Submission Details

Spermatogenic failure-18 (SPGF18) is a form of male infertility caused by multiple morphologic abnormalities of the sperm flagella. Mutations in DNAH1 were first reported in 2014 in association with Spermatogenic failure 18 (OMIM: 617576, MONDO: 0054615) involving morphologic abnormalities of the flagella (Ben Khelifa et al., 2014, PMID: 24360805). DNAH1 belongs to the axonemal inner dynein arm DHC group and is expressed in lungs and sperm flagella (Ben Khelifa et al., 2014, PMID: 24360805 and Neesen, 2001, PMID: 11371505). Per criteria outlined by the ClinGen Lumping and Splitting Working Group and due to balanced evidence and phenotypic variability, the ClinGen Motile Ciliopathy GCEP working group estimated that SPGF18 (OMIM: 617576, MONDO:0054615) and Primary Ciliary dyskinesia 37 (PCD37) (OMIM: 617577, MONDO: 0033204) represent distinct diseases and decided to split the entities. Evidence from 10 probands in 4 publications were included in this curation (PMID: 24360805, PMID: 27798045, PMID: 29449551 and PMID: 34867808) representing 10 unique variants (3 missense, 3 splice site, 3 frameshift and 1 stop-loss). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by experimental evidence. The DNAH1 mRNA and protein are proved to be expressed in testis (Ben Khelifa et al., 2014, PMID: 24360805, Sironen et al., 2020, PMID: 31781811 and Uhlen et al., 2015, PMID: 25613900). Also, by immunostaining, DNAH1 is observed in sperm flagella (Ben Khelifa et al., 2014, PMID: 24360805 and Amiri-Yekta et al., 2016, PMID: 27798045). Moreover, patients' sperm cells have shown flagellar morphological abnormalities and impaired motility (Ben Khelifa et al., 2014, PMID: 24360805 and Amiri-Yekta et al., 2016, PMID:27798045). This highlights the altered flagellar function caused by mutations in DNAH1. Mice lacking the dynein heavy chain-7 (Mdhc7) gene; a component of the inner dynein arm and the ortholog of DNAH1 in Humans, were generated (Neesen, 2001, PMID: 11371505). Homozygous males produced no offspring. Sperm cells from Mdhc7 -/- mice revealed a dramatically reduced straight line velocity and progressive movement, resulting in the inability of Mdhc7-deficient sperm to move from the uterus into the oviduct. The reduction in flagellar motility was not correlated with any clear defects in the axonemal structure. Similar results were obtained in a recent study (Khan et al., 2021, PMID: 34867808). The phenotype of DNAH1 deficient mice is similar to that observed in patients with SPGF18. Additionally, the sequence of the CG14651 gene in Drosophila is 45% similar to DNAH1 in Humans. CG14651 deficient male flies have shown immotile sperms (Bauerly et al., 2022, PMID: 34822845). Authors of this study have been able to rescue the fertility of n=9/10 male flies. In summary, DNAH1 is definitively associated with autosomal recessive Spermatogenic failure-18. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Motile Ciliopathy GCEP on May 26, 2022 (SOP Version 8).