Background: Annually 300,000 Americans experience sudden cardiac arrest (SCA). Studies in referral SCA cohorts have observed rare variants in genes associated with arrhythmia and cardiomyopathy. We sought to: (1) establish the population prevalence of rare disease-causing variants in a set of candidate genes and (2) confirm the association of disease-causing variants in these genes with SCA in two prospective population-based studies. Methods: SCA patients (n=3264) were accrued from the Oregon Sudden Unexpected Death Study and the PREdiction of Sudden death in mulTi-ethnic cOmmunities (PRESTO) study and compared to control patients (n=13713) from the Atherosclerosis Risk in Communities (ARIC) study. Whole genome sequencing was performed. Disease-causing (likely pathogenic or pathogenic) variants in candidate genes associated with arrhythmia/cardiomyopathy were identified using updated American College of Medical Genetics and Genomics criteria. Gene-collapsing case-control analysis was performed using the conditional logistic regression-sequence kernel association test. Results: We identified 300 disease-causing variants, the majority of which were in cardiomyopathy genes (71%). There were 136 patients (4.2%) in the SCA group and 351 patients (2.6%) in the control group with one or more disease-causing variants (OR 1.66, 95% confidence interval 1.33-2.07, p<0.001). We identified 13 genes associated with an increased risk of SCA, nine associated with cardiomyopathy (BAG3, DSC2, DSG2, FLNC, LMNA, MYBPC3, TNNI3, TNNT2, TTN) and four with arrhythmia (CACNA1C, CASQ2, KCNH2, KCNQ1). Conclusions: Disease-causing variants in cardiomyopathy genes were the predominant genetic cause of SCA. These findings inform which genes to include in genetic screening for SCA.

The authors have declared no competing interest.

This work is funded, in part, by National Institutes of Health, National Heart Lung and Blood Institute Grants R01HL145675 and R01HL147358 to SSC. SSC holds the Pauline and Harold Price Chair in Cardiac Electrophysiology at Cedars-Sinai

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