Primary Ciliary Dyskinesia 7 (CILD7; DNAH11-related PCD): research report

Scope and evidence caveat. This report rests on a limited set of web searches that returned mostly abstracts and bibliographic records, so I did not read most full texts. Each claim is tagged as verified in a retrieved source, or as background knowledge that needs checking before curation. Where I have no PMID I give a DOI or URL instead of guessing one. Several clinical sections (treatment, prevention, prognosis) rest on general PCD knowledge, not on DNAH11-specific sources, and are marked as such.

1. Disease information

Overview. CILD7 is an autosomal recessive form of primary ciliary dyskinesia (PCD) caused by biallelic loss-of-function variants in DNAH11, which encodes an axonemal outer dynein arm heavy chain. Its characteristic feature is normal or near-normal ciliary ultrastructure on conventional TEM with abnormal ciliary motility.

• A 2008 German family had five people with PCD and one with Kartagener syndrome. Their respiratory cilia had normal axonemal structure and intact outer dynein arms, but abnormal beating (Human Mutation 2008, via Geneva archive).
• GenCC lists the gene-disease validity as Definitive, autosomal recessive. It describes normal ultrastructure with stiff, high-frequency, low-amplitude beating (GenCC SGC-105887.2).
• The genetic basis was first suggested by Bartoloni et al., PNAS 2002;99(16):10282-6 (doi 10.1073/pnas.152337699; PMC124905). They found DNAH11 variants in a patient with situs inversus totalis and probable Kartagener syndrome. The title says "most likely" PCD, so the PCD link was less firm in that paper (PNAS abstract). The PMID appeared as 12142464 in a QxMD link in the search results, and I did not confirm it.

Identifiers.

Synonyms. - Ciliary dyskinesia, primary, 7 - CILD7 - DNAH11-related primary ciliary dyskinesia - PCD with normal ultrastructure (an overlapping phenotype description, not a synonym) - Kartagener syndrome, when situs inversus is present

Source type. Disease-level and gene-level resources, plus cohort and family studies. There is no EHR-derived content in what I retrieved.

2. Etiology

• Causal factor. Biallelic (homozygous or compound heterozygous) pathogenic variants in DNAH11 on 7p21 (OMIM 603339). The disease is purely genetic, with no environmental cause.
• Genetic risk factors. Only the causal gene is established. Variable severity in siblings with identical genotypes suggests unidentified modifiers. In the Finnish family below, three homozygous siblings had different beat patterns but similar symptom severity (BMC Med Genet 2020, PMC7690114).
• Environmental modifiers. None specific to DNAH11 retrieved. General PCD knowledge says tobacco smoke and air pollution worsen respiratory outcomes (unverified here).
• Protective factors and gene-environment interactions. Not identified in the retrieved sources.

3. Phenotypes

The retrieved sources do not give per-phenotype frequencies for DNAH11. Frequencies below are from general PCD knowledge or are qualitative, and should be checked against the HPO annotations and GeneReviews PCD chapter.

• Onset. Early childhood, with symptoms often from the neonatal period (general PCD knowledge).
• Progression. Chronic and slowly progressive lung disease (general PCD knowledge).
• Quality of life. No DNAH11-specific data retrieved.
• A point worth encoding. In the Knowles cohort, no patients with dynein arm defects, radial spoke/central pair defects, or isolated situs abnormalities carried DNAH11 mutations (Thorax 2012;67:433).

4. Genetic and molecular information

• Gene. DNAH11 (hgnc:2942), axonemal dynein heavy chain 11, at 7p21. The original report sequenced all 82 exons.
• Variants.
• Reported variants include nonsense, frameshift, splice and missense changes. One early candidate was p.R3004Q (Bartoloni 2002).
• The Finnish 2020 study reported two novel likely pathogenic variants, one a homozygous missense in a three-sibling family (PMC7690114).
• I did not retrieve ClinVar or gnomAD data.
• Functional consequence. Loss of function. By immunofluorescence, DNAH11 is lost in patients with certain loss-of-function mutations (Dougherty et al., below).
• Gene-disease validity. GenCC lists Definitive (SGC-105887.2). The ClinGen-style curation cited in the Bartoloni search result notes that the variants were collectively reported in fifteen probands in three publications.
• Frequency among PCD with normal ultrastructure. Knowles et al. sequenced DNAH11 in 163 PCD patients. Of the 58 with normal ultrastructure, 13 (22%) carried two DNAH11 mutations (Thorax 2012). I did not retrieve the PMID.
• Modifier genes, epigenetics, chromosomal abnormalities. None retrieved. The index patient in Bartoloni et al. had paternal uniparental disomy of chromosome 7 as a mechanism for homozygosity.
• Origin. Germline.

5. Environmental information

Not applicable as a cause. Infectious agents (e.g., Pseudomonas aeruginosa, Haemophilus influenzae) are secondary colonizers of damaged airways in PCD generally, not DNAH11-specific findings.

6. Mechanism and pathophysiology

Causal chain.

1. Biallelic loss-of-function variants in DNAH11 reduce or abolish the DNAH11 outer dynein arm heavy chain. This is demonstrated by immunofluorescence (Dougherty et al.).
2. DNAH11 normally sits only in the proximal region of human respiratory cilia, defining a distinct ODA complex. Its loss causes a subtle, proximal-only ODA defect, seen by IFM and by electron tomography but not by conventional TEM (Dougherty et al.; AJRCMB 2016;55:213, PMID 26909801).
3. Electron tomography of 7 DNAH11 patients showed more than 25% deficiency of proximal ODA volume in each, invisible on conventional TEM. This comes from a preprint-style record, so treat it as less certain (UCL repository).
4. The lost dynein force generation leads to abnormal ciliary beating. This is a stiff, static pattern with reduced amplitude and high frequency, with hyperkinetic movement seen in some patients (PMC7690114; GenCC).
5. Impaired beating gives defective mucociliary clearance. This is inferred from general PCD biology and was not tested in the retrieved DNAH11 papers. It leads to chronic infection, sinusitis, otitis media and bronchiectasis.
6. Dysfunctional nodal cilia in the embryo lead to randomized left-right asymmetry (situs solitus, inversus or other). Support comes from the mouse ortholog (Supp et al. 1997, Nature 389:963-6, doi 10.1038/40140, PMC1800588). In humans, laterality defects occur in only a subset.
7. Sperm flagellar dysfunction leads to reduced male fertility (mouse and NORD text).

Cell types and processes. - Ciliated airway epithelial cell: CL:0002145 (verify). - Embryonic node monocilia. - Sperm cell. - Candidate GO terms (verify by lookup before binding): - outer dynein arm assembly (GO:0036158) - cilium movement (GO:0003341) - axonemal dynein complex - determination of left/right symmetry (GO:0007368)

Immune, metabolic, omics, advanced technologies. No DNAH11-specific findings retrieved.

7. Anatomical structures affected

• Organs. Upper and lower airways (nose, paranasal sinuses, middle ear, bronchi and lungs). Also the male reproductive tract and, variably, the viscera, via laterality defects.
• Cells and tissue. Ciliated respiratory epithelium (UBERON:0000483 epithelium; verify), the embryonic node, and sperm.
• Subcellular. Axoneme, outer dynein arm, proximal region of the axoneme (GO:0005858 axonemal dynein complex; verify).
• Lateralization. Situs inversus totalis or normal situs, as described above.

8. Temporal development

Typical onset is neonatal or early childhood. The course is chronic and lifelong with slow progression. No remission patterns or critical periods were retrieved.

9. Inheritance and population

• Inheritance. Autosomal recessive (OMIM; GenCC).
• Prevalence. CILD7 is a minority subset of PCD, which overall is about 1 in 10,000 to 1 in 20,000 (general knowledge, unverified here). DNAH11 explained about 22% of the normal-ultrastructure group in one cohort (Knowles et al.), which was a selected referral population.
• Consanguinity, founder effects, carrier frequency, sex ratio. Not retrieved. Consanguinity is a known factor in homozygous PCD families generally.
• Anticipation and germline mosaicism. Not applicable. The uniparental disomy case is noted above.

10. Diagnostics

• TEM misses it. Conventional electron microscopy shows normal ultrastructure, so a normal TEM does not exclude DNAH11 disease (PMC7690114).
• High-speed video microscopy (HSVM). Shows a recognizable pattern, described as stiff, with high-frequency, low-amplitude beating. Beat patterns varied even among siblings with the same genotype. A case report suggests HSVM remains useful (PMC12070959).
• Nasal nitric oxide. That case report found levels are not consistently low in DNAH11 patients, so nNO is not a reliable screen for this subtype (PMC12070959). This contrasts with most other PCD genes, where nNO is usually very low. I only read this from a search summary, so check the full text.
• Immunofluorescence. Loss of DNAH11 staining is seen with certain loss-of-function mutations (Dougherty et al.).
• Electron tomography. Detects the proximal ODA deficit, but is a research tool.
• Genetic testing. Multigene PCD panel or exome sequencing is the practical route. Knowles et al. concluded that genetic analysis can establish the diagnosis in patients without ultrastructural defects.
• Differential diagnosis. Other PCD genes, cystic fibrosis, immunodeficiency, and secondary ciliary dyskinesia. Consensus guidelines such as the ERS statement were not retrieved.
• Screening. No newborn screening program exists. Cascade testing of siblings is advisable (general knowledge).

11. Outcome and prognosis

No DNAH11-specific survival or lung-function data were retrieved. Generally, PCD life expectancy is near normal with good care, but bronchiectasis is progressive. The Finnish family study suggests beat-pattern differences do not map neatly onto severity (PMC7690114).

12. Treatment

No disease-specific or DNAH11-specific trials were retrieved. Standard PCD care (unverified in this search) is: - airway clearance physiotherapy (NCIT:C15302 Physical Therapy; verify the appropriate term) - prompt antibiotic treatment of infections (NCIT:C15986 Pharmacotherapy) - ENT management, including hearing support - fertility counseling and assisted reproduction for males - lung transplantation in end-stage disease (NCIT:C15289 Organ Transplantation)

Gene or RNA therapies are not established for DNAH11. Check ClinicalTrials.gov for current trials before curation.

13. Prevention

• Genetic counseling. Carrier parents have a 25% recurrence risk per pregnancy, and prenatal or preimplantation testing is possible once the variants are known (NCIT:C15240 Genetic Counseling).
• Tertiary prevention. Vaccination, early infection treatment and avoidance of smoke (general knowledge).

14. Other species and natural disease

I did not find OMIA data. The mouse is the main comparative resource. The inversus viscerum mouse is described under Section 15.

15. Model organisms

• Mouse, Dnah11 (also written Dnahc11 / lrd), inversus viscerum (iv) and legless (lgl) alleles.
• Supp et al. 1997 identified left/right-dynein as the mutated gene (Nature 389:963, PMC1800588).
• Lucas et al. 2012 (Southampton) reported the iv mouse has immotile tracheal cilia with normal ultrastructure, reduced sperm motility, and rhinitis, sinusitis and otitis media (Southampton repository). This makes it a close match to human CILD7.
• A Dnah11 reporter knock-in showed expression in nodal cilia (MGI assay record, 2020).
• I found no evidence in these searches of hydrocephalus in Dnah11 mutants.
• GFP-tagged left-right dynein mice. These confirmed proximal DNAH11 localization in tracheal cilia (Dougherty et al.).
• Not retrieved. Zebrafish, other organisms, IMPC or MGI phenotype lists, and iPSC or air-liquid-interface culture models. Search MGI and ZFIN before curating any animal_models: entry.

Key references

Gaps to close before curation. - Confirm all PMIDs by running just fetch-reference on each one. - Resolve ontology terms by lookup, not from the suggestions above. - Read the GeneReviews PCD chapter for the baseline phenotype and frequencies. - Check the ClinGen assertion for DNAH11 and PCD. - Look up Orphanet and the ICD codes.

Sources: - GenCC submission SGC-105887.2 - Thorax 2012 Knowles et al. - BMC Med Genet 2020, PMC7690114 - Case report, PMC12070959 - UCL tomography record - Dougherty et al. 2016 - Bartoloni et al. 2002 - Supp et al. 1997 - Southampton iv mouse record - Human Mutation 2008, Geneva archive - NORD CILD7 page

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:

• MONDO:0012748 (1 mention) - the report calls it "MONDO"; MONDO calls it primary ciliary dyskinesia 7
• DOID:0110605 (1 mention) - the report calls it "Disease Ontology"; DOID calls it primary ciliary dyskinesia 7
• CL:0002145 (1 mention) - the report calls it "verify"; CL calls it multiciliated columnar cell of tracheobronchial tree

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.