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Inheritance

1

Autosomal recessive inheritance HP:0000007

Disease requires homozygous or compound heterozygous DNAH5 variants. The first locus was mapped by homozygosity in a consanguineous family.

Autosomal recessive inheritance

Show evidence (2 references)

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

"primary ciliary dyskinesia 3, with or without situs inversus is an autosomal recessive disorder caused by homozygous or compound heterozygous mutation in the DNAH5 gene"

ClinGen expert panel statement of the inheritance mode.

PMID:11062149 SUPPORT Human Clinical

"We localized a new gene locus for PCD to a region of homozygosity by descent on chromosome 5p15-p14"

Homozygosity-by-descent mapping in a consanguineous family is consistent with recessive inheritance.

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Pathophysiology

7

Biallelic DNAH5 Loss of Function

Nonsense, frameshift, splice and missense alleles, including several founder alleles, abolish functional DNAH5, the gamma heavy chain of the outer dynein arm.

DNAH5 hgnc:2950

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

minus-end-directed microtubule motor activity GO:0008569 ↓ DECREASED

Downstream

Failure of DNAH5 Incorporation into the Ciliary Axoneme

Show evidence (2 references)

PMID:11788826 SUPPORT Human Clinical

"Sequence analysis in individuals with PCD with randomization of LR asymmetry identified mutations resulting in non-functional DNAH5 proteins."

The defining study found DNAH5 alleles predicted to give non-functional protein.

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

"The mechanism of pathogenicity in DNAH5 mutations appears to be bi-allelic loss of function."

ClinGen summary of the disease mechanism.

Failure of DNAH5 Incorporation into the Ciliary Axoneme

Mutant DNAH5 is absent from the respiratory ciliary axoneme and instead accumulates at the microtubule-organizing centres. Some 3' splice alleles leave DNAH5 in the proximal axoneme only.

multiciliated respiratory epithelial cell CL:0005012

outer dynein arm assembly GO:0036158 ↓ DECREASED

Downstream

Loss of Outer Dynein Arms from Respiratory Cilia

Show evidence (2 references)

PMID:16627867 SUPPORT Human Clinical

"High-resolution immunofluorescence imaging of respiratory epithelial cells from eight patients with DNAH5 mutations showed mislocalization of mutant DNAH5 and accumulation at the microtubule organizing centers."

Mutant DNAH5 is not delivered into the axoneme.

PMID:16627867 SUPPORT Human Clinical

"Mutant DNAH5 was absent throughout the ciliary axoneme in seven patients and remained detectable in the proximal ciliary axoneme in one patient carrying compound heterozygous splicing mutations at the 3'-end"

Whole-length loss is the rule; 3' splice alleles can spare the proximal axoneme.

Loss of Outer Dynein Arms from Respiratory Cilia

Electron microscopy shows absent outer dynein arms. Some cohorts also report combined outer and inner arm defects.

multiciliated respiratory epithelial cell CL:0005012

outer dynein arm GO:0036157

Animal models

Mdnah5 insertional mutant mouse Mouse recapitulates Loss of axonemal outer arms, as in patients.

Downstream

Immotile Respiratory and Nodal Cilia

Absent Outer Dynein Arms

Show evidence (2 references)

PMID:16627867 SUPPORT Human Clinical

"Electron microscopic analyses in 22 patients with PCD with mutations invariably detected outer dynein arm ciliary defects."

Outer dynein arm loss in every DNAH5 patient examined.

PMID:19357118 SUPPORT Human Clinical

"these DNAH5 mutations were mainly associated with outer + inner dyneins arm ultrastructural defects (50%)"

A second cohort recorded combined outer and inner arm defects in half of DNAH5 patients.

Immotile Respiratory and Nodal Cilia

Without outer dynein arms the cilia lose their main force generator. Cilia lacking DNAH5 along their whole length are immotile; cilia that lack it only distally keep some motility.

multiciliated respiratory epithelial cell CL:0005012

cilium movement GO:0003341 ↓ DECREASED

Downstream

Impaired Mucociliary Clearance

Randomization of Left-Right Body Asymmetry

Efferent Duct Cilia Dysmotility

Immotile cilia

Show evidence (2 references)

PMID:15750039 SUPPORT Human Clinical

"Cilia with complete axonemal DNAH5 deficiency were immotile, whereas cilia with distal DNAH5 deficiency showed residual motility."

Links the extent of DNAH5 loss to the beat defect.

PMID:11062149 SUPPORT Human Clinical

"Direct examination of the respiratory cilia revealed ciliary akinesia. Electron microscopic examination of cilia showed absence of the outer dynein arms."

Akinetic cilia with absent outer dynein arms in the index family.

Impaired Mucociliary Clearance

Immotile airway cilia cannot clear mucus from the nose, sinuses, middle ear and bronchi, which leads to chronic infection.

mucociliary clearance GO:0120197 ↓ DECREASED

respiratory airway UBERON:0001005

Animal models

Mdnah5 insertional mutant mouse Mouse partially recapitulates Recurrent respiratory infections, with hydrocephalus and perinatal death.

Downstream

Neonatal respiratory distress

Chronic wet cough

Chronic nasal congestion and rhinosinusitis

Recurrent otitis media

Conductive hearing impairment

Recurrent respiratory infections

Bronchiectasis

Show evidence (1 reference)

PMID:11788826 SUPPORT Human Clinical

"Primary ciliary dyskinesia (PCD, MIM 242650) is characterized by recurrent infections of the respiratory tract due to reduced mucociliary clearance"

Background statement in the DNAH5 gene-discovery paper linking ciliary dysfunction to infection through reduced clearance.

Randomization of Left-Right Body Asymmetry

Dnah5 is expressed at the embryonic left-right organizer. Immotile nodal cilia without outer dynein arms cannot create leftward flow, so organ situs is set at random and about half of patients have situs inversus.

determination of left/right symmetry GO:0007368 ↕ DYSREGULATED

Animal models

Mdnah5 insertional mutant mouse Mouse recapitulates Situs inversus and ciliary immotility in the mutant.

Downstream

Situs inversus totalis

Heterotaxy

Show evidence (2 references)

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

"murine Dnah5 is expressed exclusively at the mouse Left Right Organizer (LRO) during early embryogenesis, consistent with the hypothesis that laterality defects (situs inversus) linked to DNAH5 mutations in humans may result from immotile LRO monocilia with defective outer dynein arms"

ClinGen summary of the expression evidence linking DNAH5 to laterality.

PMID:11062149 SUPPORT Human Clinical

"Two of four affected individuals exhibited a situs inversus, typical for Kartagener syndrome, due to randomization of the left/right body axis."

Randomized situs in the index family.

Efferent Duct Cilia Dysmotility

Sperm flagella do not depend on DNAH5, so sperm motility is normal. Motile cilia of the efferent ducts do depend on it; when they are immotile, sperm accumulate in the ducts and the ejaculate sperm count falls.

Animal models

Dnah5-deficient mouse (male reproductive tract) Mouse recapitulates Immotile efferent duct cilia and sperm accumulation, with normal sperm.

Downstream

Oligozoospermia

Show evidence (2 references)

PMID:15750039 SUPPORT Human Clinical

"In contrast to respiratory cilia, sperm tails from a patient with DNAH5 mutations had normal ODA heavy chain distribution"

Sperm flagella keep their outer dynein arm heavy chains in DNAH5 disease.

PMID:33561200 SUPPORT Human Clinical

"human individuals with loss-of-function DNAH5 mutations present with reduced sperm count in the ejaculate (oligozoospermia) and dilatations of the epididymal head but normal sperm motility, similar to DNAH5 deficient mice"

The human reproductive phenotype and the efferent duct mechanism behind it.

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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

12

Cardiovascular 1

Situs inversus totalis FREQUENT HP:0001696

Show evidence (1 reference)

PMID:11788826 SUPPORT Human Clinical

"Half of the affected offspring have situs inversus (reversed organs), which results from randomization of left-right (LR) asymmetry."

Situs inversus in half of PCD patients, the population in which DNAH5 was identified.

Ear 2

Recurrent otitis media FREQUENT HP:0000403

Show evidence (1 reference)

PMID:22184204 SUPPORT INDIRECT Human Clinical

"Most patients had neonatal respiratory distress (70%), recurrent otitis media (82%), sinusitis (95%), and bronchiectasis (70%) by chest CT scan"

Frequency in a mixed-genotype PCD cohort of 195 patients that included many with outer dynein arm defects; no DNAH5-specific otitis figure was found, so the claim is inferred from PCD as a whole.

Conductive hearing impairment HP:0000405

Show evidence (2 references)

PMID:38891105 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Conductive hearing loss has been seen in up to two-thirds of children with PCD"

Review synthesis of PCD cohort studies; the figure is for PCD as a class, so it is applied to DNAH5 disease by inference.

PMID:38891105 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"No clear genotype-phenotype relationships have emerged regarding sinus disease, ear infections, and hearing loss"

Why a PCD-wide figure is used: hearing loss has not been found to vary by genotype.

Genitourinary 1

Oligozoospermia HP:0000798

Show evidence (1 reference)

PMID:33561200 SUPPORT Human Clinical

"human individuals with loss-of-function DNAH5 mutations present with reduced sperm count in the ejaculate (oligozoospermia)"

Direct observation in DNAH5 patients.

Head and Neck 1

Chronic nasal congestion and rhinosinusitis VERY_FREQUENT Chronic sinusitis HP:0011109

Show evidence (1 reference)

PMID:25493340 SUPPORT Human Clinical

"chronic cough (99%), and chronic nasal congestion (97%)"

Chronic nasal congestion in nearly all children with PCD.

Immune 1

Recurrent respiratory infections VERY_FREQUENT HP:0002205

Show evidence (1 reference)

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

"characterized by recurrent infections of the upper and lower respiratory tract, randomization of left/right body asymmetry, and subfertility"

ClinGen description of the PCD phenotype used for this curation.

Respiratory 5

Absent Outer Dynein Arms VERY_FREQUENT HP:0012256

Show evidence (1 reference)

PMID:16627867 SUPPORT Human Clinical

"Electron microscopic analyses in 22 patients with PCD with mutations invariably detected outer dynein arm ciliary defects."

22 of 22 patients had outer dynein arm defects.

Immotile cilia VERY_FREQUENT HP:0012263

Show evidence (2 references)

PMID:15750039 SUPPORT Human Clinical

"Cilia with complete axonemal DNAH5 deficiency were immotile"

High-speed video microscopy finding in DNAH5-deficient cilia.

PMID:33589394 SUPPORT Human Clinical

"A 31-year-old woman had situs inversus, bronchiectasis, family history of PCD, and compound heterozygous mutations in DNAH5. Her cilia were immotile."

Immotile cilia in a compound heterozygous DNAH5 patient.

Neonatal respiratory distress FREQUENT HP:0002643

Show evidence (1 reference)

PMID:40344341 SUPPORT Human Clinical

"Within the DNAH5 group, those with two loss-of-function variants were more likely to have NRD compared to those with possible residual function variants"

DNAH5-specific analysis of neonatal respiratory distress by variant type.

Chronic wet cough VERY_FREQUENT Productive cough HP:0031245

Temporal: CHRONIC

Show evidence (1 reference)

PMID:25493340 SUPPORT Human Clinical

"Clinical features included neonatal respiratory distress (82%), chronic cough (99%), and chronic nasal congestion (97%)."

Frequencies in a PCD cohort in which the outer dynein arm group did not differ clinically from the others.

Bronchiectasis FREQUENT HP:0002110

Show evidence (2 references)

PMID:30067075 SUPPORT Human Clinical

"Participants with CCDC39 or CCDC40 mutations (n = 34) had lower percent predicted FEV1 and weight and height z-scores than those with DNAH5 mutations (n = 36)."

DNAH5 patients have comparatively better lung function, which bears on the severity of airway damage.

PMID:33589394 SUPPORT Human Clinical

"A 31-year-old woman had situs inversus, bronchiectasis, family history of PCD, and compound heterozygous mutations in DNAH5."

Bronchiectasis in an adult DNAH5 patient.

Growth 1

Heterotaxy OCCASIONAL HP:0030853

Show evidence (2 references)

PMID:22184204 SUPPORT INDIRECT BACKGROUND Human Clinical

"Situs inversus totalis occurs in ~50% of patients (Kartagener syndrome) and situs ambiguus occurs in at least 6%."

Frequency of situs ambiguus (heterotaxy) across PCD as a whole, stated in the paper's background. No DNAH5-specific heterotaxy frequency was found, so the claim is inferred from PCD as a class.

PMID:22184204 SUPPORT INDIRECT Human Clinical

"Situs inversus and situs ambiguus were present in 80 (41%) and 15 (8%) patients, respectively."

Situs ambiguus in 8% of a mixed-genotype cohort of 195 PCD patients that included many with outer dynein arm defects; not broken down by gene.

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Genetic Associations

1

DNAH5

Gene: DNAH5 hgnc:2950 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:11788826 SUPPORT Human Clinical

"Sequence analysis in individuals with PCD with randomization of LR asymmetry identified mutations resulting in non-functional DNAH5 proteins."

Gene identification.

PMID:16627867 SUPPORT Human Clinical

"We observed clustering of mutations within five exons harboring 27 mutant alleles (52%) of the 52 detected mutant alleles."

Allelic spectrum and mutation clustering.

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Medical Actions

1

Airway Clearance and Chronic Infection Management

Action: supportive care Ontology label: Supportive Care NCIT:C15747

There is no treatment that restores ciliary function. Management is the supportive care used across primary ciliary dyskinesia: airway clearance, prompt treatment of respiratory infections, and macrolide prophylaxis, for which a randomized trial of azithromycin in PCD reduced pulmonary exacerbations. Nothing in it is specific to DNAH5. Curated as a single scoping entry rather than an itemised regimen, because no trial has enrolled by genotype and the umbrella Primary_Ciliary_Dyskinesia entry holds the detailed management block. What is DNAH5-specific is prognostic: lung function is on average better than in the CCDC39/CCDC40 class, which is curated on the bronchiectasis phenotype.

Mechanism Target:

Impaired Mucociliary Clearance — Airway clearance techniques substitute mechanically for the mucociliary transport the immotile cilia cannot provide. They do not restore ciliary function.

Recurrent respiratory infections — Antibiotics treat exacerbations, and azithromycin prophylaxis reduces their rate.

Show evidence (2 references)

PMID:38891105 SUPPORT INDIRECT REVIEW SYNTHESIS Other

"Though there are no PCD-specific approved therapies that restore ciliary function, routine airway clearance and aggressive management of infections are important to preserve lung health and minimize complications"

The supportive management used across PCD. Applied to DNAH5 disease by inference, since no genotype-stratified treatment evidence exists.

PMID:38891105 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"A European study found that people with PCD benefitted from treatment with thrice weekly azithromycin, with decreased pulmonary exacerbation rates and without an apparent increase in antibiotic resistance"

The review's summary of a randomized trial in PCD, not stratified by genotype.

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Diagnosis

4

Nasal Nitric Oxide and High-Speed Video Microscopy

Low nasal nitric oxide is the usual screen. High-speed video microscopy shows immotile or near-immotile respiratory cilia in DNAH5 disease.

Show evidence (1 reference)

PMID:27836958 SUPPORT Other

"It focuses on clinical presentation, nasal nitric oxide, analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis, transmission electron microscopy, genotyping and immunofluorescence."

The diagnostic tests recommended by the ERS guideline.

Transmission Electron Microscopy of Respiratory Cilia

Shows absent outer dynein arms. This places the patient in the outer dynein arm class but does not distinguish DNAH5 from other genes in that class.

Show evidence (1 reference)

PMID:16627867 SUPPORT Human Clinical

"Electron microscopic analyses in 22 patients with PCD with mutations invariably detected outer dynein arm ciliary defects."

TEM finding in DNAH5 disease.

Immunofluorescence Staining for DNAH5

DNAH5 is absent from the axoneme and accumulates at the microtubule-organizing centres. DNAH5 mislocalization was found in every patient with outer dynein arm defects on electron microscopy, so DNAH5 staining is a general screen for that class.

Show evidence (2 references)

PMID:15750039 SUPPORT Human Clinical

"identified DNAH5 mislocalization in all patients diagnosed with ODA defects by electron microscopy (n = 16)"

Sensitivity of DNAH5 immunofluorescence for outer dynein arm defects.

PMID:33589394 SUPPORT Human Clinical

"Defects in the outer dynein arms were revealed by transmission electron microscopy and loss of DNAH5 proteins in the entire length of axonemes using immunofluorescence (IF)."

TEM and immunofluorescence findings in a DNAH5 patient.

Genetic Testing

Panel or exome sequencing identifies biallelic DNAH5 variants. DNAH5 and DNAH11 together explain about half of genetically solved PCD families of white European ancestry.

Show evidence (1 reference)

PMID:31879361 SUPPORT Human Clinical

"white European (52% of families carry DNAH5 or DNAH11 mutations)"

Contribution of DNAH5 to genetic diagnosis in European families.

📊

Prevalence

1

PCD patients of European ancestry

Unknown

No population prevalence exists for CILD3 itself. DNAH5 is the most frequently mutated PCD gene, explaining roughly 15-24% of PCD in white patients and about half of patients with documented outer dynein arm defects. These are shares of referral PCD cohorts, not population rates.

Show evidence (3 references)

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

"The most frequently mutated gene (15-24% of Caucasian patients) in PCD is DNAH5"

ClinGen summary of the DNAH5 share of PCD.

PMID:19357118 SUPPORT Human Clinical

"mutations on both alleles of DNAH5 were identified in 15% of our clinically heterogeneous cohort of patients"

The DNAH5 share in a cohort recruited without phenotypic preselection.

PMID:16627867 SUPPORT Human Clinical

"In a preselected subpopulation with documented outer dynein arm defects (n = 47), DNAH5 mutations were identified in 53% of patients."

The DNAH5 share among patients with outer dynein arm defects.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Primary Ciliary Dyskinesia 3:

Primary Ciliary Dyskinesia 7

Overlapping Features DNAH11 disease also affects an outer dynein arm heavy chain but gives normal ultrastructure on standard electron microscopy and stiff, hyperkinetic cilia rather than immotile cilia.

Primary Ciliary Dyskinesia 40

Overlapping Features DNAH9 disease removes outer dynein arms only from the distal cilium, with subtle beating defects and mild or absent respiratory disease.

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Animal Models

2

Mdnah5 insertional mutant mouse

An insertional mutation in mouse Dnah5 reproduces the core PCD features: loss of outer dynein arms, immotile cilia, situs inversus and respiratory infection. The mice also develop hydrocephalus and die perinatally, which is far more severe than the human disease.

Species

Mouse

Genotype

Dnah5 (Mdnah5) insertional loss-of-function mutation, homozygous

Publication

PMID:11912187

Pathograph links

Loss of Outer Dynein Arms from Respiratory Cilia recapitulates fidelity: high Loss of axonemal outer arms, as in patients.

Show evidence (1 reference)

PMID:11912187 SUPPORT Model Organism

"Electron microscopic studies demonstrate the loss of axonemal outer arms."

Same ultrastructural lesion as the human disease.

Randomization of Left-Right Body Asymmetry recapitulates fidelity: high Situs inversus and ciliary immotility in the mutant.

Show evidence (1 reference)

PMID:11912187 SUPPORT Model Organism

"reproduces most of the classical features of PCD, including recurrent respiratory infections, situs inversus and ciliary immotility"

The mouse reproduces the laterality and motility phenotypes.

Impaired Mucociliary Clearance partially recapitulates fidelity: moderate Recurrent respiratory infections, with hydrocephalus and perinatal death.

Limitations: Hydrocephalus and perinatal death make the mouse more severe than the human disease, where hydrocephalus is rare and survival is normal.

Divergences from the human mechanism

species mismatch qualifying

Homozygous Mdnah5 mice develop hydrocephalus and die perinatally, whereas hydrocephalus is rare in DNAH5 patients and survival is normal. The short lifespan means the mouse shows the early airway infection phenotype but not the chronic course, bronchiectasis included, that the clearance node leads to in patients.

Show evidence (2 references)

PMID:11912187 SUPPORT Model Organism

"reproduces most of the classical features of PCD, including recurrent respiratory infections, situs inversus and ciliary immotility"

The mouse has ciliary immotility with recurrent respiratory infections, the infection phenotype that follows from failed clearance.

+ 1 more reference

Dnah5-deficient mouse (male reproductive tract)

Dnah5-deficient mice have immotile efferent duct cilia lacking outer dynein arms, sperm accumulation in the efferent ducts, and normal sperm ultrastructure and motility, matching the oligozoospermia with normal motility seen in patients.

Species

Mouse

Genotype

Dnah5 loss of function

Publication

PMID:33561200

Pathograph links

Efferent Duct Cilia Dysmotility recapitulates fidelity: high Immotile efferent duct cilia and sperm accumulation, with normal sperm.

Show evidence (1 reference)

PMID:33561200 SUPPORT Model Organism

"These mice have immotile efferent duct cilia that lack ODAs, which are essential for ciliary beat generation. Furthermore, they show accumulation of sperm in the efferent duct. Notably, the ultrastructure and motility of sperm from these males are unaffected."

The mechanism behind the human reproductive phenotype.

{ }

Source YAML

click to show

name: Primary Ciliary Dyskinesia 3
creation_date: "2026-10-14T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: primary ciliary dyskinesia 3
  term:
    id: MONDO:0012085
    label: primary ciliary dyskinesia 3
description: >-
  Primary ciliary dyskinesia 3 (CILD3) is the form of primary ciliary
  dyskinesia (PCD) caused by biallelic loss-of-function variants in DNAH5.
  DNAH5 encodes the gamma-type heavy chain of the axonemal outer dynein arm
  (ODA), the motor that generates most of the force for ciliary beating. It
  is distributed along the whole length of the respiratory cilium and is
  present in both proximal and distal ODA types. DNAH5 is the most frequently
  mutated PCD gene in patients of European ancestry.

  Mutant DNAH5 is not built into the axoneme. It accumulates at the
  microtubule-organizing centres, the outer dynein arms are missing on
  electron microscopy, and the respiratory cilia are immotile or nearly so.
  Alleles at the 3' end of the gene can leave the protein in the proximal
  axoneme only, with some residual motility. The clinical picture is typical
  PCD: neonatal respiratory distress, lifelong wet cough and rhinosinusitis,
  recurrent otitis media and bronchiectasis. About half of patients have
  situs inversus, because nodal cilia cannot generate leftward flow. Lung
  disease is milder on average than in the microtubular-disorganisation
  (CCDC39/CCDC40) class.

  Sperm flagella use a different ODA composition, so DNAH5 patients have
  normal sperm motility. Men can still be subfertile, because immotile
  efferent duct cilia let sperm accumulate in the efferent ducts and lower
  the sperm count.
parents:
- Primary Ciliary Dyskinesia
- Ciliopathy
synonyms:
- CILD3
- ciliary dyskinesia, primary, 3
- primary ciliary dyskinesia 3 with or without situs inversus
- DNAH5-related primary ciliary dyskinesia
notes: >-
  MONDO cross-references this disease as OMIM 608644. ClinGen classifies the
  DNAH5 relationship with this disease as Definitive (autosomal recessive).
  Hydrocephalus is a regular feature of Dnah5-mutant mice but is rare in
  patients, so it is recorded only under the mouse model.
references:
- reference: PMID:20301301
  title: "Primary Ciliary Dyskinesia."
  tags:
  - GeneReviews
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Disease requires homozygous or compound heterozygous DNAH5 variants. The
    first locus was mapped by homozygosity in a consanguineous family.
  evidence:
  - reference: CGGV:assertion_4390dba1-012d-4e08-a841-ffc08ebdc737-2022-01-07T190607.723Z
    reference_title: "DNAH5 / primary ciliary dyskinesia 3 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "primary ciliary dyskinesia 3, with or without situs inversus is an autosomal recessive disorder caused by homozygous or compound heterozygous mutation in the DNAH5 gene"
    explanation: ClinGen expert panel statement of the inheritance mode.
  - reference: PMID:11062149
    reference_title: "Homozygosity mapping of a gene locus for primary ciliary dyskinesia on chromosome 5p and identification of the heavy dynein chain DNAH5 as a candidate gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We localized a new gene locus for PCD to a region of homozygosity by descent on chromosome 5p15-p14"
    explanation: Homozygosity-by-descent mapping in a consanguineous family is consistent with recessive inheritance.
prevalence:
- population: PCD patients of European ancestry
  measure_type: UNKNOWN
  notes: >-
    No population prevalence exists for CILD3 itself. DNAH5 is the most
    frequently mutated PCD gene, explaining roughly 15-24% of PCD in white
    patients and about half of patients with documented outer dynein arm
    defects. These are shares of referral PCD cohorts, not population rates.
  evidence:
  - reference: CGGV:assertion_4390dba1-012d-4e08-a841-ffc08ebdc737-2022-01-07T190607.723Z
    reference_title: "DNAH5 / primary ciliary dyskinesia 3 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The most frequently mutated gene (15-24% of Caucasian patients) in PCD is DNAH5"
    explanation: ClinGen summary of the DNAH5 share of PCD.
  - reference: PMID:19357118
    reference_title: "Mutations in DNAH5 account for only 15% of a non-preselected cohort of patients with primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mutations on both alleles of DNAH5 were identified in 15% of our clinically heterogeneous cohort of patients"
    explanation: The DNAH5 share in a cohort recruited without phenotypic preselection.
  - reference: PMID:16627867
    reference_title: "DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a preselected subpopulation with documented outer dynein arm defects (n = 47), DNAH5 mutations were identified in 53% of patients."
    explanation: The DNAH5 share among patients with outer dynein arm defects.
pathophysiology:
- name: Biallelic DNAH5 Loss of Function
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    Nonsense, frameshift, splice and missense alleles, including several
    founder alleles, abolish functional DNAH5, the gamma heavy chain of the
    outer dynein arm.
  genes:
  - preferred_term: DNAH5
    term:
      id: hgnc:2950
      label: DNAH5
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: minus-end-directed microtubule motor activity
    modifier: DECREASED
    term:
      id: GO:0008569
      label: minus-end-directed microtubule motor activity
  evidence:
  - reference: PMID:11788826
    reference_title: "Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequence analysis in individuals with PCD with randomization of LR asymmetry identified mutations resulting in non-functional DNAH5 proteins."
    explanation: The defining study found DNAH5 alleles predicted to give non-functional protein.
  - reference: CGGV:assertion_4390dba1-012d-4e08-a841-ffc08ebdc737-2022-01-07T190607.723Z
    reference_title: "DNAH5 / primary ciliary dyskinesia 3 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism of pathogenicity in DNAH5 mutations appears to be bi-allelic loss of function."
    explanation: ClinGen summary of the disease mechanism.
  downstream:
  - target: Failure of DNAH5 Incorporation into the Ciliary Axoneme
    causal_link_type: DIRECT
- name: Failure of DNAH5 Incorporation into the Ciliary Axoneme
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    Mutant DNAH5 is absent from the respiratory ciliary axoneme and instead
    accumulates at the microtubule-organizing centres. Some 3' splice alleles
    leave DNAH5 in the proximal axoneme only.
  cell_types:
  - preferred_term: multiciliated respiratory epithelial cell
    term:
      id: CL:0005012
      label: multiciliated epithelial cell
  biological_processes:
  - preferred_term: outer dynein arm assembly
    modifier: DECREASED
    term:
      id: GO:0036158
      label: outer dynein arm assembly
  evidence:
  - reference: PMID:16627867
    reference_title: "DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High-resolution immunofluorescence imaging of respiratory epithelial cells from eight patients with DNAH5 mutations showed mislocalization of mutant DNAH5 and accumulation at the microtubule organizing centers."
    explanation: Mutant DNAH5 is not delivered into the axoneme.
  - reference: PMID:16627867
    reference_title: "DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutant DNAH5 was absent throughout the ciliary axoneme in seven patients and remained detectable in the proximal ciliary axoneme in one patient carrying compound heterozygous splicing mutations at the 3'-end"
    explanation: Whole-length loss is the rule; 3' splice alleles can spare the proximal axoneme.
  downstream:
  - target: Loss of Outer Dynein Arms from Respiratory Cilia
    causal_link_type: DIRECT
- name: Loss of Outer Dynein Arms from Respiratory Cilia
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    Electron microscopy shows absent outer dynein arms. Some cohorts also
    report combined outer and inner arm defects.
  cell_types:
  - preferred_term: multiciliated respiratory epithelial cell
    term:
      id: CL:0005012
      label: multiciliated epithelial cell
  cellular_components:
  - preferred_term: outer dynein arm
    term:
      id: GO:0036157
      label: outer dynein arm
  evidence:
  - reference: PMID:16627867
    reference_title: "DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopic analyses in 22 patients with PCD with mutations invariably detected outer dynein arm ciliary defects."
    explanation: Outer dynein arm loss in every DNAH5 patient examined.
  - reference: PMID:19357118
    reference_title: "Mutations in DNAH5 account for only 15% of a non-preselected cohort of patients with primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these DNAH5 mutations were mainly associated with outer + inner dyneins arm ultrastructural defects (50%)"
    explanation: A second cohort recorded combined outer and inner arm defects in half of DNAH5 patients.
  downstream:
  - target: Immotile Respiratory and Nodal Cilia
    causal_link_type: DIRECT
  - target: Absent Outer Dynein Arms
    causal_link_type: DIRECT
- name: Immotile Respiratory and Nodal Cilia
  biological_scale: CELLULAR
  role: effector
  description: >-
    Without outer dynein arms the cilia lose their main force generator.
    Cilia lacking DNAH5 along their whole length are immotile; cilia that
    lack it only distally keep some motility.
  cell_types:
  - preferred_term: multiciliated respiratory epithelial cell
    term:
      id: CL:0005012
      label: multiciliated epithelial cell
  biological_processes:
  - preferred_term: cilium movement
    modifier: DECREASED
    term:
      id: GO:0003341
      label: cilium movement
  evidence:
  - reference: PMID:15750039
    reference_title: "Mislocalization of DNAH5 and DNAH9 in respiratory cells from patients with primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cilia with complete axonemal DNAH5 deficiency were immotile, whereas cilia with distal DNAH5 deficiency showed residual motility."
    explanation: Links the extent of DNAH5 loss to the beat defect.
  - reference: PMID:11062149
    reference_title: "Homozygosity mapping of a gene locus for primary ciliary dyskinesia on chromosome 5p and identification of the heavy dynein chain DNAH5 as a candidate gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Direct examination of the respiratory cilia revealed ciliary akinesia. Electron microscopic examination of cilia showed absence of the outer dynein arms."
    explanation: Akinetic cilia with absent outer dynein arms in the index family.
  downstream:
  - target: Impaired Mucociliary Clearance
    causal_link_type: DIRECT
  - target: Randomization of Left-Right Body Asymmetry
    causal_link_type: DIRECT
  - target: Efferent Duct Cilia Dysmotility
    causal_link_type: DIRECT
  - target: Immotile cilia
    causal_link_type: DIRECT
- name: Impaired Mucociliary Clearance
  biological_scale: TISSUE
  role: effector
  description: >-
    Immotile airway cilia cannot clear mucus from the nose, sinuses, middle
    ear and bronchi, which leads to chronic infection.
  locations:
  - preferred_term: respiratory airway
    term:
      id: UBERON:0001005
      label: respiratory airway
  biological_processes:
  - preferred_term: mucociliary clearance
    modifier: DECREASED
    term:
      id: GO:0120197
      label: mucociliary clearance
  evidence:
  - reference: PMID:11788826
    reference_title: "Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Primary ciliary dyskinesia (PCD, MIM 242650) is characterized by recurrent infections of the respiratory tract due to reduced mucociliary clearance"
    explanation: Background statement in the DNAH5 gene-discovery paper linking ciliary dysfunction to infection through reduced clearance.
  downstream:
  - target: Neonatal respiratory distress
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Chronic wet cough
    causal_link_type: DIRECT
  - target: Chronic nasal congestion and rhinosinusitis
    causal_link_type: DIRECT
  - target: Recurrent otitis media
    causal_link_type: DIRECT
  - target: Conductive hearing impairment
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Recurrent respiratory infections
    causal_link_type: DIRECT
  - target: Bronchiectasis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Randomization of Left-Right Body Asymmetry
  biological_scale: ORGANISM
  role: consequence
  description: >-
    Dnah5 is expressed at the embryonic left-right organizer. Immotile nodal
    cilia without outer dynein arms cannot create leftward flow, so organ
    situs is set at random and about half of patients have situs inversus.
  biological_processes:
  - preferred_term: determination of left/right symmetry
    modifier: DYSREGULATED
    term:
      id: GO:0007368
      label: determination of left/right symmetry
  evidence:
  - reference: CGGV:assertion_4390dba1-012d-4e08-a841-ffc08ebdc737-2022-01-07T190607.723Z
    reference_title: "DNAH5 / primary ciliary dyskinesia 3 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "murine Dnah5 is expressed exclusively at the mouse Left Right Organizer (LRO) during early embryogenesis, consistent with the hypothesis that laterality defects (situs inversus) linked to DNAH5 mutations in humans may result from immotile LRO monocilia with defective outer dynein arms"
    explanation: ClinGen summary of the expression evidence linking DNAH5 to laterality.
  - reference: PMID:11062149
    reference_title: "Homozygosity mapping of a gene locus for primary ciliary dyskinesia on chromosome 5p and identification of the heavy dynein chain DNAH5 as a candidate gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two of four affected individuals exhibited a situs inversus, typical for Kartagener syndrome, due to randomization of the left/right body axis."
    explanation: Randomized situs in the index family.
  downstream:
  - target: Situs inversus totalis
    causal_link_type: DIRECT
  - target: Heterotaxy
    causal_link_type: DIRECT
- name: Efferent Duct Cilia Dysmotility
  biological_scale: TISSUE
  role: consequence
  description: >-
    Sperm flagella do not depend on DNAH5, so sperm motility is normal.
    Motile cilia of the efferent ducts do depend on it; when they are
    immotile, sperm accumulate in the ducts and the ejaculate sperm count
    falls.
  evidence:
  - reference: PMID:15750039
    reference_title: "Mislocalization of DNAH5 and DNAH9 in respiratory cells from patients with primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to respiratory cilia, sperm tails from a patient with DNAH5 mutations had normal ODA heavy chain distribution"
    explanation: Sperm flagella keep their outer dynein arm heavy chains in DNAH5 disease.
  - reference: PMID:33561200
    reference_title: "Motility of efferent duct cilia aids passage of sperm cells through the male reproductive system."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "human individuals with loss-of-function DNAH5 mutations present with reduced sperm count in the ejaculate (oligozoospermia) and dilatations of the epididymal head but normal sperm motility, similar to DNAH5 deficient mice"
    explanation: The human reproductive phenotype and the efferent duct mechanism behind it.
  downstream:
  - target: Oligozoospermia
    causal_link_type: DIRECT
phenotypes:
- category: Cellular
  name: Absent Outer Dynein Arms
  description: >-
    The diagnostic ultrastructural defect. Seen in all DNAH5 patients in the
    largest early series.
  phenotype_term:
    preferred_term: Absent outer dynein arms
    term:
      id: HP:0012256
      label: Absent outer dynein arms
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:16627867
    reference_title: "DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopic analyses in 22 patients with PCD with mutations invariably detected outer dynein arm ciliary defects."
    explanation: 22 of 22 patients had outer dynein arm defects.
- category: Cellular
  name: Immotile cilia
  description: >-
    Respiratory cilia are immotile or nearly so; residual motility is seen
    when DNAH5 is lost only from the distal axoneme.
  phenotype_term:
    preferred_term: Immotile cilia
    term:
      id: HP:0012263
      label: Immotile cilia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:15750039
    reference_title: "Mislocalization of DNAH5 and DNAH9 in respiratory cells from patients with primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cilia with complete axonemal DNAH5 deficiency were immotile"
    explanation: High-speed video microscopy finding in DNAH5-deficient cilia.
  - reference: PMID:33589394
    reference_title: "Multifaceted analysis of Japanese cases of primary ciliary dyskinesia: Value of immunofluorescence for ciliary protein detection in patients with DNAH5 and DNAH11 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 31-year-old woman had situs inversus, bronchiectasis, family history of PCD, and compound heterozygous mutations in DNAH5. Her cilia were immotile."
    explanation: Immotile cilia in a compound heterozygous DNAH5 patient.
- category: Respiratory
  name: Neonatal respiratory distress
  description: >-
    Common in DNAH5 disease, and more common when both alleles are
    loss-of-function than when one may retain residual function.
  phenotype_term:
    preferred_term: Neonatal respiratory distress
    term:
      id: HP:0002643
      label: Neonatal respiratory distress
  frequency: FREQUENT
  evidence:
  - reference: PMID:40344341
    reference_title: "The Association of Neonatal Respiratory Distress With Ciliary Ultrastructure and Genotype in Primary Ciliary Dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Within the DNAH5 group, those with two loss-of-function variants were more likely to have NRD compared to those with possible residual function variants"
    explanation: DNAH5-specific analysis of neonatal respiratory distress by variant type.
- category: Respiratory
  name: Chronic wet cough
  description: >-
    Daily wet cough from infancy, reported in nearly all children with PCD
    of every genotype, including the outer dynein arm class.
  phenotype_term:
    preferred_term: Productive cough
    term:
      id: HP:0031245
      label: Productive cough
    temporality: CHRONIC
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25493340
    reference_title: "Clinical features of childhood primary ciliary dyskinesia by genotype and ultrastructural phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical features included neonatal respiratory distress (82%), chronic cough (99%), and chronic nasal congestion (97%)."
    explanation: Frequencies in a PCD cohort in which the outer dynein arm group did not differ clinically from the others.
- category: Respiratory
  name: Chronic nasal congestion and rhinosinusitis
  description: >-
    Year-round nasal congestion from early life and chronic sinusitis.
  phenotype_term:
    preferred_term: Chronic sinusitis
    term:
      id: HP:0011109
      label: Chronic sinusitis
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:25493340
    reference_title: "Clinical features of childhood primary ciliary dyskinesia by genotype and ultrastructural phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "chronic cough (99%), and chronic nasal congestion (97%)"
    explanation: Chronic nasal congestion in nearly all children with PCD.
- category: Respiratory
  name: Recurrent respiratory infections
  description: >-
    Recurrent upper and lower respiratory tract infections are the defining
    clinical feature.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  frequency: VERY_FREQUENT
  evidence:
  - reference: CGGV:assertion_4390dba1-012d-4e08-a841-ffc08ebdc737-2022-01-07T190607.723Z
    reference_title: "DNAH5 / primary ciliary dyskinesia 3 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "characterized by recurrent infections of the upper and lower respiratory tract, randomization of left/right body asymmetry, and subfertility"
    explanation: ClinGen description of the PCD phenotype used for this curation.
- category: Otologic
  name: Recurrent otitis media
  description: >-
    Middle ear disease from impaired clearance of the Eustachian tube and
    middle ear mucosa. Reported for PCD as a whole; no DNAH5-specific
    frequency was found.
  phenotype_term:
    preferred_term: Recurrent otitis media
    term:
      id: HP:0000403
      label: Recurrent otitis media
  frequency: FREQUENT
  evidence:
  - reference: PMID:22184204
    reference_title: "Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Most patients had neonatal respiratory distress (70%), recurrent otitis media (82%), sinusitis (95%), and bronchiectasis (70%) by chest CT scan"
    explanation: >-
      Frequency in a mixed-genotype PCD cohort of 195 patients that included
      many with outer dynein arm defects; no DNAH5-specific otitis figure was
      found, so the claim is inferred from PCD as a whole.
- category: Otologic
  name: Conductive hearing impairment
  description: >-
    Conductive hearing loss from persistent middle ear effusion. Reported for
    PCD as a whole; no DNAH5-specific frequency was found, and no clear
    genotype-phenotype relationship for hearing loss has been described.
  phenotype_term:
    preferred_term: Conductive hearing impairment
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:38891105
    reference_title: "Primary Ciliary Dyskinesia: A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "Conductive hearing loss has been seen in up to two-thirds of children with PCD"
    explanation: >-
      Review synthesis of PCD cohort studies; the figure is for PCD as a
      class, so it is applied to DNAH5 disease by inference.
  - reference: PMID:38891105
    reference_title: "Primary Ciliary Dyskinesia: A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "No clear genotype-phenotype relationships have emerged regarding sinus disease, ear infections, and hearing loss"
    explanation: >-
      Why a PCD-wide figure is used: hearing loss has not been found to vary
      by genotype.
- category: Respiratory
  name: Bronchiectasis
  description: >-
    Bronchiectasis develops from chronic infection. Lung disease in DNAH5
    patients is milder on average than in patients with CCDC39 or CCDC40
    variants.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  frequency: FREQUENT
  evidence:
  - reference: PMID:30067075
    reference_title: "Primary Ciliary Dyskinesia: Longitudinal Study of Lung Disease by Ultrastructure Defect and Genotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Participants with CCDC39 or CCDC40 mutations (n = 34) had lower percent predicted FEV1 and weight and height z-scores than those with DNAH5 mutations (n = 36)."
    explanation: DNAH5 patients have comparatively better lung function, which bears on the severity of airway damage.
  - reference: PMID:33589394
    reference_title: "Multifaceted analysis of Japanese cases of primary ciliary dyskinesia: Value of immunofluorescence for ciliary protein detection in patients with DNAH5 and DNAH11 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 31-year-old woman had situs inversus, bronchiectasis, family history of PCD, and compound heterozygous mutations in DNAH5."
    explanation: Bronchiectasis in an adult DNAH5 patient.
- category: Cardiovascular
  name: Situs inversus totalis
  description: >-
    Mirror-image organ arrangement in about half of patients, from
    randomized left-right patterning.
  phenotype_term:
    preferred_term: Situs inversus totalis
    term:
      id: HP:0001696
      label: Situs inversus totalis
  frequency: FREQUENT
  evidence:
  - reference: PMID:11788826
    reference_title: "Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Half of the affected offspring have situs inversus (reversed organs), which results from randomization of left-right (LR) asymmetry."
    explanation: Situs inversus in half of PCD patients, the population in which DNAH5 was identified.
- category: Cardiovascular
  name: Heterotaxy
  description: >-
    A minority of patients with randomized situs have heterotaxy rather than
    complete mirror-image reversal.
  phenotype_term:
    preferred_term: Heterotaxy
    term:
      id: HP:0030853
      label: Heterotaxy
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:22184204
    reference_title: "Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: BACKGROUND
    snippet: "Situs inversus totalis occurs in ~50% of patients (Kartagener syndrome) and situs ambiguus occurs in at least 6%."
    explanation: >-
      Frequency of situs ambiguus (heterotaxy) across PCD as a whole, stated in
      the paper's background. No DNAH5-specific heterotaxy frequency was found,
      so the claim is inferred from PCD as a class.
  - reference: PMID:22184204
    reference_title: "Mutations of DNAH11 in patients with primary ciliary dyskinesia with normal ciliary ultrastructure."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Situs inversus and situs ambiguus were present in 80 (41%) and 15 (8%) patients, respectively."
    explanation: >-
      Situs ambiguus in 8% of a mixed-genotype cohort of 195 PCD patients that
      included many with outer dynein arm defects; not broken down by gene.
- category: Reproductive
  name: Oligozoospermia
  description: >-
    Reduced sperm count with normal sperm motility, from sperm accumulating
    in the efferent ducts. This differs from the asthenozoospermia seen in
    PCD genes that also affect the sperm flagellum.
  phenotype_term:
    preferred_term: Oligozoospermia
    term:
      id: HP:0000798
      label: Oligozoospermia
  evidence:
  - reference: PMID:33561200
    reference_title: "Motility of efferent duct cilia aids passage of sperm cells through the male reproductive system."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "human individuals with loss-of-function DNAH5 mutations present with reduced sperm count in the ejaculate (oligozoospermia)"
    explanation: Direct observation in DNAH5 patients.
genetic:
- name: DNAH5
  gene_term:
    preferred_term: DNAH5
    term:
      id: hgnc:2950
      label: DNAH5
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    The only gene for CILD3. Reported alleles are mostly truncating
    (nonsense, frameshift, splice) with some missense; variants cluster in
    five exons, and c.10815del is a founder allele in North American
    families.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_4390dba1-012d-4e08-a841-ffc08ebdc737-2022-01-07T190607.723Z
    evidence:
    - reference: CGGV:assertion_4390dba1-012d-4e08-a841-ffc08ebdc737-2022-01-07T190607.723Z
      reference_title: "DNAH5 / primary ciliary dyskinesia 3 (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "DNAH5 | HGNC:2950 | primary ciliary dyskinesia 3 | MONDO:0012085 | AR | Definitive"
      explanation: ClinGen Motile Ciliopathy GCEP classifies DNAH5 / primary ciliary dyskinesia 3 as Definitive (AR).
  evidence:
  - reference: PMID:11788826
    reference_title: "Mutations in DNAH5 cause primary ciliary dyskinesia and randomization of left-right asymmetry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequence analysis in individuals with PCD with randomization of LR asymmetry identified mutations resulting in non-functional DNAH5 proteins."
    explanation: Gene identification.
  - reference: PMID:16627867
    reference_title: "DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed clustering of mutations within five exons harboring 27 mutant alleles (52%) of the 52 detected mutant alleles."
    explanation: Allelic spectrum and mutation clustering.
diagnosis:
- name: Nasal Nitric Oxide and High-Speed Video Microscopy
  description: >-
    Low nasal nitric oxide is the usual screen. High-speed video microscopy
    shows immotile or near-immotile respiratory cilia in DNAH5 disease.
  evidence:
  - reference: PMID:27836958
    reference_title: "European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It focuses on clinical presentation, nasal nitric oxide, analysis of ciliary beat frequency and pattern by high-speed video-microscopy analysis, transmission electron microscopy, genotyping and immunofluorescence."
    explanation: The diagnostic tests recommended by the ERS guideline.
- name: Transmission Electron Microscopy of Respiratory Cilia
  description: >-
    Shows absent outer dynein arms. This places the patient in the outer
    dynein arm class but does not distinguish DNAH5 from other genes in that
    class.
  evidence:
  - reference: PMID:16627867
    reference_title: "DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electron microscopic analyses in 22 patients with PCD with mutations invariably detected outer dynein arm ciliary defects."
    explanation: TEM finding in DNAH5 disease.
- name: Immunofluorescence Staining for DNAH5
  description: >-
    DNAH5 is absent from the axoneme and accumulates at the
    microtubule-organizing centres. DNAH5 mislocalization was found in every
    patient with outer dynein arm defects on electron microscopy, so DNAH5
    staining is a general screen for that class.
  evidence:
  - reference: PMID:15750039
    reference_title: "Mislocalization of DNAH5 and DNAH9 in respiratory cells from patients with primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified DNAH5 mislocalization in all patients diagnosed with ODA defects by electron microscopy (n = 16)"
    explanation: Sensitivity of DNAH5 immunofluorescence for outer dynein arm defects.
  - reference: PMID:33589394
    reference_title: "Multifaceted analysis of Japanese cases of primary ciliary dyskinesia: Value of immunofluorescence for ciliary protein detection in patients with DNAH5 and DNAH11 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Defects in the outer dynein arms were revealed by transmission electron microscopy and loss of DNAH5 proteins in the entire length of axonemes using immunofluorescence (IF)."
    explanation: TEM and immunofluorescence findings in a DNAH5 patient.
- name: Genetic Testing
  description: >-
    Panel or exome sequencing identifies biallelic DNAH5 variants. DNAH5 and
    DNAH11 together explain about half of genetically solved PCD families of
    white European ancestry.
  evidence:
  - reference: PMID:31879361
    reference_title: "Clinical utility of NGS diagnosis and disease stratification in a multiethnic primary ciliary dyskinesia cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "white European (52% of families carry DNAH5 or DNAH11 mutations)"
    explanation: Contribution of DNAH5 to genetic diagnosis in European families.
animal_models:
- name: Mdnah5 insertional mutant mouse
  species: Mouse
  genotype: Dnah5 (Mdnah5) insertional loss-of-function mutation, homozygous
  publication: PMID:11912187
  description: >-
    An insertional mutation in mouse Dnah5 reproduces the core PCD features:
    loss of outer dynein arms, immotile cilia, situs inversus and respiratory
    infection. The mice also develop hydrocephalus and die perinatally, which
    is far more severe than the human disease.
  modeled_mechanisms:
  - target: Loss of Outer Dynein Arms from Respiratory Cilia
    relationship: RECAPITULATES
    fidelity: HIGH
    description: Loss of axonemal outer arms, as in patients.
    evidence:
    - reference: PMID:11912187
      reference_title: "Loss of function of axonemal dynein Mdnah5 causes primary ciliary dyskinesia and hydrocephalus."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Electron microscopic studies demonstrate the loss of axonemal outer arms."
      explanation: Same ultrastructural lesion as the human disease.
  - target: Randomization of Left-Right Body Asymmetry
    relationship: RECAPITULATES
    fidelity: HIGH
    description: Situs inversus and ciliary immotility in the mutant.
    evidence:
    - reference: PMID:11912187
      reference_title: "Loss of function of axonemal dynein Mdnah5 causes primary ciliary dyskinesia and hydrocephalus."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "reproduces most of the classical features of PCD, including recurrent respiratory infections, situs inversus and ciliary immotility"
      explanation: The mouse reproduces the laterality and motility phenotypes.
  - target: Impaired Mucociliary Clearance
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: Recurrent respiratory infections, with hydrocephalus and perinatal death.
    limitations: >-
      Hydrocephalus and perinatal death make the mouse more severe than the
      human disease, where hydrocephalus is rare and survival is normal.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Homozygous Mdnah5 mice develop hydrocephalus and die perinatally,
        whereas hydrocephalus is rare in DNAH5 patients and survival is
        normal. The short lifespan means the mouse shows the early airway
        infection phenotype but not the chronic course, bronchiectasis
        included, that the clearance node leads to in patients.
    evidence:
    - reference: PMID:11912187
      reference_title: "Loss of function of axonemal dynein Mdnah5 causes primary ciliary dyskinesia and hydrocephalus."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "reproduces most of the classical features of PCD, including recurrent respiratory infections, situs inversus and ciliary immotility"
      explanation: >-
        The mouse has ciliary immotility with recurrent respiratory
        infections, the infection phenotype that follows from failed
        clearance.
    - reference: PMID:11912187
      reference_title: "Loss of function of axonemal dynein Mdnah5 causes primary ciliary dyskinesia and hydrocephalus."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These mice also suffer from hydrocephalus and die perinatally."
      explanation: >-
        The main divergence from human DNAH5 disease, recorded in
        limitations and divergences; it qualifies the link rather than
        supporting it.
- name: Dnah5-deficient mouse (male reproductive tract)
  species: Mouse
  genotype: Dnah5 loss of function
  publication: PMID:33561200
  description: >-
    Dnah5-deficient mice have immotile efferent duct cilia lacking outer
    dynein arms, sperm accumulation in the efferent ducts, and normal sperm
    ultrastructure and motility, matching the oligozoospermia with normal
    motility seen in patients.
  modeled_mechanisms:
  - target: Efferent Duct Cilia Dysmotility
    relationship: RECAPITULATES
    fidelity: HIGH
    description: Immotile efferent duct cilia and sperm accumulation, with normal sperm.
    evidence:
    - reference: PMID:33561200
      reference_title: "Motility of efferent duct cilia aids passage of sperm cells through the male reproductive system."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These mice have immotile efferent duct cilia that lack ODAs, which are essential for ciliary beat generation. Furthermore, they show accumulation of sperm in the efferent duct. Notably, the ultrastructure and motility of sperm from these males are unaffected."
      explanation: The mechanism behind the human reproductive phenotype.
treatments:
- name: Airway Clearance and Chronic Infection Management
  description: >-
    There is no treatment that restores ciliary function. Management is the
    supportive care used across primary ciliary dyskinesia: airway clearance,
    prompt treatment of respiratory infections, and macrolide prophylaxis,
    for which a randomized trial of azithromycin in PCD reduced pulmonary
    exacerbations. Nothing in it is specific to DNAH5.

    Curated as a single scoping entry rather than an itemised regimen,
    because no trial has enrolled by genotype and the umbrella
    Primary_Ciliary_Dyskinesia entry holds the detailed management block.
    What is DNAH5-specific is prognostic: lung function is on average better
    than in the CCDC39/CCDC40 class, which is curated on the bronchiectasis
    phenotype.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Impaired Mucociliary Clearance
    description: >-
      Airway clearance techniques substitute mechanically for the mucociliary
      transport the immotile cilia cannot provide. They do not restore
      ciliary function.
  - target: Recurrent respiratory infections
    description: >-
      Antibiotics treat exacerbations, and azithromycin prophylaxis reduces
      their rate.
  evidence:
  - reference: PMID:38891105
    reference_title: "Primary Ciliary Dyskinesia: A Clinical Review."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "Though there are no PCD-specific approved therapies that restore ciliary function, routine airway clearance and aggressive management of infections are important to preserve lung health and minimize complications"
    explanation: >-
      The supportive management used across PCD. Applied to DNAH5 disease by
      inference, since no genotype-stratified treatment evidence exists.
  - reference: PMID:38891105
    reference_title: "Primary Ciliary Dyskinesia: A Clinical Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    snippet: "A European study found that people with PCD benefitted from treatment with thrice weekly azithromycin, with decreased pulmonary exacerbation rates and without an apparent increase in antibiotic resistance"
    explanation: >-
      The review's summary of a randomized trial in PCD, not stratified by
      genotype.
differential_diagnoses:
- name: Primary Ciliary Dyskinesia 7
  description: >-
    DNAH11 disease also affects an outer dynein arm heavy chain but gives
    normal ultrastructure on standard electron microscopy and stiff,
    hyperkinetic cilia rather than immotile cilia.
- name: Primary Ciliary Dyskinesia 40
  description: >-
    DNAH9 disease removes outer dynein arms only from the distal cilium,
    with subtle beating defects and mild or absent respiratory disease.

📚

References & Deep Research

References

1

PMID:20301301

Primary Ciliary Dyskinesia.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Primary Ciliary Dyskinesia 3 (DNAH5) · 2026-10-14T20:30:36Z · View source

New gene-specific entry for CILD3 (MONDO:0012085, DNAH5). Deep research: falcon (Edison) returned 503 'Failed to authenticate' on every attempt, including with --fallback, which did not engage, so the report used is research/Primary_Ciliary_Dyskinesia_3-deep-research-claude_code.md, run directly with the claude_code provider. preflight-dr returned PASS. The report was used only as a lead; all evidence comes from primary abstracts and the ClinGen CGGV record fetched with just fetch-reference. Pathograph: biallelic DNAH5 loss of function, then failure of axonemal incorporation, then outer dynein arm loss, then immotile cilia, branching to mucociliary clearance failure, laterality randomization and efferent duct cilia dysmotility (oligozoospermia with normal sperm motility). ClinGen Definitive tier copied from the cached CGGV record. Validated with just validate, validate-terms, count-verified-snippets, check-entity-refs, check-causal-targets, check-duplicate-keys and validate-disorders.

Claude Code ▸

Research report: Primary Ciliary Dyskinesia 3 (CILD3, DNAH5-related PCD)

claude-haiku-5-5, claude-sonnet-5-5 3 citations 2026-10-14T20:13:13.428450

I'll start by checking the repo for an existing entry or stub and loading the web tools to verify the gene and identifiers.

I'm pulling the cached abstracts for the key DNAH5 papers so the report's quotes are exact.

Research report: Primary Ciliary Dyskinesia 3 (CILD3, DNAH5-related PCD)

Verification status

Web access was limited in this session: PubMed pages were blocked, and only one search returned usable results. I checked the following against repository sources:

MONDO:0012085 is "primary ciliary dyskinesia 3". It is already used in kb/disorders/Primary_Ciliary_Dyskinesia_3.yaml.
The causal gene is DNAH5, hgnc:2950. The ClinGen row in kb/genes/ingest/clingen_gene_validity.tsv reads DNAH5 | primary ciliary dyskinesia 3 | MONDO:0012085 | AR | Definitive | 2022-01-07 | Motile Ciliopathy GCEP | CGGV:assertion_4390dba1-012d-4e08-a841-ffc08ebdc737-2022-01-07T190607.723Z.
Two papers were read in references_cache/: PMID:11788826 and PMID:16627867. Their quotes below are exact.
Search result consistent with the above: OMIM 608644 is PCD caused by DNAH5 mutation. The DNAH5 gene entry is OMIM 603335. This came from secondary sources only, not omim.org.

Everything else is background knowledge and is marked [unverified]. That includes every ontology CURIE except MONDO:0012085 and hgnc:2950. Per repo policy, look each one up before binding it.

A KB entry already exists. It is a minimal stub with only the description, disease_term and parent. This report is intended to enrich it.

1. Disease information

Overview. Primary ciliary dyskinesia 3 is the PCD subtype caused by biallelic loss-of-function variants in DNAH5. DNAH5 encodes an outer dynein arm (ODA) heavy chain of motile cilia. The disease is a motile ciliopathy. It features chronic sino-pulmonary disease from impaired mucociliary clearance, randomized left-right body asymmetry, and male infertility.

Identifiers - MONDO:0012085 (verified in the repo). - OMIM 608644 (CILD3), with the DNAH5 gene entry at 603335. These are consistent across secondary sources but not checked on omim.org. - Parent PCD phenotypic series: OMIM 242650. The Olbrich 2002 abstract (PMID:11788826) cites "PCD, MIM 242650". - Orphanet, ICD-10/11 and MeSH IDs: not verified. The generic Kartagener syndrome / PCD terms would apply.

Synonyms. CILD3; ciliary dyskinesia, primary, 3; DNAH5-related PCD; Kartagener syndrome when situs inversus is present. [unverified]

Data source. This is an aggregated, disease-level description from the literature and databases, not EHR-derived.

2. Etiology

Cause: purely genetic. Autosomal recessive biallelic DNAH5 variants. The ClinGen Motile Ciliopathy GCEP classifies the DNAH5–PCD3 relationship as Definitive (verified in the repo).
Genetic risk factors: the causal variants only. Modifier genes are not established.
Environmental risk and protective factors: none define the disease. Environmental exposures such as tobacco smoke and respiratory infections worsen lung disease but do not cause it.
Gene–environment interactions: none established in the sources I could verify.

3. Phenotypes

Frequencies below are qualitative. They are from background knowledge unless a quote is given. [unverified] HPO CURIEs need lookup.

Phenotype	Notes	Suggested HPO label
Chronic wet cough, recurrent lower respiratory infections	Neonatal or childhood onset, very frequent	Recurrent respiratory infections; Chronic productive cough
Neonatal respiratory distress	Often present in term infants	Neonatal respiratory distress
Bronchiectasis	Progressive, develops in childhood and adulthood	Bronchiectasis
Chronic rhinosinusitis, nasal polyps	Very frequent	Chronic sinusitis
Recurrent otitis media, conductive hearing loss	Childhood	Recurrent otitis media; Conductive hearing impairment
Situs inversus totalis	About half of patients, from randomized laterality	Situs inversus totalis
Heterotaxy, congenital heart disease	Minority	Heterotaxy
Male infertility (sperm immotility)	Frequent	Asthenozoospermia
Reduced female fertility; ectopic pregnancy	Occasional	—

Supporting quote (PMID:11788826): "Primary ciliary dyskinesia (PCD, MIM 242650) is characterized by recurrent infections of the respiratory tract due to reduced mucociliary clearance and by sperm immobility. Half of the affected offspring have situs inversus (reversed organs), which results from randomization of left-right (LR) asymmetry."

Quality of life: no verified data. Chronic cough and sinus disease are the main burdens.

4. Genetic and molecular information

Gene: DNAH5, hgnc:2950, chromosome 5p15.
Variants: mostly loss-of-function. Hornef et al. (PMID:16627867) found in 30 families "33 novel (12 nonsense, 8 frameshift, 5 splicing, and 8 missense mutations) and two known DNAH5 mutations."
Hotspots: "We observed clustering of mutations within five exons harboring 27 mutant alleles (52%) of the 52 detected mutant alleles."
Founder variant: in North America, "6 (32%) of 19 PCD families with DNAH5 mutations from North America carry the novel founder mutation 10815delT."
Share of PCD: "In a preselected subpopulation with documented outer dynein arm defects (n = 47), DNAH5 mutations were identified in 53% of patients." DNAH5 is commonly cited as the most frequently mutated PCD gene, at roughly 15–21% of all PCD. This figure comes from a secondary search snippet.
Gene identification: Olbrich et al. 2002 (PMID:11788826) reported that "Sequence analysis in individuals with PCD with randomization of LR asymmetry identified mutations resulting in non-functional DNAH5 proteins."
Origin: germline.
Epigenetic and chromosomal abnormalities: none known. Large deletions and copy-number variants are described in some cases [unverified].
Allele frequencies: not checked in gnomAD.

5. Environmental information

No disease-defining environmental factors. Airway pollutants and tobacco smoke are aggravating factors. Infectious agents act as complications, not causes. Common colonizers include Haemophilus influenzae, Pseudomonas aeruginosa and nontuberculous mycobacteria [unverified].

6. Mechanism and pathophysiology

Causal chain 1. Biallelic DNAH5 variants, mostly nonsense, frameshift or splice, abolish or truncate the ODA heavy chain. 2. Mutant DNAH5 is absent from the axoneme or mislocalized. Hornef et al. reported "mislocalization of mutant DNAH5 and accumulation at the microtubule organizing centers. Mutant DNAH5 was absent throughout the ciliary axoneme in seven patients." 3. Outer dynein arms fail to assemble. "Electron microscopic analyses in 22 patients with PCD with mutations invariably detected outer dynein arm ciliary defects." 4. Without ODAs, motile cilia beat abnormally or are immotile. Ciliary beat frequency is reduced and the cilia are stiff or immotile [unverified, inferred from mechanism]. 5. Branch A, airway: impaired mucociliary clearance leads to mucus retention, then recurrent infection and inflammation. This leads to bronchiectasis and chronic rhinosinusitis and otitis media. This step is inferred, not directly demonstrated in the verified papers. 6. Branch B, embryonic node: nodal motile cilia fail to generate leftward flow. This leads to randomized left-right asymmetry, with situs inversus in about half of cases. Olbrich et al. state this "results from randomization of left-right (LR) asymmetry." 7. Branch C, reproductive tract: immotile sperm flagella lead to male infertility. Dysfunctional cilia in the fallopian tube and ependyma are proposed to reduce female fertility and to cause rare hydrocephalus [unverified].

Pathway and process details - Axonemal dynein ATPase activity drives microtubule sliding and ciliary beat. - Suggested GO terms, to be verified: cilium movement (GO:0003341), outer dynein arm (GO:0036157), axonemal dynein complex assembly, determination of left/right symmetry. - Suggested CL terms, to be verified: ciliated columnar epithelial cell, respiratory epithelial cell, spermatozoon, node cell. - Omics and immune involvement: not verified.

7. Anatomical structures affected

Primary: lower and upper airways (trachea, bronchi, nose, paranasal sinuses), middle ear and Eustachian tube, the embryonic node (laterality), sperm flagella, and the fallopian tube.
Secondary: heart and viscera (laterality defects).
Subcellular: the ciliary axoneme, specifically the outer dynein arm.
Lateralization: symmetric organ disease. Laterality defects are bilateral/global (situs solitus or inversus).

Suggested UBERON terms are lung, bronchus, nasal cavity, paranasal sinus, middle ear, fallopian tube, and sperm flagellum. All need lookup.

8. Temporal development

Onset: neonatal or early childhood, often with neonatal respiratory distress and daily wet cough from infancy.
Course: chronic and lifelong. Lung function declines slowly. Bronchiectasis develops with age.
Remission: none.
Staging systems: none established.

9. Inheritance and population

Inheritance: autosomal recessive (ClinGen row, verified; HP term for autosomal recessive inheritance, to be looked up).
Penetrance: appears complete for the respiratory phenotype. Laterality is variable (about 50% situs inversus).
Founder variant: 10815delT in North American families (PMID:16627867).
PCD prevalence: roughly 1 in 10,000–20,000 [unverified]. DNAH5-specific prevalence is not verified.
Consanguinity: increases the rate of homozygous cases [unverified].
Sex ratio: equal for disease. Infertility is more evident in males.

10. Diagnostics

Confirmed from verified sources: transmission electron microscopy shows ODA defects, and immunofluorescence shows DNAH5 mislocalization or absence.

The rest is standard practice and [unverified]: - Nasal nitric oxide, which is very low in PCD. - High-speed video microscopy of ciliary beat. - Genetic testing by PCD gene panel or exome sequencing. DNAH5 is a large gene, so full coding coverage matters. - Chest CT for bronchiectasis and situs. - Semen analysis and audiometry. - Differential diagnosis: cystic fibrosis, immunodeficiency, and other motile ciliopathies. - Screening: none by newborn screening. Situs inversus with neonatal respiratory distress should prompt PCD evaluation.

11. Prognosis

Survival is generally near normal with good care. Lung function declines slowly and bronchiectasis can cause respiratory failure in some patients. Transplantation is rarely needed. I have no verified quantitative survival data for the DNAH5 subtype.

12. Treatment

There are no approved disease-modifying drugs and no verified trial identifiers. Management is supportive and [unverified]: - Airway clearance physiotherapy (NCIT supportive care or physical therapy terms). - Prompt antibiotics for exacerbations, and sometimes prophylactic macrolide. - Vaccination. - ENT care, including hearing aids, with caution about tympanostomy tubes. - Fertility support through ICSI. - Experimental approaches include gene therapy and read-through approaches. These are not clinically established for DNAH5.

13. Prevention

Prevention is limited to genetic counseling, carrier testing and prenatal or preimplantation diagnosis for families with known DNAH5 variants. Tertiary prevention covers vaccination, avoiding smoke, and early treatment of infections. [unverified]

14. Other species

Naturally occurring PCD is known in dogs and other mammals. DNAH5 orthologs are conserved. I did not verify OMIA entries or breed ontology terms.

15. Model organisms

Mouse Dnahc5/Dnah5 mutants have randomized laterality and ciliary defects [unverified; I believe Ibañez-Tallon et al., 2002, PMID:11809718, but I could not retrieve the abstract and the paper was not in the local cache]. Zebrafish and Chlamydomonas ODA models are also used. I did not verify fidelity details.

Suggested next steps for curation

Run just validate-terms on every CURIE above that you decide to bind.
Fetch further references with just fetch-reference. I could not run that command in this session because of a permission prompt.
Curate against GeneReviews "Primary Ciliary Dyskinesia" as the baseline. Check it with just check-genereviews.
Existing PCD research files in research/ (Falcon and Cyberian Codex PCD reports) may cover shared mechanisms.

Sources

Olbrich H et al. 2002, Nat Genet. PMID:11788826 (read from references_cache/PMID_11788826.md)
Hornef N et al. 2006, Am J Respir Crit Care Med. PMID:16627867 (read from references_cache/PMID_16627867.md)
ClinGen gene–disease validity row via kb/genes/ingest/clingen_gene_validity.tsv
DNAH5 (Wikipedia)
Genomics England PanelApp: DNAH5, respiratory ciliopathies
NCBI Gene 1767

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	3
Resolved	3
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	3
On topic	2
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	3
Resolved	3
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	1
Terms named correctly	0
Terms named as a different term	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0012085 (4 mentions) - the report calls it "verified in the repo"; MONDO calls it primary ciliary dyskinesia 3

Primary Ciliary Dyskinesia 3

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OpenScientist Report

Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Research report: Primary Ciliary Dyskinesia 3 (CILD3, DNAH5-related PCD)

Verification status

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Prognosis

12. Treatment

13. Prevention

14. Other species

15. Model organisms

Suggested next steps for curation

Sources

Reference Validation

Term Validation

Terms the report names something else