Abstract
BackgroundCatecholaminergic polymorphic ventricular tachycardia (CPVT) is often a life-threatening arrhythmia disorder with variable penetrance and expressivity. Little is known about the incidence or outcomes of CPVT patients with ≥2 variants.MethodsThe phenotypes, genotypes and outcomes of patients in the Pediatric and Congenital Electrophysiology Society CPVT Registry with ≥2 variants in genes linked to CPVT were ascertained. The American College of Medical Genetics & Genomics (ACMG) criteria and structural mapping were used to predict the pathogenicity of variants (3D model of pig RyR2 in open-state).ResultsAmong 237 CPVT subjects, 193 (81%) had genetic testing. Fifteen patients (8%) with a median age of 9 years (IQR 5–12) had ≥2 variants. Sudden cardiac arrest occurred in 11 children (73%), although none died during a median follow-up of 4.3 years (IQR 2.5–6.1). Thirteen patients (80%) had at least two RYR2 variants, while the remaining two patients had RYR2 variants plus variants in other CPVT-linked genes. Among all variants identified, re-classification of the commercial laboratory interpretation using ACMG criteria led to the upgrade from variant of unknown significance (VUS) to pathogenic/likely pathogenic (P/LP) for 5 variants, and downgrade from P/LP to VUS for 6 variants. For RYR2 variants, 3D mapping using the RyR2 model suggested that 2 VUS by ACMG criteria were P/LP, while 2 variants were downgraded to likely benign.ConclusionsThis severely affected cohort demonstrates that a minority of CPVT cases are related to ≥2 variants, which may have implications on family-based genetic counselling. While multi-variant CPVT patients were at high-risk for sudden cardiac arrest, there are insufficient data to conclude that this genetic phenomenon has prognostic implications at present. Further research is needed to determine the significance and generalizability of this observation. This study also shows that a rigorous approach to variant re-classification using the ACMG criteria and 3D mapping is important in reaching an accurate diagnosis, especially in the multi-variant population.
Highlights
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia syndrome characterized by ventricular tachycardia (VT) provoked by adrenergic stress. [1] The condition is caused by excessive calcium leak from the sarcoplasmic reticulum, leading to delayed after-depolarizations and arrhythmias. [1] Most cases are attributed to mutations in RYR2-coded ryanodine receptor (RyR2) or CASQ2-coded calsequestrin-2 [1]
Sudden cardiac arrest occurred in 11 children (73%), none died during a median follow-up of 4.3 years (IQR 2.5–6.1)
Re-classification of the commercial laboratory interpretation using American College of Medical Genetics & Genomics (ACMG) criteria led to the upgrade from variant of unknown significance (VUS) to pathogenic/likely pathogenic (P/LP)
Summary
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia syndrome characterized by ventricular tachycardia (VT) provoked by adrenergic stress. [1] The condition is caused by excessive calcium leak from the sarcoplasmic reticulum, leading to delayed after-depolarizations and arrhythmias. [1] Most cases are attributed to mutations in RYR2-coded ryanodine receptor (RyR2) or CASQ2-coded calsequestrin-2 [1]. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inherited arrhythmia syndrome characterized by ventricular tachycardia (VT) provoked by adrenergic stress. In other inherited arrhythmic conditions, like long QT syndrome (LQTS) and hypertrophic and arrhythmogenic cardiomyopathies, patients with double and compound mutations fare especially poorly. [8,9,10,11,12] We used the Pediatric and Congenital Electrophysiology Society (PACES) Registry [13, 14] to characterize CPVT patients with 2 variants. To systematically assess the likelihood of pathogenicity, variants were mapped on to the 3D structure of RyR2, which provides mechanistic insights into their function and enhances the analysis compared to sequence-based scoring algorithms alone. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is often a life-threatening arrhythmia disorder with variable penetrance and expressivity. Little is known about the incidence or outcomes of CPVT patients with 2 variants
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