The genetics underlying acquired long QT syndrome: impact for genetic screening
The genetics underlying acquired long QT syndrome: impact for genetic screening
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获得性长 QT 综合征的遗传学：对基因筛查的影响
DOI：
10.1093/eurheartj/ehv695
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发表时间：
2016-05-07
影响因子：
39.3
通讯作者：
Horie, Minoru
中科院分区：
文献类型：
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作者：
Itoh, Hideki;Crotti, Lia;Horie, Minoru
目的 获得性长 QT 综合征 (aLQTS) 表现为 QT 间期延长和由药物、低钾血症或心动过缓引发的尖端扭转型室性心动过速。有时，尽管消除了触发因素，QTc 仍然延长，这表明存在潜在的遗传底物。在 aLQTS 受试者中，我们根据临床因素评估了主要 LQTS 基因突变的发生率以及它们成为致病遗传变异携带者的概率。 方法和结果 我们在来自日本、法国和意大利的 188 名 aLQTS 先证者（55 +/- 20 岁，140 名女性）中筛选了 5 个主要 LQTS 基因。根据对照 QTc（无触发因素），受试者被指定为“真正的 aLQTS”（QTc 在正常范围内）或“未掩蔽的 cLQTS”（所有其他），并与 1010 个基因型先天性长 QT 综合征 (cLQTS) 家族的 2379 名成员进行 QTc 和遗传学比较。 86% 的 aLQTS 受试者存在心脏症状。 aLQTS 的对照 QTc 为 453 +/- 39 ms，比 cLQTS 短（478 +/- 46 ms，P < 0.001），比非携带者长（406 +/- 26 ms，P < 0.001）。在 53 名 (28%) aLQTS 受试者中，鉴定出 47 种致病突变。与 cLQTS 相比，在“真正的 aLQTS”中，KCNQ1 突变的频率远低于 KCNH2（20% [95% CI 7-41%] vs. 64% [95% CI 43-82%]，P < 0.01）。基于对照 QTc、年龄和症状的临床评分可以识别更有可能携带 LQTS 突变的患者。结论 三分之一的 aLQTS 患者携带 cLQTS 突变，其中 KCNH2 突变更为常见。可以通过简单的临床参数来预测成为 cLQTS 致病突变携带者的可能性，从而可以进行可能具有成本效益的基因检测，从而进行级联筛查，以识别其他高危家庭成员。
Aims Acquired long QT syndrome (aLQTS) exhibits QT prolongation and Torsades de Pointes ventricular tachycardia triggered by drugs, hypokalaemia, or bradycardia. Sometimes, QTc remains prolonged despite elimination of triggers, suggesting the presence of an underlying genetic substrate. In aLQTS subjects, we assessed the prevalence of mutations in major LQTS genes and their probability of being carriers of a disease-causing genetic variant based on clinical factors.Methods and results We screened for the five major LQTS genes among 188 aLQTS probands (55 +/- 20 years, 140 females) from Japan, France, and Italy. Based on control QTc (without triggers), subjects were designated 'true aLQTS' (QTc within normal limits) or 'unmasked cLQTS' (all others) and compared for QTc and genetics with 2379 members of 1010 genotyped congenital long QT syndrome (cLQTS) families. Cardiac symptoms were present in 86% of aLQTS subjects. Control QTc of aLQTS was 453 +/- 39 ms, shorter than in cLQTS (478 +/- 46 ms, P < 0.001) and longer than in non-carriers (406 +/- 26 ms, P < 0.001). In 53 (28%) aLQTS subjects, 47 disease-causing mutations were identified. Compared with cLQTS, in 'true aLQTS', KCNQ1 mutations were much less frequent than KCNH2 (20% [95% CI 7-41%] vs. 64% [95% CI 43-82%], P < 0.01). A clinical score based on control QTc, age, and symptoms allowed identification of patients more likely to carry LQTS mutations.Conclusion A third of aLQTS patients carry cLQTS mutations, those on KCNH2 being more common. The probability of being a carrier of cLQTS disease-causing mutations can be predicted by simple clinical parameters, thus allowing possibly cost-effective genetic testing leading to cascade screening for identification of additional at-risk family members.