Broader impact and outcome of human NR5A1/SF1 variants.

Nuclear Receptor Subfamily 5 Group A Member 1, also known as Steroidogenic Factor 1 (NR5A1/SF-1), plays a crucial role in human sex development and steroidogenesis. Pathogenic variants in the NR5A1 gene are well-established causes of 46,XY and 46,XX differences in sex development (DSD) and primary ovarian insufficiency. While numerous studies have demonstrated that these variants impair puberty and fertility, the full spectrum of pubertal and reproductive effects in affected individuals remains difficult to define. Emerging evidence suggests broader, long-term implications beyond gonadal function, including effects on spleen function and metabolic health, not only in individuals with DSD, but also in asymptomatic carriers of NR5A1/SF-1 variants within the general population. However, these findings require validation through larger, longitudinal studies. This review provides a comprehensive overview of current knowledge and existing gaps, emphasizing the broader impact and long-term effects of NR5A1/SF-1 variants.