Abstract
PURPOSE: Human male infertility is a significant reproductive condition, with non-obstructive azoospermia (NOA) being the most severe form, resulting from impaired spermatogenesis. Many genetic variants have been identified as negatively impacting sperm development and maturation at multiple stages, leading to spermatogenic failure (SPGF). Here, we aim to study such variants, particularly those in the critical, highly conserved, meiosis-specific DMC1 (DNA meiotic recombinase 1) gene, to identify genetic candidates for male infertility and to strengthen DMC1's existing genotype-phenotype relationships. METHODS: We used whole exome sequencing (WES) and in silico analysis to investigate select DMC1 variants in a large cohort of infertile sporadic and familial cases (n = 3150). RESULTS: Our familial analyses identified a homozygous DMC1 missense variant, p.Thr55Ile, in two NOA-affected male siblings. We also report additional homozygous missense variants, p.Thr164Ala and p.Tyr194Cys, and one notable, rare single heterozygous variant, p.Asp160Gly, in unrelated sporadic patients. Our 3D protein modeling indicates that each of our identified variants would significantly impact the structure and functional activity of DMC1 protein. CONCLUSION: Our extensive genomic study identified three rare, recessive DMC1 variants in human NOA patients. Further, we report an alternative maturation arrest phenotype than previously observed in DMC1-related NOA. We also provide preliminary support for the possible exploration of select single heterozygous variants in the DMC1 gene, potentially expanding the male infertility field's understanding of the disease states and inheritance patterns associated with variants in DMC1.