Exploring oligogenicity as a contributor to the broad phenotypic spectrum of 46,XY differences in sex development associated with NR5A1/SF-1 variants: findings from the international SF1next study

Chrysanthi Kouri; Lapiscina Idoia Martinez de; Rawda Naamneh-Elzenaty; Grit Sommer; Kay-Sara Sauter; Christa E Fluck; study group  SF1next

doi:10.1530/endoabs.110.P39

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Endocrine Abstracts (2025) 110 P39 | DOI: 10.1530/endoabs.110.P39

ECEESPE2025 Poster Presentations Adrenal and Cardiovascular Endocrinology (169 abstracts)

Exploring oligogenicity as a contributor to the broad phenotypic spectrum of 46,XY differences in sex development associated with NR5A1/SF-1 variants: findings from the international SF1next study

Chrysanthi Kouri ^1,2,3,4 , Idoia Martinez de Lapiscina ^2,5,6 , Rawda Naamneh-Elzenaty ^1,6,7 , Grit Sommer ^6,8 , Kay-Sara Sauter ^6,7 , Christa E Flück ^6,7 & SF1next study group ⁶

Author affiliations

¹Graduate School for Cellular and Biomedical Sciences, University of Bern, 3012 Bern, Switzerland, Bern, Switzerland; ²Department for BioMedical Research, University of Bern, 3008 Bern, Switzerland., Bern, Switzerland; ³Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland., Bern, Switzerland; ⁴University of Bern, Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland., Bern, Switzerland; ⁵Research into the genetics and control of diabetes and other endocrine disorders, Biobizkaia Health Research Institute, Cruces University Hospital, Barakaldo, 48903, Spain., Barakaldo, Spain; ⁶Pediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; ⁷Department for BioMedical Research, University of Bern, Bern, Switzerland; ⁸Swiss Childhood Cancer Registry, Institute of Social and Preventive Medicine, University of Bern, 3012 Bern, Switzerland., Bern, Switzerland

JOINT324

Background: Individuals with NR5A1/SF-1 variants encompass a wide spectrum of phenotypes, ranging from asymptomatic carriers to severe forms of differences of sex development (DSD). The mechanisms contributing to this wide variability of observed phenotypes remains elusive. Oligogenicity has been suggested as a potential mechanism. We aimed to investigate the oligogenicity patterns in individuals with NR5A1/SF-1 variants from the international SF1next study cohort, shedding light on how multiple genetic variants collectively influence DSD phenotypes.

Methods: DNA samples and comprehensive DSD phenotype data from individuals carrying NR5A1/SF-1 variants, and available family members, were collected from the SF1next study cohort. Whole exome sequencing (WES) data of 30 individuals/families were utilised. WES data were analysed using a tailored filtering algorithm to identify rare variants in SF-1- and DSD-related genes. Identified variants were assessed for potential pathogenicity based on American College of Medical Genetics and Genomics (ACMG) and clinical disease associations in related databases. Oligogenic combinations between the additional variants and the specific NR5A1/SF-1 variants were tested using Oligogenic Resource for Variant Analysis (ORVAL). Genotype–phenotype correlations were explored by integrating these findings with the phenotype data.

Results: Novel genetic workup of 30 individuals detected rare, additional variants in SF-1- and DSD-related genes. The phenotype of these individuals, all with 46,XY karyotype, ranged from severe to opposite-sex DSD. Using ORVAL, oligogenic pathogenic combinations were found in 73% (22/30) individuals, with one to seven additional variants per individual, predominantly in DSD-related genes. We found identical variants in eight unrelated individuals with DSD in DSD-related genes (e.g., TBCE, FLNB, GLI3 and PDGFRA) and different variants in eight genes frequently associated with DSD (e.g., CDH23, FLNB, GLI2, KAT6B, MYO7A, PKD1, SPRY4 and ZFPM2) in 15 index cases. Our study also identified combinations with NR5A1/SF-1 variants and variants in novel candidate genes.

Conclusion: Our study shows that in 3 out of 4 individuals with a NR5A1/SF-1 variant and a 46,XY DSD, additional genetic variants may explain the broad variability of the DSD phenotype, indicating oligogenicity. Thus, the genetics explaining the DSD phenotype in many individuals and their families might be more complex than previously thought.