Association of Pathogenic Variants for Cardiomyopathy and Mortality

Quick Takes

  • Analyses of the ARIC and UK Biobank cohorts showed a prevalence of 0.7% for pathogenic variants in 13 genes causally associated with DCM and HCM and middle-aged individuals.
  • These pathogenic variants had highly variable penetrance with no characteristic clinical markers on ECG or imaging studies.
  • Carriers of these pathogenic variants had a higher risk for all-cause mortality and hospitalization for heart failure and atrial fibrillation.

Study Questions:

What is the prevalence of pathogenic variants associated with cardiomyopathy, and what is the association between these variants and mortality and cardiovascular outcomes?


The authors used the ARIC (Atherosclerosis in Risk Communities) study, a prospective cohort with participants 45-64 years of age as a discovery cohort and the UK Biobank, a prospective cohort with participants 40-69 years of age for validation. Both cohorts had whole exome sequencing on participants with some also having an electrocardiogram (ECG), echocardiogram, and cardiac magnetic resonance imaging (MRI). A certified lab geneticist blinded to phenotype classified the pathogenicity of variants observed in 13 genes that have been causally linked to inherited cardiomyopathies. Outcomes of interest included all-cause mortality, hospitalizations for heart failure (HF) and atrial fibrillation (AF), and incidence of dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM).


A total of 9,667 ARIC participants and 49,735 UK Biobank participants were included in this study. After filtering all variants in the 13 genes selected, a total of 59 variants met criteria for pathogenicity. The prevalence in these 59 variants was 0.6% in ARIC. Individuals with these variants did not display distinct phenotype when data on ECG, echo, and cardiac MRI were assessed. However, these carriers had a higher risk for all-cause mortality compared to those without these variants (hazard ratio, 1.5; 95% confidence interval, 1.1-2.2). These variants were associated with higher risk for HF hospitalization and AF compared to noncarriers. While risk for being diagnosed with DCM or HCM was higher, the absolute incidence of these events was low. Similar findings were duplicated in the UK Biobank registry.


In this study using two large prospective cohorts, pathogenic variants associated with DCM or HCM were prevalent in 0.7% individuals with highly variable penetrance. Imaging or ECG data did not show any characteristic abnormality associated with these variants. However, these variants were associated with a high risk for mortality, AF, and HF.


Inherited cardiomyopathies remain vastly underdiagnosed with poor uptake of genetic testing for patients with DCMs. This study addresses if population genomic screening for inherited cardiomyopathies could potentially have any healthy benefits. Important highlights include overall low prevalence of 0.7% for pathogenic variants. However, it could be argued that the authors limited themselves to strictly 13 genes and the study cohorts comprised of middle-aged individuals. Younger individuals with higher odds for inherited cardiomyopathy are missing. Other notable findings include highly variable penetrance with overall low incidence of HCM and DCM despite presence of a pathogenic variant with no phenotypic correlates identifiable on ECG or other imaging data. This makes identifying individuals harboring these variants in clinical practice challenging without genetic testing. Yet, these individuals are at a higher risk for mortality and cardiovascular disease. While population screening for these genes will help identify these high-risk individuals, these data do not suggest that such an approach would be cost-effective from a societal perspective.

Clinical Topics: Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Echocardiography/Ultrasound, Magnetic Resonance Imaging

Keywords: Arrhythmias, Cardiac, Atherosclerosis, Atrial Fibrillation, Cardiomyopathies, Cardiomyopathy, Dilated, Cardiomyopathy, Hypertrophic, Diagnostic Imaging, Echocardiography, Electrocardiography, Genetic Testing, Heart Failure, Magnetic Resonance Imaging, Metagenomics, Middle Aged, Virulence, Whole Exome Sequencing

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