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 - http://www.scopus.com/inward/record.url?scp=85168258429&partnerID=8YFLogxK
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 -