SOX17 as a candidate gene for ovarian dysgenesis: functional characterisation of a novel homozygous variant

Background Ovarian dysgenesis is a genetically heterogeneous disorder, and recent studies have implicated novel candidate genes that continue to emerge beyond the classical regulators of gonadal development. SOX17 is a transcription factor essential for human primordial germ cell specification and early germline development. While heterozygous variants have been associated with congenital anomalies of the kidney and urinary tract, their potential role in ovarian development remains unclear. Methods We investigated a consanguineous family in which two sisters presented with clinical features consistent with 46, XX ovarian dysgenesis. Whole-exome sequencing was performed under an autosomal recessive inheritance model. Variant interpretation followed American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. Pathogenicity was further explored using conservation analysis, in silico prediction tools, homology-based structural modelling, protein stability analysis and protein–DNA docking simulations. Results A novel homozygous SOX17 missense variant (c.366G>C; p.Glu122Asp) was identified in both affected siblings and segregated with disease within the family. The variant is extremely rare in population databases and affects a highly conserved residue within the high-mobility group DNA-binding domain. Multiple computational tools predicted a deleterious effect. Structural modelling and stability analyses suggested localised destabilisation and increased flexibility, while docking simulations indicated reduced predicted DNA-binding affinity compared with the wild-type protein. Conclusion Our findings support SOX17 as a plausible candidate gene for autosomal recessive ovarian dysgenesis. Although functional validation studies are required to establish causality, the combined segregation data, conservation analysis and in silico modelling suggest that the identified variant may impair SOX17 DNA-binding capacity and contribute to abnormal ovarian development.