Variants in DNAH12 were first described as causal for spermatogenic failure in 2021 (Oud et al. 2021, PMID: 34089056). These cases represent one of at least one hundred different forms of spermatogenic failure distinguished by a single monogenic cause. Some of the most commonly reported patient phenotypes are male infertility, short sperm flagella, reduced sperm motility, abnormal sperm head and tail morphology, absent, coiled or bent sperm flagella, and absent sperm axoneme central pair complex. As a member of the DNAH gene family of axonemal dynein arm components, DNAH12 has also been viewed as a candidate gene for primary ciliary dyskinesia (PCD). Currently, there is no published case level genetic evidence or experimental data to support a gene/disease relationship between DNAH12 and PCD. Per the recommendations of the ClinGen Lumping & Splitting Working Group, DNAH12 was recommended for splitting, in order to focus the present curation specifically on the relationship between DNAH12 and spermatogenic failure.
This curation includes 15 variants (3 nonsense, 9 missense, and 3 disrupting splicing) that have been collectively reported in 11 male probands in 4 publications (PMID: 40146200, PMID: 39071892, PMID: 34089056, PMID: 34791246). Overall, the mechanism of pathogenicity appears to be biallelic loss-of-function.
This gene-disease relationship is also supported by experimental evidence showing that DNAH12 is primarily expressed in the lung, fallopian tube, and testis (PMID: 23715323, PMID: 40146200, PMID: 39071892). A mouse model with a 4-bp deletion in exon 5 recapitulates the abnormal sperm morphology, abnormal sperm motility, male infertility and absent sperm axoneme central pair complex seen in the human probands, as well as no obvious symptoms of primary ciliary dyskinesia (PMID: 40146200). A second mouse model producing a truncated DNAH12 protein showed abnormal sperm morphology and abnormal sperm motility ((PMID: 40146200)). Finally, a mouse model with a targeted excision of exons 3 to exon 5 of Dnah12 recapitulated the male infertility, abnormal sperm motility, abnormal sperm head morphology and coiled sperm flagella seen in human probands (PMID: 39071892).
In conclusion, DNAH12 has a Definitive association with spermatogenic failure. This classification has been clearly demonstrated and confirmed in both clinical and research settings and has been upheld over time without the emergence of conflicting evidence. This classification was approved by the Motile Ciliopathy GCEP on May 8th, 2025 (SOP Version 11).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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