Key result
PKP2 truncating variants linked to ~6.9-fold higher odds of ACM diagnoses.
Why the study?
The genetic architecture of PKP2 cardiomyopathy can inform our understanding of variant pathogenicity and protein function.
Are PKP2 truncating and missense variants associated with arrhythmogenic cardiomyopathy and ARVC, and do variants map to specific regional functional domains?
Case-Control
Yes
Are PKP2 truncating and missense variants associated with arrhythmogenic cardiomyopathy and ARVC, and do variants map to specific regional functional domains?
Odds Ratio: 6.9 (95% CI 4.9–9.8)
Absolute Event Rate: 0.9% vs 0.1%
p-value: p=<2 × 10−16
Regional and gene-wide genetic architecture assessment of PKP2 validates the high specificity of truncating variants for ARVC and identifies the C-terminus as a potential novel functional domain.
Supports refined PKP2 variant classification in ACM/ARVC testing; extends regional analysis by nominating the C-terminus as a candidate domain.
PurposeThe genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function.MethodsWe assess the gene-wide and regional association of truncating and missense variants in PKP2 with arrhythmogenic cardiomyopathy (ACM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) specifically. A discovery data set compares genetic testing requisitions to gnomAD. Validation is performed in a rigorously phenotyped definite ARVC cohort and non-ACM individuals in the Geisinger MyCode cohort.ResultsThe etiologic fraction (EF) of ACM-related diagnoses from truncating variants in PKP2 is significant (0.85 [0.80,0.88], p < 2 × 10−16), increases for ARVC specifically (EF = 0.96 [0.94,0.97], p < 2 × 10−16), and is highest in definite ARVC versus non-ACM individuals (EF = 1.00 [1.00,1.00], p < 2 × 10−16). Regions of missense variation enriched for ACM probands include known functional domains and the C-terminus, which was not previously known to contain a functional domain. No regional enrichment was identified for truncating variants.ConclusionThis multicohort evaluation of the genetic architecture of PKP2 demonstrates the specificity of PKP2 truncating variants for ARVC within the ACM disease spectrum. We identify the PKP2 C-terminus as a potential functional domain and find that truncating variants likely cause disease irrespective of transcript position.
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Dries et al. (2021) conducted a case-control in Arrhythmogenic cardiomyopathy (ACM) and arrhythmogenic right ventricular cardiomyopathy (ARVC). PKP2 truncating variants vs. General population cohorts (gnomAD and MyCode) was evaluated on Association of PKP2 truncating variants with ACM-related diagnoses (OR 6.9, 95% CI 4.9-9.8, p=<2 × 10−16). PKP2 truncating variants explained a significant etiologic fraction of ACM diagnoses (OR 6.9), with even higher specificity for definite ARVC (OR 853), and regional missense variant analysis identified the C-terminus as a potential novel functional domain.
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