Targeted Exome Sequencing in Pre-Hospital Sudden Cardiac Arrest Reveals a High Genetic Diagnostic Yield

Background: The role of genetic testing in sudden cardiac arrest (SCA) among young and middle-aged adults remains incompletely understood, particularly in pre-hospital settings and in individuals with established clinical diagnoses such as coronary artery disease. Methods: We performed whole-exome sequencing with targeted analysis in a city-wide cohort of individuals who experienced pre-hospital SCA in Hangzhou, China. Variants were evaluated using a virtual panel of 2151 cardiovascular-related genes. Variant classification followed the American College of Medical Genetics and Genomics guidelines. Results: A total of 69 individuals (mean age 38 ± 14.6 years) were included. Pathogenic or likely pathogenic variants were identified in 13 individuals, corresponding to a diagnostic yield of 18.8%. One individual carried two variants. The identified variants involved genes associated with cardiomyopathies, arrhythmia syndromes, metabolic disorders, and lipid metabolism. Genetic findings were observed both in individuals without a clear clinical diagnosis and in those with apparently established causes of cardiac arrest, including coronary artery disease. When rare variants of uncertain significance with supportive evidence were considered, up to 47.8% of individuals carried potentially relevant variants. Broader gene panels identified more variants than narrower panels limited to established sudden cardiac death genes. Conclusions: Systematic exome sequencing in young and middle-aged individuals with pre-hospital SCA identifies clinically relevant genetic variants in a substantial proportion of cases. Genetic testing may complement conventional clinical investigation and may contribute to molecular autopsy and family-based risk assessment in selected patients.