Understanding repeat expansion diseases using population-scale genomic data

DNA repeat expansions are a major cause of neurological disease, but their study has historically been limited to clinically ascertained cohorts. My research has helped shift this perspective by combining genomic technologies with population-scale datasets to investigate repeat expansion diseases beyond affected individuals. We developed a clinical-grade pipeline for detecting pathogenic expansions using short-read genome sequencing, enabling diagnoses in previously unsolved cases and supporting its adoption as diagnostic test in the National Health Service in the UK. Applying these approaches to over 500,000 individuals revealed that pathogenic expansions are substantially more frequent than previously recognised, suggesting disease prevalence may be two- to threefold higher than clinical estimates and challenging assumptions about penetrance and disease recognition,  highlighting the need to identify modifiers of disease expression. Lastly, analysing over 10,000 family trios, we quantified germline repeat instability and identified determinants of repeat-length mutations, including risks associated with intermediate alleles. Together, these advances establish a population-scale framework for understanding disease prevalence, penetrance and repeat mutability, informing genetic risk prediction and disease classification.