Submission Details

DNAH1 was first reported in association with autosomal recessive primary ciliary dyskinesia 37 in 2015 (Imitaz et al., PMID: 25927852). DNAH1 belongs to the axonemal inner dynein arm DHC group and is expressed in lungs and sperm flagella (PMIDs: 24360805,11371505). Primary Ciliary dyskinesia (PCD) is a motile ciliopathy caused by mutations in a heterogeneous group of genes expressed in the tracheal tissues. The clinical phenotype of PCD includes respiratory signs (neonatal respiratory distress, chronic cough, recurrent chest infections, rhinosinusitis, otitis, bronchiectasis, etc.) and body laterality defects in about 50% of cases. Infertility is also reported in a considerable number of patients (PMID: 33279404).

DNAH1 has been noted to be associated with two disease entities: primary ciliary dyskinesia 37 (PCD37) and spermatogenic failure 18. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern. There is observable phenotypic variability, with infertility being the only commonality in two cases (PMIDs: 24360805, 27798045, 23550210, 31765523, 34210339, 11371505, 32719396, 27573432, 34672773). Therefore, the following have been split into two disease entities: PCD37 (OMIM: 617577, MONDO: 0033204) and spermatogenic failure 18 (OMIM: 617576, MONDO: 0017173). The split curation for autosomal recessive spermatogenic failure 18 has been curated separately.

Evidence from 7 probands in 4 publications were included in this curation, representing 10 unique variants (6 missense, 2 frameshift, 1 nonsense and 1 splice site) (PMIDs: 25927852, 31765523, 33577779, 34210339). The genetic evidence for this curation is scarce, therefore, the maximum score was not reached (1.2/12 points.). This gene-disease relationship is supported by some experimental evidence. The DNAH1 mRNA and protein are proved to be expressed in testis and lungs (PMIDs: 24360805, 31781811, 25613900). This pattern of expression is compatible with PCD. Mice lacking the dynein heavy chain-7 (Mdhc7) gene (the ortholog of DNAH1 in Humans) were generated (PMID: 11371505). Mdhc7 -/- mice revealed sperm motility anomalies. Additionally, a decreased beat frequency in tracheal cilia of 50% was observed. The reduction in both ciliary and flagellar motility was not correlated with structural ciliary defects.

In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Motile Ciliopathy GCEP on February 10th, 2022 (SOP Version 8).