Population Prevalence of Premature Truncating Variants in Plakophilin-2 and Association With Arrhythmogenic Right Ventricular Cardiomyopathy: A UK Biobank Analysis

Population Prevalence of Premature Truncating Variants in Plakophilin-2 and Association With Arrhythmogenic Right Ventricular Cardiomyopathy: A UK Biobank Analysis

Circulation: Genomic and Precision Medicine, <a href=»https://www.ahajournals.org/toc/circgen/15/3″>Volume 15, Issue 3</a>, Page e003507, June 1, 2022.
Background:Truncating variants in the desmosomal genePKP2 (PKP2tv) cause arrhythmogenic right ventricular cardiomyopathy (ARVC) yet display varied penetrance and expressivity.Methods:We identified individuals withPKP2tv from the UK Biobank (UKB) and determined the prevalence of an ARVC phenotype and other cardiovascular traits based on clinical and procedural data. ThePKP2tv minor allelic frequency in the UKB was compared with a second cohort of probands with a clinical diagnosis of ARVC (ARVC cohort), with a figure of 1:5000 assumed for disease prevalence. In silico predictors of variant pathogenicity (combined annotation-dependent depletion and Splice AI [Illumina, Inc.]) were assessed.Results:PKP2tv were identified in 193/200 643 (0.10%) UKB participants, with 47 uniquePKP2tv. Features consistent with ARVC were present in 3 (1.6%), leaving 190 withPKP2tv without manifest disease (UKB cohort; minor allelic frequency 4.73×10−4). The ARVC cohort included 487 ARVC probands with 144 distinctPKP2tv, with 25PKP2tv common to both cohorts. The odds ratio for ARVC for the 25 commonPKP2tv was 0.047 (95% CI, 0.001–0.268;P=2.43×10−6), and only favored ARVC (odds ratio &gt;1) for a single variant, p.Arg79*. In silico variant analysis did not differentiatePKP2tv between the 2 cohorts. Atrial fibrillation was over-represented in the UKB cohort in those withPKP2tv (7.9% versus 4.3%; odds ratio, 2.11;P=0.005).Conclusions:PKP2tv are prevalent in the population and associated with ARVC in only a small minority, necessitating a more detailed understanding of howPKP2tv cause ARVC in combination with associated genetic and environmental risk factors.