Primary_Ciliary_Dyskinesia

Genetic MONDO:0016575 Pathograph 90 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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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.

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

"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

"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

"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

"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

"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

"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

"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

"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

"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 (1 reference)

PMID:24213915 SUPPORT Model Organism

"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 without previously citing it. It does not demonstrate the route in human PCD.

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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.

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 RSPH1 hgnc:12371 RSPH4A hgnc:21558 RSPH9 hgnc:21057 ODAD1 hgnc:26560 SPEF2 hgnc:26293

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

"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

"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

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

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

CCDC39-CCDC40 Axonemal Scaffold Loss

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

"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

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

"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

"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

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

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

"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.

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 (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."

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.

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

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

"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

"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.

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Pathograph

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 (5 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:11893720 SUPPORT

"Mutations in DNAI1 (IC78) cause primary ciliary dyskinesia."

This study directly links mutations in DNAI1 to the cause of 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.

+ 2 more references

DNAH5 (Pathogenic Variants)

Gene: DNAH5 hgnc:2950

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

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

"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

"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

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

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

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

"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

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

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

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

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

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 (Limited evidence for PCD association)

Gene: NME8 hgnc:16473

Show evidence (1 reference)

CGGV:assertion_57ca8383-55b6-4edd-9be2-67b1c5142ed1-2023-06-08T160000.000Z SUPPORT Other

ClinGen classifies the NME8-primary ciliary dyskinesia gene-disease relationship as limited with autosomal recessive inheritance.

SPEF2 (Pathogenic Variants)

Gene: SPEF2 hgnc:26293

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

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

Autosomal dominant

Show evidence (1 reference)

PMID:38662826 SUPPORT In Vitro

"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

"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.

💊

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 (5 references)

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."

Joint guideline limits diagnostic use of nasal NO and other tests.

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.

PMID:39362668 SUPPORT In Vitro

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

+ 2 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

"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.

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

Birth Prevalence 1.0–9.0 per 100,000 1–9 per 100,000 (births) Prevalence at birth

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 Point prevalence

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

"We were not diagnosing PCD, but rather estimating prevalence based on known variants."

Primary study explicitly distinguishes genetic modeling from diagnosis-based prevalence.

🔀

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 (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."

Integrated assessment and relevant alternative diagnoses are needed; nasal NO alone cannot distinguish all chronic airway 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

"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 (2 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.

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 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

"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

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

Supports use of expanded nasal ALI cultures as a disease-relevant PCD model that preserves mutation-associated ciliary defects.

PMID:33795320 SUPPORT In Vitro

"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

"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 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

"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

"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

"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

"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

"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 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

"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

Shows that hiPSC-derived airway epithelium reproduces the molecular and functional consequences of PCD mutations, including impaired transport.

Impaired Mucociliary Clearance recapitulates fidelity: moderate 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

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

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

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

"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

"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 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

"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

Documents partial cellular expression and reassembly of associated proteins in treated patient airway cultures.

Impaired Mucociliary Clearance rescues fidelity: moderate 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

"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

"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

"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 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

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

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 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

"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

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

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

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

"Transport was partially recovered after treating cells with catalase, an enzyme that 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 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

"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

"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

"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 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

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

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

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

"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

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 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

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

Show evidence (1 reference)

PMID:34233948 SUPPORT In Vitro

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

Show evidence (1 reference)

PMID:34233948 SUPPORT In Vitro

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 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

"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

Supports a dyskinetic ciliary phenotype in BCi-NS1.1, without establishing a PCD patient genotype.

Show evidence (1 reference)

PMID:29481304 SUPPORT In Vitro

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 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

"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

"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

"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 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

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

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

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

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

"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."

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

"The frog embryonic epidermis possesses mucus-secreting and multiciliated cells, and has served as an excellent model system for the biogenesis of cilia."

Establishes the tissue's standing as a mucociliary surrogate, which is why a frog epidermal result bears on airway cilia at all.

🧮

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
prevalence:
- population: Europe
  subtype: Prevalence at birth
  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
  subtype: Point prevalence
  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: We were not diagnosing PCD, but rather estimating prevalence based on known variants.
    explanation: >-
      Primary study explicitly distinguishes genetic modeling from diagnosis-based prevalence.
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.
  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: RSPH1
    term:
      id: hgnc:12371
      label: RSPH1
  - preferred_term: RSPH4A
    term:
      id: hgnc:21558
      label: RSPH4A
  - preferred_term: RSPH9
    term:
      id: hgnc:21057
      label: RSPH9
  - preferred_term: ODAD1
    term:
      id: hgnc:26560
      label: ODAD1
  - preferred_term: SPEF2
    term:
      id: hgnc:26293
      label: SPEF2
  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: heterotaxy, defined as situs ambiguus with complex cardiovascular defects, was present in 14 (2.5%).
      explanation: >-
        The 559-person study uses a restrictive complex-cardiovascular definition; this frequency 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.
  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.
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: 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: 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: >-
      Joint guideline limits diagnostic use of nasal NO and other tests.
  - 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: 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: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: >-
    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
  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:11893720
    reference_title: Mutations in DNAI1 (IC78) cause primary ciliary dyskinesia.
    supports: SUPPORT
    snippet: Mutations in DNAI1 (IC78) cause primary ciliary dyskinesia.
    explanation: This study directly links mutations in DNAI1 to the cause of primary ciliary dyskinesia.
  - 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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  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
  association: Limited evidence for PCD association
  evidence:
  - reference: CGGV:assertion_57ca8383-55b6-4edd-9be2-67b1c5142ed1-2023-06-08T160000.000Z
    reference_title: NME8 / primary ciliary dyskinesia (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: NME8 | HGNC:16473 | primary ciliary dyskinesia | MONDO:0016575 | AR | Limited
    explanation: ClinGen classifies the NME8-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: 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
  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
  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.
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.
  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.
- 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: 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 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: The frog embryonic epidermis possesses mucus-secreting and multiciliated cells, and has served as an excellent model system for the biogenesis of cilia.
    explanation: Establishes the tissue's standing as a mucociliary surrogate, which is why a frog epidermal result bears on airway cilia at all.
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: Transport was partially recovered after treating cells with catalase, an enzyme that 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: Transport was partially recovered after treating cells with catalase, an enzyme that 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: 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: >-
      Integrated assessment and relevant alternative diagnoses are needed; nasal NO alone cannot
      distinguish all chronic airway 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: 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 without previously citing it. It does not demonstrate the route in human PCD.

📚

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.
(a.2025primaryciliarydyskinesia pages 2-3): Maimoona A. Zariwala, Peadar G. Noone, and Jason Lobo. Primary ciliary dyskinesia. Text, 2025. URL: https://doi.org/10.17615/qgfk-y329, doi:10.17615/qgfk-y329. This article has 243 citations and is from a peer-reviewed journal.
(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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