Penetrance and disease expression of (likely) pathogenic variants associated with inherited cardiomyopathies in the general population

Background. (Likely) pathogenic variants associated with arrhythmogenic cardiomyopathy (ACM), dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are recommended to be reported as secondary findings in genome sequencing studies. This provides opportunities for early diagnosis, but also fuels uncertainty in variant carriers (G+), since disease penetrance is incomplete. We assessed the prevalence and disease expression of G+ in the general population. Methods. We identified (likely) pathogenic variants associated with ACM, DCM and/or HCM in 200,643 UK Biobank individuals, who underwent whole exome sequencing. We calculated the prevalence of G+ and analysed the frequency of cardiomyopathy/heart failure diagnosis. In undiagnosed individuals, we analysed early signs of disease expression. Results. We found a prevalence of 1:578, 1:251 and 1:149 for (likely) pathogenic variants associated with ACM, DCM and HCM respectively. Compared to controls, cardiovascular mortality was higher in DCM G+ (OR 1.67 [95% CI 1.04;2.59], p=0.030), but similar in ACM and HCM G+ (p[≥]0.100). More specifically, cardiomyopathy or heart failure diagnosis were more frequent in DCM G+ (OR 3.66 [95% CI 2.24;5.81], p=4.9x10-7) and HCM G+ (OR 3.03 [95% CI 1.98;4.56], p=5.8x10-7), but comparable in ACM G+ (p=0.172). In contrast, ACM G+ had more ventricular arrhythmias (p=3.3x10-4). In undiagnosed individuals, left ventricular ejection fraction was reduced in DCM G+ (p=0.009). Conclusions. In the general population, (likely) pathogenic variants associated with ACM, DCM or HCM are not uncommon. Although G+ have increased mortality and morbidity, disease expression in these carriers from the general population remains low. Decisions on application of cascade screening and frequency of cardiological examination should be based on multiple factors, such as the variant and disease expression.