EBioMedicine (Jan 2024)
Clinical and genetic characteristics of a large international cohort of individuals with rare NR5A1/SF-1 variants of sex developmentResearch in context
- Chrysanthi Kouri,
- Grit Sommer,
- Idoia Martinez de Lapiscina,
- Rawda Naamneh Elzenaty,
- Lloyd J.W. Tack,
- Martine Cools,
- S. Faisal Ahmed,
- Christa E. Flück,
- Saygin Abali,
- Zehra Yavas Abali,
- Leyla Akin,
- Maricruz Almaraz,
- Laura Audí,
- Murat Aydin,
- Antonio Balsamo,
- Federico Baronio,
- Jillian Bryce,
- Kanetee Busiah,
- Maria Caimari,
- Núria Camats-Tarruella,
- Ariadna Campos-Martorell,
- Luis Castaño,
- Anna Casteràs,
- Semra Çetinkaya,
- Yee-Ming Chan,
- Hedi L. Claahsen-van der Grinten,
- Ines Costa,
- Fatma Feyza Darendeliler,
- Justin H. Davies,
- Isabel Esteva,
- Helena Fabbri-Scallet,
- Courtney A. Finlayson,
- Emilio Garcia,
- Beatriz Garcia Cuartero,
- Alina German,
- Evgenia Globa,
- Gil Guerra-Junior,
- Julio Guerrero,
- Tulay Guran,
- Sabine E. Hannema,
- Olaf Hiort,
- Josephine Hirsch,
- Leuan Hughes,
- Marco Janner,
- Zofia Kolesinska,
- Katherine Lachlan,
- Anna Lauber-Biason,
- Jana Krenek Malikova,
- Dagmar l'Allemand,
- Nina Lenhnerr-Taube,
- Angela Lucas-Herald,
- Jamala Mammadova,
- Kenneth MсElreavey,
- Veronica Mericq,
- Isabel Mönig,
- Francisca Moreno,
- Julia Mührer,
- Marek Niedziela,
- Anna Nordenstrom,
- Burçe Orman,
- Sukran Poyrazoglu,
- Jose M. Rial,
- Meilan M. Rutter,
- Amaia Rodríguez,
- Tara Schafer-Kalkhoff,
- Kay-Sara Sauter,
- Sumudu Nimali Seneviratne,
- Maria Sredkova-Ruskova,
- Rieko Tadokoro-Cuccaro,
- Ajay Thankamony,
- Mónica Tomé,
- Amaia Vela,
- Malgorzata Wasniewska,
- David Zangen,
- Nataliya Zelinska
Affiliations
- Chrysanthi Kouri
- Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland; Department for BioMedical Research, University of Bern, Bern 3008, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern 3012, Switzerland
- Grit Sommer
- Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland; Department for BioMedical Research, University of Bern, Bern 3008, Switzerland; Institute of Social and Preventive Medicine, University of Bern, Switzerland, University of Bern, Bern 3012, Switzerland
- Idoia Martinez de Lapiscina
- Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland; Department for BioMedical Research, University of Bern, Bern 3008, Switzerland; Research into the Genetics and Control of Diabetes and Other Endocrine Disorders, Biobizkaia Health Research Institute, Cruces University Hospital, Barakaldo 48903, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid 28029, Spain; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid 28029, Spain; Endo-ERN, Amsterdam 1081 HV, the Netherlands
- Rawda Naamneh Elzenaty
- Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland; Department for BioMedical Research, University of Bern, Bern 3008, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern 3012, Switzerland
- Lloyd J.W. Tack
- Department of Paediatric Endocrinology, Department of Paediatrics and Internal Medicine, Ghent University Hospital, Ghent University, Ghent 9000, Belgium
- Martine Cools
- Department of Paediatric Endocrinology, Department of Paediatrics and Internal Medicine, Ghent University Hospital, Ghent University, Ghent 9000, Belgium
- S. Faisal Ahmed
- Developmental Endocrinology Research Group, University of Glasgow, Royal Hospital for Sick Children, Glasgow G51 4TF, UK
- Christa E. Flück
- Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland; Department for BioMedical Research, University of Bern, Bern 3008, Switzerland; Corresponding author. University Children's Hospital Bern, Freiburgstrasse 65 / C845, Bern 3010, Switzerland.
- Saygin Abali
- Zehra Yavas Abali
- Leyla Akin
- Maricruz Almaraz
- Laura Audí
- Murat Aydin
- Antonio Balsamo
- Federico Baronio
- Jillian Bryce
- Kanetee Busiah
- Maria Caimari
- Núria Camats-Tarruella
- Ariadna Campos-Martorell
- Luis Castaño
- Anna Casteràs
- Semra Çetinkaya
- Yee-Ming Chan
- Hedi L. Claahsen-van der Grinten
- Ines Costa
- Fatma Feyza Darendeliler
- Justin H. Davies
- Isabel Esteva
- Helena Fabbri-Scallet
- Courtney A. Finlayson
- Emilio Garcia
- Beatriz Garcia Cuartero
- Alina German
- Evgenia Globa
- Gil Guerra-Junior
- Julio Guerrero
- Tulay Guran
- Sabine E. Hannema
- Olaf Hiort
- Josephine Hirsch
- Leuan Hughes
- Marco Janner
- Zofia Kolesinska
- Katherine Lachlan
- Anna Lauber-Biason
- Jana Krenek Malikova
- Dagmar l'Allemand
- Nina Lenhnerr-Taube
- Angela Lucas-Herald
- Jamala Mammadova
- Kenneth MсElreavey
- Veronica Mericq
- Isabel Mönig
- Francisca Moreno
- Julia Mührer
- Marek Niedziela
- Anna Nordenstrom
- Burçe Orman
- Sukran Poyrazoglu
- Jose M. Rial
- Meilan M. Rutter
- Amaia Rodríguez
- Tara Schafer-Kalkhoff
- Kay-Sara Sauter
- Sumudu Nimali Seneviratne
- Maria Sredkova-Ruskova
- Rieko Tadokoro-Cuccaro
- Ajay Thankamony
- Mónica Tomé
- Amaia Vela
- Malgorzata Wasniewska
- David Zangen
- Nataliya Zelinska
- Journal volume & issue
-
Vol. 99
p. 104941
Abstract
Summary: 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.
