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

TY - JOUR

T1 - Basic science methods for the characterization of variants of uncertain significance in hypertrophic cardiomyopathy

AU - Doh, Chang Yoon

AU - Kampourakis, Thomas

AU - Campbell, Kenneth S

AU - Stelzer, Julian E

N1 - Funding Information: This work was supported by grants awarded by the NIH National Heart, Lung, and Blood Institute (NHLBI) grants R01 HL146676 and R01 HL114770. Publisher Copyright: 2023 Doh, Kampourakis, Campbell and Stelzer.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85168258429

U2 - 10.3389/fcvm.2023.1238515

DO - 10.3389/fcvm.2023.1238515

M3 - Review article

C2 - 37600050

SN - 2297-055X

VL - 10

SP - 1238515

JO - Frontiers in Cardiovascular Medicine

JF - Frontiers in Cardiovascular Medicine

M1 - 1238515

ER -