title: TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT.
abstract: Genetic causes of many familial arrhythmia syndromes remain elusive. In this study, whole-exome sequencing (WES) was carried out on patients from three different families that presented with life-threatening arrhythmias and high risk of sudden cardiac death (SCD). Two French Canadian probands carried identical homozygous rare variant in TECRL gene (p.Arg196Gln), which encodes the trans-2,3-enoyl-CoA reductase-like protein. Both patients had cardiac arrest, stress-induced atrial and ventricular tachycardia, and QT prolongation on adrenergic stimulation. A third patient from a consanguineous Sudanese family diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT) had a homozygous splice site mutation (c.331+1G>A) in TECRL Analysis of intracellular calcium ([Ca2+]i) dynamics in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from this individual (TECRLHom-hiPSCs), his heterozygous but clinically asymptomatic father (TECRLHet-hiPSCs), and a healthy individual (CTRL-hiPSCs) from the same Sudanese family, revealed smaller [Ca2+]itransient amplitudes as well as elevated diastolic [Ca2+]iin TECRLHom-hiPSC-CMs compared with CTRL-hiPSC-CMs. The [Ca2+]itransient also rose markedly slower and contained lower sarcoplasmic reticulum (SR) calcium stores, evidenced by the decreased magnitude of caffeine-induced [Ca2+]itransients. In addition, the decay phase of the [Ca2+]itransient was slower in TECRLHom-hiPSC-CMs due to decreased SERCA and NCX activities. Furthermore, TECRLHom-hiPSC-CMs showed prolonged action potentials (APs) compared with CTRL-hiPSC-CMs. TECRL knockdown in control human embryonic stem cell-derived CMs (hESC-CMs) also resulted in significantly longer APs. Moreover, stimulation by noradrenaline (NA) significantly increased the propensity for triggered activity based on delayed afterdepolarizations (DADs) in TECRLHom-hiPSC-CMs and treatment with flecainide, a class Ic antiarrhythmic drug, significantly reduced the triggered activity in these cells. In summary, we report that mutations in TECRL are associated with inherited arrhythmias characterized by clinical features of both LQTS and CPVT Patient-specific hiPSC-CMs recapitulated salient features of the clinical phenotype and provide a platform for drug screening evidenced by initial identification of flecainide as a potential therapeutic. These findings have implications for diagnosis and treatment of inherited cardiac arrhythmias.
authors.affiliation: Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands h.d.devalla@lumc.nl john.david.rioux@umontreal.ca z.a.bhuiyan@chuv.ch r.passier@lumc.nl.
authors.forename: Harsha D
authors.identifier: 0000-0001-5343-1021
authors.initials: HD
authors.lastname: Devalla
authors.affiliation: Montreal Heart Institute, Montreal, QC, Canada.|Department of Medicine, Université de Montréal, Montreal, QC, Canada.
authors.forename: Roselle
authors.initials: R
authors.lastname: Gélinas
authors.affiliation: Department of Pediatrics, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
authors.forename: Elhadi H
authors.initials: EH
authors.lastname: Aburawi
authors.affiliation: Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Abdelaziz
authors.identifier: 0000-0003-1390-5821
authors.initials: A
authors.lastname: Beqqali
authors.affiliation: Montreal Heart Institute, Montreal, QC, Canada.
authors.forename: Philippe
authors.initials: P
authors.lastname: Goyette
authors.affiliation: Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands.|Leiden University Medical Center hiPSC Core Facility, Leiden, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Freund
authors.affiliation: Montreal Heart Institute, Montreal, QC, Canada.|Department of Medicine, Université de Montréal, Montreal, QC, Canada.
authors.forename: Marie-A
authors.initials: MA
authors.lastname: Chaix
authors.affiliation: Montreal Heart Institute, Montreal, QC, Canada.|Department of Medicine, Université de Montréal, Montreal, QC, Canada.|Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Rafik
authors.initials: R
authors.lastname: Tadros
authors.affiliation: Beijing Genomics Institute, Shenzhen, China.|Shenzhen Key Laboratory of Genomics, Shenzhen, China.|The Guangdong Enterprise Key Laboratory of Human Disease Genomics, Shenzhen, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Vital-IT group, Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Antony
authors.initials: A
authors.lastname: Le Béchec
authors.affiliation: Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Jantine J
authors.initials: JJ
authors.lastname: Monshouwer-Kloots
authors.affiliation: Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Zwetsloot
authors.affiliation: Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Georgios
authors.initials: G
authors.lastname: Kosmidis
authors.affiliation: Montreal Heart Institute, Montreal, QC, Canada.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Latour
authors.affiliation: Montreal Heart Institute, Montreal, QC, Canada.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Alikashani
authors.affiliation: Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Maaike
authors.initials: M
authors.lastname: Hoekstra
authors.affiliation: Service de Cardiologie, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Jurg
authors.initials: J
authors.lastname: Schlaepfer
authors.affiliation: Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Mummery
authors.affiliation: Vital-IT group, Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Brian
authors.initials: B
authors.lastname: Stevenson
authors.affiliation: Vital-IT group, Swiss Institute of Bioinformatics, Lausanne, Switzerland.|Institute of Social and Preventive Medicine, University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Kutalik
authors.affiliation: Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.|ICIN-Netherlands Heart Institute, Utrecht, The Netherlands.
authors.forename: Antoine Af
authors.initials: AA
authors.lastname: de Vries
authors.affiliation: Montreal Heart Institute, Montreal, QC, Canada.|Department of Medicine, Université de Montréal, Montreal, QC, Canada.
authors.forename: Léna
authors.initials: L
authors.lastname: Rivard
authors.affiliation: Heart Center, Department of Clinical and Experimental Cardiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.|Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders, Jeddah, Saudi Arabia.
authors.forename: Arthur Am
authors.initials: AA
authors.lastname: Wilde
authors.affiliation: Montreal Heart Institute, Montreal, QC, Canada.|Department of Medicine, Université de Montréal, Montreal, QC, Canada.
authors.forename: Mario
authors.initials: M
authors.lastname: Talajic
authors.affiliation: Heart Failure Research Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Arie O
authors.initials: AO
authors.lastname: Verkerk
authors.affiliation: Department of Pediatrics, College of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates.
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
authors.affiliation: Montreal Heart Institute, Montreal, QC, Canada h.d.devalla@lumc.nl john.david.rioux@umontreal.ca z.a.bhuiyan@chuv.ch r.passier@lumc.nl.|Department of Medicine, Université de Montréal, Montreal, QC, Canada.
authors.forename: John D
authors.initials: JD
authors.lastname: Rioux
authors.affiliation: Laboratoire Génétiqué Moléculaire, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland h.d.devalla@lumc.nl john.david.rioux@umontreal.ca z.a.bhuiyan@chuv.ch r.passier@lumc.nl.
authors.forename: Zahurul A
authors.initials: ZA
authors.lastname: Bhuiyan
authors.affiliation: Department of Anatomy & Embryology, Leiden University Medical Center, Leiden, The Netherlands h.d.devalla@lumc.nl john.david.rioux@umontreal.ca z.a.bhuiyan@chuv.ch r.passier@lumc.nl.|Department of Applied Stem Cell Technologies, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Passier
mesh_terms: D000293:Adolescent; D000328:Adult; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000473:pathology*; D002478:Cells, Cultured; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D006801:Humans; D008297:Male; D009154:Mutation; D010088:Oxidoreductases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D010088:Oxidoreductases; C000622700:TECRL protein, human
keywords: Arrhythmia; CPVT; LQTS; SRD5A2L2; iPSC