Basic science methods for the characterization of variants of uncertain significance in hypertrophic cardiomyopathy

Chang Yoon Doh, Thomas Kampourakis, Kenneth S. Campbell, Julian E. Stelzer

Research output: Contribution to journalShort surveypeer-review

4 Scopus citations

Abstract

With the advent of next-generation whole genome sequencing, many variants of uncertain significance (VUS) have been identified in individuals suffering from inheritable hypertrophic cardiomyopathy (HCM). Unfortunately, this classification of a genetic variant results in ambiguity in interpretation, risk stratification, and clinical practice. Here, we aim to review some basic science methods to gain a more accurate characterization of VUS in HCM. Currently, many genomic data-based computational methods have been developed and validated against each other to provide a robust set of resources for researchers. With the continual improvement in computing speed and accuracy, in silico molecular dynamic simulations can also be applied in mutational studies and provide valuable mechanistic insights. In addition, high throughput in vitro screening can provide more biologically meaningful insights into the structural and functional effects of VUS. Lastly, multi-level mathematical modeling can predict how the mutations could cause clinically significant organ-level dysfunction. We discuss emerging technologies that will aid in better VUS characterization and offer a possible basic science workflow for exploring the pathogenicity of VUS in HCM. Although the focus of this mini review was on HCM, these basic science methods can be applied to research in dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM), arrhythmogenic cardiomyopathy (ACM), or other genetic cardiomyopathies.

Original languageEnglish
Article number1238515
JournalFrontiers in Cardiovascular Medicine
Volume10
DOIs
StatePublished - 2023

Bibliographical note

Publisher Copyright:
2023 Doh, Kampourakis, Campbell and Stelzer.

Keywords

  • arrhythmogenic cardiomyopathy
  • cardiac myosin binding protein C (cMyBP-C)
  • dilated cardiomyopathy (DCM)
  • high throughput screen (HTS)
  • hypertrophic cardiomyopathy (HCM)
  • mathematical modeling & simulation
  • restrictive cardiomyopathy (RCM)
  • variants of uncertain clinical significance (VUS)

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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