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

Rare predicted deleterious variants in 25 validated dilated and arrhythmogenic cardiomyopathy genes, identified by exome sequencing in participants unselected for a cardiac phenotype.

The clinical role of variants in dilated (DCM) and arrhythmogenic (ACM) cardiomyopathy genes in the general population remains debated. Using UK Biobank whole-exome sequencing data, the authors identified rare predicted deleterious variants in 25 validated DCM and ACM genes among 469,671 participants (54.2% women, median age 53.5 years) and assessed, with competing-risk Cox models, the risk of sudden cardiac death or malignant ventricular arrhythmia and that of heart failure death or transplantation. A predicted deleterious variant was present in 12,973 individuals (2.8%) and, despite low penetrance for DCM (1.0%), carriers had a higher risk of sudden cardiac death or malignant ventricular arrhythmia (HR 1.28; 95% CI 1.11-1.48) and of heart failure death or transplantation (HR 1.32; 95% CI 1.08-1.62) over a median follow-up of 14 years. Among participants free from DCM or other heart disease at recruitment, the excess arrhythmic risk was confined to ACM genes (HR 1.34; 95% CI 1.07-1.69).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The signal is small in absolute terms but consistent, and it concerns exactly the situation that troubles us, the carrier identified out of context through family investigation or a secondary finding. The limitation that matters is variant definition, predicted deleterious in silico rather than ACMG-curated, which certainly mixes truly pathogenic variants with background noise: the HR of 1.28 is therefore probably an underestimate for genuinely pathogenic variants. Use it to justify cardiological follow-up of asymptomatic carriers of ACM gene variants, not to build population screening.

Analysis by Dr Thibaut Benquey