Genetic testing in the long QT syndrome - Development and validation of an efficient approach to genotyping in clinical practice
Genetic testing in the long QT syndrome - Development and validation of an efficient approach to genotyping in clinical practice
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DOI：
10.1001/jama.294.23.2975
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发表时间：
2005-12-21
影响因子：
120.7
通讯作者：
Leonardi, S
中科院分区：
文献类型：
--
作者：
Napolitano, C;Priori, SG;Leonardi, S
背景 在长 QT 综合征 (LQTS) 中，疾病的严重程度和对治疗的反应根据基因位点的不同而不同。迫切需要制定加快遗传分析的策略。目的对患有 LQTS 的患者进行遗传筛查，以确定基因检测的产量以及突变的类型和患病率。设计、患者和环境我们研究了 KCNQ1、KCNH2 和 SCN5A 基因中一组频繁突变密码子的检测是否可以转化为快速有效遗传的新策略。 对 1996 年 6 月至 2004 年 6 月期间转诊至我们中心的 430 名连续患者进行了测试。通过变性高效液相色谱和 DNA 测序筛选了 KCNQ1、KCNH2、SCN5A、KCNE1 和 KCNE2 的整个编码区。定义突变的频率和类型来识别一组重复出现的突变。由 75 名连续先证者组成的单独队列被用作验证组，以前瞻性地量化在主要 LQTS 人群中发现的重复突变的患病率。主要结果指标开发一种新的 LQTS 基因分型方法。结果我们在 430 名先证者中的 310 名（72%）（49% KCNQ1，39%）中鉴定出了 235 种不同的突变，其中 138 种是新的。 KCNH2、10% SCN5A、1.7% KCNE1 和 0.7% KCNE2)。 58% 的先证者在 KCNQ1、KCNH2 和 SCN5A 基因的 64 个密码子中携带非私人突变。在由 75 名先证者组成的前瞻性队列和之前发表的 LQTS 队列中，证实了这些密码子的突变发生率相似 (52%)。 结论 我们已经开发出一种方法来提高 LQTS 基因筛查的效率。这种新方法可能有助于更广泛地进行基因分型，从而更好地对 LQTS 患者进行风险分层和治疗。
Context In long QT syndrome (LQTS), disease severity and response to therapy vary according to the genetic loci. There exists a critical need to devise strategies to expedite genetic analysis.Objective To perform genetic screening inpatients with LQTS to determine the yield of genetic testing, as well as the type and the prevalence of mutations.Design, Patients, and Setting We investigated whether the detection of a set of frequently mutated codons in the KCNQ1, KCNH2, and SCN5A genes may translate in a novel strategy for rapid efficient genetic testing of 430 consecutive patients referred to our center between June 1996 and June 2004. The entire coding regions of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 were screened by denaturing high-performance liquid chromatography and DNA sequencing. The frequency and the type of mutations were defined to identify a set of recurring mutations. A separate cohort of 75 consecutive probands was used as a validation group to quantify prospectively the prevalence of the recurring mutations identified in the primary LQTS population.Main Outcome Measures Development of a novel approach to LQTS genotyping.Results We identified 235 different mutations, 138 of which were novel, in 310 (72%) of 430 probands (49% KCNQ1, 39% KCNH2, 10% SCN5A, 1.7% KCNE1, and 0.7% KCNE2). Fifty-eight percent of probands carried nonprivate mutations in 64 codons of KCNQ1, KCNH2, and SCN5A genes. A similar occurrence of mutations at these codons (52%) was confirmed in the prospective cohort of 75 probands and in previously published LQTS cohorts.Conclusions We have developed an approach to improve the efficiency of genetic screening for LQTS. This novel method may facilitate wider access to genotyping resulting in better risk stratification and treatment of LQTS patients.