Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1/SF-1 variants of sex development
Chrysanthi Kouri, Grit Sommer, Idoia Martinez de la Piscina, Rawda Naamneh Elzenaty, Lloyd Tack, Martine Cools, S. Faisal Ahmed, Christa E. Flück, Saygın Abalı, Zehra Yavaş Abalı, Leyla Akın, Maricruz Almaraz, Laura Audí, Murat Aydın, Antonio Balsamo, Federico Baronio, Jillian Bryce, Kanetee Busiah, María Caimari, Núria Camats, Ariadna Campos-Martorell, Luís Castaño, Anna Casteràs, Semra Çeti̇nkaya, Yee-Ming Chan, Hedi L. Claahsen‐van der Grinten, Ines M. Costa, Fatma Darendeliler, Justin H. Davies, Isabel Esteva, Helena Fabbri‐Scallet, Courtney Finlayson, Emilio García García, B. García Cuartero, Alina German, Evgenia Globa, Gil Guerra‐Júnior, Júlio Guerrero, Tülay Güran, Sabine E Hannema, Olaf Hiort, Josephine Hirsch, Leuan Hughes, Marco Janner, Zofia Kolesińska, Katherine Lachlan, Anna Lauber-Biason, Jana Malíková, Dagmar l’Allemand, Nina Lenhnerr-Taube, Angela Lucas-Herald, Jamala Mammadova, Kenneth MсElreavey, Verónica Mericq, Isabel Mönig, Francisca Moreno, Julia Mührer, Marek Niedziela, Anna Nordenström, Burçe Orman, Şükran Poyrazoğlu, Jose M. Rial, Meilan M. Rutter, Amaia Rodrı́guez, Tara Schafer-Kalkhoff, Kay‐Sara Sauter, Sumudu Nimali Seneviratne, Maria Sredkova-Ruskova, Rieko Tadokoro‐Cuccaro, Ajay Thankamony, Mónica Tomé, Amaia Vela, Małgorzata Waśniewska, David Zangen, Н. Б. Зелінська
Abstract
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 Zürich, Switzerland.