RESUMEN
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-QT-syndrome (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.