TECRL – Catecholaminergic Polymorphic Ventricular Tachycardia

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening inherited arrhythmia characterized by adrenergically mediated ventricular tachycardia and risk of sudden cardiac death. TECRL encodes trans-2,3-enoyl-CoA reductase-like protein, localized to the endoplasmic reticulum in cardiomyocytes, and was first implicated in CPVT through autosomal recessive variants in a single family. The association between TECRL and Catecholaminergic polymorphic ventricular tachycardia has since been corroborated by multiple lines of evidence.

In 2019, a 13-year-old boy presenting with exercise-induced bidirectional ventricular tachycardia was found to harbor compound heterozygous TECRL variants: c.587G>A (p.Arg196Gln) and c.918+3A>G. Functional assays in patient-derived iPSC-cardiomyocytes with a homozygous c.331+1G>A splice mutation demonstrated impaired Ca2+ transport, affirming a critical role for TECRL in calcium handling (PMID:30790670).

A follow-up NGS panel study of 631 CPVT/LQTS referrals identified four unrelated families with recessive TECRL variants, including homozygous c.55C>T (p.Gln19Ter), c.893T>C (p.Val298Ala), c.926C>G (p.Ser309Ter), and compound heterozygous Ser309Ter/Val298Ala. These cases define CPVT type 3, with TECRL variants accounting for up to 5% of CPVT presentations (PMID:32173957).

Mechanistic studies in Tecrl knockout mice revealed aggravated exercise-induced ventricular dysfunction, reduced ejection fraction, and disrupted mitochondrial respiration—marked by decreased ATP production, elevated reactive oxygen species, and altered PI3K/AKT signaling. Rescue via TECRL overexpression normalized mitochondrial function, corroborating a loss-of-function mechanism (PMID:35577932).

An evidence-based reappraisal by a ClinGen Channelopathy Expert Panel classified TECRL as an autosomal recessive CPVT gene with moderate clinical validity, distinguishing it from disputed CPVT genes and endorsing its inclusion in diagnostic panels (PMID:34557911).

Integration of genetic and functional data supports a loss-of-function model for TECRL in CPVT, with consistent segregation in multiple families and concordant in vitro and in vivo assays. Additional large-scale studies may further refine variant spectrum and penetrance. Key Take-home: TECRL should be included in genetic testing for autosomal recessive CPVT3, facilitating diagnosis and management.

References

• European journal of medical genetics • 2019 • A compound heterozygosity of Tecrl gene confirmed in a catecholaminergic polymorphic ventricular tachycardia family. PMID:30790670
• Journal of cardiovascular electrophysiology • 2020 • Novel variants in TECRL cause recessive inherited CPVT type 3 with severe and variable clinical symptoms. PMID:32173957
• Communications biology • 2022 • TECRL deficiency results in aberrant mitochondrial function in cardiomyocytes. PMID:35577932
• European heart journal • 2022 • Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death. PMID:34557911

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