Genetic Variant Score and Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Plakophilin-2 Mutation Carriers

Anneli Svensson, Pyotr G. Platonov, Kristina H. Haugaa, Wojciech Zareba, Henrik Kjærulf Jensen, Henning Bundgaard, Thomas Gilljam, Trine Madsen, Jim Hansen, Lars A. Dejgaard, Lars O. Karlsson, Anna Gréen, Bronislava Polonsky, Thor Edvardsen, Jesper Hastrup Svendsen, Cecilia Gunnarsson

Research output: Contribution to journalArticlepeer-review


Introduction: Whether detailed genetic information contributes to risk stratification of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) remains uncertain. Pathogenic genetic variants in some genes seem to carry a higher risk for arrhythmia and earlier disease onset than others, but comparisons between variants in the same gene have not been done. Combined Annotation Dependent Depletion (CADD) score is a bioinformatics tool that measures the pathogenicity of each genetic variant. We hypothesized that a higher CADD score is associated with arrhythmic events and earlier age at ARVC manifestations in individuals carrying pathogenic or likely pathogenic genetic variants in plakophilin-2 (PKP2). Methods: CADD scores were calculated using the data from pooled Scandinavian and North American ARVC cohorts, and their association with cardiac events defined as ventricular tachycardia/ventricular fibrillation (VT/VF) or syncope and age at definite ARVC diagnosis were assessed. Results: In total, 33 unique genetic variants were reported in 179 patients (90 males, 71 probands, 96 with definite ARVC diagnosis at a median age of 35 years). Cardiac events were reported in 76 individuals (43%), of whom 53 had sustained VT/VF (35%). The CADD score was neither associated with age at cardiac events (HR 1.002, 95% CI: 0.953-1.054, p = 0.933) nor with age at definite ARVC diagnosis (HR 0.992, 95% CI: 0.947-1.039, p = 0.731). Conclusion: No correlation was found between CADD scores and clinical manifestations of ARVC, indicating that the score has no additional risk stratification value among carriers of pathogenic or likely pathogenic PKP2 genetic variants.

Original languageEnglish
Pages (from-to)763-771
Number of pages9
Issue number6
Publication statusPublished - 2021 Dec

Subject classification (UKÄ)

  • Cardiac and Cardiovascular Systems

Free keywords

  • Arrhythmia
  • Arrhythmogenic right ventricular cardiomyopathy
  • Combined Annotation Dependent Depletion score
  • Plakophilin-2
  • Ventricular tachycardia


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