M04: Identification of novel structural and non-coding variants associated with differences of sex development

Our understanding of the genetic control of gonadal development remains incomplete, with diagnostic sequencing uncovering genetic deviations in only 30% of cases of gonadal dysgenesis. Structural variation or non-coding sequence changes may contribute to gene regulatory changes, causing a broad range of phenotypic effects. To map regulatory effects of promoter and enhancer regions, we will investigate regulatory effects in elements associated with known differences of sex development (DSD) genes through saturation mutagenesis and massively parallel reporter assays (MPRAs). Further, we will perform long-read genome sequencing for patients selected based on clinical findings and inconclusive exome analysis. Advanced computational methods will be employed to search for structural variants and investigate non-coding and gene regulatory effects. Identified non-coding variants will undergo functional characterization and follow-up analysis.