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 Lapiscina; Rawda Naamneh Elzenaty; Lloyd J W Tack; Martine Cools; S Faisal Ahmed; Christa E Flück; SF1next study group

doi:10.1016/j.ebiom.2023.104941

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

EBioMedicine. 2024 Jan:99:104941. doi: 10.1016/j.ebiom.2023.104941. Epub 2024 Jan 1.

Authors

Chrysanthi Kouri¹, Grit Sommer², Idoia Martinez de Lapiscina³, Rawda Naamneh Elzenaty¹, Lloyd J W Tack⁴, Martine Cools⁴, S Faisal Ahmed⁵, Christa E Flück⁶; SF1next study group

Collaborators

SF1next study group:
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

¹ 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.
² 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.
³ 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.
⁴ Department of Paediatric Endocrinology, Department of Paediatrics and Internal Medicine, Ghent University Hospital, Ghent University, Ghent 9000, Belgium.
⁵ Developmental Endocrinology Research Group, University of Glasgow, Royal Hospital for Sick Children, Glasgow G51 4TF, UK.
⁶ 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. Electronic address: [email protected].

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.

Keywords: Broad phenotype; Differences of sex development (DSD); Genetics of sex determination and differentiation; Intersex; Steroidogenic factor 1 (SF-1/NR5A1).

MeSH terms

Female
Humans
Infant, Newborn
Mutation
Phenotype
Retrospective Studies
Sexual Development* / genetics
Steroidogenic Factor 1 / genetics

Substances

Steroidogenic Factor 1
NR5A1 protein, human