Prevalence and disease expression of pathogenic and likely pathogenic variants associated with ARVC in a large cohort

Background Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a leading cause of sudden cardiac death in the young. However, the prevalence and clinical penetrance of ARVC-associated pathogenic/likely pathogenic (P/LP) variants in the general population remain poorly defined. Methods In 34,202 UK Biobank participants with WES, CMR, and ECGs, Putative pathogenic variants in 10 ACM genes were strictly curated. Python-reconstructed ECGs underwent blinded cardiological review. Penetrance was defined by 2010 ARVC Task Force Criteria (TFC). Result Among 693 carriers (2.03%), penetrance was low (61.8% phenotype-negative). Per TFC, 6.8% had Definite ARVC, 10.1% Borderline, and 21.4% isolated features. Definite ARVC exhibited significant RV impairment (p<0.001). Longitudinally, cardiac arrest risk was confined to Definite ARVC (HR 27.3, p<0.05). Conversely, incident cardiomyopathy risk was substantial for Definite (HR 46.1) and Borderline (HR 18.4) carriers. Among 693 carriers, 93 exhibited arrhythmias (overlapping: 44 bradyarrhythmia, 37 supraventricular [SVT], 57 ventricular [VT]). Compared to non-arrhythmic carriers (n=600), the arrhythmic cohort showed profound RV remodeling and milder left ventricular changes with preserved LVEF. Crucially, SVT and VT profoundly elevated risks for incident heart failure (HR 79.0 and 32.2, p<0.01) and mortality (HR 11.3 and 8.0, p≤0.01). Bradyarrhythmia did not affect HF or survival. Gene-specific phenotypes exhibited marked heterogeneity, with cardiac impairment predominantly concentrated in desmosomal variants. Specifically, DSP variants strongly drove LV involvement (reduced LVEF, LV dilation), whereas DSG2 and DSC2 caused biventricular remodeling. Conversely, JUP carriers presented a classic right-dominant phenotype with prominent RV impairment and preserved LV function. Notably, carriers of non-desmosomal variants lacked consistent structural abnormalities, presenting with baseline parameters comparable to the general population. Comprehensive sensitivity analyses underscored the remarkably low baseline penetrance. Following matching, baseline cardiac parameters did not differ significantly between the carriers and non-carriers. Furthermore, phenotypic expression remained invariant irrespective of variant multiplicity mutation type, or P/LP curation source. Conclusion ACM-associated variants exhibit remarkably low penetrance; genetic carriage alone does not equate to structural impairment. Fatal arrhythmic risk is confined to Clinical ARVC, whereas subclinical carriers risk progressive cardiomyopathy. Expression is predominantly desmosomal-driven. Crucially, arrhythmia nature (supraventricular/ventricular)—not mere presence—dictates heart failure and mortality risks. These findings advocate against prophylactic ICDs for incidental carriers, emphasizing personalized, longitudinal electro-structural surveillance instead.figure1figure2