Arrhythmogenic Cardiomyopathy in a Patient With a Rare Loss‐of‐Function KCNQ1 Mutation

Abstract

BackgroundVentricular tachycardia (VT) is a common manifestation of advanced cardiomyopathies. In a subset of patients with dilated cardiomyopathy, VT is the initial and the cardinal manifestation of the disease. The molecular genetic basis of this subset of dilated cardiomyopathy is largely unknown.Methods and ResultsWe identified 10 patients with dilated cardiomyopathy who presented with VT and sequenced 14 common causal genes for cardiomyopathies and arrhythmias. Functional studies included cellular patch clamp, confocal microscopy, and immunoblotting. We identified nonsynonymous variants in 4 patients, including a rare missense p.R397Q mutation in the KCNQ1 gene in a 60‐year‐old man who presented with incessant VT and had mild cardiac dysfunction. The p.R397Q mutation was absent in an ethnically matched control group, affected a conserved amino acid, and was predicted by multiple algorithms to be pathogenic. Co‐expression of the mutant KCNQ1 with its partner unit KCNE1 was associated with reduced tail current density of slowly activating delayed rectifier K+ current (IKs). The mutation reduced membrane localization of the protein.ConclusionsDilated cardiomyopathy with an initial presentation of VT may be a forme fruste of arrhythmogenic cardiomyopathy caused by mutations in genes encoding the ion channels. The findings implicate KCNQ1 as a possible causal gene for arrhythmogenic cardiomyopathy.

Electrical and mechanical stimulation of cardiac cells and tissue constructs

“…Human induced pluripotent stem cell (hiPSC)-derived CMs lacking voltage-gated ion channel expression are unable to mature into functional myocytes [202]. In addition, alterations in expression levels or mutations in voltage-gated ion channels and Cxs have been reported in cardiac disease and are associated with the development of arrhythmias [166,203–207]. For example, investigation of a murine model of calcineurin-induced hypertrophy demonstrated a down-regulation of Cx40 and Nav1.5, leading to the development of arrhythmias and increased mortality [203].…”

“…For example, investigation of a murine model of calcineurin-induced hypertrophy demonstrated a down-regulation of Cx40 and Nav1.5, leading to the development of arrhythmias and increased mortality [203]. In addition, the analysis of patients with dilated cardiomyopathy presenting with ventricular tachycardia as the initial and cardinal manifestation of the disease were found to have mutations in the KCNQ1 gene, which codes for a voltage-gated potassium channel [207]. These results demonstrate that alterations to the expression of voltage gated ion channels, which impacts ability of CMs to respond to electrical stimulation and activation, play a crucial role in a number of potential disease states.…”

Long QT syndrome and left ventricular noncompaction in 4 family members across 2 generations with KCNQ1 mutation

“…More work needs to be done to understand how changes in KCNQ1 could lead to LVNC. It is notable that a recent report has linked a KCNQ1 mutation (p.R397Q) with arrhythmogenic cardiomyopathy, although the underlying mechanism remains to be established (22). This report highlights 4 familial cases of long QT syndrome and LVNC across 2 generations, all of which have a pathogenic KCNQ1 mutation, and illustrates the importance of considering testing for KCNQ1 mutations in these patients, especially in the context of long QT or arrhythmia.…”

Genetics and Genomics of Single-Gene Cardiovascular Diseases

“…Moreover, noncoding variants in the TGFB3 gene have been associated with ARVC (150). Likewise, a missense mutation in KCNQ1 , encoding a potassium channel, has been reported in a patient with AC (151). Mutations in RYR2 , encoding ryanodine receptor 2, cause the phenotype of catecholaminergic (stress-induced) polymorphic ventricular tachycardia, which is a phenocopy of AC.…”