| Title: | Arrhythmic Risk in Carriers of Predicted Deleterious Rare Variants in Dilated and Arrhythmogenic Cardiomyopathy Genes |
| Journal: | JACC Advances |
| Published: | 28 Jul 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42520655/ |
| DOI: | https://doi.org/10.1016/j.jacadv.2026.103066 |
Publication 21268
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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.</p>
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.</p>
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.</p>
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.</p>
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.</p>
12 Authors
- Ilaria Gandin
- Andrea Mario Vergani
- Michela Carlotta Massi
- Alessia Paldino
- Martina Setti
- Maria Perotto
- Marco Merlo
- Gianfranco Sinagra
- Giulia Barbati
- Emanuele Di Angelantonio
- Francesca Ieva
- Matteo Dal Ferro
1 Application
| Application ID | Title |
|---|---|
| 82779 | Computational phenotyping to understand disease progression across the human lifespan |
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