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Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
07:15

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation

Published on: January 16, 2019

New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic

Charlotte Andreasen1, Jonas B Nielsen, Lena Refsgaard

  • 1The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark.

European Journal of Human Genetics : EJHG
|January 10, 2013
PubMed

Insights

Many genetic variants linked to hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) are not disease-causing. Our study found these variants are more common than expected, suggesting they are often benign and not true monogenic causes.

Area of Science:

  • Genetics
  • Cardiology
  • Genomic Medicine

Background:

  • Cardiomyopathies encompass diverse diseases with varied causes.
  • Genetic factors are implicated in hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC).
  • The pathogenicity of many reported cardiomyopathy-associated genetic variants remains uncertain.

Purpose of the Study:

  • To investigate the prevalence of known cardiomyopathy-associated variants in a large exome dataset.
  • To identify potentially false-positive variants in genetic testing for HCM, DCM, and ARVC.
  • To assess the actual genotype prevalence of these variants in the general population.

Main Methods:

  • Searched the NHLBI-Go Exome Sequencing Project (ESP) for reported missense and nonsense variants associated with HCM, DCM, and ARVC.
  • Analyzed variant frequencies in 6500 individuals within the ESP dataset.
  • Utilized PolyPhen-2 predictions for missense variants and validated findings through genotyping in a control population.

Main Results:

  • Identified significant percentages of previously reported variants (14% for HCM, 17% for DCM, 18% for ARVC) within the ESP.
  • Observed genotype prevalences substantially higher than expected phenotype prevalences (e.g., 1:4 for HCM).
  • Found an overrepresentation of benign-predicted variants among those present in the ESP.

Conclusions:

  • A high proportion of variants associated with HCM, DCM, and ARVC may be benign and not causative.
  • Current genotype prevalences for these cardiomyopathies are likely overestimated.
  • Re-evaluation of variant interpretation is crucial for accurate genetic diagnosis of cardiomyopathies.

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