Primary Ciliary Dyskinesia 37

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

• 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.

All extracted references resolved successfully.

Term Validation

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

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