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

Ilaria Gandin1, Andrea Mario Vergani2, Michela Carlotta Massi3

  • 1Biostatistics Unit, Department of Medicine, Surgery and Health Sciences, University of Trieste, Trieste, Italy.

JACC. Advances
|July 28, 2026
PubMed

Insights

Rare genetic variants in heart disease genes increase the risk of sudden cardiac death and heart failure, even in individuals without diagnosed heart conditions. These predicted deleterious variants (PDrV) are important prognostic factors.

Area of Science:

  • Cardiovascular Genetics
  • Population Genomics
  • Precision Medicine

Background:

  • Monogenic variants in dilated (DCM) and arrhythmogenic cardiomyopathies (ACM) genes are key prognostic factors.
  • The role of these variants in the general population is not well understood.

Purpose of the Study:

  • To investigate the association between rare, predicted deleterious variants (PDrV) in DCM/ACM genes and cardiac outcomes in the general population.
  • To assess the risk of sudden cardiac death/malignant ventricular arrhythmias (SCD/MVA) and heart failure death/heart transplant (HF/HT) in PDrV carriers.

Main Methods:

  • Whole-exome sequencing data from the UK Biobank (n=469,671) were analyzed.
  • PDrVs in 25 DCM/ACM genes were identified and their association with SCD/MVA and HF/HT events assessed.
  • Cause-specific Cox models were used to account for competing risks.

Main Results:

  • 2.8% of individuals carried a PDrV.
  • PDrV carriers showed an increased risk for SCD/MVA (HR: 1.28) and HF/HT (HR: 1.32).
  • In individuals without pre-existing heart disease, PDrV in ACM genes were associated with increased SCD/MVA risk (HR: 1.34).

Conclusions:

  • PDrV carriers face a higher risk of severe cardiac events, irrespective of baseline phenotype.
  • Variants in ACM genes significantly elevate SCD/MVA risk, even without a DCM diagnosis.
Abstract

Keywords:
arrhythmogenic cardiomyopathydilated cardiomyopathyrare variantsrisk predictionwhole exome sequencing

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