title: Evaluation of genes encoding for the transient outward current (Ito) identifies the KCND2 gene as a cause of J-wave syndrome associated with sudden cardiac death.
abstract: BACKGROUND
  J-wave ECG patterns are associated with an increased risk of sudden arrhythmic death, and experimental evidence supports a transient outward current (I(to))-mediated mechanism of J-wave formation. This study aimed to determine the frequency of genetic mutations in genes encoding the I(to) in patients with J waves on ECG.
  
  
  RESULTS
  Comprehensive mutational analysis was performed on I(to)-encoding KCNA4, KCND2, and KCND3 genes, as well as the previously described J-wave-associated KCNJ8 gene, in 51 unrelated patients with ECG evidence defining a J-wave syndrome. Only patients with a resuscitated cardiac arrest or type 1 Brugada ECG pattern were included for analysis. A rare genetic mutation of the KCND2 gene, p.D612N, was identified in a single patient. Co-expression of mutant and wild-type KCND2 with KChIP2 in HEK293 cells demonstrated a gain-of-function phenotype, including an increase in peak I(to) density of 48% (P<0.05) in the heterozygous state. Using computer modeling, this increase in Ito resulted in loss of the epicardial action potential dome, predicting an increased ventricular transmural Ito gradient. The previously described KCNJ8-S422L mutation was not identified in this cohort of patients with ECG evidence of J-wave syndrome.
  
  
  CONCLUSIONS
  These findings are the first to implicate the KCND2 gene as a novel cause of J-wave syndrome associated with sudden cardiac arrest. However, genetic defects in I(to)-encoding genes seem to be an uncommon cause of sudden cardiac arrest in patients with apparent J-wave syndromes.
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Perrin
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: Arnon
authors.initials: A
authors.lastname: Adler
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: Sharon
authors.initials: S
authors.lastname: Green
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: Foad
authors.initials: F
authors.lastname: Al-Zoughool
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: Petro
authors.initials: P
authors.lastname: Doroshenko
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: Nathan
authors.initials: N
authors.lastname: Orr
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: Shaheen
authors.initials: S
authors.lastname: Uppal
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Healey
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: David
authors.initials: D
authors.lastname: Birnie
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: Shubhayan
authors.initials: S
authors.lastname: Sanatani
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: Martin
authors.initials: M
authors.lastname: Gardner
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: Jean
authors.initials: J
authors.lastname: Champagne
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: Chris
authors.initials: C
authors.lastname: Simpson
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: Kamran
authors.initials: K
authors.lastname: Ahmad
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: Maarten P
authors.initials: MP
authors.lastname: van den Berg
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: Vijay
authors.initials: V
authors.lastname: Chauhan
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: Peter H
authors.initials: PH
authors.lastname: Backx
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: J Peter
authors.initials: JP
authors.lastname: van Tintelen
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.).
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Krahn
authors.affiliation: From the Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa (M.J.P., A.A., S.G., F.A.-Z., P.D., N.O., S.U., D.B.); Population Health Research Institute, McMaster University, Hamilton, ON (J.S.H.); Division of Cardiology, Department of Medicine, University of British Columbia, Vancouver, BC (S.S., A.D.K.); Division of Cardiology, Department of Medicine, Dalhousie University, Halifax, NS (M.G.); Division of Cardiology, Department of Medicine, Laval University, Québec, QC (J.C.); Division of Cardiology, Department of Medicine, Queens University, Kingston (C.S.); Division of Cardiology, St Michael's Hospital, University of Toronto, Toronto, ON, Canada (K.A.); Department of Genetics, University of Groningen, University Medical Center, Groningen, the Netherlands (M.P.v.d.B., J.P.v.T.); Division of Cardiology, Toronto General Hospital, University of Toronto, Toronto, ON, Canada (V.C., P.H.B., M.H.G.). michael.gollob@uhn.ca.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gollob
mesh_terms: D000200:Action Potentials; D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D053840:Brugada Syndrome / Q000150:complications* / Q000235:genetics*; D004252:DNA Mutational Analysis; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D005260:Female; D005838:Genotype; D057809:HEK293 Cells; D006352:Heart Ventricles / Q000503:physiopathology; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010641:Phenotype; D051672:Shal Potassium Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: C497018:KCND2 protein, human; D051672:Shal Potassium Channels
keywords: arrhythmias, cardiac; death, sudden, cardiac