TY - JOUR
T1 - Prevalence and Disease Expression of Pathogenic and Likely Pathogenic Variants Associated with Inherited Cardiomyopathies in the General Population
AU - Bourfiss, Mimount
AU - Van Vugt, Marion
AU - Alasiri, Abdulrahman I.
AU - Ruijsink, Bram
AU - Van Setten, Jessica
AU - Schmidt, A. Floriaan
AU - Dooijes, Dennis
AU - Puyol-Antón, Esther
AU - Velthuis, Birgitta K.
AU - Van Tintelen, J. Peter
AU - Te Riele, Anneline S.J.M.
AU - Baas, Annette F.
AU - Asselbergs, Folkert W.
N1 - Funding Information:
The work was financially supported by the Netherlands Cardiovascular Research Initiative, an initiative supported by the Dutch Heart Foundation (CardioVasculair Onderzoek Nederland (CVON) projects: DOUBLE-DOSE 2020B005 (AB), PREDICT2 2018-30, eDETECT 2015-12 (PvT, Art and FA) and PREDICT Young Talent Program (Art)). In addition, this work was supported by the Dutch Heart Foundation (2015T058 (Art), 2015T041 (AB) and 2019T045 (MvV and JvS)). Furthermore, MB is supported by the Alexandre Suerman Stipend of the UMC Utrecht (2017), Art by the UMC Utrecht Fellowship Clinical Research Talent and FA by the UCL Hospitals NIHR Biomedical Research Center.
Publisher Copyright:
© 2022 Lippincott Williams and Wilkins. All rights reserved.
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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.
AB - 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.
KW - Arrhythmogenic Right Ventricular Dysplasia/epidemiology
KW - Cardiomyopathies/epidemiology
KW - Cardiomyopathy, Dilated/genetics
KW - Cardiomyopathy, Hypertrophic
KW - Heart Failure
KW - Humans
KW - Prevalence
KW - Stroke Volume
KW - Ventricular Function, Left
KW - whole exome sequencing
KW - genetics
KW - arrhythmogenic right ventricular cardiomyopathy
KW - hypertrophic cardiomyopathy
KW - dilated cardiomyopathy
UR - http://www.scopus.com/inward/record.url?scp=85145165624&partnerID=8YFLogxK
U2 - 10.1161/CIRCGEN.122.003704
DO - 10.1161/CIRCGEN.122.003704
M3 - Article
C2 - 36264615
SN - 2574-8300
VL - 15
JO - Circulation. Genomic and precision medicine
JF - Circulation. Genomic and precision medicine
IS - 6
M1 - e003704
ER -