Elucidating the genetic etiology of arrhythmias in hypertrophic cardiomyopathy patients: a comparative analysis using whole-exome and next-generation sequencing

Abstract

Malignant cardiac arrhythmia, a prevalent cause of mortality in hypertrophic cardiomyopathy (HCM) patients, is often perceived as a natural progression of HCM. However, the genetic mechanisms contributing to arrhythmias in HCM remain unexplored. The study aimed to elucidate the concurrent genetic etiology of arrhythmias in HCM patients. We employed a combination of whole-exome sequencing (WES) and massively targeted next-generation sequencing to scrutinize seven specific HCM pedigrees with arrhythmias. Additionally, two distinct cohorts comprising 1222 unrelated sporadic HCM patients were recruited from three medical centers. These cohorts were divided into 583 patients with arrhythmias (HCM-A group) and 639 patients without arrhythmias (HCM-NA group). We detected arrhythmia-associated pathogenic or likely pathogenic variants in 5.49% (32/583) of patients in the sporadic HCM-A group, compared to only 0.31% (2/639) of patients in the HCM-NA group (P = 3.54 × 10⁻⁹). The identified arrhythmia syndromes included long QT syndrome, atrial fibrillation, Wolff−Parkinson−White syndrome, cardiac conduction defect, sick sinus syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. Interestingly, WES overlooked pathogenic variants that were detected by targeted sequencing in 6.25% (2/32) patients. This study suggests that genes associated with arrhythmias contribute to the arrhythmias in HCM-A patients. Therefore, genetic screening in HCM patients with arrhythmias may also consider including both HCM-related genes and arrhythmia-inducing genes.

Keywords

arrhythmia / hypertrophic cardiomyopathy / next-generation sequencing / whole-exome sequencing / genetic diagnosis

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Higher Education Press 2026

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