NR5A1 gene variants in infertile Senegalese men: Discovery of a novel missense variant and genotype-phenotype correlation

The NR5A1 gene, encoding Steroidogenic Factor 1 (SF-1), plays a critical role in sex differentiation and spermatogenesis. However, data on NR5A1 variants in sub-Saharan African populations remain limited. This exploratory pilot study aimed to identify and characterize NR5A1 variants in infertile Senegalese men and to assess genotype-phenotype correlations. We conducted a cross-sectional study in 23 infertile Senegalese men, and exons 2 -7 of NR5A1 were sequenced using the Sanger method. Detected variants were analyzed with in silico prediction tools and filtered for rarity (minor allele frequency < 1 %) using the gnomAD database. Genotype-phenotype associations were analyzed using Fisher's exact test. Eighty-three percent of patients harbored at least one NR5A1 variant. A novel heterozygous missense variant, c.584C > T (p.Ser195Phe), located in the hinge region of SF-1, was identified in three unrelated individuals presenting with micropenis, testicular hypotrophy, and azoospermia. Several previously described variants were also detected. Genotype-phenotype correlation analysis revealed significant associations between NR5A1 variants and spermatogenic failure, the most common clinical feature (60.8 %). These findings demonstrate substantial genetic variability in NR5A1 among Senegalese men with infertility, and identify a novel missense variant. Our study highlights the relevance of NR5A1 in male infertility screening and emphasizes the importance of incorporating African populations into reproductive genetics research.