Long-term follow-up of patients with catecholaminergic polymorphic ventricular tachycardia related to a novel CALM2...

Genes encoding calmodulin (CALM1, CALM2, and CALM3) have been recently reported as causative for lethal arrhythmias including catecholaminergic polymorphic ventricular tachycardia (CPVT), especially in severe cases with young onset. Inherited arrhythmias caused by pathogenic variants in calmodulin-related genes are known as calmodulinopathy. Most of the pathogenic variants in calmoduinopathy are de novo ones, which reflect the severe phenotypes of the diseases. We recently identified a novel variant in CALM2, c.188 C>A, p.T63K, by targeted gene sequencing methods in a 42-year-old woman who was asymptomatic and being treated with a beta-blocker. She first experienced syncope during exercise as a 13-year-old, and bidirectional ventricular tachycardia was induced by exercise stress test. She was diagnosed with CPVT, and taking beta-blockers prevented her symptoms. No pathogenic variant was identified in the genetic testing targeted only for RYR2 and CASQ2 at that time. Here we report on the importance of repeated genetic testing for non-genotyped patients with inherited arrhythmias and the long follow-up of a calmodulinopathy patient with mild phenotype.

Genetic testing for inherited arrhythmias has been greatly improved, and many novel causative genes have been identified. If a patient received genetic testing a few decades ago and was non-genotyped, a pathogenic variant might be identified by repeated genetic testing. In addition, some of the calmodulinopathy patients might have milder phenotypes than previously observed.