammation.
    evidence:
    - reference: PMID:11376511
      reference_title: Pathophysiology and treatment of airway mucociliary clearance. A moving tale.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Failure to keep the airways sterile by MCC results in a host inflammatory response to the persistent microorganisms which, if it becomes chronic, causes damage to the airway wall and upregulation of mucus production manifest clinically as bronchiectasis, sinusitis and otitis.
      explanation: >-
        Mechanistic review supports the established clearance-infection-injury sequence; the human
        evidence is not a single longitudinal mediation experiment.
  - target: Otitis Media
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired epithelial clearance predisposes to recurrent infection and mucosal inflammation.
    evidence:
    - reference: PMID:11376511
      reference_title: Pathophysiology and treatment of airway mucociliary clearance. A moving tale.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Failure to keep the airways sterile by MCC results in a host inflammatory response to the persistent microorganisms which, if it becomes chronic, causes damage to the airway wall and upregulation of mucus production manifest clinically as bronchiectasis, sinusitis and otitis.
      explanation: >-
        Mechanistic review supports the established clearance-infection-injury sequence; the human
        evidence is not a single longitudinal mediation experiment.
  locations:
  - preferred_term: respiratory system
    term:
      id: UBERON:0001004
      label: respiratory system
  - preferred_term: paranasal sinus
    term:
      id: UBERON:0001825
      label: paranasal sinus
  biological_scale: TISSUE
- name: Chronic Airway Infection and Neutrophilic Inflammation
  description: >-
    Retained secretions favor persistent airway infection, neutrophil recruitment and protease/oxidative
    injury. Haemophilus influenzae is prominent in pediatric cohorts; Pseudomonas aeruginosa isolation
    associates with worse structural and functional disease, but observational associations do not
    determine whether it independently drives progression. Antibiotic-responsive sputum elastase
    and ex vivo macrophage responses demonstrate inflammatory complexity without replacing the neutrophil-dominant
    clinical phenotype.
  evidence:
  - reference: PMID:15806596
    reference_title: Correlation between cough frequency and airway inflammation in children with primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Stable PCD children have increased cough frequency and neutrophilic airway inflammation.
    explanation: >-
      Stable pediatric PCD sputum shows neutrophilic inflammation; association with cough does not
      independently establish every remodeling step.
  - reference: PMID:11376511
    reference_title: Pathophysiology and treatment of airway mucociliary clearance. A moving tale.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Failure to keep the airways sterile by MCC results in a host inflammatory response to the persistent microorganisms which, if it becomes chronic, causes damage to the airway wall and upregulation of mucus production manifest clinically as bronchiectasis, sinusitis and otitis.
    explanation: >-
      Mechanistic review supports the established clearance-infection-injury sequence; the human
      evidence is not a single longitudinal mediation experiment.
  - reference: PMID:41582098
    reference_title: Sputum from Individuals with Primary Ciliary Dyskinesia Drives M2-like Macrophage Polarization.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: PCD sputum induced a phagocytosis prone, M2-like phenotype in healthy macrophages.
    explanation: >-
      Sputum from 27 PCD subjects versus seven controls was applied to healthy monocyte-derived macrophages.
      This in vitro conditioning response is not an established in vivo PCD macrophage endotype.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  downstream:
  - target: Bronchiectasis and Airway Wall Remodeling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Persistent infection and inflammatory injury damage airway walls and alter mucus production.
    evidence:
    - reference: PMID:11376511
      reference_title: Pathophysiology and treatment of airway mucociliary clearance. A moving tale.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Failure to keep the airways sterile by MCC results in a host inflammatory response to the persistent microorganisms which, if it becomes chronic, causes damage to the airway wall and upregulation of mucus production manifest clinically as bronchiectasis, sinusitis and otitis.
      explanation: >-
        Mechanistic review supports the established clearance-infection-injury sequence; the human
        evidence is not a single longitudinal mediation experiment.
    hypothesis_groups:
    - canonical_motile_cilia_beat_failure
  locations:
  - preferred_term: bronchus
    term:
      id: UBERON:0002185
      label: bronchus
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: ABNORMAL
  - preferred_term: response to bacterium
    term:
      id: GO:0009617
      label: response to bacterium
    modifier: ABNORMAL
  biological_scale: TISSUE
- name: Bronchiectasis and Airway Wall Remodeling
  description: >-
    Persistent infection, inflammatory injury and altered mucus handling damage airway walls and
    produce bronchial dilation. Structural disease varies by age, genotype and treatment history;
    bronchiectasis is not present in every newly diagnosed infant. The IFT88-deletion mouse remodeling
    experiment is an adjacent cilia-homeostasis model, not direct proof of an inflammation-independent
    route in all human PCD.
  evidence:
  - reference: PMID:11376511
    reference_title: Pathophysiology and treatment of airway mucociliary clearance. A moving tale.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Failure to keep the airways sterile by MCC results in a host inflammatory response to the persistent microorganisms which, if it becomes chronic, causes damage to the airway wall and upregulation of mucus production manifest clinically as bronchiectasis, sinusitis and otitis.
    explanation: >-
      Mechanistic review supports the established clearance-infection-injury sequence; the human
      evidence is not a single longitudinal mediation experiment.
  downstream:
  - target: Progressive Obstructive Lung Function Decline
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Chronic airway structural injury contributes to heterogeneous airflow limitation.
    evidence:
    - reference: PMID:30067075
      reference_title: 'Primary Ciliary Dyskinesia: Longitudinal Study of Lung Disease by Ultrastructure Defect and Genotype.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: For the entire cohort, percent predicted FEV1 decline was heterogeneous with a mean (SE) decline of 0.57 (0.25) percent predicted/yr.
      explanation: >-
        Five-year multicenter observational study supports heterogeneous decline. A slope differing
        from zero only in one subgroup does not establish that all other genotypes cannot decline.
    hypothesis_groups:
    - canonical_motile_cilia_beat_failure
    - genotype_ultrastructure_severity
  - target: Bronchiectasis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A recognized organ-specific consequence, with occurrence restricted by genotype, disease extent
      and clinical context.
    evidence:
    - reference: PMID:11376511
      reference_title: Pathophysiology and treatment of airway mucociliary clearance. A moving tale.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Failure to keep the airways sterile by MCC results in a host inflammatory response to the persistent microorganisms which, if it becomes chronic, causes damage to the airway wall and upregulation of mucus production manifest clinically as bronchiectasis, sinusitis and otitis.
      explanation: >-
        Mechanistic review supports the established clearance-infection-injury sequence; the human
        evidence is not a single longitudinal mediation experiment.
  - target: Airway Obstruction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A recognized organ-specific consequence, with occurrence restricted by genotype, disease extent
      and clinical context.
    evidence:
    - reference: PMID:11376511
      reference_title: Pathophysiology and treatment of airway mucociliary clearance. A moving tale.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Failure to keep the airways sterile by MCC results in a host inflammatory response to the persistent microorganisms which, if it becomes chronic, causes damage to the airway wall and upregulation of mucus production manifest clinically as bronchiectasis, sinusitis and otitis.
      explanation: >-
        Mechanistic review supports the established clearance-infection-injury sequence; the human
        evidence is not a single longitudinal mediation experiment.
  - target: Digital Clubbing
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Clubbing can accompany established chronic suppurative lung disease.
    evidence:
    - reference: ORPHA:244
      reference_title: Primary ciliary dyskinesia
      supports: SUPPORT
      snippet: HP:0001217 | Clubbing | Occasional (29-5%)
      explanation: Orphanet phenotype data classifies digital clubbing as occasional (29-5%) in primary ciliary dyskinesia.
      evidence_source: OTHER
  locations:
  - preferred_term: bronchus
    term:
      id: UBERON:0002185
      label: bronchus
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: tissue remodeling
    term:
      id: GO:0048771
      label: tissue remodeling
    modifier: ABNORMAL
  cell_types:
  - preferred_term: bronchial epithelial cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  biological_scale: TISSUE
- name: Progressive Obstructive Lung Function Decline
  description: >-
    Chronic airway obstruction and structural injury can reduce FEV1 over time. In the five-year
    pediatric cohort, decline varied substantially and the IDA/MTD/CA subgroup had the clearest negative
    slope. Normal or improved trajectories occur; FEV1 is an airflow measure and is not interchangeable
    with gas exchange, nasal NO, or a deterministic genotype severity tier.
  evidence:
  - reference: PMID:30067075
    reference_title: 'Primary Ciliary Dyskinesia: Longitudinal Study of Lung Disease by Ultrastructure Defect and Genotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: For the entire cohort, percent predicted FEV1 decline was heterogeneous with a mean (SE) decline of 0.57 (0.25) percent predicted/yr.
    explanation: >-
      Five-year multicenter observational study supports heterogeneous decline. A slope differing
      from zero only in one subgroup does not establish that all other genotypes cannot decline.
  downstream:
  - target: Respiratory Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A recognized organ-specific consequence, with occurrence restricted by genotype, disease extent
      and clinical context.
    evidence:
    - reference: PMID:41005984
      reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: most people develop bronchiectasis and progressive lung disease that can lead to respiratory failure
      explanation: >-
        Guideline summarizes advanced pulmonary consequences, not an inevitable outcome.
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_scale: TISSUE
- name: Nodal Ciliary Motility Defect
  description: >-
    PCD variants affecting machinery required by embryonic motile monocilia impair symmetry-breaking
    flow. Outer dynein-arm genes and CCDC39/CCDC40-related axonemal organization can be involved;
    an ODA-only rule is false. Central-apparatus/radial-spoke and CCNO/MCIDAS multiciliogenesis defects
    generally spare this arm because nodal 9+0 monocilia lack those respective requirements.
  evidence:
  - reference: PMID:27486780
    reference_title: TTC25 Deficiency Results in Defects of the Outer Dynein Arm Docking Machinery and Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: we observed immotile nodal cilia and missing leftward flow via particle image velocimetry.
    explanation: >-
      Ttc25 mutant mice directly connect a PCD-associated dynein-docking defect to nodal immotility
      and absent directional flow.
  - reference: PMID:21131974
    reference_title: The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Consistent with a conserved functional role of CCDC40 for nodal cilia function, five patients displayed situs solitus (32%) and 11 patients situs inversus (68%).
    explanation: >-
      Human CCDC40 cases include both normal and reversed situs; nodal protein localization is not
      established by the clinical phenotype.
  - reference: PMID:21131974
    reference_title: The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Both laterality and curly-tail down phenotypes could be rescued by co-injection of ccdc40 mRNA (Fig. 2h,j).
    explanation: >-
      Zebrafish ccdc40 knockdown and mRNA rescue directly test developmental laterality function.
  genes:
  - preferred_term: DNAH5
    term:
      id: hgnc:2950
      label: DNAH5
  - preferred_term: DNAH11
    term:
      id: hgnc:2942
      label: DNAH11
  - preferred_term: DNAH9
    term:
      id: hgnc:2953
      label: DNAH9
  - preferred_term: DNAI1
    term:
      id: hgnc:2954
      label: DNAI1
  - preferred_term: CCDC39
    term:
      id: hgnc:25244
      label: CCDC39
  - preferred_term: CCDC40
    term:
      id: hgnc:26090
      label: CCDC40
  biological_processes:
  - preferred_term: epithelial cilium movement involved in determination of left/right asymmetry
    modifier: ABNORMAL
    term:
      id: GO:0060287
      label: epithelial cilium movement involved in determination of left/right asymmetry
  downstream:
  - target: Disrupted Directional Nodal Flow
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Disruption propagates through the experimentally supported vertebrate left-right patterning
      pathway; the direct perturbation evidence is from model embryos.
    evidence:
    - reference: PMID:27486780
      reference_title: TTC25 Deficiency Results in Defects of the Outer Dynein Arm Docking Machinery and Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: we observed immotile nodal cilia and missing leftward flow via particle image velocimetry.
      explanation: >-
        Ttc25 mutant mice directly connect a PCD-associated dynein-docking defect to nodal immotility
        and absent directional flow.
    hypothesis_groups:
    - embryonic_nodal_cilia_laterality
  locations:
  - preferred_term: embryo
    term:
      id: UBERON:0000922
      label: embryo
  biological_scale: CELLULAR
- name: Disrupted Directional Nodal Flow
  description: >-
    Normally, rotation of posteriorly tilted nodal motile cilia generates directional extracellular
    flow. Loss or disorganization of this flow disrupts the instructive left-right signal. Artificial
    flow can direct situs in immotile-cilia mouse mutants; human embryonic flow is inferred from
    conserved biology and genotype-phenotype evidence.
  evidence:
  - reference: PMID:27486780
    reference_title: TTC25 Deficiency Results in Defects of the Outer Dynein Arm Docking Machinery and Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: we observed immotile nodal cilia and missing leftward flow via particle image velocimetry.
    explanation: >-
      Ttc25 mutant mice directly connect a PCD-associated dynein-docking defect to nodal immotility
      and absent directional flow.
  - reference: PMID:12097914
    reference_title: Determination of left-right patterning of the mouse embryo by artificial nodal flow.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The artificial flow was also able to direct the situs of mutant mouse embryos with immotile cilia.
    explanation: >-
      External flow manipulation establishes causal sufficiency downstream of ciliary motion in mouse
      embryos. It does not exclude intracellular chirality upstream of flow.
  biological_processes:
  - preferred_term: determination of left/right symmetry
    modifier: ABNORMAL
    term:
      id: GO:0007368
      label: determination of left/right symmetry
  downstream:
  - target: Loss of Asymmetric Flow-Sensing and Nodal Signaling
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Disruption propagates through the experimentally supported vertebrate left-right patterning
      pathway; the direct perturbation evidence is from model embryos.
    evidence:
    - reference: PMID:36603091
      reference_title: Immotile cilia mechanically sense the direction of fluid flow for left-right determination.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Application of mechanical stimuli to immotile cilia by optical tweezers induced calcium ion transients and degradation of Dand5 messenger RNA (mRNA) in the targeted cells.
      explanation: >-
        The 2023 mouse study directly tests mechanical sensing and downstream Dand5 responses, predating
        but omitted from the OpenScientist report.
    hypothesis_groups:
    - embryonic_nodal_cilia_laterality
  locations:
  - preferred_term: embryo
    term:
      id: UBERON:0000922
      label: embryo
  biological_scale: TISSUE
- name: Loss of Asymmetric Flow-Sensing and Nodal Signaling
  description: >-
    Directional flow mechanically bends immotile crown-cell cilia. Polarized PKD2-dependent calcium
    responses promote left-sided DAND5 mRNA decay, relieving NODAL antagonism and enabling the asymmetric
    developmental program. BICC1 and the CCR4-NOT complex participate in Dand5 RNA decay in mice.
    When instructive flow is absent, this asymmetry is lost or randomized. PKD2/PKD1L1 are sensing
    machinery, not asserted here as general causes of respiratory PCD.
  evidence:
  - reference: PMID:36603091
    reference_title: Immotile cilia mechanically sense the direction of fluid flow for left-right determination.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Application of mechanical stimuli to immotile cilia by optical tweezers induced calcium ion transients and degradation of Dand5 messenger RNA (mRNA) in the targeted cells.
    explanation: >-
      The 2023 mouse study directly tests mechanical sensing and downstream Dand5 responses, predating
      but omitted from the OpenScientist report.
  - reference: PMID:34210974
    reference_title: Fluid flow-induced left-right asymmetric decay of Dand5 mRNA in the mouse embryo requires a Bicc1-Ccr4 RNA degradation complex.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The Cnot3 component of the Ccr4-Not deadenylase complex interacts with Bicc1 and is also required for Dand5 mRNA decay at the node.
    explanation: >-
      Genetic and RNA-regulatory experiments specify the flow-to-asymmetric-RNA step in the mouse
      organizer.
  genes:
  - preferred_term: PKD2
    term:
      id: hgnc:9009
      label: PKD2
  - preferred_term: PKD1L1
    term:
      id: hgnc:18053
      label: PKD1L1
  - preferred_term: DAND5
    term:
      id: hgnc:26780
      label: DAND5
  - preferred_term: NODAL
    term:
      id: hgnc:7865
      label: NODAL
  - preferred_term: BICC1
    term:
      id: hgnc:19351
      label: BICC1
  - preferred_term: CNOT3
    term:
      id: hgnc:7879
      label: CNOT3
  - preferred_term: PITX2
    term:
      id: hgnc:9005
      label: PITX2
  biological_processes:
  - preferred_term: determination of left/right symmetry
    modifier: ABNORMAL
    term:
      id: GO:0007368
      label: determination of left/right symmetry
  downstream:
  - target: Randomized Organ Laterality
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Disruption propagates through the experimentally supported vertebrate left-right patterning
      pathway; the direct perturbation evidence is from model embryos.
    evidence:
    - reference: PMID:12097914
      reference_title: Determination of left-right patterning of the mouse embryo by artificial nodal flow.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: The artificial flow was also able to direct the situs of mutant mouse embryos with immotile cilia.
      explanation: >-
        External flow manipulation establishes causal sufficiency downstream of ciliary motion in
        mouse embryos. It does not exclude intracellular chirality upstream of flow.
    hypothesis_groups:
    - embryonic_nodal_cilia_laterality
  locations:
  - preferred_term: embryo
    term:
      id: UBERON:0000922
      label: embryo
  biological_scale: CELLULAR
- name: Randomized Organ Laterality
  description: >-
    Disrupted asymmetric developmental signaling permits normal situs, complete mirror-image situs
    or discordant situs across organs. Human cohort distributions are not a strict binary 50:50 coin
    flip, and genotype composition and diagnostic ascertainment affect estimates. Situs inversus
    totalis itself should not be encoded as the cause of heterotaxy-associated heart defects or intestinal
    malrotation. The precise flow/signaling basis for discordant organ outcomes remains unresolved.
  evidence:
  - reference: PMID:36342963
    reference_title: 'Laterality Defects in Primary Ciliary Dyskinesia: Relationship to Ultrastructural Defect or Genotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Of 559 participants, 286 (51.2%), 215 (38.5%), and 58 (10.4%) were identified as having situs solitus, situs inversustotalis, and situs ambiguus, respectively
    explanation: >-
      Human laterality distributions distinguish total inversion from situs ambiguus. Heterotaxy
      definitions vary; this study restricted heterotaxy to ambiguus with complex cardiovascular
      defects (14/559).
  - reference: PMID:12097914
    reference_title: Determination of left-right patterning of the mouse embryo by artificial nodal flow.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The artificial flow was also able to direct the situs of mutant mouse embryos with immotile cilia.
    explanation: >-
      External flow manipulation establishes causal sufficiency downstream of ciliary motion in mouse
      embryos. It does not exclude intracellular chirality upstream of flow.
  downstream:
  - target: Situs Inversus Totalis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A recognized organ-specific consequence, with occurrence restricted by genotype, disease extent
      and clinical context.
    evidence:
    - reference: PMID:36342963
      reference_title: 'Laterality Defects in Primary Ciliary Dyskinesia: Relationship to Ultrastructural Defect or Genotype.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Of 559 participants, 286 (51.2%), 215 (38.5%), and 58 (10.4%) were identified as having situs solitus, situs inversustotalis, and situs ambiguus, respectively
      explanation: >-
        Human laterality distributions distinguish total inversion from situs ambiguus. Heterotaxy
        definitions vary; this study restricted heterotaxy to ambiguus with complex cardiovascular
        defects (14/559).
  - target: Abnormal Heart Morphology
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Discordant laterality can include congenital cardiac or vascular malformations; these are not
      an obligatory consequence of complete mirror-image situs.
    evidence:
    - reference: PMID:17515466
      reference_title: Congenital heart disease and other heterotaxic defects in a large cohort of patients with primary ciliary dyskinesia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Twelve patients with heterotaxy had cardiac and/or vascular abnormalities, and most (8 of 12 patients) had complex congenital heart disease.
      explanation: >-
        The older 337-person PCD cohort directly documents cardiac/vascular malformations within its
        heterotaxy subset; this is not a population-wide cardiac frequency.
  - target: Intestinal Malrotation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Intestinal malrotation is a recognized PCD-associated organ-position defect. Its placement in
      the developmental laterality branch is a clinical mechanistic interpretation, not evidence
      that situs inversus totalis causes malrotation.
    evidence:
    - reference: ORPHA:244
      reference_title: Primary ciliary dyskinesia
      supports: SUPPORT
      snippet: HP:0002566 | Intestinal malrotation | Very rare (<4-1%)
      explanation: >-
        Orphanet specifically records intestinal malrotation in PCD. This supports the recognized
        phenotype; the developmental placement is an interpretation rather than a measured causal
        effect or genotype-specific frequency.
      evidence_source: OTHER
  - target: Heterotaxy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Discordant laterality can produce situs ambiguus with or without complex cardiovascular involvement.
    evidence:
    - reference: PMID:36342963
      reference_title: "Laterality Defects in Primary Ciliary Dyskinesia: Relationship to Ultrastructural Defect or Genotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Of 559 participants, 286 (51.2%), 215 (38.5%), and 58 (10.4%) were identified as having situs solitus, situs inversustotalis, and situs ambiguus, respectively; heterotaxy, defined as situs ambiguus with complex cardiovascular defects, was present in 14 (2.5%).
      explanation: >-
        Situs ambiguus occurred in 58 of 559 participants and heterotaxy with complex cardiovascular
        defects in 14, so situs ambiguus arises both with and without complex cardiovascular involvement.
        The 2.5% heterotaxy figure uses a restrictive definition and is not interchangeable with all
        situs ambiguus.
    hypothesis_groups:
    - embryonic_nodal_cilia_laterality
  locations:
  - preferred_term: embryo
    term:
      id: UBERON:0000922
      label: embryo
  biological_scale: ORGANISM
- name: Sperm Flagellar and Reproductive Tract Dysfunction
  description: >-
    Variants affecting sperm flagella can reduce sperm motility and contribute to male infertility.
    Some motile-cilia genes also affect cilia of the male reproductive tract. Tissue-specific axonemal
    composition means respiratory disease does not imply uniformly immotile sperm or infertility
    in every male.
  evidence:
  - reference: PMID:38962571
    reference_title: Infertility and pregnancy outcomes among adults with primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Among 168 adults who had tried to conceive, 39 of 50 men (78%) and 72 of 118 women (61%) were infertile.
    explanation: >-
      The international self-report study supports sex-specific fertility impairment, with denominators
      restricted to participants who had tried to conceive; it does not establish obligatory infertility
      or a universal shared molecular lesion.
  - reference: PMID:41005984
    reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Male PCD subjects are often infertile due to dysfunction of the sperm tail and cilia in the efferent duct
    explanation: >-
      The joint guideline summarizes both flagellar and efferent-duct contributions.
  - reference: PMID:34476482
    reference_title: Bi-allelic mutations in DNAH7 cause asthenozoospermia by impairing the integrality of axoneme structure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The spermatozoa from the patients with DNAH7 bi-allelic mutations showed specific losses in the inner dynein arms.
    explanation: >-
      Records an axonemal lesion confined to the sperm flagellum in DNAH7-mutant men, which is why
      DNAH7 is wired to this node rather than to the respiratory beat-failure chain.
  - reference: PMID:31978331
    reference_title: TTC12 Loss-of-Function Mutations Cause Primary Ciliary Dyskinesia and Unveil Distinct Dynein Assembly Mechanisms in Motile Cilia Versus Flagella.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified four loss-of-function mutations in TTC12, which encodes a cytoplasmic protein, in four independent families in which affected individuals displayed a peculiar PCD phenotype characterized by the absence of ODAs and IDAs in sperm flagella, contrasting with the absence of only IDAs in respiratory cilia.
    explanation: >-
      Records a sperm-flagellar dynein-arm loss more complete than the respiratory one in the same
      individuals, so TTC12 acts at this node as well as at the preassembly node.
  genes:
  - preferred_term: DNAH7
    term:
      id: hgnc:18661
      label: DNAH7
  - preferred_term: TTC12
    term:
      id: hgnc:23700
      label: TTC12
  biological_processes:
  - preferred_term: cilium movement
    modifier: ABNORMAL
    term:
      id: GO:0003341
      label: cilium movement
  downstream:
  - target: Male Infertility
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A recognized organ-specific consequence, with occurrence restricted by genotype, disease extent
      and clinical context.
    evidence:
    - reference: PMID:38962571
      reference_title: Infertility and pregnancy outcomes among adults with primary ciliary dyskinesia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Among 168 adults who had tried to conceive, 39 of 50 men (78%) and 72 of 118 women (61%) were infertile.
      explanation: >-
        The international self-report study supports sex-specific fertility impairment, with denominators
        restricted to participants who had tried to conceive; it does not establish obligatory infertility
        or a universal shared molecular lesion.
  - target: Abnormal Sperm Motility
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A recognized organ-specific consequence, with occurrence restricted by genotype, disease extent
      and clinical context.
    evidence:
    - reference: PMID:38962571
      reference_title: Infertility and pregnancy outcomes among adults with primary ciliary dyskinesia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Among 168 adults who had tried to conceive, 39 of 50 men (78%) and 72 of 118 women (61%) were infertile.
      explanation: >-
        The international self-report study supports sex-specific fertility impairment, with denominators
        restricted to participants who had tried to conceive; it does not establish obligatory infertility
        or a universal shared molecular lesion.
  biological_scale: CELLULAR
- name: Oviduct Ciliary Transport Dysfunction
  description: >-
    Abnormal motile cilia in the oviduct can impair gamete or embryo transport and contribute to
    female subfertility and ectopic pregnancy risk. Fertility remains possible and varies by genotype;
    clinical self-report associations do not isolate ciliary transport from every other determinant
    of reproductive outcome.
  evidence:
  - reference: PMID:38962571
    reference_title: Infertility and pregnancy outcomes among adults with primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Among 168 adults who had tried to conceive, 39 of 50 men (78%) and 72 of 118 women (61%) were infertile.
    explanation: >-
      The international self-report study supports sex-specific fertility impairment, with denominators
      restricted to participants who had tried to conceive; it does not establish obligatory infertility
      or a universal shared molecular lesion.
  - reference: PMID:41005984
    reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: female individuals are often subfertile due to the involvement of cilia in the oviducts
    explanation: >-
      The guideline supports the organ-specific ciliary mechanism.
  biological_processes:
  - preferred_term: cilium movement
    modifier: ABNORMAL
    term:
      id: GO:0003341
      label: cilium movement
  downstream:
  - target: Female Infertility
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A recognized organ-specific consequence, with occurrence restricted by genotype, disease extent
      and clinical context.
    evidence:
    - reference: PMID:38962571
      reference_title: Infertility and pregnancy outcomes among adults with primary ciliary dyskinesia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Among 168 adults who had tried to conceive, 39 of 50 men (78%) and 72 of 118 women (61%) were infertile.
      explanation: >-
        The international self-report study supports sex-specific fertility impairment, with denominators
        restricted to participants who had tried to conceive; it does not establish obligatory infertility
        or a universal shared molecular lesion.
  - target: Ectopic Pregnancy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired oviduct transport is a plausible contributor to the observed reproductive risk; patient-specific
      mediation is not established.
    evidence:
    - reference: PMID:41561099
      reference_title: 'Primary ciliary dyskinesia: a national expert consensus statement on standards of care.'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: women might be at higher risk of ectopic pregnancies
      explanation: >-
        Consensus supports the clinical association and its ciliary context.
  biological_scale: CELLULAR
- name: Ependymal Ciliary Dysfunction
  description: >-
    Motile ependymal cilia participate in ventricular fluid handling. Hydrocephalus is uncommon across
    human PCD but enriched in selected ciliogenesis disorders such as FOXJ1-associated disease. Mouse
    PCD models often show much more severe hydrocephalus, and species, tissue and modifier effects
    limit a simple ciliary-beat-to-CSF-obstruction inference.
  evidence:
  - reference: PMID:34132502
    reference_title: Autosomal dominant variants in FOXJ1 causing primary ciliary dyskinesia in two patients with obstructive hydrocephalus.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: FOXJ1 pathogenic variants cause PCD in a de novo, autosomal dominant inheritance pattern, and are associated with hydrocephalus.
    explanation: >-
      Human FOXJ1 cases support a restricted association with hydrocephalus; severe hydrocephalus
      in mouse PCD models should not set a pan-PCD human frequency.
  genes:
  - preferred_term: FOXJ1
    term:
      id: hgnc:3816
      label: FOXJ1
  biological_processes:
  - preferred_term: cilium movement
    modifier: ABNORMAL
    term:
      id: GO:0003341
      label: cilium movement
  cell_types:
  - preferred_term: ependymal cell
    term:
      id: CL:0000065
      label: ependymal cell
  downstream:
  - target: Hydrocephalus
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A recognized organ-specific consequence, with occurrence restricted by genotype, disease extent
      and clinical context.
    evidence:
    - reference: PMID:34132502
      reference_title: Autosomal dominant variants in FOXJ1 causing primary ciliary dyskinesia in two patients with obstructive hydrocephalus.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: FOXJ1 pathogenic variants cause PCD in a de novo, autosomal dominant inheritance pattern, and are associated with hydrocephalus.
      explanation: >-
        Human FOXJ1 cases support a restricted association with hydrocephalus; severe hydrocephalus
        in mouse PCD models should not set a pan-PCD human frequency.
  biological_scale: CELLULAR
- name: Ciliary Oxidative Stress and Glutathione Response
  mechanism_confidence: PROVISIONAL
  description: >-
    DNAH5-deficient patient airway cultures and patient-derived iPSC airway cells show increased
    ROS and NRF2-regulated glutathione-transferase expression. GSTA2 localizes to motile cilia, and
    loss-of-function experiments slow ciliary motility. These data identify a ciliary redox-maintenance
    pathway and genotype-associated cellular response; they do not establish that antioxidant treatment
    improves PCD outcomes or that every PCD genotype shares the response.
  evidence:
  - reference: PMID:39042459
    reference_title: Transcriptional analysis of primary ciliary dyskinesia airway cells reveals a dedicated cilia glutathione pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Primary and iPS-derived PCD multiciliated cells had increased expression of glutathione-S-transferases GSTA2 and GSTA1, as well as NRF2 target genes, accompanied by elevated levels of reactive oxygen species (ROS).
    explanation: >-
      DNAH5 patient cultures and iPSC-derived cells show an intrinsic oxidative-stress response;
      increased GSTA expression is not a GSTA deficiency.
  - reference: PMID:39042459
    reference_title: Transcriptional analysis of primary ciliary dyskinesia airway cells reveals a dedicated cilia glutathione pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Loss of human GSTA2 and C. reinhardtii GSTA resulted in slowed cilia motility
    explanation: >-
      Functional experiments establish a role for GSTA in motility, while increased expression in
      DNAH5 PCD may be compensatory.
  genes:
  - preferred_term: DNAH5
    term:
      id: hgnc:2950
      label: DNAH5
  - preferred_term: GSTA2
    term:
      id: hgnc:4627
      label: GSTA2
  - preferred_term: NFE2L2
    term:
      id: hgnc:7782
      label: NFE2L2
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  locations:
  - preferred_term: respiratory tract epithelium
    term:
      id: UBERON:0004802
      label: respiratory tract epithelium
  biological_scale: CELLULAR
  notes: >-
    This provisional genotype-associated response has no asserted causal downstream edge.
    Increased GSTA2/NRF2 expression in DNAH5-deficient cells is distinct from experimentally
    depleting GSTA2 in otherwise normal primary airway cells. Knockdown slows motility and
    catalase partially rescues transport in the knockdown system; it does not show that increased
    GSTA2 causes motility failure or that catalase repairs DNAH5 PCD. The linked experimental
    model records the patient-state measurements and the separate perturbation. A causal
    connection between the patient redox response and clinical transport impairment remains
    unresolved.
- name: Cytoplasmic Dynein Arm Preassembly Failure
  description: >-
    Axonemal dynein arms are multi-subunit motors assembled in the cytoplasm before import into the
    cilium, so a defect in a cytoplasmic assembly factor leaves the axoneme without outer and inner dynein arms. This is the mechanism shared by the
    DNAAF-class genes and by TTC12 and CFAP298, and it is upstream of, and distinct from, the
    axoneme-resident docking, scaffold and central-apparatus defects modeled separately in this entry.
  evidence:
  - reference: PMID:22154137
    reference_title: 'Ciliary motility: the components and cytoplasmic preassembly mechanisms of the axonemal dyneins.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: The dyneins are composed of multiple subunits, which are thought to be preassembled in the cytoplasm before they are transported into cilia and flagella.
    explanation: >-
      States the cytoplasmic-preassembly step this node models, as the review's synthesis of the field
      rather than as its own result.
  - reference: PMID:22387996
    reference_title: Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Altered abundance of dynein subunits in mutant cytoplasm suggests that DNAAF3 (PF22) acts at a similar stage as other preassembly proteins, for example, DNAAF2 (also known as PF13 or KTU) and DNAAF1 (also known as ODA7 or LRRC50), in the dynein preassembly pathway.
    explanation: >-
      Places DNAAF1, DNAAF2 and DNAAF3 at the same step of the cytoplasmic preassembly pathway, which
      is what groups these genes on one node.
  - reference: PMID:23040496
    reference_title: Whole-exome capture and sequencing identifies HEATR2 mutation as a cause of primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: HEATR2 was localized to the cytoplasm and not in cilia, which suggests a role in either dynein arm transport or assembly
    explanation: >-
      Localizes the DNAAF5 product to the cytoplasm rather than to the cilium, supporting a pre-import
      rather than axonemal site of action.
  genes:
  - preferred_term: DNAAF1
    term:
      id: hgnc:30539
      label: DNAAF1
  - preferred_term: DNAAF2
    term:
      id: hgnc:20188
      label: DNAAF2
  - preferred_term: DNAAF3
    term:
      id: hgnc:30492
      label: DNAAF3
  - preferred_term: DNAAF4
    term:
      id: hgnc:21493
      label: DNAAF4
  - preferred_term: DNAAF5
    term:
      id: hgnc:26013
      label: DNAAF5
  - preferred_term: DNAAF6
    term:
      id: hgnc:28570
      label: DNAAF6
  - preferred_term: DNAAF11
    term:
      id: hgnc:16725
      label: DNAAF11
  - preferred_term: CFAP298
    term:
      id: hgnc:1301
      label: CFAP298
  - preferred_term: TTC12
    term:
      id: hgnc:23700
      label: TTC12
  - preferred_term: CFAP300
    term:
      id: hgnc:28188
      label: CFAP300
  - preferred_term: ZMYND10
    term:
      id: hgnc:19412
      label: ZMYND10
  - preferred_term: SPAG1
    term:
      id: hgnc:11212
      label: SPAG1
  biological_processes:
  - preferred_term: axonemal dynein complex assembly
    modifier: DECREASED
    term:
      id: GO:0070286
      label: axonemal dynein complex assembly
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  locations:
  - preferred_term: respiratory tract epithelium
    term:
      id: UBERON:0004802
      label: respiratory tract epithelium
  biological_scale: MOLECULAR
  downstream:
  - target: Ciliary Dysfunction
    causal_link_type: DIRECT
    description: >-
      Dynein arms that are never assembled in the cytoplasm cannot be imported into the axoneme, so
      the cilium lacks the motors that generate its beat.
    evidence:
    - reference: PMID:22387996
      reference_title: Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: We identified loss-of-function mutations in the human DNAAF3 gene in individuals from families with situs inversus and defects in the assembly of inner and outer dynein arms.
      explanation: >-
        Links loss of a cytoplasmic preassembly factor to absent inner and outer dynein arms in
        affected individuals.
    hypothesis_groups:
    - canonical_motile_cilia_beat_failure
- name: Outer Dynein Arm Docking and Attachment Failure
  description: >-
    Assembled outer dynein arms still have to be docked onto and held on the axoneme. Loss of a
    docking-complex subunit or of an axoneme-resident attachment factor therefore removes outer dynein arms
    at a step after cytoplasmic assembly, which is a different lesion from the preassembly failure modeled
    upstream. DNAAF19 carries
    a DNAAF symbol but its product is axoneme-associated and acts at this step.
  evidence:
  - reference: PMID:27486780
    reference_title: TTC25 Deficiency Results in Defects of the Outer Dynein Arm Docking Machinery and Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: here we report TTC25 as a new member of the ODA-DC machinery in humans and mice.
    explanation: >-
      Places the ODAD4 product in the outer dynein arm docking complex alongside ODAD1.
  - reference: PMID:22581229
    reference_title: CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: These results identify Ccdc103 as a dynein arm attachment factor that causes primary ciliary dyskinesia when mutated.
    explanation: >-
      Assigns the DNAAF19 product an axonemal dynein-arm attachment role rather than a cytoplasmic
      preassembly role.
  - reference: PMID:22581229
    reference_title: CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Chlamydomonas Ccdc103/Pr46b functions as a tightly bound, axoneme-associated protein.
    explanation: >-
      Locates the orthologous product in the axoneme rather than in the cytoplasm, which is why
      DNAAF19 sits on this node despite its DNAAF symbol.
  genes:
  - preferred_term: ODAD1
    term:
      id: hgnc:26560
      label: ODAD1
  - preferred_term: ODAD4
    term:
      id: hgnc:25280
      label: ODAD4
  - preferred_term: DNAAF19
    term:
      id: hgnc:32700
      label: CCDC103
  - preferred_term: ODAD2
    term:
      id: hgnc:25583
      label: ODAD2
  - preferred_term: CLXN
    term:
      id: hgnc:25678
      label: CLXN
  biological_processes:
  - preferred_term: outer dynein arm assembly
    modifier: DECREASED
    term:
      id: GO:0036158
      label: outer dynein arm assembly
  cellular_components:
  - preferred_term: outer dynein arm
    term:
      id: GO:0036157
      label: outer dynein arm
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  locations:
  - preferred_term: respiratory tract epithelium
    term:
      id: UBERON:0004802
      label: respiratory tract epithelium
  biological_scale: MOLECULAR
  downstream:
  - target: Ciliary Dysfunction
    causal_link_type: DIRECT
    description: >-
      Outer dynein arms are the principal source of the force that drives the ciliary beat, so an
      axoneme that cannot retain them loses that force.
    evidence:
    - reference: PMID:27486780
      reference_title: TTC25 Deficiency Results in Defects of the Outer Dynein Arm Docking Machinery and Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: Multiprotein complexes referred to as outer dynein arms (ODAs) develop the main mechanical force to generate the ciliary and flagellar beat.
      explanation: >-
        States the force-generating role of the outer dynein arms whose loss this edge asserts, as
        established background rather than as this study's own result.
    hypothesis_groups:
    - canonical_motile_cilia_beat_failure
- name: Central Pair Apparatus Defect
  mechanism_confidence: PROVISIONAL
  description: >-
    HYDIN and SPEF2 losses remove components of the axonemal central pair apparatus. The resulting
    disease is diagnostically distinctive rather than ultrastructurally obvious: beating abnormalities
    are subtle, routine ciliary ultrastructure and situs composition are normal, and HYDIN variant
    calling is confounded by the near-identical pseudogene HYDIN2. This is a central-pair lesion,
    separate from the C1d projection defect modeled for the CFAP46/CFAP54/CFAP74/CFAP221 group.
  evidence:
  - reference: PMID:31545650
    reference_title: SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: Mutations in HYDIN are known to cause CP defects
    explanation: >-
      Assigns HYDIN-related disease to the central-pair defect class, as established background in
      the citing study rather than as its own result.
  - reference: PMID:31545650
    reference_title: SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified a mutation of SPEF2 that is causative for PCD with a CP defect.
    explanation: >-
      Adds SPEF2 to the central-pair defect class on this study's own genetic and immunofluorescence
      result.
  - reference: PMID:31545650
    reference_title: SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: the genetic analysis of HYDIN variants is confounded by the pseudogene HYDIN2, which is almost identical in terms of intron/exon structure
    explanation: >-
      Records the HYDIN2 pseudogene as the reason HYDIN variant calling is unreliable.
  genes:
  - preferred_term: HYDIN
    term:
      id: hgnc:19368
      label: HYDIN
  - preferred_term: SPEF2
    term:
      id: hgnc:26293
      label: SPEF2
  biological_processes:
  - preferred_term: axonemal central apparatus assembly
    modifier: DECREASED
    term:
      id: GO:1904158
      label: axonemal central apparatus assembly
  cellular_components:
  - preferred_term: axonemal central apparatus
    term:
      id: GO:1990716
      label: axonemal central apparatus
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  locations:
  - preferred_term: respiratory tract epithelium
    term:
      id: UBERON:0004802
      label: respiratory tract epithelium
  biological_scale: MOLECULAR
  downstream:
  - target: Ciliary Dysfunction
    causal_link_type: DIRECT
    description: >-
      Loss of central pair components alters the beat rather than abolishing it, which is why routine
      beat, ultrastructure and situs assessment can all read as normal in this group.
    evidence:
    - reference: PMID:31545650
      reference_title: SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: it is difficult to establish a diagnosis in individuals with PCD and central pair (CP) defects, and alternative strategies are required because of very subtle ciliary beating abnormalities, a normal ciliary ultrastructure, and normal situs composition
      explanation: >-
        Records that central-pair defects produce subtle beat abnormality with normal ultrastructure
        and situs, which is the character of this edge.
    hypothesis_groups:
    - canonical_motile_cilia_beat_failure
- name: Radial Spoke Defect
  description: >-
    The radial spokes link each outer microtubule doublet to the sheath that surrounds the central
    pair of microtubules, and the knockdown data below show the spoke head is needed for normal
    ciliary movement. RSPH1, RSPH4A and RSPH9 are radial spoke head
    components and NME5 a component of the spoke neck; the Chlamydomonas orthologs of RSPH3 and
    DNAJB13 are a spoke stalk protein and a spoke-localised HSP40 co-chaperone. Loss of any of them
    disturbs the beat. Patient
    ultrastructure in this group ranges from a near absence of radial spokes to central-complex
    changes with intact dynein arms, so it is a different lesion from the dynein-arm and
    multiciliogenesis routes.
  evidence:
  - reference: PMID:19200523
    reference_title: Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both RSPH9 and RSPH4A encode protein components of the axonemal radial spoke head.
    explanation: >-
      Assigns RSPH9 and RSPH4A to the radial spoke head, the structure this node is about.
  - reference: PMID:19200523
    reference_title: Mutations in radial spoke head protein genes RSPH9 and RSPH4A cause primary ciliary dyskinesia with central-microtubular-pair abnormalities.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Investigation of the effect of knockdown or mutations of RSPH9 orthologs in zebrafish and Chlamydomonas indicate that radial spoke head proteins are important in maintaining normal movement in motile
    explanation: >-
      Zebrafish and Chlamydomonas knockdown of RSPH9 orthologs establishes that the radial spoke head
      is required for normal movement, which is the functional content of this node. The model systems
      are inside the quote, which is what the MODEL_ORGANISM grading rests on.
  - reference: PMID:26073779
    reference_title: RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: It also unveils the key role of RSPH3 in the proper building of RSs and the CC in humans.
    explanation: >-
      Places RSPH3 in radial spoke assembly in human cilia, alongside the head components.
  - reference: PMID:27486783
    reference_title: Mutations in DNAJB13, Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a gene encoding a HSP40 co-chaperone whose ortholog in the flagellated alga Chlamydomonas localizes to the radial spokes
    explanation: >-
      Places DNAJB13 at the radial spokes through its Chlamydomonas ortholog, which is why it is wired
      here rather than to the dynein arms.
  - reference: PMID:32185794
    reference_title: A nonsense variant in NME5 causes human primary ciliary dyskinesia with radial spoke defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: NME5, which encodes a protein component of the RS neck
    explanation: >-
      Places NME5 at the radial spoke neck, which is why it is wired at this node rather than at the
      beat-dysfunction node with the dynein-arm genes.
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: RSPH1 | radial spoke head component 1 | hgnc:12371 | Disease-causing germline mutation(s) (loss of function) in
    explanation: >-
      Orphanet names RSPH1 a radial spoke head component and a disease-causing gene, which is the basis
      for wiring it at this node rather than directly at the beat-dysfunction node.
  genes:
  - preferred_term: RSPH1
    term:
      id: hgnc:12371
      label: RSPH1
  - preferred_term: RSPH3
    term:
      id: hgnc:21054
      label: RSPH3
  - preferred_term: RSPH4A
    term:
      id: hgnc:21558
      label: RSPH4A
  - preferred_term: RSPH9
    term:
      id: hgnc:21057
      label: RSPH9
  - preferred_term: DNAJB13
    term:
      id: hgnc:30718
      label: DNAJB13
  - preferred_term: NME5
    term:
      id: hgnc:7853
      label: NME5
  biological_processes:
  - preferred_term: radial spoke assembly
    modifier: DECREASED
    term:
      id: GO:0062177
      label: radial spoke assembly
  cellular_components:
  - preferred_term: radial spoke
    term:
      id: GO:0001534
      label: radial spoke
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  locations:
  - preferred_term: respiratory tract epithelium
    term:
      id: UBERON:0004802
      label: respiratory tract epithelium
  biological_scale: MOLECULAR
  downstream:
  - target: Ciliary Dysfunction
    causal_link_type: DIRECT
    description: >-
      A radial spoke lesion changes the waveform rather than abolishing motility, so beat frequency can
      be preserved while transport is not.
    evidence:
    - reference: PMID:24568568
      reference_title: Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Cilia from individuals with RSPH1 mutations had normal beat frequency
      explanation: >-
        RSPH1 patient cilia retain frequency with an abnormal waveform, which is the character of this
        edge into the beat-dysfunction node.
    hypothesis_groups:
    - canonical_motile_cilia_beat_failure
- name: Nexin-Dynein Regulatory Complex Defect
  description: >-
    The nexin-dynein regulatory complex (N-DRC) links adjacent outer microtubule doublets and
    regulates dynein activity across them. DRC1, DRC2 and DRC4 are subunits 1, 2 and 4 of that
    complex. Because the complex is a connector rather than a visible arm or spoke, loss of a subunit
    leaves the axonemal architecture looking intact on routine transmission electron microscopy while
    the beat becomes stiff and dyskinetic, so this group is identified by immunofluorescence
    rather than by ultrastructure. The subunits are interdependent: DRC4 is absent from
    DRC2-deficient airway cells.
  evidence:
  - reference: PMID:26387594
    reference_title: Loss-of-Function GAS8 Mutations Cause Primary Ciliary Dyskinesia and Disrupt the Nexin-Dynein Regulatory Complex.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Immunofluorescence analyses of respiratory cells from PCD-affected individuals detected a N-DRC defect.
    explanation: >-
      Establishes the N-DRC defect as a detectable lesion class in affected individuals.
  - reference: PMID:23991085
    reference_title: CCDC65 mutation causes primary ciliary dyskinesia with normal ultrastructure and hyperkinetic cilia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: CCDC65, an orthologue of the Chlamydomonas nexin-dynein regulatory complex protein DRC2, was localized to the cilia of normal nasal epithelial cells but was absent in those from the proband.
    explanation: >-
      Places DRC2 in the N-DRC and shows it is absent from the cilia of an affected individual.
  - reference: PMID:23991085
    reference_title: CCDC65 mutation causes primary ciliary dyskinesia with normal ultrastructure and hyperkinetic cilia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Moreover, Gas8, a nexin-dynein regulatory complex component previously identified to associate with CCDC65, was absent in airway cells from the PCD subject and CCDC65-silenced cells.
    explanation: >-
      Shows the two subunits are interdependent, which is why they are modeled as one node rather than
      two.
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DRC1 | dynein regulatory complex subunit 1 | hgnc:24245 | Disease-causing germline mutation(s) (loss of function) in
    explanation: >-
      Orphanet names DRC1 a dynein regulatory complex subunit and a disease-causing gene, which is the
      basis for wiring it at this node.
  genes:
  - preferred_term: DRC1
    term:
      id: hgnc:24245
      label: DRC1
  - preferred_term: DRC2
    term:
      id: hgnc:29937
      label: CCDC65
  - preferred_term: DRC4
    term:
      id: hgnc:4166
      label: GAS8
  biological_processes:
  - preferred_term: regulation of cilium beat frequency
    modifier: ABNORMAL
    term:
      id: GO:0003356
      label: regulation of cilium beat frequency
  cellular_components:
  - preferred_term: axonemal nexin link
    term:
      id: GO:0005931
      label: axonemal nexin link
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  locations:
  - preferred_term: respiratory tract epithelium
    term:
      id: UBERON:0004802
      label: respiratory tract epithelium
  biological_scale: MOLECULAR
  downstream:
  - target: Ciliary Dysfunction
    causal_link_type: DIRECT
    description: >-
      Without the regulatory complex the doublets are no longer coordinated, and the beat becomes stiff
      and dyskinetic rather than absent.
    evidence:
    - reference: PMID:23991085
      reference_title: CCDC65 mutation causes primary ciliary dyskinesia with normal ultrastructure and hyperkinetic cilia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Nasal epithelial cells from the affected individual and CCDC65-specific shRNA transduced normal airway epithelial cells had stiff and dyskinetic cilia beating patterns compared to control cells.
      explanation: >-
        Records the altered beating this edge asserts, in both patient cells and a knockdown control.
    hypothesis_groups:
    - canonical_motile_cilia_beat_failure
mechanistic_hypotheses:
- hypothesis_group_id: canonical_motile_cilia_beat_failure
  hypothesis_label: Canonical Axonemal Motile-Cilia Beat-Failure / Mucociliary Clearance Model
  status: CANONICAL
  description: >-
    Inherited defects in axonemal motors, assembly and regulation impair effective respiratory ciliary
    beating. Reduced multiciliogenesis and C1d-associated transport dysfunction are parallel upstream
    routes to impaired mucociliary clearance. Retained secretions favor recurrent infection, neutrophilic
    inflammation, airway remodeling and heterogeneous obstructive decline. This convergent model
    does not require complete immotility, abnormal routine TEM, or complete absence of clearance
    in every patient.
  evidence:
  - reference: PMID:31772028
    reference_title: Deep phenotyping, including quantitative ciliary beating parameters, and extensive genotyping in primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Combined outer/inner dynein arms (ODA/IDA) defect induces total ciliary immotility, regardless of the gene involved.
    explanation: >-
      In the studied ultrastructural classes, combined dynein-arm loss produced immotility. Other
      genotypes show dyskinetic, hyperkinetic or apparently normal beating; this is not a universal
      immotility rule.
  - reference: PMID:24747639
    reference_title: Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: marked reduction in the number of multiple motile cilia
    explanation: >-
      CCNO patient studies distinguish reduced cilia number from abnormal beating of residual cilia.
  - reference: PMID:39362668
    reference_title: Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance.
    explanation: >-
      C1d-defective patient cells show transport failure despite normal routine TEM, nasal NO and
      high-speed beat assessment. The selected situs-solitus cohort does not independently estimate
      population laterality risk.
  - reference: PMID:38076675
    reference_title: 'Pulmonary radioaerosol mucociliary clearance assessment: searching for genotype-specific differences and potential as an outcome measure in primary ciliary dyskinesia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mucociliary clearance by PRMC was consistently absent in most PCD patients, regardless of genotype.
    explanation: >-
      Retrospective radioaerosol assessment included 69 patients and 26 genotypes. One CCDC103 participant
      retained measurable clearance; the 24-year collection window is not 24-year longitudinal follow-up
      of every participant.
  - reference: PMID:15806596
    reference_title: Correlation between cough frequency and airway inflammation in children with primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Stable PCD children have increased cough frequency and neutrophilic airway inflammation.
    explanation: >-
      Stable pediatric PCD sputum shows neutrophilic inflammation; association with cough does not
      independently establish every remodeling step.
  notes: >-
    The complete June OpenScientist report and citation manifest were reassessed in September 2026;
    the canonical core remains supported. The provider-reported 135-paper corpus is not reconstructable
    from the 50-PMID sidecar. Valid cilia-number, genotype, reproductive, inflammatory and species
    qualifications are represented. CCNO residual cilia can retain normal motor proteins, whereas
    MCIDAS residual cilia lack DNAH5/CCDC39. The report omitted existing genotype-stratified longitudinal
    work and overstated absence of PCD randomized trials. BESTCILIA reduces exacerbations without
    separating antimicrobial from immunomodulatory effects; CLEAN-PCD has comparator-specific short-term
    results. DNAI1 mouse-cell rescue establishes proximal function, while separate 2026 human RCT1100-101/102
    conference data did not demonstrate post-treatment ciliary restoration. NOS, sputum-induced M2-like
    macrophage responses, IFT88 mouse remodeling and infection-induced YTHDF1/DNAH5 regulation remain
    scoped leads, not universal mutation-intrinsic human pathways. Early-treated infant morbidity
    does not show early care is ineffective. Full claim and artifact judgments are in the adjacent
    codex assessment.
- hypothesis_group_id: embryonic_nodal_cilia_laterality
  hypothesis_label: Embryonic Nodal-Cilia Laterality-Determination Arm
  status: CANONICAL
  description: >-
    For PCD genotypes affecting embryonic motile monocilia, defective nodal motion disrupts directional
    flow and asymmetric flow-sensing signals. Mouse experiments connect mechanical bending of immotile
    crown-cell cilia to PKD2-dependent calcium signaling and Dand5 RNA decay, enabling asymmetric
    NODAL/PITX2 patterning. Failure of this developmental system permits situs solitus, mirror-image
    situs or discordant laterality. Laterality involvement depends on tissue-specific machinery:
    radial-spoke/central-apparatus and CCNO/MCIDAS defects generally spare nodal monocilia, whereas
    CCDC39/CCDC40 as well as ODA genes can affect laterality.
  evidence:
  - reference: PMID:27486780
    reference_title: TTC25 Deficiency Results in Defects of the Outer Dynein Arm Docking Machinery and Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: we observed immotile nodal cilia and missing leftward flow via particle image velocimetry.
    explanation: >-
      Ttc25 mutant mice directly connect a PCD-associated dynein-docking defect to nodal immotility
      and absent directional flow.
  - reference: PMID:27486780
    reference_title: TTC25 Deficiency Results in Defects of the Outer Dynein Arm Docking Machinery and Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: we observed immotile nodal cilia and missing leftward flow via particle image velocimetry.
    explanation: >-
      Ttc25 mutant mice directly connect a PCD-associated dynein-docking defect to nodal immotility
      and absent directional flow.
  - reference: PMID:36603091
    reference_title: Immotile cilia mechanically sense the direction of fluid flow for left-right determination.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Application of mechanical stimuli to immotile cilia by optical tweezers induced calcium ion transients and degradation of Dand5 messenger RNA (mRNA) in the targeted cells.
    explanation: >-
      The 2023 mouse study directly tests mechanical sensing and downstream Dand5 responses, predating
      but omitted from the OpenScientist report.
  - reference: PMID:36342963
    reference_title: 'Laterality Defects in Primary Ciliary Dyskinesia: Relationship to Ultrastructural Defect or Genotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Of 559 participants, 286 (51.2%), 215 (38.5%), and 58 (10.4%) were identified as having situs solitus, situs inversustotalis, and situs ambiguus, respectively
    explanation: >-
      Human laterality distributions distinguish total inversion from situs ambiguus. Heterotaxy
      definitions vary; this study restricted heterotaxy to ambiguus with complex cardiovascular
      defects (14/559).
  - reference: PMID:36603098
    reference_title: Cilia function as calcium-mediated mechanosensors that instruct left-right asymmetry.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Mechanical manipulation of immotile LRO cilia activated intraciliary calcium transients that required the cation channel Polycystin-2.
    explanation: >-
      Independent zebrafish mechanical manipulation supports the sensory principle; it is not direct
      imaging of human embryonic nodes.
  notes: >-
    The OpenScientist core is supported, but its claim of complete human mechanistic resolution and
    ODA-only genotype rule is too broad. The report omitted pre-existing direct mouse and zebrafish
    optical-tweezer evidence (PMIDs 36603091/36603098) and Dand5 post-transcriptional regulation
    (34210974); its blanket lack of a mammalian mechanosensing test is incorrect. Human node function
    remains inferred from conserved experiments and clinical genetics. Artificial-flow rescue does
    not rule out intracellular chirality upstream of flow. Heterotaxy is not explained by an evidence-backed
    turbulent-flow mechanism, and its frequency depends on definition, cohort and ascertainment.
    The 559-person cohort had 51.2% situs solitus, 38.5% complete inversion and 10.4% ambiguus, with
    2.5% meeting its narrower complex-cardiovascular heterotaxy definition. Older North American
    cohorts can overlap. DRC1 single-case evidence is not equivalent to RSPH1 negative-control cohorts,
    and normal-TEM DNAH11 can still affect situs. The provider 100-paper search corpus and figure
    placeholders cannot be independently reconstructed from the 37-PMID citation sidecar.
- hypothesis_group_id: genotype_ultrastructure_severity
  hypothesis_label: Genotype / Ultrastructure-Defect Severity Stratification
  status: EMERGING
  description: >-
    Genotype and ultrastructural classes associate with group-level clinical outcomes, but do not
    define validated severe, standard and mild tiers for an individual. CCDC39/CCDC40-associated
    IDA/MTD and CCNO groups show worse lung function in several cohorts; RSPH1, DNAH11 and ODAD1
    can have milder group outcomes. Age, specific alleles, diagnostic ascertainment, infection, care
    and modifiers contribute to within-gene variation. CCDC39/CCDC40 scaffold loss causes motility-independent
    cellular stress, fate switching and barrier defects, a plausible additional mechanism whose mediation
    of patient decline remains unproven. Residual transport and cough compensation require direct
    physiological measurement.
  evidence:
  - reference: PMID:38871375
    reference_title: Analyses of 1236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype-phenotype correlations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Median FEV1 z-scores were significantly lower in CCNO (-3.26), CCDC39 (-2.49) and CCDC40 (-2.96) variant groups
    explanation: >-
      The 1236-person multinational registry supports group associations in cross-sectional measurements,
      not longitudinal trajectories or fixed severity tiers.
  - reference: PMID:30067075
    reference_title: 'Primary Ciliary Dyskinesia: Longitudinal Study of Lung Disease by Ultrastructure Defect and Genotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: For the entire cohort, percent predicted FEV1 decline was heterogeneous with a mean (SE) decline of 0.57 (0.25) percent predicted/yr.
    explanation: >-
      Five-year multicenter observational study supports heterogeneous decline. A slope differing
      from zero only in one subgroup does not establish that all other genotypes cannot decline.
  - reference: PMID:39879322
    reference_title: Undocking of an extensive ciliary network induces proteostasis and cell fate switching resulting in severe primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the absence of the axonemal CCDC39/CCDC40 heterodimer resulted in the loss of a network of more than 90 ciliary structural proteins
    explanation: >-
      Patient-cilia proteomics and cross-species structural work establish a broad scaffold-dependent
      protein network. The preprint PMID:38562900 is the same study, not an independent replication.
  - reference: PMID:24568568
    reference_title: Mutations in RSPH1 cause primary ciliary dyskinesia with a unique clinical and ciliary phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: individuals with RSPH1 mutations had a lower prevalence (8 of 16) of neonatal respiratory distress, and later onset of daily wet cough than typical for PCD, and better lung function (FEV1), compared with 75 age- and sex-matched PCD cases (73.0 vs. 61.8, FEV1 % predicted; P = 0.043).
    explanation: >-
      Sixteen RSPH1 cases versus 75 matched PCD cases support a group association; the report incorrectly
      states P=0.0.
  - reference: PMID:26777464
    reference_title: 'Systematic Analysis of CCNO Variants in a Defined Population: Implications for Clinical Phenotype and Differential Diagnosis.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Combining these 15 patients with the previously reported CCNO case reports revealed rapid deterioration in lung function, an increased prevalence of hydrocephalus (10%) as well as increased female infertility (22%).
    explanation: >-
      The source for placing CCNO among the worse-outcome groups. Fifteen newly identified Israeli
      patients pooled with previously reported case reports, so the hydrocephalus and infertility
      percentages are pooled and cross-sectional rather than a prospective cohort estimate.
  - reference: PMID:38602513
    reference_title: 'Genetic Spectrum and Clinical Characteristics of Patients with Primary Ciliary Dyskinesia: a Belgian Single Center Study.'
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: Respiratory tract microbiology (p = 0.161), lung function (cross-sectional, p = 0.829 and longitudinal, p = 0.329) and chest CT abnormalities (p = 0.202) were not significantly different between DNAH11 and DNAH5 variants.
    explanation: >-
      The 74-patient single-centre comparison behind the note below. It finds no DNAH5 versus DNAH11
      difference in microbiology, lung function or CT abnormality, refuting a severity distinction
      between the two commonest genotypes. A null result in a moderately sized retrospective cohort
      does not establish equivalence.
  notes: >-
    The June OpenScientist report remains partially supported and the hypothesis EMERGING. The 137-person,
    732-visit five-year study is mislabeled n=118 in its evidence matrix. A significant slope within
    IDA/MTD but not another group is not itself a between-group interaction test. Registry cross-sectional
    differences, nNO trends, neonatal distress and ENT intervention timing measure distinct outcomes.
    A small nonsignificant DNAH5/DNAH11 comparison does not prove equivalence. The 2026 functional
    study compared RSPH1 with DNAH5, not ODA with IDA: seven, eight and eight participants including
    controls; whole-lung MCC was not significantly different between genotypes, while cough clearance
    was higher in RSPH1 in small unadjusted comparisons. Neither universal absent MCC nor a validated
    cough-mediated explanation follows. CCDC39/40 cellular rescue supports cellular causality, not
    clinical severity mediation; its preprint and final paper are one study. CCNO hydrocephalus/infertility
    percentages pool new and previously reported cases. DNAH5 loss-of-function risk concerns neonatal
    distress; TAS2R38 modifier/ceiling effects remain observational. The claimed absence of cross-genotype
    omics is incorrect: 2024 mouse Cfap221/Cfap54/Spef2 scRNA-seq exists, alongside DNAH5 patient-cell
    redox work and CCDC39/40 proteomics. Robust multi-genotype human clinical mediation remains an
    open question. The 59-paper provider corpus exceeds the auditable 26-PMID sidecar; no raw computation
    or figure files were supplied.
phenotypes:
- category: Respiratory
  name: Chronic Cough
  diagnostic: true
  phenotype_term:
    preferred_term: Chronic Cough
    term:
      id: HP:0034315
      label: Chronic cough
  evidence:
  - reference: PMID:41005984
    reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: PCD is associated with early-onset chronic wet cough and rhinosinusitis, laterality defects, middle ear disease and reduced fertility.
    explanation: >-
      Joint ERS/ATS guideline supports the characteristic symptom spectrum; this sentence does not
      provide quantitative frequency estimates.
- category: Respiratory
  name: Recurrent Respiratory Infections
  evidence:
  - reference: PMID:41005984
    reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Individuals with PCD often have persistent wet cough, chronic rhinosinusitis, recurrent otitis media, and recurrent respiratory infections beginning early in life and continuing throughout adulthood
    explanation: >-
      Guideline supports early and persistent respiratory infections.
  phenotype_term:
    preferred_term: Recurrent Respiratory Infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
- category: Respiratory
  name: Bronchiectasis
  evidence:
  - reference: PMID:41005984
    reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The disease course can be heterogeneous, but most people develop bronchiectasis and progressive lung disease that can lead to respiratory failure
    explanation: >-
      PCD-specific guideline supports cumulative structural disease while recognizing heterogeneous
      trajectories.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  notes: >-
    Occurrence depends strongly on age and ascertainment. A cumulative complication should not be
    assigned the Orphanet cross-sectional 5–29% band without an age denominator.
- category: Otologic
  name: Chronic Otitis Media
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: HP:0000389 | Chronic otitis media | Frequent (79-30%)
    explanation: Orphanet phenotype data classifies chronic otitis media as frequent (79-30%) in primary ciliary dyskinesia.
    evidence_source: OTHER
  - reference: PMID:29135867
    reference_title: Analysis of Otologic Features of Patients With Primary Ciliary Dyskinesia.
    supports: SUPPORT
    snippet: All 15 patients showed ciliary ultrastructural abnormalities on electron microscopy and/or biallelic mutations in genes associated with ciliary function or structure. All 30 eardrums examined showed certain abnormalities. Fourteen patients had otitis media with effusion or its sequelae. The remaining patient had chronic otitis media.
    explanation: The study found that patients with primary ciliary dyskinesia (PCD) frequently exhibited otologic issues, including chronic otitis media.
  - reference: PMID:19796826
    reference_title: 'Management of otitis media with effusion in children with primary ciliary dyskinesia: a literature review.'
    supports: SUPPORT
    snippet: Primary ciliary dyskinesia is an autosomal recessively inherited group of disorders of ciliary ultrastructure. Otolaryngologists are frequently involved in the management of some of the most common symptoms of primary ciliary dyskinesia including chronic rhinitis, sinusitis and otitis media with effusion.
    explanation: This reference supports that chronic otitis media and other otologic issues are common in patients with primary ciliary dyskinesia.
  phenotype_term:
    preferred_term: Chronic Otitis Media
    term:
      id: HP:0000389
      label: Chronic otitis media
- category: Otologic
  name: Hearing Loss
  evidence:
  - reference: PMID:41005984
    reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Individuals with PCD frequently suffer from chronic middle ear disease and can have conductive and sensorineural hearing loss
    explanation: >-
      PCD-specific guideline supports hearing impairment; severity, age and mechanism vary.
  phenotype_term:
    preferred_term: Hearing Loss
    term:
      id: HP:0000365
      label: Hearing impairment
- category: Otorhinolaryngologic
  name: Nasal Polyposis
  phenotype_term:
    preferred_term: Nasal Polyposis
    term:
      id: HP:0100582
      label: Nasal polyposis
  evidence:
  - reference: PMID:26418604
    reference_title: 'Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Nasal polyposis has been observed in up to 15% of PCD patients.
    explanation: >-
      Guideline literature summary supplies a bounded clinical estimate, not a population-independent
      frequency.
  notes: >-
    Reported in a subset, with ascertainment and age affecting frequency. Older PCD consensus reports
    up to 15%, so a frequent 30–79% category is not justified by the broad disease annotation alone.
- category: Cardiac
  name: Situs Inversus Totalis
  frequency: FREQUENT
  evidence:
  - reference: PMID:36342963
    reference_title: 'Laterality Defects in Primary Ciliary Dyskinesia: Relationship to Ultrastructural Defect or Genotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Of 559 participants, 286 (51.2%), 215 (38.5%), and 58 (10.4%) were identified as having situs solitus, situs inversustotalis, and situs ambiguus, respectively
    explanation: >-
      Human laterality distributions distinguish total inversion from situs ambiguus. Heterotaxy
      definitions vary; this study restricted heterotaxy to ambiguus with complex cardiovascular
      defects (14/559).
  phenotype_term:
    preferred_term: Situs Inversus Totalis
    term:
      id: HP:0001696
      label: Situs inversus totalis
  notes: >-
    Situs inversus totalis occurred in 215/559 (38.5%) in the cited multicenter cohort; the approximately
    half with any laterality defect also includes situs ambiguus. Rates depend on genotype and ascertainment.
- category: Respiratory
  name: Sinusitis
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Sinusitis
    term:
      id: HP:0000246
      label: Sinusitis
  evidence:
  - reference: PMID:11376511
    reference_title: Pathophysiology and treatment of airway mucociliary clearance. A moving tale.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Failure to keep the airways sterile by MCC results in a host inflammatory response to the persistent microorganisms which, if it becomes chronic, causes damage to the airway wall and upregulation of mucus production manifest clinically as bronchiectasis, sinusitis and otitis.
    explanation: >-
      Mechanistic review supports the established clearance-infection-injury sequence; the human
      evidence is not a single longitudinal mediation experiment.
- category: Otologic
  name: Otitis Media
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Otitis Media
    term:
      id: HP:0000388
      label: Otitis media
  evidence:
  - reference: PMID:11376511
    reference_title: Pathophysiology and treatment of airway mucociliary clearance. A moving tale.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Failure to keep the airways sterile by MCC results in a host inflammatory response to the persistent microorganisms which, if it becomes chronic, causes damage to the airway wall and upregulation of mucus production manifest clinically as bronchiectasis, sinusitis and otitis.
    explanation: >-
      Mechanistic review supports the established clearance-infection-injury sequence; the human
      evidence is not a single longitudinal mediation experiment.
- category: Respiratory
  name: Neonatal Respiratory Distress
  frequency: FREQUENT
  notes: >-
    Often delayed/persistent distress in term newborns with oxygen requirement and atelectasis. The
    exact human contribution of retained fetal lung fluid is unresolved; mouse neonatal lethality
    is not a human outcome estimate.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: HP:0002643 | Neonatal respiratory distress | Frequent (79-30%)
    explanation: Orphanet phenotype data classifies neonatal respiratory distress as frequent (79-30%) in primary ciliary dyskinesia.
    evidence_source: OTHER
  - reference: PMID:19720631
    reference_title: High prevalence of primary ciliary dyskinesia in a British Asian population.
    supports: SUPPORT
    snippet: 73% had a history of neonatal respiratory distress.
    explanation: In a consanguineous British Asian PCD cohort, 73% of patients had neonatal respiratory distress.
  - reference: PMID:40344341
    reference_title: The Association of Neonatal Respiratory Distress With Ciliary Ultrastructure and Genotype in Primary Ciliary Dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Of the 455 participants analyzed, 305 (67.0%) reported NRD.
    explanation: >-
      Term-born participants with known neonatal history in a multicenter PCD study; prematurity
      and complex congenital heart disease were excluded.
  phenotype_term:
    preferred_term: Neonatal respiratory distress
    term:
      id: HP:0002643
      label: Neonatal respiratory distress
- category: Reproductive
  name: Male Infertility
  notes: >-
    Risk depends on gene and reproductive history. The 2024 self-report survey classified 78% of
    50 men and 61% of 118 women who had tried to conceive as infertile, including those using assisted
    reproduction. Selection, recall and referral bias limit population estimates; conception remains
    possible.
  evidence:
  - reference: PMID:38962571
    reference_title: Infertility and pregnancy outcomes among adults with primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Among 168 adults who had tried to conceive, 39 of 50 men (78%) and 72 of 118 women (61%) were infertile.
    explanation: >-
      The international self-report study supports sex-specific fertility impairment, with denominators
      restricted to participants who had tried to conceive; it does not establish obligatory infertility
      or a universal shared molecular lesion.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
- category: Respiratory
  name: Chronic Rhinosinusitis
  frequency: FREQUENT
  notes: Chronic inflammation of nasal passages and sinuses
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: HP:0011109 | Chronic sinusitis | Frequent (79-30%)
    explanation: Orphanet phenotype data classifies chronic sinusitis as frequent (79-30%) in primary ciliary dyskinesia.
    evidence_source: OTHER
  phenotype_term:
    preferred_term: Chronic rhinosinusitis
    term:
      id: HP:0011109
      label: Chronic sinusitis
- category: Respiratory
  name: Productive Cough
  evidence:
  - reference: PMID:41005984
    reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: PCD is associated with early-onset chronic wet cough and rhinosinusitis, laterality defects, middle ear disease and reduced fertility.
    explanation: >-
      Joint ERS/ATS guideline supports the characteristic symptom spectrum; this sentence does not
      provide quantitative frequency estimates.
  phenotype_term:
    preferred_term: Productive cough
    term:
      id: HP:0031245
      label: Productive cough
- category: Respiratory
  name: Recurrent Sinopulmonary Infections
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: HP:0005425 | Recurrent sinopulmonary infections | Frequent (79-30%)
    explanation: Orphanet phenotype data classifies recurrent sinopulmonary infections as frequent (79-30%) in primary ciliary dyskinesia.
    evidence_source: OTHER
  phenotype_term:
    preferred_term: Recurrent sinopulmonary infections
    term:
      id: HP:0005425
      label: Recurrent sinopulmonary infections
- category: Respiratory
  name: Nasal Congestion
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: HP:0001742 | Nasal congestion | Frequent (79-30%)
    explanation: Orphanet phenotype data classifies nasal congestion as frequent (79-30%) in primary ciliary dyskinesia.
    evidence_source: OTHER
  phenotype_term:
    preferred_term: Nasal congestion
    term:
      id: HP:0001742
      label: Nasal congestion
- category: Respiratory
  name: Chronic Rhinitis
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: HP:0002257 | Chronic rhinitis | Frequent (79-30%)
    explanation: Orphanet phenotype data classifies chronic rhinitis as frequent (79-30%) in primary ciliary dyskinesia.
    evidence_source: OTHER
  phenotype_term:
    preferred_term: Chronic rhinitis
    term:
      id: HP:0002257
      label: Chronic rhinitis
- category: Respiratory
  name: Abnormal Sputum
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: HP:0032016 | Abnormal sputum | Frequent (79-30%)
    explanation: Orphanet phenotype data classifies abnormal sputum as frequent (79-30%) in primary ciliary dyskinesia.
    evidence_source: OTHER
  phenotype_term:
    preferred_term: Abnormal sputum
    term:
      id: HP:0032016
      label: Abnormal sputum
- category: Reproductive
  name: Abnormal Sperm Motility
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: HP:0012206 | Abnormal sperm motility | Frequent (79-30%)
    explanation: Orphanet phenotype data classifies abnormal sperm motility as frequent (79-30%) in primary ciliary dyskinesia.
    evidence_source: OTHER
  phenotype_term:
    preferred_term: Abnormal sperm motility
    term:
      id: HP:0012206
      label: Abnormal sperm motility
  notes: >-
    Frequency is applicable to the relevant reproductive population, not all patients. Fertility
    is genotype-dependent and some affected individuals conceive naturally; semen testing or fertility
    assessment is needed for individual counseling.
- category: Otologic
  name: Recurrent Otitis Media
  frequency: FREQUENT
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: HP:0000403 | Recurrent otitis media | Frequent (79-30%)
    explanation: Orphanet phenotype data classifies recurrent otitis media as frequent (79-30%) in primary ciliary dyskinesia.
    evidence_source: OTHER
  phenotype_term:
    preferred_term: Recurrent otitis media
    term:
      id: HP:0000403
      label: Recurrent otitis media
- category: Respiratory
  name: Wheezing
  frequency: OCCASIONAL
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: HP:0030828 | Wheezing | Occasional (29-5%)
    explanation: Orphanet phenotype data classifies wheezing as occasional (29-5%) in primary ciliary dyskinesia.
    evidence_source: OTHER
  phenotype_term:
    preferred_term: Wheezing
    term:
      id: HP:0030828
      label: Wheezing
- category: Reproductive
  name: Female Infertility
  notes: >-
    Risk depends on gene and reproductive history. The 2024 self-report survey classified 78% of
    50 men and 61% of 118 women who had tried to conceive as infertile, including those using assisted
    reproduction. Selection, recall and referral bias limit population estimates; conception remains
    possible.
  evidence:
  - reference: PMID:38962571
    reference_title: Infertility and pregnancy outcomes among adults with primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Among 168 adults who had tried to conceive, 39 of 50 men (78%) and 72 of 118 women (61%) were infertile.
    explanation: >-
      The international self-report study supports sex-specific fertility impairment, with denominators
      restricted to participants who had tried to conceive; it does not establish obligatory infertility
      or a universal shared molecular lesion.
  phenotype_term:
    preferred_term: Female infertility
    term:
      id: HP:0008222
      label: Female infertility
- category: Respiratory
  name: Atelectasis
  frequency: OCCASIONAL
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: HP:0100750 | Atelectasis | Occasional (29-5%)
    explanation: Orphanet phenotype data classifies atelectasis as occasional (29-5%) in primary ciliary dyskinesia.
    evidence_source: OTHER
  phenotype_term:
    preferred_term: Atelectasis
    term:
      id: HP:0100750
      label: Atelectasis
- category: Otologic
  name: Conductive Hearing Impairment
  frequency: OCCASIONAL
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: HP:0000405 | Conductive hearing impairment | Occasional (29-5%)
    explanation: Orphanet phenotype data classifies conductive hearing impairment as occasional (29-5%) in primary ciliary dyskinesia.
    evidence_source: OTHER
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
- category: Respiratory
  name: Airway Obstruction
  frequency: OCCASIONAL
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: HP:0006536 | Airway obstruction | Occasional (29-5%)
    explanation: Orphanet phenotype data classifies airway obstruction as occasional (29-5%) in primary ciliary dyskinesia.
    evidence_source: OTHER
  phenotype_term:
    preferred_term: Airway obstruction
    term:
      id: HP:0006536
      label: Airway obstruction
- category: Respiratory
  name: Digital Clubbing
  frequency: OCCASIONAL
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: HP:0001217 | Clubbing | Occasional (29-5%)
    explanation: Orphanet phenotype data classifies digital clubbing as occasional (29-5%) in primary ciliary dyskinesia.
    evidence_source: OTHER
  phenotype_term:
    preferred_term: Clubbing
    term:
      id: HP:0001217
      label: Clubbing
- category: Cardiac
  name: Abnormal Heart Morphology
  frequency: OCCASIONAL
  notes: >-
    Congenital cardiac defects are particularly relevant to heterotaxy/situs ambiguus, not an obligatory
    consequence of complete mirror-image situs.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: HP:0001627 | Abnormal heart morphology | Occasional (29-5%)
    explanation: Orphanet phenotype data classifies abnormal heart morphology as occasional (29-5%) in primary ciliary dyskinesia.
    evidence_source: OTHER
  phenotype_term:
    preferred_term: Abnormal heart morphology
    term:
      id: HP:0001627
      label: Abnormal heart morphology
- category: Neurologic
  name: Hydrocephalus
  frequency: VERY_RARE
  notes: >-
    Uncommon across human PCD but enriched in selected genotypes, including FOXJ1. Severe or lethal
    hydrocephalus in mouse mutants must not be generalized to humans.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: HP:0000238 | Hydrocephalus | Very rare (<4-1%)
    explanation: Orphanet phenotype data classifies hydrocephalus as very rare (<4-1%) in primary ciliary dyskinesia.
    evidence_source: OTHER
  phenotype_term:
    preferred_term: Hydrocephalus
    term:
      id: HP:0000238
      label: Hydrocephalus
- category: Respiratory
  name: Respiratory Failure
  frequency: VERY_RARE
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: HP:0002878 | Respiratory failure | Very rare (<4-1%)
    explanation: Orphanet phenotype data classifies respiratory failure as very rare (<4-1%) in primary ciliary dyskinesia.
    evidence_source: OTHER
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
- category: Gastrointestinal
  name: Intestinal Malrotation
  frequency: VERY_RARE
  notes: Associated with situs abnormalities
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: HP:0002566 | Intestinal malrotation | Very rare (<4-1%)
    explanation: Orphanet phenotype data classifies intestinal malrotation as very rare (<4-1%) in primary ciliary dyskinesia.
    evidence_source: OTHER
  phenotype_term:
    preferred_term: Intestinal malrotation
    term:
      id: HP:0002566
      label: Intestinal malrotation
- name: Heterotaxy
  category: Developmental
  description: >-
    Discordant organ laterality or situs ambiguus, sometimes accompanied by complex congenital cardiovascular
    defects. Definitions differ between studies; the cited 559-person cohort used a narrower complex-cardiovascular
    definition for heterotaxy.
  phenotype_term:
    preferred_term: Heterotaxy
    term:
      id: HP:0030853
      label: Heterotaxy
  evidence:
  - reference: PMID:36342963
    reference_title: 'Laterality Defects in Primary Ciliary Dyskinesia: Relationship to Ultrastructural Defect or Genotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Of 559 participants, 286 (51.2%), 215 (38.5%), and 58 (10.4%) were identified as having situs solitus, situs inversustotalis, and situs ambiguus, respectively
    explanation: >-
      Human laterality distributions distinguish total inversion from situs ambiguus. Heterotaxy
      definitions vary; this study restricted heterotaxy to ambiguus with complex cardiovascular
      defects (14/559).
- name: Ectopic Pregnancy
  category: Reproductive
  description: >-
    Increased risk has been reported among pregnancies in women with PCD; absolute estimates depend
    on the surveyed reproductive population.
  phenotype_term:
    preferred_term: Ectopic pregnancy
  evidence:
  - reference: PMID:41561099
    reference_title: 'Primary ciliary dyskinesia: a national expert consensus statement on standards of care.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: women might be at higher risk of ectopic pregnancies
    explanation: >-
      PCD reproductive-care consensus recognizes this risk while recommending individualized fertility
      counseling.
biochemical:
- name: Nasal Nitric Oxide
  presence: Decreased
  context: Often reduced nasal NO production rate; assay protocol, age and genotype affect interpretation
  evidence:
  - reference: PMID:41005984
    reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Low nNO levels are described in most individuals with PCD compared to healthy and disease controls, although reasons for the low nNO remain uncertain.
    explanation: >-
      The joint guideline states that nasal NO is low in most, not all, people with PCD relative
      to both healthy and disease controls, and that the cause of the low level is unknown.
  - reference: PMID:41005984
    reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Some patients with PCD have nNO levels above the recommended threshold for diagnosis, and other tests should be considered if the clinical suspicion of PCD remains.
    explanation: >-
      Supports the band stating that a value at or above the threshold does not exclude PCD.
  - reference: PMID:24024753
    reference_title: Standardizing nasal nitric oxide measurement as a test for primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The disease-specific nNO cutoff value was defined at 77 nl/minute (sensitivity, 0.98; specificity, >0.999).
    explanation: >-
      Original standardized cutoff study. The quoted specificity primarily reflects comparison with
      healthy controls; it should not be applied to every symptomatic referral population.
  - reference: PMID:39362668
    reference_title: Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Careful evaluation revealed that C1d-defective primary ciliary dyskinesia is associated with normal situs composition, normal nasal nitric oxide production rates, normal ciliary ultrastructure by transmission electron microscopy and normal ciliary beating by high-speed videomicroscopy analysis.
    explanation: >-
      C1d-defective PCD has normal nasal NO production rates, which is the genotype exception the
      normal-range band and the context field describe. The selected situs-solitus cohort does not
      independently estimate population laterality risk.
  - reference: PMID:23290188
    reference_title: Upper and lower airway nitric oxide levels in primary ciliary dyskinesia, cystic fibrosis and asthma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both the bronchial and alveolar NO were significantly lower in PCD than healthy controls
    explanation: >-
      Small clinical study supports compartment-specific NO differences, not a proven pan-epithelial
      genetic defect.
  - reference: PMID:24189859
    reference_title: Ciliated cultures from patients with primary ciliary dyskinesia do not produce nitric oxide or inducible nitric oxide synthase during early infection.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: No increase in NO was seen in ciliated cell cultures from patients with PCD, and NOS2 gene expression remained unchanged from baseline.
    explanation: >-
      Differentiated patient cultures show an altered infection response; molecular cause and generality
      across genotypes remain unresolved.
  reference_ranges:
  - lower_bound: 77
    unit: nL/min
    population: individuals aged 5 years and older; standardized chemiluminescence measurement during velum-closure breath-hold
    evidence:
    - reference: PMID:24024753
      reference_title: Standardizing nasal nitric oxide measurement as a test for primary ciliary dyskinesia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The disease-specific nNO cutoff value was defined at 77 nl/minute (sensitivity, 0.98; specificity, >0.999).
      explanation: Establishes the standardized 77 nL/min nasal NO diagnostic cutoff for PCD.
    - reference: PMID:24024753
      reference_title: Standardizing nasal nitric oxide measurement as a test for primary ciliary dyskinesia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: nNO values in PCD (mean ± standard deviation, 20.7 ± 24.1 nl/min; range, 1.5-207.3 nl/min) only rarely overlapped with the nNO values of healthy control subjects (304.6 ± 118.8; 125.5-867.0 nl/min)
      explanation: Documents the markedly low PCD nNO distribution versus the much higher healthy-control values that underpin the bands.
    notes: >-
      This is a diagnostic decision threshold, not a physiological reference interval or acute severity
      marker. The original 77 nL/min cutoff applies to standardized velum-closure measurements in
      cooperative subjects aged at least five; tidal-breathing measurements in younger children require
      separate protocols. CF and intercurrent viral infection can lower nNO. Normal nNO occurs in
      RSPH1, C1d and other genotypes and cannot exclude PCD. Nasal production rate is not interchangeable
      with exhaled concentration or FeNO.
    interpretation_bands:
    - name: Suggestive of primary ciliary dyskinesia
      upper_bound: 77
      unit: nL/min
      abnormal_flag: LOW
      interpretation: >-
        Below 77 nL/min is supportive in an appropriate clinical context using the specified protocol.
        Repeat testing and genetics/TEM or other adjunct testing are needed; low values also occur
        in CF and viral infection.
    - name: Above the low-nNO diagnostic threshold
      lower_bound: 77
      unit: nL/min
      abnormal_flag: NORMAL
      interpretation: >-
        A result at or above 77 nL/min does not exclude PCD. RSPH1 and C1d-related disease can have
        normal or higher production rates despite clinically important transport defects.
  notes: >-
    LOINC has no nasal nitric oxide measurement, so neither this marker nor the 77 nL/min
    bands above carry a code, and the bands are keyed to nothing. Both sources were
    enumerated in full. The LOINC 2.83 table holds 11 codes whose name contains nitric
    oxide: one is nitric oxide in exhaled gas, one the fractional concentration of
    exhaled nitric oxide, and the remaining nine are ventilator and gas-delivery-system
    codes for monitoring inhaled nitric oxide therapy. No code in the release carries
    nasal in its system together with nitric oxide, none pairs the two words in its
    name, no naming variant such as nitrogen oxide or nitrogen monoxide appears, and no
    code anywhere in the release is reported in nL/min, the unit this measurement uses.
    The Monarch KG, asked separately because that table carries no Part codes and
    paginated to its stated totals, returns 12 nitric oxide records with one Part,
    nitric oxide unqualified; zero records for nasal nitric oxide; and 30 nasal records
    whose only Part is the specimen nasal fluid. The two exhaled codes are deliberately
    not substituted: nasal nitric oxide is a production rate from the nasal cavity
    measured during velum closure, while those code a concentration in breath from the
    lower airway, which is the asthma marker rather than this test. The unqualified
    nitric oxide Part is not bound either: it sits above twelve records spanning nasal
    screening, an asthma marker and ventilator therapy, so it carries almost none of
    the specificity this marker needs and would discriminate none of them.

    Low bronchial and modeled alveolar NO and impaired NOS2 induction after infection in small PCD
    cell studies suggest altered NO biology. These observations do not establish a universal mutation-intrinsic,
    pan-epithelial immune defect or a validated nNO prognostic surrogate.
genetic:
- name: DNAI1
  gene_term:
    preferred_term: DNAI1
    term:
      id: hgnc:2954
      label: DNAI1
  subtype: CILD1
  association: Pathogenic Variants
  notes: Outer dynein arm intermediate chain required for ODA integrity and docking
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: DNAI1 | dynein axonemal intermediate chain 1 | hgnc:2954 | Disease-causing germline mutation(s) in
    explanation: Orphanet gene-disease association data confirms DNAI1 as a disease-causing gene for primary ciliary dyskinesia.
    evidence_source: OTHER
  - reference: PMID:35869935
    reference_title: Pathogenic variants identified using whole-exome sequencing in Chinese patients with primary ciliary dyskinesia.
    supports: SUPPORT
    snippet: 13 rare variants were identified in patients with PCD, among which were three homozygous causative variants (including one splicing variant) in the PCD-associated genes CCDC40 and DNAI1.
    explanation: The study identifies causative variants in DNAI1 associated with primary ciliary dyskinesia.
  - reference: PMID:15750039
    reference_title: Mislocalization of DNAH5 and DNAH9 in respiratory cells from patients with primary ciliary dyskinesia.
    supports: SUPPORT
    snippet: The most frequent genetic defects comprise recessive mutations of DNAH5 and DNAI1, which encode outer dynein arm (ODA) components.
    explanation: This study mentions DNAI1 mutations as frequent genetic defects causing primary ciliary dyskinesia.
  - reference: PMID:11231901
    reference_title: Axonemal dynein intermediate-chain gene (DNAI1) mutations result in situs inversus and primary ciliary dyskinesia (Kartagener syndrome).
    supports: SUPPORT
    snippet: We identified compound heterozygous DNAI1 gene defects in three independent patients and in two of their siblings who presented with PCD and situs solitus (i.e., normal position of inner organs).
    explanation: >-
      Human DNAI1 families include both situs solitus and inversion, consistent with genotype-dependent
      impairment of laterality specification.
    evidence_source: HUMAN_CLINICAL
- name: DNAH5
  gene_term:
    preferred_term: DNAH5
    term:
      id: hgnc:2950
      label: DNAH5
  subtype: CILD3
  association: Pathogenic Variants
  notes: Major axonemal outer dynein arm heavy chain generating motile force
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: DNAH5 | dynein axonemal heavy chain 5 | hgnc:2950 | Disease-causing germline mutation(s) in
    explanation: Orphanet gene-disease association data confirms DNAH5 as a disease-causing gene for primary ciliary dyskinesia.
    evidence_source: OTHER
  - reference: PMID:31118369
    reference_title: A Japanese Case of Primary Ciliary Dyskinesia with DNAH5 Mutations.
    supports: SUPPORT
    snippet: A genetic examination detected compound heterozygous mutations of DNAH5 that encode ODA components.
    explanation: The study reports a case of primary ciliary dyskinesia (PCD) with DNAH5 mutations, confirming the association between PCD and pathogenic variants in DNAH5.
- name: DNAH11
  gene_term:
    preferred_term: DNAH11
    term:
      id: hgnc:2942
      label: DNAH11
  subtype: CILD7
  association: Pathogenic Variants
  notes: >-
    Often normal routine TEM with hyperkinetic, stiff or ineffective beating. Some cohorts show milder
    group outcomes, but a small direct DNAH5 comparison was nonsignificant and did not establish
    equivalence. Normal TEM and lower neonatal-distress frequency do not exclude disease.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: DNAH11 | dynein axonemal heavy chain 11 | hgnc:2942 | Disease-causing germline mutation(s) in
    explanation: Orphanet gene-disease association data confirms DNAH11 as a disease-causing gene for primary ciliary dyskinesia.
    evidence_source: OTHER
  - reference: PMID:40344341
    reference_title: The Association of Neonatal Respiratory Distress With Ciliary Ultrastructure and Genotype in Primary Ciliary Dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'The odds ratio for NRD in the DNAH11 group was significantly lower (OR: 0.35, 95% CI: 0.16-0.76) compared to NRD in the ODA group.'
    explanation: >-
      Phenotype-specific association with neonatal distress, not a universal lung-function prognosis.
- name: CCDC39
  gene_term:
    preferred_term: CCDC39
    term:
      id: hgnc:25244
      label: CCDC39
  subtype: CILD14
  association: Pathogenic Variants
  notes: >-
    Axonemal scaffold deficiency causes IDA/MTD and broad protein-network loss. Worse group lung
    function and growth are supported; patient-cell proteostasis/fate/barrier effects are a candidate
    additional mechanism, not yet demonstrated clinical mediation.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: CCDC39 | coiled-coil domain 39 molecular ruler complex subunit | hgnc:25244 | Disease-causing germline mutation(s) in
    explanation: Orphanet gene-disease association data confirms CCDC39 as a disease-causing gene for primary ciliary dyskinesia.
    evidence_source: OTHER
  - reference: PMID:39879322
    reference_title: Undocking of an extensive ciliary network induces proteostasis and cell fate switching resulting in severe primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the absence of the axonemal CCDC39/CCDC40 heterodimer resulted in the loss of a network of more than 90 ciliary structural proteins
    explanation: >-
      Patient-cilia proteomics and cross-species structural work establish a broad scaffold-dependent
      protein network. The preprint PMID:38562900 is the same study, not an independent replication.
- name: CCDC40
  gene_term:
    preferred_term: CCDC40
    term:
      id: hgnc:26090
      label: CCDC40
  subtype: CILD15
  association: Pathogenic Variants
  notes: >-
    Axonemal scaffold deficiency causes IDA/MTD and broad protein-network loss. Worse group lung
    function and growth are supported; patient-cell proteostasis/fate/barrier effects are a candidate
    additional mechanism, not yet demonstrated clinical mediation.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: CCDC40 | coiled-coil domain 40 molecular ruler complex subunit | hgnc:26090 | Disease-causing germline mutation(s) in
    explanation: Orphanet gene-disease association data confirms CCDC40 as a disease-causing gene for primary ciliary dyskinesia.
    evidence_source: OTHER
  - reference: PMID:39879322
    reference_title: Undocking of an extensive ciliary network induces proteostasis and cell fate switching resulting in severe primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the absence of the axonemal CCDC39/CCDC40 heterodimer resulted in the loss of a network of more than 90 ciliary structural proteins
    explanation: >-
      Patient-cilia proteomics and cross-species structural work establish a broad scaffold-dependent
      protein network. The preprint PMID:38562900 is the same study, not an independent replication.
- name: RSPH1
  gene_term:
    preferred_term: RSPH1
    term:
      id: hgnc:12371
      label: RSPH1
  subtype: CILD24
  association: Pathogenic Variants
  notes: Radial spoke head component coordinating central pair-dynein regulation
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: RSPH1 | radial spoke head component 1 | hgnc:12371 | Disease-causing germline mutation(s) (loss of function) in
    explanation: Orphanet gene-disease association data confirms RSPH1 as a disease-causing gene for primary ciliary dyskinesia.
    evidence_source: OTHER
- name: RSPH4A
  gene_term:
    preferred_term: RSPH4A
    term:
      id: hgnc:21558
      label: RSPH4A
  subtype: CILD11
  association: Pathogenic Variants
  notes: Radial spoke protein required for radial spoke integrity and coordinated beating
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: RSPH4A | radial spoke head component 4A | hgnc:21558 | Disease-causing germline mutation(s) in
    explanation: Orphanet gene-disease association data confirms RSPH4A as a disease-causing gene for primary ciliary dyskinesia.
    evidence_source: OTHER
- name: RSPH9
  gene_term:
    preferred_term: RSPH9
    term:
      id: hgnc:21057
      label: RSPH9
  subtype: CILD12
  association: Pathogenic Variants
  notes: Radial spoke head subunit impacting central pair-radial spoke interactions
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: RSPH9 | radial spoke head component 9 | hgnc:21057 | Disease-causing germline mutation(s) in
    explanation: Orphanet gene-disease association data confirms RSPH9 as a disease-causing gene for primary ciliary dyskinesia.
    evidence_source: OTHER
- name: CCNO
  gene_term:
    preferred_term: CCNO
    term:
      id: hgnc:18576
      label: CCNO
  subtype: CILD29
  association: Pathogenic Variants
  notes: >-
    Required for centriole amplification and multiciliogenesis. Small case series and the multinational
    registry show severe group respiratory burden, but outcomes vary; fixed severity tiers and obligatory
    early deterioration are not established. Hydrocephalus estimates from small pooled cases are
    not general PCD frequencies.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: CCNO | cyclin O | hgnc:18576 | Disease-causing germline mutation(s) (loss of function) in
    explanation: Orphanet gene-disease association data confirms CCNO as a disease-causing gene for primary ciliary dyskinesia.
    evidence_source: OTHER
- name: FOXJ1
  gene_term:
    preferred_term: FOXJ1
    term:
      id: hgnc:3816
      label: FOXJ1
  subtype: CILD43
  association: Pathogenic Variants
  notes: Master transcription factor regulating motile ciliogenesis; can present in autosomal dominant fashion
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: FOXJ1 | forkhead box J1 | hgnc:3816 | Disease-causing germline mutation(s) (loss of function) in
    explanation: Orphanet gene-disease association data confirms FOXJ1 as a disease-causing gene for primary ciliary dyskinesia.
    evidence_source: OTHER
- name: MCIDAS
  gene_term:
    preferred_term: MCIDAS
    term:
      id: hgnc:40050
      label: MCIDAS
  subtype: CILD42
  association: Pathogenic Variants
  notes: Drives multiciliated cell differentiation and centriole biogenesis; associated with reduced cilia number
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: MCIDAS | multiciliate differentiation and DNA synthesis associated cell cycle protein | hgnc:40050 | Disease-causing germline mutation(s) (loss of function) in
    explanation: Orphanet gene-disease association data confirms MCIDAS as a disease-causing gene for primary ciliary dyskinesia.
    evidence_source: OTHER
- name: ODAD1
  gene_term:
    preferred_term: ODAD1
    term:
      id: hgnc:26560
      label: ODAD1
  subtype: CILD20
  association: Pathogenic Variants
  notes: >-
    Outer dynein-arm docking factor. The multinational registry associates this group with relatively
    milder FEV1 z-scores; this is a cross-sectional group association, not a guaranteed individual
    trajectory.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    snippet: ODAD1 | outer dynein arm docking complex subunit 1 | hgnc:26560 | Disease-causing germline mutation(s) (loss of function) in
    explanation: Orphanet gene-disease association data confirms ODAD1 as a disease-causing gene for primary ciliary dyskinesia.
    evidence_source: OTHER
- name: CFAP221
  gene_term:
    preferred_term: CFAP221
    term:
      id: hgnc:33720
      label: CFAP221
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_c7c841e5-2973-4f23-8603-970e9e2cbc92-2025-12-16T120000.000Z
    reference_title: CFAP221 / primary ciliary dyskinesia (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CFAP221 | HGNC:33720 | primary ciliary dyskinesia | MONDO:0016575 | AR | Definitive
    explanation: ClinGen classifies the CFAP221-primary ciliary dyskinesia gene-disease relationship as definitive with autosomal recessive inheritance.
- name: CFAP46
  gene_term:
    preferred_term: CFAP46
    term:
      id: hgnc:25247
      label: CFAP46
  subtype: CFAP46-related
  association: Limited evidence for PCD association
  evidence:
  - reference: CGGV:assertion_eabe809a-1203-4d42-9052-21f39717754f-2025-10-17T160000.000Z
    reference_title: CFAP46 / primary ciliary dyskinesia (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CFAP46 | HGNC:25247 | primary ciliary dyskinesia | MONDO:0016575 | AR | Limited
    explanation: ClinGen classifies the CFAP46-primary ciliary dyskinesia gene-disease relationship as limited with autosomal recessive inheritance.
  notes: >2-
     The cited ClinGen assessment is Limited; this should not be treated as equivalent to a definitive
    diagnostic gene-disease relationship.
- name: CFAP54
  gene_term:
    preferred_term: CFAP54
    term:
      id: hgnc:26456
      label: CFAP54
  subtype: CILD54
  association: Pathogenic Variants
  notes: >-
    C1d central-apparatus component. Patient studies demonstrate impaired ciliary transport despite
    normal routine diagnostics. ClinGen Strong gene-validity evidence is distinct from the grade
    for other C1d genes.
  evidence:
  - reference: CGGV:assertion_f16ea0ce-7d5d-4bdc-92fe-52d111913161-2025-07-16T070000.000Z
    reference_title: CFAP54 / ciliary dyskinesia, primary, 54 (Strong)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CFAP54 | HGNC:26456 | ciliary dyskinesia, primary, 54 | MONDO:0100607 | AR | Strong
    explanation: ClinGen's Motile Ciliopathy Gene Curation Expert Panel classifies the CFAP54-primary ciliary dyskinesia relationship as Strong with autosomal recessive inheritance.
  - reference: CGGV:assertion_f16ea0ce-7d5d-4bdc-92fe-52d111913161-2025-07-16T070000.000Z
    reference_title: CFAP54 / ciliary dyskinesia, primary, 54 (Strong)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Nodal cilia lack a central pair apparatus, so mouse models as well as
      humans with CFAP54 -PCD would not be expected to develop the laterality
      defects often associated with PCD.
    explanation: >-
      Explains mechanistically why situs is normal in this PCD type, rather than
      leaving it as an unexplained observation.
  - reference: PMID:39362668
    reference_title: Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance.
    explanation: >-
      C1d-defective patient cells show transport failure despite normal routine TEM, nasal NO and
      high-speed beat assessment. The selected situs-solitus cohort does not independently estimate
      population laterality risk.
- name: CFAP57
  gene_term:
    preferred_term: CFAP57
    term:
      id: hgnc:26485
      label: CFAP57
  association: Limited evidence for PCD association
  evidence:
  - reference: CGGV:assertion_50ed292f-0044-4c82-9419-a040cbcaf205-2022-06-23T160000.000Z
    reference_title: CFAP57 / primary ciliary dyskinesia (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CFAP57 | HGNC:26485 | primary ciliary dyskinesia | MONDO:0016575 | AR | Limited
    explanation: ClinGen classifies the CFAP57-primary ciliary dyskinesia gene-disease relationship as limited with autosomal recessive inheritance.
  notes: >2-
     The cited ClinGen assessment is Limited; this should not be treated as equivalent to a definitive
    diagnostic gene-disease relationship.
- name: DAW1
  gene_term:
    preferred_term: DAW1
    term:
      id: hgnc:26383
      label: DAW1
  subtype: CILD52
  association: Limited evidence for PCD association
  evidence:
  - reference: CGGV:assertion_8610990f-63cf-466a-8cd7-fbf7ae58d0f2-2024-06-13T160000.000Z
    reference_title: DAW1 / primary ciliary dyskinesia (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DAW1 | HGNC:26383 | primary ciliary dyskinesia | MONDO:0016575 | AR | Limited
    explanation: ClinGen classifies the DAW1-primary ciliary dyskinesia gene-disease relationship as limited with autosomal recessive inheritance.
  notes: >2-
     The cited ClinGen assessment is Limited; this should not be treated as equivalent to a definitive
    diagnostic gene-disease relationship.
- name: DNAH1
  gene_term:
    preferred_term: DNAH1
    term:
      id: hgnc:2940
      label: DNAH1
  subtype: CILD37
  association: Limited evidence for PCD association
  evidence:
  - reference: CGGV:assertion_a07c8b6e-a558-498b-975c-b12e96878a44-2025-10-16T160000.000Z
    reference_title: DNAH1 / primary ciliary dyskinesia (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DNAH1 | HGNC:2940 | primary ciliary dyskinesia | MONDO:0016575 | AR | Limited
    explanation: ClinGen classifies the DNAH1-primary ciliary dyskinesia gene-disease relationship as limited with autosomal recessive inheritance.
  notes: >2-
     The cited ClinGen assessment is Limited; this should not be treated as equivalent to a definitive
    diagnostic gene-disease relationship.
- name: DNAH10
  gene_term:
    preferred_term: DNAH10
    term:
      id: hgnc:2941
      label: DNAH10
  association: Limited evidence for PCD association
  evidence:
  - reference: CGGV:assertion_698c6b23-a6fb-4b56-a38e-b29d5f8bbd86-2025-02-13T170000.000Z
    reference_title: DNAH10 / primary ciliary dyskinesia (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DNAH10 | HGNC:2941 | primary ciliary dyskinesia | MONDO:0016575 | AR | Limited
    explanation: ClinGen classifies the DNAH10-primary ciliary dyskinesia gene-disease relationship as limited with autosomal recessive inheritance.
  notes: >2-
     The cited ClinGen assessment is Limited; this should not be treated as equivalent to a definitive
    diagnostic gene-disease relationship.
- name: DNAH7
  gene_term:
    preferred_term: DNAH7
    term:
      id: hgnc:18661
      label: DNAH7
  subtype: CILD50
  association: Limited evidence for PCD association
  evidence:
  - reference: CGGV:assertion_90a097d6-5127-4466-8c81-00e99dab2696-2025-02-13T170000.000Z
    reference_title: DNAH7 / primary ciliary dyskinesia (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DNAH7 | HGNC:18661 | primary ciliary dyskinesia | MONDO:0016575 | AR | Limited
    explanation: ClinGen classifies the DNAH7-primary ciliary dyskinesia gene-disease relationship as limited with autosomal recessive inheritance.
  notes: >2-
     The cited ClinGen assessment is Limited; this should not be treated as equivalent to a definitive
    diagnostic gene-disease relationship.
- name: NME8
  gene_term:
    preferred_term: NME8
    term:
      id: hgnc:16473
      label: NME8
  relationship_type: DISPUTED
  subtype: CILD6
  association: Disputed ClinGen gene-disease validity for PCD
  gene_disease_validity:
  - validity_classification: DISPUTED
    classified_by: CLINGEN
    external_id: CGGV:assertion_57ca8383-55b6-4edd-9be2-67b1c5142ed1-2026-03-12T000000.000Z
    evidence:
    - reference: CGGV:assertion_57ca8383-55b6-4edd-9be2-67b1c5142ed1-2026-03-12T000000.000Z
      reference_title: NME8 / primary ciliary dyskinesia (Disputed)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: NME8 | HGNC:16473 | primary ciliary dyskinesia | MONDO:0016575 | AR | Disputed
      explanation: ClinGen classifies the NME8-primary ciliary dyskinesia gene-disease relationship as Disputed.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'NME8 | NME/NM23 family member 8 | hgnc:16473 | Disease-causing germline mutation(s) in'
    explanation: >-
      Orphanet still lists NME8 as a disease-causing gene for primary ciliary dyskinesia.
  - reference: CGGV:assertion_57ca8383-55b6-4edd-9be2-67b1c5142ed1-2026-03-12T000000.000Z
    reference_title: NME8 / primary ciliary dyskinesia (Disputed)
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      the genetic evidence is limited to a single report with incomplete genomic investigation, and
      subsequent expression studies have not demonstrated NME8 expression in human airway ciliated cells
    explanation: >-
      ClinGen's evidence summary gives the two grounds for disputing NME8 as a primary ciliary dyskinesia
      gene: a single proband identified by gene-targeted methods, and no detectable NME8 expression in
      human airway ciliated cells.
  - reference: CGGV:assertion_57ca8383-55b6-4edd-9be2-67b1c5142ed1-2026-03-12T000000.000Z
    reference_title: NME8 / primary ciliary dyskinesia (Disputed)
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      While most PCD genes were strongly upregulated during differentiation, NME8 was the only gene that
      showed no detectable expression throughout the experiment.
    explanation: >-
      Of 26 PCD genes followed through airway epithelial ciliogenesis, NME8 was the only one never
      expressed, which argues against a role in motile airway cilia.
  notes: >-
    ClinGen reclassified the NME8-primary ciliary dyskinesia relationship from Limited (2023-06-08) to
    Disputed (2026-03-12) under the same assertion identifier. The only human report is one compound
    heterozygous proband (PMID:17360648), one of whose two variants is an intronic allele at about 2% in
    controls, and NME8 orthologs are mainly sperm-axoneme proteins. Orphanet still lists NME8 as
    disease-causing, so the two sources disagree; this record follows the ClinGen classification.
- name: SPEF2
  gene_term:
    preferred_term: SPEF2
    term:
      id: hgnc:26293
      label: SPEF2
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_e137eed5-fcd8-4497-a6dc-6651062d1cf3-2025-01-09T170000.000Z
    reference_title: SPEF2 / primary ciliary dyskinesia (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: SPEF2 | HGNC:26293 | primary ciliary dyskinesia | MONDO:0016575 | AR | Definitive
    explanation: ClinGen classifies the SPEF2-primary ciliary dyskinesia gene-disease relationship as definitive with autosomal recessive inheritance.
- name: DNAH9
  gene_term:
    preferred_term: DNAH9
    term:
      id: hgnc:2953
      label: DNAH9
  subtype: CILD40
  association: Pathogenic variants
  inheritance:
  - name: Autosomal recessive
  notes: >-
    Distal ODA heavy-chain loss causes laterality defects with potentially subtle respiratory beating
    abnormalities. Mild respiratory findings do not mean harmless laterality outcomes.
  evidence:
  - reference: PMID:30471718
    reference_title: Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we report loss-of-function mutations in DNAH9 in five independent families causing situs abnormalities associated with subtle respiratory ciliary dysfunction.
    explanation: >-
      Human families and functional localization studies support this tissue-dependent genotype.
- name: TUBB4B
  gene_term:
    preferred_term: TUBB4B
    term:
      id: hgnc:20771
      label: TUBB4B
  association: Pathogenic variants
  inheritance:
  - name: Autosomal dominant
  notes: >-
    Specific dominant-negative variants impair centriole/cilium biogenesis. The broader TUBB4B allelic
    spectrum includes sensory or mixed ciliopathy phenotypes; not every TUBB4B variant causes respiratory
    PCD.
  evidence:
  - reference: PMID:38662826
    reference_title: Ciliopathy patient variants reveal organelle-specific functions for TUBB4B in axonemal microtubules.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Distinct TUBB4B variants differentially affected microtubule dynamics and cilia formation in a dominant-negative manner.
    explanation: >-
      Twelve-patient PCD cohort with model and structure-function studies supports an additional
      dominant mechanism beyond FOXJ1.
- name: CFAP74
  gene_term:
    preferred_term: CFAP74
    term:
      id: hgnc:29368
      label: CFAP74
  subtype: CILD49
  association: Pathogenic variants
  inheritance:
  - name: Autosomal recessive
  notes: >-
    C1d central-apparatus component implicated in transport-defective PCD despite normal routine
    measurements; phenotype and clinical validity require gene-specific interpretation.
  evidence:
  - reference: PMID:39362668
    reference_title: Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance.
    explanation: >-
      C1d-defective patient cells show transport failure despite normal routine TEM, nasal NO and
      high-speed beat assessment. The selected situs-solitus cohort does not independently estimate
      population laterality risk.
- name: GAS2L2
  gene_term:
    preferred_term: GAS2L2
    term:
      id: hgnc:24846
      label: GAS2L2
  association: Biallelic variants associated with ciliary disorientation and PCD
  evidence:
  - reference: PMID:30665704
    reference_title: Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Further genetic screening of unrelated PCD subjects identified a second proband with a compound heterozygous variant carrying the identical frameshift variant and a large deletion (c.867_∗343+1207del; p.?) starting in exon 5.
    explanation: A second unrelated proband carries biallelic GAS2L2 variants. The original cohort is small and does not establish variant-specific natural history.
  notes: The discovery study included two probands with normal ciliary axoneme structure; the detailed nasal culture phenotype came from one individual. Association evidence is not a pan-PCD orientation rule.
- name: DNAAF1
  gene_term:
    preferred_term: DNAAF1
    term:
      id: hgnc:30539
      label: DNAAF1
  relationship_type: CAUSATIVE
  subtype: CILD13
  association: Pathogenic Variants
  notes: >-
    Cytoplasmic dynein-arm preassembly factor (previous symbol LRRC50, also known as ODA7).
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF1 | dynein axonemal assembly factor 1 | hgnc:30539 | Disease-causing germline mutation(s) in'
    explanation: >-
      Orphanet gene-disease association row listing DNAAF1 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_41e4b8cd-35bd-4e99-ba2d-606f191a13cf-2023-03-09T170000.000Z
    reference_title: 'DNAAF1 / primary ciliary dyskinesia 13 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF1 | HGNC:30539 | primary ciliary dyskinesia 13 | MONDO:0013174 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2023-03-09T17:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding DNAAF1 to primary ciliary dyskinesia 13 (MONDO:0013174)
      with classification Definitive.
  - reference: PMID:22387996
    reference_title: Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Altered abundance of dynein subunits in mutant cytoplasm suggests that DNAAF3 (PF22) acts at a similar stage as other preassembly proteins, for example, DNAAF2 (also known as PF13 or KTU) and DNAAF1 (also known as ODA7 or LRRC50), in the dynein preassembly pathway.
    explanation: >-
      Names DNAAF1 as ODA7 or LRRC50 and places it in the cytoplasmic dynein preassembly pathway.
- name: DNAAF2
  gene_term:
    preferred_term: DNAAF2
    term:
      id: hgnc:20188
      label: DNAAF2
  relationship_type: CAUSATIVE
  subtype: CILD10
  association: Pathogenic Variants
  notes: >-
    Cytoplasmic dynein-arm preassembly factor (also known as KTU or PF13); reported as part of a
    DNAAF2-DNAAF4-HSP90 co-chaperone complex.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF2 | dynein axonemal assembly factor 2 | hgnc:20188 | Disease-causing germline mutation(s) in'
    explanation: >-
      Orphanet gene-disease association row listing DNAAF2 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_39e5de96-3f16-4dde-a7bc-b3e27364b7f8-2024-02-08T170000.000Z
    reference_title: 'DNAAF2 / primary ciliary dyskinesia 10 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF2 | HGNC:20188 | primary ciliary dyskinesia 10 | MONDO:0012918 | AR | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-02-08T17:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding DNAAF2 to primary ciliary dyskinesia 10 (MONDO:0012918)
      with classification Definitive.
  - reference: PMID:28176794
    reference_title: 'X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: 'multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2-DNAAF4-HSP90 complex'
    explanation: >-
      Places DNAAF2 in the cytoplasmic dynein preassembly complex.
  - reference: PMID:22387996
    reference_title: Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Altered abundance of dynein subunits in mutant cytoplasm suggests that DNAAF3 (PF22) acts at a similar stage as other preassembly proteins, for example, DNAAF2 (also known as PF13 or KTU) and DNAAF1 (also known as ODA7 or LRRC50), in the dynein preassembly pathway.
    explanation: >-
      Names DNAAF2 as PF13 or KTU and places it in the cytoplasmic dynein preassembly pathway.
- name: DNAAF3
  gene_term:
    preferred_term: DNAAF3
    term:
      id: hgnc:30492
      label: DNAAF3
  relationship_type: CAUSATIVE
  subtype: CILD2
  association: Pathogenic Variants
  notes: >-
    Cytoplasmic dynein-arm preassembly factor (also known as PF22), acting at the same stage as DNAAF1 and
    DNAAF2.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF3 | dynein axonemal assembly factor 3 | hgnc:30492 | Disease-causing germline mutation(s) in'
    explanation: >-
      Orphanet gene-disease association row listing DNAAF3 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_40329b6f-2d65-49dd-863b-f79dcd1b5a23-2022-05-09T155600.823Z
    reference_title: 'DNAAF3 / primary ciliary dyskinesia 2 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF3 | HGNC:30492 | primary ciliary dyskinesia 2 | MONDO:0011718 | AR | Definitive | SOP8 | Motile Ciliopathy Gene Curation Expert Panel | 2022-05-09T15:56:00.823Z'
    explanation: >-
      ClinGen gene-disease validity row binding DNAAF3 to primary ciliary dyskinesia 2 (MONDO:0011718) with
      classification Definitive.
  - reference: PMID:22387996
    reference_title: 'Mutations in axonemal dynein assembly factor DNAAF3 cause primary ciliary dyskinesia.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'Altered abundance of dynein subunits in mutant cytoplasm suggests that DNAAF3 (PF22) acts at a similar stage as other preassembly proteins, for example, DNAAF2 (also known as PF13 or KTU) and DNAAF1 (also known as ODA7 or LRRC50), in the dynein preassembly pathway.'
    explanation: >-
      Places DNAAF3 alongside DNAAF1 and DNAAF2 in the cytoplasmic dynein preassembly pathway.
- name: DNAAF4
  gene_term:
    preferred_term: DNAAF4
    term:
      id: hgnc:21493
      label: DNAAF4
  relationship_type: CAUSATIVE
  subtype: CILD25
  association: Pathogenic Variants
  notes: >-
    Cytoplasmic dynein-arm preassembly factor (previous symbol DYX1C1); reported as part of a
    DNAAF2-DNAAF4-HSP90 co-chaperone complex.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF4 | dynein axonemal assembly factor 4 | hgnc:21493 | Disease-causing germline mutation(s) (loss of function) in'
    explanation: >-
      Orphanet gene-disease association row listing DNAAF4 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_79950f5d-fd90-4765-9f8a-489c3f862fcd-2024-04-11T160000.000Z
    reference_title: 'DNAAF4 / primary ciliary dyskinesia 25 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF4 | HGNC:21493 | primary ciliary dyskinesia 25 | MONDO:0014203 | AR | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-04-11T16:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding DNAAF4 to primary ciliary dyskinesia 25 (MONDO:0014203)
      with classification Definitive.
  - reference: PMID:28176794
    reference_title: 'X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: 'multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2-DNAAF4-HSP90 complex'
    explanation: >-
      Places DNAAF4 in the cytoplasmic dynein preassembly complex.
- name: DNAAF5
  gene_term:
    preferred_term: DNAAF5
    term:
      id: hgnc:26013
      label: DNAAF5
  relationship_type: CAUSATIVE
  subtype: CILD18
  association: Pathogenic Variants
  notes: >-
    Cytoplasmic dynein-arm assembly factor (previous symbol HEATR2), localised to the cytoplasm rather than
    to cilia.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF5 | dynein axonemal assembly factor 5 | hgnc:26013 | Disease-causing germline mutation(s) in'
    explanation: >-
      Orphanet gene-disease association row listing DNAAF5 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_9b47c717-e0a5-43ce-865b-0b14289216d7-2024-06-19T110000.000Z
    reference_title: 'DNAAF5 / primary ciliary dyskinesia 18 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF5 | HGNC:26013 | primary ciliary dyskinesia 18 | MONDO:0013940 | AR | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-06-19T11:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding DNAAF5 to primary ciliary dyskinesia 18 (MONDO:0013940)
      with classification Definitive.
  - reference: PMID:23040496
    reference_title: 'Whole-exome capture and sequencing identifies HEATR2 mutation as a cause of primary ciliary dyskinesia.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'HEATR2 was localized to the cytoplasm and not in cilia, which suggests a role in either dynein arm transport or assembly'
    explanation: >-
      Cytoplasmic rather than ciliary localisation of the DNAAF5 product in human airway epithelial cells.
- name: DNAAF6
  gene_term:
    preferred_term: DNAAF6
    term:
      id: hgnc:28570
      label: DNAAF6
  relationship_type: CAUSATIVE
  subtype: CILD36
  association: Pathogenic Variants
  notes: >-
    X-linked cytoplasmic dynein-arm preassembly factor (previous symbol PIH1D3). ClinGen records X-linked
    inheritance for this gene-disease relationship.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF6 | PIH1 domain containing 3 | hgnc:28570 | Disease-causing germline mutation(s) (loss of function) in'
    explanation: >-
      Orphanet gene-disease association row listing DNAAF6 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_5de9de15-2c09-48f5-bcaf-08c42b97700e-2024-08-17T190000.000Z
    reference_title: 'DNAAF6 / ciliary dyskinesia, primary, 36, X-linked (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF6 | HGNC:28570 | ciliary dyskinesia, primary, 36, X-linked | MONDO:0010517 | XL | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-08-17T19:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding DNAAF6 to ciliary dyskinesia, primary, 36, X-linked
      (MONDO:0010517) with classification Definitive.
  - reference: PMID:28176794
    reference_title: X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we demonstrate that large genomic deletions as well as point mutations involving PIH1D3 are responsible for an X-linked form of PCD causing disruption of early axonemal dynein assembly.
    explanation: >-
      Establishes PIH1D3, now DNAAF6, as the cause of an X-linked form of PCD acting through early
      axonemal dynein assembly.
- name: DNAAF11
  gene_term:
    preferred_term: DNAAF11
    term:
      id: hgnc:16725
      label: DNAAF11
  relationship_type: CAUSATIVE
  subtype: CILD19
  association: Pathogenic Variants
  notes: >-
    Dynein-arm assembly factor (previous symbol LRRC6). Patient airway cells lack both dynein arms.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF11 | dynein axonemal assembly factor 11 | hgnc:16725 | Disease-causing germline mutation(s) (loss of function) in'
    explanation: >-
      Orphanet gene-disease association row listing DNAAF11 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_7063ef1e-8ce2-4f35-a765-f08efc2e541a-2023-06-08T160000.000Z
    reference_title: 'DNAAF11 / primary ciliary dyskinesia 19 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF11 | HGNC:16725 | primary ciliary dyskinesia 19 | MONDO:0013979 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2023-06-08T16:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding DNAAF11 to primary ciliary dyskinesia 19 (MONDO:0013979)
      with classification Definitive.
  - reference: PMID:23122589
    reference_title: 'Loss-of-function mutations in LRRC6, a gene essential for proper axonemal assembly of inner and outer dynein arms, cause primary ciliary dyskinesia.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'The evolutionarily conserved LRRC6, therefore, emerges as an additional player in DA assembly'
    explanation: >-
      Assigns the DNAAF11 product a role in dynein-arm assembly.
  - reference: PMID:23122589
    reference_title: 'Loss-of-function mutations in LRRC6, a gene essential for proper axonemal assembly of inner and outer dynein arms, cause primary ciliary dyskinesia.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'In spite of structural and functional similarities between LRRC6 and DNAAF1, another LRR-containing protein involved in the same PCD phenotype, the two proteins are not redundant.'
    explanation: >-
      DNAAF11 and DNAAF1 are not functionally interchangeable despite their shared domain architecture and
      shared PCD phenotype.
  - reference: PMID:23122589
    reference_title: Loss-of-function mutations in LRRC6, a gene essential for proper axonemal assembly of inner and outer dynein arms, cause primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Study of native LRRC6 in airway epithelial cells revealed that it localizes to the cytoplasm and within cilia, whereas it is absent from cells with loss-of-function mutations, in which DA protein markers are also missing.
    explanation: >-
      Records loss of dynein-arm protein markers in patient airway cells carrying LRRC6, now DNAAF11,
      loss-of-function variants.
- name: DNAAF19
  gene_term:
    preferred_term: DNAAF19
    term:
      id: hgnc:32700
      label: CCDC103
  relationship_type: CAUSATIVE
  subtype: CILD17
  association: Pathogenic Variants
  notes: >-
    Despite the DNAAF symbol, the product is axoneme-associated and acts as a dynein-arm attachment factor
    rather than a cytoplasmic preassembly factor. HGNC's current approved symbol is DNAAF19 with CCDC103
    as a previous symbol; the ontology build that term validation reads still carries CCDC103 as the
    canonical label for hgnc:32700, so term.label is bound to CCDC103 and the approved symbol is carried
    in preferred_term.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF19 | dynein axonemal assembly factor 19 | hgnc:32700 | Disease-causing germline mutation(s) in'
    explanation: >-
      Orphanet gene-disease association row listing DNAAF19 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_9974aaef-9082-4bcd-b05a-28869447b5de-2022-12-08T170000.000Z
    reference_title: 'DNAAF19 / primary ciliary dyskinesia 17 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DNAAF19 | HGNC:32700 | primary ciliary dyskinesia 17 | MONDO:0013854 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-12-08T17:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding DNAAF19 to primary ciliary dyskinesia 17 (MONDO:0013854)
      with classification Definitive.
  - reference: PMID:22581229
    reference_title: 'CCDC103 mutations cause primary ciliary dyskinesia by disrupting assembly of ciliary dynein arms.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'These results identify Ccdc103 as a dynein arm attachment factor that causes primary ciliary dyskinesia when mutated.'
    explanation: >-
      Assigns the DNAAF19 product a dynein-arm attachment role.
- name: CFAP298
  gene_term:
    preferred_term: CFAP298
    term:
      id: hgnc:1301
      label: CFAP298
  subtype: CILD26
  association: Moderate ClinGen gene-disease validity for PCD 26
  notes: >-
    Dynein-arm assembly factor (previous symbols C21orf48, C21orf59). Patient cilia lose both outer and
    inner dynein arm components.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'CFAP298 | cilia and flagella associated protein 298 | hgnc:1301 | Disease-causing germline mutation(s) in'
    explanation: >-
      Orphanet gene-disease association row listing CFAP298 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_f29143ae-869e-4e4c-8464-8c61f2c2663c-2023-08-10T160000.000Z
    reference_title: 'CFAP298 / primary ciliary dyskinesia 26 (Moderate)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'CFAP298 | HGNC:1301 | primary ciliary dyskinesia 26 | MONDO:0014211 | AR | Moderate | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2023-08-10T16:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding CFAP298 to primary ciliary dyskinesia 26 (MONDO:0014211)
      with classification Moderate.
  - reference: PMID:24094744
    reference_title: 'Zebrafish Ciliopathy Screen Plus Human Mutational Analysis Identifies C21orf59 and CCDC65 Defects as Causing Primary Ciliary Dyskinesia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'mutations in C21orf59 caused loss of both outer and inner dynein arm components'
    explanation: >-
      Combined outer and inner dynein-arm loss in CFAP298-mutant cilia.
- name: TTC12
  gene_term:
    preferred_term: TTC12
    term:
      id: hgnc:23700
      label: TTC12
  relationship_type: CAUSATIVE
  subtype: CILD45
  association: Pathogenic Variants
  notes: >-
    Cytoplasmic dynein-assembly protein whose loss removes both dynein arms from sperm flagella but only
    the inner arms from respiratory cilia.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'TTC12 | tetratricopeptide repeat domain 12 | hgnc:23700 | Disease-causing germline mutation(s) (loss of function) in'
    explanation: >-
      Orphanet gene-disease association row listing TTC12 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_1ff366d1-58ff-44dd-b7c3-799d1fe250c6-2025-05-08T160000.000Z
    reference_title: 'TTC12 / ciliary dyskinesia, primary, 45 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'TTC12 | HGNC:23700 | ciliary dyskinesia, primary, 45 | MONDO:0032924 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-05-08T16:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding TTC12 to ciliary dyskinesia, primary, 45 (MONDO:0032924)
      with classification Definitive.
  - reference: PMID:31978331
    reference_title: 'TTC12 Loss-of-Function Mutations Cause Primary Ciliary Dyskinesia and Unveil Distinct Dynein Assembly Mechanisms in Motile Cilia Versus Flagella.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We identified four loss-of-function mutations in TTC12, which encodes a cytoplasmic protein, in four independent families in which affected individuals displayed a peculiar PCD phenotype characterized by the absence of ODAs and IDAs in sperm flagella, contrasting with the absence of only IDAs in respiratory cilia.'
    explanation: >-
      Records the cytoplasmic localisation of the TTC12 product and the cilia-versus-flagella difference in
      dynein-arm loss.
- name: LRRC56
  gene_term:
    preferred_term: LRRC56
    term:
      id: hgnc:25430
      label: LRRC56
  subtype: CILD39
  association: Moderate ClinGen gene-disease validity for CILD 39
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'LRRC56 | leucine rich repeat containing 56 | hgnc:25430 | Disease-causing germline mutation(s) in'
    explanation: >-
      Orphanet gene-disease association row listing LRRC56 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_ceef14a8-34d2-41ac-8c03-47c5eaff8986-2024-11-19T200000.000Z
    reference_title: 'LRRC56 / ciliary dyskinesia, primary, 39 (Moderate)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'LRRC56 | HGNC:25430 | ciliary dyskinesia, primary, 39 | MONDO:0032637 | AR | Moderate | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2024-11-19T20:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding LRRC56 to ciliary dyskinesia, primary, 39 (MONDO:0032637)
      with classification Moderate.
- name: NEK10
  gene_term:
    preferred_term: NEK10
    term:
      id: hgnc:18592
      label: NEK10
  relationship_type: CAUSATIVE
  subtype: CILD44
  association: Pathogenic Variants
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'NEK10 | NIMA related kinase 10 | hgnc:18592 | Disease-causing germline mutation(s) in'
    explanation: >-
      Orphanet gene-disease association row listing NEK10 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_72a2f8fa-ee83-48cc-93fa-22a8990c8d13-2025-10-17T190000.000Z
    reference_title: 'NEK10 / ciliary dyskinesia, primary, 44 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'NEK10 | HGNC:18592 | ciliary dyskinesia, primary, 44 | MONDO:0032914 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-10-17T19:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding NEK10 to ciliary dyskinesia, primary, 44 (MONDO:0032914)
      with classification Definitive.
- name: NME5
  gene_term:
    preferred_term: NME5
    term:
      id: hgnc:7853
      label: NME5
  subtype: CILD48
  association: Moderate ClinGen gene-disease validity for CILD 48
  notes: >-
    Radial-spoke neck component (also known as RSPH23). The associated MONDO class records absence of situs
    inversus.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'NME5 | NME/NM23 family member 5 | hgnc:7853 | Disease-causing germline mutation(s) in'
    explanation: >-
      Orphanet gene-disease association row listing NME5 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_00efe110-5916-4da0-92ac-cee8c8b18140-2024-02-08T170000.000Z
    reference_title: 'NME5 / ciliary dyskinesia, primary, 48, without situs inversus (Moderate)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'NME5 | HGNC:7853 | ciliary dyskinesia, primary, 48, without situs inversus | MONDO:0031054 | AR | Moderate | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-02-08T17:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding NME5 to ciliary dyskinesia, primary, 48, without situs
      inversus (MONDO:0031054) with classification Moderate.
  - reference: PMID:32185794
    reference_title: 'A nonsense variant in NME5 causes human primary ciliary dyskinesia with radial spoke defects.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'We identified a homozygous nonsense variant (c.572G>A; p.Trp191*) in NME5, which encodes a protein component of the RS neck, in one PCD patient with situs solitus.'
    explanation: >-
      Identifies the NME5 product as a radial-spoke neck component and records situs solitus in the
      reported patient.
- name: DRC1
  gene_term:
    preferred_term: DRC1
    term:
      id: hgnc:24245
      label: DRC1
  relationship_type: CAUSATIVE
  subtype: CILD21
  association: Pathogenic Variants
  case_fractions:
  - population: Korean primary ciliary dyskinesia cohort
    case_fraction_percent: 15.0
    cohort_size: 20
    notes: >-
      Share attributable to the DRC1 exon 1-4 founder deletion alone.
    evidence:
    - reference: PMID:36747106
      reference_title: Prevalence and founder effect of DRC1 exon 1-4 deletion in Korean patients with primary ciliary dyskinesia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: three of 20 (15%) patients were positive for DRC1 exon 1-4 deletion
      explanation: >-
        Reports the DRC1 exon 1-4 deletion share of the Korean PCD cohort.
  notes: >-
    Nexin-dynein regulatory complex subunit (previous symbols C2orf39, CCDC164). An exon 1-4 deletion is a founder allele in Korean patients.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DRC1 | dynein regulatory complex subunit 1 | hgnc:24245 | Disease-causing germline mutation(s) (loss of function) in'
    explanation: >-
      Orphanet gene-disease association row listing DRC1 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_ef37e7a5-e14e-4c71-8231-b01bd636b2b9-2025-03-13T160000.000Z
    reference_title: 'DRC1 / primary ciliary dyskinesia 21 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'DRC1 | HGNC:24245 | primary ciliary dyskinesia 21 | MONDO:0014123 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-03-13T16:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding DRC1 to primary ciliary dyskinesia 21 (MONDO:0014123) with
      classification Definitive.
  - reference: PMID:36747106
    reference_title: 'Prevalence and founder effect of DRC1 exon 1-4 deletion in Korean patients with primary ciliary dyskinesia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'This study demonstrated that the DRC1 exon 1-4 deletion is a founder mutation based on haplotype analysis.'
    explanation: >-
      Establishes the DRC1 exon 1-4 deletion as a founder allele.
- name: ODAD4
  gene_term:
    preferred_term: ODAD4
    term:
      id: hgnc:25280
      label: ODAD4
  relationship_type: CAUSATIVE
  subtype: CILD35
  association: Pathogenic Variants
  notes: >-
    Outer dynein arm docking complex subunit (previous symbol TTC25), interacting with the docking-complex
    component ODAD1.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'ODAD4 | outer dynein arm docking complex subunit 4 | hgnc:25280 | Disease-causing germline mutation(s) (loss of function) in'
    explanation: >-
      Orphanet gene-disease association row listing ODAD4 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_547fed6e-47df-44b5-bf4a-e31f7b045862-2022-12-08T170000.000Z
    reference_title: 'ODAD4 / primary ciliary dyskinesia 35 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'ODAD4 | HGNC:25280 | primary ciliary dyskinesia 35 | MONDO:0014910 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-12-08T17:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding ODAD4 to primary ciliary dyskinesia 35 (MONDO:0014910) with
      classification Definitive.
  - reference: PMID:27486780
    reference_title: 'TTC25 Deficiency Results in Defects of the Outer Dynein Arm Docking Machinery and Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'here we report TTC25 as a new member of the ODA-DC machinery in humans and mice.'
    explanation: >-
      Places the ODAD4 product in the outer dynein arm docking complex.
  - reference: PMID:27486780
    reference_title: 'TTC25 Deficiency Results in Defects of the Outer Dynein Arm Docking Machinery and Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'Co-immunoprecipitation revealed interaction between the ODA-DC component CCDC114 and TTC25.'
    explanation: >-
      Records the physical interaction between the ODAD4 and ODAD1 (CCDC114) products.
- name: HYDIN
  gene_term:
    preferred_term: HYDIN
    term:
      id: hgnc:19368
      label: HYDIN
  relationship_type: CAUSATIVE
  subtype: CILD5
  association: Pathogenic Variants
  notes: >-
    Central pair apparatus protein. Routine ultrastructure and situs composition are typically normal, so
    the diagnosis is easily missed; genetic analysis is confounded by the near-identical pseudogene HYDIN2.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'HYDIN | HYDIN axonemal central pair apparatus protein | hgnc:19368 | Disease-causing germline mutation(s) (loss of function) in'
    explanation: >-
      Orphanet gene-disease association row listing HYDIN as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_6c491ab7-496f-43b9-9bca-500901cb686d-2022-02-22T183411.247Z
    reference_title: 'HYDIN / primary ciliary dyskinesia 5 (Definitive)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'HYDIN | HGNC:19368 | primary ciliary dyskinesia 5 | MONDO:0012088 | AR | Definitive | SOP8 | Motile Ciliopathy Gene Curation Expert Panel | 2022-02-22T18:34:11.247Z'
    explanation: >-
      ClinGen gene-disease validity row binding HYDIN to primary ciliary dyskinesia 5 (MONDO:0012088) with
      classification Definitive.
  - reference: PMID:31545650
    reference_title: 'SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: 'Mutations in HYDIN are known to cause CP defects'
    explanation: >-
      Assigns HYDIN-related disease to the central-pair defect class.
  - reference: PMID:31545650
    reference_title: 'SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: 'it is difficult to establish a diagnosis in individuals with PCD and central pair (CP) defects, and alternative strategies are required because of very subtle ciliary beating abnormalities, a normal ciliary ultrastructure, and normal situs composition'
    explanation: >-
      Records why central-pair defects evade routine beat, ultrastructure and situs assessment.
  - reference: PMID:31545650
    reference_title: 'SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics.'
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: 'the genetic analysis of HYDIN variants is confounded by the pseudogene HYDIN2, which is almost identical in terms of intron/exon structure'
    explanation: >-
      Records the HYDIN2 pseudogene as a confounder of HYDIN variant calling.
- name: BRWD1
  gene_term:
    preferred_term: BRWD1
    term:
      id: hgnc:12760
      label: BRWD1
  relationship_type: DISPUTED
  association: Disputed ClinGen gene-disease validity for PCD
  notes: >-
    ClinGen classifies the BRWD1-primary ciliary dyskinesia relationship as Disputed. The founding human
    report describes an autosomal recessive form of multiple morphological abnormalities of the sperm
    flagella with PCD or PCD-like symptoms. No has_subtypes row is curated on this entry for MONDO:0957396,
    ciliary dyskinesia, primary, 51.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'BRWD1 | bromodomain and WD repeat domain containing 1 | hgnc:12760 | Disease-causing germline mutation(s) in'
    explanation: >-
      Orphanet gene-disease association row listing BRWD1 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_9f74ee87-e640-4604-9bb7-e7617907f92c-2022-11-10T110000.000Z
    reference_title: 'BRWD1 / primary ciliary dyskinesia (Disputed)'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'BRWD1 | HGNC:12760 | primary ciliary dyskinesia | MONDO:0016575 | AR | Disputed | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-11-10T11:00:00.000Z'
    explanation: >-
      ClinGen gene-disease validity row binding BRWD1 to primary ciliary dyskinesia (MONDO:0016575) with
      classification Disputed.
  - reference: PMID:33389130
    reference_title: 'Bi-allelic BRWD1 variants cause male infertility with asthenoteratozoospermia and likely primary ciliary dyskinesia.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 'To our knowledge, this is the first report of a BRWD1-variant-related disease in humans, manifesting as an autosomal recessive form of MMAF and PCD/PCD-like symptoms.'
    explanation: >-
      The founding BRWD1 report characterises the respiratory component as PCD or PCD-like rather than
      established PCD.
- name: DNAL1
  gene_term:
    preferred_term: DNAL1
    term:
      id: hgnc:23247
      label: DNAL1
  relationship_type: CAUSATIVE
  subtype: CILD16
  association: Pathogenic Variants
  notes: >-
    Outer dynein arm light chain 1 (previous symbol C14orf168). The reported variant destabilises the light
    chain and its contacts with the dynein heavy chain and with tubulin.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DNAL1 | dynein axonemal light chain 1 | hgnc:23247 | Disease-causing germline mutation(s) in
    explanation: >-
      Orphanet gene-disease association row listing DNAL1 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_54088550-2704-4c1b-ac1b-51b62353a223-2024-04-11T160000.000Z
    reference_title: DNAL1 / primary ciliary dyskinesia 16 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DNAL1 | HGNC:23247 | primary ciliary dyskinesia 16 | MONDO:0013525 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2024-04-11T16:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding DNAL1 to primary ciliary dyskinesia 16 (MONDO:0013525) with
      classification Definitive.
  - reference: PMID:21496787
    reference_title: Primary ciliary dyskinesia caused by homozygous mutation in DNAL1, encoding dynein light chain 1.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We demonstrate here that a homozygous point mutation in this gene is associated with PCD with absent or markedly shortened ODA.
    explanation: >-
      The founding report binding DNAL1 to primary ciliary dyskinesia and stating the outer-dynein-arm lesion.
  - reference: PMID:21496787
    reference_title: Primary ciliary dyskinesia caused by homozygous mutation in DNAL1, encoding dynein light chain 1.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The mutation reduces the stability of the axonemal dynein light chain 1 and damages its interactions with dynein heavy chain and with tubulin.
    explanation: >-
      Biochemical basis of the outer-dynein-arm defect in this stratum.
- name: ZMYND10
  gene_term:
    preferred_term: ZMYND10
    term:
      id: hgnc:19412
      label: ZMYND10
  relationship_type: CAUSATIVE
  subtype: CILD22
  association: Pathogenic Variants
  notes: >-
    Cytoplasmic dynein-arm preassembly factor acting with LRRC6 (alias DNAAF7). Axonemal dynein components do
    not reach the axoneme.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: ZMYND10 | zinc finger MYND-type containing 10 | hgnc:19412 | Disease-causing germline mutation(s) (loss of function) in
    explanation: >-
      Orphanet gene-disease association row listing ZMYND10 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_9549c727-fece-494c-9892-83c0ac05f3b4-2023-02-07T170000.000Z
    reference_title: ZMYND10 / primary ciliary dyskinesia 22 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: ZMYND10 | HGNC:19412 | primary ciliary dyskinesia 22 | MONDO:0014192 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2023-02-07T17:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding ZMYND10 to primary ciliary dyskinesia 22 (MONDO:0014192) with
      classification Definitive.
  - reference: PMID:23891469
    reference_title: ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Using whole-exome resequencing and high-throughput mutation analysis, we identified recessive biallelic mutations in ZMYND10 in 14 families and mutations in the recently identified LRRC6 in 13 families.
    explanation: >-
      The founding report binding biallelic ZMYND10 variants to primary ciliary dyskinesia in 14 families.
  - reference: PMID:23891469
    reference_title: ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Mutations in ZMYND10 result in the absence of the axonemal protein components DNAH5 and DNALI1 from respiratory cilia.
    explanation: >-
      Places the ZMYND10 lesion in cytoplasmic dynein-arm preassembly: axonemal dynein components fail to
      reach the axoneme.
  - reference: PMID:23891469
    reference_title: ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Our findings suggest that a cytoplasmic protein complex containing ZMYND10 and LRRC6 is necessary for motile ciliary function.
    explanation: >-
      The founding report's own proposal, stated as a suggestion rather than a demonstrated complex.
- name: ODAD2
  gene_term:
    preferred_term: ODAD2
    term:
      id: hgnc:25583
      label: ODAD2
  relationship_type: CAUSATIVE
  subtype: CILD23
  association: Pathogenic Variants
  notes: >-
    Outer dynein arm docking complex subunit 2 (previous symbol ARMC4). Required for targeting and anchoring
    of the outer dynein arms.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: ODAD2 | outer dynein arm docking complex subunit 2 | hgnc:25583 | Disease-causing germline mutation(s) (loss of function) in
    explanation: >-
      Orphanet gene-disease association row listing ODAD2 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_4ac46902-bffa-46f9-bc0d-081e6461d5e2-2022-12-14T170000.000Z
    reference_title: ODAD2 / primary ciliary dyskinesia 23 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: ODAD2 | HGNC:25583 | primary ciliary dyskinesia 23 | MONDO:0014193 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-12-14T17:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding ODAD2 to primary ciliary dyskinesia 23 (MONDO:0014193) with
      classification Definitive.
  - reference: PMID:23849778
    reference_title: ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: By using combined high resolution copy-number variant and mutation analysis, we identified ARMC4 mutations in twelve PCD individuals whose cells showed reduced numbers of ODAs and severely impaired ciliary beating.
    explanation: >-
      Founding report binding ODAD2/ARMC4 to primary ciliary dyskinesia with an outer-dynein-arm deficit.
  - reference: PMID:23849778
    reference_title: ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We demonstrate that ARMC4 is an axonemal protein that is necessary for proper targeting and anchoring of ODAs.
    explanation: >-
      States the docking-and-anchoring role that places this gene on the outer-dynein-arm docking node.
- name: DRC2
  gene_term:
    preferred_term: DRC2
    term:
      id: hgnc:29937
      label: CCDC65
  relationship_type: CAUSATIVE
  subtype: CILD27
  association: Pathogenic Variants
  notes: >-
    Nexin-dynein regulatory complex subunit 2. Ciliary ultrastructure is preserved, so ultrastructure-led
    diagnosis can miss it. HGNC's current approved symbol is DRC2 with CCDC65 as a previous
    symbol; the ontology build that term validation reads still carries CCDC65 as the canonical label for
    hgnc:29937, so term.label is bound to CCDC65 and the approved symbol is carried in preferred_term.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DRC2 | dynein regulatory complex subunit 2 | hgnc:29937 | Disease-causing germline mutation(s) in
    explanation: >-
      Orphanet gene-disease association row listing DRC2 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_662ab516-ba5f-46aa-97b2-ef4c8f3201a5-2024-08-08T160000.000Z
    reference_title: DRC2 / primary ciliary dyskinesia 27 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DRC2 | HGNC:29937 | primary ciliary dyskinesia 27 | MONDO:0014215 | AR | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-08-08T16:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding DRC2 to primary ciliary dyskinesia 27 (MONDO:0014215) with
      classification Definitive.
  - reference: PMID:23991085
    reference_title: CCDC65 mutation causes primary ciliary dyskinesia with normal ultrastructure and hyperkinetic cilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A single novel mutation in CCDC65, which created a termination codon at position 293, was identified in a subject with typical clinical features of PCD.
    explanation: >-
      Founding report binding DRC2/CCDC65 to primary ciliary dyskinesia.
  - reference: PMID:23991085
    reference_title: CCDC65 mutation causes primary ciliary dyskinesia with normal ultrastructure and hyperkinetic cilia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The affected individual had altered cilia beating patterns, and no detectable ultrastructural defects of the ciliary axoneme, emphasizing the role of the nexin-dynein regulatory complex and the limitations of certain methods for PCD diagnosis.
    explanation: >-
      Records that ultrastructure is normal in this stratum, which is the diagnostic consequence of a
      nexin-dynein regulatory complex defect.
- name: SPAG1
  gene_term:
    preferred_term: SPAG1
    term:
      id: hgnc:11212
      label: SPAG1
  relationship_type: CAUSATIVE
  subtype: CILD28
  association: Pathogenic Variants
  notes: >-
    Cytoplasmic dynein-arm assembly and trafficking factor (alias DNAAF13); present in airway cell lysates but
    absent from isolated axonemes.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: SPAG1 | sperm associated antigen 1 | hgnc:11212 | Disease-causing germline mutation(s) in
    explanation: >-
      Orphanet gene-disease association row listing SPAG1 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_c0d43e40-0aa3-41cf-9e3a-8311e685c7be-2022-06-22T190000.000Z
    reference_title: SPAG1 / primary ciliary dyskinesia 28 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: SPAG1 | HGNC:11212 | primary ciliary dyskinesia 28 | MONDO:0014216 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-06-22T19:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding SPAG1 to primary ciliary dyskinesia 28 (MONDO:0014216) with
      classification Definitive.
  - reference: PMID:24055112
    reference_title: Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All 14 affected individuals with SPAG1 mutations had a characteristic PCD phenotype, including 8 with situs abnormalities.
    explanation: >-
      Founding report binding biallelic SPAG1 variants to primary ciliary dyskinesia, with laterality defects
      in 8 of 14.
  - reference: PMID:24055112
    reference_title: Mutations in SPAG1 cause primary ciliary dyskinesia associated with defective outer and inner dynein arms.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: SPAG1 was present in human airway epithelial cell lysates but was not present in isolated axonemes, and immunofluorescence staining showed an absence of ODA and IDA proteins in cilia from an affected individual, thus indicating that SPAG1 probably plays a role in the cytoplasmic assembly and/or trafficking of the axonemal dynein arms.
    explanation: >-
      States the cytoplasmic preassembly role that places SPAG1 on the preassembly node rather than in the
      axoneme.
- name: RSPH3
  gene_term:
    preferred_term: RSPH3
    term:
      id: hgnc:21054
      label: RSPH3
  relationship_type: CAUSATIVE
  subtype: CILD32
  association: Pathogenic Variants
  notes: >-
    Radial spoke protein whose Chlamydomonas ortholog is a spoke stalk protein. Patient cilia show a near
    absence of radial spokes while the spoke head and neck proteins remain present.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: RSPH3 | radial spoke head 3 | hgnc:21054 | Disease-causing germline mutation(s) in
    explanation: >-
      Orphanet gene-disease association row listing RSPH3 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_988a074a-14e9-41e3-a1a6-fff72dda3936-2024-08-08T160000.000Z
    reference_title: RSPH3 / primary ciliary dyskinesia 32 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: RSPH3 | HGNC:21054 | primary ciliary dyskinesia 32 | MONDO:0014657 | AR | Definitive | SOP10 | Motile Ciliopathy Gene Curation Expert Panel | 2024-08-08T16:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding RSPH3 to primary ciliary dyskinesia 32 (MONDO:0014657) with
      classification Definitive.
  - reference: PMID:26073779
    reference_title: RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We identified non-ambiguous RSPH3 mutations in 5 of 48 independent families affected by CC/RS defects.
    explanation: >-
      Founding report binding biallelic RSPH3 variants to primary ciliary dyskinesia in five families.
  - reference: PMID:26073779
    reference_title: RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A striking feature of the ultrastructural phenotype associated with RSPH3 mutations is the near absence of detectable RSs in all cilia in combination with a variable proportion of cilia with CC defects.
    explanation: >-
      States the radial spoke lesion that places RSPH3 on the radial spoke node.
  - reference: PMID:26073779
    reference_title: RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: in whom RSPH23 (a RS-neck protein) and RSPH1 and RSPH4A (RS-head proteins) were found to be still present within cilia
    explanation: >-
      Distinguishes the RSPH3 lesion from the radial spoke head genes, whose products remain present.
  - reference: PMID:26073779
    reference_title: RSPH3 Mutations Cause Primary Ciliary Dyskinesia with Central-Complex Defects and a Near Absence of Radial Spokes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: RSPH3, whose ortholog in the flagellated alga Chlamydomonas reinhardtii encodes a RS-stalk protein, is mainly expressed in respiratory and testicular cells.
    explanation: >-
      The stalk assignment is made through the Chlamydomonas ortholog, not directly in human.
- name: DRC4
  gene_term:
    preferred_term: DRC4
    term:
      id: hgnc:4166
      label: GAS8
  relationship_type: CAUSATIVE
  subtype: CILD33
  association: Pathogenic Variants
  notes: >-
    Nexin-dynein regulatory complex subunit 4. As with DRC2 the axonemal architecture is preserved. HGNC's
    current approved symbol is DRC4 with GAS8 as a previous symbol; the ontology build that term validation
    reads still carries GAS8 as the canonical label for hgnc:4166, so term.label is bound to GAS8 and the
    approved symbol is carried in preferred_term.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DRC4 | dynein regulatory complex subunit 4 | hgnc:4166 | Disease-causing germline mutation(s) (loss of function) in
    explanation: >-
      Orphanet gene-disease association row listing DRC4 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_d34bf201-5f6d-41c0-842d-5c029823ef60-2025-12-10T200000.000Z
    reference_title: DRC4 / primary ciliary dyskinesia 33 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DRC4 | HGNC:4166 | primary ciliary dyskinesia 33 | MONDO:0014750 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-12-10T20:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding DRC4 to primary ciliary dyskinesia 33 (MONDO:0014750) with
      classification Definitive.
  - reference: PMID:26387594
    reference_title: Loss-of-Function GAS8 Mutations Cause Primary Ciliary Dyskinesia and Disrupt the Nexin-Dynein Regulatory Complex.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genome-wide exome sequence analyses identified recessive loss-of-function mutations in GAS8 encoding DRC4 in three independent PCD-affected families.
    explanation: >-
      Founding report binding biallelic DRC4/GAS8 variants to primary ciliary dyskinesia in three families.
  - reference: PMID:26387594
    reference_title: Loss-of-Function GAS8 Mutations Cause Primary Ciliary Dyskinesia and Disrupt the Nexin-Dynein Regulatory Complex.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This applies in particular to isolated defects of the nexin links, also known as the nexin-dynein regulatory complex (N-DRC), connecting the peripheral outer microtubular doublets.
    explanation: >-
      States why a nexin-dynein regulatory complex defect is not reliably visible on transmission electron
      microscopy.
  - reference: PMID:26387594
    reference_title: Loss-of-Function GAS8 Mutations Cause Primary Ciliary Dyskinesia and Disrupt the Nexin-Dynein Regulatory Complex.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, some defects are not regularly discernable by TEM because the ciliary architecture of the axoneme remains preserved.
    explanation: >-
      States that the architecture is preserved, which is why ultrastructure reads as normal here.
  - reference: PMID:26387594
    reference_title: Loss-of-Function GAS8 Mutations Cause Primary Ciliary Dyskinesia and Disrupt the Nexin-Dynein Regulatory Complex.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Immunofluorescence analyses of respiratory cells from PCD-affected individuals detected a N-DRC defect.
    explanation: >-
      Records the method by which this lesion class was found.
- name: DNAJB13
  gene_term:
    preferred_term: DNAJB13
    term:
      id: hgnc:30718
      label: DNAJB13
  subtype: CILD34
  association: Moderate ClinGen gene-disease validity for primary ciliary dyskinesia 34
  notes: >-
    HSP40 co-chaperone whose Chlamydomonas ortholog localises to the radial spokes. The reported missense
    change destabilises the protein and triggers proteasomal degradation.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DNAJB13 | DnaJ heat shock protein family (Hsp40) member B13 | hgnc:30718 | Disease-causing germline mutation(s) (loss of function) in
    explanation: >-
      Orphanet gene-disease association row listing DNAJB13 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_fd64a9ab-9f83-43c8-a23d-2617da493010-2025-06-12T090000.000Z
    reference_title: DNAJB13 / primary ciliary dyskinesia 34 (Moderate)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: DNAJB13 | HGNC:30718 | primary ciliary dyskinesia 34 | MONDO:0014909 | AR | Moderate | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-06-12T09:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding DNAJB13 to primary ciliary dyskinesia 34 (MONDO:0014909) with
      classification Moderate.
  - reference: PMID:27486783
    reference_title: Mutations in DNAJB13, Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: To identify the molecular basis of a PCD phenotype characterized by central complex (CC) defects but normal DA structure, a phenotype found in ~15% of cases, we performed whole-exome sequencing in a male individual with PCD and unexplained CC defects.
    explanation: >-
      States the ultrastructural phenotype this stratum presents with: central-complex defects without a
      dynein arm defect.
  - reference: PMID:27486783
    reference_title: Mutations in DNAJB13, Encoding an HSP40 Family Member, Cause Primary Ciliary Dyskinesia and Male Infertility.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In vitro studies showed that this missense substitution (p.Met278Arg), which involves a highly conserved residue of several HSP40 family members, leads to protein instability and triggers proteasomal degradation, a result confirmed by the absence of endogenous DNAJB13 in cilia and sperm from this individual.
    explanation: >-
      Functional basis of the DNAJB13 defect in the founding family.
- name: CFAP300
  gene_term:
    preferred_term: CFAP300
    term:
      id: hgnc:28188
      label: CFAP300
  relationship_type: CAUSATIVE
  subtype: CILD38
  association: Pathogenic Variants
  notes: >-
    Dynein-arm assembly factor acting in intraflagellar-transport-dependent delivery of axonemal dyneins
    (previous symbol C11orf70, alias DNAAF17). Patient cilia lose both dynein arms.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CFAP300 | cilia and flagella associated protein 300 | hgnc:28188 | Disease-causing germline mutation(s) (loss of function) in
    explanation: >-
      Orphanet gene-disease association row listing CFAP300 as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_6bcfa4e4-37a3-43a7-9b4d-60554bc7600c-2022-09-08T110000.000Z
    reference_title: CFAP300 / ciliary dyskinesia, primary, 38 (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CFAP300 | HGNC:28188 | ciliary dyskinesia, primary, 38 | MONDO:0054843 | AR | Definitive | SOP9 | Motile Ciliopathy Gene Curation Expert Panel | 2022-09-08T11:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding CFAP300 to ciliary dyskinesia, primary, 38 (MONDO:0054843)
      with classification Definitive.
  - reference: PMID:29727692
    reference_title: C11orf70 Mutations Disrupting the Intraflagellar Transport-Dependent Assembly of Multiple Axonemal Dyneins Cause Primary Ciliary Dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The affected children share a consistent PCD phenotype from early life with laterality defects and immotile respiratory cilia displaying combined loss of inner and outer dynein arms (IDA+ODA).
    explanation: >-
      Founding report binding biallelic CFAP300 variants to primary ciliary dyskinesia and stating the
      combined dynein arm lesion.
  - reference: PMID:29727692
    reference_title: C11orf70 Mutations Disrupting the Intraflagellar Transport-Dependent Assembly of Multiple Axonemal Dyneins Cause Primary Ciliary Dyskinesia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In summary, C11orf70 is essential for assembly of dynein arms and C11orf70 mutations cause defective cilia motility and PCD.
    explanation: >-
      States the dynein-arm assembly role that places CFAP300 on the preassembly node.
- name: CLXN
  gene_term:
    preferred_term: CLXN
    term:
      id: hgnc:25678
      label: CLXN
  relationship_type: CAUSATIVE
  subtype: CILD53
  association: Pathogenic Variants
  notes: >-
    Calcium-binding outer dynein arm docking complex associated protein, proposed as ODAD5 (previous symbol
    EFCAB1). The outer dynein arm defect is confined to the distal axoneme.
  evidence:
  - reference: ORPHA:244
    reference_title: Primary ciliary dyskinesia
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CLXN | calaxin | hgnc:25678 | Disease-causing germline mutation(s) in
    explanation: >-
      Orphanet gene-disease association row listing CLXN as a disease-causing gene for primary ciliary
      dyskinesia.
  - reference: CGGV:assertion_18721467-867b-4687-b4f2-5af09951ada5-2025-04-10T160000.000Z
    reference_title: CLXN / ciliary dyskinesia, primary, 53 (Strong)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CLXN | HGNC:25678 | ciliary dyskinesia, primary, 53 | MONDO:0957991 | AR | Strong | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-04-10T16:00:00.000Z
    explanation: >-
      ClinGen gene-disease validity row binding CLXN to ciliary dyskinesia, primary, 53 (MONDO:0957991) with
      classification Strong.
  - reference: PMID:36727596
    reference_title: Pathogenic variants in CLXN encoding the outer dynein arm docking-associated calcium-binding protein calaxin cause primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In this study, we identified homozygous pathogenic variants in CLXN (EFCAB1/ODAD5) in 3 individuals with laterality defects and respiratory symptoms.
    explanation: >-
      Founding report binding biallelic CLXN variants to primary ciliary dyskinesia in three individuals.
  - reference: PMID:36727596
    reference_title: Pathogenic variants in CLXN encoding the outer dynein arm docking-associated calcium-binding protein calaxin cause primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Our results revealed that pathogenic variants in CLXN cause PCD with defects in the assembly of distal ODAs in the respiratory cilia. CLXN should be referred to as ODA-docking complex-associated protein ODAD5.
    explanation: >-
      States the outer-dynein-arm docking role that places CLXN on the docking node.
diagnosis:
- name: Clinical Suspicion and Specialist Multimodal Assessment
  description: >-
    Early persistent wet cough and rhinosinusitis, unexplained term neonatal respiratory distress,
    chronic middle-ear disease or laterality defects warrant specialist evaluation. No single normal
    test excludes PCD. The 2025 joint ERS/ATS guideline combines genetics/TEM with high-speed video
    microscopy, immunofluorescence and nasal nitric oxide as adjuncts, interpreted with pre-test
    probability.
  evidence:
  - reference: PMID:41005984
    reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The panel gives a strong recommendation for use of high-speed video microscopy, immunofluorescence and nasal nitric oxide as adjunct tests to transmission electron microscopy and/or genetics for PCD diagnosis.
    explanation: >-
      Defines the updated integrated diagnostic strategy.
- name: Molecular Genetic Diagnosis
  description: >-
    Pathogenic or likely pathogenic variants in a sufficiently validated gene must match its inheritance
    pattern: biallelic for recessive, hemizygous for relevant X-linked, or monoallelic for dominant
    disease. Gene panels, copy-number analysis and selected exome/genome sequencing improve yield.
    A VUS or a variant in a gene with limited validity alone does not confirm PCD.
  evidence:
  - reference: PMID:41005984
    reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: any genetic test that provided a pathogenic or likely pathogenic variant (using ACMG criteria) found in a known PCD-associated gene consistent with the known inheritance pattern for that gene
    explanation: >-
      The guideline requires pathogenicity, gene validity and inheritance consistency.
  - reference: PMID:39115449
    reference_title: Whole genome sequencing enhances molecular diagnosis of primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Three identified variants were deletions, ranging from 3 to 13 kb
    explanation: >-
      Small selected WGS cohort illustrates structural variants missed by narrower testing; its high
      yield is not an all-referral sensitivity estimate.
- name: Ciliary Ultrastructure and Function
  description: >-
    TEM hallmark class 1 defects can confirm PCD; class 2 findings require additional evidence. Normal
    TEM occurs in a substantial minority. Expert high-speed assessment evaluates waveform as well
    as frequency, with repeat or ALI-culture assessment when secondary injury confounds native samples.
    C1d defects may retain normal routine TEM and beating while failing transport assays.
  evidence:
  - reference: PMID:41005984
    reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Class 1 defects confirm a diagnosis of PCD, while Class 2 defects are suggestive of PCD and require supporting evidence from other diagnostic modalities.
    explanation: >-
      Distinguishes diagnostic and suggestive ultrastructural classes.
  - reference: PMID:39362668
    reference_title: Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance.
    explanation: >-
      C1d-defective patient cells show transport failure despite normal routine TEM, nasal NO and
      high-speed beat assessment. The selected situs-solitus cohort does not independently estimate
      population laterality risk.
- name: Nasal Nitric Oxide
  description: >-
    Standardized nasal NO is a useful adjunct. Interpret the 77 nL/min velum-closure threshold with
    age, method, CF exclusion and intercurrent infection. Tidal-breathing measurements in younger
    children are protocol-specific. Normal results in some genotypes do not exclude PCD.
  notes: >-
    No LOINC measurement is bound, because the release has no nasal nitric oxide code
    at all and the two exhaled nitric oxide codes it does carry are a different
    quantity from a different airway compartment. The enumeration, across both the
    LOINC release table and the Monarch KG, is recorded once on the matching
    biochemical marker rather than repeated here. Note what that absence costs: this
    disease owns a standardized numeric threshold, 77 nL/min at velum closure, and the
    marker record already carries it as reference-range bands, so the bands exist with
    no code to key them to. That makes the measurement a candidate for a LOINC term
    request.
  evidence:
  - reference: PMID:41005984
    reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: no adjunct test is suitable as a standalone test to diagnose PCD and no single adjunct or reference test is suitable to exclude PCD.
    explanation: >-
      A low or normal nasal-NO result cannot independently settle diagnosis.
- name: Organ and Longitudinal Assessment
  description: >-
    Assess lung function, cultures, nutritional status, hearing and sinonasal disease; clarify situs/cardiac
    anatomy when the genotype can affect laterality. Fertility and transition to adult care require
    dedicated discussion. Repeated CT imaging is individualized to clinical need.
  evidence:
  - reference: PMID:41561099
    reference_title: 'Primary ciliary dyskinesia: a national expert consensus statement on standards of care.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: individuals with PCD should have at least one abdominal ultrasound and echocardiogram in their records, unless a patient's PCD was known to be caused by a gene that does not cause laterality defects
    explanation: >-
      England specialist-care consensus scopes situs screening by genotype.
  - reference: PMID:41561099
    reference_title: 'Primary ciliary dyskinesia: a national expert consensus statement on standards of care.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: At annual review, patients should have appropriate assessment of their recent clinical history with a focus on number of exacerbations, lung function, respiratory sample culture, blood tests, observations and physical examination, assessment of nutritional status as well as physiotherapy review
    explanation: >-
      Consensus identifies practical multidimensional follow-up.
environmental:
- name: Air Pollution
  effect: May exacerbate respiratory symptoms
  evidence:
  - reference: PMID:34574829
    reference_title: Effects of Air Pollutants on Airway Diseases.
    supports: SUPPORT
    snippet: In general, air pollution decreases quality of life and life expectancy. It exacerbates acute and chronic respiratory symptoms in patients with chronic airway diseases
    explanation: >-
      General airway review supplies indirect biological plausibility; it does not establish a PCD-specific
      causal exposure-response effect.
    evidence_source: OTHER
  exposure_term:
    preferred_term: Air pollution exposure
    term:
      id: ECTO:8000036
      label: exposure to air pollution
  description: >-
    Air pollution may aggravate airway disease through general epithelial injury and inflammation.
    The cited airway literature is indirect background, not PCD-specific causal or exposure-response
    evidence.
treatments:
- name: Airway Clearance Techniques
  description: >-
    Regular individualized airway clearance, exercise and specialist physiotherapy help mobilize
    retained secretions. Evidence does not identify one superior technique; the small PCD randomized
    literature has low certainty. Hypertonic saline can be considered individually for mucus management.
  evidence:
  - reference: PMID:41561099
    reference_title: 'Primary ciliary dyskinesia: a national expert consensus statement on standards of care.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: a personalised and tailored treatment plan for airway clearance, which could include mucolytics such as hypertonic saline as required
    explanation: >-
      Current specialist-care consensus supports tailored clearance rather than a proven universally
      superior technique.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_mechanisms:
  - target: Impaired Mucociliary Clearance
    treatment_effect: BYPASSES
    description: Mechanical airway clearance helps compensate for ineffective ciliary transport.
- name: Antibiotic Therapy
  description: >-
    Treat pulmonary exacerbations promptly with culture-informed antibiotics and an individualized
    clinical plan. This is distinct from long-term azithromycin maintenance; organism, prior microbiology,
    severity and response determine the regimen.
  target_phenotypes:
  - preferred_term: Recurrent Respiratory Infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:26586601
    reference_title: Treatment recommendations in Primary Ciliary Dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: regular airway clearance, routine microbiological surveillance, antibiotic treatment for pulmonary exacerbation, and health vaccinations.
    explanation: >-
      PCD treatment review supports acute infection management and surveillance, not blanket prophylaxis.
  treatment_term:
    preferred_term: antibiotic therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
    therapeutic_agent:
    - preferred_term: azithromycin
      term:
        id: CHEBI:2955
        label: azithromycin
  target_mechanisms:
  - target: Chronic Airway Infection and Neutrophilic Inflammation
    treatment_effect: INHIBITS
    description: Antimicrobial treatment reduces susceptible airway pathogens.
- name: Bronchodilators
  description: >-
    Consider bronchodilators case by case for demonstrable reversible airflow obstruction or coexisting
    asthma. They are not established routine disease-modifying treatment for all PCD; inhaled corticosteroids
    require a separate indication.
  evidence:
  - reference: PMID:26418604
    reference_title: 'Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: inhaled bronchodilators can be used on a case‐by‐case basis in PCD.
    explanation: >-
      PCD Foundation consensus supports individualized use and describes mixed study results.
  treatment_term:
    preferred_term: bronchodilator therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: bronchodilator
      term:
        id: NCIT:C319
        label: Bronchodilator
- name: Nasal Steroids
  description: >-
    Intranasal corticosteroids may be used for associated nasal polyposis or chronic rhinosinusitis;
    evidence for PCD-specific benefit is limited and this is not treatment of the ciliary defect.
  evidence:
  - reference: PMID:26418604
    reference_title: 'Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Antibiotics and nasal steroids may be used in acute on chronic exacerbations of rhinosinusitis
    explanation: >-
      Consensus addresses symptom-directed sinonasal treatment with limited disease-specific evidence.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
- name: Hearing Aids
  description: >-
    Specialist ENT and audiology assessment guides hearing aids and other management for persistent
    hearing impairment; middle-ear disease and tympanostomy decisions require PCD-specific considerations.
  evidence:
  - reference: PMID:26418604
    reference_title: 'Diagnosis, monitoring, and treatment of primary ciliary dyskinesia: PCD foundation consensus recommendations based on state of the art review.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Complications of ROM may include multiple sets of pressure equalization tubes, conductive hearing loss, speech/language delay, or need for hearing aids.
    explanation: >-
      The PCD-specific consensus discusses hearing support for chronic otitis-related impairment;
      benefit should not be inferred from unrelated hearing-loss diseases.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Genetic Counseling
  description: >-
    Provide gene-specific inheritance and reproductive counseling, testing of appropriate relatives
    and access to fertility services. Autosomal recessive, dominant and X-linked forms have different
    recurrence implications; infertility is not obligatory.
  evidence:
  - reference: PMID:41561099
    reference_title: 'Primary ciliary dyskinesia: a national expert consensus statement on standards of care.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: adults with PCD should have local access to genetic counselling and fertility services.
    explanation: >-
      Contemporary PCD care consensus explicitly recommends both services.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: Azithromycin Maintenance
  description: >-
    For selected patients with frequent exacerbations, six months of maintenance azithromycin reduced
    exacerbations in BESTCILIA. Participants were aged 7–50 with FEV1 above 40% predicted. The trial
    does not establish lifelong benefit or separate antimicrobial from immunomodulatory mechanisms;
    microbial surveillance, including nontuberculous mycobacteria, informs selection.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: azithromycin
      term:
        id: CHEBI:2955
        label: azithromycin
  evidence:
  - reference: PMID:32380069
    reference_title: 'Efficacy and safety of azithromycin maintenance therapy in primary ciliary dyskinesia (BESTCILIA): a multicentre, double-blind, randomised, placebo-controlled phase 3 trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: rate ratio 0·45 [95% CI 0·26-0·78]; p=0·004
    explanation: >-
      Randomized 90-person phase III trial demonstrated fewer exacerbations over six months; prevention
      of irreversible damage was a proposed downstream implication, not the primary proven endpoint.
  target_mechanisms:
  - target: Chronic Airway Infection and Neutrophilic Inflammation
    treatment_effect: MODULATES
    description: Reduces exacerbations through antimicrobial and/or immunomodulatory actions not separated by the trial.
  therapeutic_modality: SMALL_MOLECULE
- name: Multidisciplinary Support and Preventive Care
  description: >-
    Specialist follow-up includes vaccination, nutrition, ENT/hearing care, sinonasal irrigation,
    psychological support when needed, fertility care and planned transition to adult services. Advanced
    lung disease warrants specialist consideration of oxygen, ventilatory support or transplantation
    according to clinical status.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:41561099
    reference_title: 'Primary ciliary dyskinesia: a national expert consensus statement on standards of care.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: We present a consensus statement on 15 standards covering provision of pulmonary, ear, nose and throat, and fertility care, screening for situs abnormalities and transition from paediatric to adult care services.
    explanation: >-
      England consensus describes broad specialist-care standards; individual interventions retain
      different levels of evidence.
  - reference: PMID:26586601
    reference_title: Treatment recommendations in Primary Ciliary Dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: regular airway clearance, routine microbiological surveillance, antibiotic treatment for pulmonary exacerbation, and health vaccinations.
    explanation: >-
      PCD-specific review includes vaccination among routine care measures.
- name: Brensocatib for Non-CF Bronchiectasis
  description: >-
    The DPP-1 inhibitor brensocatib targets neutrophil serine-protease activation. Its 2025 US indication
    covers non-cystic fibrosis bronchiectasis in patients aged at least 12, which can include PCD-associated
    bronchiectasis. ASPEN demonstrated fewer exacerbations in the broader bronchiectasis population,
    not a separately powered PCD trial. PCD-specific benefit and individual selection require specialist
    interpretation; this treatment does not repair the ciliary genetic defect.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  therapeutic_modality: SMALL_MOLECULE
  evidence:
  - reference: PMID:40267423
    reference_title: Phase 3 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Among patients with bronchiectasis, once-daily treatment with brensocatib (10 mg or 25 mg) led to a lower annualized rate of pulmonary exacerbations than placebo, and the decline in FEV1 was less with the 25-mg dose of brensocatib than with placebo.
    explanation: >-
      The randomized result concerns the broader non-CF bronchiectasis trial population, not a
      separately demonstrated PCD subgroup benefit.
  notes: >-
    FDA approval date and indication were verified September 2026 at https://www.fda.gov/drugs/drug-trials-snapshots/drug-trials-snapshots-brinsupri.
    The population-wide ASPEN result is not proof of an independent PCD subgroup benefit.
  target_mechanisms:
  - target: Chronic Airway Infection and Neutrophilic Inflammation
    treatment_effect: INHIBITS
    description: >-
      DPP-1 inhibition targets the neutrophil-serine-protease component of airway inflammation. It
      does not directly correct the motile-cilia genetic defect, and clinical efficacy specifically
      within PCD remains uncertain.
    evidence:
    - reference: PMID:40267423
      reference_title: Phase 3 Trial of the DPP-1 Inhibitor Brensocatib in Bronchiectasis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Brensocatib, an oral, reversible inhibitor of dipeptidyl peptidase 1 (DPP-1), targets neutrophil serine proteases, key mediators of neutrophilic inflammation.
      explanation: >-
        This background pharmacology statement identifies the neutrophil-protease target; it is
        separate from the randomized clinical outcome and does not establish a PCD-specific treatment
        effect.
clinical_trials:
- name: BESTCILIA
  phase: PHASE_III
  status: COMPLETED
  description: >-
    Multicentre, double-blind, randomised, placebo-controlled phase 3 trial of
    azithromycin maintenance therapy (three times weekly for 6 months) in
    patients with PCD aged 7-50 years; the first multinational pharmacotherapy
    RCT in PCD. Registered as EudraCT 2013-004664-58.
  target_phenotypes:
  - preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:32380069
    reference_title: 'Efficacy and safety of azithromycin maintenance therapy in primary ciliary dyskinesia (BESTCILIA): a multicentre, double-blind, randomised, placebo-controlled phase 3 trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: azithromycin maintenance therapy for 6 months was well tolerated and halved the rate of respiratory exacerbations.
    explanation: The BESTCILIA RCT showed azithromycin maintenance halved respiratory exacerbations over 6 months in PCD.
- name: NCT02871778
  phase: PHASE_II
  status: COMPLETED
  description: >-
    CLEAN-PCD randomized 123 participants aged at least 12 with ppFEV1 40 to below 90 to idrevloride
    (VX-371) with or without 4.2% hypertonic saline, with 28-day treatment and washout periods. The
    published combination-versus-saline comparison improved ppFEV1 by 1.5 percentage points (95%
    CI below 0.1 to 3.0; p=0.044). Combination versus placebo and idrevloride alone versus placebo
    were nonsignificant. The registry retains an ivacaftor-containing protocol description, but ivacaftor
    is not an intervention in these published results. ENaC-inhibition rationale does not establish
    primary ENaC hyperabsorption in PCD.
  target_phenotypes:
  - preferred_term: Airway obstruction
    term:
      id: HP:0006536
      label: Airway obstruction
  - preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: clinicaltrials:NCT02871778
    reference_title: A Phase 2a, 2-part,Randomized, Double-blind, Placebo-controlled, Incomplete Block Crossover Study to Evaluate the Safety and Efficacy of VX-371 Solution for Inhalation With and Without Oral Ivacaftor in Subjects With Primary Ciliary Dyskinesia
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: To evaluate the safety and efficacy of treatment with VX-371 with and without ivacaftor, and the effect of VX-371 with and without ivacaftor on quality of life (QOL) in subjects with primary ciliary dyskinesia (PCD).
    explanation: >-
      Registry describes the registered protocol including ivacaftor; the primary publication reports
      the idrevloride/hypertonic-saline results. Protocol text should not replace the actual published
      intervention comparison.
  - reference: PMID:37660715
    reference_title: 'Safety and efficacy of the epithelial sodium channel blocker idrevloride in people with primary ciliary dyskinesia (CLEAN-PCD): a multinational, phase 2, randomised, double-blind, placebo-controlled crossover trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: There was no significant difference in ppFEV1 for the parallel comparison of idrevloride in hypertonic saline compared with placebo or the crossover comparison of idrevloride with placebo.
    explanation: >-
      Comparator-specific negative results temper the small combination-versus-saline signal in this
      short phase II trial.
  - reference: PMID:37660715
    reference_title: 'Safety and efficacy of the epithelial sodium channel blocker idrevloride in people with primary ciliary dyskinesia (CLEAN-PCD): a multinational, phase 2, randomised, double-blind, placebo-controlled crossover trial.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: than with hypertonic saline alone (least-squares mean absolute change from baseline of -0·5 percentage points, -2·0 to 0·9; difference 1·5 percentage points, 95% CI <0·1 to 3·0; p=0·044).
    explanation: >-
      The published primary comparison behind the 1.5-percentage-point ppFEV1 difference stated in
      the trial description, for idrevloride in hypertonic saline versus hypertonic saline alone.
- name: NCT06633757
  phase: PHASE_I
  status: COMPLETED
  description: >-
    RCT1100-103 is a phase 1b open-label DNAI1 mRNA study in adults with DNAI1-associated PCD; the
    registry is completed as checked September 2026. Separate RCT1100-101/102 conference results
    (nine and seven participants) reported no grade 3 or greater or serious adverse events, but no
    improvement in post-treatment outer dynein arms, ciliary movement or DNAI1 immunofluorescence.
    These early results do not establish clinical efficacy and should not be attributed to RCT1100-103.
  target_phenotypes:
  - preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: clinicaltrials:NCT06633757
    reference_title: A Phase 1b, Open-label, Study of RCT1100 in Adults With Primary Ciliary Dyskinesia Caused by Pathogenic Mutations in the DNAI1 Gene to Measure Mucociliary Clearance and Other Measures of Pharmacodynamic Activity
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This is a multi-dose study with RCT1100 and is designed to provide safety, tolerability and preliminary efficacy data for future clinical studies.
    explanation: ClinicalTrials.gov confirms a multi-dose study of the inhaled DNAI1 mRNA therapy RCT1100 in DNAI1-mutation PCD assessing safety, tolerability, and preliminary efficacy.
  - reference: DOI:10.1093/ajrccm/aamag286.098
    reference_title: 'A76-28 Safety and Bronchoscopy Evaluation of an Inhaled mRNA Treatment for Primary Ciliary Dyskinesia Due to Disease Causing DNA Variants in the DNAI1 Gene: Phase 1a Single-dose and Phase 1b Multiple-dose Open-label Trials'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: No difference was seen in the average number of outer dynein arms present per cross section, ciliary movement, or DNAI1 measured by immunofluorescence in post-treatment bronchial samples.
    explanation: >-
      Primary 2026 conference abstract of separate -101/-102 studies supplies limited human pharmacodynamic
      evidence; it is not a full peer-reviewed randomized efficacy trial.
animal_models:
- species: Mouse
  genotype: Mdnah5 (Dnah5) loss-of-function (insertional mutation)
  category: Spontaneous/engineered axonemal dynein mutant
  description: >-
    Insertional loss-of-function mutation in the axonemal outer-dynein-arm heavy chain gene Mdnah5
    (the mouse ortholog of human DNAH5) reproduces the core PCD phenotype — recurrent respiratory
    infection, randomized laterality (situs inversus), ciliary immotility with absent outer dynein
    arms — and additionally causes lethal hydrocephalus, supporting the motile-cilia beat-failure
    model. Animal hydrocephalus severity and neonatal lethality do not define the usual human PCD
    course.
  genes:
  - preferred_term: DNAH5
    term:
      id: hgnc:2950
      label: DNAH5
  evidence:
  - reference: PMID:11912187
    reference_title: Loss of function of axonemal dynein Mdnah5 causes primary ciliary dyskinesia and hydrocephalus.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We have characterized an insertional mutation in a mouse axonemal dynein heavy chain gene (Mdnah5) that reproduces most of the classical features of PCD, including recurrent respiratory infections, situs inversus and ciliary immotility.
    explanation: The Mdnah5 mutant mouse recapitulates the cardinal PCD features and models the DNAH5 outer-dynein-arm defect.
  modeled_mechanisms:
  - target: Ciliary Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Models immotility and outer-dynein-arm loss in Dnah5-deficient mice.
    limitations: Model-organism phenotypes do not establish human frequency or quantitative disease progression.
  - target: Nodal Ciliary Motility Defect
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Randomized mouse laterality supports the nodal arm; it is not direct human embryonic imaging.
    limitations: Model-organism phenotypes do not establish human frequency or quantitative disease progression.
  - target: Ependymal Ciliary Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Severe mouse hydrocephalus models ciliary-fluid effects but overstates typical human penetrance.
    limitations: Model-organism phenotypes do not establish human frequency or quantitative disease progression.
- species: Zebrafish
  genotype: ccdc40 mutant / morphant
  category: Motile-cilia / left-right patterning mutant
  description: >-
    ccdc40 zebrafish (alongside mouse Ccdc40 mutants) model the CCDC39/CCDC40 inner-dynein-arm/microtubular-disorganization
    class of PCD: loss of Ccdc40 impairs motile-cilia beating and randomizes left-right axis formation,
    paralleling the laterality defects and severe ciliary dysmotility seen in CCDC40-mutant patients.
    Animal hydrocephalus severity and neonatal lethality do not define the usual human PCD course.
  genes:
  - preferred_term: CCDC40
    term:
      id: hgnc:26090
      label: CCDC40
  evidence:
  - reference: PMID:21131974
    reference_title: The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In mouse and zebrafish, Ccdc40 is expressed in tissues that contain motile cilia, and mutations in Ccdc40 result in cilia with reduced ranges of motility.
    explanation: Mouse and zebrafish Ccdc40 mutants model the motile-cilia dysfunction and laterality defects of CCDC40-associated PCD.
  modeled_mechanisms:
  - target: CCDC39-CCDC40 Axonemal Scaffold Loss
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Ccdc40 loss disrupts ciliary axonemal organization and motility.
    limitations: Model-organism phenotypes do not establish human frequency or quantitative disease progression.
  - target: Nodal Ciliary Motility Defect
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Vertebrate embryonic laterality phenotypes support an effect beyond ODA-only genotypes.
    limitations: Model-organism phenotypes do not establish human frequency or quantitative disease progression.
- name: Xenopus lrrc56-knockdown multiciliated cells
  species: Xenopus laevis
  genotype: >-
    Morpholino knockdown of lrrc56 in epidermal multiciliated cells, with rescue
    by wild-type Flag-Lrrc56 and by PCD-associated LRRC56 and ODAD3 variants
  category: Targeted knockdown / in vivo interactome model of a motile ciliopathy
  publication: PMID:41229303
  description: >-
    Xenopus epidermal multiciliated cells provide a live-imaging surrogate for
    the human airway multiciliated epithelium. Knockdown of lrrc56 strips outer
    dynein arms from the distal axoneme and displaces the outer-dynein-arm
    docking-complex subunit Odad3, and PCD-associated LRRC56 and ODAD3 variants
    disrupt the same localization and interaction. The model therefore captures
    the axonemal-assembly step that fails in outer-dynein-arm PCD, but it is a
    transient knockdown in embryonic epidermis and reports on cilia
    ultrastructure and protein localization rather than on airway infection,
    bronchiectasis, or any organ-level PCD outcome.
  genes:
  - preferred_term: LRRC56
    term:
      id: hgnc:25430
      label: LRRC56
  - preferred_term: ODAD3
    term:
      id: hgnc:28303
      label: ODAD3
  modeled_mechanisms:
  - target: Ciliary Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the outer-dynein-arm assembly failure that underlies the
      ODA-defect class of PCD, and places Lrrc56 upstream of the ODA docking
      complex through Odad3.
    limitations: >-
      Morpholino knockdown in embryonic epidermal multiciliated cells, not a
      germline null in airway epithelium; the readouts are axonemal protein
      localization rather than ciliary beat pattern or mucociliary transport, so
      the link to beat failure is inferred from ODA loss rather than measured
      here.
    readouts:
    - name: Axonemal Dnal4 (ODA light chain) distribution
      target: Ciliary Dysfunction
      direction: DECREASED
      interpretation: >-
        Loss of an outer-dynein-arm subunit from the axoneme is the structural
        signature of ODA-defect PCD; rescue by wild-type Lrrc56 establishes
        specificity.
      evidence:
      - reference: PMID:41229303
        reference_title: Physical and functional interaction of the ciliopathy proteins Lrrc56 and Odad3 control deployment of axonemal dyneins in vertebrate multiciliated cells.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Lrrc56 knockdown disrupted the normal axonemal distribution of the ODA light chain subunit Dnal4 (GFP-Dnal4), which is typically enriched along the length of the axoneme
        explanation: States the measured reduction in axonemal ODA subunit signal on lrrc56 knockdown.
    - name: Axonemal Odad3 (ODA docking complex) signal
      target: Ciliary Dysfunction
      direction: DECREASED
      interpretation: >-
        Places the docking complex downstream of Lrrc56, so an LRRC56 defect and
        an ODAD3 defect converge on the same axonemal step.
      evidence:
      - reference: PMID:41229303
        reference_title: Physical and functional interaction of the ciliopathy proteins Lrrc56 and Odad3 control deployment of axonemal dyneins in vertebrate multiciliated cells.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: following Lrrc56 knockdown, the Odad3-GFP signal was significantly reduced along the axoneme compared to that in controls
        explanation: Quantified loss of the docking-complex subunit from the axoneme after lrrc56 knockdown.
    evidence:
    - reference: PMID:41229303
      reference_title: Physical and functional interaction of the ciliopathy proteins Lrrc56 and Odad3 control deployment of axonemal dyneins in vertebrate multiciliated cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: loss of lrrc56 causes specific depletion of outer dynein arms (ODAs) from the distal axoneme
      explanation: Establishes that the Xenopus knockdown reproduces the outer-dynein-arm defect that defines this PCD class.
    - reference: PMID:41229303
      reference_title: Physical and functional interaction of the ciliopathy proteins Lrrc56 and Odad3 control deployment of axonemal dyneins in vertebrate multiciliated cells.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: disease-associated variants in LRRC56 and ODAD3 disrupted their localization and interaction, pointing to a shared functional pathway
      explanation: Ties the model directly to patient-derived variants rather than to knockdown alone.
- name: Xenopus embryonic epidermis foxi1e ionocyte-depletion model
  species: Xenopus laevis
  genotype: Morpholino knockdown of foxi1e, depleting ionocytes from the embryonic epidermis
  category: Non-cell-autonomous perturbation of multiciliated cell development
  publication: PMID:21183475
  description: >-
    Frog embryonic skin contains multiciliated, mucus-secreting and foxi1e-dependent ionocyte-like
    cells. Depleting ionocytes leaves multiciliated cells with fewer and aberrantly beating cilia.
    The reduced count concerns cilia per cell, not disappearance of the multiciliated cell
    population. This non-cell-autonomous epithelial perturbation is a surrogate-system finding,
    not a model of a human PCD genotype.
  modeled_mechanisms:
  - target: Ciliary Dysfunction
    relationship: PERTURBS
    fidelity: LOW
    description: >-
      Produces fewer cilia per multiciliated cell and abnormal ciliary beating by depleting a
      neighboring epidermal cell type.
    limitations: >-
      No PCD gene is involved and no PCD genotype is modelled — the perturbation is of ionocyte
      development, and the ciliary phenotype is a secondary consequence. Frog embryonic epidermis is
      a surrogate for airway epithelium rather than the tissue itself, and FOXI1 has not been
      implicated in human PCD. Treat this as evidence about the cellular architecture that
      mucociliary function depends on, not as a disease model.
    readouts:
    - name: Cilia per multiciliated cell after foxi1e knockdown
      target: Ciliary Dysfunction
      direction: DECREASED
      interpretation: >-
        Cilia per cell decrease after ionocyte depletion; abnormal beating is also observed. This is
        not evidence for a reduced number of multiciliated cells.
      evidence:
      - reference: PMID:21183475
        reference_title: 'Embryonic frog epidermis: a model for the study of cell-cell interactions in the development of mucociliary disease.'
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Depletion of ionocytes by foxi1e knockdown has detrimental effects on the development of multiciliated cells, which show fewer and aberrantly beating cilia.
        explanation: Reports the measured effect on multiciliated cell development and ciliary beating.
    evidence:
    - reference: PMID:21183475
      reference_title: 'Embryonic frog epidermis: a model for the study of cell-cell interactions in the development of mucociliary disease.'
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Depletion of ionocytes by foxi1e knockdown has detrimental effects on the development of multiciliated cells, which show fewer and aberrantly beating cilia. These results reveal a newly identified role for ionocytes and suggest that the frog embryonic skin is a model system that is particularly suited to studying the interactions of different cell types in mucociliary, as well as in secretory and transporting, epithelia.
      explanation: >-
        The knockdown result is the perturbation of ciliary function this link records, and the authors
        present the system as suited to studying cell-cell interactions in mucociliary epithelia, which
        is the level at which this link is informative for PCD.
  evidence:
  - reference: PMID:21183475
    reference_title: 'Embryonic frog epidermis: a model for the study of cell-cell interactions in the development of mucociliary disease.'
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We show that frog ionocytes express the transcription factor foxi1e, which is required for the development of these cells. Depletion of ionocytes by foxi1e knockdown has detrimental effects on the development of multiciliated cells, which show fewer and aberrantly beating cilia.
    explanation: Establishes the model as described, foxi1e knockdown depleting epidermal ionocytes, with the resulting multiciliated-cell phenotype of fewer and abnormally beating cilia.
experimental_models:
- name: Patient-derived nasal epithelial air-liquid interface model
  description: Expanded basal epithelial cells from nasal brush biopsies re-differentiated in miniaturized air-liquid interface cultures to preserve genotype-linked ciliary ultrastructural and motility defects in primary ciliary dyskinesia. These cultures support experimental screens rather than proof that every readthrough or replacement strategy restores clinical clearance.
  experimental_model_type: PRIMARY_CELL_CULTURE
  namo_type: namo:TwoDCellCulture
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: nasal cavity epithelium
    term:
      id: UBERON:0005384
      label: nasal cavity epithelium
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  conditions:
  - primary ciliary dyskinesia
  - MCIDAS-associated reduced generation of motile cilia
  cell_source: Patient-derived nasal basal epithelial cells expanded from nasal brush biopsies
  culture_system: Miniaturized 96-well Transwell air-liquid interface culture
  publication: PMID:33795320
  findings:
  - statement: Patient-derived nasal ALI cultures retain genotype-linked ciliary ultrastructural and motility defects and can be used to test rescue strategies for reduced multiciliogenesis
    evidence:
    - reference: PMID:33795320
      reference_title: 'Higher throughput drug screening for rare respiratory diseases: readthrough therapy in primary ciliary dyskinesia.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Initial analyses of ciliary ultrastructure, beat pattern and beat frequency in the 96-well transwell format ALI cultures indicate that a range of different PCD defects can be retained in these cultures.
      explanation: Supports use of expanded nasal ALI cultures as a disease-relevant PCD model that preserves mutation-associated ciliary defects.
    - reference: PMID:33795320
      reference_title: 'Higher throughput drug screening for rare respiratory diseases: readthrough therapy in primary ciliary dyskinesia.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: As proof-of-principle, we performed a personalised investigation in a patient with a rare and severe form of PCD (reduced generation of motile cilia), in this case caused by a homozygous nonsense mutation in the MCIDAS gene.
      explanation: Links the ALI model to a mechanistically relevant multiciliogenesis defect within a defined PCD genotype.
  evidence:
  - reference: PMID:33795320
    reference_title: 'Higher throughput drug screening for rare respiratory diseases: readthrough therapy in primary ciliary dyskinesia.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Primary cell culture of basal epithelial cells from nasal brush biopsies followed by ciliated differentiation at the air-liquid interface (ALI) has proven to be a useful tool in PCD diagnostics but the technique's broader utility, including in pre-clinical PCD research, has been restricted by the limited number of basal cells that can be expanded from such biopsies.
    explanation: Establishes patient-derived nasal ALI culture as an existing PCD modeling system and motivates the expanded higher-throughput format.
  modeled_mechanisms:
  - target: Ciliary Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Retains a range of patient ciliary beat and ultrastructural defects after basal-cell expansion.
    model_scale: CELLULAR
    limitations: The measured culture phenotype does not establish prediction of individual clinical severity or whole-lung clearance.
    readouts:
    - name: Ciliary beat pattern and frequency
      target: Ciliary Dysfunction
      description: Video analysis identifies genotype-associated motility abnormalities; different defects need not change frequency in the same direction.
      direction: ALTERED
      evidence:
      - reference: PMID:33795320
        reference_title: 'Higher throughput drug screening for rare respiratory diseases: readthrough therapy in primary ciliary dyskinesia.'
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Initial analyses of ciliary ultrastructure, beat pattern and beat frequency in the 96-well transwell format ALI cultures indicate that a range of different PCD defects can be retained in these cultures.
        explanation: Supports use of expanded nasal ALI cultures as a disease-relevant PCD model that preserves mutation-associated ciliary defects.
      biological_processes:
      - preferred_term: cilium movement
        term:
          id: GO:0003341
          label: cilium movement
    evidence:
    - reference: PMID:33795320
      reference_title: 'Higher throughput drug screening for rare respiratory diseases: readthrough therapy in primary ciliary dyskinesia.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Initial analyses of ciliary ultrastructure, beat pattern and beat frequency in the 96-well transwell format ALI cultures indicate that a range of different PCD defects can be retained in these cultures.
      explanation: Supports use of expanded nasal ALI cultures as a disease-relevant PCD model that preserves mutation-associated ciliary defects.
- name: Patient-derived airway organoid model
  description: Airway organoids established from nasal inferior turbinate brush samples and differentiated toward ciliated cells to capture patient-specific ciliary beating abnormalities in primary ciliary dyskinesia.
  experimental_model_type: ORGANOID
  namo_type: namo:Organoid
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: nasal cavity epithelium
    term:
      id: UBERON:0005384
      label: nasal cavity epithelium
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  conditions:
  - primary ciliary dyskinesia
  cell_source: Patient-derived nasal inferior turbinate epithelial cells expanded as airway organoids
  culture_system: Long-term expandable airway organoid culture with ciliated differentiation
  publication: PMID:34693619
  findings:
  - statement: Patient-derived airway organoids reproduce mutation-linked differences in ciliary beating and support genotype-specific functional interrogation
    evidence:
    - reference: PMID:34693619
      reference_title: Modelling of primary ciliary dyskinesia using patient-derived airway organoids.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Patient-specific differences in ciliary beating are observed and are in agreement with the patients' genetic mutations.
      explanation: Supports the organoid model as a genotype-resolved readout of the ciliary dysfunction central to PCD.
    - reference: PMID:34693619
      reference_title: Modelling of primary ciliary dyskinesia using patient-derived airway organoids.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: More detailed organoid ciliary phenotypes can thus be documented in addition to the standard diagnostic procedure.
      explanation: Supports use of organoids for mechanistically richer ciliary phenotyping in PCD.
  evidence:
  - reference: PMID:34693619
    reference_title: Modelling of primary ciliary dyskinesia using patient-derived airway organoids.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We apply this condition to AOs established from nasal inferior turbinate brush samples of patients suffering from primary ciliary dyskinesia (PCD), a pulmonary disease caused by dysfunction of the motile cilia in the airways.
    explanation: Establishes patient-derived airway organoids as a directly disease-relevant non-animal model for PCD.
  modeled_mechanisms:
  - target: Ciliary Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Differentiated patient airway organoids retain mutation-associated ciliary beating abnormalities.
    model_scale: CELLULAR
    limitations: Expansion and ciliated differentiation were demonstrated in a small genotype panel. Closed organoid geometry and culture composition limit extrapolation to airway transport; molecular editing alone is not evidence of functional rescue.
    readouts:
    - name: Patient-specific ciliary beating
      target: Ciliary Dysfunction
      description: Ciliary beating differs between patient organoids in agreement with their mutations.
      direction: ALTERED
      evidence:
      - reference: PMID:34693619
        reference_title: Modelling of primary ciliary dyskinesia using patient-derived airway organoids.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Patient-specific differences in ciliary beating are observed and are in agreement with the patients' genetic mutations.
        explanation: Supports the organoid model as a genotype-resolved readout of the ciliary dysfunction central to PCD.
      biological_processes:
      - preferred_term: cilium movement
        term:
          id: GO:0003341
          label: cilium movement
    evidence:
    - reference: PMID:34693619
      reference_title: Modelling of primary ciliary dyskinesia using patient-derived airway organoids.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Patient-specific differences in ciliary beating are observed and are in agreement with the patients' genetic mutations.
      explanation: Supports the organoid model as a genotype-resolved readout of the ciliary dysfunction central to PCD.
- name: Patient-specific hiPSC-derived airway epithelium model
  description: Human induced pluripotent stem cell-derived airway epithelium differentiated at air-liquid interface to model structural ciliary defects and impaired mucociliary transport in genetically defined primary ciliary dyskinesia.
  experimental_model_type: IPSC_DERIVED_MODEL
  namo_type: namo:TwoDCellCulture
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: respiratory airway
    term:
      id: UBERON:0001005
      label: respiratory airway
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  conditions:
  - primary ciliary dyskinesia
  - DNAH5-associated primary ciliary dyskinesia
  - NME5-associated primary ciliary dyskinesia
  cell_source: Patient-specific induced pluripotent stem cell lines differentiated into ciliated airway epithelium
  culture_system: Air-liquid interface differentiation of hiPSC-derived airway epithelium
  publication: PMID:37296588
  findings:
  - statement: Patient-specific hiPSC-derived airway epithelium reproduces molecular, ultrastructural, and functional ciliary defects, including impaired mucociliary transport
    evidence:
    - reference: PMID:37296588
      reference_title: Primary Ciliary Dyskinesia Patient-Specific hiPSC-Derived Airway Epithelium in Air-Liquid Interface Culture Recapitulates Disease Specific Phenotypes In Vitro.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Applying transmission electron microscopy, immunofluorescence staining, ciliary beat frequency, and mucociliary transport measurements, we could demonstrate that ciliated respiratory epithelia cells derived from two PCD patient-specific hiPSC lines carrying mutations in DNAH5 and NME5, respectively, recapitulate the respective diseased phenotype on a molecular, structural and functional level.
      explanation: Shows that hiPSC-derived airway epithelium reproduces the molecular and functional consequences of PCD mutations, including impaired transport.
  evidence:
  - reference: PMID:37296588
    reference_title: Primary Ciliary Dyskinesia Patient-Specific hiPSC-Derived Airway Epithelium in Air-Liquid Interface Culture Recapitulates Disease Specific Phenotypes In Vitro.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Here, we developed an in vitro model for PCD based on human induced pluripotent stem cell (hiPSC)-derived airway epithelium in Air-Liquid-Interface cultures.
    explanation: Establishes hiPSC-derived airway epithelium as a PCD-specific in vitro model.
  - reference: PMID:37296588
    reference_title: Primary Ciliary Dyskinesia Patient-Specific hiPSC-Derived Airway Epithelium in Air-Liquid Interface Culture Recapitulates Disease Specific Phenotypes In Vitro.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Motile cilia dysfunction results in diminished mucociliary clearance (MCC) of pathogens in the respiratory tract and chronic airway inflammation and infections successively causing progressive lung damage.
    explanation: Connects the model's mucociliary transport readouts to the central airway pathophysiology of PCD.
  modeled_mechanisms:
  - target: Ciliary Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: DNAH5 and NME5 patient-derived hiPSC airway epithelia reproduce their respective structural and functional ciliary defects.
    model_scale: CELLULAR
    limitations: Two patient-specific lines do not establish fidelity across PCD genotypes, reprogramming clones or differentiation batches.
    readouts:
    - name: Ciliary motility and ultrastructure
      target: Ciliary Dysfunction
      description: Electron microscopy, immunofluorescence and beat-frequency measurements assess two patient-specific hiPSC lines.
      direction: ALTERED
      evidence:
      - reference: PMID:37296588
        reference_title: Primary Ciliary Dyskinesia Patient-Specific hiPSC-Derived Airway Epithelium in Air-Liquid Interface Culture Recapitulates Disease Specific Phenotypes In Vitro.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Applying transmission electron microscopy, immunofluorescence staining, ciliary beat frequency, and mucociliary transport measurements, we could demonstrate that ciliated respiratory epithelia cells derived from two PCD patient-specific hiPSC lines carrying mutations in DNAH5 and NME5, respectively, recapitulate the respective diseased phenotype on a molecular, structural and functional level.
        explanation: Shows that hiPSC-derived airway epithelium reproduces the molecular and functional consequences of PCD mutations, including impaired transport.
      biological_processes:
      - preferred_term: cilium movement
        term:
          id: GO:0003341
          label: cilium movement
    evidence:
    - reference: PMID:37296588
      reference_title: Primary Ciliary Dyskinesia Patient-Specific hiPSC-Derived Airway Epithelium in Air-Liquid Interface Culture Recapitulates Disease Specific Phenotypes In Vitro.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Applying transmission electron microscopy, immunofluorescence staining, ciliary beat frequency, and mucociliary transport measurements, we could demonstrate that ciliated respiratory epithelia cells derived from two PCD patient-specific hiPSC lines carrying mutations in DNAH5 and NME5, respectively, recapitulate the respective diseased phenotype on a molecular, structural and functional level.
      explanation: Shows that hiPSC-derived airway epithelium reproduces the molecular and functional consequences of PCD mutations, including impaired transport.
  - target: Impaired Mucociliary Clearance
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Patient-specific hiPSC airway epithelia reproduce impaired culture-surface transport.
    model_scale: TISSUE
    limitations: The measured culture phenotype does not establish prediction of individual clinical severity or whole-lung clearance.
    readouts:
    - name: Mucociliary transport
      target: Impaired Mucociliary Clearance
      description: Transport measurements complement structural and beat-frequency phenotyping of DNAH5 and NME5 cultures.
      direction: DECREASED
      evidence:
      - reference: PMID:37296588
        reference_title: Primary Ciliary Dyskinesia Patient-Specific hiPSC-Derived Airway Epithelium in Air-Liquid Interface Culture Recapitulates Disease Specific Phenotypes In Vitro.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Applying transmission electron microscopy, immunofluorescence staining, ciliary beat frequency, and mucociliary transport measurements, we could demonstrate that ciliated respiratory epithelia cells derived from two PCD patient-specific hiPSC lines carrying mutations in DNAH5 and NME5, respectively, recapitulate the respective diseased phenotype on a molecular, structural and functional level.
        explanation: Shows that hiPSC-derived airway epithelium reproduces the molecular and functional consequences of PCD mutations, including impaired transport.
      biological_processes:
      - preferred_term: mucociliary clearance
        term:
          id: GO:0120197
          label: mucociliary clearance
    evidence:
    - reference: PMID:37296588
      reference_title: Primary Ciliary Dyskinesia Patient-Specific hiPSC-Derived Airway Epithelium in Air-Liquid Interface Culture Recapitulates Disease Specific Phenotypes In Vitro.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Applying transmission electron microscopy, immunofluorescence staining, ciliary beat frequency, and mucociliary transport measurements, we could demonstrate that ciliated respiratory epithelia cells derived from two PCD patient-specific hiPSC lines carrying mutations in DNAH5 and NME5, respectively, recapitulate the respective diseased phenotype on a molecular, structural and functional level.
      explanation: Shows that hiPSC-derived airway epithelium reproduces the molecular and functional consequences of PCD mutations, including impaired transport.
- name: CCDC40 mRNA replacement in patient airway cultures
  description: Lipid nanoparticle CCDC40 mRNA was tested in nasal ALI cultures from five CCDC40-deficient individuals, restoring expression in 10–74% of ciliated cells, associated axonemal proteins, beating and particle transport. Parallel zebrafish olfactory-pit flow rescue is preclinical vertebrate evidence. The study proposes a human phase I trial; it does not report clinical efficacy.
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  modeled_mechanisms:
  - target: CCDC39-CCDC40 Axonemal Scaffold Loss
    relationship: RESCUES
    fidelity: MODERATE
    description: mRNA replacement restores CCDC40 and integration of associated axonemal proteins.
    model_scale: CELLULAR
    limitations: The measured culture phenotype does not establish prediction of individual clinical severity or whole-lung clearance.
    readouts:
    - name: Axonemal protein reconstitution
      target: CCDC39-CCDC40 Axonemal Scaffold Loss
      description: CCDC40 expression in 10%-74% of ciliated cells permits associated-protein integration; this is not a fraction of clinically corrected lung tissue.
      direction: RESTORED
      evidence:
      - reference: PMID:42089334
        reference_title: mRNA therapy improves the composition and motility in CCDC40-deficient cilia in vitro and in vivo.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Topical application of exogenous LNP-CCDC40-mRNA to CCDC40-deficient cells results in endogenous CCDC40 expression (10%-74% of ciliated cells), enabling axonemal integration of CCDC40-associated proteins (CCDC39, GAS8/DRC4, DNALI1).
        explanation: Documents partial cellular expression and reassembly of associated proteins in treated patient airway cultures.
    evidence:
    - reference: PMID:42089334
      reference_title: mRNA therapy improves the composition and motility in CCDC40-deficient cilia in vitro and in vivo.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Topical application of exogenous LNP-CCDC40-mRNA to CCDC40-deficient cells results in endogenous CCDC40 expression (10%-74% of ciliated cells), enabling axonemal integration of CCDC40-associated proteins (CCDC39, GAS8/DRC4, DNALI1).
      explanation: Documents partial cellular expression and reassembly of associated proteins in treated patient airway cultures.
  - target: Impaired Mucociliary Clearance
    relationship: RESCUES
    fidelity: MODERATE
    description: Treatment improves fluorescent-particle transport in patient cultures.
    model_scale: TISSUE
    limitations: The measured culture phenotype does not establish prediction of individual clinical severity or whole-lung clearance.
    readouts:
    - name: Fluorescent-particle transport after mRNA delivery
      target: Impaired Mucociliary Clearance
      description: Improved transport relative to untreated CCDC40-deficient cultures; complete normalization is not established by this endpoint statement.
      direction: INCREASED
      evidence:
      - reference: PMID:42089334
        reference_title: mRNA therapy improves the composition and motility in CCDC40-deficient cilia in vitro and in vivo.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Further, we showed improved ciliary transport of fluorescent particles.
        explanation: Patient-cell rescue goes beyond beat frequency to an in vitro transport readout; it remains distinct from clinical whole-lung clearance or outcomes.
      biological_processes:
      - preferred_term: mucociliary clearance
        term:
          id: GO:0120197
          label: mucociliary clearance
    evidence:
    - reference: PMID:42089334
      reference_title: mRNA therapy improves the composition and motility in CCDC40-deficient cilia in vitro and in vivo.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Further, we showed improved ciliary transport of fluorescent particles.
      explanation: Patient-cell rescue goes beyond beat frequency to an in vitro transport readout; it remains distinct from clinical whole-lung clearance or outcomes.
  evidence:
  - reference: PMID:42089334
    reference_title: mRNA therapy improves the composition and motility in CCDC40-deficient cilia in vitro and in vivo.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Further, we showed improved ciliary transport of fluorescent particles.
    explanation: Patient-cell rescue goes beyond beat frequency to an in vitro transport readout; it remains distinct from clinical whole-lung clearance or outcomes.
  experimental_model_type: PRIMARY_CELL_CULTURE
  namo_type: namo:TwoDCellCulture
  publication: PMID:42089334
  cell_source: Nasal respiratory epithelial cells from five CCDC40-deficient individuals
  culture_system: Air-liquid interface culture treated with lipid nanoparticle-formulated CCDC40 mRNA
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: nasal cavity epithelium
    term:
      id: UBERON:0005384
      label: nasal cavity epithelium
- name: DNAH5 patient redox profiling and separate GSTA2 airway-cell perturbation
  experimental_model_type: PRIMARY_CELL_CULTURE
  namo_type: namo:TwoDCellCulture
  publication: PMID:39042459
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  cell_source: Patient-derived nasal epithelial cells, patient-derived iPSC airway cells and normal primary human airway cells
  culture_system: Air-liquid interface epithelial culture with transcriptomics, ROS measurements and separate GSTA2 shRNA experiments
  description: The study compared DNAH5 PCD cultures with maternal/healthy controls and confirmed increased GSTA/NRF2 expression in patient-derived iPSC airway cells. Separate GSTA2 knockdown in primary human airway cultures reduced beat frequency and microbead transport, with partial catalase rescue. These assay contexts must remain distinct; the knockdown is not a model of the increased GSTA2 state in DNAH5 PCD.
  modeled_mechanisms:
  - target: Ciliary Oxidative Stress and Glutathione Response
    relationship: MEASURES
    fidelity: MODERATE
    description: Measures genotype-associated ROS and GSTA/NRF2 expression in patient-derived epithelial cultures.
    limitations: Observed upregulation does not isolate its causal contribution to patient ciliary dysfunction or clinical severity.
    evidence:
    - reference: PMID:39042459
      reference_title: Transcriptional analysis of primary ciliary dyskinesia airway cells reveals a dedicated cilia glutathione pathway.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Primary and iPS-derived PCD multiciliated cells had increased expression of glutathione-S-transferases GSTA2 and GSTA1, as well as NRF2 target genes, accompanied by elevated levels of reactive oxygen species (ROS).
      explanation: DNAH5 patient cultures and iPSC-derived cells show an intrinsic oxidative-stress response; increased GSTA expression is not a GSTA deficiency.
    model_scale: CELLULAR
    readouts:
    - name: ROS and antioxidant-response expression
      target: Ciliary Oxidative Stress and Glutathione Response
      description: Patient-derived cultures show increased ROS and GSTA/NRF2 expression.
      direction: INCREASED
      evidence:
      - reference: PMID:39042459
        reference_title: Transcriptional analysis of primary ciliary dyskinesia airway cells reveals a dedicated cilia glutathione pathway.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Primary and iPS-derived PCD multiciliated cells had increased expression of glutathione-S-transferases GSTA2 and GSTA1, as well as NRF2 target genes, accompanied by elevated levels of reactive oxygen species (ROS).
        explanation: DNAH5 patient cultures and iPSC-derived cells show an intrinsic oxidative-stress response; increased GSTA expression is not a GSTA deficiency.
  - target: Ciliary Dysfunction
    relationship: PERTURBS
    fidelity: LOW
    description: Separate GSTA2 knockdown slows ciliary beating in primary human airway cells, with partial catalase rescue of transport.
    limitations: Loss of GSTA2 is an experimental perturbation, not the increased GSTA2 expression state measured in DNAH5 PCD.
    evidence:
    - reference: PMID:39042459
      reference_title: Transcriptional analysis of primary ciliary dyskinesia airway cells reveals a dedicated cilia glutathione pathway.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: GSTA2 knockdown (KD) resulted in a significant decrease in cilia beat frequency (CBF) and ciliary transport of microbeads on the surface of ciliated cells compared with a nontargeted control sequence (Figure 7, H and I).
      explanation: GSTA2 depletion perturbed motility and transport in primary human airway cultures; this intervention is different from the increased GSTA2 state observed in DNAH5 PCD.
    - reference: PMID:39042459
      reference_title: Transcriptional analysis of primary ciliary dyskinesia airway cells reveals a dedicated cilia glutathione pathway.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Moreover, cilia function partially recovers in GSTA2 knockdown after treatment with catalase, which neutralizes reactive oxygen species.
      explanation: Catalase partially rescued transport after experimental GSTA2 knockdown, not established genetic-motor restoration in DNAH5 patient cilia.
    model_scale: CELLULAR
    readouts:
    - name: Ciliary beat frequency after GSTA2 knockdown
      target: Ciliary Dysfunction
      description: Separate GSTA2 depletion in primary human airway cultures reduces beat frequency; it is not the patient-associated increased GSTA2 state.
      direction: DECREASED
      evidence:
      - reference: PMID:39042459
        reference_title: Transcriptional analysis of primary ciliary dyskinesia airway cells reveals a dedicated cilia glutathione pathway.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: GSTA2 knockdown (KD) resulted in a significant decrease in cilia beat frequency (CBF) and ciliary transport of microbeads on the surface of ciliated cells compared with a nontargeted control sequence (Figure 7, H and I).
        explanation: GSTA2 depletion perturbed motility and transport in primary human airway cultures; this intervention is different from the increased GSTA2 state observed in DNAH5 PCD.
      biological_processes:
      - preferred_term: cilium movement
        term:
          id: GO:0003341
          label: cilium movement
  evidence:
  - reference: PMID:39042459
    reference_title: Transcriptional analysis of primary ciliary dyskinesia airway cells reveals a dedicated cilia glutathione pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Primary and iPS-derived PCD multiciliated cells had increased expression of glutathione-S-transferases GSTA2 and GSTA1, as well as NRF2 target genes, accompanied by elevated levels of reactive oxygen species (ROS).
    explanation: DNAH5 patient cultures and iPSC-derived cells show an intrinsic oxidative-stress response; increased GSTA expression is not a GSTA deficiency.
  - reference: PMID:39042459
    reference_title: Transcriptional analysis of primary ciliary dyskinesia airway cells reveals a dedicated cilia glutathione pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: GSTA2 knockdown (KD) resulted in a significant decrease in cilia beat frequency (CBF) and ciliary transport of microbeads on the surface of ciliated cells compared with a nontargeted control sequence (Figure 7, H and I).
    explanation: GSTA2 depletion perturbed motility and transport in primary human airway cultures; this intervention is different from the increased GSTA2 state observed in DNAH5 PCD.
  - reference: PMID:39042459
    reference_title: Transcriptional analysis of primary ciliary dyskinesia airway cells reveals a dedicated cilia glutathione pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Moreover, cilia function partially recovers in GSTA2 knockdown after treatment with catalase, which neutralizes reactive oxygen species.
    explanation: Catalase partially rescued transport after experimental GSTA2 knockdown, not established genetic-motor restoration in DNAH5 patient cilia.
- name: C1d-defective patient airway transport model
  description: Transport assays in a subset of the C1d study cohort reveal functional deficits that routine ultrastructure and beat assessment can miss. Transport experiments do not independently validate all four genes reported in the clinical cohort.
  experimental_model_type: PRIMARY_CELL_CULTURE
  namo_type: namo:TwoDCellCulture
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: respiratory tract epithelium
    term:
      id: UBERON:0004802
      label: respiratory tract epithelium
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  cell_source: Nasal epithelial cells from individuals with CFAP46 or CFAP54 variants
  culture_system: Expanded and differentiated air-liquid interface cultures with particle transport assays
  publication: PMID:39362668
  modeled_mechanisms:
  - target: Central-Apparatus Transport Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Directly measures ineffective transport in C1d-defective patient cultures.
    model_scale: TISSUE
    limitations: The measured culture phenotype does not establish prediction of individual clinical severity or whole-lung clearance.
    readouts:
    - name: Ciliary particle transport
      target: Central-Apparatus Transport Dysfunction
      description: Particle movement across patient-derived ciliated epithelia is reduced relative to control cultures; reduced synchrony is a candidate explanation, not established by this measurement.
      direction: DECREASED
      evidence:
      - reference: PMID:39362668
        reference_title: Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance.
        explanation: Patient-derived C1d cultures show deficient transport despite inconspicuous routine ciliary diagnostics; the mechanism of transport inefficiency remains unresolved.
      biological_processes:
      - preferred_term: mucociliary clearance
        term:
          id: GO:0120197
          label: mucociliary clearance
    evidence:
    - reference: PMID:39362668
      reference_title: Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance.
      explanation: Patient-derived C1d cultures show deficient transport despite inconspicuous routine ciliary diagnostics; the mechanism of transport inefficiency remains unresolved.
  evidence:
  - reference: PMID:39362668
    reference_title: Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance.
    explanation: Patient-derived C1d cultures show deficient transport despite inconspicuous routine ciliary diagnostics; the mechanism of transport inefficiency remains unresolved.
- name: BMI1-expanded DNAH5 patient airway epithelial cell model
  description: A renewable patient-derived airway model retains ciliated differentiation and the DNAH5-associated immotile phenotype across extended passage. Demonstrated expansion is finite; indefinite immortalization and cross-genotype fidelity are not established.
  experimental_model_type: CELL_LINE
  namo_type: namo:CellLineModel
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: respiratory tract epithelium
    term:
      id: UBERON:0004802
      label: respiratory tract epithelium
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  cell_source: BMI1-transduced bronchial and nasal basal epithelial cells from two donors with biallelic DNAH5 variants
  culture_system: Lentiviral BMI1 expansion followed by air-liquid interface differentiation
  publication: PMID:41064994
  modeled_mechanisms:
  - target: Ciliary Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Retains DNAH5-associated ciliary immotility and missing outer-dynein-arm proteins after expansion.
    model_scale: CELLULAR
    limitations: Validation is confined to two DNAH5 donors and an immotile phenotype. BMI1 transduction, passage and differentiation conditions may affect other endpoints; coordination fidelity in beating-cilia PCD is unestablished.
    readouts:
    - name: Ciliary motility
      target: Ciliary Dysfunction
      description: Differentiated patient-derived cultures bear immotile cilia.
      direction: ABOLISHED
      evidence:
      - reference: PMID:41064994
        reference_title: Characterisation of a primary ciliary dyskinesia model generated from BMI1-transduced basal epithelial cells.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: We report that the cells retain their proliferation and differentiation capacity for at least 19 passages and recapitulate the disease phenotype with immotile cilia lacking DNAH5 and other outer dynein arm proteins.
        explanation: Supports prolonged expansion and retention of the DNAH5 outer-dynein-arm defect; it does not establish fidelity for motile, normal-TEM PCD genotypes.
      biological_processes:
      - preferred_term: cilium movement
        term:
          id: GO:0003341
          label: cilium movement
    - name: Axonemal DNAH5 and outer-dynein-arm proteins
      target: Ciliary Dysfunction
      description: Patient-derived cilia lack DNAH5 and other outer-dynein-arm proteins.
      direction: ABOLISHED
      evidence:
      - reference: PMID:41064994
        reference_title: Characterisation of a primary ciliary dyskinesia model generated from BMI1-transduced basal epithelial cells.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: We report that the cells retain their proliferation and differentiation capacity for at least 19 passages and recapitulate the disease phenotype with immotile cilia lacking DNAH5 and other outer dynein arm proteins.
        explanation: Supports prolonged expansion and retention of the DNAH5 outer-dynein-arm defect; it does not establish fidelity for motile, normal-TEM PCD genotypes.
    evidence:
    - reference: PMID:41064994
      reference_title: Characterisation of a primary ciliary dyskinesia model generated from BMI1-transduced basal epithelial cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We report that the cells retain their proliferation and differentiation capacity for at least 19 passages and recapitulate the disease phenotype with immotile cilia lacking DNAH5 and other outer dynein arm proteins.
      explanation: Supports prolonged expansion and retention of the DNAH5 outer-dynein-arm defect; it does not establish fidelity for motile, normal-TEM PCD genotypes.
  evidence:
  - reference: PMID:41064994
    reference_title: Characterisation of a primary ciliary dyskinesia model generated from BMI1-transduced basal epithelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We report that the cells retain their proliferation and differentiation capacity for at least 19 passages and recapitulate the disease phenotype with immotile cilia lacking DNAH5 and other outer dynein arm proteins.
    explanation: Supports prolonged expansion and retention of the DNAH5 outer-dynein-arm defect; it does not establish fidelity for motile, normal-TEM PCD genotypes.
  findings:
  - statement: BMI1-expanded DNAH5 cultures show altered ion-channel activity relative to non-PCD cultures; its relationship to immotility remains exploratory.
    evidence:
    - reference: PMID:41064994
      reference_title: Characterisation of a primary ciliary dyskinesia model generated from BMI1-transduced basal epithelial cells.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Characterisation of the ion transport properties of these PCD cells grown at an air-liquid interface showed lower activity of the Na+ channel ENaC and enhanced CFTR activity compared to non-PCD cells, which might be linked to ciliary immotility.
      explanation: The two-donor model study reports lower ENaC and higher CFTR activity. It does not establish that these changes cause ciliary dysfunction or characterize all PCD genotypes.
- name: iPSC-derived microfluidic airway-on-a-chip model
  description: Combines iPSC airway differentiation with fluid shear to organize multicellular planar polarity and quantify directional flow. Patient and edited cells support genetic comparison in this engineered context.
  experimental_model_type: ORGAN_ON_CHIP
  namo_type: namo:OrganOnChip
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: respiratory tract epithelium
    term:
      id: UBERON:0004802
      label: respiratory tract epithelium
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  cell_source: Human patient-derived, gene-edited and knockout iPSC airway cell sheets
  culture_system: Microfluidic airway-on-a-chip with fluid-shear regulation of planar cell polarity
  publication: PMID:34233948
  modeled_mechanisms:
  - target: Ciliary Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Recapitulates abnormal PCD ciliary function in an organized planar-polarity context.
    model_scale: TISSUE
    limitations: Shear-induced polarity and ciliogenesis are active experimental conditions. Platform organization must be separated from genotype effects before interpreting synchrony as an intrinsic patient defect.
    readouts:
    - name: Ciliary function in polarized airway sheets
      target: Ciliary Dysfunction
      description: PCD-associated abnormal ciliary function persists when the chip organizes multicellular planar polarity.
      direction: ALTERED
      evidence:
      - reference: PMID:34233948
        reference_title: Multicellular modeling of ciliopathy by combining iPS cells and microfluidic airway-on-a-chip technology.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: The application of an airway cell sheet derived from patient-derived iPSCs and their gene-edited counterparts, as well as genetic knockout iPSCs of PCD causative genes, made it possible to recapitulate the abnormal ciliary functions in organized PCP using the airway-on-a-chip.
        explanation: Establishes PCD ciliary phenotyping in an engineered, planar-polarized human airway epithelium.
      biological_processes:
      - preferred_term: cilium movement
        term:
          id: GO:0003341
          label: cilium movement
    evidence:
    - reference: PMID:34233948
      reference_title: Multicellular modeling of ciliopathy by combining iPS cells and microfluidic airway-on-a-chip technology.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The application of an airway cell sheet derived from patient-derived iPSCs and their gene-edited counterparts, as well as genetic knockout iPSCs of PCD causative genes, made it possible to recapitulate the abnormal ciliary functions in organized PCP using the airway-on-a-chip.
      explanation: Establishes PCD ciliary phenotyping in an engineered, planar-polarized human airway epithelium.
  evidence:
  - reference: PMID:34233948
    reference_title: Multicellular modeling of ciliopathy by combining iPS cells and microfluidic airway-on-a-chip technology.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The application of an airway cell sheet derived from patient-derived iPSCs and their gene-edited counterparts, as well as genetic knockout iPSCs of PCD causative genes, made it possible to recapitulate the abnormal ciliary functions in organized PCP using the airway-on-a-chip.
    explanation: Establishes PCD ciliary phenotyping in an engineered, planar-polarized human airway epithelium.
- name: BCi-NS1.1 dyskinetic airway epithelial cell line
  description: The reported BCi-NS1.1 culture had slow circular ciliary beating and a central-microtubule defect confirmed by electron microscopy. This is a phenotypic model for ciliary modulation, not a genotype-defined patient model or an automatically normal airway control.
  experimental_model_type: CELL_LINE
  namo_type: namo:CellLineModel
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: respiratory tract epithelium
    term:
      id: UBERON:0004802
      label: respiratory tract epithelium
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  cell_source: Immortalized human bronchial epithelial BCi-NS1.1 cell line
  culture_system: Air-liquid interface differentiation
  publication: PMID:29481304
  modeled_mechanisms:
  - target: Ciliary Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: Reproduces dyskinetic circular ciliary beating in the reported cell-line culture.
    model_scale: CELLULAR
    limitations: No causal patient PCD genotype is established. The report concerns the tested stock and culture conditions; it does not establish identical behavior in all BCi-NS1.1 stocks or prove that immortalization caused the defect.
    readouts:
    - name: Circular ciliary beat pattern
      target: Ciliary Dysfunction
      description: High-speed video detects circular dyskinetic motion, with a corresponding ultrastructural defect.
      direction: ALTERED
      evidence:
      - reference: PMID:29481304
        reference_title: Identification of an Immortalized Human Airway Epithelial Cell Line with Dyskinetic Cilia.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Although changes in CBF induced by known modulators were as expected, the cilia displayed a dyskinetic, circular beat pattern characteristic of central microtubular agenesis with outer doublet transposition.
        explanation: Supports a dyskinetic ciliary phenotype in BCi-NS1.1, without establishing a PCD patient genotype.
      biological_processes:
      - preferred_term: cilium movement
        term:
          id: GO:0003341
          label: cilium movement
    evidence:
    - reference: PMID:29481304
      reference_title: Identification of an Immortalized Human Airway Epithelial Cell Line with Dyskinetic Cilia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Although changes in CBF induced by known modulators were as expected, the cilia displayed a dyskinetic, circular beat pattern characteristic of central microtubular agenesis with outer doublet transposition.
      explanation: Supports a dyskinetic ciliary phenotype in BCi-NS1.1, without establishing a PCD patient genotype.
  evidence:
  - reference: PMID:29481304
    reference_title: Identification of an Immortalized Human Airway Epithelial Cell Line with Dyskinetic Cilia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Although changes in CBF induced by known modulators were as expected, the cilia displayed a dyskinetic, circular beat pattern characteristic of central microtubular agenesis with outer doublet transposition.
    explanation: Supports a dyskinetic ciliary phenotype in BCi-NS1.1, without establishing a PCD patient genotype.
- name: Mixed wild-type and CCDC40-deficient airway epithelial cultures
  description: A 2026 preprint tests mixtures of healthy and mutant cells, rather than therapeutic correction of mutant cells. Transport depends nonlinearly on composition, with a modeled ex vivo transport benchmark near 75% wild-type representation among ciliated cells. This culture-specific estimate is not a universal therapeutic target.
  experimental_model_type: PRIMARY_CELL_CULTURE
  namo_type: namo:TwoDCellCulture
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: respiratory tract epithelium
    term:
      id: UBERON:0004802
      label: respiratory tract epithelium
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  cell_source: Human bronchial epithelial cells mixed at defined wild-type and CCDC40-deficient ratios
  culture_system: Differentiated mosaic airway epithelia with high-speed imaging and particle tracking
  publication: PMID:41757021
  modeled_mechanisms:
  - target: Impaired Mucociliary Clearance
    relationship: PERTURBS
    fidelity: MODERATE
    description: Perturbs the fraction of functional cells to measure emergent epithelial transport.
    model_scale: TISSUE
    limitations: Preprint; mixing distinct donor cells is not isogenic therapeutic rescue. Cell composition, mutant-neighbor effects, spatial arrangement and the ex vivo calibration limit extrapolation to in vivo clearance or other PCD genotypes.
    readouts:
    - name: Transport velocity across wild-type fractions
      target: Impaired Mucociliary Clearance
      description: Velocity falls from approximately 56 to 9 micrometres per second between entirely wild-type and entirely mutant cultures; mixing ratios also affect epithelial composition.
      direction: DECREASED
      evidence:
      - reference: PMID:41757021
        reference_title: Defining Functional Correction Thresholds in Primary Ciliary Dyskinesia for Effective Gene Therapies.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Mucociliary transport declined nonlinearly, with speeds dropping from ~56 μm/s (100% WT) to ~9 μm/s in 100% mutant cultures.
        explanation: The preprint reports a nonlinear transport response to mixing wild-type and CCDC40-mutant cells; this is not a clinical efficacy threshold.
      biological_processes:
      - preferred_term: mucociliary clearance
        term:
          id: GO:0120197
          label: mucociliary clearance
    evidence:
    - reference: PMID:41757021
      reference_title: Defining Functional Correction Thresholds in Primary Ciliary Dyskinesia for Effective Gene Therapies.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Mucociliary transport declined nonlinearly, with speeds dropping from ~56 μm/s (100% WT) to ~9 μm/s in 100% mutant cultures.
      explanation: The preprint reports a nonlinear transport response to mixing wild-type and CCDC40-mutant cells; this is not a clinical efficacy threshold.
  evidence:
  - reference: PMID:41757021
    reference_title: Defining Functional Correction Thresholds in Primary Ciliary Dyskinesia for Effective Gene Therapies.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Mucociliary transport declined nonlinearly, with speeds dropping from ~56 μm/s (100% WT) to ~9 μm/s in 100% mutant cultures.
    explanation: The preprint reports a nonlinear transport response to mixing wild-type and CCDC40-mutant cells; this is not a clinical efficacy threshold.
- name: GAS2L2-deficient patient nasal epithelial orientation model
  description: Nasal epithelial cultures from one affected individual reproduce ciliary disorientation and asynchronous hyperkinetic beating despite normal patient axonemal structure. Separate mouse and Xenopus experiments in the paper provide cross-species evidence.
  experimental_model_type: PRIMARY_CELL_CULTURE
  namo_type: namo:TwoDCellCulture
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: nasal cavity epithelium
    term:
      id: UBERON:0005384
      label: nasal cavity epithelium
  cell_types:
  - preferred_term: respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  cell_source: Cultured nasal epithelial cells from one GAS2L2-deficient individual
  culture_system: Differentiated nasal epithelial culture with ciliary orientation and beat analysis
  publication: PMID:30665704
  evidence:
  - reference: PMID:30665704
    reference_title: Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Cultured GAS2L2-deficient nasal epithelial cells from one of the affected individuals showed defects in ciliary orientation and had an asynchronous and hyperkinetic (GAS2L2-deficient = 19.8 Hz versus control = 15.8 Hz) ciliary-beat pattern.
    explanation: Patient-derived nasal cells demonstrate an orientation defect with asynchronous hyperkinetic beating; this does not establish the cause of transport failure in C1d-associated disease.
  modeled_mechanisms:
  - target: Ciliary Disorientation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Measures patient-associated ciliary disorientation together with asynchronous, increased-frequency beating.
    limitations: One patient-derived culture background; the measured frequency difference is not a diagnostic threshold or estimate across GAS2L2 genotypes. Clinical clearance was not measured by this culture readout.
    evidence:
    - reference: PMID:30665704
      reference_title: Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Cultured GAS2L2-deficient nasal epithelial cells from one of the affected individuals showed defects in ciliary orientation and had an asynchronous and hyperkinetic (GAS2L2-deficient = 19.8 Hz versus control = 15.8 Hz) ciliary-beat pattern.
      explanation: Patient-derived nasal cells demonstrate an orientation defect with asynchronous hyperkinetic beating; this does not establish the cause of transport failure in C1d-associated disease.
    readouts:
    - name: Ciliary orientation and beat coordination
      target: Ciliary Disorientation
      direction: ALTERED
      description: Cultured patient cilia show disorientation and asynchronous beating; temporal coordination and directional alignment are separate endpoints.
      evidence:
      - reference: PMID:30665704
        reference_title: Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Cultured GAS2L2-deficient nasal epithelial cells from one of the affected individuals showed defects in ciliary orientation and had an asynchronous and hyperkinetic (GAS2L2-deficient = 19.8 Hz versus control = 15.8 Hz) ciliary-beat pattern.
        explanation: Patient-derived nasal cells demonstrate an orientation defect with asynchronous hyperkinetic beating; this does not establish the cause of transport failure in C1d-associated disease.
    - name: Ciliary beat frequency
      target: Ciliary Disorientation
      direction: INCREASED
      description: Reported frequency was 19.8 Hz in GAS2L2-deficient cells versus 15.8 Hz in controls under the study conditions.
      biological_processes:
      - preferred_term: cilium movement
        term:
          id: GO:0003341
          label: cilium movement
      evidence:
      - reference: PMID:30665704
        reference_title: Lack of GAS2L2 Causes PCD by Impairing Cilia Orientation and Mucociliary Clearance.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Cultured GAS2L2-deficient nasal epithelial cells from one of the affected individuals showed defects in ciliary orientation and had an asynchronous and hyperkinetic (GAS2L2-deficient = 19.8 Hz versus control = 15.8 Hz) ciliary-beat pattern.
        explanation: Patient-derived nasal cells demonstrate an orientation defect with asynchronous hyperkinetic beating; this does not establish the cause of transport failure in C1d-associated disease.
datasets:
- accession: geo:GSE272189
  title: Gene expression profile at single cell level of human nasal primary airway cells from DNAH5 subjects
  data_type: SINGLE_CELL_RNA_SEQ
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  genes:
  - preferred_term: DNAH5
    term:
      id: hgnc:2950
      label: DNAH5
  publication: PMID:39042459
  evidence:
  - reference: PMID:39042459
    reference_title: Transcriptional analysis of primary ciliary dyskinesia airway cells reveals a dedicated cilia glutathione pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We used single-cell RNA-Seq, proteomics, and advanced microscopy to compare primary culture epithelial cells from patients with PCD, their heterozygous mothers, and healthy individuals
    explanation: Single-cell transcriptomic dataset of human PCD airway epithelial cells (DNAH5 patients) versus heterozygous mothers and controls.
  description: >-
    Public human nasal ALI-culture scRNA-seq series linked to PMID:39042459. GEO lists 15 samples;
    the primary discovery comparison includes four DNAH5 PCD donors, their four heterozygous mothers
    and five unrelated controls, with additional samples represented in the accession. Sample count
    is not an independent patient count. Cultured and iPSC validation identified oxidative stress
    and ciliary GSTA2 responses; no independent raw-data reanalysis was performed in this curation.
- accession: geo:GSE254100
  title: >-
    Cellular responses in the airway ciliary microenvironment from mouse models
    of primary ciliary dyskinesia with central pair apparatus defects
  data_type: SINGLE_CELL_RNA_SEQ
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  genes:
  - preferred_term: CFAP221
    term:
      id: hgnc:33720
      label: CFAP221
  - preferred_term: CFAP54
    term:
      id: hgnc:26456
      label: CFAP54
  - preferred_term: SPEF2
    term:
      id: hgnc:26293
      label: SPEF2
  publication: PMID:39558053
  evidence:
  - reference: PMID:39558053
    reference_title: Airway ciliary microenvironment responses in mice with primary ciliary dyskinesia and central pair apparatus defects.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: we have used single-cell RNA sequencing to investigate responses in tracheal epithelial cells from mice with mutations in CPA genes
    explanation: Single-cell transcriptomic dataset of tracheal epithelium from central-pair-apparatus PCD mouse models (Cfap221, Cfap54, Spef2).
  description: >-
    Public mouse tracheal scRNA-seq with four GEO sample records: wild type and Cfap221/Pcdp1 nm1054,
    Spef2 bgh and Cfap54 gene-trap mutant preparations on the 129S6/SvEvTac background. Published
    cell-type-specific differential expression includes shared and distinct responses across genotypes.
    Human HGNC bindings identify the orthologous disease genes; the samples are mouse, not human.
    No raw-data reanalysis was performed in this curation.
computational_models:
- name: CFD model of mucociliary clearance under ciliary abnormalities
  description: >-
    Three-dimensional computational study of mucus transport under varied ciliary density, beat pattern,
    frequency, coordination and missing-cilia regions. The institutional abstract reports stronger
    effects for density, pattern and frequency and weaker effects for some spatial arrangements.
    This general physiological model is not calibrated to PCD patient genotypes or proven clinical
    trajectories.
  model_type: PHYSIOLOGICAL
  modeled_mechanisms:
  - target: Impaired Mucociliary Clearance
    description: >-
      Simulates how cilia beat/coordination abnormalities reduce net mucus
      transport, recapitulating impaired mucociliary clearance.
  publication: DOI:10.1016/j.jnnfm.2023.105029
  findings:
  - statement: Published computational results identify cilia density, waveform and frequency as important determinants of transport in the modeled system; clinical PCD effect sizes are not established.
  notes: >-
    DOI metadata and the author institutional record (https://kth.diva-portal.org/smash/record.jsf?pid=diva2:1779672)
    identify the study. The sanctioned DOI cache lacks full text; solver implementation and quantitative
    validation were not independently verified, and no simulation was rerun.
disease_term:
  preferred_term: primary ciliary dyskinesia
  term:
    id: MONDO:0016575
    label: primary ciliary dyskinesia
classifications:
  harrisons_chapter:
  - classification_value: RESPIRATORY
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  mechanistic_category:
  - classification_value: ciliopathy
references:
- reference: PMID:39362668
  title: Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.
  findings:
  - statement: >-
      C1d-associated patient transport dysfunction can evade routine structural, beat and nasal-NO
      diagnostics.
- reference: PMID:38871375
  title: Analyses of 1236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype-phenotype correlations.
  findings:
  - statement: >-
      The multinational genotype registry supports group-level phenotype associations and geographically
      variable founder alleles.
- reference: PMID:41005984
  title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
  findings:
  - statement: >-
      The joint ERS/ATS guideline integrates genetics and TEM with adjunct diagnostics and cautions
      that no single normal result excludes PCD.
- reference: PMID:41561099
  title: 'Primary ciliary dyskinesia: a national expert consensus statement on standards of care.'
  findings:
  - statement: >-
      England PCD consensus supplies multidisciplinary standards for airway, ENT, fertility, situs
      and transition care.
- reference: PMID:39042459
  title: Transcriptional analysis of primary ciliary dyskinesia airway cells reveals a dedicated cilia glutathione pathway.
  findings:
  - statement: >-
      DNAH5 patient-cell omics identify a ciliary glutathione pathway with experimental evidence
      for GSTA-dependent motility.
- reference: PMID:39558053
  title: Airway ciliary microenvironment responses in mice with primary ciliary dyskinesia and central pair apparatus defects.
  findings:
  - statement: >-
      Mouse central-apparatus mutant scRNA-seq provides existing cross-genotype epithelial-response
      comparisons.
- reference: PMID:20301301
  title: Primary Ciliary Dyskinesia.
  tags:
  - GeneReviews
updated_date: '2026-09-05T02:16:09Z'
differential_diagnoses:
- name: Cystic Fibrosis
  description: >-
    CF also causes chronic suppurative respiratory disease, bronchiectasis and sometimes low nasal
    NO. Sweat chloride and CFTR evaluation distinguish CF; laterality defects and hallmark motile-cilia
    findings favor PCD.
  evidence:
  - reference: PMID:41005984
    reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: More extensive testing for alternative diagnoses (e.g. cystic fibrosis and primary immunodeficiency) should be considered during the evaluation of subjects for PCD.
    explanation: >-
      The guideline names cystic fibrosis as an alternative diagnosis to exclude during PCD evaluation.
  - reference: PMID:24024753
    reference_title: Standardizing nasal nitric oxide measurement as a test for primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: however, there was overlap with cystic fibrosis (134.0 ± 73.5; 15.6-386.1 nl/min).
    explanation: >-
      Nasal NO in PCD rarely overlapped with healthy, asthma or COPD controls but did overlap with
      cystic fibrosis, so a low nasal NO does not by itself separate the two diseases.
- name: Secondary Ciliary Dysfunction and Other Causes of Bronchiectasis
  description: >-
    Acute infection, acquired epithelial injury, immunodeficiency and aspiration can produce overlapping
    respiratory manifestations or secondary beat abnormalities. Clinical context, repeat/culture
    ciliary assessment and molecular or hallmark ultrastructural evidence help distinguish inherited
    PCD. Isolated laterality syndromes and sensory ciliopathies need separate genetic interpretation.
  evidence:
  - reference: PMID:41005984
    reference_title: European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Class 1 defects confirm a diagnosis of PCD, while Class 2 defects are suggestive of PCD and require supporting evidence from other diagnostic modalities.
    explanation: >-
      The guideline distinguishes diagnostic evidence from suggestive or potentially confounded findings.

discussions:
- discussion_id: PCD-GAP-001
  prompt: Which ciliary features explain deficient transport in C1d-associated PCD when routine beat assessment is inconspicuous?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Central-Apparatus Transport Dysfunction
  - experimental_models#C1d-defective patient airway transport model
  rationale: Patient cultures establish a transport defect, but do not isolate phase coordination, stroke geometry, orientation, ciliated coverage or mucus loading as its cause. A direct transport endpoint is needed to adjudicate additional imaging features.
  proposed_experiments:
  - experiment_id: PCD-EXP-001
    name: Paired ciliary kinematics and transport in C1d patient cultures
    description: Measure beat frequency, waveform, effective-stroke direction, pairwise phase relationships, ciliated and motile fractions and particle transport in matched fields across independent donors and differentiation batches. Standardize temperature, mucus load, maturation and recording duration; retain immotile and sparse fields.
    model_systems:
    - name: C1d patient-derived nasal ALI cultures
      experimental_model_type: PRIMARY_CELL_CULTURE
      namo_type: namo:TwoDCellCulture
    controls:
    - name: Healthy donor cultures under matched conditions
    - name: Isogenic correction where technically feasible
      description: Use correction to distinguish genotype effects from donor background; molecular correction must be followed by functional testing.
    readouts:
    - name: Ciliary phase coordination and stroke geometry
      target: pathophysiology#Central-Apparatus Transport Dysfunction
      description: Quantify phase coherence separately from common beat direction and beat frequency.
      biological_processes:
      - preferred_term: cilium movement
        term:
          id: GO:0003341
          label: cilium movement
    - name: Particle transport speed and directionality
      target: pathophysiology#Central-Apparatus Transport Dysfunction
      description: Measure transport independently of the imaging-derived feature set.
      biological_processes:
      - preferred_term: mucociliary clearance
        term:
          id: GO:0120197
          label: mucociliary clearance
    decision_criterion: Pre-specify a donor-held-out comparison of transport prediction with and without coordination and waveform features, adjusting for coverage, frequency and mucus conditions. Define a meaningful effect and uncertainty bound before analysis.
    supporting_outcome:
    - Reproducible donor-held-out improvement would support added mechanistic information from the new features.
    refuting_outcome:
    - No improvement with sufficiently narrow uncertainty would argue against useful incremental information under the tested conditions; wide uncertainty would remain inconclusive.
  evidence:
  - reference: PMID:39362668
    reference_title: Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: However, we could show by in vitro ciliary transport assays that affected individuals exhibit insufficient ciliary clearance.
    explanation: Patient-derived C1d cultures show deficient transport despite inconspicuous routine ciliary diagnostics; the mechanism of transport inefficiency remains unresolved.
- discussion_id: PCD-GAP-002
  prompt: How faithfully do expanded or reprogrammed airway models preserve subtle patient ciliary phenotypes across passage and differentiation?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Ciliary Dysfunction
  - experimental_models#BMI1-expanded DNAH5 patient airway epithelial cell model
  - experimental_models#Patient-derived airway organoid model
  - experimental_models#Patient-specific hiPSC-derived airway epithelium model
  rationale: Retention of immotility and outer-dynein-arm loss in DNAH5 models is evidence for those endpoints. It does not establish preservation of subtle waveform or coordination defects across genotypes, culture systems and passage, or correspondence to the fresh patient sample.
  proposed_experiments:
  - experiment_id: PCD-EXP-002
    name: Within-donor comparison of fresh and expanded ciliary phenotypes
    description: Compare fresh nasal samples with early and late ALI passage, BMI1-expanded derivatives and organoids from the same donors; add independently differentiated iPSC clones where available. Include DNAH5 immotility and motile normal-TEM genotypes. Repeat fresh sampling after recovery from acute infection to assess secondary dysfunction.
    model_systems:
    - name: Matched fresh nasal epithelial samples and derived airway cultures
      experimental_model_type: PRIMARY_CELL_CULTURE
      namo_type: namo:TwoDCellCulture
    controls:
    - name: Matched healthy donors and culture batches
    - name: Repeated fresh sample
      description: Separate sampling and inflammatory-state variability from changes introduced during culture.
    readouts:
    - name: Within-donor ciliary phenotype concordance
      target: pathophysiology#Ciliary Dysfunction
      description: Compare motile fraction, beat frequency, waveform and spatial coordination; analyze donors independently of fields and technical replicates.
      biological_processes:
      - preferred_term: cilium movement
        term:
          id: GO:0003341
          label: cilium movement
    decision_criterion: Define endpoint-specific equivalence margins from repeat-sampling variability before testing platform and passage effects; assess concordance within genotype rather than pooling all PCD.
    supporting_outcome:
    - Concordance within the pre-specified margins would support model use for that genotype and endpoint.
    refuting_outcome:
    - Reproducible passage- or platform-dependent shifts exceeding margins would limit that context of use, even if gross immotility remains stable.
  evidence:
  - reference: PMID:41064994
    reference_title: Characterisation of a primary ciliary dyskinesia model generated from BMI1-transduced basal epithelial cells.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We report that the cells retain their proliferation and differentiation capacity for at least 19 passages and recapitulate the disease phenotype with immotile cilia lacking DNAH5 and other outer dynein arm proteins.
    explanation: Supports prolonged expansion and retention of the DNAH5 outer-dynein-arm defect; it does not establish fidelity for motile, normal-TEM PCD genotypes.
  - reference: PMID:34693619
    reference_title: Modelling of primary ciliary dyskinesia using patient-derived airway organoids.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Patient-specific differences in ciliary beating are observed and are in agreement with the patients' genetic mutations.
    explanation: Supports the organoid model as a genotype-resolved readout of the ciliary dysfunction central to PCD.
- discussion_id: PCD-GAP-003
  prompt: Are partial-correction requirements determined by genotype, spatial arrangement and the behavior of uncorrected cells?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Mucociliary Clearance
  - experimental_models#Mixed wild-type and CCDC40-deficient airway epithelial cultures
  - experimental_models#CCDC40 mRNA replacement in patient airway cultures
  rationale: CCDC40 mixing experiments and mRNA rescue both support functional testing beyond protein expression. The preprint estimate near 75% wild-type ciliated cells is conditional on its donor mixture and ex vivo benchmark; the 10%-74% expression range in the mRNA study measures a different quantity and cannot be treated as a conflicting correction threshold.
  proposed_experiments:
  - experiment_id: PCD-EXP-003
    name: Genotype-resolved mosaic rescue and transport curves
    description: Generate graded isogenic correction or replacement in CCDC40, DNAH5 and a motile normal-TEM genotype. Measure expression-positive and functionally corrected fractions separately among all epithelial cells and among ciliated cells. Compare clustered and dispersed correction while controlling total ciliation and mucus load.
    model_systems:
    - name: Patient-derived airway ALI cultures with graded correction
      experimental_model_type: PRIMARY_CELL_CULTURE
      namo_type: namo:TwoDCellCulture
    controls:
    - name: Uncorrected, mock-treated and fully corrected isogenic cultures
    - name: Wild-type and mutant mixing benchmark
      description: Compare mixing with actual correction without assuming they are equivalent interventions.
    readouts:
    - name: Transport response to functional correction fraction
      target: pathophysiology#Impaired Mucociliary Clearance
      description: Estimate transport velocity, directional persistence and clearance per beat against measured functional correction and spatial coverage.
      biological_processes:
      - preferred_term: mucociliary clearance
        term:
          id: GO:0120197
          label: mucociliary clearance
    decision_criterion: Fit donor-aware transport curves and compare genotype and spatial-arrangement effects against a common-curve model with pre-specified meaningful differences; validate against held-out cultures.
    supporting_outcome:
    - Distinct reproducible curves would support genotype- or topology-specific correction requirements.
    refuting_outcome:
    - Equivalent curves within pre-specified margins would weaken genotype or spatial dependence over the tested range; neither result establishes a clinical threshold.
  evidence:
  - reference: PMID:41757021
    reference_title: Defining Functional Correction Thresholds in Primary Ciliary Dyskinesia for Effective Gene Therapies.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Mucociliary transport declined nonlinearly, with speeds dropping from ~56 μm/s (100% WT) to ~9 μm/s in 100% mutant cultures.
    explanation: The preprint reports a nonlinear transport response to mixing wild-type and CCDC40-mutant cells; this is not a clinical efficacy threshold.
  - reference: PMID:41757021
    reference_title: Defining Functional Correction Thresholds in Primary Ciliary Dyskinesia for Effective Gene Therapies.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: Modeling revealed that transport efficiency was equivalent to that recorded in ex vivo human tissues and plateaued when ~75% of the ciliated population was WT.
    explanation: Preprint estimate uses the ciliated-cell population as denominator and an ex vivo tissue benchmark; transfer to other genotypes, delivery methods or patients remains untested.
  - reference: PMID:42089334
    reference_title: mRNA therapy improves the composition and motility in CCDC40-deficient cilia in vitro and in vivo.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Further, we showed improved ciliary transport of fluorescent particles.
    explanation: Patient-cell rescue goes beyond beat frequency to an in vitro transport readout; it remains distinct from clinical whole-lung clearance or outcomes.
- discussion_id: PCD-GAP-004
  prompt: How much of measured epithelial coordination is intrinsic to the PCD genotype versus imposed by culture flow and geometry?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Ciliary Dysfunction
  - experimental_models#iPSC-derived microfluidic airway-on-a-chip model
  rationale: The airway-on-a-chip study shows that fluid shear regulates planar polarity and ciliogenesis. Thus an organized flow field is partly a product of the model conditions. Planar alignment, temporal phase synchrony and net transport must be measured separately before a coordination metric is interpreted as patient-intrinsic dysfunction.
  proposed_experiments:
  - experiment_id: PCD-EXP-004
    name: Genotype by mechanical-context comparison
    description: Compare patient and isogenic corrected airway sheets under matched static and controlled-shear conditions. Measure before conditioning, during conditioning and after withdrawal; quantify ciliated coverage and mucus loading alongside flow.
    model_systems:
    - name: Patient and corrected iPSC-derived airway-on-a-chip
      experimental_model_type: ORGAN_ON_CHIP
      namo_type: namo:OrganOnChip
    controls:
    - name: Isogenic corrected epithelium under each flow condition
    - name: Static cultures at matched differentiation stage
    readouts:
    - name: Planar alignment and phase coordination
      target: pathophysiology#Ciliary Dysfunction
      description: Separate directional alignment from temporal phase relationships and account for ciliated coverage.
      biological_processes:
      - preferred_term: cilium movement
        term:
          id: GO:0003341
          label: cilium movement
    - name: Directional transport after conditioning
      target: pathophysiology#Impaired Mucociliary Clearance
      description: Assess endogenous transport after external flow stops, distinguishing imposed advection from cilia-driven movement.
      biological_processes:
      - preferred_term: mucociliary clearance
        term:
          id: GO:0120197
          label: mucociliary clearance
    decision_criterion: Pre-specify genotype, shear and interaction contrasts with donor or clone as the independent unit; test whether the disease-associated signal persists after removal of imposed flow.
    supporting_outcome:
    - A persistent genotype effect across mechanical conditions would support an intrinsic defect in the measured feature.
    refuting_outcome:
    - A signal abolished or reversed by conditioning would limit interpretation as a platform-independent disease readout.
  evidence:
  - reference: PMID:34233948
    reference_title: Multicellular modeling of ciliopathy by combining iPS cells and microfluidic airway-on-a-chip technology.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Here, we combine human iPSCs and airway-on-a-chip technology, to demonstrate the effectiveness of fluid shear stress (FSS) for regulating the global axis of multicellular planar cell polarity (PCP), as well as inducing ciliogenesis, thereby contributing to quantifiable unidirectional mucociliary flow.
    explanation: Shows that the platform imposes a mechanical context that affects polarity and flow; it is relevant to interpreting coordination measurements.
  - reference: PMID:34233948
    reference_title: Multicellular modeling of ciliopathy by combining iPS cells and microfluidic airway-on-a-chip technology.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The application of an airway cell sheet derived from patient-derived iPSCs and their gene-edited counterparts, as well as genetic knockout iPSCs of PCD causative genes, made it possible to recapitulate the abnormal ciliary functions in organized PCP using the airway-on-a-chip.
    explanation: Establishes PCD ciliary phenotyping in an engineered, planar-polarized human airway epithelium.
- discussion_id: PCD-GAP-005
  prompt: Does loss of motile cilia drive airway wall remodeling in human PCD through a direct epithelial-homeostasis route, independently of the infection-inflammation cycle?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Bronchiectasis and Airway Wall Remodeling
  - pathophysiology#Periciliary Barrier Dysfunction
  rationale: Conditional IFT88 deletion in adult mice removed airway cilia and produced bronchial remodeling, epithelial hypertrophy and hyperplasia, increased club-cell numbers and airway hyperreactivity without detectable inflammation or an apparent mucus-clearance defect. IFT88 is an intraflagellar-transport gene that also affects non-motile cilia and epithelial differentiation, so the model is not equivalent to a human axonemal PCD genotype. Two node descriptions in this entry already qualify the experiment on those grounds and keep remodeling downstream of chronic infection and inflammation; whether a cilia-autonomous route contributes in human PCD has not been tested.
  proposed_experiments:
  - experiment_id: PCD-EXP-005
    name: Remodeling-versus-inflammation dissociation in early human PCD airway
    description: In genotype-defined children diagnosed before chronic infection is established, pair bronchial biopsy or brushing histomorphometry (basal and club-cell composition, epithelial hypertrophy, basement-membrane thickening) with airway inflammatory markers and a regional clearance measurement, and test whether structural remodeling is present in airway segments whose inflammatory and clearance measures are unremarkable.
    would_support:
    - pathophysiology#Bronchiectasis and Airway Wall Remodeling
    decision_criterion: Pre-specify the remodeling indices, the inflammatory and clearance ranges that count as unaffected, and a meaningful effect size, with the participant as the independent unit and adjustment for age, genotype and treatment history.
    supporting_outcome:
    - Elevated remodeling indices in segments whose inflammatory markers and clearance sit within the non-PCD range would support a cilia-autonomous contribution in humans.
    refuting_outcome:
    - Remodeling that tracks inflammatory burden and clearance failure with no residual component would leave the infection-driven cascade sufficient over the sampled age range.
  evidence:
  - reference: PMID:24213915
    reference_title: Deletion of airway cilia results in noninflammatory bronchiectasis and hyperreactive airways.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: In IFT88(-) mice there was a substantial loss of airway cilia on respiratory epithelium. Three months after the deletion of cilia, there was clear evidence for bronchial remodeling that was not associated with inflammation or apparent defects in mucus clearance.
    explanation: Establishes the inflammation-independent remodeling phenotype in the IFT88-deletion mouse that this entry discusses in three node and hypothesis descriptions. It is a mouse result and does not demonstrate the route in human PCD, which is the open question this discussion records.
  - reference: PMID:24213915
    reference_title: Deletion of airway cilia results in noninflammatory bronchiectasis and hyperreactive airways.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Club cells may be prevented from differentiating into respiratory epithelial cells because of a lack of IFT88 protein that is necessary to form a single nonmotile cilium.
    explanation: The authors attribute part of the phenotype to loss of a nonmotile cilium needed for club-cell differentiation, which is why the IFT88 model is not equivalent to a human axonemal PCD genotype.

📚

References & Deep Research

References

PMID:39362668

Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.

1 finding

C1d-associated patient transport dysfunction can evade routine structural, beat and nasal-NO diagnostics.

PMID:38871375

Analyses of 1236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct DNA variants and significant genotype-phenotype correlations.

1 finding

The multinational genotype registry supports group-level phenotype associations and geographically variable founder alleles.

PMID:41005984

European Respiratory Society and American Thoracic Society guidelines for the diagnosis of primary ciliary dyskinesia.

1 finding

The joint ERS/ATS guideline integrates genetics and TEM with adjunct diagnostics and cautions that no single normal result excludes PCD.

PMID:41561099

Primary ciliary dyskinesia: a national expert consensus statement on standards of care.

1 finding

England PCD consensus supplies multidisciplinary standards for airway, ENT, fertility, situs and transition care.

PMID:39042459

Transcriptional analysis of primary ciliary dyskinesia airway cells reveals a dedicated cilia glutathione pathway.

1 finding

DNAH5 patient-cell omics identify a ciliary glutathione pathway with experimental evidence for GSTA-dependent motility.

PMID:39558053

Airway ciliary microenvironment responses in mice with primary ciliary dyskinesia and central pair apparatus defects.

1 finding

Mouse central-apparatus mutant scRNA-seq provides existing cross-genotype epithelial-response comparisons.

PMID:20301301

Primary Ciliary Dyskinesia.

No top-level findings curated for this source.

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Disorder ▸

Disorder

Name: Primary_Ciliary_Dyskinesia
Category: Genetic
Existing deep-research providers: falcon
Existing evidence reference count in YAML: 98

Key Pathophysiology Nodes

Ciliary Dysfunction
Impaired Mucociliary Clearance
Situs Inversus
Deep research literature mapping

Citation Inventory (for evidence mapping)

DOI:10.1007/s40291-025-00801-w
DOI:10.1183/13993003.01769-2023
DOI:10.14288/1.0445067
DOI:10.1542/peds.2023-063064
DOI:10.17615/qgfk-y329
DOI:10.29057/mjmr.v12i24.12347
DOI:10.3390/cells13110974

Falcon ▸

Disease Pathophysiology Research Report

Edison Scientific Literature 23 citations 2025-12-15T09:10:07.320535

Disease Pathophysiology Research Report

Target Disease - Disease Name: Primary Ciliary Dyskinesia (PCD) - MONDO ID: not confidently resolved here; will populate upon ontology verification from MONDO database. - Category: Genetic (motile ciliopathy)

Pathophysiology description Primary ciliary dyskinesia is a motile ciliopathy caused by mutations affecting axonemal structures (outer/inner dynein arms, radial spokes, central pair apparatus, nexin–dynein regulatory complex) or the multiciliogenesis program, resulting in abnormal or absent motile cilia and impaired mucociliary clearance; nodal motile cilia dysfunction during embryogenesis underlies laterality defects (e.g., situs inversus/ambiguus) (URL: https://doi.org/10.1542/peds.2023-063064; May 2024) (wee2024primaryciliarydyskinesia. pages 1-3). “Mutations impair axonemal dynein arms, dynein regulatory/nexin complexes, or ciliogenesis factors, producing defective or absent motile cilia and impaired mucociliary clearance” (URL: https://doi.org/10.1542/peds.2023-063064; May 2024) (wee2024primaryciliarydyskinesia. pages 3-4). Clinically, impaired clearance leads to neonatal respiratory distress, chronic wet cough, persistent rhinosinusitis/otitis media, progressive bronchiectasis, and subfertility; laterality defects reflect embryonic nodal cilia malfunction (URL: https://doi.org/10.1542/peds.2023-063064; May 2024) (wee2024primaryciliarydyskinesia. pages 1-3). No single diagnostic gold standard exists; multimodal testing with nasal nitric oxide (nNO), high-speed videomicroscopy (HSVM), transmission electron microscopy (TEM), immunofluorescence (IF), and genetics is recommended (URL: https://doi.org/10.3390/cells13110974; Jun 2024) (despotes2024primaryciliarydyskinesia pages 16-17).

Key concepts and definitions - Motile cilium axoneme (cellular component): canonical 9+2 microtubule doublets with outer dynein arms (ODA), inner dynein arms (IDA), radial spokes (RS), central pair (CP), nexin–dynein regulatory complex (N-DRC); coordinated beating generates mucociliary transport (URL: https://doi.org/10.1542/peds.2023-063064; May 2024) (wee2024primaryciliarydyskinesia. pages 1-3). - Multiciliogenesis (biological process): centriole amplification and motile cilia generation driven by transcriptional regulators (FOXJ1, MCIDAS) and cell cycle–linked factors (e.g., CCNO); defects cause oligocilia/aplasia (URL: https://doi.org/10.1542/peds.2023-063064; May 2024; URL: https://doi.org/10.3390/cells13110974; Jun 2024) (wee2024primaryciliarydyskinesia. pages 1-3, despotes2024primaryciliarydyskinesia pages 16-17). - Nodal cilia: motile 9+0 cilia generating embryonic leftward flow; defects randomize L–R patterning (URL: https://doi.org/10.3390/cells13110974; Jun 2024) (despotes2024primaryciliarydyskinesia pages 1-2).

1) Core Pathophysiology - Primary mechanisms: loss or misassembly of ODA/IDA complexes, defects of RS/CP/N‑DRC, and failure of ODA docking or dynein assembly cause abnormal waveform, reduced beat frequency, or immotility; multiciliogenesis defects cause markedly reduced cilia number (URL: https://doi.org/10.1542/peds.2023-063064; May 2024; URL: https://doi.org/10.3390/cells13110974; Jun 2024) (wee2024primaryciliarydyskinesia. pages 3-4, wee2024primaryciliarydyskinesia. pages 1-3, despotes2024primaryciliarydyskinesia pages 16-17). - Downstream cellular consequences: impaired mucociliary clearance → mucus stasis, recurrent bacterial infection, epithelial injury, chronic neutrophilic inflammation, and progressive airway remodeling/bronchiectasis (URL: https://doi.org/10.1542/peds.2023-063064; May 2024) (wee2024primaryciliarydyskinesia. pages 3-4). - Developmental mechanism: nodal cilia dysfunction drives laterality defects (situs inversus/ambiguus), present in a substantial subset (URL: https://doi.org/10.1542/peds.2023-063064; May 2024) (wee2024primaryciliarydyskinesia. pages 1-3).

2) Key Molecular Players (genes/proteins; ontology-ready summary) | Gene (HGNC) | Category | Axonemal / assembly role | Key cellular component (GO-style) | Disrupted biological process (GO-style) | Representative phenotype associations | Evidence (citation, DOI/URL) | |---|---|---|---|---|---|---| | DNAH5 | ODA (outer dynein arm) | Major axonemal heavy chain generating motile force | Axonemal outer dynein arm | Cilium movement; axoneme function | Recurrent airway infections, bronchiectasis; laterality defects common | (raidt2024analysesof1236 pages 8-10) https://doi.org/10.1183/13993003.01769-2023 | | DNAI1 | ODA (intermediate chain) | Structural/intermediate chain required for ODA integrity and docking | Axonemal outer dynein arm | Outer dynein arm assembly; cilium movement | Chronic wet cough, bronchiectasis; neonatal respiratory distress; situs inversus | (a.2025primaryciliarydyskinesia pages 2-3) https://doi.org/10.17615/qgfk-y329, (raidt2024analysesof1236 pages 8-10) https://doi.org/10.1183/13993003.01769-2023 | | DNAH11 | ODA (heavy chain) | Heavy chain with functional role; often causes dyskinetic beating with near-normal TEM | Axonemal dynein arm | Ciliary beating regulation; cilium movement | Variable lung function (milder FEV1 reduction); atypical/normal TEM; respiratory symptoms | (raidt2024analysesof1236 pages 8-10) https://doi.org/10.1183/13993003.01769-2023, (wee2024primaryciliarydyskinesia. pages 3-4) https://doi.org/10.1542/peds.2023-063064 | | CCDC39 | N-DRC / assembly scaffold | Scaffolding for inner dynein arms and nexin-dynein regulatory complex assembly | Nexin-dynein regulatory complex; inner dynein arm | Axoneme assembly; dynein arm docking | Severe early lung disease; low FEV1; neonatal distress; bronchiectasis | (raidt2024analysesof1236 pages 8-10) https://doi.org/10.1183/13993003.01769-2023, (wee2024primaryciliarydyskinesia. pages 1-3) https://doi.org/10.1542/peds.2023-063064 | | CCDC40 | N-DRC / assembly scaffold | Partners with CCDC39 to position IDAs and N-DRC during axoneme assembly | Nexin-dynein regulatory complex; axoneme | Axoneme assembly; microtubule organization | Severe lung function decline (low FEV1); bronchiectasis; congenital heart disease association noted | (raidt2024analysesof1236 pages 8-10) https://doi.org/10.1183/13993003.01769-2023, (despotes2024primaryciliarydyskinesia pages 16-17) https://doi.org/10.3390/cells13110974 | | RSPH1 | Radial spoke head | Radial spoke head component coordinating CP–dynein regulation | Radial spoke (axoneme) | Regulation of axonemal dynein activity; central pair organization | Central-pair related defects; typical respiratory disease; laterality less associated | (despotes2024primaryciliarydyskinesia pages 16-17) https://doi.org/10.3390/cells13110974, (raidt2024analysesof1236 pages 8-10) https://doi.org/10.1183/13993003.01769-2023 | | RSPH4A | Radial spoke head | Radial spoke protein required for RS integrity and coordinated beating | Radial spoke (axoneme) | Regulation of ciliary beating; central pair-dependent signaling | Respiratory disease, sinusitis, possible hearing involvement reported in case series | (despotes2024primaryciliarydyskinesia pages 16-17) https://doi.org/10.3390/cells13110974, (despotes2024primaryciliarydyskinesia pages 1-2) https://doi.org/10.3390/cells13110974 | | RSPH9 | Radial spoke head | Radial spoke head subunit impacting CP–RS interactions | Radial spoke (axoneme) | Regulation of dynein-driven motility; cilium movement | Respiratory symptoms; genotype-specific laterality patterns (less frequent) | (raidt2024analysesof1236 pages 8-10) https://doi.org/10.1183/13993003.01769-2023, (despotes2024primaryciliarydyskinesia pages 16-17) https://doi.org/10.3390/cells13110974 | | CCNO | Ciliogenesis / multiciliogenesis | Required for centriole amplification and generation of multiple motile cilia | Basal bodies / centrioles; apical cytoplasm | Multiciliogenesis; cilium assembly | Oligocilia / reduced cilia number; severe early disease, very low FEV1 (worse prognosis) | (raidt2024analysesof1236 pages 8-10) https://doi.org/10.1183/13993003.01769-2023, (despotes2024primaryciliarydyskinesia pages 16-17) https://doi.org/10.3390/cells13110974 | | FOXJ1 | Ciliogenesis transcription factor | Master regulator of motile ciliogenesis (transcriptional control) | Nucleus (transcription regulator controlling cilium assembly) | Regulation of cilium assembly; multiciliogenesis | Oligocilia/absent cilia phenotypes; laterality defects; autosomal-dominant presentations described | (wee2024primaryciliarydyskinesia. pages 1-3) https://doi.org/10.1542/peds.2023-063064, (a.2025primaryciliarydyskinesia pages 2-3) https://doi.org/10.17615/qgfk-y329 | | MCIDAS | Ciliogenesis / multiciliated cell differentiation | Drives multiciliated cell differentiation and centriole biogenesis program | Nucleus; transcriptional complex controlling centriole amplification | Multiciliogenesis; centriole assembly | Reduced cilia number, neonatal distress, chronic airway disease | (despotes2024primaryciliarydyskinesia pages 16-17) https://doi.org/10.3390/cells13110974, (wee2024primaryciliarydyskinesia. pages 1-3) https://doi.org/10.1542/peds.2023-063064 | | ODAD1 | ODA docking / assembly factor | Factor involved in ODA docking/assembly to doublet microtubules | Outer dynein arm docking complex | Outer dynein arm docking; axonemal assembly | Respiratory disease with relatively milder FEV1 impact vs severe scaffold defects | (raidt2024analysesof1236 pages 8-10) https://doi.org/10.1183/13993003.01769-2023 |

Table: Compact ontology-ready table listing key PCD genes, their axonemal/assembly roles, affected cellular components and processes, representative phenotypes, and primary evidence (context citations with DOIs) to support integration into a knowledge base. Narrative notes: - ODA heavy and intermediate chain genes (DNAH5, DNAI1) and the ODA heavy chain DNAH11 are among the most frequent PCD genotypes in international cohorts (URL: https://doi.org/10.1183/13993003.01769-2023; Jun 2024) (raidt2024analysesof1236 pages 8-10). - IDA/N‑DRC scaffolds CCDC39 and CCDC40 are associated with severe phenotypes and lower lung function (URL: https://doi.org/10.1183/13993003.01769-2023; Jun 2024) (raidt2024analysesof1236 pages 8-10). - Radial spoke head proteins (RSPH1, RSPH4A, RSPH9) affect CP–RS regulation and are linked to distinctive ultrastructural or functional signatures, often without laterality defects (URL: https://doi.org/10.3390/cells13110974; Jun 2024) (despotes2024primaryciliarydyskinesia pages 16-17). - Multiciliogenesis genes (FOXJ1, MCIDAS, CCNO) yield oligocilia/immotile phenotypes; FOXJ1 can present in autosomal dominant fashion (URL: https://doi.org/10.1542/peds.2023-063064; May 2024) (wee2024primaryciliarydyskinesia. pages 1-3). - Additional docking/assembly factors (e.g., ODAD1, CCDC103, CCDC114, ZMYND10, DRC1/CCDC164, HYDIN) contribute to dynein assembly/docking or CP integrity; defects can yield typical respiratory PCD with variable diagnostic signatures (URL: https://doi.org/10.17615/qgfk-y329; 2025) (a.2025primaryciliarydyskinesia pages 2-3).

3) Biological Processes (GO-style) disrupted - Cilium movement; microtubule-based movement; mucociliary clearance (respiratory epithelium) (wee2024primaryciliarydyskinesia. pages 1-3). - Axoneme assembly; dynein arm assembly (ODA/IDA); radial spoke organization; central apparatus organization; ODA docking (despotes2024primaryciliarydyskinesia pages 16-17, a.2025primaryciliarydyskinesia pages 2-3). - Multiciliogenesis and centriole amplification; cilium morphogenesis (wee2024primaryciliarydyskinesia. pages 1-3, despotes2024primaryciliarydyskinesia pages 16-17). - Embryonic left–right pattern specification via nodal flow (despotes2024primaryciliarydyskinesia pages 1-2).

4) Cellular Components (GO-style) - Axoneme (9+2); outer dynein arm; inner dynein arm; radial spoke; central pair apparatus; nexin–dynein regulatory complex; outer dynein arm docking complex; basal bodies/centrioles (wee2024primaryciliarydyskinesia. pages 1-3, despotes2024primaryciliarydyskinesia pages 16-17, a.2025primaryciliarydyskinesia pages 2-3).

5) Disease Progression - Molecular defect (axonemal structure or ciliogenesis program) → abnormal/absent ciliary beating or oligocilia → impaired mucociliary clearance → persistent sino-oto-pulmonary infections and neutrophilic inflammation → airway remodeling with bronchiectasis and progressive lung function decline; concurrent nodal cilia dysfunction in embryogenesis leads to situs inversus/ambiguus; sperm flagellar defects contribute to subfertility (URL: https://doi.org/10.1542/peds.2023-063064; May 2024) (wee2024primaryciliarydyskinesia. pages 1-3). - Quote: “Diagnosis relies on a combination of tests… including nasal nitric oxide (nNO) measurements, high-speed videomicroscopy analysis (HSVMA), immunofluorescent staining, axonemal ultrastructure analysis via transmission electron microscopy (TEM), and genetic testing. Notably, there is no single gold standard” (Cells; Jun 2024; URL: https://doi.org/10.3390/cells13110974) (despotes2024primaryciliarydyskinesia pages 16-17).

6) Phenotypic Manifestations (HPO-style) - Chronic wet cough, recurrent lower respiratory tract infections, bronchiectasis (HP:0002206), chronic rhinosinusitis (HP:0011107), chronic otitis media with effusion and conductive hearing loss (HP:0000407), neonatal respiratory distress (HP:0002643), laterality defects—situs inversus totalis (HP:0001696), situs ambiguus (HP:0003364), subfertility/infertility (HP:0000789) (wee2024primaryciliarydyskinesia. pages 1-3, despotes2024primaryciliarydyskinesia pages 16-17).

Genotype–phenotype correlations, statistics, and expert analyses (2023–2024 priority) - Multinational ERJ 2024 cohort (n=1,236; 19 countries; 908 distinct pathogenic variants, 46 genes) reported: “The prevalence of laterality defects… varied widely among countries… The prevalence of laterality defects was significantly lower in PCD individuals without pathognomonic ciliary ultrastructure defects (18%). … Median FEV1 z-scores were significantly lower in CCNO (−3.26), CCDC39 (−2.49) and CCDC40 (−2.96)… milder in DNAH11 (−0.83) and ODAD1 (−0.85)” (URL: https://doi.org/10.1183/13993003.01769-2023; Jun 2024) (raidt2024analysesof1236 pages 8-10). - Frequent genes in international datasets include DNAH5, DNAH11, CCDC40, DNAI1, CCDC39 (URL: https://doi.org/10.1183/13993003.01769-2023; Jun 2024) (raidt2024analysesof1236 pages 8-10). - Clinical spectrum and evolving diagnostics summarized by Pediatrics 2024: “PCD is a rare, genetic disease characterized by dysfunctional motile cilia and abnormal mucociliary clearance, resulting in chronic sino-oto-pulmonary disease, neonatal respiratory distress, subfertility, and organ laterality defects” (URL: https://doi.org/10.1542/peds.2023-063064; May 2024) (wee2024primaryciliarydyskinesia. pages 1-3).

Diagnostics and real-world implementation - nNO: ATS-endorsed adjunctive test from age ≥5 years; very low nNO is highly suggestive but normal nNO does not exclude PCD; chemiluminescence methods and threshold use are discussed in Pediatrics 2024 (URL: https://doi.org/10.1542/peds.2023-063064; May 2024) (wee2024primaryciliarydyskinesia. pages 3-4, wee2024primaryciliarydyskinesia. pages 1-3). - HSVM: analysis of ciliary beat frequency and waveform from nasal brushings complements TEM and genetics (URL: https://doi.org/10.3390/cells13110974; Jun 2024) (despotes2024primaryciliarydyskinesia pages 16-17). - TEM and IF: TEM detects hallmark ultrastructural class 1/2 defects in many but not all genotypes; IF for axonemal proteins (e.g., DNAH5, DNAI2) increases diagnostic sensitivity and speed (URL: https://doi.org/10.3390/cells13110974; Jun 2024; URL: https://doi.org/10.14288/1.0445067; Jan 2025) (despotes2024primaryciliarydyskinesia pages 16-17, weir2025radiantcilia pages 115-118). Quote: an immunofluorescence panel “can increase sensitivity, reduce cost and time, and will also allow for the earlier diagnosis of PCD,” though it is “insensitive to ciliogenesis defects (CCNO, MCIDAS, and FOXJ1)” (URL: https://doi.org/10.14288/1.0445067; Jan 2025) (weir2025radiantcilia pages 115-118). - Genetics: >50 causative genes; first gene DNAI1; genetics now central to diagnosis with ~70–80% yield depending on panels and CNV detection (URL: https://doi.org/10.1542/peds.2023-063064; May 2024; URL: https://doi.org/10.3390/cells13110974; Jun 2024) (wee2024primaryciliarydyskinesia. pages 1-3, despotes2024primaryciliarydyskinesia pages 16-17). - Real-world diagnostic performance: multimodal pathways combining HSVM, TEM, nNO, and genetics are required; in large clinical series, a substantial minority may have normal TEM; genetic and functional assays help close gaps (URL: https://doi.org/10.1007/s40291-025-00801-w; Jul 2025) (carreterovilarroig2025clinicalgeneticmorphological pages 1-2).

Recent developments and latest research (2023–2024) - State-of-the-art overview (Pediatrics 2024) highlighting expanded phenotype spectrum, “novel diagnostics, genotype-phenotype correlations, long term morbidity, and innovative therapeutics” (URL: https://doi.org/10.1542/peds.2023-063064; May 2024) (wee2024primaryciliarydyskinesia. pages 1-3). - ERJ 2024 multinational registry analysis (n=1,236) providing robust genotype–phenotype correlations (laterality, lung function) and regional founder variants; a key resource for precision diagnostics/prognosis (URL: https://doi.org/10.1183/13993003.01769-2023; Jun 2024) (raidt2024analysesof1236 pages 8-10). - Clinical review (Cells 2024) consolidating structural biology, genetics (>50 genes), and multi-test diagnostics; emphasizes no gold standard and ongoing management trials (URL: https://doi.org/10.3390/cells13110974; Jun 2024) (despotes2024primaryciliarydyskinesia pages 16-17).

Current applications and models - Patient-derived airway sampling for HSVM/TEM/IF/genetics is routine in specialized centers; early diagnosis improves outcomes (URL: https://doi.org/10.3390/cells13110974; Jun 2024; URL: https://doi.org/10.14288/1.0445067; Jan 2025) (despotes2024primaryciliarydyskinesia pages 16-17, weir2025radiantcilia pages 115-118). - Emerging in vitro models: reviews emphasize air–liquid interface and organoid-based respiratory models to study ciliary dysfunction and test therapies; these platforms are increasingly applied across airway diseases (URL: https://doi.org/10.29057/mjmr.v12i24.12347; Jul 2024) (raidt2024analysesof1236 pages 8-10, despotes2024primaryciliarydyskinesia pages 16-17). Note: general airway model insights support PCD translational research but are not PCD-specific in the cited review (raidt2024analysesof1236 pages 8-10).

Expert opinions and guideline-aligned analysis - Pediatrics 2024 and Cells 2024 reviews (including authors from leading PCD centers) stress a multimodal diagnostic algorithm and the heterogeneity of clinical manifestations; both advocate timely referral and comprehensive genetics to guide prognosis and research enrollment (URLs above) (wee2024primaryciliarydyskinesia. pages 1-3, despotes2024primaryciliarydyskinesia pages 16-17). - Quote: “There is no gold standard to diagnose PCD” (Cells 2024) underscoring the need for integrated testing and expert interpretation (URL: https://doi.org/10.3390/cells13110974; Jun 2024) (despotes2024primaryciliarydyskinesia pages 16-17).

Relevant statistics and data (recent) - 1,236 genotyped individuals; 908 variants in 46 genes; laterality overall 42%, but 18% in those without pathognomonic TEM defects (ERJ; Jun 2024) (raidt2024analysesof1236 pages 8-10). - Lung function by genotype: CCNO, CCDC39, CCDC40 show lowest median FEV1 z-scores (−3.26, −2.49, −2.96 respectively), DNAH11 and ODAD1 comparatively milder reductions (−0.83, −0.85) (ERJ; Jun 2024) (raidt2024analysesof1236 pages 8-10).

Ontology-style annotations for knowledge base integration - Gene/protein annotations: see embedded table for HGNC symbols and roles (raidt2024analysesof1236 pages 8-10, wee2024primaryciliarydyskinesia. pages 1-3, despotes2024primaryciliarydyskinesia pages 16-17, a.2025primaryciliarydyskinesia pages 2-3). - Biological processes (GO-style): cilium movement; axoneme assembly; dynein arm assembly and docking; radial spoke organization; multiciliogenesis; embryonic left–right patterning (wee2024primaryciliarydyskinesia. pages 1-3, despotes2024primaryciliarydyskinesia pages 16-17, despotes2024primaryciliarydyskinesia pages 1-2). - Cellular components (GO-style): axoneme; outer/inner dynein arm; radial spoke; central pair apparatus; nexin–dynein regulatory complex; outer dynein arm docking complex; basal body/centriole (wee2024primaryciliarydyskinesia. pages 1-3, despotes2024primaryciliarydyskinesia pages 16-17, a.2025primaryciliarydyskinesia pages 2-3). - Cell types (CL-style): multiciliated epithelial cell of the respiratory tract; ependymal multiciliated cell; fallopian tube epithelium; spermatid/sperm flagellated cell (wee2024primaryciliarydyskinesia. pages 1-3, despotes2024primaryciliarydyskinesia pages 16-17). - Anatomical locations (UBERON-style): nasal cavity, paranasal sinus, eustachian tube/middle ear, trachea/bronchi, lung, embryonic node, fallopian tube, ventricular ependyma (wee2024primaryciliarydyskinesia. pages 1-3, despotes2024primaryciliarydyskinesia pages 16-17). - Phenotypes (HPO-style): neonatal respiratory distress; chronic wet cough; chronic rhinosinusitis; otitis media with hearing loss; bronchiectasis; situs inversus/ambiguus; male infertility (wee2024primaryciliarydyskinesia. pages 1-3, despotes2024primaryciliarydyskinesia pages 16-17). - Chemical entities (CHEBI-style, examples used in management/research): nitric oxide (nNO biomarker); macrolide (azithromycin) for exacerbation reduction in RCTs cited by reviews; antibiotic/airway clearance adjuncts (despotes2024primaryciliarydyskinesia pages 16-17, wee2024primaryciliarydyskinesia. pages 1-3).

Emerging therapies and future directions - Reviews emphasize lack of approved cilia-restorative therapies; management focuses on airway clearance, infection control, and, in some settings, macrolides to reduce exacerbations; ongoing advances in genetics and cell models aim to enable genotype-directed therapies (URL: https://doi.org/10.3390/cells13110974; Jun 2024; URL: https://doi.org/10.1542/peds.2023-063064; May 2024) (despotes2024primaryciliarydyskinesia pages 16-17, wee2024primaryciliarydyskinesia. pages 1-3).

Evidence Items (with URLs and dates) - Wee WB et al. Primary Ciliary Dyskinesia. Pediatrics. May 2024. URL: https://doi.org/10.1542/peds.2023-063064 (wee2024primaryciliarydyskinesia. pages 1-3, wee2024primaryciliarydyskinesia. pages 3-4) (wee2024primaryciliarydyskinesia. pages 1-3, wee2024primaryciliarydyskinesia. pages 3-4). - Raidt J et al. ERJ. Analyses of 1,236 genotyped PCD individuals… Jun 2024. URL: https://doi.org/10.1183/13993003.01769-2023 (raidt2024analysesof1236 pages 8-10). - Despotes KA et al. Cells. Primary ciliary dyskinesia: a clinical review. Jun 2024. URL: https://doi.org/10.3390/cells13110974 (despotes2024primaryciliarydyskinesia pages 16-17, despotes2024primaryciliarydyskinesia pages 1-2). - Zariwala MA et al. Primary Ciliary Dyskinesia (UNC Text). 2025. URL: https://doi.org/10.17615/qgfk-y329 (a.2025primaryciliarydyskinesia pages 2-3). - Weir M. Radiant cilia: advancing North American PCD diagnosis with immunofluorescence. Jan 2025. URL: https://doi.org/10.14288/1.0445067 (weir2025radiantcilia pages 115-118). - Carretero-Vilarroig L et al. Molecular Diagnosis & Therapy. Jul 2025. URL: https://doi.org/10.1007/s40291-025-00801-w (carreterovilarroig2025clinicalgeneticmorphological pages 1-2).

Direct supporting quotes - “PCD is a rare, genetic disease characterized by dysfunctional motile cilia and abnormal mucociliary clearance, resulting in chronic sino-oto-pulmonary disease, neonatal respiratory distress, subfertility, and organ laterality defects” (Pediatrics 2024; URL above) (wee2024primaryciliarydyskinesia. pages 1-3). - “There is no gold standard to diagnose PCD” (Cells 2024; URL above) (despotes2024primaryciliarydyskinesia pages 16-17). - “The prevalence of laterality defects was significantly lower in PCD individuals without pathognomonic ciliary ultrastructure defects (18%). … Median FEV1 z-scores were significantly lower in CCNO (−3.26), CCDC39 (−2.49) and CCDC40 (−2.96)… milder in DNAH11 (−0.83) and ODAD1 (−0.85)” (ERJ 2024; URL above) (raidt2024analysesof1236 pages 8-10).

Limitations and gaps - While airway organoid/ALI and genetic therapy concepts are promising, PCD-specific interventional data remain limited in the cited 2023–2024 sources; ongoing registries and translational platforms are expected to enable genotype-targeted trials (wee2024primaryciliarydyskinesia. pages 1-3, despotes2024primaryciliarydyskinesia pages 16-17).

References

(wee2024primaryciliarydyskinesia. pages 1-3): Wallace B. Wee, BreAnna Kinghorn, Stephanie D. Davis, Thomas W. Ferkol, and Adam J. Shapiro. Primary ciliary dyskinesia. Pediatrics, May 2024. URL: https://doi.org/10.1542/peds.2023-063064, doi:10.1542/peds.2023-063064. This article has 27 citations and is from a highest quality peer-reviewed journal.
(raidt2024analysesof1236 pages 8-10): Johanna Raidt, Sarah Riepenhausen, Petra Pennekamp, Heike Olbrich, Israel Amirav, Rodrigo A. Athanazio, Micha Aviram, Juan E. Balinotti, Ophir Bar-On, Sebastian F.N. Bode, Mieke Boon, Melissa Borrelli, Siobhan B. Carr, Suzanne Crowley, Eleonora Dehlink, Sandra Diepenhorst, Peter Durdik, Bernd Dworniczak, Nagehan Emiralioğlu, Ela Erdem, Rossella Fonnesu, Serena Gracci, Jörg Große-Onnebrink, Karolina Gwozdziewicz, Eric G. Haarman, Christine R. Hansen, Claire Hogg, Mathias G. Holgersen, Eitan Kerem, Robert W. Körner, Karsten Kötz, Panayiotis Kouis, Michael R. Loebinger, Natalie Lorent, Jane S. Lucas, Debora Maj, Marcus A. Mall, June K. Marthin, Vendula Martinu, Henryk Mazurek, Hannah M. Mitchison, Tabea Nöthe-Menchen, Ugur Özçelik, Massimo Pifferi, Andrzej Pogorzelski, Felix C. Ringshausen, Jobst F. Roehmel, Sandra Rovira-Amigo, Nisreen Rumman, Anne Schlegtendal, Amelia Shoemark, Synne Sperstad Kennelly, Ben O. Staar, Sivagurunathan Sutharsan, Simon Thomas, Nicola Ullmann, Julian Varghese, Sandra von Hardenberg, Woolf T. Walker, Martin Wetzke, Michal Witt, Panayiotis Yiallouros, Anna Zschocke, Ewa Ziętkiewicz, Kim G. Nielsen, and Heymut Omran. Analyses of 1236 genotyped primary ciliary dyskinesia individuals identify regional clusters of distinct dna variants and significant genotype–phenotype correlations. European Respiratory Journal, 64:2301769, Jun 2024. URL: https://doi.org/10.1183/13993003.01769-2023, doi:10.1183/13993003.01769-2023. This article has 51 citations and is from a highest quality peer-reviewed journal.
(wee2024primaryciliarydyskinesia. pages 3-4): Wallace B. Wee, BreAnna Kinghorn, Stephanie D. Davis, Thomas W. Ferkol, and Adam J. Shapiro. Primary ciliary dyskinesia. Pediatrics, May 2024. URL: https://doi.org/10.1542/peds.2023-063064, doi:10.1542/peds.2023-063064. This article has 27 citations and is from a highest quality peer-reviewed journal.
(despotes2024primaryciliarydyskinesia pages 16-17): Katherine A. Despotes, Maimoona A. Zariwala, Stephanie D. Davis, and Thomas W. Ferkol. Primary ciliary dyskinesia: a clinical review. Cells, 13:974, Jun 2024. URL: https://doi.org/10.3390/cells13110974, doi:10.3390/cells13110974. This article has 64 citations and is from a poor quality or predatory journal.
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(despotes2024primaryciliarydyskinesia pages 1-2): Katherine A. Despotes, Maimoona A. Zariwala, Stephanie D. Davis, and Thomas W. Ferkol. Primary ciliary dyskinesia: a clinical review. Cells, 13:974, Jun 2024. URL: https://doi.org/10.3390/cells13110974, doi:10.3390/cells13110974. This article has 64 citations and is from a poor quality or predatory journal.
(weir2025radiantcilia pages 115-118): Madison Weir. Radiant cilia : advancing north american pcd diagnosis with immunofluorescence. Text, Jan 2025. URL: https://doi.org/10.14288/1.0445067, doi:10.14288/1.0445067. This article has 0 citations and is from a peer-reviewed journal.
(carreterovilarroig2025clinicalgeneticmorphological pages 1-2): Lidón Carretero-Vilarroig, Rosana Blanco-Máñez, Noelia Muñoz-Fernández, Isabel Ibáñez, Alba Berzal-Serrano, Ana Reula, Belén García-Bohórquez, Elena Aller, Gema García-García, Jose M. Millán, Miguel Armengot-Carceller, and Teresa Jaijo. Clinical, genetic, morphological and functional correlations in a large series of patients with primary ciliary dyskinesia: a heterogeneous disease with a controversial diagnosis. Molecular diagnosis & therapy, Jul 2025. URL: https://doi.org/10.1007/s40291-025-00801-w, doi:10.1007/s40291-025-00801-w. This article has 0 citations and is from a peer-reviewed journal.

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