Evidence map›Paper›PMID 40037090›Full record

ArticleEBioMedicine2025

Oligogenic analysis across broad phenotypes of 46,XY differences in sex development associated with NR5A1/SF-1 variants: findings from the international SF1next study.

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

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Article in EBioMedicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

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0cells of the map it votes in
3citing papers in PubMed
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1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

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4 · The record

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5 · Who and what money

Authors and funding

7 authors.

Chrysanthi KouriPediatric 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.
Idoia Martinez de LapiscinaPediatric 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-ElzenatyPediatric 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 SommerPediatric Endocrinology, Diabetology and Metabolism, Department of Pediatrics, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland; Swiss Childhood Cancer Registry, Institute of Social and Preventive Medicine, University of Bern, Bern 3012, Switzerland.
Kay-Sara SauterPediatric 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.
Christa E FlückPediatric 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: christa.flueck@unibe.ch.
SF1next study group

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundOligogenic inheritance has been suggested as a possible mechanism to explain the broad phenotype observed in individuals with differences of sex development (DSD) harbouring NR5A1/SF-1 variants.

methodsWe investigated genetic patterns of possible oligogenicity in a cohort of 30 individuals with NR5A1/SF-1 variants and 46,XY DSD recruited from the international SF1next study, using whole exome sequencing (WES) on family trios whenever available. WES data were analysed using a tailored filtering algorithm designed to identify rare variants in DSD and SF-1-related genes. Identified variants were subsequently tested using the Oligogenic Resource for Variant Analysis (ORVAL) bioinformatics platform for a possible combined pathogenicity with the individual NR5A1/SF-1 variant.

findingsIn 73% (22/30) of the individuals with NR5A1/SF-1 related 46,XY DSD, we identified one to seven additional variants, predominantly in known DSD-related genes, that might contribute to the phenotype. 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.

interpretationThese findings highlight the complex genetic landscape of DSD associated with NR5A1/SF-1, where in several cases, the use of advanced genetic testing and filtering with specific algorithms and machine learning tools revealed additional genetic hits that may contribute to the phenotype.

fundingSwiss National Science Foundation and Boveri Foundation Zurich.

Indexed as

Disorder of Sex Development, 46,XYGenetic VariationSteroidogenic Factor 1AdolescentChildChild, PreschoolComputational BiologyExome SequencingFemaleGenetic Association StudiesGenetic Predisposition to DiseaseHumansMaleMutationPhenotypeNR5A1 protein, humanSteroidogenic Factor 146,XY DSDDifferences of sex development (DSD)OligogenicitySteroidogenic factor 1 (SF-1/NR5A1)

Identifiers

PMID40037090
PMCPMC11925193

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.