Key result
Rare disease-causing arrhythmia and cardiomyopathy variants are linked to ~59% higher sudden cardiac arrest risk.
Why the study?
A subgroup of sudden cardiac arrest is caused by rare genetic variants, but existing studies have not been population based and have been limited to nonsurvivors.
Are disease-causing rare genetic variants in arrhythmia and cardiomyopathy genes associated with an increased risk of sudden cardiac arrest in the general population?
Case-Control (n=16,522)
Yes
Are disease-causing rare genetic variants in arrhythmia and cardiomyopathy genes associated with an increased risk of sudden cardiac arrest in the general population?
Odds Ratio: 1.59
Absolute Event Rate: 4% vs 2.4%
p-value: p=<0.001
Disease-causing variants in 15 arrhythmia and cardiomyopathy genes are significantly associated with sudden cardiac arrest in the general population, supporting targeted genetic screening for prevention in family members.
Rare variants may flag SCA risk; leaves open whether testing improves outcomes or prevention.
BACKGROUND 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. OBJECTIVES This study sought to establish the prevalence of disease-causing rare genetic variants in both survivors and nonsurvivors of SCA in the general population. METHODS 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. RESULTS 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. CONCLUSIONS 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.
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Kransdorf et al. (2026) conducted a case-control in Sudden cardiac arrest (n=16,522). Disease-causing rare genetic variants in arrhythmia/cardiomyopathy genes vs. Controls without sudden cardiac arrest was evaluated on Presence of disease-causing variants (OR 1.59, p=<0.001). Disease-causing rare genetic variants in arrhythmia and cardiomyopathy genes were associated with an increased risk of sudden cardiac arrest (4.0% vs 2.4%; OR 1.59; P<0.001).
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