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

• Published in: EBioMedicine Vol. 99; p. 104941
• Main Authors: Kouri, Chrysanthi, Sommer, Grit, Martinez de Lapiscina, Idoia, Elzenaty, Rawda Naamneh, Tack, Lloyd J.W., Cools, Martine, Ahmed, S. Faisal, Flück, Christa E., Abali, Saygin, Abali, Zehra Yavas, Akin, Leyla, Almaraz, Maricruz, Audí, Laura, Aydin, Murat, Balsamo, Antonio, Baronio, Federico, Bryce, Jillian, Busiah, Kanetee, Caimari, Maria, Camats-Tarruella, Núria, Campos-Martorell, Ariadna, Castaño, Luis, Casteràs, Anna, Çetinkaya, Semra, Chan, Yee-Ming, Claahsen-van der Grinten, Hedi L., Costa, Ines, Darendeliler, Fatma Feyza, Davies, Justin H., Esteva, Isabel, Fabbri-Scallet, Helena, Finlayson, Courtney A., Garcia, Emilio, Garcia Cuartero, Beatriz, German, Alina, Globa, Evgenia, Guerra-Junior, Gil, Guerrero, Julio, Guran, Tulay, Hannema, Sabine E., Hiort, Olaf, Hirsch, Josephine, Hughes, Leuan, Janner, Marco, Kolesinska, Zofia, Lachlan, Katherine, Lauber-Biason, Anna, Malikova, Jana Krenek, l'Allemand, Dagmar, Lenhnerr-Taube, Nina, Lucas-Herald, Angela, Mammadova, Jamala, MсElreavey, Kenneth, Mericq, Veronica, Mönig, Isabel, Moreno, Francisca, Mührer, Julia, Niedziela, Marek, Nordenstrom, Anna, Orman, Burçe, Poyrazoglu, Sukran, Rial, Jose M., Rutter, Meilan M., Rodríguez, Amaia, Schafer-Kalkhoff, Tara, Sauter, Kay-Sara, Seneviratne, Sumudu Nimali, Sredkova-Ruskova, Maria, Tadokoro-Cuccaro, Rieko, Thankamony, Ajay, Tomé, Mónica, Vela, Amaia, Wasniewska, Malgorzata, Zangen, David, Zelinska, Nataliya
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2024
• Subjects: Broad phenotype; Differences of sex development (DSD); Female; Genetics of sex determination and differentiation; Humans; Infant, Newborn; Intersex; Mutation; Phenotype; Retrospective Studies; Sexual Development - genetics; Steroidogenic factor 1 (SF-1/NR5A1); Steroidogenic Factor 1 - genetics; Intersex; Broad phenotype; Steroidogenic factor 1 (SF-1/NR5A1); Genetics of sex determination and differentiation; Differences of sex development (DSD)
• ISSN: 2352-3964; 2352-3964
• DOI: 10.1016/j.ebiom.2023.104941

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. 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. 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. 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. Swiss National Science Foundation (320030-197725) and Boveri Foundation Zürich, Switzerland.