The role of DNA mismatch repair mutS/mutL homolog genes in spermatogenesis and male infertility

Background: Recent research in male infertility genetics has identified numerous candidate genes, some of which were also involved in DNA repair. Mismatch repair (MMR) genes, such as MSH4 and MSH5, have been linked to male infertility due to their role in meiosis, suggesting that other MMR genes may also contribute to impaired spermatogenesis. To investigate the role of MMR genes in male infertility, we first conducted a systematic review focusing on their involvement in impaired spermatogenesis, which was followed by a multicenter cohort study assessing the occurrence of rare deleterious variants in MMR genes among men with severely impaired fertility. The present study aimed to assess the contribution of MMR genes to male infertility and to evaluate their potential clinical utility in the diagnostic workup of men with severely impaired fertility. Methods: A systematic review was conducted through a PubMed database search with a focus on the role of MMR genes in spermatogenesis. We additionally prepared a cohort study, including whole-exome sequencing data from 244 infertile men presenting azoospermia or severe oligozoospermia (< 5 million spermatozoa/ml). Rare, deleterious variants in MMR genes were classified using the ACGS Guidelines for Variant Classification 2020. Results: Following a systematic review of the literature, we gathered robust evidence supporting the strong involvement of MSH4 and MSH5 variants in male infertility, moderate evidence for MLH3, and limited evidence for other MMR genes. From our cohort, we identified likely pathogenic or pathogenic variants in two individuals: one with two MSH4 variants and another with a PMS2 variant. Conclusions: The present study identifies MSH4 and MSH5 as strong candidate genes for male infertility, supporting the integration of their testing into the clinical diagnosis of infertile men, particularly those exhibiting non-obstructive azoospermia. Although current evidence suggests that genetic variants in most MMR genes do not cause infertility, genetic defects in MMR genes can still impair spermatogenesis due to their critical role in sperm DNA repair and maintenance of genome integrity.