Rare missense variants identified by whole-genome sequencing in men with oligoasthenoteratozoospermia: An experimental study

Background: Oligoasthenoteratozoospermia (OAT) is a major cause of male infertility, characterized by low sperm count, poor motility, and abnormal morphology. While genetic factors contribute to a substantial proportion of cases, the specific variants underlying OAT remain largely unknown, especially in populations with high rates of consanguinity. Objective: To identify rare candidate variants potentially associated with OAT using whole-genome sequencing (WGS) in ۷ men from consanguineous families. Materials and Methods: ۷ men with OAT from consanguineous families, with normal karyotypes and no Y-chromosome microdeletions, were selected. WGS was performed, and variants were called using DeepVariant. These variants were then annotated using the Ensembl variant effect predictor. Rare variants were prioritized based on their predicted pathogenicity and relevance to reproduction, and candidate variants were validated. Protein structure modeling and analysis of mutation-induced effects on molecular interactions were carried out using Swiss model and AlphaFold. Results: We identified ۲ rare homozygous missense variants in DNAH۹ (p.Pro۳۵۵Leu) and CFAP۴۵ (p.Arg۴۹۳Trp) in the index case with OAT. Both genes have been implicated in sperm flagellar structure and motility. Additional variants in genes associated with spermiogenesis, acrosomal integrity, and testicular function were also identified. Conclusion: Our findings demonstrate the potential utility of WGS in identifying rare candidate variants potentially associated with OAT. The identified DNAH۹ and CFAP۴۵ variants, together with additional candidate variants, may contribute to the impaired sperm function observed in this man. This study also highlights the value of genome-wide analyses in improving our understanding of male infertility, particularly in consanguineous populations, and provides a foundation for future functional studies and personalized diagnostic approaches.

کلیدواژه ها:

Male infertility ، Oligoasthenoteratozoospermia ، Whole-genome sequencing ، DNAH۹ ، CFAP۴۵. ، ناباروری مردان ، الیگواستنوتراتوزواسپرمی ، توالی یابی کل ژنوم ، DNAH۹ ، CFAP۴۵.