Identifying potential genetic biomarkers for sperm dysfunction through whole-genome sequencing

Abstract

Infertility affects approximately 15% of couples globally, with male factors contributing to nearly 50% of cases. However, the genetic basis of male infertility, particularly idiopathic forms, remains poorly understood. In this study, we performed whole-genome sequencing (WGS) on eight normozoospermic men and nine men with oligozoospermia, asthenozoospermia, or both, followed by Sanger sequencing for validation. Comparative analysis revealed a higher burden of genomic variants in the sperm dysfunction infertility group (SDIG) than in the normozoospermic group (NG). Several nonsynonymous missense variants were exclusively identified in SDIG, including DNAJB13 (p.Ile159Asn), MNS1 (p.Asp217Asn), DNAH6 (p.Ser2210Leu), HYDIN (p.Gly901Ala, p.Arg568Trp), DNAH7 (p.Arg1486His, p.Gly171Arg, p.Ser2368Phe), DNAH17 (p.Ala3135Val), and CATSPER1 (p.Arg558Trp). These variants are predicted to affect protein structure, stability, or interactions, and were classified as variants of uncertain significance. Moreover, several variants were classified as likely pathogenic: a frameshift mutation in DNAH2 (p.Lys1414ArgfsTer29) likely resulting in a truncated protein, a missense mutation in CFAP61 (p.Arg568Trp) predicted to impair protein function, and two nonsense mutations in FSIP2 (p.Gln5809Ter and p.Cys8Ter) introducing premature stop codons. These alterations implicate key components of sperm flagellar function and motility. Our findings reveal novel and potentially deleterious genetic variants associated with male infertility, offering new insights into its molecular underpinnings and informing future diagnostic and therapeutic approaches.