Contribution of a KCNH2 variant in genotyped long QT syndrome: Romano-Ward syndrome under double mutations and acquired long QT syndrome under heterozygote.
Contribution of a KCNH2 variant in genotyped long QT syndrome: Romano-Ward syndrome under double mutations and acquired long QT syndrome under heterozygote.
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DOI：
10.1016/j.jjcc.2016.09.010
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发表时间：
2017-07
影响因子：
2.5
通讯作者：
Y. Fujii;Yuichi Matsumoto;K. Hayashi;W. Ding;Yukinori Tomita;D. Fukumoto;Y. Wada;Mari Ichikawa;K. Sonoda;Junichi Ozawa;T. Makiyama;S. Ohno;M. Yamagishi;H. Matsuura;M. Horie;H. Itoh
中科院分区：
文献类型：
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作者：
Y. Fujii;Yuichi Matsumoto;K. Hayashi;W. Ding;Yukinori Tomita;D. Fukumoto;Y. Wada;Mari Ichikawa;K. Sonoda;Junichi Ozawa;T. Makiyama;S. Ohno;M. Yamagishi;H. Matsuura;M. Horie;H. Itoh
背景长QT综合征（LQTS）呈现两种临床表型：先天性和后天性。本研究旨在评估aKCNH2变异对两种LQTS表型的遗传贡献。方法1996年至2014年对LQTS先证者进行KCNQ1、KCNH2、SCN5A、KCNE1和KCNE2 5个主要基因的遗传筛查，发现389名先证者为突变携带者。我们分析了KCNH2中p.His492Tyr携带者的临床表型。结果在10个LQTS家族中鉴定出杂合p.His492Tyr变异。六名先证者（平均年龄，26 ± 23 岁）携带另一种突变，六人中有两人患有与情绪压力或电话铃声相关的晕厥。其余四名先证者在诊断时年龄明显较大（平均年龄，42 ± 33 岁），并且不携带其他复合突变。所有四名先证者在存在其他诱发因素（如 2 号罪魁祸首药物、1 号低钾血症和 1 号心动过缓）的情况下均发生致命性心律失常事件。单独 p.His492Tyr 携带者的 QTc 间期为 445 ± 10 ms，明显短于双突变携带者(481 ± 40 ms,p= 0.041).结论KCNH2p.His492Tyr 变异在存在另一种突变的情况下呈现 Romano-Ward 综合征，杂合子携带者具有轻度表型，而即使是杂合子携带者也应注意不要遇到次要因素，因为偶然因素可能会表现出 p.His492Tyr 杂合子携带者的“潜在”形式。
BackgroundLong QT syndrome (LQTS) presents two clinical phenotypes, congenital and acquired forms. This study aims to evaluate the genetic contribution of aKCNH2variant for the two LQTS phenotypes.MethodsFrom 1996 to 2014, genetic screening for LQTS probands was performed for five major genes:KCNQ1,KCNH2,SCN5A,KCNE1, andKCNE2and 389 probands were found to be mutation carriers. We analyzed the clinical phenotypes of p.His492Tyr carriers inKCNH2.ResultsHeterozygous p.His492Tyr variant was identified in 10 LQTS families. Six probands (mean age, 26 ± 23 years) carried another mutation, and two of six had syncope associated with emotional stress or telephone ringing. The remaining four probands were significantly older at diagnosis (mean age, 42 ± 33 years) and carried no other compound mutations. All the four probands had fatal arrhythmic events in the presence of additional precipitating factors such as culprit drugs in 2, hypokalemia in 1, and bradycardia in 1. The QTc interval of carriers with p.His492Tyr alone was 445 ± 10 ms and significantly shorter than that in double mutation carriers (481 ± 40 ms,p= 0.041).ConclusionsKCNH2p.His492Tyr variant presented Romano–Ward syndrome in the presence of another mutation and heterozygous carriers had mild phenotypes while even heterozygous carriers should be cared for not to encounter secondary factors because incidental factors could manifest “latent” form of p.His492Tyr heterozygous carriers.