Submission Details

The DNAH11 gene was first reported in relation to primary ciliary dyskinesia in 2002 (Bartoloni et al., PMID: 12142464). The specific disease entity, Primary Ciliary Dyskinesia 7, is one of at least 40 different primary ciliary dyskinesias distinguished by a specific monogenic cause. Affected patients frequently present as neonates or in early childhood with recurrent respiratory infections including sinusitis, as well as decreased nasal nitric oxide, otitis media, and/or bronchiectasis. Biopsies of the airway epithelium exhibit normal ciliary ultrastructure but ciliary motility is abnormal, characterized by a stiff ciliary appearance and beating with abnormally high frequency and low amplitude (PMID: 33243178). Evidence of randomization of left-right abdominal symmetry is also observed, with approximately 50% penetrance of heterotaxy (often in the form of situs inversus totalis). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found the molecular mechanism and mode of inheritance (autosomal recessive) to be consistent among unrelated patients, while the phenotypic variability among them appeared to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited DNAH11 variants have been lumped into a single disease entity, referred to as Primary Ciliary Dyskinesia 7 (MONDO:0012748, OMIM #611884). Twenty-eight suspected pathogenic variants were scored as part of this curation (seven missense, two small in-frame deletions, nine nonsense, four frameshift, and six affecting splicing), which have been collectively reported in fifteen probands in three publications (PMID: 22184204, PMID: 22102620, PMID: 18022865). More case-level evidence is available in the literature (PMID: 12142464, PMID: 26909801, PMID: 32633470, PMID: 33243178), but its inclusion in this curation was not necessary to reach the maximum score for genetic evidence (12 points). This gene-disease relationship has not been studied in case-control studies at the single variant level or aggregate variant level. The mechanism of pathogenicity appears to be biallelic loss of function, characterized in some cases by the absence of a gene product (PMID: 26909801). All probands scored in this curation harbored two variant alleles within the DNAH11 locus. This gene-disease association is also supported by experimental evidence of DNAH11 localization specifically to tissue types relevant to disease and known to have motile cilia, including respiratory epithelium (PMID: 12859898) and the node region of the developing embryo (PMID: 9353118). Biochemical evidence indicates that DNAH11 is one of the most abundant components of the airway ciliary proteome but only a minor constituent of the sperm proteome (PMID: 31178125). DNAH11 localizes to proximal but not distal regions of respiratory cilia (PMID: 26909801), and longitudinal electron tomography can detect reduced outer dynein arm volume in proximal but not distal regions of motile cilia from patient nasal epithelial cells (PMID: 33479112). Normal ciliary motility was successfully restored to patient-derived airway cells by correcting the pathogenic DNAH11 variant at the DNA level using TALEN-based homology-directed gene editing (PMID: 26729821). Two homozygous mouse models harboring Dnah11 defects (one spontaneously occurring and one genetically engineered for loss-of-function) share ciliary, upper respiratory, and organ asymmetry phenotypes with affected human patients (PMID: 9353118, PMID: 22102620, PMID: 10556073). Additional evidence is available in the literature but its inclusion in this curation was not necessary to reach the maximum score for experimental evidence (6 points). In summary, DNAH11 is definitively associated with Primary Ciliary Dyskinesia 7. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen Motile Ciliopathy GCEP on September 13, 2021 (SOP Version 8).