Genetic arrhythmias complicating patients with dilated cardiomyopathy

Abstract

Background: Sudden cardiac death due to malignant arrhythmias is a common cause of death in dilated cardiomyopathy (DCM). Whether genetic variants increase the risk of arrhythmias in DCM is unknown.

Objective: The purpose of this study was to investigate the genetic causes of arrhythmias in DCM patients.

Methods: Whole-exome sequencing and high-depth targeted next-generation sequencing (142-gene panel) were used. Eight specific DCM pedigrees with arrhythmias and 2 separate cohorts of 1232 consecutive unrelated sporadic DCM patients from 3 medical centers (550 in the discovery cohort, 682 in the replication cohort) were analyzed; 470 (250 in the discovery cohort, 220 in the replication cohort) suffered from arrhythmias (DCM-A group) and 762 (300 in the discovery cohort, 462 in the replication cohort) did not (DCM-NA group). All identified causative variants were Sanger sequenced to eliminate false-positive results and then screened in 700 unrelated matched arrhythmia- and DCM-free healthy controls.

Results: We identified long QT syndrome (LQTS)-causative variants that independently cosegregated in 2 unrelated DCM-LQTS pedigrees. Pathogenic variants in arrhythmia-related genes (ion channelopathies) were identified in 4.9% (23/470) of sporadic DCM-A patients (4.0% in the discovery cohort, 5.9% in the replication cohort) but only 0.1% (1/762) of sporadic DCM-NA patients (P = 2.16 × 10^-9). These arrhythmia-related pathogenic variants included long QT syndrome, atrial fibrillation, sick sinus syndrome, cardiac conduction disease, and Brugada syndrome.

Conclusion: Some arrhythmias in DCM patients are caused by arrhythmia-related pathogenic variants. For DCM patients with explicit arrhythmias, arrhythmia-causative genetic screening may help to explain the etiology and decision-making.

Keywords: Arrhythmia; Dilated cardiomyopathy; Genetic diagnosis; Next-generation sequencing; Whole-exome sequencing.