title: High incidence of functional ion-channel abnormalities in a consecutive Long QT cohort with novel missense genetic variants of unknown significance.
abstract: The Long QT syndrome (LQTS) is a disorder characterized by a prolongation of the QT interval and a propensity to ventricular tachyarrhythmias, which may lead to syncope, cardiac arrest, or sudden death. Our objective was to (1) determine the incidence of variants with unknown significance (VUS) in a cohort of consecutive LQTS patients and (2) to determine the percentage of those with novel missense VUS that have demonstrable functional channel abnormalities from a single referral center. We performed genetic screening of candidate genes in 39 probands with a diagnosis of LQTS to identify mutations and variants. Seven variants of unknown significance were identified, six were missense variants and one was a splice site variant. We investigated the six novel missense VUS in five patients; three missense variants in KCNQ1 (L236R, W379R, Y522S) and three missense variants in KCNH2 (R35W, S620G, V491I). We employed two-electrode voltage-clamp experiments in Xenopus laevis oocytes and confocal imaging to characterize the novel missense mutations functionally. We revealed electrophysiological and trafficking loss-of-function phenotypes. This report emphasizes the frequency of adverse channel function in patients with LQTS and the importance of heterologous studies to define channel function.
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Annette Buur
authors.initials: AB
authors.lastname: Steffensen
authors.affiliation: Department of Internal Medicine, Division of Cardiology, American University of Beirut Medical Center, Beirut, Lebanon.
authors.forename: Marwan M
authors.initials: MM
authors.lastname: Refaat
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jens-Peter
authors.initials: JP
authors.lastname: David
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Amer
authors.initials: A
authors.lastname: Mujezinovic
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Kirstine
authors.initials: K
authors.lastname: Calloe
authors.affiliation: 1] Department of Medicine and [2] Institute for Human Genetics, University of California San Francisco, California, U.S.A.
authors.forename: Julianne
authors.initials: J
authors.lastname: Wojciak
authors.affiliation: 1] Department of Medicine and [2] Institute for Human Genetics, University of California San Francisco, California, U.S.A.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Nussbaum
authors.affiliation: 1] Department of Medicine and [2] Institute for Human Genetics, University of California San Francisco, California, U.S.A.
authors.forename: Melvin M
authors.initials: MM
authors.lastname: Scheinman
authors.affiliation: Danish National Research Foundation Centre for Cardiac Arrhythmia, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Nicole
authors.initials: N
authors.lastname: Schmitt
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015331:Cohort Studies; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D006801:Humans; D051657:KCNQ1 Potassium Channel / Q000235:genetics*; D008133:Long QT Syndrome / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D014982:Xenopus laevis
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051657:KCNQ1 Potassium Channel; C496909:KCNQ1 protein, human