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Updated: Aug 24, 2025
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Prevalence and Disease Expression of Pathogenic and Likely Pathogenic Variants Associated With Inherited
Mimount Bourfiss1, Marion van Vugt1, Abdulrahman I Alasiri1
1Dept of Cardiology, Univ Medical Center Utrecht, Utrecht Univ, Utrecht, the Netherlands (M.B., M.v.V., A.I.A., A.S.J.M.t.R., B.R., J.v.S., A.F.S., F.W.A.).
Insights
Pathogenic variants for cardiomyopathies like ARVC, DCM, and HCM are common in the general population. However, disease penetrance remains low, indicating that genetic findings alone should not dictate clinical decisions.
Area of Science:
- Cardiovascular Genetics
- Genomic Medicine
- Population Health
Background:
- Pathogenic variants for arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy (HCM) are increasingly identified as secondary findings in genome sequencing.
- Incomplete disease penetrance in variant carriers (G+) creates uncertainty regarding clinical outcomes.
- Assessing the prevalence and clinical expression of these variants in the general population is crucial for informed genetic counseling and patient management.
Purpose of the Study:
- To determine the prevalence of pathogenic and likely pathogenic variants associated with ARVC, DCM, and HCM in the UK Biobank population.
- To analyze the disease expression and clinical outcomes, including cardiovascular mortality and diagnosis of cardiomyopathy/heart failure, in individuals carrying these variants.
- To investigate early signs of disease in undiagnosed individuals using electrocardiography and cardiac magnetic resonance imaging.
Main Methods:
- Whole exome sequencing data from 200,643 UK Biobank participants were analyzed to identify pathogenic and likely pathogenic variants.
- Prevalence of variant carriers (G+) for ARVC, DCM, and HCM was calculated.
- Cardiovascular mortality, cardiomyopathy/heart failure diagnoses, and ventricular arrhythmias were compared between carriers and controls.
- Early disease expression in undiagnosed individuals was assessed using electrocardiography and cardiac magnetic resonance imaging data.
Main Results:
- Prevalence rates for pathogenic/likely pathogenic variants were 1:578 for ARVC, 1:251 for DCM, and 1:149 for HCM.
- DCM G+ showed increased cardiovascular mortality (OR 1.67) and higher frequency of cardiomyopathy/heart failure diagnosis (OR 3.66).
- HCM G+ also had a higher frequency of cardiomyopathy/heart failure diagnosis (OR 3.03), while ARVC G+ exhibited more ventricular arrhythmias.
- Undiagnosed DCM G+ individuals showed reduced left ventricular ejection fraction.
Conclusions:
- Pathogenic and likely pathogenic variants for ARVC, DCM, and HCM are relatively common in the general population.
- Despite increased risks for mortality and morbidity, disease penetrance in these general population carriers is low (1.2-3.1%).
- Clinical management decisions for incidental genetic findings should integrate variant data with family history and observed disease expression.
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.
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