Kouri Chrysanthi, Martinez de Lapiscina Idoia, Naamneh-Elzenaty Rawda, Sommer Grit, Sauter Kay-Sara, Flück Christa E
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.
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.
EBioMedicine. 2025 Mar;113:105624. doi: 10.1016/j.ebiom.2025.105624. Epub 2025 Mar 3.
Oligogenic 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.
We 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.
In 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.
These 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.
Swiss National Science Foundation and Boveri Foundation Zurich.
寡基因遗传被认为是一种可能的机制，用以解释携带NR5A1/SF-1变异的性发育差异（DSD）个体中观察到的广泛表型。
我们对从国际SF1next研究中招募的30名携带NR5A1/SF-1变异且核型为46,XY的DSD个体进行了研究，只要条件允许，就对三联体家庭进行全外显子测序（WES）。使用专门设计的过滤算法分析WES数据，以识别DSD和SF-1相关基因中的罕见变异。随后，使用寡基因变异分析资源（ORVAL）生物信息学平台对鉴定出的变异进行测试，以确定其与个体NR5A1/SF-1变异可能的联合致病性。
在73%（22/30）携带NR5A1/SF-1相关46,XY DSD的个体中，我们鉴定出一至七个其他变异，主要存在于已知的DSD相关基因中，这些变异可能对表型有影响。我们在八名不相关的DSD个体的DSD相关基因（如TBCE、FLNB、GLI3和PDGFRA）中发现了相同变异，在15例索引病例的八个经常与DSD相关的基因（如CDH23、FLNB、GLI2、KAT6B、MYO7A、PKD1、SPRY4和ZFPM2）中发现了不同变异。我们的研究还确定了NR5A1/SF-1变异与新候选基因变异的组合。
这些发现突出了与NR5A1/SF-1相关的DSD复杂的遗传格局，在几种情况下，使用先进的基因检测以及特定算法和机器学习工具进行过滤，揭示了可能对表型有影响的其他遗传因素。
瑞士国家科学基金会和苏黎世博韦里基金会。
