ESPE Yearbook of Paediatric Endocrinology

EBioMedicine. 2025 Mar;113:105624. doi: 10.1016/j.ebiom.2025.105624

Brief summary: This study examined 30 individuals with 46,XY DSD carrying NR5A1/SF-1 variants and finds that co-existing variants in other DSD-related genes may explain their diverse phenotypic variability. The findings support an oligogenic rather than monogenic model of DSD. This has important implications for diagnosis, genetic counseling, and management.

Despite >100 genes being linked to DSD, nearly half of all DSD patients still lack a clear genetic diagnosis. While standard testing methods typically identify coding SNVs and CNVs, other contributors, such as intronic variants, mosaicism, structural or epigenetic alterations, and oligogenic inheritance, may go undetected. Next-generation sequencing (NGS) has enabled the identification of oligogenic causes in endocrine disorders, including DSD. Among these, NR5A1/SF-1 variants stand out for their highly variable phenotypes, ranging from severe DSD to isolated infertility or even asymptomatic individuals. Although several mechanisms have been proposed to explain this variability, including haploinsufficiency and dominant-negative effects, none have been conclusively proven. The recent international SF1next study, involving 197 individuals with NR5A1/SF-1 variants, the largest such cohort to date, found no clear genotype–phenotype correlation (1). However, it revealed a higher prevalence of associated anomalies, especially affecting the spleen, and noted that severe DSD cases frequently showed atypical puberty and predicted fertility issues. These observations support oligogenic inheritance as a likely explanation. To explore this, Kouri et al. conducted whole exome sequencing (WES) on family trios and applied disease-specific bioinformatic tools. Their findings identified additional variants in genes like TBCE, FLNB, GLI3, PDGFRA, and others frequently associated with DSD (e.g., CDH23, GLI2, KAT6B, MYO7A, PKD1, SPRY4, ZFPM2), suggesting multilocus contributions to the DSD phenotype.

This study underscores the need for advanced genetic testing and bioinformatic analyses using disease-specific algorithms to comprehensively identify and interpret the full spectrum of genetic variants involved in DSD. The complexity of DSD associated with NR5A1/SF-1 variants suggests the involvement of additional genetic factors, highlighting the importance of further research into potential multilocus contributions.

Reference: 1. Kouri C, Sommer G, Martinez de Lapiscina I, Elzenaty RN, Tack LJW, Cools M, Ahmed SF, Flück CE; SF1next study group. Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1/SF-1 variants of sex development. EBioMedicine. 2024 Jan;99:104941. PMID: 38168586.