Deciphering the pathogenic role of a variant with uncertain significance for short QT and Brugada syndromes using gene‐edited human‐induced pluripotent stem cell‐derived cardiomyocytes and preclinical drug screening

Ibrahim El‐Battrawy,Ardan M Saguner,Siegfried Lang,Lena Rose,Sebastian Diecke,Andreas Hierlemann,Alyssa Hohn,Hendrik Dinkel,Qiang Xu,Sebastian Albers,Guang Li,Mengying Huang,Xuehui Fan,Zhenxing Liao,Lukas Cyganek,Rujia Zhong,Feng Zhang,Boldizsar Kovacs,Lasse Maywald,Zhen Yang,Assem Aweimer,Yingrui Li,Xiaobo Zhou,Mandy Kleinsorge,Eliane Duperrex,Lin Qiao,Andreas Mügge,Fırat Duru ,Ji–Hyun Lee ,İbrahim Akın ,Huan Liu ,Judith Müller

doi:10.1002/ctm2.646

Abstract

Deciphering the pathogenic role of a variant with uncertain significance for short QT and Brugada syndromes using gene‐edited human‐induced pluripotent stem cell‐derived cardiomyocytes and preclinical drug screening

Highlights

The SQTS is characterized by a shortening of the corrected QT (QTc) interval, which has been linked to sudden cardiac death.[1,2] Implantable cardioverter-defibrillator therapy is associated with numerous complications.[3]
Based on the limited evidence of the clear role of variants in calcium channel subunits in SQTS and the absence of alternative therapies in this rare cohort,[6] we aimed to use cardiomyocytes from induced pluripotent stem cells derived from a SQTS5-patient overlapped with BrS carrying a variant in CACNB2 to study the significance of the variant for the clinical phenotype by combining gene editing and electrophysiological analysis in order to identify possible effective drugs for the disease
The hiPSC lines were verified for pluripotency (Figure S1C–E) and were differentiated into cardiomyocytes (Figure S1F), showing cardiac action potential (AP) features (Figure S2)

Summary

Introduction

The SQTS is characterized by a shortening of the corrected QT (QTc) interval, which has been linked to sudden cardiac death.[1,2] Implantable cardioverter-defibrillator therapy is associated with numerous complications.[3]. Human iPSC lines from one SQTS patient, from two healthy donors, and two Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas[9] gene-edited hiPSC lines were used (Figure S1A,B). A genetic screening of SQTS related genes of this patient detected a variant, namely c.1439C>T/p.S480L (dbSNP rs121917812; Clinvar RCV000010155.3; NM_000724.4: c.1439C>T; NM_201590.3: c.1442C>T) in CACNB2, a beta-subunit of L-type calcium channel (Figure 1C).

Objectives

Results

Conclusion