Abstract
BACKGROUND: Population genomic screening for desmosome variants associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) may facilitate early disease detection and protective intervention. The validated ARVC risk calculator offers a novel means to risk stratify individuals with diagnosed ARVC, but predicted risk in the context of genomic screening identification has not been explored. METHODS: Individuals harboring a pathogenic/likely pathogenic variant in a desmosome gene (PKP2, DSP, DSG2, or DSC2) were identified through the Geisinger MyCode Genomic Screening and Counseling program. The ARVC risk calculator was applied to patients with a subsequent evaluation of right ventricular function. This predicted risk was compared with outcomes in the first 5 years (range, 0.3-5.0 years) after genetic result return. RESULTS: Of 254 individuals with a clinically confirmed pathogenic/likely pathogenic desmosome variant, 113 (median age, 56 [interquartile range, 42-66]; 71% female) had cardiac imaging in follow-up and no prior sustained ventricular arrhythmia (VA). Eighty-two (73%) had no ARVC task force criteria (TFC) besides the variant (possible diagnosis), 22 (19%) had a single additional minor criterion (borderline diagnosis), and 9 (8%) met criteria for definite diagnosis. The median 5-year predicted VA risk was 3.9% (2.3%-6.6%), notably lower than that of the calculator derivation cohort (20.6%). The risk of fast VA was 1.6% (1.0%-2.9%). The predicted VA risk was higher in individuals with any nongenetic ARVC task force criteria (6.3% [2.5-13.2%]) versus those without (3.7% [2.2-5.6%]; P=0.01), and in individuals with DSP variants (6.1% [3.9-7.8%] versus PKP2 3.4% [2.2-5.3%]; P=0.01). Over a median 3.0 years of follow-up (≤5 years only), no sustained VA events were observed in this cohort. CONCLUSIONS: The predicted 5-year risk of VA in individuals ascertained via population genomic screening for desmosome variants is low (3.9%; 1.6% for fast VA) but may vary by affected gene and ARVC task force criteria burden.