Perrin Mark J, Adler Arnon, Green Sharon, Al-Zoughool Foad, Doroshenko Petro, Orr Nathan, Uppal Shaheen, Healey Jeff S, Birnie David, Sanatani Shubhayan, Gardner Martin, Champagne Jean, Simpson Chris, Ahmad Kamran, van den Berg Maarten P, Chauhan Vijay, Backx Peter H, van Tintelen J Peter, Krahn Andrew D, Gollob Michael H
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.).
Circ Cardiovasc Genet. 2014 Dec;7(6):782-9. doi: 10.1161/CIRCGENETICS.114.000623. Epub 2014 Sep 11.
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.
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.
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.
J波心电图模式与心律失常性猝死风险增加相关，实验证据支持瞬时外向电流（I(to)）介导的J波形成机制。本研究旨在确定心电图出现J波的患者中编码I(to)的基因突变频率。
对51例经心电图证据确诊为J波综合征的无亲缘关系患者的编码I(to)的KCNA4、KCND2和KCND3基因，以及先前描述的与J波相关的KCNJ8基因进行了全面的突变分析。仅纳入心脏骤停复苏患者或1型Brugada心电图模式患者进行分析。在1例患者中发现KCND2基因存在罕见基因突变p.D612N。在HEK293细胞中，突变型和野生型KCND2与KChIP2共表达表现出功能获得性表型，杂合状态下峰值I(to)密度增加48%（P<0.05）。通过计算机建模分析，Ito的这种增加导致心外膜动作电位圆顶消失，预示心室跨壁Ito梯度增加。在这组有J波综合征心电图证据的患者中未发现先前描述的KCNJ8-S422L突变。
这些发现首次表明KCND2基因是与心脏骤停相关的J波综合征的新病因。然而，编码I(to)的基因中的遗传缺陷似乎并非明显J波综合征患者心脏骤停的常见病因。
