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

BACKGROUND

Truncating variants in the desmosomal gene tv) cause arrhythmogenic right ventricular cardiomyopathy (ARVC) yet display varied penetrance and expressivity.

METHODS

We identified individuals with tv from the UK Biobank (UKB) and determined the prevalence of an ARVC phenotype and other cardiovascular traits based on clinical and procedural data. The tv 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

tv were identified in 193/200 643 (0.10%) UKB participants, with 47 unique tv. Features consistent with ARVC were present in 3 (1.6%), leaving 190 with tv without manifest disease (UKB cohort; minor allelic frequency 4.73×10). The ARVC cohort included 487 ARVC probands with 144 distinct tv, with 25 tv common to both cohorts. The odds ratio for ARVC for the 25 common tv was 0.047 (95% CI, 0.001-0.268; 2.43×10), and only favored ARVC (odds ratio >1) for a single variant, p.Arg79*. In silico variant analysis did not differentiate tv between the 2 cohorts. Atrial fibrillation was over-represented in the UKB cohort in those with tv (7.9% versus 4.3%; odds ratio, 2.11; =0.005).

CONCLUSIONS

tv are prevalent in the population and associated with ARVC in only a small minority, necessitating a more detailed understanding of how tv cause ARVC in combination with associated genetic and environmental risk factors.