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

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.