Using genome sequencing to increase the diagnostic yield of genetic testing

Yuchen Chang, University of Sydney

Postgraduate Scholarship

Years funded: 2025 - 2027

Project1: Characterise genomic variants causing sudden cardiac death (SCD) in the young using genome sequencing (GS)

This project will describe the autopsy findings and circumstances of death in a cohort of 350 young SCD cases (under the age of 35 years) and use GS to identify the underlying genetic causes. Clinical samples and information from an initial cohort of 160 SCD has already been collected with GS performed in 98 probands. The autopsy report to the coroner will be evaluated to define the death as SCD and investigation will be recorded. Post-mortem DNA samples will be collected for GS analysis of a panel of established cardiac disease genes. The anticipated outcome is to improve our current understanding of the causes of SCD in the young to directly influence clinical management in surviving family members. Project2: Identification of novel genetic risk factors for SCD in the young This extends the investigation of Project 1 into the genetic risk factors for SCD. This study will widen the range of genetic risk factors for SCD by performing statistical burden tests of rare variants comparing the 350 SCD cases with 2500 healthy controls. I will look for an excess of rare variants in important protein domains of cardiac disease genes, or variants that result in a gain or loss of protein function. The outcome is improved risk stratification in family members to prompt the early initiation of targeted SCD prevention strategies. Project3: Identification of essential protein regions to enhance variant curation I will develop a bioinformatics tool to functionally categorise essential protein domains of cardiac disease genes, with an emphasis on evolutionarily conserved amino acids. This tool will aid the interpretation of genetic variant pathogenicity using current guidelines for variant curation. The predicted domains will be made available with a user-friendly website interface that aids clinicians and researchers in rare variant interpretations of pathogenicity. This project will help define ‘hotspots’ of disease-causing variants, reduce discrepancies in the curation of genetic variants, and implement an approach that can be used in laboratory workflows.