Rare Genetic Variants Associated with Sudden Cardiac Arrest in the Young: A Prospective, Population-Based Study

Abstract

Background: Sudden cardiac arrest (SCA) is a rare and tragic event among the young and often caused by inherited cardiac disease. Previous studies have investigated referral cohorts, but the prevalence of disease-associated variants is unclear at the community level. We investigated the prevalence of genetic variants among community-based cases of SCA aged <21 years. Methods: The study sample is obtained from two prospective, community-based studies of out-of-hospital SCA ongoing in the Portland, OR metro area (population ~1 million) and Ventura County CA (population ~850,000). We performed next-generation whole genome sequencing and then rare variant analysis of candidate genes associated with arrhythmic syndromes and cardiomyopathy in ClinGen. Results: The mean age of the study subjects was 11.3 years (SD 8.0 years, 30% non-white, 45% female). We found that 36 of 52 young SCA victims (69%) harbored uncertain, likely pathogenic (LP), or pathogenic (P) variants. Eight subjects (15%) carried 9 LP/P variants. Patients with clinical histories suggesting primary arrhythmic syndromes or hypertrophic cardiomyopathy were more likely to harbor clinically actionable variants or variants of unknown significance (VUS), than subjects with myocarditis, sudden infant death syndrome, or sudden arrhythmic death. Variants were more likely to be classified as LP/P among Whites (8/9, 88.9%) as compared to non-Whites (1/9, 11.1%, p = 0.036). Conclusions: A notable proportion of young SCA victims in the community harbor rare, potentially disease-associated gene variants, and further studies are needed to understand variants of unknown significance. We identified differences by phenotype groups and race that have potential implications for genetic testing.