Background: Whether genetic information may contribute to risk stratification of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) remains uncertain. The Combined Annotation Dependent Depletion (CADD) score, a bioinformatic tool that measures the pathogenicity of genetic variants, has not been tested for its association with clinical manifestations of ARVC.
Objective: We aimed to assess whether CADD score is associated with cardiac events in individuals carrying pathogenic variants of plakophilin-2 (PKP-2) gene.
Methods: In this retrospective study, all individuals enrolled in the Nordic ARVC Registry and the North American Multidisciplinary ARVC Study carrying PKP-2 variants that according to the American College of Medical Genetics and Genomics (ACMG) were classified as pathogenic or likely pathogenic were included. In total, 36 unique genetic variants were reported in 187 patients (93 males, 75 probands, 101 with definite ARVC diagnosis by Task Force 2010 and median age of 38 [IQR 24–52] years). No individuals had a pathogenic genetic variant in any other ARVC-related gene. CADD scores were calculated and their association with age at (1) first ventricular tachycardia/ventricular fibrillation (VT/VF) defined as ventricular tachycardia, appropriate ICD therapy or aborted cardiac arrest or (2) cardiac event (VT/VF or syncope) evaluated. Kaplan–Meier analysis and Cox regression analysis adjusted for gender were used to assess relationship between CADD score and the risk of cardiac events before the age of 60 years.
Results: Cardiac events were reported in 81 patients (43%) and VT/VF in 63 (34%). CADD score was higher in patients with cardiac events than in those without (30.9 vs. 28.7, p=0.023) and Kaplan-Meier analysis indicated higher frequency of cardiac events in those with CADD score >30 (log rank p=0.011, Figure). In the Cox regression analysis, CADD >30 (upper tertile) was significantly associated with the risk of cardiac events (HR=1.80, 95% CI 1.12–2.88, p=0.014). No association between cardiac event rates and the most common genetic variant types (splice site, deletion, nonsense) was observed.
Conclusions: We are the first to report a significant correlation between PKP-2 mutation characteristics assessed using CADD-score and the age at first clinical manifestations of ARVC, thus indicating the potential of genetic information for risk stratification.