Clinical and Genetic Characteristics of a Large International Cohort of Individuals with Rare NR5A1/SF-1 Variants of Sex Development

Overview

Journal EBioMedicine

Specialty Biomedical Engineering

Date 2024 Jan 3

PMID 38168586

Authors

Chrysanthi Kouri

Grit Sommer

Idoia Martinez de Lapiscina

Rawda Naamneh Elzenaty

Lloyd J W Tack

Martine Cools

S Faisal Ahmed

Christa E Fluck

Affiliations

Soon will be listed here.

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.

Citing Articles

Molecular genetic diagnosis and surgical management in a cohort of children with 46,XY disorders/differences of sex development.

Wong Y, Luk H, Yau H, Wong L, Poon S, Tung J Front Pediatr. 2025; 13:1456227.

PMID: 39936125 PMC: 11810906. DOI: 10.3389/fped.2025.1456227.

Clinical spectrum and molecular basis in 19 Chinese patients with 46, XY disorder of sexual development caused by NR5A1 mutations.

Xu Y, Liu X, Liu Y, Zhu H, Wu J, Han B Orphanet J Rare Dis. 2024; 19(1):453.

PMID: 39623453 PMC: 11610102. DOI: 10.1186/s13023-024-03472-8.

Population-Based Study of Rare Coding Variants in /SF-1.

Kouri C, Jia R, Kentistou K, Gardner E, Perry J, Fluck C J Endocr Soc. 2024; 8(12):bvae178.

PMID: 39479520 PMC: 11521259. DOI: 10.1210/jendso/bvae178.

/SF-1 Collaborates with Inhibin α and the Androgen Receptor.

Elzenaty R, Kouri C, Martinez de Lapiscina I, Sauter K, Moreno F, Camats-Tarruella N Int J Mol Sci. 2024; 25(18).

PMID: 39337600 PMC: 11432463. DOI: 10.3390/ijms251810109.

Phenotype-Genotype Discordance and a Case of a Disorder of Sexual Differentiation.

Snipes M, Stokes S, Vidalin A, Moore L, Schlabritz-Lutsevich N, Maher 3rd J Case Rep Genet. 2024; 2024:9936936.

PMID: 39050587 PMC: 11268958. DOI: 10.1155/2024/9936936.

References

Hoivik E, Lewis A, Aumo L, Bakke M . Molecular aspects of steroidogenic factor 1 (SF-1). Mol Cell Endocrinol. 2009; 315(1-2):27-39. DOI: 10.1016/j.mce.2009.07.003. View

Eggers S, Sadedin S, van den Bergen J, Robevska G, Ohnesorg T, Hewitt J . Disorders of sex development: insights from targeted gene sequencing of a large international patient cohort. Genome Biol. 2016; 17(1):243. PMC: 5126855. DOI: 10.1186/s13059-016-1105-y. View

van der Straaten S, Springer A, Zecic A, Hebenstreit D, Tonnhofer U, Gawlik A . The External Genitalia Score (EGS): A European Multicenter Validation Study. J Clin Endocrinol Metab. 2019; 105(3). DOI: 10.1210/clinem/dgz142. View

Harris P, Taylor R, Thielke R, Payne J, Gonzalez N, Conde J . Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2008; 42(2):377-81. PMC: 2700030. DOI: 10.1016/j.jbi.2008.08.010. View

Eggers S, Smith K, Bahlo M, Looijenga L, Drop S, Juniarto Z . Whole exome sequencing combined with linkage analysis identifies a novel 3 bp deletion in NR5A1. Eur J Hum Genet. 2014; 23(4):486-93. PMC: 4666572. DOI: 10.1038/ejhg.2014.130. View

Suntharalingham J, Buonocore F, Duncan A, Achermann J . DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease. Best Pract Res Clin Endocrinol Metab. 2015; 29(4):607-19. PMC: 5159745. DOI: 10.1016/j.beem.2015.07.004. View

Akcan N, Uyguner O, Bas F, Altunoglu U, Toksoy G, Karaman B . Mutations in or Genes: Clinical Findings, Endocrine Pitfalls, and Genetic Features of Children with 46,XY DSD. J Clin Res Pediatr Endocrinol. 2022; 14(2):153-171. PMC: 9176093. DOI: 10.4274/jcrpe.galenos.2022.2021-9-19. View

Mazen I, Abdel-Hamid M, Mekkawy M, Bignon-Topalovic J, Boudjenah R, Gammal M . Identification of NR5A1 Mutations and Possible Digenic Inheritance in 46,XY Gonadal Dysgenesis. Sex Dev. 2016; 10(3):147-51. DOI: 10.1159/000445983. View

Lucas-Herald A, Bertelloni S, Juul A, Bryce J, Jiang J, Rodie M . The Long-Term Outcome of Boys With Partial Androgen Insensitivity Syndrome and a Mutation in the Androgen Receptor Gene. J Clin Endocrinol Metab. 2016; 101(11):3959-3967. PMC: 5095251. DOI: 10.1210/jc.2016-1372. View

10.

Meinsohn M, Smith O, Bertolin K, Murphy B . The Orphan Nuclear Receptors Steroidogenic Factor-1 and Liver Receptor Homolog-1: Structure, Regulation, and Essential Roles in Mammalian Reproduction. Physiol Rev. 2019; 99(2):1249-1279. DOI: 10.1152/physrev.00019.2018. View

11.

Zangen D, Kaufman Y, Banne E, Weinberg-Shukron A, Abulibdeh A, Garfinkel B . Testicular differentiation factor SF-1 is required for human spleen development. J Clin Invest. 2014; 124(5):2071-5. PMC: 4001552. DOI: 10.1172/JCI73186. View

12.

Wu D, Chen H, Gong C . Physical assessment and reference growth curves for children with 46, XY disorders of sex development. Pediatr Investig. 2020; 1(1):13-19. PMC: 7331437. DOI: 10.1002/ped4.12010. View

13.

Kohler S, Schulz M, Krawitz P, Bauer S, Dolken S, Ott C . Clinical diagnostics in human genetics with semantic similarity searches in ontologies. Am J Hum Genet. 2009; 85(4):457-64. PMC: 2756558. DOI: 10.1016/j.ajhg.2009.09.003. View

14.

Luo X, Ikeda Y, Parker K . A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell. 1994; 77(4):481-90. DOI: 10.1016/0092-8674(94)90211-9. View

15.

Cox K, Bryce J, Jiang J, Rodie M, Sinnott R, Alkhawari M . Novel associations in disorders of sex development: findings from the I-DSD Registry. J Clin Endocrinol Metab. 2013; 99(2):E348-55. PMC: 3955252. DOI: 10.1210/jc.2013-2918. View

16.

Shinoda K, Lei H, Yoshii H, Nomura M, Nagano M, Shiba H . Developmental defects of the ventromedial hypothalamic nucleus and pituitary gonadotroph in the Ftz-F1 disrupted mice. Dev Dyn. 1995; 204(1):22-9. DOI: 10.1002/aja.1002040104. View

17.

Martinez de Lapiscina I, Mahmoud R, Sauter K, Esteva I, Alonso M, Costa I . Variants of and May Contribute towards the Broad Phenotype Observed in 46,XY DSD Patients with Heterozygous Variants of . Int J Mol Sci. 2020; 21(22). PMC: 7696449. DOI: 10.3390/ijms21228554. View

18.

Poyrazoglu S, Darendeliler F, Ahmed S, Hughes I, Bryce J, Jiang J . Birth Weight in Different Etiologies of Disorders of Sex Development. J Clin Endocrinol Metab. 2017; 102(3):1044-1050. DOI: 10.1210/jc.2016-3460. View

19.

Baxter R, Arboleda V, Lee H, Barseghyan H, Adam M, Fechner P . Exome sequencing for the diagnosis of 46,XY disorders of sex development. J Clin Endocrinol Metab. 2014; 100(2):E333-44. PMC: 4318895. DOI: 10.1210/jc.2014-2605. View

20.

Zidoune H, Ladjouze A, Chellat-Rezgoune D, Boukri A, Dib S, Nouri N . Novel Genomic Variants, Atypical Phenotypes and Evidence of a Digenic/Oligogenic Contribution to Disorders/Differences of Sex Development in a Large North African Cohort. Front Genet. 2022; 13:900574. PMC: 9468775. DOI: 10.3389/fgene.2022.900574. View