Prevalence and Disease Expression of Pathogenic and Likely Pathogenic Variants Associated With Inherited Cardiomyopathies in the General Population

Abstract

Background: Pathogenic and likely pathogenic variants associated with arrhythmogenic right ventricular cardiomyopathy (ARVC), 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 pathogenic and likely pathogenic variants associated with ARVC, DCM and/or HCM in 200 643 UK Biobank individuals, who underwent whole exome sequencing. We calculated the prevalence of G+ and analyzed the frequency of cardiomyopathy/heart failure diagnosis. In undiagnosed individuals, we analyzed early signs of disease expression using available electrocardiography and cardiac magnetic resonance imaging data.

Results: We found a prevalence of 1:578, 1:251, and 1:149 for pathogenic and likely pathogenic variants associated with ARVC, DCM and HCM respectively. Compared with controls, cardiovascular mortality was higher in DCM G+ (odds ratio 1.67 [95% CI 1.04; 2.59], P=0.030), but similar in ARVC and HCM G+ (P≥0.100). Cardiomyopathy or heart failure diagnosis were more frequent in DCM G+ (odds ratio 3.66 [95% CI 2.24; 5.81], P=4.9×10^-7) and HCM G+ (odds ratio 3.03 [95% CI 1.98; 4.56], P=5.8×10^-7), but comparable in ARVC G+ (P=0.172). In contrast, ARVC G+ had more ventricular arrhythmias (P=3.3×10^-4). In undiagnosed individuals, left ventricular ejection fraction was reduced in DCM G+ (P=0.009).

Conclusions: In the general population, pathogenic and likely pathogenic variants associated with ARVC, DCM, or HCM are not uncommon. Although G+ have increased mortality and morbidity, disease penetrance in these carriers from the general population remains low (1.2-3.1%). Follow-up decisions in case of incidental findings should not be based solely on a variant, but on multiple factors, including family history and disease expression.

Keywords: arrhythmogenic right ventricular cardiomyopathy; dilated cardiomyopathy; genetics; hypertrophic cardiomyopathy; whole exome sequencing.

Figure 1.

Included curated genes per cardiomyopathy. The Venn diagram of curated genes included in this study shows the overlap in genes per cardiomyopathy. Unless otherwise indicated, pathogenicity of genes are classified as definitive. If a superscript S or M is given, genes are classified as having a strong or moderate pathogenicity, respectively. In the overlapping circles, yellow, black, and red colors refer to ARVC, DCM, and HCM, respectively. Table S1 gives an overview of the included genes and pathogenicity classification per gene and abbreviation per gene. ARVC indicates arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy.

Figure 2.

Flowchart inclusion of variants. Flowchart depicting the inclusion of pathogenic and likely pathogenic variants associated with arrhythmogenic cardiomyopathy, dilated cardiomyopathy, and hypertrophic cardiomyopathy from the ClinVar and VKGL database. ARVC indicates arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; and VKGL, Vereniging Klinische Genetische Laboratoriumdiagnostiek.

Figure 3.

Distribution of genes per cardiomyopathy. Piecharts with the distribution of curated genes for (A) arrhythmogenic right ventricular cardiomyopathy (ARVC); (B) dilated cardiomyopathy (DCM); (C) hypertrophic cardiomyopathy (HCM). Abbreviations of the different genes are given in Table S3. G+ indicates pathogenic variant carrier.

Figure 4.

Forest plot cardiac outcomes stratified per inherited cardiomyopathy. Odds ratios and 95% confidence interval are given for the associations between cardiac outcomes and ARVC, DCM, or HCM pathogenic variant carriers. ARVC indicates arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; G+, pathogenic variant carrier; and HCM= hypertrophic cardiomyopathy.

Figure 5.

CMR parameters stratified per inherited cardiomyopathy. Boxplots of the following CMR parameters: (A) LVEF; (B) RVEF; (C) LVEDVi; (D) RVEDVi; (E) maximum wall thickness; and (F) peak longitudinal strain. Boxplots show the summary statistics of CMR parameters stratified by controls and individuals with a pathogenic variant associated with ARVC, DCM, or HCM. Displayed summary statistics include the median, first and third quartile (lower and upper box edges), and the whiskers represent values within 1.5 times the interquartile range from the box edges. ARVC indicates arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; EDVi, body surface area corrected end-diastolic volume; EF, ejection fraction; G+, pathogenic variant carrier; HCM, hypertrophic cardiomyopathy; LV, left ventricular; RV, right ventricular.