Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1/SF-1 variants of sex development.

Kouri C., Sommer G., Martinez de Lapiscina I., Elzenaty R. N., Tack L. J. W., Cools M., ...More

EBioMedicine, vol.99, pp.104941, 2024 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 99
  • Publication Date: 2024
  • Doi Number: 10.1016/j.ebiom.2023.104941
  • Journal Name: EBioMedicine
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, EMBASE, MEDLINE, Directory of Open Access Journals
  • Page Numbers: pp.104941
  • Istanbul University Affiliated: Yes


Background Steroidogenic factor 1 (SF-1/NR5A1) is essential for human sex development. Heterozygous NR5A1/SF-1 variants manifest with a broad range of phenotypes of differences of sex development (DSD), which remain unexplained. Methods We conducted a retrospective analysis on the so far largest international cohort of individuals with NR5A1/ SF -1 variants, identified through the I-DSD registry and a research network. Findings Among 197 individuals with NR5A1/SF-1 variants, we confirmed diverse phenotypes. Over 70% of 46, XY individuals had a severe DSD phenotype, while 90% of 46, XX individuals had female-typical sex development. Close to 100 different novel and known NR5A1/SF-1 variants were identified, without specific hot spots. Additionally, likely disease-associated variants in other genes were reported in 32 individuals out of 128 tested (25%), particularly in those with severe or opposite sex DSD phenotypes. Interestingly, 48% of these variants were found in known DSD or SF -1 interacting genes, but no frequent gene-clusters were identified. Sex registration at birth varied, with <10% undergoing reassignment. Gonadectomy was performed in 30% and genital surgery in 58%. Associated organ anomalies were observed in 27% of individuals with a DSD, mainly concerning the spleen. Intrafamilial phenotypes also varied considerably. Interpretation The observed phenotypic variability in individuals and families with NR5A1/SF-1 variants is large and remains unpredictable. It may often not be solely explained by the monogenic pathogenicity of the NR5A1/SF-1 variants but is likely influenced by additional genetic variants and as -yet -unknown factors. Funding Swiss National Science Foundation (320030-197725) and Boveri Foundation Zurich, Switzerland. Copyright Crown Copyright (c) 2023 Published by Elsevier B.V. This is an open access article under the CC BY -NCND license (