NR5A1 Gene Variants: Variable Phenotypes, New Variants, and Genotype-Phenotype Correlations

NR5A1 variants are among the most frequent monogenic causes of disorders of sex development (DSD). However, genotype–phenotype correlations remain unclear, and oligogenic contributions to variability are underexplored in non-consanguineous Chinese populations. This study aimed to investigate the clinical, hormonal, and genetic features of a single-center Chinese pediatric cohort with NR5A1 variants, as well as assess genotype–phenotype correlations and intrafamilial variability. A total of 46 patients with NR5A1 variants were evaluated, and whole-exome sequencing was performed in a subset to identify additional candidate variants. The results showed that gonads were testes in all evaluated cases, with three patients having residual Müllerian structures and three patients having primary adrenal insufficiency. The median external masculinization score was 3.0 (2.5–5.0), indicating variable degrees of external genitalia development. Among individuals initially assigned female, 73% later underwent sex reassignment to male. Follicle-stimulating hormone levels increased significantly during puberty, suggesting hormonal dysregulation. The study identified 76 NR5A1 variants, most commonly in the hinge region (37/76), followed by the DNA-binding (28/76) and ligand-binding (7/76) domains. Intrafamilial phenotypes varied markedly, including primary ovarian insufficiency or irregular menstruation in women and oligospermia or DSD in men. Notably, the external masculinization score and penile length standard deviation score did not differ between missense and loss-of-function variants, suggesting that genotype does not consistently predict phenotype. The study also found that concomitant variants in other DSD-related genes support an oligogenic contribution to disease expression. In conclusion, NR5A1-related DSD shows substantial phenotypic and intrafamilial variability without consistent genotype–phenotype correlations, highlighting the need for further research into the underlying genetic mechanisms.