A Compound Heterozygous Missense Variant in The DNAH5 Gene Could Be A Significant Factor in Unexplained Male Infertility: A Case Study.

Abstract

Background: Infertility affects approximately 50 million couples worldwide, with both men and women being equally affected. Male infertility is a complex issue with genetic factors playing a significant role. Conditions such as Klinefelter syndrome (XXY), Y chromosome microdeletions (YCMDs), and monogenic mutations can contribute to male infertility. Currently, hereditary factors account for 4% of male infertility cases, while the causes of 60-70% of cases remain unknown. Ongoing research aims to identify new genes and variants related to male fertility to improve diagnostic methods. More than 2000 genes are believed to be involved in preserving germ cells and ensuring normal meiosis, with more than 100 genes already identified for male infertility.

Materials and methods: In this case series study, we assessed a patient with unexplained male infertility, who also had a brother with a similar issue. We used whole exome sequencing (WES) technology, segregation analysis and analyzed the data through bioinformatics tools.

Results: Bioinformatics analysis and Sanger sequencing revealed that two infertile brothers had a compound heterozygous (CH) mutation with missense variants in dynein axonemal heavy chain 5 (DNAH5) gene: one variant in exon 9, (c.1121T>C: p.Ile374Thr), and another in exon 66, (c.11437C>T: p.Arg3813Trp). The protein structure analysis showed that the Ile374Thr variant is located near the outer dynein arm-docking subunit 1 (ODA-D1) and ODA-D3. Additionally, the Arg3813Trp variant replaces the positively charged arginine with a hydrophobic tryptophan residue, which may lead to local instability in the protein structure, particularly in the ATP-binding site.

Conclusion: Our study reports a CH presence of a missense variant in DNAH5 within a family experiencing male infertility. In silico structural predictions suggest a potential role of these DNAH5 variants in causing fertility issues.