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Classifications

Harrison's Part

Mechanistic Nosology

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Every reported patient carries two ODAD3 loss-of-function alleles. The defining series found them in five affected individuals from three independent families by combined mapping and sequencing; subsequent reports are homozygous cases from consanguineous families. Nothing in the human literature suggests a heterozygous carrier phenotype - see the discussion below on why the mouse data raise that question anyway.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:25192045 SUPPORT Human Clinical

"Here, by combined high-throughput mapping and sequencing, we identified CCDC151 loss-of-function mutations in five affected individuals from three independent families whose cilia showed a complete loss of ODAs and severely impaired ciliary beating."

Establishes recessive loss-of-function inheritance in the defining families.

PMID:25224326 SUPPORT Human Clinical

"We observed a novel nonsense mutation in a homozygous state in the CCDC151 gene"

An independent homozygous case confirming the recessive mode. The snippet stops before the variant's HGVS string because the protein change is written with square brackets, which the reference validator strips before matching; the allele itself is recorded in the genetic notes.

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Discussions and Knowledge Gaps

3

Why is hydrocephalus the lethal phenotype of the Ccdc151-null mouse when human ODAD3 patients survive to adulthood without it?

HUMAN MODEL MISMATCH OPEN pcd30_mouse_hydrocephalus_not_human

Attached to

pathophysiology#Motile Ciliary Beat Failure animal_models#Ccdc151 knockout mouse (targeted gene deletion)

Curated as HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP because the evidence is not missing. The mouse phenotype is well characterised: targeted deletion of Ccdc151 causes perinatal lethality and congenital communicating hydrocephalus, with reporter expression localising the gene to the ependymal cells lining the ventricular system and micro-computed tomography confirming the aqueduct of Sylvius is patent. It is a coherent mechanism - ependymal motile cilia drive cerebrospinal fluid flow, and they carry the same outer dynein arms as airway cilia. The mismatch is one of frequency and severity, and it should be stated exactly rather than as a flat contradiction. Hydrocephalus is a recognised possible complication of primary ciliary dyskinesia in humans - one of the papers cited by this entry lists it among the consequences of ciliary dysfunction in the brain and spinal ependyma, alongside conductive deafness and subfertility. What is absent is any hydrocephalus in a reported *ODAD3* patient: none of the five human ODAD3 reports consulted for this entry describes it, and the individually described 35-year-old woman's reported problems are sinusitis, bronchiectasis, dextrocardia and infertility. So the consequence that is occasional and survivable in human PCD, and unreported in this genotype, is in the mouse the phenotype that kills the animal before it can develop the airway disease which defines the human illness. Orphanet puts a number on the human side: hydrocephalus is graded Very rare, under four percent, across primary ciliary dyskinesia as a class - against a mouse null in which it is the cause of death. That is the mismatch stated quantitatively rather than as an impression. This is not peculiar to ODAD3 - hydrocephalus is a recurrent feature of mouse motile-ciliopathy models and a rare one in human PCD. The usual explanation offered for that gap is anatomical, that the rodent aqueduct is narrow and rodent cerebrospinal-fluid circulation depends more on ependymal ciliary flow than the human one does. That explanation is not tested by anything cited here and is recorded as the standing hypothesis rather than as a finding. It matters well beyond this gene, because it means a mouse motile-ciliopathy model's most conspicuous phenotype may be its least transferable one. The practical consequence for this entry: hydrocephalus is not curated as a phenotype of PCD30, and the mouse link that carries it is graded PARTIALLY_RECAPITULATES with the lethality stated as a limitation.

Proposed experiments

Systematic ventricular imaging in ODAD3 and other ODA-defect patients

exp_pcd30_human_ventricular_imaging

Measure ventricular volume and aqueductal patency in a genotyped PCD cohort stratified by ultrastructural defect class, and ask whether subclinical ventriculomegaly is present in humans at a frequency that routine care would miss. A positive result would make the mouse phenotype a quantitative rather than a qualitative mismatch.

Show evidence (2 references)

PMID:32490514 SUPPORT Other

"As cilia or flagella are also distributed in middle ear, sperm, fallopian tube, brain, and spinal ependymal, KS may be accompanied by conductive deafness, sub- or infertility, ectopic pregnancy, and hydrocephalus"

Graded PARTIAL because it cuts both ways: it establishes that hydrocephalus is a recognised human PCD complication, which is why the mismatch is one of frequency rather than of kind, while saying nothing about any ODAD3 patient. Graded OTHER because it is a background statement about Kartagener syndrome as a class within a case report.

ORPHA:244 SUPPORT Other

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

Orphanet's graded frequency for hydrocephalus in primary ciliary dyskinesia, which is what makes this a mismatch of frequency rather than of kind: under four percent in humans as a class, against the lethal phenotype of the mouse null. Graded PARTIAL for the same reason as the item above - it establishes that hydrocephalus occurs in human PCD while saying nothing about any ODAD3 patient.

Do heterozygous ODAD3 carriers have reduced male fertility, as heterozygous Odad3 mice do?

OPEN QUESTION OPEN pcd30_heterozygote_fertility_effect

Attached to

animal_models#Odad3 conditional knockout mouse (adult male) genetic#ODAD3

A gene-dosage finding in the mouse with a direct counselling implication and no human evidence either way. Odad3 heterozygous null males have reduced sperm count and motility, abnormal sperm morphology, and a shorter fertile lifespan. The authors state the finding may bear on genetic and fertility counselling for carriers, which is an unusually direct clinical suggestion from a mouse study. Nobody has looked in humans. PCD carrier parents are ascertained routinely in the course of diagnosing their children, so the cohort exists; semen analysis in fathers of ODAD3 probands would answer the question directly and has never been reported. Until it is, the recessive counselling given to ODAD3 families should not be modified, and this entry curates no carrier phenotype - the finding is recorded here so that a future carrier study is recognised as testing a prediction rather than making an incidental observation. One caution on how far to generalise it. The reduced fertile lifespan is an age-dependent effect, and mouse and human reproductive ageing are on different scales, so even a real human effect need not be detectable at the ages at which carrier fathers are typically ascertained.

Proposed experiments

Semen analysis in heterozygous ODAD3 carriers

exp_pcd30_carrier_semen_analysis

Compare sperm concentration, motility and morphology between confirmed heterozygous ODAD3 carriers (fathers of probands) and age-matched non-carrier controls, with stratification by age to test the fertile-lifespan component of the mouse finding.

Does ODAD3 disease differ in course or treatment response from other forms of PCD?

KNOWLEDGE GAP OPEN pcd30_no_gene_specific_natural_history

Attached to

pathophysiology#Bronchiectasis and Airway Wall Destruction phenotypes#Bronchiectasis

Curated as a genuine absence. There is no ODAD3-specific cohort, no lung function trajectory, no survival data, and no treatment study. Everything known about how to manage these patients comes from PCD as a class. That is why this entry has no `treatments:` block and no `progression:` block. Airway clearance, antibiotics and surveillance are the standard of care for PCD and would certainly be given to an ODAD3 patient, but curating them here would state that they have been studied in this genotype, which they have not, and the exported graph would not preserve the difference. The `Primary Ciliary Dyskinesia` umbrella entry carries the class-level treatment content, and that is the right place for it. Whether the distinction is worth drawing is itself open. Genotype-stratified outcome data are beginning to appear for PCD, and the ODA-defect genes are thought to sit at the more severe end. If that holds, ODAD3-specific management guidance could eventually exist; if it does not, the class-level content is all there will ever be.

Proposed experiments

Genotype-stratified outcomes for docking-complex PCD

exp_pcd30_genotype_stratified_outcomes

Within an international PCD registry, compare lung-function trajectory, exacerbation rate and age at bronchiectasis between patients with docking-complex defects (ODAD1-4) and other ultrastructural classes, with ODAD3 identified separately where numbers allow.

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Pathophysiology

8

Biallelic ODAD3 Loss of Function

The initiating lesion. ODAD3 encodes a 595-amino-acid protein with three highly conserved coiled-coil domains, and every reported disease allele is loss-of-function. Seven had been reported as of the 2021 review cited below: three nonsense, three frameshift, and - the one that does not fit a simple truncation story - a canonical splice-donor variant, c.244+1G>A. No missense allele has been reported. That matters for variant interpretation, because it leaves no worked example of an ODAD3 change that alters the protein without destroying it, and so nothing to calibrate a new missense variant against. The splice-donor allele is the nearest thing available and is not close: donor-site loss usually produces exon skipping or intron retention with a frameshifted, decay-prone transcript, which lands back in the same functional class rather than giving a graded one. So the disease as described remains the phenotype of complete protein loss, and nothing is known about partial loss in humans.

ODAD3 hgnc:28303

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Curated as loss of function on the strength of the allele classes reported - three nonsense, three frameshift and one canonical splice-donor variant - together with the measured consequence: ODAD3 protein is absent from patients' respiratory cilia. `zygosity` is left unset at the disease level because reported patients are variously homozygous and compound heterozygous.

Downstream

Outer Dynein Arm Docking Complex Assembly Failure

Show evidence (3 references)

PMID:25192045 SUPPORT Human Clinical

"We demonstrate that CCDC151 encodes an axonemal coiled coil protein, mutations in which abolish assembly of CCDC151 into respiratory cilia"

States both the protein's nature and the immediate molecular consequence of the variants.

PMID:33719352 SUPPORT Other

"ODAD3 encodes a protein of 595 amino acids and contain three highly conserved coiled-coil domains, which is essential for cilia axoneme dynein arm assembly and docking."

Describes the protein architecture that the loss-of-function alleles disrupt. Graded OTHER because it is background prose from the paper's introduction rather than a finding from its study.

PMID:33719352 SUPPORT Other

"To date, a total of seven likely loss-of-function variants in ODAD3 have been reported in PCD (Supplementary Table 2)."

The allelic spectrum as of 2021, and the reason this node says "loss-of-function" rather than "nonsense or frameshift" - the seven include a splice-donor variant that is neither. Graded OTHER because it is the paper's survey of prior reports rather than its own finding.

Outer Dynein Arm Docking Complex Assembly Failure

The step that defines the disease. The ODA docking complex is a multi-subunit structure, and ODAD3's loss takes the rest of it with it: in patients' respiratory cilia the docking-complex members ODAD1 (CCDC114) and ODAD2 (ARMC4) fail to assemble onto the axoneme along with ODAD3 itself. The physical basis for the co-dependence is that ODAD3 and ODAD1 are binding partners - they co-immunoprecipitate. The functional distinction worth holding onto: outer dynein arms are *produced and preassembled in the cytosol* and then transported into the cilium, so a docking-complex defect is not a failure to build motors. It is a failure to install them.

multiciliated respiratory epithelial cell CL:0005012

axonemal dynein complex assembly GO:0070286 ↓ DECREASED

Animal models

Ccdc151 morphant zebrafish Zebrafish recapitulates Ccdc151 depletion impairs motile ciliary function by controlling dynein arm assembly, which is the same molecular step as the human lesion, established in this species before the human disease existed.

Downstream

Absence of Outer Dynein Arms from the Axoneme

Show evidence (3 references)

PMID:25192045 SUPPORT Human Clinical

"cause a failure in axonemal assembly of the ODA component DNAH5 and the ODA-DC-associated components CCDC114 and ARMC4"

The core observation: losing ODAD3 removes the rest of the docking complex and the outer-arm heavy chain from the axoneme.

PMID:25192045 SUPPORT In Vitro

"Furthermore, CCDC151 coimmunoprecipitates CCDC114 and thus appears to be a highly evolutionarily conserved ODA-DC-related protein involved in mediating assembly of both ODAs and their axonemal docking machinery onto ciliary microtubules."

The physical interaction that explains why the docking complex fails as a unit.

PMID:25192045 SUPPORT Other

"Multisubunit outer dynein arm (ODA) motor complexes, produced and preassembled in the cytosol, are transported to the ciliary or flagellar compartment and anchored into the axonemal microtubular scaffold via the ODA docking complex (ODA-DC) system."

Establishes that the motors are preassembled elsewhere, which is what makes this an installation defect rather than an assembly defect. Graded OTHER because it is background from the paper's introduction.

Absence of Outer Dynein Arms from the Axoneme

The structural endpoint, and the one a diagnostic laboratory sees. Patients' cilia show a complete loss of outer dynein arms on electron microscopy. The arms are what generate most of the sliding force between axonemal doublets, so their absence is sufficient to explain the beat failure without invoking any additional lesion.

multiciliated respiratory epithelial cell CL:0005012

bronchus UBERON:0002185

Downstream

Motile Ciliary Beat Failure

Show evidence (1 reference)

PMID:25192045 SUPPORT Human Clinical

"we identified CCDC151 loss-of-function mutations in five affected individuals from three independent families whose cilia showed a complete loss of ODAs and severely impaired ciliary beating"

The ultrastructural and functional observation in patients.

Motile Ciliary Beat Failure

Cilia that are assembled but cannot beat. In the airway this abolishes mucociliary clearance; at the embryonic left-right organiser the same failure in motile monocilia removes the directional flow that breaks symmetry. Both limbs of the module node are evidenced here rather than assumed: the ciliary-dysmotility half from patients' severely impaired beating, and the laterality half from expression of Ccdc151 in vertebrate left-right organisers together with the situs defects seen in patients and in three model species. Conformance note: this node matches the module's motile-cilia node directly and completely, which is the expected shape for a classical axonemal PCD gene. It is a different relationship from the one the module has with the reduced-generation-of-multiple-motile-cilia forms of PCD, where the cilia are too few rather than immotile.

multiciliated respiratory epithelial cell CL:0005012

cilium movement GO:0003341 ⚠ ABNORMAL determination of left/right symmetry GO:0007368 ⚠ ABNORMAL

Animal models

Ccdc151 knockout mouse (targeted gene deletion) Mouse partially recapitulates The null reproduces motile-cilia failure in the ependyma and the male reproductive tract, but the tissue whose failure defines the human disease - the conducting airway - cannot be assessed because the animals die perinatally.

Odad3 conditional knockout mouse (adult male) Mouse recapitulates The sperm flagellum is a motile axoneme with the same outer dynein arm and docking machinery as an airway cilium, so flagellar failure in this model is the same lesion read out in a different cell. The model additionally shows that Odad3 loss disrupts flagellar *morphogenesis*, not only motility.

Downstream

Mucociliary Clearance Failure

Randomised Left-Right Body Asymmetry

Show evidence (2 references)

PMID:25192045 SUPPORT Model Organism

"Consistent with the laterality defects observed in these individuals, we found Ccdc151 expressed in vertebrate left-right organizers."

Ties the laterality half of this node to the gene's expression at the structure responsible for it. Graded MODEL_ORGANISM because the finding reported is expression in vertebrate model organisms; the human laterality defects it is consistent with are evidenced separately.

PMID:25192045 SUPPORT Other

"In humans, defects in ODA assembly are the major cause of primary ciliary dyskinesia (PCD), an inherited disorder of ciliary and flagellar dysmotility characterized by chronic upper and lower respiratory infections and defects in laterality."

Places outer-dynein-arm defects as the major mechanism of PCD and names the two clinical consequences this node produces. Graded OTHER because it is a background statement about the disease class.

Mucociliary Clearance Failure

The immediate tissue-level consequence of cilia that cannot beat: the mucus escalator stops. Nothing is yet infected or destroyed at this step - the airway surface simply loses the directional fluid movement that normally clears it, and with it the host defence that movement constitutes. Curated as its own node rather than folded into the airway disease below because it is the step a therapy would have to act on. Everything downstream is secondary damage; this is the primary functional loss.

multiciliated respiratory epithelial cell CL:0005012

mucociliary clearance GO:0120197 ↓ DECREASED

Downstream

Chronic Airway Infection and Neutrophilic Inflammation

Show evidence (1 reference)

PMID:32490514 SUPPORT Other

"In KS patients, defective fluid movement basing on cilia across the surface of the respiratory airway multiciliated epithelial cell can impair the mucociliary clearance host-defense mechanisms"

The mechanistic link from ciliary failure to impaired clearance. Graded OTHER because it is background about Kartagener syndrome as a class rather than an observation in the reported family.

Chronic Airway Infection and Neutrophilic Inflammation

Retained mucus is colonised, and the airway mounts a neutrophilic response that never resolves because the stimulus is never cleared. This is the self-sustaining middle of the disease and the reason it is progressive rather than static: each cycle of infection recruits inflammation that damages the airway, and the damaged airway clears even less well. Typed as an amplifier for that reason. It is also the step at which the disease becomes treatable in practice - airway clearance and antibiotics act here, not on the axoneme - which is why it is worth having as a node even though no ODAD3-specific study addresses it.

bronchus UBERON:0002185

Downstream

Bronchiectasis and Airway Wall Destruction

Show evidence (2 references)

PMID:32490514 SUPPORT Human Clinical

"The patient in the present study presented with recurrent upper and lower airways infections such as chronic cough, bronchiectasis, sinusitis, and chest infections"

Recurrent infection of both airway compartments in a reported CCDC151 patient.

PMID:25192045 SUPPORT Other

"an inherited disorder of ciliary and flagellar dysmotility characterized by chronic upper and lower respiratory infections and defects in laterality"

Establishes chronic upper and lower respiratory infection as a defining feature of the disease class this entity belongs to. Graded OTHER because it is background from the paper's introduction.

Bronchiectasis and Airway Wall Destruction

The irreversible endpoint, and the reason early diagnosis matters: the bronchial wall is destroyed by the inflammation above and does not recover. Diffuse bronchiectasis is documented in the individually described 35-year-old ODAD3 patient and in the Kartagener-syndrome case. What is ODAD3-specific here is that clinical observation. The sequence that produces it - retention, infection, inflammation, wall destruction - is the general PCD mechanism, cited as such on the nodes above, and no study has examined it in this genotype.

bronchus UBERON:0002185

Show evidence (1 reference)

PMID:33719352 SUPPORT Human Clinical

"The 35 year-old female patient exhibited chronic sinusitis, diffuse bronchiectasis, dextrocardia and infertility."

The clinical picture in an individually described ODAD3 patient, including the bronchiectasis this node records.

Randomised Left-Right Body Asymmetry

Laterality is not reversed by this disease; it is randomised. That is the correct way to describe a nodal-flow defect and it explains the observed spread - situs solitus, situs inversus totalis, and complex heterotaxy with congenital heart disease all occur, and all three were seen in the vertebrate models. On frequency: the defining paper's abstract records laterality defects in the reported individuals but gives no fraction, and its cached record is abstract-only. The deep-research report committed with this entry, which read the full text, records four of the five with a laterality defect and one with a ventricular septal defect. That is an uncited lead, and with a denominator of five it would in any case describe those three families rather than estimate penetrance.

determination of left/right symmetry GO:0007368 ⚠ ABNORMAL

Animal models

Ccdc151 knockout mouse (targeted gene deletion) Mouse recapitulates Congenital left-right asymmetry defects occur in the null animals, matching the human laterality phenotype and its nodal-cilia mechanism.

Show evidence (2 references)

PMID:25192045 SUPPORT Model Organism

"Homozygous zebrafish ccdc151(ts272a) and mouse Ccdc151(Snbl) mutants display a spectrum of situs defects associated with complex heart defects."

Establishes that the laterality consequence is a spectrum rather than a simple reversal, in two model species.

PMID:30504913 SUPPORT Human Clinical

"our study provides additional support that CCDC151 plays important roles in left-right patterning and ciliary function"

An independent human case with situs inversus supporting the laterality role.

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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

16

Cardiovascular 3

Ventricular Septal Defect OCCASIONAL HP:0001629

Show evidence (1 reference)

PMID:32490514 SUPPORT Other

"Affected individuals with CCDC151 mutations also showed varied phenotypes, including dextrocardia, SI, cardiac ventricular septal defect and hearing disease"

A gene-specific summary of the reported CCDC151 phenotype range naming ventricular septal defect. Graded OTHER because it summarises the primary reports rather than describing the citing paper's own patient.

Dextrocardia HP:0001651

Show evidence (1 reference)

PMID:33719352 SUPPORT Human Clinical

"The 35 year-old female patient exhibited chronic sinusitis, diffuse bronchiectasis, dextrocardia and infertility."

Documents dextrocardia in a reported ODAD3 patient.

Situs Inversus FREQUENT Situs inversus totalis HP:0001696

Show evidence (2 references)

PMID:30504913 SUPPORT Human Clinical

"We identified a novel CCDC151 mutation, c.325G>T (p.E109X), in a patient with primary ciliary dyskinesia and situs inversus."

An ODAD3 patient with situs inversus.

ORPHA:244 SUPPORT Other

"HP:0001696 | Situs inversus totalis | Occasional (29-5%)"

Graded PARTIAL because the band sits below what this entry itself states and what the literature reports - roughly half of PCD patients have a laterality defect, and situs inversus totalis is the commonest form of it. `frequency` is set to FREQUENT accordingly, matching how the umbrella `Primary Ciliary Dyskinesia` entry handles this same Orphanet row. The row is still worth quoting because it is the only graded source available and because a reader should see that the graded value and the narrative value disagree.

Ear 2

Hearing Impairment OCCASIONAL HP:0000365

Show evidence (3 references)

PMID:32490514 SUPPORT Other

"Affected individuals with CCDC151 mutations also showed varied phenotypes, including dextrocardia, SI, cardiac ventricular septal defect and hearing disease"

The same gene-specific phenotype summary, naming hearing disease. Graded OTHER for the same reason.

ORPHA:244 SUPPORT Other

"HP:0000365 | Hearing impairment | Occasional (29-5%)"

Independent corroboration of the OCCASIONAL band already assigned here, which was reasoned from a narrative hedge rather than from a graded source. Orphanet reaches the same band for the class.

ORPHA:244 SUPPORT Other

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

Orphanet grades the conductive subtype at the same band, which supports the mechanism this phenotype's description gives - middle-ear disease following from the same ciliated epithelium failing in the Eustachian tube - without changing the decision to bind the general HP:0000365 term, since the sources describing ODAD3 patients say only "hearing disease".

Recurrent Otitis Media FREQUENT HP:0000403

Show evidence (2 references)

PMID:32490514 SUPPORT Other

"Patients with CILD30 may have respiratory symptoms, nasal blockages, nasal polyps, otitis media, and laterality defects"

A summary of the CILD30 phenotype naming otitis media. Graded OTHER because it is a secondary summary of the primary reports rather than an observation the citing paper made.

ORPHA:244 SUPPORT Other

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

Orphanet's frequency band for the class, and independent corroboration of a phenotype otherwise carried only by a gene-specific narrative summary.

Genitourinary 2

Male Infertility FREQUENT HP:0003251

Show evidence (2 references)

ORPHA:244 SUPPORT Other

"HP:0003251 | Male infertility | Frequent (79-30%)"

Orphanet's graded frequency for male infertility in primary ciliary dyskinesia, and the band that carries this phenotype. It is the class's, not ODAD3's.

PMID:31383820 SUPPORT Model Organism

"Congenital defects in left-right asymmetry and male infertility have been also observed in Ccdc151-null animals."

Gene-specific support from the constitutive null, which is what raises this above a phenotype carried by a class band alone.

Female Infertility OCCASIONAL HP:0008222

Show evidence (2 references)

PMID:33719352 SUPPORT Human Clinical

"The 35 year-old female patient exhibited chronic sinusitis, diffuse bronchiectasis, dextrocardia and infertility."

Records infertility in the reported female patient. The paper separately states that female infertility in ODAD3-related PCD had not previously been reported, but that sentence evidences novelty rather than the phenotype and is not used here.

ORPHA:244 SUPPORT Other

"HP:0008222 | Female infertility | Occasional (29-5%)"

Orphanet grades female infertility Occasional for the class. Recorded alongside the individually described ODAD3 patient, and worth comparing with male infertility below, which Orphanet grades Frequent.

Head and Neck 2

Chronic Sinusitis FREQUENT HP:0011109

Show evidence (2 references)

PMID:33719352 SUPPORT Human Clinical

"The 35 year-old female patient exhibited chronic sinusitis, diffuse bronchiectasis, dextrocardia and infertility."

Documents chronic sinusitis in a reported ODAD3 patient.

ORPHA:244 SUPPORT Other

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

Orphanet's frequency band for chronic sinusitis in the class. Not an ODAD3-specific figure.

Nasal Polyposis FREQUENT HP:0100582

Show evidence (2 references)

PMID:32490514 SUPPORT Other

"Patients with CILD30 may have respiratory symptoms, nasal blockages, nasal polyps, otitis media, and laterality defects"

The same CILD30 phenotype summary, naming nasal blockage and polyps.

ORPHA:244 SUPPORT Other

"HP:0100582 | Nasal polyposis | Frequent (79-30%)"

Orphanet's frequency band for the class, corroborating a phenotype otherwise carried only by a narrative summary.

Immune 1

Recurrent Respiratory Infections FREQUENT HP:0002205

Temporal: RECURRENT

Show evidence (3 references)

PMID:33719352 SUPPORT Human Clinical

"She has been inflicted by recurrent infections of the lower and upper airways since newborn."

Lifelong recurrent airway infection in the reported ODAD3 patient, from the newborn period.

PMID:32490514 SUPPORT Human Clinical

"The patient in the present study presented with recurrent upper and lower airways infections such as chronic cough, bronchiectasis, sinusitis, and chest infections"

The same picture in an independently reported CCDC151 patient.

ORPHA:244 SUPPORT Other

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

Graded PARTIAL because the row is not this phenotype's own term. Orphanet grades HP:0005425 recurrent sinopulmonary infections, which is narrower than the HP:0002205 recurrent respiratory infections bound here; it is the nearest graded row in the table and is what the FREQUENT band rests on. Recorded explicitly so the mismatch is visible rather than implied.

Respiratory 3

Bronchiectasis FREQUENT HP:0002110

Show evidence (2 references)

PMID:33719352 SUPPORT Human Clinical

"The 35 year-old female patient exhibited chronic sinusitis, diffuse bronchiectasis, dextrocardia and infertility."

Documents bronchiectasis in a reported ODAD3 patient.

ORPHA:244 SUPPORT Other

"HP:0002110 | Bronchiectasis | Occasional (29-5%)"

Graded PARTIAL because the band understates this phenotype rather than measuring it: Orphanet's Occasional is a class figure that most likely reflects cross-sectional point prevalence rather than cumulative incidence, and both individually described ODAD3 patients have bronchiectasis. `frequency` is set to FREQUENT on that gene-specific evidence, matching how the umbrella `Primary Ciliary Dyskinesia` entry handles this same Orphanet row.

Productive Cough FREQUENT HP:0031245

Temporal: CHRONIC

Show evidence (2 references)

PMID:32490514 SUPPORT Human Clinical

"The proband, a 34-year-old male with chief complaints of recurrent productive cough and intermittent fever, was admitted to the Third Xiangya Hospital, Central South University, Changsha, China."

Productive cough as the presenting complaint in the reported CCDC151 patient.

ORPHA:244 SUPPORT Other

"HP:0031245 | Productive cough | Frequent (79-30%)"

Orphanet's frequency band for productive cough in primary ciliary dyskinesia as a class. Not an ODAD3-specific figure.

Neonatal Respiratory Distress FREQUENT HP:0002643

Onset: NEONATAL

Show evidence (1 reference)

ORPHA:244 SUPPORT Other

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

Orphanet's graded frequency for neonatal respiratory distress in primary ciliary dyskinesia. The band is the class's, not ODAD3's.

Other 3

Absent Outer Dynein Arms HP:0012256

Show evidence (1 reference)

PMID:25192045 SUPPORT Human Clinical

"whose cilia showed a complete loss of ODAs and severely impaired ciliary beating"

Documents complete outer dynein arm loss in the defining patients.

Abnormal Ciliary Motility HP:0012262

Show evidence (2 references)

PMID:25192045 SUPPORT Human Clinical

"whose cilia showed a complete loss of ODAs and severely impaired ciliary beating"

Documents the beat defect in patients.

PMID:25192045 SUPPORT Model Organism

"CCDC151-deficient zebrafish, planaria, and mice also display ciliary dysmotility accompanied by ODA loss."

Cross-species reproduction of the same coupled defect.

Abnormal Sperm Motility FREQUENT HP:0012206

Show evidence (2 references)

ORPHA:244 SUPPORT Other

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

Orphanet's graded frequency for abnormal sperm motility in the class.

PMID:31383820 SUPPORT Model Organism

"Ccdc151 gene deletion in adult animals results in abnormal sperm counts and defective sperm motility."

The adult-deletion measurement, which isolates the motility defect from the developmental absence of sperm seen in the constitutive null.

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Genetic Associations

1

ODAD3

Gene: ODAD3 hgnc:28303 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:25224326 SUPPORT Human Clinical

"The variant was absent in 238 randomly selected individuals indicating that the variant is rare and likely not to be a founder mutation."

The published argument against a founder effect, quoted so a reader can see what it actually rests on.

PMID:33719352 SUPPORT Human Clinical

"We identified a novel homozygous variant in ODAD3, c.1166_1169dupAGAC, p.(Leu391Aspfs*105) in the PCD patient by exome sequencing and Sanger sequencing."

One of the reported frameshift alleles.

PMID:32490514 SUPPORT Human Clinical

"In the present study, we identified a frame shift mutation, c.167delG (p.G56Dfs*26), in the coiled-coil domain containing 151 gene (CCDC151) responsible for KS in a Han-Chinese family."

A further frameshift allele, reported under the CCDC151 symbol.

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External Assertions

1

OMIM primary ciliary dyskinesia 30 record

OMIM disease record OMIM:616037

OMIM's record for CILD30, the ODAD3-related form of primary ciliary dyskinesia. Recorded here because the identifier is easy to get wrong: the deep-research report committed with this entry cites the umbrella primary ciliary dyskinesia number, 244400, instead.

Show evidence (1 reference)

PMID:33719352 SUPPORT Other

"Up to now, PCD caused by ODAD3 variants (MIM 616037, CILD30) are rarely reported"

Ties the OMIM identifier and the CILD30 designation to ODAD3-related disease specifically. Graded OTHER because it is a background statement rather than a finding of the citing study.

🔬

Biochemical Markers

1

Nasal Nitric Oxide (Decreased)

Reference Ranges

77.0– nl/min (patients assessed for primary ciliary dyskinesia)

Below the PCD diagnostic cut-off (–77.0 nl/min) At or above the PCD diagnostic cut-off (77.0– nl/min)

Below the PCD diagnostic cut-off: Supports referral for ciliary ultrastructural and genetic testing. It does not diagnose PCD on its own and says nothing about which gene. The reported ODAD3 patient measured 6 nl/min, an order of magnitude below the threshold rather than marginally under it.

At or above the PCD diagnostic cut-off: Argues against PCD, though it does not exclude it - some genotypes, notably RSPH1, retain higher nasal nitric oxide.

A one-sided diagnostic threshold rather than a laboratory normal interval, which is why `upper_bound` is unset: values at or above 77 nl/min argue against PCD, and there is no upper limit at which the test becomes abnormal again. `loinc_term` is likewise unset - nasal nitric oxide has no LOINC code in the caches this repository carries, and inventing one would be worse than leaving it out.

Show evidence (1 reference)

PMID:33719352 SUPPORT Human Clinical

"Her nasal nitric oxide concentration (nNO) (6 nl/min) was far below the reference nNO cutoff value of PCD (77 nl/min)"

The source of both the cut-off and the patient value.

Show evidence (1 reference)

PMID:33719352 SUPPORT Human Clinical

"Her nasal nitric oxide concentration (nNO) (6 nl/min) was far below the reference nNO cutoff value of PCD (77 nl/min)"

The measured value in the reported ODAD3 patient, against the diagnostic cut-off.

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Diagnosis

2

Nasal Nitric Oxide Screening

What happens before the electron microscope. Nasal nitric oxide is the first-line screen for PCD, and it was very low in the reported ODAD3 patient - 6 nl/min against a cut-off of 77. It is a triage test, not a diagnosis: it selects who goes on to ultrastructural and genetic testing, and it neither identifies the gene nor, on its own, confirms the disease.

Show evidence (1 reference)

PMID:33719352 SUPPORT Human Clinical

"Her nasal nitric oxide concentration (nNO) (6 nl/min) was far below the reference nNO cutoff value of PCD (77 nl/min)"

The screening result in the reported ODAD3 patient.

Ultrastructural and Immunofluorescence Assessment of Outer Dynein Arms

ODAD3 disease is one of the PCD forms that a diagnostic laboratory can localise before sequencing. Electron microscopy shows outer dynein arms missing with inner arms preserved, and immunofluorescence shows the docking-complex members and the outer-arm heavy chain DNAH5 absent from the axoneme. That pattern narrows the genetic differential to the ODA and ODA-docking genes, which is a useful reduction from the fifty-odd PCD genes. What it cannot do is name ODAD3. The docking complex fails as a unit, so a defect in any of its members produces the same immunofluorescence picture - which is why the diagnosis is completed by sequencing.

Show evidence (1 reference)

PMID:25192045 SUPPORT Human Clinical

"cause a failure in axonemal assembly of the ODA component DNAH5 and the ODA-DC-associated components CCDC114 and ARMC4"

The immunofluorescence pattern that identifies a docking-complex defect, and the reason it cannot discriminate between the complex's members.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Fewer than a dozen patients: five individuals from three families in the defining series, plus single independently reported cases from Arabic, mainland Chinese and Han-Chinese families. No ODAD3-specific prevalence estimate exists, and none should be derived from the PCD population figure (commonly quoted as roughly 1 in 10,000 to 1 in 20,000 live births) by division, because the share of PCD attributable to any single one of the fifty-odd known genes has not been established for ODAD3.

Show evidence (3 references)

PMID:25192045 SUPPORT Human Clinical

"we identified CCDC151 loss-of-function mutations in five affected individuals from three independent families"

The defining series and its size.

PMID:33719352 SUPPORT Other

"The estimated prevalence of PCD is 1:10 000 to 1:20 000 live-born children"

The prevalence of the disease class, given for context. It is not this entity's prevalence.

ORPHA:244 SUPPORT Other

"1-9 / 100 000 | Europe | Prevalence at birth | PMID:23871404"

Orphanet's birth-prevalence class for primary ciliary dyskinesia as a whole. Recorded for context, and to make the point that Orphanet holds one epidemiological record for the entire disease rather than per gene - the same record that lists 53 causal genes including ODAD3.

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Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Primary Ciliary Dyskinesia 30:

Other outer dynein arm docking complex deficiencies (ODAD1, ODAD2, ODAD4)

Overlapping Features The closest differential, and the one that ultrastructure cannot resolve. ODAD1 (CCDC114), ODAD2 (ARMC4) and ODAD4 (TTC25) are the other members of the same complex, and defects in any of them give outer dynein arm loss with randomised laterality. ODAD3 is distinguished from them only by sequencing. Note that this knowledge base currently curates ODAD1 as a causal gene on the umbrella `Primary Ciliary Dyskinesia` entry rather than as its own disease entry, so a reader looking for its counterpart to this file will not find one.

Show evidence (1 reference)

PMID:27486780 SUPPORT Human Clinical

"Additionally, IF analyses revealed an absence of the ODA docking complex (ODA-DC), along with its known components CCDC114, CCDC151, and ARMC4."

A different docking-complex gene's defect removes ODAD3 (CCDC151) from the axoneme along with the rest of the complex - which is precisely why immunofluorescence cannot discriminate ODAD3 disease from its siblings.

Non-genetic causes of chronic suppurative airway disease

Overlapping Features The differential a clinician actually works through before any of the genetic ones become relevant. A child with a chronic wet cough, recurrent infection and bronchiectasis is far more likely to have cystic fibrosis, an antibody deficiency or recurrent aspiration than a motile ciliopathy, and all three were excluded in the reported Kartagener case before ciliary testing. The feature that redirects the workup toward PCD is laterality: situs inversus or heterotaxy belongs to none of these three, and its presence in a patient with suppurative airway disease is close to diagnostic of a motile-cilia disorder. Its absence excludes nothing, though - roughly half of PCD patients have normal situs, and this disease's own MONDO term is explicitly "with or without situs inversus".

Show evidence (1 reference)

PMID:32490514 SUPPORT Human Clinical

"Cystic fibrosis, primary immunodeficiency diseases, and aspiration pneumonia were excluded"

The exclusions performed in a reported CCDC151 patient before the ciliary diagnosis was made.

Outer dynein arm heavy-chain and dynein-preassembly deficiencies

Overlapping Features DNAH5 and other outer-arm components give outer dynein arm loss directly rather than through a docking failure, and are clinically indistinguishable. The dynein-preassembly factors are separable on ultrastructure, because they remove inner arms as well as outer ones - which is exactly the distinction that the HPO term chosen for the phenotype above preserves.

Show evidence (1 reference)

PMID:25192045 SUPPORT Other

"In humans, defects in ODA assembly are the major cause of primary ciliary dyskinesia (PCD), an inherited disorder of ciliary and flagellar dysmotility characterized by chronic upper and lower respiratory infections and defects in laterality."

Establishes that outer-arm assembly defects as a class are the largest slice of the PCD differential.

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Animal Models

3

Ccdc151 knockout mouse (targeted gene deletion)

A targeted-deletion mouse null for Ccdc151. It reproduces the laterality defect and the male infertility of human ODAD3 disease, and adds a phenotype the human disease does not have: perinatally lethal communicating hydrocephalus. A beta-galactosidase reporter localises the gene's expression to the ependymal cells lining the ventricular system, which explains the hydrocephalus mechanistically - the ependymal motile cilia that drive cerebrospinal fluid flow are the same machinery - without making it a human finding.

Species

Mouse

Genotype

Ccdc151 targeted deletion, homozygous null

Publication

PMID:31383820

Pathograph links

Randomised Left-Right Body Asymmetry recapitulates fidelity: high Congenital left-right asymmetry defects occur in the null animals, matching the human laterality phenotype and its nodal-cilia mechanism.

Limitations: Perinatal lethality means the model cannot be followed into the chronic airway disease that dominates the human illness, so its usefulness is confined to developmental phenotypes.

Readouts

Left-right asymmetry in Ccdc151-null animals

Direction: ALTERED

Interpretation: Presence of congenital laterality defects in the null, matching the human phenotype.

Show evidence (1 reference)

PMID:31383820 SUPPORT Model Organism

"Congenital defects in left-right asymmetry and male infertility have been also observed in Ccdc151-null animals."

The laterality observation in the null mouse.

Show evidence (1 reference)

PMID:31383820 SUPPORT Other

"The CCDC151 gene encodes for a coiled-coil axonemal protein that ensures correct attachment of outer dynein arm (ODA) complexes to microtubules."

Establishes that the gene has the same molecular role across species, which is what makes the model informative for this node. Graded OTHER because it is background prose from the paper's introduction rather than a result measured in the mouse.

Motile Ciliary Beat Failure partially recapitulates fidelity: moderate The null reproduces motile-cilia failure in the ependyma and the male reproductive tract, but the tissue whose failure defines the human disease - the conducting airway - cannot be assessed because the animals die perinatally.

Limitations: Perinatal lethality from hydrocephalus prevents any study of chronic airway disease, bronchiectasis, or the natural history that constitutes most of the human illness. The dominant phenotype of the model is one the human disease does not have; see the HUMAN_MODEL_MISMATCH discussion.

Readouts

Sperm count and motility after adult Ccdc151 deletion

Direction: DECREASED

Interpretation: Deleting the gene in adults, which bypasses the perinatal lethality, gives an isolated flagellar-motility readout of the same lesion.

Show evidence (1 reference)

PMID:31383820 SUPPORT Model Organism

"Ccdc151 gene deletion in adult animals results in abnormal sperm counts and defective sperm motility."

The adult-deletion motility measurement.

Show evidence (1 reference)

PMID:31383820 SUPPORT Model Organism

"Here, we demonstrate that loss of Ccdc151 gene function via targeted gene deletion in mice leads to perinatal lethality and congenital hydrocephalus."

Graded PARTIAL because this is the limitation on the link as much as support for it: the phenotype that dominates the model is not the phenotype that dominates the disease.

Odad3 conditional knockout mouse (adult male)

A conditional deletion that removes Odad3 in adult males and so escapes the perinatal lethality of the constitutive null. It gives the only detailed account of what ODAD3 loss does to a flagellum: asthenoteratozoospermia with multiple morphological abnormalities of the sperm flagella, and spermatogenesis arrested at the spermiogenesis and spermiation stages. The same study reports a heterozygote effect - reduced sperm count and motility, abnormal morphology, and a shorter fertile lifespan in Odad3+/- males - which is a gene-dosage claim with no human counterpart and is the subject of an open discussion below.

Species

Mouse

Genotype

Odad3 conditional deletion in adult males; and Odad3 heterozygous null

Publication

PMID:38920681

Pathograph links

Motile Ciliary Beat Failure recapitulates fidelity: moderate The sperm flagellum is a motile axoneme with the same outer dynein arm and docking machinery as an airway cilium, so flagellar failure in this model is the same lesion read out in a different cell. The model additionally shows that Odad3 loss disrupts flagellar *morphogenesis*, not only motility.

Limitations: Fidelity is graded MODERATE, not HIGH, for two reasons. The readout is a single motile cell type and not the multiciliated airway epithelium whose failure defines the human disease. And the conditional deletion is imposed on an adult animal whose spermatogenic machinery developed normally, which is not the situation of a patient who has lacked ODAD3 since conception.

Readouts

Sperm flagellar morphology and motility after adult Odad3 ablation

Direction: ALTERED

Interpretation: Multiple morphological abnormalities of the flagella with impaired motility, in an axoneme built without ODAD3.

Show evidence (1 reference)

PMID:38920681 SUPPORT Model Organism

"we conditionally deleted the Odad3 gene in adult males and demonstrated that even partial ablation of the Odad3 gene leads to asthenoteratozoospermia with multiple morphological abnormalities of sperm flagella (MMAF) in mice"

The flagellar phenotype underlying this readout.

Show evidence (1 reference)

PMID:38920681 SUPPORT Model Organism

"Previously, we demonstrated that knockout of the Odad3 gene in mice replicates several features of PCD, such as hydrocephalus, defects in left-right body symmetry, and male infertility, with a complete absence of sperm in the reproductive tract."

Establishes the model lineage and which human features the mouse reproduces, which is what makes it informative for this node.

Ccdc151 morphant zebrafish

The zebrafish work that identified CCDC151 as an outer-dynein-arm docking protein before any human patient was known - it shares ancient features with the outer dynein arm-docking complex 2 of Chlamydomonas. Depletion gives left-right asymmetry defects and kidney cysts, and the motility defect was localised to the two motile-ciliated structures that matter: Kupffer's vesicle, the fish left-right organiser, and the pronephros.

Species

Zebrafish

Genotype

ccdc151 morpholino knockdown; and homozygous ccdc151(ts272a)

Publication

PMID:24067530

Pathograph links

Outer Dynein Arm Docking Complex Assembly Failure recapitulates fidelity: moderate Ccdc151 depletion impairs motile ciliary function by controlling dynein arm assembly, which is the same molecular step as the human lesion, established in this species before the human disease existed.

Limitations: Morpholino knockdown is transient and incomplete rather than a null, and the same study reports that vertebrate CCDC151 has acquired functions beyond motility - a role in oriented cell division in the pronephros and in the regulation of primary cilium length in mammalian cells. Those additional functions are not part of the human PCD phenotype, so a zebrafish phenotype cannot be assumed to be the motility phenotype.

Readouts

Dynein arm assembly in Kupffer's vesicle and pronephric cilia

Direction: DECREASED

Interpretation: Loss of motile function attributable to defective dynein arm assembly in the two motile-ciliated organs assayed.

Show evidence (1 reference)

PMID:24067530 SUPPORT Model Organism

"We demonstrate that Ccdc151 is required for proper motile function of cilia in the Kupffer's vesicle and in the pronephros by controlling dynein arm assembly"

The assembly measurement underlying this readout.

Show evidence (1 reference)

PMID:24067530 SUPPORT Model Organism

"We identified a previously uncharacterized coiled-coil domain containing protein CCDC151, which is evolutionarily conserved in motile ciliated species and shares ancient features with the outer dynein arm-docking complex 2 of Chlamydomonas."

Establishes the protein's identity as a docking-complex component, conserved from the alga that defined the structure.

{ }

Source YAML

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name: Primary Ciliary Dyskinesia 30
creation_date: "2026-08-28T00:00:00Z"
category: Genetic
disease_term:
  preferred_term: Primary ciliary dyskinesia 30
  term:
    id: MONDO:0014465
    label: primary ciliary dyskinesia 30
description: >-
  Primary ciliary dyskinesia 30 (CILD30) is the form of PCD caused by biallelic
  loss-of-function variants in ODAD3, the gene formerly called CCDC151. The
  protein is a subunit of the outer dynein arm docking complex - the structure
  that anchors preassembled outer dynein arms onto the axonemal microtubules.
  Losing it does not damage the dynein motors themselves; it removes the place
  they attach. The result is a fully built cilium with nothing to power it.

  The lesion is unusually legible in the cell. In patients' respiratory cilia,
  ODAD3 is absent from the axoneme, and so are the two other docking-complex
  members ODAD1 (CCDC114) and ODAD2 (ARMC4) and the outer-arm heavy chain DNAH5,
  while inner dynein arms remain in place. That selective picture - outer arms
  gone, inner arms present - is what transmission electron microscopy reports as
  isolated outer dynein arm loss, and it is why the docking complex, rather than
  dynein assembly, is the level at which this disease acts. ODAD3
  co-immunoprecipitates ODAD1, so the docking complex is understood to fail as a
  unit.

  Clinically this produces conventional PCD: lifelong wet cough, recurrent upper
  and lower airway infection, chronic rhinosinusitis, otitis media,
  bronchiectasis, and - because the same axonemal machinery drives the embryonic
  node's motile monocilia - laterality defects, which the defining series
  reports in its patients without giving a fraction in its abstract. Fewer than a
  dozen patients have been reported.

  Two things make this entity worth curating separately rather than as one more
  gene on the umbrella PCD entry, and both concern what happens outside the
  airway. The mouse null is perinatally lethal with communicating hydrocephalus,
  a phenotype that human ODAD3 patients do not have; and mouse work has followed
  the gene into spermatogenesis far enough to find a heterozygote effect - a
  gene-dosage claim with counselling implications that no human study has
  examined. Both are curated here with their translational limits stated
  explicitly rather than transferred to patients.
parents:
- Primary Ciliary Dyskinesia
- Ciliopathy
synonyms:
- CILD30
- ciliary dyskinesia, primary, 30, with or without situs inversus
- ODAD3-related primary ciliary dyskinesia
- CCDC151-related primary ciliary dyskinesia
- CCDC151 deficiency
classifications:
  harrisons_chapter:
  - classification_value: RESPIRATORY
    notes: >-
      The dominant clinical burden is chronic suppurative airway disease and
      bronchiectasis.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian recessive disorder identified and confirmed by sequencing.
  mechanistic_category:
  - classification_value: ciliopathy
references:
- reference: PMID:25192045
  title: "CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation."
- reference: PMID:25224326
  title: "Nonsense mutation in coiled-coil domain containing 151 gene (CCDC151) causes primary ciliary dyskinesia."
- reference: PMID:33719352
  title: "Case Report: Identification of a Novel ODAD3 Variant in a Patient With Primary Ciliary Dyskinesia."
- reference: PMID:32490514
  title: "Identification of a frame shift mutation in the CCDC151 gene in a Han-Chinese family with Kartagener syndrome."
- reference: PMID:30504913
  title: "Whole-exome sequencing identifies a novel CCDC151 mutation, c.325G>T (p.E109X), in a patient with primary ciliary dyskinesia and situs inversus."
- reference: PMID:31383820
  title: "Functional loss of Ccdc151 leads to hydrocephalus in a mouse model of primary ciliary dyskinesia."
- reference: PMID:38920681
  title: "The Odad3 Gene Is Necessary for Spermatozoa Development and Male Fertility in Mice."
- reference: PMID:24067530
  title: "The coiled-coil domain containing protein CCDC151 is required for the function of IFT-dependent motile cilia in animals."
- reference: PMID:27486780
  title: "TTC25 Deficiency Results in Defects of the Outer Dynein Arm Docking Machinery and Primary Ciliary Dyskinesia with Left-Right Body Asymmetry Randomization."
- reference: PMID:20301301
  title: "Primary Ciliary Dyskinesia."
  tags:
  - GeneReviews
- reference: ORPHA:244
  title: "Primary ciliary dyskinesia"
external_assertions:
- name: OMIM primary ciliary dyskinesia 30 record
  source: OMIM
  assertion_type: disease_record
  external_id: OMIM:616037
  description: >-
    OMIM's record for CILD30, the ODAD3-related form of primary ciliary
    dyskinesia. Recorded here because the identifier is easy to get wrong: the
    deep-research report committed with this entry cites the umbrella primary
    ciliary dyskinesia number, 244400, instead.
  evidence:
  - reference: PMID:33719352
    reference_title: "Case Report: Identification of a Novel ODAD3 Variant in a Patient With Primary Ciliary Dyskinesia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Up to now, PCD caused by ODAD3 variants (MIM 616037, CILD30) are rarely
      reported
    explanation: >-
      Ties the OMIM identifier and the CILD30 designation to ODAD3-related
      disease specifically. Graded OTHER because it is a background statement
      rather than a finding of the citing study.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Every reported patient carries two ODAD3 loss-of-function alleles. The
    defining series found them in five affected individuals from three
    independent families by combined mapping and sequencing; subsequent reports
    are homozygous cases from consanguineous families. Nothing in the human
    literature suggests a heterozygous carrier phenotype - see the discussion
    below on why the mouse data raise that question anyway.
  evidence:
  - reference: PMID:25192045
    reference_title: "CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, by combined high-throughput mapping and sequencing, we identified
      CCDC151 loss-of-function mutations in five affected individuals from three
      independent families whose cilia showed a complete loss of ODAs and
      severely impaired ciliary beating.
    explanation: >-
      Establishes recessive loss-of-function inheritance in the defining
      families.
  - reference: PMID:25224326
    reference_title: "Nonsense mutation in coiled-coil domain containing 151 gene (CCDC151) causes primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We observed a novel nonsense mutation in a homozygous state in the CCDC151
      gene
    explanation: >-
      An independent homozygous case confirming the recessive mode. The snippet
      stops before the variant's HGVS string because the protein change is
      written with square brackets, which the reference validator strips before
      matching; the allele itself is recorded in the genetic notes.
pathophysiology:
- name: Biallelic ODAD3 Loss of Function
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    The initiating lesion. ODAD3 encodes a 595-amino-acid protein with three
    highly conserved coiled-coil domains, and every reported disease allele is
    loss-of-function. Seven had been reported as of the 2021 review cited below:
    three nonsense, three frameshift, and - the one that does not fit a simple
    truncation story - a canonical splice-donor variant, c.244+1G>A.

    No missense allele has been reported. That matters for variant
    interpretation, because it leaves no worked example of an ODAD3 change that
    alters the protein without destroying it, and so nothing to calibrate a new
    missense variant against. The splice-donor allele is the nearest thing
    available and is not close: donor-site loss usually produces exon skipping or
    intron retention with a frameshifted, decay-prone transcript, which lands
    back in the same functional class rather than giving a graded one. So the
    disease as described remains the phenotype of complete protein loss, and
    nothing is known about partial loss in humans.
  genes:
  - preferred_term: ODAD3
    term:
      id: hgnc:28303
      label: ODAD3
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    description: >-
      Curated as loss of function on the strength of the allele classes reported
      - three nonsense, three frameshift and one canonical splice-donor variant -
      together with the measured consequence: ODAD3 protein is absent from
      patients' respiratory cilia. `zygosity` is left unset at the
      disease level because reported patients are variously homozygous and
      compound heterozygous.
  evidence:
  - reference: PMID:25192045
    reference_title: "CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We demonstrate that CCDC151 encodes an axonemal coiled coil protein,
      mutations in which abolish assembly of CCDC151 into respiratory cilia
    explanation: >-
      States both the protein's nature and the immediate molecular consequence of
      the variants.
  - reference: PMID:33719352
    reference_title: "Case Report: Identification of a Novel ODAD3 Variant in a Patient With Primary Ciliary Dyskinesia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ODAD3 encodes a protein of 595 amino acids and contain three highly
      conserved coiled-coil domains, which is essential for cilia axoneme dynein
      arm assembly and docking.
    explanation: >-
      Describes the protein architecture that the loss-of-function alleles
      disrupt. Graded OTHER because it is background prose from the paper's
      introduction rather than a finding from its study.
  - reference: PMID:33719352
    reference_title: "Case Report: Identification of a Novel ODAD3 Variant in a Patient With Primary Ciliary Dyskinesia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      To date, a total of seven likely loss-of-function variants in ODAD3 have
      been reported in PCD (Supplementary Table 2).
    explanation: >-
      The allelic spectrum as of 2021, and the reason this node says
      "loss-of-function" rather than "nonsense or frameshift" - the seven include
      a splice-donor variant that is neither. Graded OTHER because it is the
      paper's survey of prior reports rather than its own finding.
  downstream:
  - target: Outer Dynein Arm Docking Complex Assembly Failure
    causal_link_type: DIRECT
- name: Outer Dynein Arm Docking Complex Assembly Failure
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    The step that defines the disease. The ODA docking complex is a multi-subunit
    structure, and ODAD3's loss takes the rest of it with it: in patients'
    respiratory cilia the docking-complex members ODAD1 (CCDC114) and ODAD2
    (ARMC4) fail to assemble onto the axoneme along with ODAD3 itself. The
    physical basis for the co-dependence is that ODAD3 and ODAD1 are binding
    partners - they co-immunoprecipitate.

    The functional distinction worth holding onto: outer dynein arms are
    *produced and preassembled in the cytosol* and then transported into the
    cilium, so a docking-complex defect is not a failure to build motors. It is a
    failure to install them.
  biological_processes:
  - preferred_term: axonemal dynein complex assembly
    term:
      id: GO:0070286
      label: axonemal dynein complex assembly
    modifier: DECREASED
  cell_types:
  - preferred_term: multiciliated respiratory epithelial cell
    term:
      id: CL:0005012
      label: multiciliated epithelial cell
  evidence:
  - reference: PMID:25192045
    reference_title: "CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cause a failure in axonemal assembly of the ODA component DNAH5 and the
      ODA-DC-associated components CCDC114 and ARMC4
    explanation: >-
      The core observation: losing ODAD3 removes the rest of the docking complex
      and the outer-arm heavy chain from the axoneme.
  - reference: PMID:25192045
    reference_title: "CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, CCDC151 coimmunoprecipitates CCDC114 and thus appears to be a
      highly evolutionarily conserved ODA-DC-related protein involved in
      mediating assembly of both ODAs and their axonemal docking machinery onto
      ciliary microtubules.
    explanation: >-
      The physical interaction that explains why the docking complex fails as a
      unit.
  - reference: PMID:25192045
    reference_title: "CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Multisubunit outer dynein arm (ODA) motor complexes, produced and
      preassembled in the cytosol, are transported to the ciliary or flagellar
      compartment and anchored into the axonemal microtubular scaffold via the
      ODA docking complex (ODA-DC) system.
    explanation: >-
      Establishes that the motors are preassembled elsewhere, which is what makes
      this an installation defect rather than an assembly defect. Graded OTHER
      because it is background from the paper's introduction.
  downstream:
  - target: Absence of Outer Dynein Arms from the Axoneme
    causal_link_type: DIRECT
- name: Absence of Outer Dynein Arms from the Axoneme
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    The structural endpoint, and the one a diagnostic laboratory sees. Patients'
    cilia show a complete loss of outer dynein arms on electron microscopy. The
    arms are what generate most of the sliding force between axonemal doublets,
    so their absence is sufficient to explain the beat failure without invoking
    any additional lesion.
  cell_types:
  - preferred_term: multiciliated respiratory epithelial cell
    term:
      id: CL:0005012
      label: multiciliated epithelial cell
  locations:
  - preferred_term: bronchus
    term:
      id: UBERON:0002185
      label: bronchus
  evidence:
  - reference: PMID:25192045
    reference_title: "CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified CCDC151 loss-of-function mutations in five affected
      individuals from three independent families whose cilia showed a complete
      loss of ODAs and severely impaired ciliary beating
    explanation: >-
      The ultrastructural and functional observation in patients.
  downstream:
  - target: Motile Ciliary Beat Failure
    causal_link_type: DIRECT
- name: Motile Ciliary Beat Failure
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: ESTABLISHED
  conforms_to: "ciliopathy_dysfunction#Motile Cilia Beat Dysfunction"
  description: >-
    Cilia that are assembled but cannot beat. In the airway this abolishes
    mucociliary clearance; at the embryonic left-right organiser the same failure
    in motile monocilia removes the directional flow that breaks symmetry. Both
    limbs of the module node are evidenced here rather than assumed: the
    ciliary-dysmotility half from patients' severely impaired beating, and the
    laterality half from expression of Ccdc151 in vertebrate left-right
    organisers together with the situs defects seen in patients and in three
    model species.

    Conformance note: this node matches the module's motile-cilia node directly
    and completely, which is the expected shape for a classical axonemal PCD
    gene. It is a different relationship from the one the module has with the
    reduced-generation-of-multiple-motile-cilia forms of PCD, where the cilia are
    too few rather than immotile.
  biological_processes:
  - preferred_term: cilium movement
    term:
      id: GO:0003341
      label: cilium movement
    modifier: ABNORMAL
  - preferred_term: determination of left/right symmetry
    term:
      id: GO:0007368
      label: determination of left/right symmetry
    modifier: ABNORMAL
  cell_types:
  - preferred_term: multiciliated respiratory epithelial cell
    term:
      id: CL:0005012
      label: multiciliated epithelial cell
  evidence:
  - reference: PMID:25192045
    reference_title: "CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Consistent with the laterality defects observed in these individuals, we
      found Ccdc151 expressed in vertebrate left-right organizers.
    explanation: >-
      Ties the laterality half of this node to the gene's expression at the
      structure responsible for it. Graded MODEL_ORGANISM because the finding
      reported is expression in vertebrate model organisms; the human laterality
      defects it is consistent with are evidenced separately.
  - reference: PMID:25192045
    reference_title: "CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In humans, defects in ODA assembly are the major cause of primary ciliary
      dyskinesia (PCD), an inherited disorder of ciliary and flagellar
      dysmotility characterized by chronic upper and lower respiratory infections
      and defects in laterality.
    explanation: >-
      Places outer-dynein-arm defects as the major mechanism of PCD and names the
      two clinical consequences this node produces. Graded OTHER because it is a
      background statement about the disease class.
  downstream:
  - target: Mucociliary Clearance Failure
    causal_link_type: DIRECT
  - target: Randomised Left-Right Body Asymmetry
    causal_link_type: DIRECT
- name: Mucociliary Clearance Failure
  biological_scale: TISSUE
  role: effector
  mechanism_confidence: ESTABLISHED
  description: >-
    The immediate tissue-level consequence of cilia that cannot beat: the mucus
    escalator stops. Nothing is yet infected or destroyed at this step - the
    airway surface simply loses the directional fluid movement that normally
    clears it, and with it the host defence that movement constitutes.

    Curated as its own node rather than folded into the airway disease below
    because it is the step a therapy would have to act on. Everything downstream
    is secondary damage; this is the primary functional loss.
  biological_processes:
  - preferred_term: mucociliary clearance
    term:
      id: GO:0120197
      label: mucociliary clearance
    modifier: DECREASED
  cell_types:
  - preferred_term: multiciliated respiratory epithelial cell
    term:
      id: CL:0005012
      label: multiciliated epithelial cell
  evidence:
  - reference: PMID:32490514
    reference_title: "Identification of a frame shift mutation in the CCDC151 gene in a Han-Chinese family with Kartagener syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In KS patients, defective fluid movement basing on cilia across the surface
      of the respiratory airway multiciliated epithelial cell can impair the
      mucociliary clearance host-defense mechanisms
    explanation: >-
      The mechanistic link from ciliary failure to impaired clearance. Graded
      OTHER because it is background about Kartagener syndrome as a class rather
      than an observation in the reported family.
  downstream:
  - target: Chronic Airway Infection and Neutrophilic Inflammation
    causal_link_type: DIRECT
- name: Chronic Airway Infection and Neutrophilic Inflammation
  biological_scale: TISSUE
  role: amplifier
  mechanism_confidence: ESTABLISHED
  description: >-
    Retained mucus is colonised, and the airway mounts a neutrophilic response
    that never resolves because the stimulus is never cleared. This is the
    self-sustaining middle of the disease and the reason it is progressive rather
    than static: each cycle of infection recruits inflammation that damages the
    airway, and the damaged airway clears even less well.

    Typed as an amplifier for that reason. It is also the step at which the
    disease becomes treatable in practice - airway clearance and antibiotics act
    here, not on the axoneme - which is why it is worth having as a node even
    though no ODAD3-specific study addresses it.
  locations:
  - preferred_term: bronchus
    term:
      id: UBERON:0002185
      label: bronchus
  evidence:
  - reference: PMID:32490514
    reference_title: "Identification of a frame shift mutation in the CCDC151 gene in a Han-Chinese family with Kartagener syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient in the present study presented with recurrent upper and lower
      airways infections such as chronic cough, bronchiectasis, sinusitis, and
      chest infections
    explanation: >-
      Recurrent infection of both airway compartments in a reported CCDC151
      patient.
  - reference: PMID:25192045
    reference_title: "CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      an inherited disorder of ciliary and flagellar dysmotility characterized by
      chronic upper and lower respiratory infections and defects in laterality
    explanation: >-
      Establishes chronic upper and lower respiratory infection as a defining
      feature of the disease class this entity belongs to. Graded OTHER because
      it is background from the paper's introduction.
  downstream:
  - target: Bronchiectasis and Airway Wall Destruction
    causal_link_type: DIRECT
- name: Bronchiectasis and Airway Wall Destruction
  biological_scale: ORGANISM
  role: outcome
  mechanism_confidence: ESTABLISHED
  description: >-
    The irreversible endpoint, and the reason early diagnosis matters: the
    bronchial wall is destroyed by the inflammation above and does not recover.
    Diffuse bronchiectasis is documented in the individually described 35-year-old
    ODAD3 patient and in the Kartagener-syndrome case.

    What is ODAD3-specific here is that clinical observation. The sequence that
    produces it - retention, infection, inflammation, wall destruction - is the
    general PCD mechanism, cited as such on the nodes above, and no study has
    examined it in this genotype.
  locations:
  - preferred_term: bronchus
    term:
      id: UBERON:0002185
      label: bronchus
  evidence:
  - reference: PMID:33719352
    reference_title: "Case Report: Identification of a Novel ODAD3 Variant in a Patient With Primary Ciliary Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 35 year-old female patient exhibited chronic sinusitis, diffuse
      bronchiectasis, dextrocardia and infertility.
    explanation: >-
      The clinical picture in an individually described ODAD3 patient, including
      the bronchiectasis this node records.
- name: Randomised Left-Right Body Asymmetry
  biological_scale: ORGANISM
  role: effector
  mechanism_confidence: ESTABLISHED
  description: >-
    Laterality is not reversed by this disease; it is randomised. That is the
    correct way to describe a nodal-flow defect and it explains the observed
    spread - situs solitus, situs inversus totalis, and complex heterotaxy with
    congenital heart disease all occur, and all three were seen in the vertebrate
    models.

    On frequency: the defining paper's abstract records laterality defects in the
    reported individuals but gives no fraction, and its cached record is
    abstract-only. The deep-research report committed with this entry, which read
    the full text, records four of the five with a laterality defect and one with
    a ventricular septal defect. That is an uncited lead, and with a denominator
    of five it would in any case describe those three families rather than
    estimate penetrance.
  biological_processes:
  - preferred_term: determination of left/right symmetry
    term:
      id: GO:0007368
      label: determination of left/right symmetry
    modifier: ABNORMAL
  evidence:
  - reference: PMID:25192045
    reference_title: "CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Homozygous zebrafish ccdc151(ts272a) and mouse Ccdc151(Snbl) mutants
      display a spectrum of situs defects associated with complex heart defects.
    explanation: >-
      Establishes that the laterality consequence is a spectrum rather than a
      simple reversal, in two model species.
  - reference: PMID:30504913
    reference_title: "Whole-exome sequencing identifies a novel CCDC151 mutation, c.325G>T (p.E109X), in a patient with primary ciliary dyskinesia and situs inversus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      our study provides additional support that CCDC151 plays important roles in
      left-right patterning and ciliary function
    explanation: >-
      An independent human case with situs inversus supporting the laterality
      role.
phenotypes:
- category: Cellular
  name: Absent Outer Dynein Arms
  description: >-
    The diagnostic ultrastructural finding, and the phenotype that names the
    mechanism. Outer arms are absent; inner arms are not. That selectivity is
    what distinguishes an ODA or ODA-docking defect from the combined
    inner-and-outer arm loss of the dynein-preassembly disorders, and it is
    curated with the specific HPO term for absent outer arms rather than the
    combined term for that reason.
  phenotype_term:
    preferred_term: Absent outer dynein arms
    term:
      id: HP:0012256
      label: Absent outer dynein arms
  evidence:
  - reference: PMID:25192045
    reference_title: "CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      whose cilia showed a complete loss of ODAs and severely impaired ciliary
      beating
    explanation: >-
      Documents complete outer dynein arm loss in the defining patients.
- category: Cellular
  name: Abnormal Ciliary Motility
  description: >-
    Severely impaired ciliary beating in patients' respiratory cilia, and
    dysmotility with outer-arm loss reproduced in three model species.
  phenotype_term:
    preferred_term: Abnormal ciliary motility
    term:
      id: HP:0012262
      label: Abnormal ciliary motility
  evidence:
  - reference: PMID:25192045
    reference_title: "CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      whose cilia showed a complete loss of ODAs and severely impaired ciliary
      beating
    explanation: >-
      Documents the beat defect in patients.
  - reference: PMID:25192045
    reference_title: "CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      CCDC151-deficient zebrafish, planaria, and mice also display ciliary
      dysmotility accompanied by ODA loss.
    explanation: >-
      Cross-species reproduction of the same coupled defect.
- category: Respiratory
  name: Bronchiectasis
  frequency: FREQUENT
  description: >-
    Diffuse bronchiectasis, the irreversible structural consequence of chronic
    retained infection. Documented in the individually described 35-year-old
    ODAD3 patient.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:33719352
    reference_title: "Case Report: Identification of a Novel ODAD3 Variant in a Patient With Primary Ciliary Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 35 year-old female patient exhibited chronic sinusitis, diffuse
      bronchiectasis, dextrocardia and infertility.
    explanation: >-
      Documents bronchiectasis in a reported ODAD3 patient.
  - reference: ORPHA:244
    reference_title: "Primary ciliary dyskinesia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002110 | Bronchiectasis | Occasional (29-5%)"
    explanation: >-
      Graded PARTIAL because the band understates this phenotype rather than
      measuring it: Orphanet's Occasional is a class figure that most likely
      reflects cross-sectional point prevalence rather than cumulative
      incidence, and both individually described ODAD3 patients have
      bronchiectasis. `frequency` is set to FREQUENT on that gene-specific
      evidence, matching how the umbrella `Primary Ciliary Dyskinesia` entry
      handles this same Orphanet row.
- category: Respiratory
  name: Recurrent Respiratory Infections
  frequency: FREQUENT
  description: >-
    Upper and lower airway infection from infancy onwards - the consequence of
    losing mucociliary clearance, and the burden that eventually produces the
    bronchiectasis curated above. Documented in two independently reported ODAD3
    patients.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
    temporality: RECURRENT
  evidence:
  - reference: PMID:33719352
    reference_title: "Case Report: Identification of a Novel ODAD3 Variant in a Patient With Primary Ciliary Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She has been inflicted by recurrent infections of the lower and upper
      airways since newborn.
    explanation: >-
      Lifelong recurrent airway infection in the reported ODAD3 patient, from the
      newborn period.
  - reference: PMID:32490514
    reference_title: "Identification of a frame shift mutation in the CCDC151 gene in a Han-Chinese family with Kartagener syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient in the present study presented with recurrent upper and lower
      airways infections such as chronic cough, bronchiectasis, sinusitis, and
      chest infections
    explanation: >-
      The same picture in an independently reported CCDC151 patient.
  - reference: ORPHA:244
    reference_title: "Primary ciliary dyskinesia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0005425 | Recurrent sinopulmonary infections | Frequent (79-30%)"
    explanation: >-
      Graded PARTIAL because the row is not this phenotype's own term. Orphanet
      grades HP:0005425 recurrent sinopulmonary infections, which is narrower
      than the HP:0002205 recurrent respiratory infections bound here; it is the
      nearest graded row in the table and is what the FREQUENT band rests on.
      Recorded explicitly so the mismatch is visible rather than implied.
- category: Respiratory
  name: Productive Cough
  frequency: FREQUENT
  description: >-
    The chronic wet cough that is the day-to-day clinical signature of impaired
    mucociliary clearance, and usually the earliest persistent symptom.
  phenotype_term:
    preferred_term: Productive cough
    term:
      id: HP:0031245
      label: Productive cough
    temporality: CHRONIC
  evidence:
  - reference: PMID:32490514
    reference_title: "Identification of a frame shift mutation in the CCDC151 gene in a Han-Chinese family with Kartagener syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband, a 34-year-old male with chief complaints of recurrent
      productive cough and intermittent fever, was admitted to the Third Xiangya
      Hospital, Central South University, Changsha, China.
    explanation: >-
      Productive cough as the presenting complaint in the reported CCDC151
      patient.
  - reference: ORPHA:244
    reference_title: "Primary ciliary dyskinesia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0031245 | Productive cough | Frequent (79-30%)"
    explanation: >-
      Orphanet's frequency band for productive cough in primary ciliary
      dyskinesia as a class. Not an ODAD3-specific figure.
- category: Cardiovascular
  name: Ventricular Septal Defect
  frequency: OCCASIONAL
  description: >-
    Congenital heart disease is part of the laterality arm rather than a separate
    lesion: disturbed left-right patterning at the embryonic node produces
    complex cardiac malformations as well as situs abnormalities, and the animal
    models show situs defects and complex heart defects together. Reported among
    the phenotypes seen in CCDC151 patients.

    Graded OCCASIONAL rather than left unqualified, deliberately. The source
    sentence lists this among "varied" phenotypes and adds its own caveat that
    the variation may reflect background genotype effects, epigenetic
    modifications and environmental factors - so it is describing a phenotype
    that appears in some CCDC151 patients and not others, without giving a count.
    OCCASIONAL is the most that supports; a higher band would read a frequency
    into a sentence that declines to give one.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:32490514
    reference_title: "Identification of a frame shift mutation in the CCDC151 gene in a Han-Chinese family with Kartagener syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Affected individuals with CCDC151 mutations also showed varied phenotypes,
      including dextrocardia, SI, cardiac ventricular septal defect and hearing
      disease
    explanation: >-
      A gene-specific summary of the reported CCDC151 phenotype range naming
      ventricular septal defect. Graded OTHER because it summarises the primary
      reports rather than describing the citing paper's own patient.
- category: Otological
  name: Hearing Impairment
  frequency: OCCASIONAL
  description: >-
    Conductive hearing loss follows from middle-ear disease, which follows from
    the same ciliated epithelium failing in the Eustachian tube. Recorded here
    from the gene-specific phenotype summary rather than from an individually
    described patient, and graded OCCASIONAL for the same reason as the
    ventricular septal defect above: the source lists it among varied phenotypes
    and attributes the variation to background genotype, epigenetic and
    environmental effects without giving a count.

    Note the term chosen is the general hearing-impairment term rather than a
    conductive-specific one. The mechanism above predicts conductive loss, but
    the source says only "hearing disease", and binding to the more specific term
    would assert an audiological characterisation nobody reported.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:32490514
    reference_title: "Identification of a frame shift mutation in the CCDC151 gene in a Han-Chinese family with Kartagener syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Affected individuals with CCDC151 mutations also showed varied phenotypes,
      including dextrocardia, SI, cardiac ventricular septal defect and hearing
      disease
    explanation: >-
      The same gene-specific phenotype summary, naming hearing disease. Graded
      OTHER for the same reason.
  - reference: ORPHA:244
    reference_title: "Primary ciliary dyskinesia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000365 | Hearing impairment | Occasional (29-5%)"
    explanation: >-
      Independent corroboration of the OCCASIONAL band already assigned here,
      which was reasoned from a narrative hedge rather than from a graded
      source. Orphanet reaches the same band for the class.
  - reference: ORPHA:244
    reference_title: "Primary ciliary dyskinesia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000405 | Conductive hearing impairment | Occasional (29-5%)"
    explanation: >-
      Orphanet grades the conductive subtype at the same band, which supports
      the mechanism this phenotype's description gives - middle-ear disease
      following from the same ciliated epithelium failing in the Eustachian
      tube - without changing the decision to bind the general HP:0000365 term,
      since the sources describing ODAD3 patients say only "hearing disease".
- category: Respiratory
  name: Chronic Sinusitis
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Chronic sinusitis
    term:
      id: HP:0011109
      label: Chronic sinusitis
  evidence:
  - reference: PMID:33719352
    reference_title: "Case Report: Identification of a Novel ODAD3 Variant in a Patient With Primary Ciliary Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 35 year-old female patient exhibited chronic sinusitis, diffuse
      bronchiectasis, dextrocardia and infertility.
    explanation: >-
      Documents chronic sinusitis in a reported ODAD3 patient.
  - reference: ORPHA:244
    reference_title: "Primary ciliary dyskinesia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0011109 | Chronic sinusitis | Frequent (79-30%)"
    explanation: >-
      Orphanet's frequency band for chronic sinusitis in the class. Not an
      ODAD3-specific figure.
- category: Cardiovascular
  name: Dextrocardia
  description: >-
    One manifestation of the randomised laterality this disease produces.
    Recorded as dextrocardia rather than as situs inversus totalis because
    dextrocardia is what the source states for this patient; the broader
    laterality spectrum is curated as its own phenotype below.
  phenotype_term:
    preferred_term: Dextrocardia
    term:
      id: HP:0001651
      label: Dextrocardia
  evidence:
  - reference: PMID:33719352
    reference_title: "Case Report: Identification of a Novel ODAD3 Variant in a Patient With Primary Ciliary Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 35 year-old female patient exhibited chronic sinusitis, diffuse
      bronchiectasis, dextrocardia and infertility.
    explanation: >-
      Documents dextrocardia in a reported ODAD3 patient.
- category: Cardiovascular
  name: Situs Inversus
  frequency: FREQUENT
  description: >-
    Situs inversus is one outcome of randomised laterality, reported in an
    independent Chinese case and in the Kartagener-syndrome family. It is not
    obligate: the MONDO term for this disease is explicitly "with or without
    situs inversus", and roughly half of PCD patients in general have normal
    situs.
  phenotype_term:
    preferred_term: Situs inversus totalis
    term:
      id: HP:0001696
      label: Situs inversus totalis
  evidence:
  - reference: PMID:30504913
    reference_title: "Whole-exome sequencing identifies a novel CCDC151 mutation, c.325G>T (p.E109X), in a patient with primary ciliary dyskinesia and situs inversus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a novel CCDC151 mutation, c.325G>T (p.E109X), in a patient
      with primary ciliary dyskinesia and situs inversus.
    explanation: >-
      An ODAD3 patient with situs inversus.
  - reference: ORPHA:244
    reference_title: "Primary ciliary dyskinesia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0001696 | Situs inversus totalis | Occasional (29-5%)"
    explanation: >-
      Graded PARTIAL because the band sits below what this entry itself states
      and what the literature reports - roughly half of PCD patients have a
      laterality defect, and situs inversus totalis is the commonest form of it.
      `frequency` is set to FREQUENT accordingly, matching how the umbrella
      `Primary Ciliary Dyskinesia` entry handles this same Orphanet row. The row
      is still worth quoting because it is the only graded source available and
      because a reader should see that the graded value and the narrative value
      disagree.
- category: Otological
  name: Recurrent Otitis Media
  frequency: FREQUENT
  description: >-
    Middle-ear disease is part of the reported CILD30 picture, and it follows
    from the same lesion: the Eustachian tube and middle-ear mucosa are lined by
    the same motile-ciliated epithelium as the airway. Curated from a
    gene-specific summary in a case report rather than from an individually
    described patient, which is why the evidence is graded OTHER.
  phenotype_term:
    preferred_term: Recurrent otitis media
    term:
      id: HP:0000403
      label: Recurrent otitis media
  evidence:
  - reference: PMID:32490514
    reference_title: "Identification of a frame shift mutation in the CCDC151 gene in a Han-Chinese family with Kartagener syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients with CILD30 may have respiratory symptoms, nasal blockages, nasal
      polyps, otitis media, and laterality defects
    explanation: >-
      A summary of the CILD30 phenotype naming otitis media. Graded OTHER
      because it is a secondary summary of the primary reports rather than an
      observation the citing paper made.
  - reference: ORPHA:244
    reference_title: "Primary ciliary dyskinesia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000403 | Recurrent otitis media | Frequent (79-30%)"
    explanation: >-
      Orphanet's frequency band for the class, and independent corroboration
      of a phenotype otherwise carried only by a gene-specific narrative
      summary.
- category: Respiratory
  name: Nasal Polyposis
  frequency: FREQUENT
  description: >-
    Nasal obstruction and polyps in the upper airway, from the same
    gene-specific summary as the otitis media above and with the same evidential
    standing.
  phenotype_term:
    preferred_term: Nasal polyposis
    term:
      id: HP:0100582
      label: Nasal polyposis
  evidence:
  - reference: PMID:32490514
    reference_title: "Identification of a frame shift mutation in the CCDC151 gene in a Han-Chinese family with Kartagener syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients with CILD30 may have respiratory symptoms, nasal blockages, nasal
      polyps, otitis media, and laterality defects
    explanation: >-
      The same CILD30 phenotype summary, naming nasal blockage and polyps.
  - reference: ORPHA:244
    reference_title: "Primary ciliary dyskinesia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0100582 | Nasal polyposis | Frequent (79-30%)"
    explanation: >-
      Orphanet's frequency band for the class, corroborating a phenotype
      otherwise carried only by a narrative summary.
- category: Respiratory
  name: Neonatal Respiratory Distress
  frequency: FREQUENT
  description: >-
    Unexplained respiratory distress in a term neonate is the earliest
    presentation of primary ciliary dyskinesia and one of the strongest reasons
    to suspect it, because the usual causes of neonatal distress do not apply to
    a term baby with no perinatal insult. Orphanet grades it Frequent across the
    disease class.

    On ODAD3 specifically: the deep-research report committed with this entry,
    which read the defining paper's full text, records it in four of the five
    patients of that series. That figure is an uncited lead - the paper's cached
    record is abstract-only and its abstract does not carry it - so the graded
    class-level band is what this phenotype is evidenced on, not the
    gene-specific fraction.
  phenotype_term:
    preferred_term: Neonatal respiratory distress
    term:
      id: HP:0002643
      label: Neonatal respiratory distress
    onset:
      onset_category: NEONATAL
  evidence:
  - reference: ORPHA:244
    reference_title: "Primary ciliary dyskinesia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0002643 | Neonatal respiratory distress | Frequent (79-30%)"
    explanation: >-
      Orphanet's graded frequency for neonatal respiratory distress in primary
      ciliary dyskinesia. The band is the class's, not ODAD3's.
- category: Reproductive
  name: Male Infertility
  frequency: FREQUENT
  description: >-
    Sperm flagella are motile axonemes carrying the same outer dynein arms and
    the same docking complex as an airway cilium, so a docking-complex defect is
    expected to impair them - and Orphanet grades male infertility Frequent
    across primary ciliary dyskinesia, a band above the Occasional it gives
    female infertility.

    The gene-specific support here is unusually strong for a phenotype curated
    from a class-level band, and it comes from the two mouse models this entry
    already carries. The constitutive Ccdc151 null shows male infertility
    alongside its laterality defects, and the adult Odad3 conditional deletion
    produces asthenoteratozoospermia with multiple morphological abnormalities of
    the sperm flagella. Neither is a human observation, which is why the class
    band carries the phenotype and the model evidence is recorded beside it.

    No ODAD3 male patient's fertility has been reported. That is a gap in the
    literature rather than evidence of absence, and it is the same gap the
    open discussion on heterozygous carriers turns on.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: ORPHA:244
    reference_title: "Primary ciliary dyskinesia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0003251 | Male infertility | Frequent (79-30%)"
    explanation: >-
      Orphanet's graded frequency for male infertility in primary ciliary
      dyskinesia, and the band that carries this phenotype. It is the class's,
      not ODAD3's.
  - reference: PMID:31383820
    reference_title: "Functional loss of Ccdc151 leads to hydrocephalus in a mouse model of primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Congenital defects in left-right asymmetry and male infertility have been
      also observed in Ccdc151-null animals.
    explanation: >-
      Gene-specific support from the constitutive null, which is what raises this
      above a phenotype carried by a class band alone.
- category: Reproductive
  name: Abnormal Sperm Motility
  frequency: FREQUENT
  description: >-
    The mechanism behind the infertility above, and the level at which this
    disease's lesion is directly visible in a gamete: the flagellar axoneme is
    built without its outer dynein arms, so it cannot generate the sliding force
    to beat.

    Curated separately from male infertility because the two are not the same
    claim and the models separate them. Deleting Odad3 in adult males gives
    abnormal sperm morphology and motility short of complete azoospermia,
    whereas the constitutive null has no sperm in the reproductive tract at all -
    so motility failure and infertility can come apart depending on when the
    gene is lost.
  phenotype_term:
    preferred_term: Abnormal sperm motility
    term:
      id: HP:0012206
      label: Abnormal sperm motility
  evidence:
  - reference: ORPHA:244
    reference_title: "Primary ciliary dyskinesia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0012206 | Abnormal sperm motility | Frequent (79-30%)"
    explanation: >-
      Orphanet's graded frequency for abnormal sperm motility in the class.
  - reference: PMID:31383820
    reference_title: "Functional loss of Ccdc151 leads to hydrocephalus in a mouse model of primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Ccdc151 gene deletion in adult animals results in abnormal sperm counts
      and defective sperm motility.
    explanation: >-
      The adult-deletion measurement, which isolates the motility defect from the
      developmental absence of sperm seen in the constitutive null.
- category: Reproductive
  name: Female Infertility
  frequency: OCCASIONAL
  description: >-
    Reported in the 35-year-old ODAD3 patient, and flagged by that paper as the
    first such report for this gene. Female subfertility in PCD is attributed to
    the motile cilia of the fallopian tube rather than to a gamete defect, but
    that attribution was not tested in this patient, so the node records the
    observation rather than the mechanism.
  phenotype_term:
    preferred_term: Female infertility
    term:
      id: HP:0008222
      label: Female infertility
  evidence:
  - reference: PMID:33719352
    reference_title: "Case Report: Identification of a Novel ODAD3 Variant in a Patient With Primary Ciliary Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The 35 year-old female patient exhibited chronic sinusitis, diffuse
      bronchiectasis, dextrocardia and infertility.
    explanation: >-
      Records infertility in the reported female patient. The paper separately
      states that female infertility in ODAD3-related PCD had not previously been
      reported, but that sentence evidences novelty rather than the phenotype and
      is not used here.
  - reference: ORPHA:244
    reference_title: "Primary ciliary dyskinesia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0008222 | Female infertility | Occasional (29-5%)"
    explanation: >-
      Orphanet grades female infertility Occasional for the class. Recorded
      alongside the individually described ODAD3 patient, and worth comparing
      with male infertility below, which Orphanet grades Frequent.
biochemical:
- name: Nasal Nitric Oxide
  presence: Decreased
  reference_ranges:
  - lower_bound: 77.0
    unit: nl/min
    population: patients assessed for primary ciliary dyskinesia
    notes: >-
      A one-sided diagnostic threshold rather than a laboratory normal interval,
      which is why `upper_bound` is unset: values at or above 77 nl/min argue
      against PCD, and there is no upper limit at which the test becomes abnormal
      again. `loinc_term` is likewise unset - nasal nitric oxide has no LOINC
      code in the caches this repository carries, and inventing one would be
      worse than leaving it out.
    interpretation_bands:
    - name: Below the PCD diagnostic cut-off
      upper_bound: 77.0
      unit: nl/min
      abnormal_flag: LOW
      interpretation: >-
        Supports referral for ciliary ultrastructural and genetic testing. It
        does not diagnose PCD on its own and says nothing about which gene. The
        reported ODAD3 patient measured 6 nl/min, an order of magnitude below the
        threshold rather than marginally under it.
    - name: At or above the PCD diagnostic cut-off
      lower_bound: 77.0
      unit: nl/min
      abnormal_flag: NORMAL
      interpretation: >-
        Argues against PCD, though it does not exclude it - some genotypes,
        notably RSPH1, retain higher nasal nitric oxide.
    evidence:
    - reference: PMID:33719352
      reference_title: "Case Report: Identification of a Novel ODAD3 Variant in a Patient With Primary Ciliary Dyskinesia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Her nasal nitric oxide concentration (nNO) (6 nl/min) was far below the
        reference nNO cutoff value of PCD (77 nl/min)
      explanation: >-
        The source of both the cut-off and the patient value.
  notes: >-
    The first-line screening test for primary ciliary dyskinesia, and the one
    ODAD3-specific diagnostic number that exists. Nasal nitric oxide is
    characteristically very low in PCD for reasons that remain unsettled, and the
    reported ODAD3 patient measured 6 nl/min against a PCD cut-off of 77 - not
    marginally low but an order of magnitude below the threshold.

    Curated here because it meets this entry's own standard, which the rest of
    the entry applies strictly: it has been measured in this genotype. That makes
    it stronger evidence than several class-level statements the entry does
    carry, and omitting it while keeping those would have been inconsistent.

    Two limits. It is one patient, so the value bounds nothing; and a low nasal
    NO does not identify ODAD3 or even confirm PCD on its own - it selects
    patients for the ultrastructural and genetic testing that does.
  evidence:
  - reference: PMID:33719352
    reference_title: "Case Report: Identification of a Novel ODAD3 Variant in a Patient With Primary Ciliary Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her nasal nitric oxide concentration (nNO) (6 nl/min) was far below the
      reference nNO cutoff value of PCD (77 nl/min)
    explanation: >-
      The measured value in the reported ODAD3 patient, against the diagnostic
      cut-off.
genetic:
- name: ODAD3
  gene_term:
    preferred_term: ODAD3
    term:
      id: hgnc:28303
      label: ODAD3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  notes: >-
    The gene's approved symbol changed from CCDC151 to ODAD3 when the outer
    dynein arm docking complex members were renamed as a family (ODAD1 =
    CCDC114, ODAD2 = ARMC4, ODAD3 = CCDC151, ODAD4 = TTC25). This matters for
    literature searching: the defining 2014 paper, the mouse hydrocephalus model
    and the zebrafish work are all published under CCDC151, while the 2021 case
    report and the 2024 mouse fertility work use ODAD3. A search on either symbol
    alone misses roughly half the literature.

    Reported alleles, all loss-of-function. Quotable here: c.925G>T p.(Glu309*),
    homozygous in a consanguineous Arabic family; c.325G>T p.(Glu109*) in
    mainland China; c.167delG p.(Gly56Aspfs*26) in a Han-Chinese Kartagener
    family; and c.1166_1169dupAGAC p.(Leu391Aspfs*105) in a consanguineous
    Chinese family.

    The defining 2014 series' own two alleles are reported but not quotable,
    because that paper's cached record is abstract-only and its abstract gives no
    variant. As uncited leads from the deep-research report committed with this
    entry, which read the full text: c.925G>T p.(Glu309*) - the same allele
    independently reported above - in two unrelated Arabic-origin pedigrees, and
    c.1256C>A p.(Ser419*) in a consanguineous UK-Pakistani family.

    Both of those alleles are transcribed inconsistently in the secondary
    literature, in two independent ways, and a curator should expect it. At the
    nucleotide level the deep-research report warns that some summaries render
    the second change as C>T where the primary full text gives C>A. At the
    protein level the 2021 review cited on the trigger node lists the same two
    Hjeij alleles as p.(Gly309*) and p.(Ser409*), against p.(Glu309*) and
    p.(Ser419*) as given here and elsewhere. Neither discrepancy is resolvable
    from the cached records, since the primary paper is abstract-only; take the
    variant from the primary full text rather than from any review.

    No missense allele has been reported, so there is no worked example of a
    partial loss-of-function ODAD3 variant to reason from when a new missense
    change turns up.

    On the founder question, the two published opinions differ and neither is
    conclusive. The recurrent c.925G>T allele appeared in two unrelated
    Arabic-ancestry pedigrees, which is suggestive; the independent report of the
    same allele found it absent from 238 controls and read that as arguing
    against a founder effect. Absence from a small control panel shows the allele
    is rare, which is not the same question - a founder allele can be rare. No
    haplotype analysis has been published either way.
  evidence:
  - reference: PMID:25224326
    reference_title: "Nonsense mutation in coiled-coil domain containing 151 gene (CCDC151) causes primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The variant was absent in 238 randomly selected individuals indicating that
      the variant is rare and likely not to be a founder mutation.
    explanation: >-
      The published argument against a founder effect, quoted so a reader can see
      what it actually rests on.
  - reference: PMID:33719352
    reference_title: "Case Report: Identification of a Novel ODAD3 Variant in a Patient With Primary Ciliary Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a novel homozygous variant in ODAD3, c.1166_1169dupAGAC,
      p.(Leu391Aspfs*105) in the PCD patient by exome sequencing and Sanger
      sequencing.
    explanation: >-
      One of the reported frameshift alleles.
  - reference: PMID:32490514
    reference_title: "Identification of a frame shift mutation in the CCDC151 gene in a Han-Chinese family with Kartagener syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the present study, we identified a frame shift mutation, c.167delG
      (p.G56Dfs*26), in the coiled-coil domain containing 151 gene (CCDC151)
      responsible for KS in a Han-Chinese family.
    explanation: >-
      A further frameshift allele, reported under the CCDC151 symbol.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Fewer than a dozen patients: five individuals from three families in the
    defining series, plus single independently reported cases from Arabic,
    mainland Chinese and Han-Chinese families. No ODAD3-specific prevalence
    estimate exists, and none should be derived from the PCD population figure
    (commonly quoted as roughly 1 in 10,000 to 1 in 20,000 live births) by
    division, because the share of PCD attributable to any single one of the
    fifty-odd known genes has not been established for ODAD3.
  evidence:
  - reference: PMID:25192045
    reference_title: "CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified CCDC151 loss-of-function mutations in five affected
      individuals from three independent families
    explanation: >-
      The defining series and its size.
  - reference: PMID:33719352
    reference_title: "Case Report: Identification of a Novel ODAD3 Variant in a Patient With Primary Ciliary Dyskinesia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The estimated prevalence of PCD is 1:10 000 to 1:20 000 live-born children
    explanation: >-
      The prevalence of the disease class, given for context. It is not this
      entity's prevalence.
  - reference: ORPHA:244
    reference_title: "Primary ciliary dyskinesia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "1-9 / 100 000 | Europe | Prevalence at birth | PMID:23871404"
    explanation: >-
      Orphanet's birth-prevalence class for primary ciliary dyskinesia as a
      whole. Recorded for context, and to make the point that Orphanet holds one
      epidemiological record for the entire disease rather than per gene - the
      same record that lists 53 causal genes including ODAD3.
animal_models:
- name: Ccdc151 knockout mouse (targeted gene deletion)
  species: Mouse
  genotype: Ccdc151 targeted deletion, homozygous null
  publication: PMID:31383820
  description: >-
    A targeted-deletion mouse null for Ccdc151. It reproduces the laterality
    defect and the male infertility of human ODAD3 disease, and adds a phenotype
    the human disease does not have: perinatally lethal communicating
    hydrocephalus. A beta-galactosidase reporter localises the gene's expression
    to the ependymal cells lining the ventricular system, which explains the
    hydrocephalus mechanistically - the ependymal motile cilia that drive
    cerebrospinal fluid flow are the same machinery - without making it a human
    finding.
  modeled_mechanisms:
  - target: Randomised Left-Right Body Asymmetry
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Congenital left-right asymmetry defects occur in the null animals, matching
      the human laterality phenotype and its nodal-cilia mechanism.
    limitations: >-
      Perinatal lethality means the model cannot be followed into the chronic
      airway disease that dominates the human illness, so its usefulness is
      confined to developmental phenotypes.
    readouts:
    - name: Left-right asymmetry in Ccdc151-null animals
      target: Randomised Left-Right Body Asymmetry
      direction: ALTERED
      interpretation: >-
        Presence of congenital laterality defects in the null, matching the human
        phenotype.
      evidence:
      - reference: PMID:31383820
        reference_title: "Functional loss of Ccdc151 leads to hydrocephalus in a mouse model of primary ciliary dyskinesia."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Congenital defects in left-right asymmetry and male infertility have
          been also observed in Ccdc151-null animals.
        explanation: >-
          The laterality observation in the null mouse.
    evidence:
    - reference: PMID:31383820
      reference_title: "Functional loss of Ccdc151 leads to hydrocephalus in a mouse model of primary ciliary dyskinesia."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The CCDC151 gene encodes for a coiled-coil axonemal protein that ensures
        correct attachment of outer dynein arm (ODA) complexes to microtubules.
      explanation: >-
        Establishes that the gene has the same molecular role across species,
        which is what makes the model informative for this node. Graded OTHER
        because it is background prose from the paper's introduction rather than
        a result measured in the mouse.
  - target: Motile Ciliary Beat Failure
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      The null reproduces motile-cilia failure in the ependyma and the male
      reproductive tract, but the tissue whose failure defines the human disease
      - the conducting airway - cannot be assessed because the animals die
      perinatally.
    limitations: >-
      Perinatal lethality from hydrocephalus prevents any study of chronic airway
      disease, bronchiectasis, or the natural history that constitutes most of
      the human illness. The dominant phenotype of the model is one the human
      disease does not have; see the HUMAN_MODEL_MISMATCH discussion.
    readouts:
    - name: Sperm count and motility after adult Ccdc151 deletion
      target: Motile Ciliary Beat Failure
      direction: DECREASED
      interpretation: >-
        Deleting the gene in adults, which bypasses the perinatal lethality,
        gives an isolated flagellar-motility readout of the same lesion.
      evidence:
      - reference: PMID:31383820
        reference_title: "Functional loss of Ccdc151 leads to hydrocephalus in a mouse model of primary ciliary dyskinesia."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Ccdc151 gene deletion in adult animals results in abnormal sperm counts
          and defective sperm motility.
        explanation: >-
          The adult-deletion motility measurement.
    evidence:
    - reference: PMID:31383820
      reference_title: "Functional loss of Ccdc151 leads to hydrocephalus in a mouse model of primary ciliary dyskinesia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, we demonstrate that loss of Ccdc151 gene function via targeted gene
        deletion in mice leads to perinatal lethality and congenital
        hydrocephalus.
      explanation: >-
        Graded PARTIAL because this is the limitation on the link as much as
        support for it: the phenotype that dominates the model is not the
        phenotype that dominates the disease.
- name: Odad3 conditional knockout mouse (adult male)
  species: Mouse
  genotype: Odad3 conditional deletion in adult males; and Odad3 heterozygous null
  publication: PMID:38920681
  description: >-
    A conditional deletion that removes Odad3 in adult males and so escapes the
    perinatal lethality of the constitutive null. It gives the only detailed
    account of what ODAD3 loss does to a flagellum: asthenoteratozoospermia with
    multiple morphological abnormalities of the sperm flagella, and
    spermatogenesis arrested at the spermiogenesis and spermiation stages. The
    same study reports a heterozygote effect - reduced sperm count and motility,
    abnormal morphology, and a shorter fertile lifespan in Odad3+/- males - which
    is a gene-dosage claim with no human counterpart and is the subject of an
    open discussion below.
  modeled_mechanisms:
  - target: Motile Ciliary Beat Failure
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The sperm flagellum is a motile axoneme with the same outer dynein arm and
      docking machinery as an airway cilium, so flagellar failure in this model is
      the same lesion read out in a different cell. The model additionally shows
      that Odad3 loss disrupts flagellar *morphogenesis*, not only motility.
    limitations: >-
      Fidelity is graded MODERATE, not HIGH, for two reasons. The readout is a
      single motile cell type and not the multiciliated airway epithelium whose
      failure defines the human disease. And the conditional deletion is imposed
      on an adult animal whose spermatogenic machinery developed normally, which
      is not the situation of a patient who has lacked ODAD3 since conception.
    readouts:
    - name: Sperm flagellar morphology and motility after adult Odad3 ablation
      target: Motile Ciliary Beat Failure
      direction: ALTERED
      interpretation: >-
        Multiple morphological abnormalities of the flagella with impaired
        motility, in an axoneme built without ODAD3.
      evidence:
      - reference: PMID:38920681
        reference_title: "The Odad3 Gene Is Necessary for Spermatozoa Development and Male Fertility in Mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          we conditionally deleted the Odad3 gene in adult males and demonstrated
          that even partial ablation of the Odad3 gene leads to
          asthenoteratozoospermia with multiple morphological abnormalities of
          sperm flagella (MMAF) in mice
        explanation: >-
          The flagellar phenotype underlying this readout.
    evidence:
    - reference: PMID:38920681
      reference_title: "The Odad3 Gene Is Necessary for Spermatozoa Development and Male Fertility in Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Previously, we demonstrated that knockout of the Odad3 gene in mice
        replicates several features of PCD, such as hydrocephalus, defects in
        left-right body symmetry, and male infertility, with a complete absence
        of sperm in the reproductive tract.
      explanation: >-
        Establishes the model lineage and which human features the mouse
        reproduces, which is what makes it informative for this node.
- name: Ccdc151 morphant zebrafish
  species: Zebrafish
  genotype: ccdc151 morpholino knockdown; and homozygous ccdc151(ts272a)
  publication: PMID:24067530
  description: >-
    The zebrafish work that identified CCDC151 as an outer-dynein-arm docking
    protein before any human patient was known - it shares ancient features with
    the outer dynein arm-docking complex 2 of Chlamydomonas. Depletion gives
    left-right asymmetry defects and kidney cysts, and the motility defect was
    localised to the two motile-ciliated structures that matter: Kupffer's
    vesicle, the fish left-right organiser, and the pronephros.
  modeled_mechanisms:
  - target: Outer Dynein Arm Docking Complex Assembly Failure
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Ccdc151 depletion impairs motile ciliary function by controlling dynein arm
      assembly, which is the same molecular step as the human lesion, established
      in this species before the human disease existed.
    limitations: >-
      Morpholino knockdown is transient and incomplete rather than a null, and
      the same study reports that vertebrate CCDC151 has acquired functions
      beyond motility - a role in oriented cell division in the pronephros and in
      the regulation of primary cilium length in mammalian cells. Those
      additional functions are not part of the human PCD phenotype, so a
      zebrafish phenotype cannot be assumed to be the motility phenotype.
    readouts:
    - name: Dynein arm assembly in Kupffer's vesicle and pronephric cilia
      target: Outer Dynein Arm Docking Complex Assembly Failure
      direction: DECREASED
      interpretation: >-
        Loss of motile function attributable to defective dynein arm assembly in
        the two motile-ciliated organs assayed.
      evidence:
      - reference: PMID:24067530
        reference_title: "The coiled-coil domain containing protein CCDC151 is required for the function of IFT-dependent motile cilia in animals."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          We demonstrate that Ccdc151 is required for proper motile function of
          cilia in the Kupffer's vesicle and in the pronephros by controlling
          dynein arm assembly
        explanation: >-
          The assembly measurement underlying this readout.
    evidence:
    - reference: PMID:24067530
      reference_title: "The coiled-coil domain containing protein CCDC151 is required for the function of IFT-dependent motile cilia in animals."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We identified a previously uncharacterized coiled-coil domain containing
        protein CCDC151, which is evolutionarily conserved in motile ciliated
        species and shares ancient features with the outer dynein arm-docking
        complex 2 of Chlamydomonas.
      explanation: >-
        Establishes the protein's identity as a docking-complex component,
        conserved from the alga that defined the structure.
diagnosis:
- name: Nasal Nitric Oxide Screening
  description: >-
    What happens before the electron microscope. Nasal nitric oxide is the
    first-line screen for PCD, and it was very low in the reported ODAD3 patient
    - 6 nl/min against a cut-off of 77. It is a triage test, not a diagnosis: it
    selects who goes on to ultrastructural and genetic testing, and it neither
    identifies the gene nor, on its own, confirms the disease.
  evidence:
  - reference: PMID:33719352
    reference_title: "Case Report: Identification of a Novel ODAD3 Variant in a Patient With Primary Ciliary Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Her nasal nitric oxide concentration (nNO) (6 nl/min) was far below the
      reference nNO cutoff value of PCD (77 nl/min)
    explanation: >-
      The screening result in the reported ODAD3 patient.
- name: Ultrastructural and Immunofluorescence Assessment of Outer Dynein Arms
  description: >-
    ODAD3 disease is one of the PCD forms that a diagnostic laboratory can
    localise before sequencing. Electron microscopy shows outer dynein arms
    missing with inner arms preserved, and immunofluorescence shows the
    docking-complex members and the outer-arm heavy chain DNAH5 absent from the
    axoneme. That pattern narrows the genetic differential to the ODA and
    ODA-docking genes, which is a useful reduction from the fifty-odd PCD genes.

    What it cannot do is name ODAD3. The docking complex fails as a unit, so a
    defect in any of its members produces the same immunofluorescence picture -
    which is why the diagnosis is completed by sequencing.
  evidence:
  - reference: PMID:25192045
    reference_title: "CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cause a failure in axonemal assembly of the ODA component DNAH5 and the
      ODA-DC-associated components CCDC114 and ARMC4
    explanation: >-
      The immunofluorescence pattern that identifies a docking-complex defect,
      and the reason it cannot discriminate between the complex's members.
differential_diagnoses:
- name: Other outer dynein arm docking complex deficiencies (ODAD1, ODAD2, ODAD4)
  description: >-
    The closest differential, and the one that ultrastructure cannot resolve.
    ODAD1 (CCDC114), ODAD2 (ARMC4) and ODAD4 (TTC25) are the other members of the
    same complex, and defects in any of them give outer dynein arm loss with
    randomised laterality. ODAD3 is distinguished from them only by sequencing.
    Note that this knowledge base currently curates ODAD1 as a causal gene on the
    umbrella `Primary Ciliary Dyskinesia` entry rather than as its own disease
    entry, so a reader looking for its counterpart to this file will not find
    one.
  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: HUMAN_CLINICAL
    snippet: >-
      Additionally, IF analyses revealed an absence of the ODA docking complex
      (ODA-DC), along with its known components CCDC114, CCDC151, and ARMC4.
    explanation: >-
      A different docking-complex gene's defect removes ODAD3 (CCDC151) from the
      axoneme along with the rest of the complex - which is precisely why
      immunofluorescence cannot discriminate ODAD3 disease from its siblings.
- name: Non-genetic causes of chronic suppurative airway disease
  description: >-
    The differential a clinician actually works through before any of the genetic
    ones become relevant. A child with a chronic wet cough, recurrent infection
    and bronchiectasis is far more likely to have cystic fibrosis, an antibody
    deficiency or recurrent aspiration than a motile ciliopathy, and all three
    were excluded in the reported Kartagener case before ciliary testing.

    The feature that redirects the workup toward PCD is laterality: situs
    inversus or heterotaxy belongs to none of these three, and its presence in a
    patient with suppurative airway disease is close to diagnostic of a
    motile-cilia disorder. Its absence excludes nothing, though - roughly half of
    PCD patients have normal situs, and this disease's own MONDO term is
    explicitly "with or without situs inversus".
  evidence:
  - reference: PMID:32490514
    reference_title: "Identification of a frame shift mutation in the CCDC151 gene in a Han-Chinese family with Kartagener syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cystic fibrosis, primary immunodeficiency diseases, and aspiration
      pneumonia were excluded
    explanation: >-
      The exclusions performed in a reported CCDC151 patient before the ciliary
      diagnosis was made.
- name: Outer dynein arm heavy-chain and dynein-preassembly deficiencies
  description: >-
    DNAH5 and other outer-arm components give outer dynein arm loss directly
    rather than through a docking failure, and are clinically indistinguishable.
    The dynein-preassembly factors are separable on ultrastructure, because they
    remove inner arms as well as outer ones - which is exactly the distinction
    that the HPO term chosen for the phenotype above preserves.
  evidence:
  - reference: PMID:25192045
    reference_title: "CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In humans, defects in ODA assembly are the major cause of primary ciliary
      dyskinesia (PCD), an inherited disorder of ciliary and flagellar
      dysmotility characterized by chronic upper and lower respiratory infections
      and defects in laterality.
    explanation: >-
      Establishes that outer-arm assembly defects as a class are the largest
      slice of the PCD differential.
discussions:
- discussion_id: pcd30_mouse_hydrocephalus_not_human
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why is hydrocephalus the lethal phenotype of the Ccdc151-null mouse when
    human ODAD3 patients survive to adulthood without it?
  attaches_to:
  - "pathophysiology#Motile Ciliary Beat Failure"
  - "animal_models#Ccdc151 knockout mouse (targeted gene deletion)"
  rationale: >-
    Curated as HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP because the
    evidence is not missing. The mouse phenotype is well characterised: targeted
    deletion of Ccdc151 causes perinatal lethality and congenital communicating
    hydrocephalus, with reporter expression localising the gene to the ependymal
    cells lining the ventricular system and micro-computed tomography confirming
    the aqueduct of Sylvius is patent. It is a coherent mechanism - ependymal
    motile cilia drive cerebrospinal fluid flow, and they carry the same outer
    dynein arms as airway cilia.

    The mismatch is one of frequency and severity, and it should be stated
    exactly rather than as a flat contradiction. Hydrocephalus is a recognised
    possible complication of primary ciliary dyskinesia in humans - one of the
    papers cited by this entry lists it among the consequences of ciliary
    dysfunction in the brain and spinal ependyma, alongside conductive deafness
    and subfertility. What is absent is any hydrocephalus in a reported *ODAD3*
    patient: none of the five human ODAD3 reports consulted for this entry
    describes it, and the individually described 35-year-old woman's reported
    problems are sinusitis, bronchiectasis, dextrocardia and infertility. So the
    consequence that is occasional and survivable in human PCD, and unreported in
    this genotype, is in the mouse the phenotype that kills the animal before it
    can develop the airway disease which defines the human illness.

    Orphanet puts a number on the human side: hydrocephalus is graded Very rare,
    under four percent, across primary ciliary dyskinesia as a class - against a
    mouse null in which it is the cause of death. That is the mismatch stated
    quantitatively rather than as an impression.

    This is not peculiar to ODAD3 - hydrocephalus is a recurrent feature of mouse
    motile-ciliopathy models and a rare one in human PCD. The usual explanation
    offered for that gap is anatomical, that the rodent aqueduct is narrow and
    rodent cerebrospinal-fluid circulation depends more on ependymal ciliary flow
    than the human one does. That explanation is not tested by anything cited
    here and is recorded as the standing hypothesis rather than as a finding. It
    matters well beyond this gene, because it means a mouse motile-ciliopathy
    model's most conspicuous phenotype may be its least transferable one.

    The practical consequence for this entry: hydrocephalus is not curated as a
    phenotype of PCD30, and the mouse link that carries it is graded
    PARTIALLY_RECAPITULATES with the lethality stated as a limitation.
  evidence:
  - reference: PMID:32490514
    reference_title: "Identification of a frame shift mutation in the CCDC151 gene in a Han-Chinese family with Kartagener syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      As cilia or flagella are also distributed in middle ear, sperm, fallopian
      tube, brain, and spinal ependymal, KS may be accompanied by conductive
      deafness, sub- or infertility, ectopic pregnancy, and hydrocephalus
    explanation: >-
      Graded PARTIAL because it cuts both ways: it establishes that
      hydrocephalus is a recognised human PCD complication, which is why the
      mismatch is one of frequency rather than of kind, while saying nothing
      about any ODAD3 patient. Graded OTHER because it is a background statement
      about Kartagener syndrome as a class within a case report.
  - reference: ORPHA:244
    reference_title: "Primary ciliary dyskinesia"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HP:0000238 | Hydrocephalus | Very rare (<4-1%)"
    explanation: >-
      Orphanet's graded frequency for hydrocephalus in primary ciliary
      dyskinesia, which is what makes this a mismatch of frequency rather than
      of kind: under four percent in humans as a class, against the lethal
      phenotype of the mouse null. Graded PARTIAL for the same reason as the
      item above - it establishes that hydrocephalus occurs in human PCD while
      saying nothing about any ODAD3 patient.
  proposed_experiments:
  - experiment_id: exp_pcd30_human_ventricular_imaging
    name: Systematic ventricular imaging in ODAD3 and other ODA-defect patients
    description: >-
      Measure ventricular volume and aqueductal patency in a genotyped PCD cohort
      stratified by ultrastructural defect class, and ask whether subclinical
      ventriculomegaly is present in humans at a frequency that routine care
      would miss. A positive result would make the mouse phenotype a quantitative
      rather than a qualitative mismatch.
- discussion_id: pcd30_heterozygote_fertility_effect
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Do heterozygous ODAD3 carriers have reduced male fertility, as heterozygous
    Odad3 mice do?
  attaches_to:
  - "animal_models#Odad3 conditional knockout mouse (adult male)"
  - "genetic#ODAD3"
  rationale: >-
    A gene-dosage finding in the mouse with a direct counselling implication and
    no human evidence either way.

    Odad3 heterozygous null males have reduced sperm count and motility, abnormal
    sperm morphology, and a shorter fertile lifespan. The authors state the
    finding may bear on genetic and fertility counselling for carriers, which is
    an unusually direct clinical suggestion from a mouse study.

    Nobody has looked in humans. PCD carrier parents are ascertained routinely in
    the course of diagnosing their children, so the cohort exists; semen analysis
    in fathers of ODAD3 probands would answer the question directly and has never
    been reported. Until it is, the recessive counselling given to ODAD3 families
    should not be modified, and this entry curates no carrier phenotype - the
    finding is recorded here so that a future carrier study is recognised as
    testing a prediction rather than making an incidental observation.

    One caution on how far to generalise it. The reduced fertile lifespan is an
    age-dependent effect, and mouse and human reproductive ageing are on
    different scales, so even a real human effect need not be detectable at the
    ages at which carrier fathers are typically ascertained.
  proposed_experiments:
  - experiment_id: exp_pcd30_carrier_semen_analysis
    name: Semen analysis in heterozygous ODAD3 carriers
    description: >-
      Compare sperm concentration, motility and morphology between confirmed
      heterozygous ODAD3 carriers (fathers of probands) and age-matched
      non-carrier controls, with stratification by age to test the
      fertile-lifespan component of the mouse finding.
- discussion_id: pcd30_no_gene_specific_natural_history
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does ODAD3 disease differ in course or treatment response from other forms of
    PCD?
  attaches_to:
  - "pathophysiology#Bronchiectasis and Airway Wall Destruction"
  - "phenotypes#Bronchiectasis"
  rationale: >-
    Curated as a genuine absence. There is no ODAD3-specific cohort, no lung
    function trajectory, no survival data, and no treatment study. Everything
    known about how to manage these patients comes from PCD as a class.

    That is why this entry has no `treatments:` block and no `progression:`
    block. Airway clearance, antibiotics and surveillance are the standard of
    care for PCD and would certainly be given to an ODAD3 patient, but curating
    them here would state that they have been studied in this genotype, which
    they have not, and the exported graph would not preserve the difference.
    The `Primary Ciliary Dyskinesia` umbrella entry carries the class-level
    treatment content, and that is the right place for it.

    Whether the distinction is worth drawing is itself open. Genotype-stratified
    outcome data are beginning to appear for PCD, and the ODA-defect genes are
    thought to sit at the more severe end. If that holds, ODAD3-specific
    management guidance could eventually exist; if it does not, the class-level
    content is all there will ever be.
  proposed_experiments:
  - experiment_id: exp_pcd30_genotype_stratified_outcomes
    name: Genotype-stratified outcomes for docking-complex PCD
    description: >-
      Within an international PCD registry, compare lung-function trajectory,
      exacerbation rate and age at bronchiectasis between patients with
      docking-complex defects (ODAD1-4) and other ultrastructural classes, with
      ODAD3 identified separately where numbers allow.
notes: >-
  On the OMIM identifier. This disease is MIM 616037, CILD30, recorded
  structurally in `external_assertions:` with the sentence that ties that number
  to ODAD3 disease specifically. It is worth having explicitly because the
  deep-research report committed with this entry cites the umbrella primary
  ciliary dyskinesia number, 244400, instead; a reader comparing the two should
  know which is right and that the entry knows it. Note that `mappings:` is not
  the place for it - `DiseaseMappings` carries ICD-10-CM, ICD-11, MONDO and NCIT
  only - and `external_assertions` is where OMIM disease records live in this
  knowledge base.

  On how the Orphanet frequency bands are used here, because they cut both ways
  and were briefly applied inconsistently. The rule is: an ORPHA row supplies
  `frequency:` where this entry has no gene-specific evidence bearing on it, and
  is graded SUPPORT; where gene-specific evidence in this entry contradicts the
  band, the gene-specific reading sets `frequency:` and the ORPHA row is graded
  PARTIAL with the disagreement stated. So male infertility takes the class's
  FREQUENT, because no ODAD3 male patient's fertility has been reported and the
  band is all there is; bronchiectasis takes FREQUENT against the class's
  Occasional, because both individually described ODAD3 patients have it; and
  situs inversus totalis takes FREQUENT against the same band, because roughly
  half of PCD patients have a laterality defect. An earlier revision let the
  band raise male infertility while also letting it lower bronchiectasis below
  what every described patient shows, which is the same rule applied in one
  direction only. Both of the raised values match how the umbrella
  `Primary Ciliary Dyskinesia` entry grades these identical Orphanet rows.

  On neonatal respiratory distress, and a mistake worth recording rather than
  quietly deleting. An earlier version of this block said the phenotype could not
  be curated because it was not quotable, and that the only way to add it was
  journal access to the 2014 paper. The premise was true - the defining paper's
  cached record is `content_type: abstract_only` and its abstract does not carry
  the finding - but the conclusion was wrong. Orphanet grades it, and
  `references_cache/ORPHA_244.md` was already committed here and already cited by
  this entry's `prevalence:` block. The phenotype is now curated from that row.

  The reason this is written down is that it was the second instance of one
  pattern in this entry: a section excluded on a confident claim about what the
  repository could supply, where the premise was checked and the conclusion was
  not. The first was the OMIM identifier, excluded from `mappings:` on the
  correct observation that `DiseaseMappings` has no OMIM slot and the incorrect
  inference that nothing else took one - `external_assertions` did, and 168
  files already used it. Before writing that something cannot be curated, check
  the caches this entry already cites.

  On GeneReviews. PMID:20301301 ("Primary Ciliary Dyskinesia") is the applicable
  chapter and is tagged in the top-level `references:` block. It is deliberately
  not cited as evidence: its cached record carries only the chapter's statement
  of purpose and no clinical content, so a snippet from it would attest to the
  chapter's aims rather than to a fact about ODAD3 disease. It is also written at
  the level of PCD as a class rather than of any gene.

  Scope decision, recorded because the alternative was defensible. This entity
  could have been curated as a `has_subtypes` entry on `Primary Ciliary
  Dyskinesia`, which is where the knowledge base currently keeps ODAD1
  (CCDC114) - the paralogous member of the very same docking complex, listed as a
  causal gene in that entry's `genetic:` block. Curating ODAD3 as a separate
  Disease therefore creates an asymmetry between two subunits of one structure,
  and a reader is entitled to notice it. The right resolution is to promote
  ODAD1 later, not to demote ODAD3, for a structural reason: the `Subtype` class
  has no `pathophysiology`, no `phenotypes` and no `animal_models` slots, so a
  subtype entry could not have carried the docking-complex causal chain, the
  three model organisms, or the two discussions that make this entry worth
  having. `Primary_Ciliary_Dyskinesia_47_and_Lissencephaly` is the existing
  precedent for a numbered PCD form as a standalone entry.

  The wider question this decision implicates, which one entry cannot settle.
  There are 49 primary-ciliary-dyskinesia stubs in the curation queue and every
  one is `entry_type: UNDECIDED`, so whatever shape this file takes is likely to
  be copied dozens of times. Two things argue against copying it uncritically.
  Orphanet does not split PCD by gene at all - `references_cache/ORPHA_244.md` is
  a single disorder record listing 53 causal genes, ODAD3 among them - which is
  an independent nosological signal against a file per gene. And the umbrella
  entry's own `genotype_ultrastructure_severity` hypothesis already reasons along
  a different axis entirely, grouping genotypes by ultrastructural defect class
  rather than by OMIM number; a `has_subtypes` axis keyed on that class would
  give all 49 stubs a home and give that hypothesis something structural to
  attach to. This entry does not attempt that, because it is a class-level policy
  decision rather than a per-disease one, and it should be made by a maintainer
  with the whole queue in view. If the ruling goes that way, the content here
  transfers: the pathograph and the animal models move to the umbrella's
  ODA-defect subtype and nothing is lost but this file.

  What this entry does not duplicate. The umbrella `Primary Ciliary Dyskinesia`
  entry mentions ODAD3 already, in an animal-model block about Xenopus Lrrc56,
  where axonemal Odad3 signal is used as the readout for a different gene's
  defect. That is LRRC56 biology observed through ODAD3, not ODAD3 disease, and
  it is not repeated here.

  On the treatment and progression sections, which are absent. Airway clearance,
  antibiotics and surveillance are the standard of care and would be given to any
  of these patients, but no study has examined them in this genotype. Curating
  them here would assert an evidence base that does not exist; the class-level
  content lives on the umbrella entry and is correct there. The same reasoning
  applies to lung-function decline rates and prevalence figures quoted for PCD as
  a whole - the prevalence block cites one such figure and says explicitly that
  it is the class's and not this entity's.

  On hydrocephalus, which is also absent from the phenotypes. It is the dominant
  phenotype of the mouse null and has no human ODAD3 counterpart. It is curated
  where it belongs - on the mouse model link, with the lethality recorded as a
  limitation - and argued out in a HUMAN_MODEL_MISMATCH discussion rather than
  silently omitted.

📚

References & Deep Research

References

11

PMID:25192045

CCDC151 mutations cause primary ciliary dyskinesia by disruption of the outer dynein arm docking complex formation.