Primary Ciliary Dyskinesia 37

Mendelian Pathograph 19 Show in embeddings browser Primary Ciliary Dyskinesia Ciliopathy

Primary ciliary dyskinesia 37 (CILD37) is the autosomal recessive form of primary ciliary dyskinesia attributed to biallelic variants in DNAH1. DNAH1 encodes an axonemal dynein heavy chain of the inner dynein arms, the motors that shape the ciliary and flagellar waveform. In human respiratory cilia DNAH1 is the heavy chain of the single-headed inner arm called IDAd. The entity rests on one family. Two sisters born to a consanguineous Saudi Arabian union had clinically diagnosed PCD with the Kartagener triad. The proband had chronic rhinitis, cough, wheezing and bronchitis from adolescence, then bronchiectasis, situs inversus with dextrocardia, mild conductive hearing loss and five years of infertility. All known PCD genes had been excluded. Homozygosity mapping and exome sequencing found a single candidate, the homozygous missense variant DNAH1 c.3460A>C (p.Lys1154Gln), which segregated with disease. The authors titled their report as DNAH1 variation that "may contribute" to PCD. No ciliary ultrastructure, beat analysis or nasal nitric oxide was reported for the family, and the variant has no functional study. ClinGen rates DNAH1 as Limited for primary ciliary dyskinesia in general. Biallelic DNAH1 variants are much better established as a cause of male infertility with multiple morphological abnormalities of the sperm flagella (MMAF), curated separately as Spermatogenic Failure 18 (SPGF18). In those men, infertility was the only PCD-type feature. How one gene gives an isolated sperm defect in some families and full Kartagener syndrome in another is not resolved. Allele severity, a modifier, or a second unidentified cause in the index family are all possible. Further DNAH1 variants turn up in PCD and Kartagener cohorts, mostly as compound heterozygous missense changes, but those reports do not test pathogenicity. Dnah1 knockout mice support a respiratory role: tracheal cilia beat at about half the normal frequency and males are infertile.

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1
Inheritance
5
Pathophys.
11
Phenotypes
19
Pathograph
1
Genes
2
Medical Actions
1
Differentials
1
Models
1
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Both affected sisters were homozygous for the DNAH1 variant, which segregated with the phenotype across twelve genotyped family members from a consanguineous union.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:25927852 SUPPORT Human Clinical
"A novel homozygous missense aberration (p.Lys1154Gln) was identified in both sisters in the DNAH1 gene that segregated completely with the disease phenotype."
Homozygous variant segregating with disease in a consanguineous family fits recessive inheritance.
⚙

Pathophysiology

5
Loss of DNAH1 Inner-Arm Dynein Heavy Chain Function
The index variant replaces a conserved lysine in the N-terminal stem of DNAH1, the part of the heavy chain that contacts other heavy chains and arm subunits. Its effect on the protein has not been tested; loss of function is inferred from conservation and prediction tools.
DNAH1 hgnc:2940 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DNAH1 (hgnc:2940). hgnc:2940 is a gene from the HUGO Gene Nomenclature Committee.
minus-end-directed microtubule motor activity GO:0008569 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased minus-end-directed microtubule motor activity (GO:0008569). GO:0008569 is a molecular function from the Gene Ontology.
Inner dynein arm GO:0036156 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Inner dynein arm (GO:0036156). GO:0036156 is a cellular component from the Gene Ontology.
Downstream
Inner Dynein Arm Dysfunction in Motile Cilia DNAH1 is the heavy chain of inner arm IDAd in human respiratory cilia, so its loss is expected to remove or disable that arm. In the CILD37 family this step is inferred; no ciliary sample was examined.
Inner Dynein Arm Dysfunction in the Sperm Flagellum Shown in men with biallelic DNAH1 variants (SPGF18) and in knockout mice, not in the CILD37 family, whose two affected members are women.
Show evidence (2 references)
PMID:25927852 SUPPORT Human Clinical
"The lysine residue altered in these patients is located in the highly conserved N-terminal stem of the DNAH1 protein."
Locates the index variant in a conserved functional region of the heavy chain.
PMID:25927852 SUPPORT Computational
"p.Lys1154Gln is predicted to be probably damaging with a score of 0.998 on Polyphen"
In silico prediction is the only functional evidence for the variant.
Inner Dynein Arm Dysfunction in Motile Cilia
Loss of an inner-arm heavy chain weakens and distorts the ciliary beat. In Dnah1 knockout mice the tracheal ciliary beat frequency falls by about half without any gross change in axonemal structure, which is why such a defect can be missed by electron microscopy. Respiratory cilia of CILD37 patients have not been examined, so this node rests on mouse data and on the location of DNAH1 in human respiratory cilia.
Respiratory tract multiciliated cell CL:4030034 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Respiratory tract multiciliated cell (CL:4030034). CL:4030034 is a cell type from the Cell Ontology.
Cilium movement GO:0003341 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Cilium movement (GO:0003341). GO:0003341 is a biological process from the Gene Ontology.
Inner dynein arm GO:0036156 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Inner dynein arm (GO:0036156). GO:0036156 is a cellular component from the Gene Ontology.
Animal models
Mdhc7 (Dnah1) knockout mouse Mouse partially recapitulates Reduced tracheal ciliary beat frequency in the absence of DNAH1.
Downstream
Impaired Mucociliary Clearance
Defective Left-Right Axis Determination Nodal cilia share the axonemal dyneins of respiratory cilia. Whether DNAH1 is needed at the embryonic node has not been tested; the link rests on the situs inversus seen in the index family.
Female infertility Oviduct cilia move the egg towards the uterus, and impaired oviduct cilia are the usual explanation for subfertility in women with PCD. The proband's oviduct cilia were not studied.
Show evidence (2 references)
PMID:11371505 SUPPORT INDIRECT Model Organism
"we measured the beat frequency of tracheal cilia and observed a decrease in the beat frequency of approximately 50% in MDHC7(-/-) mice"
Mouse Dnah1 (MDHC7) loss halves tracheal ciliary beat frequency.
PMID:11371505 SUPPORT Model Organism
"The reduction in both ciliary and flagellar motility is not correlated with any gross defects in the axonemal structure."
The motility defect occurs without visible axonemal change.
Impaired Mucociliary Clearance
Weak ciliary beating fails to move mucus out of the nose, sinuses, middle ear and bronchi. Retained secretions lead to chronic rhinitis, cough and bronchitis, and repeated infection damages the bronchial wall into bronchiectasis. This is the general PCD mechanism; it has not been measured in CILD37 patients.
Mucociliary clearance GO:0120197 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Mucociliary clearance (GO:0120197). GO:0120197 is a biological process from the Gene Ontology.
Downstream
Chronic rhinitis
Cough
Wheezing
Bronchitis
Bronchiectasis Repeated airway infection and inflammation damage the bronchial wall.
Conductive hearing impairment Middle-ear effusion from failed clearance of the middle ear is the usual cause of conductive hearing loss in PCD.
Show evidence (1 reference)
PMID:25927852 SUPPORT BACKGROUND Human Clinical
"such biological defects are demonstrated clinically by recurrent or chronic sinusitis and bronchiectasis caused by immotile cilia in the upper and lower airways"
The index paper's own statement of the general PCD mechanism linking cilia to airway disease.
Defective Left-Right Axis Determination
Situs inversus with dextrocardia in the proband implies that left-right patterning failed, which in PCD follows loss of nodal ciliary flow. The step is inferred from the phenotype.
Nodal cilium movement in left-right asymmetry GO:0060287 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Nodal cilium movement in left-right asymmetry, annotated with epithelial cilium movement involved in determination of left/right asymmetry (GO:0060287). GO:0060287 is a biological process from the Gene Ontology.
Downstream
Situs inversus totalis
Dextrocardia
Show evidence (1 reference)
PMID:25927852 SUPPORT Human Clinical
"a chest X-ray and CT scan showed the other two classic KS symptoms in combination with infertility; situs inversus (Figure 1A) and bronchiectasis (Figure 1B)"
Laterality defect in the proband.
Inner Dynein Arm Dysfunction in the Sperm Flagellum
In men with biallelic DNAH1 variants, sperm lack DNAH1 and the inner dynein arms, and the axoneme is disorganized, giving multiple morphological abnormalities of the flagella. Dnah1 knockout mouse sperm swim poorly but look normal. No man with CILD37 has been reported, so this branch comes from the allelic disorder SPGF18 and from mice.
Sperm CL:0000019 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sperm (CL:0000019). CL:0000019 is a cell type from the Cell Ontology.
Flagellated sperm motility GO:0030317 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Flagellated sperm motility (GO:0030317). GO:0030317 is a biological process from the Gene Ontology.
Sperm flagellum GO:0036126 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Sperm flagellum (GO:0036126). GO:0036126 is a cellular component from the Gene Ontology.
Animal models
Mdhc7 (Dnah1) knockout mouse Mouse partially recapitulates Poorly motile sperm and male infertility.
Downstream
Reduced sperm motility
Male infertility
Show evidence (2 references)
PMID:24360805 SUPPORT INDIRECT Human Clinical
"A general axonemal disorganization including mislocalization of the microtubule doublets and loss of the inner dynein arms was observed."
Sperm ultrastructure in a man with biallelic DNAH1 variants (SPGF18), not a CILD37 patient.
PMID:11371505 SUPPORT Model Organism
"the spermatozoa of MDHC7(-/-) mice revealed a dramatic reduced straight line velocity and progressive movement, resulting in the inability of MDHC7-deficient sperm to move from the uterus into the oviduct"
Mouse knockout sperm motility defect.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Primary Ciliary Dyskinesia 37 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

11
Cardiovascular 2
Situs inversus totalis HP:0001696 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Situs inversus, annotated with Situs inversus totalis (HP:0001696). HP:0001696 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25927852 SUPPORT Human Clinical
"AP Chest X-ray of proband indicating (i) dextrocardia with (ii) right-sided aortic arch. The gastric air bubble is also in the right side (iii) that is most likely representing situs inversus."
Mirror-image organ arrangement in the proband.
Dextrocardia HP:0001651 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dextrocardia (HP:0001651). HP:0001651 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25927852 SUPPORT Human Clinical
"AP Chest X-ray of proband indicating (i) dextrocardia with (ii) right-sided aortic arch."
Dextrocardia in the proband.
Ear 1
Conductive hearing impairment HP:0000405 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mild conductive hearing loss, annotated with Conductive hearing impairment (HP:0000405). HP:0000405 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25927852 SUPPORT Human Clinical
"Audiometric evaluation also revealed mild conductive hearing loss."
Middle-ear involvement in the proband.
Genitourinary 3
Female infertility HP:0008222 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Female infertility (HP:0008222). HP:0008222 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25927852 SUPPORT Human Clinical
"She was referred to King Faisal Specialist Hospital & Research Centre at the age of 29 for IVF for infertility spanning 5 years."
Infertility in the proband.
Male infertility HP:0003251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Male infertility (HP:0003251). HP:0003251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:11371505 SUPPORT Model Organism
"Both MDHC7(+/-) and MDHC7(-/-) mice are viable and show no malformations; however, homozygous males produce no offspring."
Male infertility in Dnah1 knockout mice.
Reduced sperm motility HP:0012207 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Asthenozoospermia, annotated with Reduced sperm motility (HP:0012207). HP:0012207 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24360805 SUPPORT INDIRECT Human Clinical
"presenting with primary infertility resulting from impaired sperm motility caused by a mosaic of multiple morphological abnormalities of the flagella (MMAF)"
Sperm motility defect in men with biallelic DNAH1 variants (SPGF18).
Head and Neck 1
Chronic rhinitis HP:0002257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic rhinitis (HP:0002257). HP:0002257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25927852 SUPPORT Human Clinical
"The proband had a previous medical history at 13 years of age with chronic rhinitis, frequent coughing and wheezing, nasal discharge, and was diagnosed with left lung bronchitis."
Upper airway disease in the proband.
Immune 1
Bronchitis HP:0012387 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchitis (HP:0012387). HP:0012387 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25927852 SUPPORT Human Clinical
"was diagnosed with left lung bronchitis"
Lower airway infection in the proband.
Respiratory 3
Cough HP:0012735 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Frequent cough, annotated with Cough (HP:0012735). HP:0012735 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25927852 SUPPORT Human Clinical
"The proband had a previous medical history at 13 years of age with chronic rhinitis, frequent coughing and wheezing"
Frequent cough in the proband.
Wheezing HP:0030828 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wheezing (HP:0030828). HP:0030828 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25927852 SUPPORT Human Clinical
"The proband had a previous medical history at 13 years of age with chronic rhinitis, frequent coughing and wheezing"
Wheezing in the proband.
Bronchiectasis HP:0002110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchiectasis (HP:0002110). HP:0002110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25927852 SUPPORT Human Clinical
"arrows are indicating bronchial wall thickening with mild bronchiectasis in the left middle lobe and also in the right lower lobe"
Imaging finding in the proband.
🧬

Genetic Associations

1
DNAH1 (Causal)
Gene: DNAH1 hgnc:2940 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DNAH1 (hgnc:2940). hgnc:2940 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
PMID:25927852 SUPPORT Human Clinical
"In exome-wide analysis on the proband the p.Lys1154Gln in DNAH1 was detected as the only possibly causative variant"
The index variant was the only candidate in the exome.
PMID:31507630 SUPPORT Human Clinical
"Six mutations in DNAH1 were identified in all individuals, indicating that DNAH1 might be a high-risk causative gene in Chinese patients with KTS."
Further DNAH1 variants in a Kartagener cohort, without functional testing.
CGGV:assertion_a07c8b6e-a558-498b-975c-b12e96878a44-2025-10-16T160000.000Z SUPPORT Other
"DNAH1 | HGNC:2940 | primary ciliary dyskinesia | MONDO:0016575 | AR | Limited"
ClinGen rates DNAH1 as Limited for primary ciliary dyskinesia in general. The assertion is for MONDO:0016575, not this numbered entity, so it is quoted here rather than recorded as gene_disease_validity.
💊

Medical Actions

2
In Vitro Fertilization
Action: In vitro fertilizationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is In vitro fertilization (NCIT:C16580). NCIT:C16580 is a clinical intervention from the NCI Thesaurus. Ontology label: In Vitro Fertilization NCIT:C16580
Platform: Other
The proband conceived by IVF after five years of infertility and delivered a healthy son. Preimplantation testing was cancelled because her husband did not carry the variant.
Show evidence (1 reference)
PMID:25927852 SUPPORT Human Clinical
"With regards to our proband, IVF was successful and pre-implantation genetic diagnosis was cancelled"
Successful IVF in the proband.
Airway Clearance and Chronic Infection Management
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Other
There is no treatment for the ciliary defect. The proband's chronic airway disease and bronchiectasis are managed with the supportive care used across primary ciliary dyskinesia: airway clearance, prompt treatment of infections, and surveillance of lung function. Nothing in it is DNAH1-specific.
Mechanism Target:
Impaired Mucociliary Clearance — Airway clearance techniques substitute mechanically for the mucus transport the cilia cannot provide, and antibiotics treat the infections that follow. Neither restores ciliary function.
Show evidence (1 reference)
PMID:38891105 SUPPORT REVIEW SYNTHESIS Human Clinical
"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"
Review statement of standard PCD airway management. It covers PCD in general and is not specific to DNAH1.
🔬

Diagnosis

1
Exome Sequencing After Negative PCD Gene Testing
DNAH1 was found only after a PCD gene panel was negative, by homozygosity mapping and exome sequencing. The authors suggest testing DNAH1 when known PCD genes are excluded. Because inner-arm defects can leave the axoneme looking normal, electron microscopy may not point to the gene.
Whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:25927852 SUPPORT Human Clinical
"Molecular variation in DNAH1 may play a role in PCD and its potential contribution should be considered in patients where all known genes are excluded."
Recommendation to test DNAH1 after negative PCD gene testing.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Primary Ciliary Dyskinesia 37:

🐁

Animal Models

1
Mdhc7 (Dnah1) knockout mouse
Mice lacking the Dnah1 ortholog are viable and well formed. Males are infertile because sperm swim poorly, and tracheal cilia beat at about half the normal frequency, with no gross axonemal defect.
Species
Mouse
Genotype
MDHC7-/- (Dnah1 knockout), homozygous
Publication
PMID:11371505
Pathograph links
Inner Dynein Arm Dysfunction in Motile Cilia partially recapitulates fidelity: moderate observes: cellular Reduced tracheal ciliary beat frequency in the absence of DNAH1.
Limitations: Beat frequency was measured, but airway disease, mucociliary clearance and laterality were not reported. The mouse is a null, whereas the CILD37 allele is a missense variant of untested effect.
Show evidence (1 reference)
PMID:11371505 SUPPORT Model Organism
"The phenotype of MDHC7(-/-) mice is similar to that observed in some patients suffering from PCD"
The authors relate the knockout to human PCD.
Inner Dynein Arm Dysfunction in the Sperm Flagellum partially recapitulates fidelity: moderate observes: cellular Poorly motile sperm and male infertility.
Limitations: Knockout sperm have normal axonemes, unlike the disorganized axonemes and MMAF of men with DNAH1 variants.
Show evidence (1 reference)
PMID:11371505 SUPPORT Model Organism
"the spermatozoa of MDHC7(-/-) mice revealed a dramatic reduced straight line velocity and progressive movement"
Sperm motility defect in the knockout.
{ }

Source YAML

click to show 
name: Primary Ciliary Dyskinesia 37
creation_date: "2026-10-14T00:00:00Z"
category: Mendelian
synonyms:
- CILD37
- ciliary dyskinesia, primary, 37
- DNAH1-related primary ciliary dyskinesia
description: >-
  Primary ciliary dyskinesia 37 (CILD37) is the autosomal recessive form of
  primary ciliary dyskinesia attributed to biallelic variants in DNAH1. DNAH1
  encodes an axonemal dynein heavy chain of the inner dynein arms, the motors
  that shape the ciliary and flagellar waveform. In human respiratory cilia
  DNAH1 is the heavy chain of the single-headed inner arm called IDAd.

  The entity rests on one family. Two sisters born to a consanguineous Saudi
  Arabian union had clinically diagnosed PCD with the Kartagener triad. The
  proband had chronic rhinitis, cough, wheezing and bronchitis from
  adolescence, then bronchiectasis, situs inversus with dextrocardia, mild
  conductive hearing loss and five years of infertility. All known PCD genes
  had been excluded. Homozygosity mapping and exome sequencing found a single
  candidate, the homozygous missense variant DNAH1 c.3460A>C (p.Lys1154Gln),
  which segregated with disease. The authors titled their report as DNAH1
  variation that "may contribute" to PCD. No ciliary ultrastructure, beat
  analysis or nasal nitric oxide was reported for the family, and the
  variant has no functional study. ClinGen rates DNAH1 as Limited for primary
  ciliary dyskinesia in general.

  Biallelic DNAH1 variants are much better established as a cause of male
  infertility with multiple morphological abnormalities of the sperm flagella
  (MMAF), curated separately as Spermatogenic Failure 18 (SPGF18). In those
  men, infertility was the only PCD-type feature. How one gene gives an
  isolated sperm defect in some families and full Kartagener syndrome in
  another is not resolved. Allele severity, a modifier, or a second
  unidentified cause in the index family are all possible. Further DNAH1
  variants turn up in PCD and Kartagener cohorts, mostly as compound
  heterozygous missense changes, but those reports do not test
  pathogenicity. Dnah1 knockout mice support a respiratory role: tracheal
  cilia beat at about half the normal frequency and males are infertile.
parents:
- Primary Ciliary Dyskinesia
- Ciliopathy
notes: >-
  Kept as a separate entry, like the other gene-numbered PCD entries
  (Primary_Ciliary_Dyskinesia_30 and others), because MONDO and OMIM (617577)
  define it as its own disease, separate from spermatogenic failure 18
  (MONDO:0054615), which is the same gene with a sperm-only
  presentation. The umbrella Primary_Ciliary_Dyskinesia entry lists DNAH1 as
  a Limited-evidence gene. ClinGen classified DNAH1 against primary ciliary
  dyskinesia (MONDO:0016575), not against this numbered entity, so no
  gene_disease_validity assertion is recorded on the genetic row; the
  ClinGen row is quoted as evidence instead. A single case report describes
  glomerulocystic kidney disease in a woman homozygous for another DNAH1
  missense variant (PMID:40896606); its authors call the association
  unproven, so kidney disease is not recorded as a phenotype here. No
  GeneReviews chapter covers CILD37 specifically (just check-genereviews);
  the general Primary Ciliary Dyskinesia chapter (PMID:20301301) is the
  clinical baseline and is tagged in references. It is not cited as
  evidence because its cached PubMed record is only the chapter's purpose
  statement, with no clinical content and no mention of DNAH1.
references:
- reference: PMID:20301301
  title: "Primary Ciliary Dyskinesia."
  tags:
  - GeneReviews
inheritance:
- name: Autosomal recessive
  description: >-
    Both affected sisters were homozygous for the DNAH1 variant, which
    segregated with the phenotype across twelve genotyped family members
    from a consanguineous union.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:25927852
    reference_title: "Variation in DNAH1 may contribute to primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel homozygous missense aberration (p.Lys1154Gln) was identified in both sisters in the DNAH1 gene that segregated completely with the disease phenotype."
    explanation: Homozygous variant segregating with disease in a consanguineous family fits recessive inheritance.
pathophysiology:
- name: Loss of DNAH1 Inner-Arm Dynein Heavy Chain Function
  description: >-
    The index variant replaces a conserved lysine in the N-terminal stem of
    DNAH1, the part of the heavy chain that contacts other heavy chains and
    arm subunits. Its effect on the protein has not been tested; loss of
    function is inferred from conservation and prediction tools.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: DNAH1
    term:
      id: hgnc:2940
      label: DNAH1
  molecular_functions:
  - preferred_term: minus-end-directed microtubule motor activity
    modifier: DECREASED
    term:
      id: GO:0008569
      label: minus-end-directed microtubule motor activity
  cellular_components:
  - preferred_term: Inner dynein arm
    term:
      id: GO:0036156
      label: inner dynein arm
  downstream:
  - target: Inner Dynein Arm Dysfunction in Motile Cilia
    causal_link_type: DIRECT
    description: >-
      DNAH1 is the heavy chain of inner arm IDAd in human respiratory cilia,
      so its loss is expected to remove or disable that arm. In the CILD37
      family this step is inferred; no ciliary sample was examined.
    evidence:
    - reference: PMID:39056782
      reference_title: "Primary Ciliary Dyskinesia Associated Disease-Causing Variants in CCDC39 and CCDC40 Cause Axonemal Absence of Inner Dynein Arm Heavy Chains DNAH1, DNAH6, and DNAH7."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "we demonstrated that CCDC39/40 deficiency not only results in abnormalities of DNALI1 but also affects the encoded heavy chains DNAH1 and DNAH7 of IDAd and IDAb/e, respectively"
      explanation: Places DNAH1 in the inner arms of human respiratory cilia. The work concerns CCDC39/40 patients, not DNAH1 patients.
  - target: Inner Dynein Arm Dysfunction in the Sperm Flagellum
    causal_link_type: DIRECT
    description: >-
      Shown in men with biallelic DNAH1 variants (SPGF18) and in knockout
      mice, not in the CILD37 family, whose two affected members are women.
  evidence:
  - reference: PMID:25927852
    reference_title: "Variation in DNAH1 may contribute to primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The lysine residue altered in these patients is located in the highly conserved N-terminal stem of the DNAH1 protein."
    explanation: Locates the index variant in a conserved functional region of the heavy chain.
  - reference: PMID:25927852
    reference_title: "Variation in DNAH1 may contribute to primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "p.Lys1154Gln is predicted to be probably damaging with a score of 0.998 on Polyphen"
    explanation: In silico prediction is the only functional evidence for the variant.
- name: Inner Dynein Arm Dysfunction in Motile Cilia
  description: >-
    Loss of an inner-arm heavy chain weakens and distorts the ciliary beat.
    In Dnah1 knockout mice the tracheal ciliary beat frequency falls by about
    half without any gross change in axonemal structure, which is why such a
    defect can be missed by electron microscopy. Respiratory cilia of CILD37
    patients have not been examined, so this node rests on mouse data and on
    the location of DNAH1 in human respiratory cilia.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Respiratory tract multiciliated cell
    term:
      id: CL:4030034
      label: respiratory tract multiciliated cell
  cellular_components:
  - preferred_term: Inner dynein arm
    term:
      id: GO:0036156
      label: inner dynein arm
  biological_processes:
  - preferred_term: Cilium movement
    modifier: DECREASED
    term:
      id: GO:0003341
      label: cilium movement
  downstream:
  - target: Impaired Mucociliary Clearance
    causal_link_type: DIRECT
  - target: Defective Left-Right Axis Determination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Nodal cilia share the axonemal dyneins of respiratory cilia. Whether
      DNAH1 is needed at the embryonic node has not been tested; the link
      rests on the situs inversus seen in the index family.
  - target: Female infertility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Oviduct cilia move the egg towards the uterus, and impaired oviduct
      cilia are the usual explanation for subfertility in women with PCD. The
      proband's oviduct cilia were not studied.
  evidence:
  - reference: PMID:11371505
    reference_title: "Disruption of an inner arm dynein heavy chain gene results in asthenozoospermia and reduced ciliary beat frequency."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "we measured the beat frequency of tracheal cilia and observed a decrease in the beat frequency of approximately 50% in MDHC7(-/-) mice"
    explanation: Mouse Dnah1 (MDHC7) loss halves tracheal ciliary beat frequency.
  - reference: PMID:11371505
    reference_title: "Disruption of an inner arm dynein heavy chain gene results in asthenozoospermia and reduced ciliary beat frequency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The reduction in both ciliary and flagellar motility is not correlated with any gross defects in the axonemal structure."
    explanation: The motility defect occurs without visible axonemal change.
- name: Impaired Mucociliary Clearance
  description: >-
    Weak ciliary beating fails to move mucus out of the nose, sinuses,
    middle ear and bronchi. Retained secretions lead to chronic rhinitis,
    cough and bronchitis, and repeated infection damages the bronchial wall
    into bronchiectasis. This is the general PCD mechanism; it has not been
    measured in CILD37 patients.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: Mucociliary clearance
    modifier: DECREASED
    term:
      id: GO:0120197
      label: mucociliary clearance
  downstream:
  - target: Chronic rhinitis
    causal_link_type: DIRECT
  - target: Cough
    causal_link_type: DIRECT
  - target: Wheezing
    causal_link_type: DIRECT
  - target: Bronchitis
    causal_link_type: DIRECT
  - target: Bronchiectasis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Repeated airway infection and inflammation damage the bronchial wall.
  - target: Conductive hearing impairment
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Middle-ear effusion from failed clearance of the middle ear is the usual cause of conductive hearing loss in PCD.
  evidence:
  - reference: PMID:25927852
    reference_title: "Variation in DNAH1 may contribute to primary ciliary dyskinesia."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "such biological defects are demonstrated clinically by recurrent or chronic sinusitis and bronchiectasis caused by immotile cilia in the upper and lower airways"
    explanation: The index paper's own statement of the general PCD mechanism linking cilia to airway disease.
- name: Defective Left-Right Axis Determination
  description: >-
    Situs inversus with dextrocardia in the proband implies that left-right
    patterning failed, which in PCD follows loss of nodal ciliary flow. The
    step is inferred from the phenotype.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: Nodal cilium movement in left-right asymmetry
    modifier: DECREASED
    term:
      id: GO:0060287
      label: epithelial cilium movement involved in determination of left/right asymmetry
  downstream:
  - target: Situs inversus totalis
    causal_link_type: DIRECT
  - target: Dextrocardia
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:25927852
    reference_title: "Variation in DNAH1 may contribute to primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a chest X-ray and CT scan showed the other two classic KS symptoms in combination with infertility; situs inversus (Figure 1A) and bronchiectasis (Figure 1B)"
    explanation: Laterality defect in the proband.
- name: Inner Dynein Arm Dysfunction in the Sperm Flagellum
  description: >-
    In men with biallelic DNAH1 variants, sperm lack DNAH1 and the inner
    dynein arms, and the axoneme is disorganized, giving multiple
    morphological abnormalities of the flagella. Dnah1 knockout mouse sperm
    swim poorly but look normal. No man with CILD37 has been reported, so
    this branch comes from the allelic disorder SPGF18 and from mice.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  cellular_components:
  - preferred_term: Sperm flagellum
    term:
      id: GO:0036126
      label: sperm flagellum
  biological_processes:
  - preferred_term: Flagellated sperm motility
    modifier: DECREASED
    term:
      id: GO:0030317
      label: flagellated sperm motility
  downstream:
  - target: Reduced sperm motility
    causal_link_type: DIRECT
  - target: Male infertility
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:24360805
    reference_title: "Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "A general axonemal disorganization including mislocalization of the microtubule doublets and loss of the inner dynein arms was observed."
    explanation: Sperm ultrastructure in a man with biallelic DNAH1 variants (SPGF18), not a CILD37 patient.
  - reference: PMID:11371505
    reference_title: "Disruption of an inner arm dynein heavy chain gene results in asthenozoospermia and reduced ciliary beat frequency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the spermatozoa of MDHC7(-/-) mice revealed a dramatic reduced straight line velocity and progressive movement, resulting in the inability of MDHC7-deficient sperm to move from the uterus into the oviduct"
    explanation: Mouse knockout sperm motility defect.
phenotypes:
- category: Respiratory
  name: Chronic rhinitis
  description: Present in the proband from adolescence, with nasal discharge; an adenoidectomy was performed.
  phenotype_term:
    preferred_term: Chronic rhinitis
    term:
      id: HP:0002257
      label: Chronic rhinitis
  evidence:
  - reference: PMID:25927852
    reference_title: "Variation in DNAH1 may contribute to primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband had a previous medical history at 13 years of age with chronic rhinitis, frequent coughing and wheezing, nasal discharge, and was diagnosed with left lung bronchitis."
    explanation: Upper airway disease in the proband.
- category: Respiratory
  name: Cough
  description: Frequent cough from adolescence in the proband.
  phenotype_term:
    preferred_term: Frequent cough
    term:
      id: HP:0012735
      label: Cough
  evidence:
  - reference: PMID:25927852
    reference_title: "Variation in DNAH1 may contribute to primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband had a previous medical history at 13 years of age with chronic rhinitis, frequent coughing and wheezing"
    explanation: Frequent cough in the proband.
- category: Respiratory
  name: Wheezing
  description: Reported with cough in the proband's adolescent history.
  phenotype_term:
    preferred_term: Wheezing
    term:
      id: HP:0030828
      label: Wheezing
  evidence:
  - reference: PMID:25927852
    reference_title: "Variation in DNAH1 may contribute to primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband had a previous medical history at 13 years of age with chronic rhinitis, frequent coughing and wheezing"
    explanation: Wheezing in the proband.
- category: Respiratory
  name: Bronchitis
  description: Left lung bronchitis was diagnosed in adolescence.
  phenotype_term:
    preferred_term: Bronchitis
    term:
      id: HP:0012387
      label: Bronchitis
  evidence:
  - reference: PMID:25927852
    reference_title: "Variation in DNAH1 may contribute to primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "was diagnosed with left lung bronchitis"
    explanation: Lower airway infection in the proband.
- category: Respiratory
  name: Bronchiectasis
  description: >-
    Mild bronchiectasis in the left middle and right lower lobes was seen on
    imaging at age 29.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:25927852
    reference_title: "Variation in DNAH1 may contribute to primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "arrows are indicating bronchial wall thickening with mild bronchiectasis in the left middle lobe and also in the right lower lobe"
    explanation: Imaging finding in the proband.
- category: Otologic
  name: Conductive hearing impairment
  description: Audiometry showed mild conductive hearing loss in the proband.
  phenotype_term:
    preferred_term: Mild conductive hearing loss
    term:
      id: HP:0000405
      label: Conductive hearing impairment
  evidence:
  - reference: PMID:25927852
    reference_title: "Variation in DNAH1 may contribute to primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Audiometric evaluation also revealed mild conductive hearing loss."
    explanation: Middle-ear involvement in the proband.
- category: Developmental
  name: Situs inversus totalis
  description: >-
    The proband had situs inversus, and her sister was also diagnosed with
    Kartagener syndrome. Whether laterality defects occur in other DNAH1
    patients is unknown; the SPGF18 men were not reported to have them.
  phenotype_term:
    preferred_term: Situs inversus
    term:
      id: HP:0001696
      label: Situs inversus totalis
  evidence:
  - reference: PMID:25927852
    reference_title: "Variation in DNAH1 may contribute to primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AP Chest X-ray of proband indicating (i) dextrocardia with (ii) right-sided aortic arch. The gastric air bubble is also in the right side (iii) that is most likely representing situs inversus."
    explanation: Mirror-image organ arrangement in the proband.
- category: Cardiovascular
  name: Dextrocardia
  description: Dextrocardia with a right-sided aortic arch, as part of situs inversus.
  phenotype_term:
    preferred_term: Dextrocardia
    term:
      id: HP:0001651
      label: Dextrocardia
  evidence:
  - reference: PMID:25927852
    reference_title: "Variation in DNAH1 may contribute to primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AP Chest X-ray of proband indicating (i) dextrocardia with (ii) right-sided aortic arch."
    explanation: Dextrocardia in the proband.
- category: Reproductive
  name: Female infertility
  description: >-
    The proband was referred for IVF after five years of infertility. IVF
    succeeded and she delivered a healthy son, so the infertility was not
    absolute.
  phenotype_term:
    preferred_term: Female infertility
    term:
      id: HP:0008222
      label: Female infertility
  evidence:
  - reference: PMID:25927852
    reference_title: "Variation in DNAH1 may contribute to primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She was referred to King Faisal Specialist Hospital & Research Centre at the age of 29 for IVF for infertility spanning 5 years."
    explanation: Infertility in the proband.
- category: Reproductive
  name: Male infertility
  description: >-
    No male with CILD37 has been described. Biallelic DNAH1 variants cause
    male infertility in the allelic disorder SPGF18 and in knockout mice, so
    affected men would be expected to be infertile. Recorded as expected
    rather than observed.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:11371505
    reference_title: "Disruption of an inner arm dynein heavy chain gene results in asthenozoospermia and reduced ciliary beat frequency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Both MDHC7(+/-) and MDHC7(-/-) mice are viable and show no malformations; however, homozygous males produce no offspring."
    explanation: Male infertility in Dnah1 knockout mice.
- category: Reproductive
  name: Reduced sperm motility
  description: >-
    Expected in affected men from the allelic SPGF18 phenotype and the mouse
    knockout; not observed in a CILD37 patient.
  phenotype_term:
    preferred_term: Asthenozoospermia
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: PMID:24360805
    reference_title: "Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "presenting with primary infertility resulting from impaired sperm motility caused by a mosaic of multiple morphological abnormalities of the flagella (MMAF)"
    explanation: Sperm motility defect in men with biallelic DNAH1 variants (SPGF18).
genetic:
- name: DNAH1
  association: Causal
  gene_term:
    preferred_term: DNAH1
    term:
      id: hgnc:2940
      label: DNAH1
  notes: >-
    The defining variant is DNAH1 c.3460A>C, p.Lys1154Gln (NM_015512.4),
    homozygous in two sisters. It was the only candidate in the proband's
    exome and was absent from 600 ethnically matched chromosomes. Further
    DNAH1 variants appear in Chinese Kartagener and PCD cohorts
    (PMID:31507630, PMID:33577779) and in Turkish PCD cohorts
    (PMID:31765523, PMID:34349594), usually without segregation or
    functional data. One Kartagener series found compound heterozygous DNAH1
    variants and proposed DNAH1 as a high-risk gene in Chinese patients. The
    evidence for PCD remains weaker than for MMAF.
  evidence:
  - reference: PMID:25927852
    reference_title: "Variation in DNAH1 may contribute to primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In exome-wide analysis on the proband the p.Lys1154Gln in DNAH1 was detected as the only possibly causative variant"
    explanation: The index variant was the only candidate in the exome.
  - reference: PMID:31507630
    reference_title: "Identification of Pathogenic Mutations and Investigation of the NOTCH Pathway Activation in Kartagener Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six mutations in DNAH1 were identified in all individuals, indicating that DNAH1 might be a high-risk causative gene in Chinese patients with KTS."
    explanation: Further DNAH1 variants in a Kartagener cohort, without functional testing.
  - reference: CGGV:assertion_a07c8b6e-a558-498b-975c-b12e96878a44-2025-10-16T160000.000Z
    reference_title: "DNAH1 / primary ciliary dyskinesia (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "DNAH1 | HGNC:2940 | primary ciliary dyskinesia | MONDO:0016575 | AR | Limited"
    explanation: >-
      ClinGen rates DNAH1 as Limited for primary ciliary dyskinesia in
      general. The assertion is for MONDO:0016575, not this numbered entity,
      so it is quoted here rather than recorded as gene_disease_validity.
diagnosis:
- name: Exome Sequencing After Negative PCD Gene Testing
  description: >-
    DNAH1 was found only after a PCD gene panel was negative, by
    homozygosity mapping and exome sequencing. The authors suggest testing
    DNAH1 when known PCD genes are excluded. Because inner-arm defects can
    leave the axoneme looking normal, electron microscopy may not point to
    the gene.
  diagnosis_term:
    preferred_term: Whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:25927852
    reference_title: "Variation in DNAH1 may contribute to primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular variation in DNAH1 may play a role in PCD and its potential contribution should be considered in patients where all known genes are excluded."
    explanation: Recommendation to test DNAH1 after negative PCD gene testing.
differential_diagnoses:
- name: Spermatogenic failure 18 (DNAH1-related MMAF)
  disease_term:
    preferred_term: spermatogenic failure 18
    term:
      id: MONDO:0054615
      label: spermatogenic failure 18
  description: >-
    Same gene, different presentation. Men with biallelic DNAH1 variants have
    MMAF and infertility without reported respiratory disease.
  distinguishing_features:
  - >-
    Chronic airway disease, bronchiectasis and situs inversus are present in
    CILD37 and absent in the reported SPGF18 men. A DNAH1 genotype does not
    by itself say which presentation to expect.
  evidence:
  - reference: PMID:24360805
    reference_title: "Mutations in DNAH1, which encodes an inner arm heavy chain dynein, lead to male infertility from multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although DNAH1 is also expressed in other ciliated cells, infertility was the only symptom of primary ciliary dyskinesia observed in affected subjects"
    explanation: SPGF18 men lack the respiratory features of CILD37.
animal_models:
- name: Mdhc7 (Dnah1) knockout mouse
  species: Mouse
  genotype: MDHC7-/- (Dnah1 knockout), homozygous
  publication: PMID:11371505
  description: >-
    Mice lacking the Dnah1 ortholog are viable and well formed. Males are
    infertile because sperm swim poorly, and tracheal cilia beat at about
    half the normal frequency, with no gross axonemal defect.
  modeled_mechanisms:
  - target: Inner Dynein Arm Dysfunction in Motile Cilia
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Reduced tracheal ciliary beat frequency in the absence of DNAH1.
    limitations: >-
      Beat frequency was measured, but airway disease, mucociliary clearance
      and laterality were not reported. The mouse is a null, whereas the
      CILD37 allele is a missense variant of untested effect.
    evidence:
    - reference: PMID:11371505
      reference_title: "Disruption of an inner arm dynein heavy chain gene results in asthenozoospermia and reduced ciliary beat frequency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The phenotype of MDHC7(-/-) mice is similar to that observed in some patients suffering from PCD"
      explanation: The authors relate the knockout to human PCD.
  - target: Inner Dynein Arm Dysfunction in the Sperm Flagellum
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Poorly motile sperm and male infertility.
    limitations: >-
      Knockout sperm have normal axonemes, unlike the disorganized axonemes
      and MMAF of men with DNAH1 variants.
    evidence:
    - reference: PMID:11371505
      reference_title: "Disruption of an inner arm dynein heavy chain gene results in asthenozoospermia and reduced ciliary beat frequency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "the spermatozoa of MDHC7(-/-) mice revealed a dramatic reduced straight line velocity and progressive movement"
      explanation: Sperm motility defect in the knockout.
treatments:
- name: In Vitro Fertilization
  description: >-
    The proband conceived by IVF after five years of infertility and
    delivered a healthy son. Preimplantation testing was cancelled because
    her husband did not carry the variant.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: In vitro fertilization
    term:
      id: NCIT:C16580
      label: In Vitro Fertilization
  evidence:
  - reference: PMID:25927852
    reference_title: "Variation in DNAH1 may contribute to primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With regards to our proband, IVF was successful and pre-implantation genetic diagnosis was cancelled"
    explanation: Successful IVF in the proband.
- name: Airway Clearance and Chronic Infection Management
  description: >-
    There is no treatment for the ciliary defect. The proband's chronic
    airway disease and bronchiectasis are managed with the supportive care
    used across primary ciliary dyskinesia: airway clearance, prompt
    treatment of infections, and surveillance of lung function. Nothing in
    it is DNAH1-specific.
  therapeutic_modality: OTHER
  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 mucus
      transport the cilia cannot provide, and antibiotics treat the
      infections that follow. Neither restores ciliary function.
  evidence:
  - reference: PMID:38891105
    reference_title: "Primary Ciliary Dyskinesia: A Clinical Review."
    supports: SUPPORT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: HUMAN_CLINICAL
    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: >-
      Review statement of standard PCD airway management. It covers PCD in
      general and is not specific to DNAH1.
📚

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 37 (DNAH1) · 2026-10-14T20:20:49Z · View source

New entry for CILD37 (MONDO:0033204), the DNAH1-related form of primary ciliary dyskinesia, kept separate from Spermatogenic_Failure_18 (MONDO:0054615, same gene, sperm-only MMAF), which is cross-referenced as a differential and was not edited. Deep research: the requested falcon provider failed authentication (503) on two attempts, including with --fallback, so the report used is research/Primary_Ciliary_Dyskinesia_37-deep-research-claude_code.md; just preflight-dr against MONDO:0033204 returned PASS. Phenotypes come from the single index family (PMID:25927852, full text cached): Kartagener triad, chronic rhinitis, cough, wheezing, bronchitis, mild conductive hearing loss, female infertility. Respiratory mechanism nodes rest on Dnah1 knockout mouse data (PMID:11371505) and the localisation of DNAH1 to inner arm IDAd in human respiratory cilia (PMID:39056782); the family had no ciliary studies. Male infertility and reduced sperm motility are recorded as expected from SPGF18 (PMID:24360805) and the mouse, not observed in CILD37. ClinGen rates DNAH1 Limited for generic PCD (MONDO:0016575), so no gene_disease_validity was recorded. Validated with just validate, count-verified-snippets (all verified), validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys and validate-disorders.

Claude Code ▸
1. Disease Information
claude-haiku-5-5, claude-sonnet-5-5 8 citations 2026-10-14T20:08:59.338308

1. Disease Information

  • Overview. CILD37 is an autosomal recessive form of primary ciliary dyskinesia (PCD). The Disease Ontology defines it as a PCD with homozygous mutation in DNAH1 on 3p21 (DOID:0080266; GlyCosmos). PCD causes defective respiratory cilia, with recurrent infection, chronic inflammation and bronchiectasis. Some patients have laterality defects, including situs inversus (Kartagener syndrome) (MalaCards).
  • Identifiers.
  • OMIM 617577, per LOVD disease #05980.
  • DOID:0080266.
  • MONDO:0033204 is taken from the task header. No page I found states it, so confirm it in MONDO.
  • A search for MONDO:0033204 surfaced MONDO:0054843, which is PCD 38, a different disease.
  • Orphanet, ICD and MeSH IDs were not retrieved.
  • Synonyms. CILD37; ciliary dyskinesia, primary, 37; primary ciliary dyskinesia 37; "…with or without situs inversus" (NORD).
  • Source level. The sources are disease-level resources and case reports, not EHR-derived.

2. Etiology

  • Cause. Biallelic (homozygous or compound heterozygous) DNAH1 variants. DNAH1 encodes an inner-arm axonemal dynein heavy chain.
  • Genetic risk.
  • The sole index report is a consanguineous Saudi family with two affected sisters. Known PCD genes were excluded. Homozygosity mapping and exome analysis found a homozygous missense, p.Lys1154Gln, that segregated with disease (Imtiaz et al. 2015, BMC Med Genet, PMID:25927852).
  • The authors concluded that DNAH1 variation "may contribute" to PCD and should be considered when known genes are negative. They did not claim definitive causality.
  • Environmental, protective and gene-environment factors. None are established for this subtype. Smoke and pollution exposure plausibly worsen general airway disease [unverified].

3. Phenotypes

Phenotype Suggested HPO Notes
Recurrent respiratory infections HP:0002205 (recurrent respiratory infections) Core PCD feature
Chronic cough / bronchiectasis HP:0012735 (cough), HP:0002110 (bronchiectasis)
Situs inversus (about 50% of PCD overall) HP:0001696 Present in some CILD37 patients, not all
Male infertility / asthenozoospermia HP:0003251 (male infertility), HP:0012206 (asthenozoospermia) See DNAH1 sperm data below
Chronic rhinosinusitis, otitis media HP:0000246, HP:0000388 General PCD; not confirmed for CILD37 [unverified]
  • Onset, severity, frequency. Not retrievable from the sources I found. The detailed Imtiaz cohort data need full-text review.
  • Quality of life. No data found.
  • Important DNAH1 caveat. In Ben Khelifa et al. 2014, DNAH1 homozygous variants were found in 5 of 18 index cases (28%) with multiple morphological abnormalities of the sperm flagella (MMAF). The authors noted that infertility was the only PCD-related symptom observed, even though DNAH1 is expressed in other ciliated cells (Ben Khelifa 2014, Am J Hum Genet, PMID:24360805). Respiratory involvement is therefore not consistent across DNAH1 carriers. This tension with CILD37 should be recorded in the KB. The dismech entry Spermatogenic Failure 18 is the related allelic or overlapping disease.

4. Genetic/Molecular Information

  • Gene. DNAH1 (HGNC ID not retrieved; use lowercase hgnc: form after lookup). Locus 3p21.
  • Variants.
  • Reported: p.Lys1154Gln, a homozygous missense (Imtiaz 2015).
  • ClinVar and ACMG classification, gnomAD frequency and the ClinGen gene-validity tier were not retrieved. Check ClinGen for a CGGV record.
  • Mechanism. Loss of function is suggested. In MMAF patients, a splice variant caused loss of transcript and protein and loss of inner dynein arms, with axonemal disorganization (Ben Khelifa 2014).
  • Origin. Germline.
  • Modifiers, epigenetics, chromosomal abnormalities. None identified.

5. Environmental Information

No specific environmental, lifestyle or infectious cause is established. Recurrent infections are secondary to impaired mucociliary clearance, not causal.

6. Mechanism / Pathophysiology

Causal chain (inferred; the respiratory links are not directly demonstrated for DNAH1): 1. Biallelic DNAH1 variants lead to loss or dysfunction of the inner dynein arm heavy chain (demonstrated in sperm: Ben Khelifa 2014). 2. This results in axonemal disorganization and impaired ciliary or flagellar beating (demonstrated in sperm; inferred for airway cilia). 3. Impaired motile cilia beating leads to defective mucociliary clearance in airway epithelium (inferred from the general PCD mechanism). 4. Mucus retention leads to recurrent infection, chronic inflammation and bronchiectasis (general PCD mechanism). 5. In some patients, dysfunction of embryonic nodal cilia leads to laterality defects such as situs inversus (general PCD mechanism). 6. Branch: in sperm, flagellar defects lead to MMAF and asthenozoospermia, then male infertility.

Ontology suggestions (to be validated): - GO: inner dynein arm (GO:0036156), cilium movement (GO:0003341), axonemal dynein complex assembly, microtubule-based movement. - CL: ciliated columnar epithelial cell of the airway (look up the exact CL ID), sperm (CL:0000019). - UBERON: respiratory epithelium, lung, nasal cavity, testis.

Omics, single-cell and functional-genomics data were not found for this subtype.

7. Anatomical Structures Affected

  • Respiratory tract: airway epithelium, nose and sinuses, bronchi, middle ear.
  • Reproductive tract: sperm flagellum.
  • Laterality: left-right organizer or node, when situs inversus is present.
  • Subcellular: motile cilium axoneme and inner dynein arms.
  • Lateralization: bilateral for airway disease. Situs inversus gives a mirrored arrangement.

8. Temporal Development

Not retrievable for CILD37 specifically. General PCD is lifelong, with onset from the neonatal period or early childhood and a chronic, slowly progressive course [unverified].

9. Inheritance and Population

  • Inheritance. Autosomal recessive (LOVD; MalaCards).
  • Consanguinity. The index family was consanguineous (Saudi Arabia). MMAF cases were North African.
  • Prevalence. No CILD37-specific figure was found. All-cause PCD is roughly 1 in 10,000 to 20,000 [unverified]. Orphanet epidemiology should be checked.
  • Founder effect, carrier frequency, sex ratio, geography. Not established.

10. Diagnostics

  • Genetic testing. PCD multigene panel or exome sequencing. DNAH1 should be included, especially when other PCD genes are negative (Imtiaz 2015).
  • Other tests. Nasal nitric oxide, high-speed video microscopy of ciliary beat, TEM of cilia, immunofluorescence and chest imaging are standard for PCD [unverified]. Respiratory ciliary ultrastructure in DNAH1 patients was not confirmed in these searches. Inner dynein arm defects are often subtle or hard to see on TEM.
  • Differential. Other PCD genes, cystic fibrosis and other causes of bronchiectasis. Also spermatogenic failure 18 when infertility is the presenting feature.
  • Screening. None established.

11. Outcome/Prognosis

Not available for CILD37. Expected outcomes are those of PCD generally: progressive lung disease with bronchiectasis and reduced fertility in males.

12. Treatment

No CILD37-specific therapy was found. Treatment is general PCD supportive care [unverified]: - Airway clearance and physiotherapy (NCIT:C15315 rehabilitation; NCIT:C15747 supportive care). - Antibiotics (NCIT:C15986 pharmacotherapy). - Assisted reproduction (ICSI) for male infertility. I did not verify ICSI outcomes in DNAH1 MMAF.

I did not search ClinicalTrials.gov for trials.

13. Prevention

  • Genetic counseling for autosomal recessive recurrence risk (NCIT:C15240).
  • Carrier and prenatal testing is possible once the familial variants are known.
  • Vaccination and early infection management are generic PCD measures [unverified].

14. Other Species / Natural Disease

Not researched. Check OMIA and the Alliance of Genome Resources for DNAH1 orthologs.

15. Model Organisms

Not researched. Check MGI, ZFIN and the Alliance for Dnah1 knockouts. Note that, as in humans, the phenotype may be sperm-predominant.

Gaps and Cautions for Curation

  1. Thin evidence. The sole index report of PCD from DNAH1 is a single consanguineous family with two sisters (PMID:25927852). That paper itself hedges ("may contribute"). Reflect this in the entry, for example in a note and ClinGen tier, rather than asserting a definitive gene-disease link.
  2. Unreconciled DNAH1 phenotypes. The Ben Khelifa cohort (PMID:24360805) reports male infertility without respiratory disease. This is a lump/split question against Spermatogenic Failure 18.
  3. Unconfirmed items. The MONDO ID, the HGNC ID, the OMIM number (via LOVD only), all HPO, GO, CL and UBERON suggestions, and all items marked [unverified] need lookup. Per the repository's rules, no CURIE here should be bound from this report without a lookup.

Sources: - LOVD CILD37 record - NORD: ciliary dyskinesia, primary, 37 - Disease Ontology DOID:0080266 - GlyCosmos entry - MalaCards CILD37 - Imtiaz et al. 2015 (PMC4422061) - Ben Khelifa et al. 2014 (PMC3882734) - dismech: Spermatogenic Failure 18

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 4
Resolved 4
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 4
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 18
Resolved 18
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 4
Terms named correctly 1
Terms named as a different term 1
Terms whose name is worth a second look 2

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:

  • NCIT:C15240 (1 mention) - the report calls it "Genetic counseling for autosomal recessive recurrence risk"; NCIT calls it Genetic Counseling

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:0001696 (1 mention) - the report calls it "Situs inversus (about 50% of PCD overall)"; HP calls it Situs inversus totalis
  • GO:0036156 (1 mention) - the report calls it "GO: inner dynein arm"; GO calls it inner dynein arm