PKP2 was originally evaluated for DCM by the ClinGen DCM GCEP on June 26th 2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on May 29th, 2025. As a result, the classification did not change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein.
PKP2 was first reported in relation to autosomal dominant dilated cardiomyopathy (DCM) in 2010 (Elliot et al., 2010, PMID 20716751) and 2011 (Garcia-Pavia et al., 2011, PMID 21859740). PKP2 has also been curated by the Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Gene Curation Expert Panel for ARVC (Definitive, March 8, 2018). Human genetic evidence supporting the relationship of PKP2 with DCM includes case-level data; however, the majority of variants reported are present in control populations (gnomAD) at frequencies incompatible with the prevalence of DCM. This gene-disease relationship has been studied in at least one case-control study at the aggregate variant level (Mazzarrotto et al., 2020, PMID 31983221); however, no significant enrichment of PKP2 variants in DCM was shown. In addition, this gene-disease assertion is supported by expression studies as PKP2 has been shown to be expressed in the cardiac desmosome and is critical for cardiac junction formation and heart morphogenesis (Grossman et al., 2004, PMID 15479741).
In summary, the evidence presented for this gene-disease relationship does not provide convincing human genetic evidence in support of or refuting the role of PKP2 and autosomal dominant DCM. The relationship of PKP2 with DCM is unclear and therefore classified as disputed. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on May 29th, 2025 (SOP Version 10).
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