Department of Pediatrics, College of Medicine, National Taiwan University Hospital, National Taiwan University, No. 7, Chung-Shan South Road, Taipei 100, Taiwan.
Hum Genet. 2012 Aug;131(8):1295-304. doi: 10.1007/s00439-012-1156-4. Epub 2012 Mar 11.
Coexisting long QT gene mutations/polymorphisms in Tetralogy of Fallot (TOF) patients may aggravate the repolarization abnormality from cardiac repair. We investigated the impact of these genes on the risk of life-threatening events. Genetic variants of the three common long QT genes were identified from patients with repaired TOF. Life-threatening events were defined as sudden cardiac death and hemodynamic unstable ventricular arrhythmia. Biophysical characterization of the alleles of the genetic variants was performed using a whole-cell voltage clamp with expression in Xenopus oocytes. A total of 84 patients (56.0 % male with 1,215 patients-year follow-up) were enrolled. Six rare variants and six non-synonymous single nucleotide polymorphisms (SNPs) were found in 40 (47.6 %) patients. Life-threatening events occurred in five patients; four received implantable cardioverter defibrillator and one died of sudden cardiac death. Life-threatening events occurred more often in those with genetic variants than those without (5/40 vs. 0/44, P = 0.021); particularly, the hERG or SCN5A gene mutations/polymorphisms (2/5 vs. 3/79, P = 0.027 and 5/27 vs. 0/57, P = 0.003, respectively). Among the five patients with life-threatening events, three had compound variants (hERG p.M645R/SCN5A p.R1193Q, hERG p.K897T/SCN5A p.H558R, and KVLQT1 p.G645S/SCN5A p.P1090L), that also increased the risk of events. Their QTc and JTc were all prolonged. Functional study of the novel variant (hERG gene p.M645R) from patients with life-threatening events revealed a dominant negative effect. In conclusion, in repaired TOF patients, coexisting long QT mutations/polymorphisms might have additive effects on the repolarization abnormality from surgery and thereby increase the risks of life-threatening events.
法洛四联症（TOF）患者中并存的长 QT 基因突变/多态性可能会加重心脏修复后的复极异常。我们研究了这些基因对威胁生命的事件的风险的影响。从接受 TOF 修复的患者中鉴定出三种常见长 QT 基因的遗传变异。威胁生命的事件定义为心源性猝死和血流动力学不稳定的室性心律失常。使用表达在非洲爪蟾卵母细胞中的全细胞膜片钳对遗传变异的等位基因进行生物物理特征分析。共纳入 84 例患者（56.0%为男性，随访 1215 例患者年）。在 40 例患者（47.6%）中发现了 6 种罕见变异和 6 种非同义单核苷酸多态性（SNPs）。5 例患者发生威胁生命的事件；4 例接受植入式心脏复律除颤器治疗，1 例死于心源性猝死。有遗传变异的患者发生威胁生命的事件的频率高于无遗传变异的患者（5/40 比 0/44，P = 0.021）；特别是 hERG 或 SCN5A 基因突变/多态性（2/5 比 3/79，P = 0.027 和 5/27 比 0/57，P = 0.003）。在发生威胁生命的事件的 5 例患者中，有 3 例患者存在复合变异（hERG p.M645R/SCN5A p.R1193Q、hERG p.K897T/SCN5A p.H558R 和 KVLQT1 p.G645S/SCN5A p.P1090L），这也增加了事件的风险。他们的 QTc 和 JTc 均延长。对来自发生威胁生命的事件的患者的新型变异（hERG 基因 p.M645R）的功能研究显示出显性负效应。总之，在修复后的 TOF 患者中，并存的长 QT 突变/多态性可能会对手术引起的复极异常产生附加效应，从而增加威胁生命的事件的风险。
