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.

In this single-center, retrospective cohort study, we evaluated clinical, hormonal, and genetic features of a single-center Chinese pediatric cohort with NR5A1 variants. We assessed genotype-phenotype correlations and intrafamilial variability and performed whole-exome sequencing in a subset to identify additional candidate variants.

In 46,XY patients, gonads were testes in all evaluated cases; three had residual Müllerian structures, and three had primary adrenal insufficiency. The median external masculinization score was 3.0 (2.5-5.0). Among individuals initially assigned female, 73% (33/45) later underwent sex reassignment to male. Follicle-stimulating hormone levels increased significantly during puberty. We 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. The external masculinization score and penile length standard deviation score did not differ between missense and loss-of-function variants (median score -3.63 vs -4.71; all P > 0.05) and remained similar across functional domains; testis location scores and sex assignment were also comparable. Whole-exome sequencing in 25 patients identified 49 potentially deleterious candidate variants in 36 additional genes.

NR5A1-related DSD shows substantial phenotypic and intrafamilial variability without consistent genotype-phenotype correlations. Concomitant variants in other DSD-related genes support an oligogenic contribution to disease expression.