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The genetic architecture of Plakophilin 2 cardiomyopathy

2021; Elsevier BV; Volume: 23; Issue: 10 Linguagem: Inglês

10.1038/s41436-021-01233-7

1530-0366

Annika M. Dries, Anna Kirillova, Chloe M. Reuter, John Garcia, Hana Zouk, Megan H. Hawley, Brittney Murray, Crystal Tichnell, Kalliopi Pilichou, Alexandros Protonotarios, Argelia Medeiros‐Domingo, Melissa Kelly, Aris Baras, Jodie Ingles, Christopher Semsarian, Barbara Bauce, Rudy Celeghin, Cristina Basso, Jan D.H. Jongbloed, Robert L. Nussbaum, Birgit H. Funke, Marina Cerrone, Luisa Mestroni, Matthew R.G. Taylor, Gianfranco Sinagra, Marco Merlo, Ardan M. Saguner, Perry Elliott, Petros Syrris, J. Peter van Tintelen, Cynthia A. James, Christopher M. Haggerty, Victoria N. Parikh,

Signaling Pathways in Disease

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.