Population-Based Analysis of Rare Genetic Variants in Sudden Cardiac Arrest

More than 360,000 Americans experience sudden cardiac arrest (SCA) annually. A subgroup is caused by rare genetic variants, but existing studies are not population based and have been limited to nonsurvivors.

This study sought to establish the prevalence of disease-causing rare genetic variants in both survivors and nonsurvivors of SCA in the general population.

Patients with SCA (n = 3,264) were accrued from 2 community-based studies in Oregon and California and compared with control participants (n = 13,258) from the ARIC (Atherosclerosis Risk in Communities) study. Whole genome sequencing was performed. Disease-causing (likely pathogenic or pathogenic) variants in 63 candidate genes associated with arrhythmia/cardiomyopathy were identified using updated American College of Medical Genetics and Genomics criteria. Gene-collapsing case-control analysis and variant proportion comparison with the Genome Aggregation Database was performed.

Disease-causing variants were present in 130 patients (4.0%) in the SCA group as compared with 323 participants (2.4%) in ARIC (OR: 1.59; P < 0.001). In the subgroup of patients with a nonischemic SCA, 39 of 638 patients (6.1%) harbored a disease-causing variant (OR: 2.52; P < 0.001). We identified 15 genes associated with an increased risk of SCA: ACTC1, BAG3, CACNA1C, DES, DSG2, DSP, FLNC, KCNH2, KCNQ1, LMNA, MYBPC3, MYH7, PKP2, RBM20, and TTN.

Specific disease-causing variants identified in 15 arrhythmia and cardiomyopathy genes were associated with an increased risk of SCA in the community. These findings will enable targeted SCA prevention strategies in family members harboring variants in these SCA-associated genes.