PKP2 – Catecholaminergic Polymorphic Ventricular Tachycardia

In a cohort of 18 unrelated patients clinically diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) but negative for RYR2, CASQ2, KCNJ2, and TRDN mutations, radical truncating variants in PKP2 were identified in 5/18 (27.7%) patients (PMID:30678776), compared with 0.069% in gnomAD (p=3.1×10⁻¹³). All variants were loss-of-function (frameshift, canonical splice site, or nonsense), including the recurrent c.253_256del (p.Glu85fs), and carriers exhibited structurally normal hearts on imaging and autopsy. No segregation with disease was reported in these families. These findings suggest a potential PKP2-dependent electropathy that can phenocopy CPVT independent of overt cardiomyopathy.

Mechanistic studies in cardiomyocyte-specific PKP2 knockout mice demonstrated downregulation of critical calcium‐handling genes and isoproterenol-triggered polymorphic ventricular arrhythmias mirroring CPVT (PMID:30678776), supporting a haploinsufficiency mechanism. However, a recent ClinGen Expert Panel reappraisal classified PKP2 as Disputed for CPVT due to nonrepresentative phenotype reports and insufficient segregation data (PMID:34557911). With limited human genetic evidence, lack of familial segregation, and conflicting expert consensus, the PKP2–Catecholaminergic Polymorphic Ventricular Tachycardia association remains uncertain. Careful interpretation of PKP2 variants is advised in CPVT diagnostic panels and risk assessment.

References

• JACC. Clinical electrophysiology • 2019 • 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 PMID:30678776
• European heart journal • 2022 • Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death PMID:34557911

Evidence Based Scoring (AI generated)