A compound heterozygosity of Tecrl gene confirmed in a catecholaminergic polymorphic ventricular tachycardia family

Xie, Lijian; Hou, Chunmei; Jiang, Xunwei; Zhao, Jian; Li, Yun

doi:10.1016/j.ejmg.2019.01.018

Cited by 25 publications

(33 citation statements)

References 25 publications

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“…The TECRL gene encoded the trans-2,3-enoyl-CoA reductase-like protein which is an endoplasmic reticulum protein predominantly expressed in the heart. More recently, a second study confirmed the association of heterozygous compound mutations in the TECRL gene with CPVT (Xie et al 2019). Of note, in the present family, no additional variants in the TECRL gene were found.…”

Section: Discussionsupporting

confidence: 83%

Multiallelic rare variants support an oligogenic origin of sudden cardiac death in the young

Jaouadi

Bouyacoub

Chabrak

et al. 2020

Herz

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Unexplained sudden death in the young is cardiovascular in most cases. Structural and conduction defects in cardiac-related genes can conspire to underlie sudden cardiac death.Here we report on a clinical investigation and an extensive genetic assessment of a Tunisian family with sudden cardiac death in young members. In order to identify the family-genetic basis of sudden cardiac death, we performed Whole Exome Sequencing (WES), read depth copy-number-variation (CNV) screening and segregation analysis. We identify 6 ultra-rare heterozygous variants in OBSCN, RYR2, DSC2, AKAP9, CACNA1C and RBM20 genes and one homozygous splicing variant in TECRL gene consistent with an oligogenic model of inheritance. CNV analysis did not reveal any causative CNV. Overall, our results are highly suggestive for a cumulative effect of several variants as disease causation and to account for a greater disease severity among offspring. Our study further confirms the complexity of the inheritance of sudden cardiac death and highlights the utility of family-based WES in the identification of family specific mutations within different cardiac genes pathways.

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Section: Discussionsupporting

confidence: 83%

Multiallelic rare variants support an oligogenic origin of sudden cardiac death in the young

Jaouadi

Bouyacoub

Chabrak

et al. 2020

Herz

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“…In 2016, Devalla et al 12 reported that the candidate gene TECRL was causal for arrhythmias in three investigated patients. However, in the last 2 years, only one other case has been reported in which two compound heterozygous variants have been detected in TECRL 19 . Thus, despite the very exclusive phenotype, the causality of TECRL is still limited.…”

Section: Discussionmentioning

confidence: 99%

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

Moscu‐Gregor

Marschall

Müntjes

et al. 2020

Cardiovasc electrophysiol

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Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by adrenergically stimulated ventricular tachycardia. The most common form of CPVT is due to autosomal dominant variants in the cardiac ryanodine-receptor gene (RYR2). However, trans-2,3-enoyl-CoA reductase-like (TECRL) was recently suggested to be a novel candidate gene for life-threatening inherited arrhythmias. Patients previously reported with pathogenic changes in TECRL showed a special mixed phenotype of CPVT and long-QTsyndrome (LQTS) termed CPVT type 3 (CPVT3), an autosomal recessive disorder. Methods and Results: We implemented TECRL into our NGS panel diagnostics for CPVT and LQTS in April 2017. By December 2018, 631 index patients with suspected CPVT or LQTS had been referred to our laboratory for genetic testing. Molecular analysis identified four Caucasian families carrying novel variants in TECRL. One patient was homozygous for Gln139* resulting in a premature stop codon and loss-of-function of the TECRL protein. Another patient was homozygous for Pro290His, probably leading to an altered folding of the 3-oxo-5-alpha steroid 4-dehydrogenase domain of the TECRL protein. The LOF-variant Ser309* and the missense-variant Val298Ala have been shown to be compound heterozygous in another individual. NGS-based copy number variation analysis and quantitative PCR revealed a quadruplication of TECRL in the last individual, which is likely to be a homozygous duplication.Conclusion: The data from our patient collective indicate that CPVT3 occurs much more frequently than previously expected. Variants in TECRL may be causative in up to 5% of all CPVT cases. According to these findings, the default analysis of this gene is recommended if CPVT is suspected. K E Y W O R D S channelopathy, CPVT, LQTS, NGS, TECRL How to cite this article: Moscu-Gregor A, Marschall C, Müntjes C, et al. Novel variants in TECRL cause recessive inherited CPVT type 3 with severe and variable clinical symptoms.

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“…CALM1-3, SCN5A and TRDN have also been implicated in CPVT [15][16][17]. However, recently published data have described a new genetic association of CPVT in the trans-2, 3-enoyl-CoA reductase-like (TECRL) gene [18]. TECRL homozygous c.331 + 1G >, a splice site mutation in iPSCs (induced pluripotent stem cells), revealed a definite correlation between TECRL and Ca 2+ transport in cardiomyocytes [18].…”

Section: Discussionmentioning

confidence: 99%

Long-Term Follow-Up of Patients with Catecholaminergic Polymorphic Ventricular Arrhythmia

Veith

El‐Battrawy

Roterberg

et al. 2020

JCM

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Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited disorder causing life-threatening arrhythmias. Long-term outcome studies of the channelopathy are limited. Objective: The aim of the present study was to summarize our knowledge on CPVT patients, including the clinical profile treatment approach and long-term outcome. Methods: In this single center study, we retrospectively and prospectively collected data from nine CPVT patients and analyzed them. Results: We reviewed nine patients with CPVT in seven families (22% male), with a median follow-up time of 8.6 years. Mean age at diagnosis was 26.4 ± 12 years. Symptoms at admission were syncope (four patients) and aborted cardiac arrest (four patients). Family history of sudden cardiac death was screened in five patients. In genetic analyses, we found five patients with ryanodine type 2 receptor (RYR2) mutations. Seven patients were treated with beta-blockers, and if symptoms persisted flecainide was added (four patients). Despite beta-blocker treatment, three patients suffered from seven adverse cardiac events. An implantable cardioverter defibrillator was implanted in seven patients (one primary, six secondary prevention). Over the follow-up period, three patients suffered from ventricular tachycardia (ten times) and five patients from ventricular fibrillation (nine times). No one died during follow-up. Conclusion: Our CPVT cohort showed a high risk of cardiac events. Family screening, optimal medical therapy and individualized treatment are necessary in affected patients in referral centers.

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A compound heterozygosity of Tecrl gene confirmed in a catecholaminergic polymorphic ventricular tachycardia family

Cited by 25 publications

References 25 publications

Multiallelic rare variants support an oligogenic origin of sudden cardiac death in the young

Multiallelic rare variants support an oligogenic origin of sudden cardiac death in the young

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

Long-Term Follow-Up of Patients with Catecholaminergic Polymorphic Ventricular Arrhythmia

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