Submission Details

DNAH6, Spermatogenic Failure, (MONDO:0004983), autosomal recessive

DNAH6 was first described as a Spermatogenic Failure-causing gene in 2017 (Gershoni et al. 2017, PMID: 28206990). The specific disease entity, Spermatogenic Failure (MONDO:0004983, OMIM:603336), is one of at least a hundred different spermatogenic failures distinguished by a single monogenic cause. Some of the most common patient phenotypes are: Absent sperm flagella, Absent sperm axoneme central pair complex, Male infertility, Reduced sperm motility, Abnormal sperm head morphology, Short sperm flagella and Coiled sperm flagella. The probands who have DNAH6 variants exhibit a spectrum of phenotypes that include infertility due to spermatogenic failure and abnormal sperm motility and morphology. Currently, none of the monogenic probands in the literature display respiratory features characteristic of primary ciliary dyskinesia. Per the recommendations of the ClinGen Lumping and Splitting Working Group, the GCEP decided to split and perform separate curations for both gene-diseases entities: One curation for the relationship between DNAH6 and PCD and another one for the relationship between DNAH6 and Spermatogenic Failure. This curation is focused on the relationship between DNAH6 and Spermatogenic Failure.

Sixteen variants: (4 types of genetic mutations: Missense (12), Splice Site (2),Frameshift (1) and Nonsense (1) that have been reported in 11 probands in 7 publications (PMIDs: 26918822, 37424858, 37594300, 29356036, 31676830, 34089056 and 28206990) are included in this curation.

Most of the siblings of the probands were also found to be affected with similar phenotypes to varying degrees of severity and were similarly genotyped. However, the fertility status of all of the siblings was not known.

Overall, the mechanism of pathogenicity appears to be loss of function as shown by the suspected disease-causing variants in the probands.

This gene-disease relationship is also supported by multiple forms of experimental evidence such as Expression A (Quantity: 1), Biochemical Function A (Quantity: 1), Model System: Zebrafish (Danio rerio) (Quantity: 1) and Model System: Cell Culture (Quantity: 1). First, GTex data showed that DNAH6 is primarily expressed in fallopian tubes and lungs, which is consistent with PCD phenotypes (PMID: 23715323).Wilken et al. 2024 found that both DNAH6 and DNAH1 are both IDA components and localized to the same region (PMID: 39056782). DNAH1 was classified as having a "limited" relationship with PCD 37 and a “defintive” relationship with spermatogenic failure 18 by the Motile Ciliopathy GCEP. Refer to the curation for further details. Next, Li et al. 2016 (PMID:26918822) contained a zebrafish model.The immotile cilia found in the model is similar to the immotile sperm seen in human probands. Additionally, the abnormal ciliary motility seen in the model is similar to the reduced sperm motility found in the human probands. The model presented a severe defect that led to a significant curvature of the spine, which has similarity to the coiled sperm found in human probands. Then, a shDNAH6 knockdown of human respiratory epithelia showed that the abnormal ciliary motility found in the model recapitulates the abnormality of sperm motility found in the human probands (Li et al. 2016, PMID:26918822).

In conclusion, DNAH6 has a strong association with Spermatogenic Failure. This classification has been clearly demonstrated and confirmed through both experimental and genetic evidence and has been upheld over time.

This classification was approved by the Motile Ciliopathy GCEP on February 13th, 2025 (SOP Version 10).