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 ( 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%]
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.