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

Mimount Bourfiss*, Marion Van Vugt, Abdulrahman I. Alasiri, Bram Ruijsink, Jessica Van Setten, A. Floriaan Schmidt, Dennis Dooijes, Esther Puyol-Antón, Birgitta K. Velthuis, J. Peter Van Tintelen, Anneline S.J.M. Te Riele, Annette F. Baas, Folkert W. Asselbergs

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Scopus)
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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.

Original languageEnglish
Article numbere003704
JournalCirculation. Genomic and precision medicine
Volume15
Issue number6
Early online date20 Oct 2022
DOIs
Publication statusPublished - 1 Dec 2022

Keywords

  • Arrhythmogenic Right Ventricular Dysplasia/epidemiology
  • Cardiomyopathies/epidemiology
  • Cardiomyopathy, Dilated/genetics
  • Cardiomyopathy, Hypertrophic
  • Heart Failure
  • Humans
  • Prevalence
  • Stroke Volume
  • Ventricular Function, Left
  • whole exome sequencing
  • genetics
  • arrhythmogenic right ventricular cardiomyopathy
  • hypertrophic cardiomyopathy
  • dilated cardiomyopathy

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