Plakophilin-2 Truncation Variants in Patients Clinically Diagnosed With Catecholaminergic Polymorphic Ventricular Tachycardia and Decedents With Exercise-Associated Autopsy Negative Sudden Unexplained Death in the Young

Abstract

Objectives: This study determined if radical plakophilin-2 (PKP2) variants might underlie some cases of clinically diagnosed catecholaminergic polymorphic ventricular tachycardia (CPVT) and exercise-associated, autopsy-negative sudden unexplained death in the young (SUDY).

Background: Pathogenic variants in PKP2 cause arrhythmogenic right ventricular cardiomyopathy (ARVC). Recently, a cardiomyocyte-specific PKP2 knockout mouse model revealed that loss of PKP2 markedly reduced expression of genes critical in intracellular calcium handling. The mice with structurally normal hearts exhibited isoproterenol-triggered polymorphic ventricular arrhythmias that mimicked CPVT.

Methods: A PKP2 gene mutational analysis was performed on DNA from 18 unrelated patients (9 males; average age at diagnosis: 19.6 ± 12.8 years) clinically diagnosed with CPVT but who were RYR2-, CASQ2-, KCNJ2-, and TRDN-negative, and 19 decedents with SUDY during exercise (13 males; average age at death: 14 ± 3 years). Only radical (i.e., frame-shift, canonical splice site, or nonsense) variants with a minor allele frequency of ≤0.00005 in the genome aggregation database (gnomAD) were considered pathogenic.

Results: Radical PKP2 variants were identified in 5 of 18 (27.7%) CPVT patients and 1 of 19 (5.3%) exercise-related SUDY cases compared with 96 of 138,632 (0.069%) individuals in gnomAD (p = 3.1 × 10^-13). Cardiac imaging or autopsy demonstrated a structurally normal heart in all patients at the time of their CPVT diagnosis or sudden death.

Conclusions: Our data suggested that the progression of the PKP2-dependent electropathy can be independent of structural perturbations and can precipitate exercise-associated sudden cardiac arrest or sudden cardiac death before the presence of overt cardiomyopathy, which clinically mimics CPVT, similar to the PKP2 knockout mouse model. Thus, CPVT and SUDY genetic test panels should now include PKP2.

Keywords: arrhythmogenic right ventricular cardiomyopathy; catecholaminergic genetic testing; plakophilin-2; polymorphic ventricular tachycardia; sudden unexplained death in the young.