Deciphering Common Long QT Syndrome Using CRISPR/Cas9 in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes

Abstract

From carrying potentially pathogenic genes to severe clinical phenotypes, the basic research in the inherited cardiac ion channel disease such as long QT syndrome (LQTS) has been a significant challenge in explaining gene-phenotype heterogeneity. These have opened up new pathways following the parallel development and successful application of stem cell and genome editing technologies. Stem cell-derived cardiomyocytes and subsequent genome editing have allowed researchers to introduce desired genes into cells in a dish to replicate the disease features of LQTS or replace causative genes to normalize the cellular phenotype. Importantly, this has made it possible to elucidate potential genetic modifiers contributing to clinical heterogeneity and hierarchically manage newly identified variants of uncertain significance (VUS) and more therapeutic options to be tested in vitro. In this paper, we focus on and summarize the recent advanced application of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) combined with clustered regularly interspaced short palindromic repeats/CRISPR-associated system 9 (CRISPR/Cas9) in the interpretation for the gene-phenotype relationship of the common LQTS and presence challenges, increasing our understanding of the effects of mutations and the physiopathological mechanisms in the field of cardiac arrhythmias.