Kouri, C.Sommer, G.Martínez de Lapiscina, I.Naamneh Elzenaty, R.Tack, L. J. W.Cools, M.Faisal Ahmed, S.Flück, C. E.García García, Emilio José2025-05-282025-05-282024-01-01Kouri, C., Sommer, G., Martínez de Lapiscina, I., Naamneh Elzenaty, R., Tack, L.J.W., Cools, M.,...,García García, E.J. (2024). Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1/SF-1 variants of sex development. EBioMedicine, 99, 104941. https://doi.org/10. 1016/j.ebiom.2023. 104941.2352-3964https://hdl.handle.net/11441/173580Background: 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.application/pdf16 p.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/steroidogenic factor 1 (SF-1/NR5A1)differences of sex development (DSD)broad phenotypegenetics of sex determination and differentiationintersexinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/openAccesshttps://doi.org/10. 1016/j.ebiom.2023. 104941