Recent studies suggest that male infertility may result from monogenic causes. Despite the growing number of candidate genes potentially associated with monogenic forms of infertility, the prevalence of such forms and the strength of gene–infertility associations remain limited. To estimate the proportion of monogenic causes of male infertility and to assess the clinical utility of monogenic testing, we designed the first clinical gene panel that includes genes with established pathogenic roles in male infertility. The study included 240 men with severe idiopathic infertility (azoospermia or severe oligozoospermia). Genomic DNA was subjected to whole-exome sequencing, and the identified sequence variants were classified according to ACGS guidelines using ACMG/AMP criteria. Based on ClinGen recommendations, we designed a panel of 21 genes with defined pathogenic roles in male infertility, the analysis of which led to the identification of pathogenic variants in 4 infertile men in the MSH4, STAG3, TEX14, and TEX15 genes (1.7%). Further analysis of additional candidate genes with currently limited evidence for pathogenicity in male infertility revealed likely pathogenic or pathogenic variants in 11 additional men, involving the ADAD1, GALNTL5, RHOXF2B, SPOCD1, SSX1, STRA8, and TDRD9 genes. In addition to the 15 patients with likely pathogenic or pathogenic variants, we identified 15 individuals carrying candidate variants of uncertain significance, suggesting that the proportion of monogenic forms may be higher than estimated in our study. The identification of likely pathogenic or pathogenic variants in a total of 6.3% of infertile men confirms the clinical utility of monogenic testing in severe forms of idiopathic infertility and indicates that the inclusion of exome sequencing in the diagnostic process could contribute to improved diagnostics and more appropriate management of these patients.
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