{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T23:32:37Z","timestamp":1776727957699,"version":"3.51.2"},"reference-count":28,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2014,12]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              J-wave ECG patterns are associated with an increased risk of sudden arrhythmic death, and experimental evidence supports a transient outward current (I\n              <jats:sub>to<\/jats:sub>\n              )-mediated mechanism of J-wave formation. This study aimed to determine the frequency of genetic mutations in genes encoding the I\n              <jats:sub>to<\/jats:sub>\n              in patients with J waves on ECG.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              Comprehensive mutational analysis was performed on I\n              <jats:sub>to<\/jats:sub>\n              -encoding\n              <jats:italic>KCNA4<\/jats:italic>\n              ,\n              <jats:italic>KCND2<\/jats:italic>\n              , and\n              <jats:italic>KCND3<\/jats:italic>\n              genes, as well as the previously described J-wave\u2013associated\n              <jats:italic>KCNJ8<\/jats:italic>\n              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\n              <jats:italic>KCND2<\/jats:italic>\n              gene, p.D612N, was identified in a single patient. Co-expression of mutant and wild-type\n              <jats:italic>KCND2<\/jats:italic>\n              with\n              <jats:italic>KChIP2<\/jats:italic>\n              in HEK293 cells demonstrated a gain-of-function phenotype, including an increase in peak I\n              <jats:sub>to<\/jats:sub>\n              density of 48% (\n              <jats:italic>P<\/jats:italic>\n              &lt;0.05) in the heterozygous state. Using computer modeling, this increase in I\n              <jats:sub>to<\/jats:sub>\n              resulted in loss of the epicardial action potential dome, predicting an increased ventricular transmural I\n              <jats:sub>to<\/jats:sub>\n              gradient. The previously described\n              <jats:italic>KCNJ8<\/jats:italic>\n              -S422L mutation was not identified in this cohort of patients with ECG evidence of J-wave syndrome.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              These findings are the first to implicate the\n              <jats:italic>KCND2<\/jats:italic>\n              gene as a novel cause of J-wave syndrome associated with sudden cardiac arrest. However, genetic defects in I\n              <jats:sub>to<\/jats:sub>\n              -encoding genes seem to be an uncommon cause of sudden cardiac arrest in patients with apparent J-wave syndromes.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgenetics.114.000623","type":"journal-article","created":{"date-parts":[[2014,9,12]],"date-time":"2014-09-12T03:18:55Z","timestamp":1410491935000},"page":"782-789","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":48,"title":["Evaluation of Genes Encoding for the Transient Outward Current (Ito) Identifies the\n            <i>KCND2<\/i>\n            Gene as a Cause of J-Wave Syndrome Associated With Sudden Cardiac Death"],"prefix":"10.1161","volume":"7","author":[{"given":"Mark J.","family":"Perrin","sequence":"first","affiliation":[{"name":"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,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arnon","family":"Adler","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharon","family":"Green","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Foad","family":"Al-Zoughool","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petro","family":"Doroshenko","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathan","family":"Orr","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaheen","family":"Uppal","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeff S.","family":"Healey","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Birnie","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shubhayan","family":"Sanatani","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Gardner","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean","family":"Champagne","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris","family":"Simpson","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kamran","family":"Ahmad","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maarten P.","family":"van den Berg","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vijay","family":"Chauhan","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter H.","family":"Backx","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Peter","family":"van Tintelen","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew D.","family":"Krahn","sequence":"additional","affiliation":[{"name":"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.); 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