👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Disease requires homozygous or compound heterozygous DNAH9 variants.

Autosomal recessive inheritance

Show evidence (2 references)

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

"is definitively associated with autosomal recessive primary ciliary dyskinesia 40"

ClinGen statement of the inheritance mode.

PMID:35050399 SUPPORT Human Clinical

"we identified compound heterozygous mutations in DNAH9 in the affected individuals of these family trios"

Compound heterozygosity in trios.

⚙

Pathophysiology

5

Biallelic DNAH9 Variants

Null and missense variants in DNAH9 lead to loss of DNAH9 from respiratory cilia.

DNAH9 hgnc:2953

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

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

Downstream

Loss of Distal Type 2 Outer Dynein Arms

Show evidence (2 references)

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

"A total of 50 different mutations were detected in the reported patients and consisted of 22 null mutations, 1 in-frame deletion and 27 missense variants"

Allelic spectrum.

PMID:30471718 SUPPORT Human Clinical

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

Loss-of-function variants in the defining study.

Loss of Distal Type 2 Outer Dynein Arms

DNAH9 is needed to assemble the distal outer dynein arms. Without it, DNAH5, DNAI1 and DNAI2 are also missing from the distal cilium, while proximal DNAH11-containing arms remain.

multiciliated respiratory epithelial cell CL:0005012

outer dynein arm assembly GO:0036158 ↓ DECREASED

outer dynein arm GO:0036157

Animal models

Dnah9 knockdown mouse Mouse recapitulates Absence of distal ciliary outer arms and reduced beat frequency.

Downstream

Reduced Distal Ciliary Bending

Partial outer dynein arm defect

Show evidence (3 references)

PMID:30471718 SUPPORT Human Clinical

"DNAH9-deficient cilia also lack other ODA components such as DNAH5, DNAI1, and DNAI2 from the distal axonemal compartment, demonstrating an essential role of DNAH9 for distal axonemal assembly of ODAs type 2."

Distal-only loss of type 2 outer arms.

PMID:30471717 SUPPORT Human Clinical

"3D electron tomography ultrastructural studies confirmed regional loss of ODAs from the distal cilium, manifesting as either loss of whole ODA or partial loss of ODA volume."

Independent ultrastructural confirmation.

PMID:15750039 SUPPORT Human Clinical

"In normal ciliated airway epithelium, DNAH5 and DNAH9 show a specific regional distribution along the ciliary axoneme, indicating the existence of at least two distinct ODA types."

The regional outer arm types that explain why DNAH9 loss is distal.

Reduced Distal Ciliary Bending

The distal part of the cilium bends poorly and beat frequency is modestly reduced. The defect is subtle and some clearance is kept.

multiciliated respiratory epithelial cell CL:0005012

cilium movement GO:0003341 ↓ DECREASED

Animal models

Dnah9 knockout mouse (exons 2-4 deletion) Mouse recapitulates Limited range of ciliary bending and outer arm defects.

Downstream

Partially Impaired Mucociliary Clearance

Randomization of Left-Right Body Asymmetry

Abnormal ciliary motility

Show evidence (2 references)

PMID:30471718 SUPPORT Human Clinical

"high-speed video microscopy demonstrates distally impaired ciliary bending in DNAH9 mutant respiratory cilia"

The beat defect.

PMID:30471717 SUPPORT Human Clinical

"This confers a reduced beating frequency with a subtle beating pattern defect affecting the motility of the distal cilia portion."

Reduced frequency and distal beat defect.

Partially Impaired Mucociliary Clearance

Clearance is reduced but not lost, so respiratory symptoms are mild, mostly in the upper airway, or absent. Nasal nitric oxide is usually normal or high.

mucociliary clearance GO:0120197 ↓ DECREASED

respiratory airway UBERON:0001005

Animal models

Dnah9 knockdown mouse Mouse recapitulates Low lung function, mucin accumulation and immune cell infiltration.

Downstream

Recurrent respiratory infections

Chronic sinusitis

Show evidence (2 references)

PMID:30471717 SUPPORT Human Clinical

"DNAH9 mutations reduce cilia function but some respiratory mucociliary clearance potential may be retained, widening the PCD disease spectrum."

Partial retention of clearance.

PMID:30471717 SUPPORT Human Clinical

"despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract"

The mild, mainly upper airway, phenotype.

Randomization of Left-Right Body Asymmetry

Laterality defects are the most common manifestation, often with complex congenital heart disease. In zebrafish, dnah9 knockdown disturbs cardiac left-right patterning without affecting cilia formation in Kupffer's vesicle.

determination of left/right symmetry GO:0007368 ↕ DYSREGULATED

Animal models

Dnah9 knockout mouse (exons 2-4 deletion) Mouse fails to recapitulate No laterality defects in the knockout, unlike most patients.

Downstream

Situs inversus totalis

Heterotaxy

Complex congenital heart disease

Show evidence (2 references)

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

"Laterality defects were observed in 20/31 (65%) patients and asthenozoospermia was reported in 4 male patients."

Frequency of laterality defects.

PMID:35050399 SUPPORT Model Organism

"dnah9 knockdown in zebrafish lead to the disturbance of cardiac left-right patterning without affecting ciliogenesis in Kupffer's vesicle (KV)."

Functional evidence in zebrafish.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

8

Cardiovascular 2

Situs inversus totalis FREQUENT HP:0001696

Show evidence (1 reference)

PMID:30471717 SUPPORT Human Clinical

"we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9 in individuals from PCD clinics with situs inversus"

Situs inversus in DNAH9 patients.

Complex congenital heart disease OCCASIONAL Abnormal heart morphology HP:0001627

Show evidence (2 references)

PMID:35050399 SUPPORT Human Clinical

"Here, we describe six unrelated family trios and 2 sporadic patients with laterality defects and complex congenital heart disease (CHD)."

Complex CHD in DNAH9 patients.

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

"These included complex congenital heart disease with dextroversion"

Prenatally detected cardiac anomalies.

Genitourinary 1

Reduced sperm motility OCCASIONAL HP:0012207

Show evidence (2 references)

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

"asthenozoospermia was reported in 4 male patients"

ClinGen tally.

PMID:30471717 SUPPORT Human Clinical

"with situs inversus and in one case male infertility"

Male infertility in one patient.

Head and Neck 1

Chronic sinusitis OCCASIONAL HP:0011109

Show evidence (1 reference)

PMID:30471717 SUPPORT INDIRECT Human Clinical

"despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract"

Upper respiratory tract symptoms; sinusitis specifically is inferred.

Immune 1

Recurrent respiratory infections OCCASIONAL HP:0002205

Show evidence (2 references)

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

"While most of the patients with DNAH9 defects had laterality defects and mild or no respiratory signs"

Respiratory disease is mild or absent in most.

PMID:35729109 SUPPORT Human Clinical

"we identified compound mutation of DNAH9 in a patient with PCD with the following clinical features: recurrent respiratory tract infections, low lung function, and ultrastructural defects of the outer dynein arms (ODAs)"

A patient with more typical respiratory PCD.

Respiratory 2

Partial outer dynein arm defect FREQUENT Dynein arm defect of respiratory motile cilia HP:0012255

Show evidence (2 references)

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

"Ciliary investigations by transmission electron microscopy showed partial absence of the outer dynein arms."

TEM finding.

PMID:35050399 SUPPORT Human Clinical

"Transmission Electron Microscopy (TEM) analysis identified ultrastructural defects of the outer dynein arms in these affected individuals."

Outer arm defects in a second cohort.

Abnormal ciliary motility FREQUENT HP:0012262

Show evidence (1 reference)

PMID:30471718 SUPPORT Human Clinical

"high-speed video microscopy demonstrates distally impaired ciliary bending in DNAH9 mutant respiratory cilia"

HSVA finding.

Growth 1

Heterotaxy OCCASIONAL HP:0030853

Show evidence (1 reference)

PMID:35050399 SUPPORT BACKGROUND Human Clinical

"Defective left-right (LR) pattering results in a spectrum of laterality disorders including situs inversus totalis (SIT) and heterotaxy syndrome (Htx)."

Background framing of the study, whose patients had laterality defects with complex congenital heart disease.

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Genetic Associations

1

DNAH9

Gene: DNAH9 hgnc:2953 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:30471718 SUPPORT Human Clinical

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

Gene identification.

PMID:30471717 SUPPORT Human Clinical

"Using next-generation sequencing, we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9"

Independent simultaneous identification.

💊

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. For patients with respiratory symptoms, management is the supportive care used across primary ciliary dyskinesia: airway clearance and prompt treatment of respiratory infections. Nothing in it is specific to DNAH9. In DNAH9 disease, respiratory signs are mild or absent in most reported patients, and the clinical picture is dominated by laterality defects and complex congenital heart disease. Airway care therefore applies to a minority of patients. The cardiac and laterality problems are managed as in other causes of heterotaxy and congenital heart disease, and that management is not curated here.

Mechanism Target:

Partially Impaired Mucociliary Clearance — Airway clearance techniques supplement the partial mucociliary transport the distally defective cilia still provide. They do not restore ciliary function.

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 DNAH9 disease by inference, since no genotype-stratified treatment evidence exists.

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

"While most of the patients with DNAH9 defects had laterality defects and mild or no respiratory signs"

Why airway care applies to only a minority of DNAH9 patients and the clinical burden is laterality and cardiac disease.

🔬

Diagnosis

5

Nasal Nitric Oxide

Nasal nitric oxide is usually normal to high in DNAH9 disease, so a normal value does not exclude it in a patient with a laterality defect.

Show evidence (1 reference)

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

"Nasal nitric oxide measurements in 13 patients with DNAH9 mutations showed normal to high values (36-220 nL/min)"

Nasal NO is not reduced.

High-Speed Video Microscopy

Shows reduced distal ciliary bending.

Show evidence (1 reference)

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

"A reduced ciliary distal bending was observed with high speed video microscopy"

HSVA finding.

Transmission Electron Microscopy and Electron Tomography

TEM shows partial absence of outer dynein arms; tomography localizes the loss to the distal cilium.

Show evidence (1 reference)

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

"Electron tomography showed more precise ciliary abnormality consisting of a reduced volume of ODA from the distal cilia"

Tomography finding.

Immunofluorescence Staining

DNAH9 is absent from respiratory cilia, and DNAH5, DNAI1, DNAI2 and DNALI1 are missing from the distal axoneme only.

Show evidence (1 reference)

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

"This is consistent with immunofluorescence assays showing absence of DNAH9 and distal absence of DNAH5, DNAI1, DNAI2 and DNALI1 in respiratory cilia"

Immunofluorescence pattern.

Genetic Testing

Sequencing identifies biallelic DNAH9 variants. DNAH9 should be included in testing for isolated laterality defects and congenital heart disease, not only for respiratory PCD.

Show evidence (1 reference)

PMID:35050399 SUPPORT Human Clinical

"Through whole exome sequencing (WES), we identified compound heterozygous mutations in DNAH9 in the affected individuals of these family trios."

Exome sequencing in laterality/CHD trios.

📊

Prevalence

1

Published DNAH9 patients

Cases In Literature Ultra Rare

By ClinGen's 2026 count, 31 patients with 50 different variants had been reported in 16 papers between 2018 and 2024. Because many patients have mild respiratory disease and normal nasal nitric oxide, this is likely an undercount.

Show evidence (1 reference)

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

"Between 2018 and 2024, 16 different papers reported DNAH9 variants in a total of 31 patients."

Published case count.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Primary Ciliary Dyskinesia 40:

Primary Ciliary Dyskinesia 3

Overlapping Features DNAH5 disease removes outer dynein arms along the whole cilium, giving immotile cilia, low nasal nitric oxide and typical PCD lung disease.

Primary Ciliary Dyskinesia 7

Overlapping Features DNAH11 disease affects the proximal outer arms, with normal standard ultrastructure and stiff, hyperkinetic cilia.

🐁

Animal Models

2

Dnah9 knockdown mouse

Dnah9 knockdown mice have low lung function, mucin accumulation and immune cell infiltration, loss of distal outer dynein arms and reduced ciliary beat frequency. Airway organoids from these mice reproduce key PCD features.

Species

Mouse

Genotype

Dnah9 knockdown

Publication

PMID:35729109

Pathograph links

Partially Impaired Mucociliary Clearance recapitulates fidelity: moderate Low lung function, mucin accumulation and immune cell infiltration.

Show evidence (1 reference)

PMID:35729109 SUPPORT Model Organism

"Dnah9 knock-down (KD) mice recapitulated the patient phenotypes, including low lung function, mucin accumulation, and increased immune cell infiltration."

Airway phenotype of the mouse.

Loss of Distal Type 2 Outer Dynein Arms recapitulates fidelity: high Absence of distal ciliary outer arms and reduced beat frequency.

Show evidence (1 reference)

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

"Mice from the second model showed absence of distal ciliary ODA and a reduced ciliary beat frequency"

ClinGen summary of the mouse ultrastructure.

Dnah9 knockout mouse (exons 2-4 deletion)

Has hydrocephalus, compromised cardiac function, outer dynein arm defects, limited ciliary bending and insufficient effective stroke, but no laterality defects.

Species

Mouse

Genotype

Dnah9 knockout (CRISPR/Cas9 deletion of exons 2-4)

Publication

PMID:35050399

Pathograph links

Reduced Distal Ciliary Bending recapitulates fidelity: moderate Limited range of ciliary bending and outer arm defects.

Show evidence (1 reference)

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

"The first model showed hydrocephalus and compromised cardiac function, ultrastructural defects in outer dynein arms, limited range of ciliary bending, and insufficient effective stroke, but no laterality defects"

Mouse ciliary phenotype.

Randomization of Left-Right Body Asymmetry fails to recapitulate fidelity: low No laterality defects in the knockout, unlike most patients.

Limitations: The knockout lacks laterality defects even though laterality defects are the most frequent human manifestation, and it has hydrocephalus, which is not reported in patients.

Divergences from the human mechanism

species mismatch invalidating

The exon 2-4 knockout mouse has no laterality defects, whereas laterality defects are present in about two thirds of DNAH9 patients. The mouse therefore cannot be used to infer how DNAH9 loss randomizes human left-right patterning.

Show evidence (1 reference)

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

"The first model showed hydrocephalus and compromised cardiac function, ultrastructural defects in outer dynein arms, limited range of ciliary bending, and insufficient effective stroke, but no laterality defects"

Absence of the laterality phenotype in the knockout.

{ }

Source YAML

click to show

name: Primary Ciliary Dyskinesia 40
creation_date: "2026-10-14T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: ciliary dyskinesia, primary, 40
  term:
    id: MONDO:0032664
    label: ciliary dyskinesia, primary, 40
description: >-
  Primary ciliary dyskinesia 40 (CILD40) is the form of primary ciliary
  dyskinesia (PCD) caused by biallelic variants in DNAH9. DNAH9 encodes a
  beta-type heavy chain of the axonemal outer dynein arm. In human
  respiratory cilia it is found only in the distal part of the axoneme,
  where it pairs with DNAH5 to form the distal (type 2) outer dynein arm;
  the proximal arms use its paralogue DNAH11 instead.

  Loss of DNAH9 removes DNAH9 and the other type 2 arm components (DNAH5,
  DNAI1, DNAI2) from the distal cilium only. Standard electron microscopy
  shows a partial loss of outer dynein arms, and high-speed video
  microscopy shows reduced bending of the distal cilium and a modestly
  reduced beat frequency. Because the proximal arms are intact, some
  mucociliary clearance is kept.

  The clinical picture is milder than typical PCD and is dominated by
  laterality defects, present in about two thirds of reported patients
  and often with complex congenital heart disease. Respiratory disease is
  mild, limited to the upper airway, or absent, and nasal nitric oxide is
  usually normal or high, so the standard PCD screen can miss it.
  Asthenozoospermia has been reported in a few men.
parents:
- Primary Ciliary Dyskinesia
- Ciliopathy
synonyms:
- CILD40
- ciliary dyskinesia, primary, 40
- DNAH9-related primary ciliary dyskinesia
notes: >-
  MONDO cross-references this disease as OMIM 618300. ClinGen classifies the
  DNAH9 relationship with this disease as Definitive (autosomal recessive,
  2026). ClinGen notes that DNAH9 was not detected in sperm flagella by
  immunofluorescence, yet asthenozoospermia was reported in four men; this
  has not been reconciled, so the sperm phenotype is recorded without a
  mechanistic edge.
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 DNAH9 variants.
  evidence:
  - reference: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
    reference_title: "DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "is definitively associated with autosomal recessive primary ciliary dyskinesia 40"
    explanation: ClinGen statement of the inheritance mode.
  - reference: PMID:35050399
    reference_title: "Biallelic DNAH9 mutations are identified in Chinese patients with defective left-right patterning and cilia-related complex congenital heart disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified compound heterozygous mutations in DNAH9 in the affected individuals of these family trios"
    explanation: Compound heterozygosity in trios.
prevalence:
- population: Published DNAH9 patients
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    By ClinGen's 2026 count, 31 patients with 50 different variants had been
    reported in 16 papers between 2018 and 2024. Because many patients have
    mild respiratory disease and normal nasal nitric oxide, this is likely
    an undercount.
  evidence:
  - reference: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
    reference_title: "DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Between 2018 and 2024, 16 different papers reported DNAH9 variants in a total of 31 patients."
    explanation: Published case count.
pathophysiology:
- name: Biallelic DNAH9 Variants
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    Null and missense variants in DNAH9 lead to loss of DNAH9 from
    respiratory cilia.
  genes:
  - preferred_term: DNAH9
    term:
      id: hgnc:2953
      label: DNAH9
  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: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
    reference_title: "DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A total of 50 different mutations were detected in the reported patients and consisted of 22 null mutations, 1 in-frame deletion and 27 missense variants"
    explanation: Allelic spectrum.
  - reference: PMID:30471718
    reference_title: "Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report loss-of-function mutations in DNAH9 in five independent families causing situs abnormalities associated with subtle respiratory ciliary dysfunction."
    explanation: Loss-of-function variants in the defining study.
  downstream:
  - target: Loss of Distal Type 2 Outer Dynein Arms
    causal_link_type: DIRECT
- name: Loss of Distal Type 2 Outer Dynein Arms
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    DNAH9 is needed to assemble the distal outer dynein arms. Without it,
    DNAH5, DNAI1 and DNAI2 are also missing from the distal cilium, while
    proximal DNAH11-containing arms remain.
  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
  biological_processes:
  - preferred_term: outer dynein arm assembly
    modifier: DECREASED
    term:
      id: GO:0036158
      label: outer dynein arm assembly
  evidence:
  - reference: PMID:30471718
    reference_title: "Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNAH9-deficient cilia also lack other ODA components such as DNAH5, DNAI1, and DNAI2 from the distal axonemal compartment, demonstrating an essential role of DNAH9 for distal axonemal assembly of ODAs type 2."
    explanation: Distal-only loss of type 2 outer arms.
  - reference: PMID:30471717
    reference_title: "Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "3D electron tomography ultrastructural studies confirmed regional loss of ODAs from the distal cilium, manifesting as either loss of whole ODA or partial loss of ODA volume."
    explanation: Independent ultrastructural confirmation.
  - 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 normal ciliated airway epithelium, DNAH5 and DNAH9 show a specific regional distribution along the ciliary axoneme, indicating the existence of at least two distinct ODA types."
    explanation: The regional outer arm types that explain why DNAH9 loss is distal.
  downstream:
  - target: Reduced Distal Ciliary Bending
    causal_link_type: DIRECT
  - target: Partial outer dynein arm defect
    causal_link_type: DIRECT
- name: Reduced Distal Ciliary Bending
  biological_scale: CELLULAR
  role: effector
  description: >-
    The distal part of the cilium bends poorly and beat frequency is
    modestly reduced. The defect is subtle and some clearance is kept.
  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:30471718
    reference_title: "Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high-speed video microscopy demonstrates distally impaired ciliary bending in DNAH9 mutant respiratory cilia"
    explanation: The beat defect.
  - reference: PMID:30471717
    reference_title: "Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This confers a reduced beating frequency with a subtle beating pattern defect affecting the motility of the distal cilia portion."
    explanation: Reduced frequency and distal beat defect.
  downstream:
  - target: Partially Impaired Mucociliary Clearance
    causal_link_type: DIRECT
  - target: Randomization of Left-Right Body Asymmetry
    causal_link_type: DIRECT
  - target: Abnormal ciliary motility
    causal_link_type: DIRECT
- name: Partially Impaired Mucociliary Clearance
  biological_scale: TISSUE
  role: effector
  description: >-
    Clearance is reduced but not lost, so respiratory symptoms are mild,
    mostly in the upper airway, or absent. Nasal nitric oxide is usually
    normal or high.
  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:30471717
    reference_title: "Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNAH9 mutations reduce cilia function but some respiratory mucociliary clearance potential may be retained, widening the PCD disease spectrum."
    explanation: Partial retention of clearance.
  - reference: PMID:30471717
    reference_title: "Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract"
    explanation: The mild, mainly upper airway, phenotype.
  downstream:
  - target: Recurrent respiratory infections
    causal_link_type: DIRECT
  - target: Chronic sinusitis
    causal_link_type: DIRECT
- name: Randomization of Left-Right Body Asymmetry
  biological_scale: ORGANISM
  role: consequence
  description: >-
    Laterality defects are the most common manifestation, often with
    complex congenital heart disease. In zebrafish, dnah9 knockdown disturbs
    cardiac left-right patterning without affecting cilia formation in
    Kupffer's vesicle.
  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_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
    reference_title: "DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Laterality defects were observed in 20/31 (65%) patients and asthenozoospermia was reported in 4 male patients."
    explanation: Frequency of laterality defects.
  - reference: PMID:35050399
    reference_title: "Biallelic DNAH9 mutations are identified in Chinese patients with defective left-right patterning and cilia-related complex congenital heart disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "dnah9 knockdown in zebrafish lead to the disturbance of cardiac left-right patterning without affecting ciliogenesis in Kupffer's vesicle (KV)."
    explanation: Functional evidence in zebrafish.
  downstream:
  - target: Situs inversus totalis
    causal_link_type: DIRECT
  - target: Heterotaxy
    causal_link_type: DIRECT
  - target: Complex congenital heart disease
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Cellular
  name: Partial outer dynein arm defect
  description: >-
    Standard TEM shows partial absence of outer dynein arms; tomography
    places the loss in the distal cilium.
  phenotype_term:
    preferred_term: Partial distal outer dynein arm defect
    term:
      id: HP:0012255
      label: Dynein arm defect of respiratory motile cilia
  frequency: FREQUENT
  evidence:
  - reference: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
    reference_title: "DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Ciliary investigations by transmission electron microscopy showed partial absence of the outer dynein arms."
    explanation: TEM finding.
  - reference: PMID:35050399
    reference_title: "Biallelic DNAH9 mutations are identified in Chinese patients with defective left-right patterning and cilia-related complex congenital heart disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transmission Electron Microscopy (TEM) analysis identified ultrastructural defects of the outer dynein arms in these affected individuals."
    explanation: Outer arm defects in a second cohort.
- category: Cellular
  name: Abnormal ciliary motility
  description: Reduced distal bending and a modestly reduced beat frequency.
  phenotype_term:
    preferred_term: Abnormal ciliary motility
    term:
      id: HP:0012262
      label: Abnormal ciliary motility
  frequency: FREQUENT
  evidence:
  - reference: PMID:30471718
    reference_title: "Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "high-speed video microscopy demonstrates distally impaired ciliary bending in DNAH9 mutant respiratory cilia"
    explanation: HSVA finding.
- category: Cardiovascular
  name: Situs inversus totalis
  description: Mirror-image organ arrangement, the presenting feature in many reported patients.
  phenotype_term:
    preferred_term: Situs inversus totalis
    term:
      id: HP:0001696
      label: Situs inversus totalis
  frequency: FREQUENT
  evidence:
  - reference: PMID:30471717
    reference_title: "Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9 in individuals from PCD clinics with situs inversus"
    explanation: Situs inversus in DNAH9 patients.
- category: Cardiovascular
  name: Heterotaxy
  description: Laterality defects other than complete reversal.
  phenotype_term:
    preferred_term: Heterotaxy
    term:
      id: HP:0030853
      label: Heterotaxy
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35050399
    reference_title: "Biallelic DNAH9 mutations are identified in Chinese patients with defective left-right patterning and cilia-related complex congenital heart disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Defective left-right (LR) pattering results in a spectrum of laterality disorders including situs inversus totalis (SIT) and heterotaxy syndrome (Htx)."
    explanation: >-
      Background framing of the study, whose patients had laterality defects
      with complex congenital heart disease.
    quote_role: BACKGROUND
- category: Cardiovascular
  name: Complex congenital heart disease
  description: >-
    Complex congenital heart disease, including dextroversion, is reported
    with DNAH9 laterality defects and can be detected prenatally.
  phenotype_term:
    preferred_term: Complex congenital heart disease
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:35050399
    reference_title: "Biallelic DNAH9 mutations are identified in Chinese patients with defective left-right patterning and cilia-related complex congenital heart disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe six unrelated family trios and 2 sporadic patients with laterality defects and complex congenital heart disease (CHD)."
    explanation: Complex CHD in DNAH9 patients.
  - reference: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
    reference_title: "DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These included complex congenital heart disease with dextroversion"
    explanation: Prenatally detected cardiac anomalies.
- category: Respiratory
  name: Recurrent respiratory infections
  description: >-
    Mild or absent in most patients; when present, mostly upper airway.
    Some patients have recurrent infections and low lung function.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  frequency: OCCASIONAL
  evidence:
  - reference: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
    reference_title: "DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While most of the patients with DNAH9 defects had laterality defects and mild or no respiratory signs"
    explanation: Respiratory disease is mild or absent in most.
  - reference: PMID:35729109
    reference_title: "Dnah9 mutant mice and organoid models recapitulate the clinical features of patients with PCD and provide an excellent platform for drug screening."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified compound mutation of DNAH9 in a patient with PCD with the following clinical features: recurrent respiratory tract infections, low lung function, and ultrastructural defects of the outer dynein arms (ODAs)"
    explanation: A patient with more typical respiratory PCD.
- category: Respiratory
  name: Chronic sinusitis
  description: Upper airway disease is the main respiratory manifestation.
  phenotype_term:
    preferred_term: Chronic sinusitis
    term:
      id: HP:0011109
      label: Chronic sinusitis
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30471717
    reference_title: "Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "despite DNAH9 mutations appearing to confer symptoms restricted to the upper respiratory tract"
    explanation: Upper respiratory tract symptoms; sinusitis specifically is inferred.
- category: Reproductive
  name: Reduced sperm motility
  description: Asthenozoospermia has been reported in a few men, including one with male infertility.
  phenotype_term:
    preferred_term: Asthenozoospermia
    term:
      id: HP:0012207
      label: Reduced sperm motility
  frequency: OCCASIONAL
  evidence:
  - reference: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
    reference_title: "DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "asthenozoospermia was reported in 4 male patients"
    explanation: ClinGen tally.
  - reference: PMID:30471717
    reference_title: "Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with situs inversus and in one case male infertility"
    explanation: Male infertility in one patient.
genetic:
- name: DNAH9
  gene_term:
    preferred_term: DNAH9
    term:
      id: hgnc:2953
      label: DNAH9
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    The only gene for CILD40. About half of reported variants are missense,
    which complicates interpretation; ClinGen downscored cases with a likely
    pathogenic variant in trans with a likely benign variant.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
    evidence:
    - reference: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
      reference_title: "DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "DNAH9 | HGNC:2953 | ciliary dyskinesia, primary, 40 | MONDO:0032664 | AR | Definitive"
      explanation: ClinGen Motile Ciliopathy GCEP classifies DNAH9 / ciliary dyskinesia, primary, 40 as Definitive (AR).
  evidence:
  - reference: PMID:30471718
    reference_title: "Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report loss-of-function mutations in DNAH9 in five independent families causing situs abnormalities associated with subtle respiratory ciliary dysfunction."
    explanation: Gene identification.
  - reference: PMID:30471717
    reference_title: "Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using next-generation sequencing, we detected mutations in the ciliary outer dynein arm (ODA) heavy chain gene DNAH9"
    explanation: Independent simultaneous identification.
diagnosis:
- name: Nasal Nitric Oxide
  description: >-
    Nasal nitric oxide is usually normal to high in DNAH9 disease, so a
    normal value does not exclude it in a patient with a laterality defect.
  evidence:
  - reference: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
    reference_title: "DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nasal nitric oxide measurements in 13 patients with DNAH9 mutations showed normal to high values (36-220 nL/min)"
    explanation: Nasal NO is not reduced.
- name: High-Speed Video Microscopy
  description: Shows reduced distal ciliary bending.
  evidence:
  - reference: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
    reference_title: "DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A reduced ciliary distal bending was observed with high speed video microscopy"
    explanation: HSVA finding.
- name: Transmission Electron Microscopy and Electron Tomography
  description: >-
    TEM shows partial absence of outer dynein arms; tomography localizes
    the loss to the distal cilium.
  evidence:
  - reference: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
    reference_title: "DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Electron tomography showed more precise ciliary abnormality consisting of a reduced volume of ODA from the distal cilia"
    explanation: Tomography finding.
- name: Immunofluorescence Staining
  description: >-
    DNAH9 is absent from respiratory cilia, and DNAH5, DNAI1, DNAI2 and
    DNALI1 are missing from the distal axoneme only.
  evidence:
  - reference: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
    reference_title: "DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This is consistent with immunofluorescence assays showing absence of DNAH9 and distal absence of DNAH5, DNAI1, DNAI2 and DNALI1 in respiratory cilia"
    explanation: Immunofluorescence pattern.
- name: Genetic Testing
  description: >-
    Sequencing identifies biallelic DNAH9 variants. DNAH9 should be
    included in testing for isolated laterality defects and congenital
    heart disease, not only for respiratory PCD.
  evidence:
  - reference: PMID:35050399
    reference_title: "Biallelic DNAH9 mutations are identified in Chinese patients with defective left-right patterning and cilia-related complex congenital heart disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Through whole exome sequencing (WES), we identified compound heterozygous mutations in DNAH9 in the affected individuals of these family trios."
    explanation: Exome sequencing in laterality/CHD trios.
animal_models:
- name: Dnah9 knockdown mouse
  species: Mouse
  genotype: Dnah9 knockdown
  publication: PMID:35729109
  description: >-
    Dnah9 knockdown mice have low lung function, mucin accumulation and
    immune cell infiltration, loss of distal outer dynein arms and reduced
    ciliary beat frequency. Airway organoids from these mice reproduce key
    PCD features.
  modeled_mechanisms:
  - target: Partially Impaired Mucociliary Clearance
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Low lung function, mucin accumulation and immune cell infiltration.
    evidence:
    - reference: PMID:35729109
      reference_title: "Dnah9 mutant mice and organoid models recapitulate the clinical features of patients with PCD and provide an excellent platform for drug screening."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Dnah9 knock-down (KD) mice recapitulated the patient phenotypes, including low lung function, mucin accumulation, and increased immune cell infiltration."
      explanation: Airway phenotype of the mouse.
  - target: Loss of Distal Type 2 Outer Dynein Arms
    relationship: RECAPITULATES
    fidelity: HIGH
    description: Absence of distal ciliary outer arms and reduced beat frequency.
    evidence:
    - reference: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
      reference_title: "DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice from the second model showed absence of distal ciliary ODA and a reduced ciliary beat frequency"
      explanation: ClinGen summary of the mouse ultrastructure.
- name: Dnah9 knockout mouse (exons 2-4 deletion)
  species: Mouse
  genotype: Dnah9 knockout (CRISPR/Cas9 deletion of exons 2-4)
  publication: PMID:35050399
  description: >-
    Has hydrocephalus, compromised cardiac function, outer dynein arm
    defects, limited ciliary bending and insufficient effective stroke, but
    no laterality defects.
  modeled_mechanisms:
  - target: Reduced Distal Ciliary Bending
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Limited range of ciliary bending and outer arm defects.
    evidence:
    - reference: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
      reference_title: "DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The first model showed hydrocephalus and compromised cardiac function, ultrastructural defects in outer dynein arms, limited range of ciliary bending, and insufficient effective stroke, but no laterality defects"
      explanation: Mouse ciliary phenotype.
  - target: Randomization of Left-Right Body Asymmetry
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: No laterality defects in the knockout, unlike most patients.
    limitations: >-
      The knockout lacks laterality defects even though laterality defects
      are the most frequent human manifestation, and it has hydrocephalus,
      which is not reported in patients.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: INVALIDATING
      description: >-
        The exon 2-4 knockout mouse has no laterality defects, whereas
        laterality defects are present in about two thirds of DNAH9 patients.
        The mouse therefore cannot be used to infer how DNAH9 loss randomizes
        human left-right patterning.
    evidence:
    - reference: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
      reference_title: "DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The first model showed hydrocephalus and compromised cardiac function, ultrastructural defects in outer dynein arms, limited range of ciliary bending, and insufficient effective stroke, but no laterality defects"
      explanation: Absence of the laterality phenotype in the knockout.
treatments:
- name: Airway Clearance and Chronic Infection Management
  description: >-
    There is no treatment that restores ciliary function. For patients with
    respiratory symptoms, management is the supportive care used across
    primary ciliary dyskinesia: airway clearance and prompt treatment of
    respiratory infections. Nothing in it is specific to DNAH9.

    In DNAH9 disease, respiratory signs are mild or absent in most reported
    patients, and the clinical picture is dominated by laterality defects and
    complex congenital heart disease. Airway care therefore applies to a
    minority of patients. The cardiac and laterality problems are managed as
    in other causes of heterotaxy and congenital heart disease, and that
    management is not curated here.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Partially Impaired Mucociliary Clearance
    description: >-
      Airway clearance techniques supplement the partial mucociliary transport
      the distally defective cilia still provide. They do not restore ciliary
      function.
  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 DNAH9 disease by
      inference, since no genotype-stratified treatment evidence exists.
  - reference: CGGV:assertion_7d4c2324-1f4e-48d6-b7e9-cc66f7a9dda3-2026-06-11T100000.000Z
    reference_title: "DNAH9 / ciliary dyskinesia, primary, 40 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While most of the patients with DNAH9 defects had laterality defects and mild or no respiratory signs"
    explanation: >-
      Why airway care applies to only a minority of DNAH9 patients and the
      clinical burden is laterality and cardiac disease.
differential_diagnoses:
- name: Primary Ciliary Dyskinesia 3
  description: >-
    DNAH5 disease removes outer dynein arms along the whole cilium, giving
    immotile cilia, low nasal nitric oxide and typical PCD lung disease.
- name: Primary Ciliary Dyskinesia 7
  description: >-
    DNAH11 disease affects the proximal outer arms, with normal standard
    ultrastructure and stiff, hyperkinetic cilia.

📚

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 40 (DNAH9) · 2026-10-14T20:30:37Z · View source

New gene-specific entry for CILD40 (MONDO:0032664, DNAH9). 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_40-deep-research-claude_code.md, run directly with the claude_code provider. preflight-dr returned WARN because DNAH5 is mentioned often; those mentions concern DNAH5 as the distal type 2 ODA partner lost with DNAH9, not a different disease. The ClinGen 2026 Definitive record (CGGV) supplied the case count, phenotype frequencies, normal-to-high nasal NO and mouse model summaries. The reduced sperm motility phenotype is deliberately left without a causal edge, because ClinGen reports DNAH9 absent from sperm flagella. The exon 2-4 knockout is recorded as FAILS_TO_RECAPITULATE for laterality. Same validation set as PCD3.

Claude Code ▸

Primary Ciliary Dyskinesia 40 (CILD40, DNAH9-related)

claude-haiku-5-5, claude-sonnet-5-5 22 citations 2026-10-14T20:13:42.721771

Status: I've confirmed PCD40 (CILD40) is caused by biallelic DNAH9 variants and have the key PMIDs. I'm now pulling the Loges and Fassad abstracts so I can quote them exactly.

Primary Ciliary Dyskinesia 40 (CILD40, DNAH9-related)

Method and limits. This report rests on web searches and PubMed E-utilities lookups. I could not read OMIM, Orphanet or ClinGen directly (the MalaCards fetch returned 403). Where a statement comes from a secondary aggregator, I say so. Not every detail below was checked against a primary abstract. Items marked [unverified] are from my background knowledge or an aggregator and should be checked before curation. Direct quotes below are short and come from search or abstract summaries, not full-text reading. Run just fetch-reference PMID:<id> and re-extract exact snippets before using any quote as evidence. The PMIDs listed here came from the PubMed search, but I did not confirm every one against the full record.

1. Disease information

Overview. PCD40, or CILD40, is an autosomal recessive form of primary ciliary dyskinesia. It is caused by homozygous or compound heterozygous variants in DNAH9 on chromosome 17p12. DNAH9 encodes an outer dynein arm (ODA) heavy chain. The distinguishing feature is a mild respiratory phenotype with prominent laterality defects. (MalaCards; MedGen via NCBI mirror)
Identifiers. MONDO:0032664; OMIM #618300; MedGen C4749028 (per the MedGen mirror URL; "1648365" in one search summary is probably a mis-transcription, so check it); gene DNAH9 (HGNC symbol; the KB form is lowercase hgnc:<n>, and I did not look up the number). (DrugMap; NORD/MONDO)
Synonyms. CILD40; "Ciliary dyskinesia, primary, 40, with or without situs inversus"; PCD40.
Data source. This is an aggregated, disease-level description built from case series. It is not EHR-derived.
Parent and relatives. This is one of the genetically defined PCD subtypes, each of which has its own MONDO ID (MONDO:0014910 is another PCD subtype that appeared in the GenCC results, not this one).

2. Etiology

Cause. Biallelic loss-of-function (LoF) variants in DNAH9. Loges et al. reported "loss-of-function mutations in DNAH9 in five independent families" (PMID:30471718). Fassad et al. identified DNAH9 mutations in PCD-clinic individuals with situs inversus and, in one case, male infertility (PMID:30471717).
Risk and protective factors. None are established for this recessive monogenic condition. A common-variant study reported an interaction between DNAH9 and early-life smoke exposure for bronchial hyperresponsiveness (PMID:26797031), but that concerns asthma-type traits in the general population, not CILD40.
Gene–environment. Tobacco smoke and airway infections plausibly worsen respiratory disease in any PCD. I found no CILD40-specific data [unverified].

3. Phenotypes

Phenotype	Suggested HPO	Frequency / note
Situs inversus totalis	HP:0001696	Reported in all CILD40 patients in the MalaCards/OMIM summary. Caution: a single family in Fassad had an affected sibling pair, both with situs inversus.
Heterotaxy / laterality defect	HP:0031318	Several patients with severe congenital heart disease (PMID:35050399; PMID:40376972)
Congenital heart defect	HP:0001627	Cilia-related CHD in Chinese cohort (Chen 2022)
Chronic rhinosinusitis	HP:0004429 (verify)	Reported in the Somali sibling pair
Recurrent respiratory infections / productive cough	HP:0002205 (verify)	Pediatric productive cough (PMID:33452233)
Bronchiectasis	HP:0002110	Not well documented in the sources I found; typically late and mild if present [unverified]
Male infertility / asthenozoospermia	HP:0012206 (verify)	Fassad (one case); PMID:33610189; PMID:39523437
Jejunal atresia	HP:0005214 (verify)	Single Bahraini child (PMID:36712782); a single report, so treat as an anecdotal association

Respiratory course. MalaCards says "compared with other CILDs the respiratory phenotype is relatively mild and patients typically do not develop serious lung disease." Symptoms typically begin in childhood as mild upper respiratory infections.
Normal screening tests. One conference abstract reports normal nasal nitric oxide, normal ciliary beat frequency and preserved mucociliary clearance in three patients (ERJ abstract). This conflicts with Fassad, who found a reduced beat frequency in the distal cilia (see below). Likely explanation: the defect is subtle and regional, so results vary by method.
Quality of life. No CILD40-specific data found.

4. Genetic / molecular information

Gene. DNAH9, 17p12, dynein axonemal heavy chain 9, with ~70 exons [unverified]. The original gene description is Bartoloni et al. (PMID:11247663).
Variants. Biallelic LoF (nonsense, frameshift, splice) and some missense variants have been reported across the case series above. I did not extract specific variant nomenclature or ClinVar classifications.
Variant origin. Germline.
Allele frequency / founder effects. Not checked. Check gnomAD and ClinVar before curation.
Modifiers and epigenetics. None known.
Chromosomal abnormalities. Not applicable.
Gene-disease validity. The DrugMap/GenCC data list the DNAH9 association as strong; I could not read the ClinGen record. If a ClinGen assertion exists, cache it as CGGV: rather than recording a tier from memory.

5. Environmental information

No specific environmental or infectious causes. Secondary respiratory pathogens (e.g., Haemophilus influenzae, Pseudomonas aeruginosa) are expected as in other PCD forms [unverified for CILD40].

6. Mechanism / pathophysiology

Causal chain

Biallelic germline DNAH9 LoF variants lead to absent or truncated DNAH9 protein. (Demonstrated: Loges 2018, Fassad 2018.)
Loss of DNAH9 results in loss of DNAH9/DNAH5-containing type 2 ODAs, which is restricted to the distal region of the cilium. Fassad et al.: "DNAH9 and its partner heavy chain DNAH5 localize to type 2 ODAs of the distal cilium... a loss of DNAH9/DNAH5-containing type 2 ODAs that was restricted to the distal cilia region." Electron tomography confirmed regional loss of whole or partial ODAs. Loges et al. found that DNAH9-deficient cilia also lack other ODA components in the distal axoneme, and that DNAH9 interacts with DNAH5, DNAI2 and CCDC114. (Demonstrated, in human cells.)
Loss of distal type 2 ODAs leads to a reduced beat frequency with a subtle beat-pattern defect in the distal cilium portion. (Demonstrated, Fassad.) Proximal ODAs, which contain DNAH11 and DNAH5, are preserved, which explains the milder, sometimes near-normal, standard tests.
In motile monocilia of the embryonic node, impaired motility leads to defective leftward flow and randomized left-right axis determination. This is inferred from the genotype–phenotype pattern and from the general model of ODA-related laterality defects; I did not verify a DNAH9-specific node study.
Randomized laterality results in situs inversus and, in some cases, heterotaxy with congenital heart disease. (Observed in patients.)
In the airway, partially preserved ciliary function results in milder mucociliary clearance impairment, with childhood-onset cough and upper-airway infections. (Observed.)
In the male reproductive tract, impaired sperm flagellar motility results in asthenozoospermia and infertility. (Observed in a subset.)

Suggested ontology terms (check each with a lookup before binding): GO "outer dynein arm assembly" (GO:0036158, verify), "cilium movement" (GO:0003341, verify), "determination of left/right symmetry" (GO:0007368, verify); CL ciliated columnar epithelial cell of the airway, sperm (CL:0000019), embryonic node monocilia cells; GO:CC "outer dynein arm" (GO:0005858, verify).

Immune, metabolic and omics findings. None established for CILD40 in the humans reported. A mouse study (below) describes mucin accumulation and immune cell infiltration.

7. Anatomical structures affected

Primary: motile cilia of the respiratory tract (nose, paranasal sinuses, bronchi), the embryonic left-right organizer (node), and sperm flagella.
Secondary: heart (laterality-related CHD), middle ear (in other PCD forms; not verified here), gut (single jejunal atresia report).
Subcellular: distal ciliary axoneme, outer dynein arms.
Lateralization: the laterality phenotype is a mirror image, not an asymmetric loss.

8. Temporal development

Onset: congenital, because laterality defects are present at birth. Respiratory symptoms appear in childhood.
Progression: generally mild and slowly progressive or stable. Long-term data are lacking [unverified].
Critical period: embryonic left-right patterning. This cannot be reversed postnatally.

9. Inheritance and population

Inheritance: autosomal recessive (HP:0000007).
Prevalence: CILD40 prevalence is not established. Overall PCD prevalence is roughly 1 in 10,000–20,000 [unverified for this report; check Orphanet]. DNAH9 variants appear to be a rare cause among PCD cases.
Case series origins: European, Somali-British, Japanese, Chinese, and Bahraini patients have been reported, which suggests no single population is dominant. See Fassad, Loges, PMID:35050399, PMID:34008076 (Japanese fetus), PMID:39115416.
Carrier frequency, penetrance, consanguinity: not examined.

10. Diagnostics

Hallmark findings. Situs abnormality in a child with chronic respiratory symptoms should prompt PCD evaluation.
Why standard tests can mislead. Because the defect is restricted to distal cilia, nasal NO, high-speed video analysis and routine transmission electron microscopy can look normal or near-normal. Loges et al. and Fassad et al. both describe this. The conference abstract reports normal nasal NO and ciliary beat frequency. So a normal screen does not rule out CILD40.
More informative tests. Immunofluorescence for DNAH9 and DNAH5 along the cilium (showing a distal-only pattern), electron tomography, and genetic testing.
Genetic testing. PCD multigene panel or exome sequencing including DNAH9; several of the cited cases were found by exome sequencing (PMID:34008076, PMID:33452233).
Differential: other ODA defects (DNAH5, DNAI1, DNAH11), other laterality disorders (heterotaxy from ZIC3, MMP21, PKD1L1, GDF1; see PMID:42630107), and CF.
Guideline. The practical guide for PCD diagnosis and management is a general PCD reference.

11. Prognosis

The lung disease is expected to be milder than other PCD forms. I found no CILD40-specific survival data. Prognosis in patients with complex CHD depends mainly on the cardiac lesion.

12. Treatment

No CILD40-specific trials were found. Management follows general PCD care: airway clearance physiotherapy (NCIT: verify), prompt antibiotic treatment of infections (NCIT:C15986 Pharmacotherapy; agents vary), vaccination (NCIT:C15346), management of sinus and ear disease, and surgical or medical care of CHD where present. Assisted reproduction is an option for infertile men. Mucolytics, long-term macrolides and inhaled antibiotics are used in other PCD forms [unverified for this subtype]. Experimental: a mouse/organoid study screened mitochondria-targeting drugs that partly improved cilia beating (see below); this is preclinical only. Gene therapy is not available.

13. Prevention

Genetic counseling for a recessive condition (25% recurrence risk per pregnancy, NCIT:C15240); carrier testing for relatives; prenatal or preimplantation testing where the familial variants are known. Early diagnosis is useful so that respiratory care can start even when screening tests look normal.

14. Other species / natural disease

Not checked (OMIA was not searched). Dynein arm defects cause PCD-like disease in dogs and other species, but I have no DNAH9-specific entries [unverified].

15. Model organisms

Mouse, Dnah9 knockdown, plus airway organoids. Zheng et al. studied a patient with compound DNAH9 mutation. Per the summary I retrieved, the knockdown mice "recapitulated the patient phenotypes", with low lung function, mucin accumulation and immune cell infiltration; airway organoids were used to screen drugs, with mitochondria-targeting compounds partly improving cilia beating (PMID:35729109). Evidence source: model organism / in vitro. Limitation: this is a knockdown, not a null, and the cited patient's phenotype is what is "recapitulated", so fidelity to the laterality phenotype is not established here.
Earlier work. Mislocalization of DNAH5 and DNAH9 in PCD respiratory cells (PMID:15750039), human cell evidence.
Zebrafish, Chlamydomonas and other models: not searched.

Gaps to close before curation

Pull OMIM #618300 text, ClinVar/ClinGen entries and the Orphanet record through the repo's structured-source routes.
Read the Loges and Fassad full texts for variant nomenclature, cohort sizes and quotable snippets.
Check whether an HP term is appropriate for "distal ODA loss" or whether to leave it unbound.
Verify each HPO, GO and CL ID marked "verify" with a lookup. I did not run any term lookup, so no CURIE here is checked.
Resolve the conflict between normal ciliary beat frequency (conference abstract) and reduced frequency (Fassad).

Sources

MalaCards, CILD40
NORD/MONDO, ciliary dyskinesia, primary, 40
DrugMap disease DISJWDP0
MedGen C4749028 mirror
Fassad et al. 2018, AJHG, PMID:30471717
Loges et al. 2018, AJHG, PMID:30471718
ERJ 2018 conference abstract on DNAH9 cilia
PubMed E-utilities lookups for the other PMIDs cited above

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	15
Resolved	15
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	1
Quoted claims not found in source	0
References weighed for topical relevance	15
On topic	10
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	19
Resolved	19
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	9
Terms named correctly	3
Terms named as a different term	5
Terms whose name is worth a second look	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:

HP:0031318 (1 mention) - the report calls it "Heterotaxy / laterality defect"; HP calls it Myofiber disarray
HP:0004429 (1 mention) - the report calls it "verify"; HP calls it Recurrent viral infections
HP:0002205 (1 mention) - the report calls it "verify"; HP calls it Recurrent respiratory infections
HP:0012206 (1 mention) - the report calls it "verify"; HP calls it Abnormal sperm motility
HP:0005214 (1 mention) - the report calls it "verify"; HP calls it Intestinal obstruction

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0001627 (1 mention) - the report calls it "Congenital heart defect"; HP calls it Abnormal heart morphology, and lists "Congenital heart defect" among its other names

Primary Ciliary Dyskinesia 40

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Primary Ciliary Dyskinesia 40 (CILD40, DNAH9-related)

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic / molecular information

5. Environmental information

6. Mechanism / pathophysiology

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Prognosis

12. Treatment

13. Prevention

14. Other species / natural disease

15. Model organisms

Gaps to close before curation

Sources

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look