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

• Subject Area: Human Genetics ; Pediatric and Adolescent Medicine ; Medical Informatics and Medical Bioinformatics
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 515637292

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.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 1665: Sexdiversity - Determinants, meanings and implications of sex diversity in sociocultural, medical and biological landscapes
• Applicant Institution: Universität zu Lübeck
• Project Heads: Professor Dr. Olaf Hiort; Professor Dr. Martin Kircher