TECRL, a new life‐threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT

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.

Calcium Signaling and Cardiac Arrhythmias

“…Initially identified by linkage analysis in a consanguineous Sudanese family with multiple SCDs among children while playing, subsequent whole exome sequencing (WES) identified mutations in a handful of families and probands in TECRL . 101,102 Each patient demonstrated VT and VF, particularly with exertion, and had SCD. Interestingly, while the subjects had normal QT intervals at baseline, adrenergic stimulation caused QT interval prolongation.…”

“…AP recordings revealed prolonged APD also suggesting a clinical overlap between TECRL mutation-positive individuals with features of both CPVT and LQTS. 102 At present, the mechanisms by which loss of TECRL function alters SR Ca 2+ -handling or ionic currents resulting in prolonged APD remain unknown.…”

Novel variants in TECRL cause recessive inherited CPVT type 3 with severe and variable clinical symptoms

“…Since there are still IAD cases without known disease‐causing variants, several studies have focused on the discovery of novel Mendelian disease‐causing loci associated with arrhythmogenic channelopathies. One recent study identified two different variants in the trans‐2,3‐enoyl‐CoA reductase‐like ( TECRL ) gene in three patients with clinical arrhythmias using whole‐exome sequencing 12 . Notably, these patients showed features of both LQTS and CPVT‐like adrenergic VT with a high prevalence of cardiac arrest, atrial tachycardia sometimes triggering ventricular arrhythmias, and normal or mildly prolonged QTc at rest with a QTc increase during adrenergic stimulation.…”

TECRL: connecting sequence to consequence for a new sudden cardiac death gene

“…Devalla et al () also identified two other unrelated patients, both of whom had experienced stress‐ or exercise‐induced arrhythmias with aborted sudden cardiac arrest, who were also found to be carriers of a novel homozygous mutation in the TECRL gene. In all three case studies, the clinical phenotypes showed overlapping characteristics of two primary arrhythmia syndromes: long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT).…”

“…In the case of the Sudanese family reported in this issue of EMBO Molecular Medicine (Devalla et al , ), solving the genetics was made considerably easier by the fact that the condition showed autosomal recessive inheritance and the parents were first cousins. Using whole‐exome sequencing, Devalla and colleagues identified a homozygous loss‐of‐function mutation in a novel gene, called trans ‐2,3‐enoyl‐CoA reductase‐like ( TECRL ), that was present in all affected family members.…”