Arrhythmic Risk in Carriers of Predicted Deleterious Rare Variants in Dilated and Arrhythmogenic Cardiomyopathy Genes

Abstract

Background In dilated (DCM) and arrhythmogenic cardiomyopathies (ACM), monogenic variants in causative genes are key prognostic factors. In the general population, the clinical role of these variants remains debated. Objectives This study aimed to determine the association between rare, predicted deleterious variants (PDrV) in DCM- and ACM-associated genes and disease-related outcomes in the general population. Methods Using United Kingdom Biobank whole-exome sequencing data, we identified PDrVs in 25 DCM/ACM-validated genes. We assessed disease penetrance in carriers and their risk for two primary outcomes—sudden cardiac death/malignant ventricular arrhythmias (SCD/MVA) and heart failure death/heart transplant (HF/HT)—using cause-specific Cox models accounting for competing risks. Results Among 469,671 participants, 54.2% were females and the median age at baseline was 53.5 (IQR: 10.3). During a median follow-up of 14 years (IQR: 2), 5786 SCD/MVA and 4611 HF/HT events occurred. A PDrV was found in 12,973 (2.8%) individuals. Despite low penetrance for DCM (1.0%), PDrV impacted on both outcomes. Compared to noncarriers, PDrV carriers had a higher risk of SCD/MVA (HR: 1.28; 95% CI: 1.11-1.48). In participants free from DCM or other heart diseases at recruitment, SCD/MVA risk was solely associated with ACM genes (HR: 1.34; 95% CI: 1.07-1.69). Carriers also exhibited a higher risk of HF/HT (HR: 1.32; 95% CI: 1.08-1.62), which was not confirmed in subgroup without other heart diseases. Conclusions PDrV carriers have a higher risk of severe cardiac events, even without a clinical overt disease phenotype at baseline evaluation. Moreover, PDrV in arrhythmic genes significantly influence SCD/MVA risk, regardless of phenotypic diagnosis of DCM.