Abstract
Genetic causes of many familial arrhythmia syndromes remain elusive. In this study, whole‐exome sequencing (WES) was carried out on patients from three different families that presented with life‐threatening arrhythmias and high risk of sudden cardiac death (SCD). Two French Canadian probands carried identical homozygous rare variant in TECRL gene (p.Arg196Gln), which encodes the trans‐2,3‐enoyl‐CoA reductase‐like protein. Both patients had cardiac arrest, stress‐induced atrial and ventricular tachycardia, and QT prolongation on adrenergic stimulation. A third patient from a consanguineous Sudanese family diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) had a homozygous splice site mutation (c.331+1G>A) in TECRL. Analysis of intracellular calcium ([Ca2+]i) dynamics in human induced pluripotent stem cell‐derived cardiomyocytes (hiPSC‐CMs) generated from this individual (TECRLH om‐hiPSCs), his heterozygous but clinically asymptomatic father (TECRLH et‐hiPSCs), and a healthy individual (CTRL‐hiPSCs) from the same Sudanese family, revealed smaller [Ca2+]i transient amplitudes as well as elevated diastolic [Ca2+]i in TECRLH om‐hiPSC‐CMs compared with CTRL‐hiPSC‐CMs. The [Ca2+]i transient also rose markedly slower and contained lower sarcoplasmic reticulum (SR) calcium stores, evidenced by the decreased magnitude of caffeine‐induced [Ca2+]i transients. In addition, the decay phase of the [Ca2+]i transient was slower in TECRLH om‐hiPSC‐CMs due to decreased SERCA and NCX activities. Furthermore, TECRLH om‐hiPSC‐CMs showed prolonged action potentials (APs) compared with CTRL‐hiPSC‐CMs. TECRL knockdown in control human embryonic stem cell‐derived CMs (hESC‐CMs) also resulted in significantly longer APs. Moreover, stimulation by noradrenaline (NA) significantly increased the propensity for triggered activity based on delayed afterdepolarizations (DADs) in TECRLH om‐hiPSC‐CMs and treatment with flecainide, a class Ic antiarrhythmic drug, significantly reduced the triggered activity in these cells. In summary, we report that mutations in TECRL are associated with inherited arrhythmias characterized by clinical features of both LQTS and CPVT. Patient‐specific hiPSC‐CMs recapitulated salient features of the clinical phenotype and provide a platform for drug screening evidenced by initial identification of flecainide as a potential therapeutic. These findings have implications for diagnosis and treatment of inherited cardiac arrhythmias.
Highlights
Inherited arrhythmogenic diseases (IADs) are one of the prevalent causes of sudden cardiac death (SCD) in the young (Wilde & Behr, 2013)
The third patient was from a large consanguineous family with two sub-families and several children affected with adrenergic-related lethal events and were previously diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) (Bhuiyan et al, 2007)
During follow-up, the patient presented with recurrent episodes of exercise- or emotion-induced atrial and ventricular arrhythmias resulting in multiple shocks from an implantable cardioverter– defibrillator (ICD)
Summary
Inherited arrhythmogenic diseases (IADs) are one of the prevalent causes of sudden cardiac death (SCD) in the young (Wilde & Behr, 2013). IADs can be classified into disorders with or without structural heart defects. The latter include channelopathies such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT), caused by mutations in genes encoding ion channel or calcium-handling proteins that primarily affect the electrical activity of the heart (Schwartz et al, 2013; Wilde & Behr, 2013). LQTS is most commonly inherited in an autosomal dominant mode, where mutations in KCNH2, KCNQ1, and SCN5A account for the majority of cases (Wilde & Behr, 2013). A very rare autosomal recessive form of LQTS, often accompanied with sensorineural deafness (Jervell–Lange-Nielsen syndrome), has been linked to mutations in KCNQ1 and KCNE1. The mechanism of arrhythmia in LQTS mainly involves QT prolongation with early afterdepolarization-mediated triggered activity, which can lead to torsades de pointes (TdP) and ventricular fibrillation
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