PKP2 was evaluated for autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT). Variants in PKP2 (in particular truncating loss of function variants) are associated with arrhythmogenic cardiomyopathy (ACM/ARVC) and it has been classified as a Definitive gene by the ARVC Gene Curation Expert Panel. The evidence for a role of PKP2 variants in CPVT comes from a single study in which PKP2 was sequenced in a cohort of 18 patients that had been diagnosed with CPVT and were negative for variants in established CPVT genes (in addition to 19 sudden cardiac death cases with structurally normal hearts) (Tester et al, 2019, PMID:30678776). Although truncating variants in PKP2 were detected in 6 cases, the expert panel (and indeed the authors of the paper) believed that these patients were likely to have concealed ARVC and had been diagnosed with CPVT due to exercise-associated arrhythmias prior to structural heart changes. Indeed one of these cases was subsequently diagnosed with ARVC and right ventricular structural changes were subsequently observed in two others. A cardiomyocyte-specific PKP2 mouse knockout model displayed similar phenotypes, with isoproterenol triggered polymorphic ventricular arrhythmias mimicking CPVT observed prior to structural changes (Cerrone et al, 2017, PMID:28740174). In conclusion, we believe that PKP2 variants are not associated with CPVT and therefore the expert panel decided to classify PKP2 as disputed for CPVT. However, as a CPVT-like phenotype can be observed in ARVC patients with truncating PKP2 variants (during the concealed cardiomyopathy phase of the disease), it may be beneficial to include this gene in extended arrhythmia genetic testing panels for patients with a CPVT-like phenotype if no causative variants are found when sequencing validated CPVT genes. If truncating variants in PKP2 are detected in such cases, it would suggest a diagnosis of ARVC. Note: All CPVT genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the CPVT Gene Curation Expert Panel (GCEP). The classification and summary presented here is the conclusion of this GCEP's analysis according to evidence teams' efforts. This classification was approved by the ClinGen Catecholaminergic Polymorphic Ventricular Tachycardia Gene Curation Expert Panel on 20th January, 2021 (SOP Version 7).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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