An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing.
An international compendium of mutations in the SCN5A-encoded cardiac sodium channel in patients referred for Brugada syndrome genetic testing.
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DOI：
10.1016/j.hrthm.2009.09.069
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发表时间：
2010-01
期刊：
影响因子：
5.5
通讯作者：
Ackerman, Michael J.
中科院分区：
文献类型：
--
作者：
Kapplinger, Jamie D.;Tester, David J.;Alders, Marielle;Benito, Begona;Berthet, Myriam;Brugada, Josep;Brugada, Pedro;Fressart, Veronique;Guerchicoff, Alejandra;Harris-Kerr, Carole;Kamakura, Shiro;Kyndt, Florence;Koopmann, Tamara T.;Miyamoto, Yoshihiro;Pfeiffer, Ryan;Pollevick, Guido D.;Probst, Vincent;Zumhagen, Sven;Vatta, Matteo;Towbin, Jeffrey A.;Shimizu, Wataru;Schulze-Bahr, Eric;Antzelevitch, Charles;Salisbury, Benjamin A.;Guicheney, Pascale;Wilde, Arthur A. M.;Brugada, Ramon;Schott, Jean-Jacques;Ackerman, Michael J.
Brugada综合征（BrS）是一种常见的遗传性通道病。SCN 5A编码的钠通道（BrS 1）的突变在最常见的基因型中达到顶峰。本研究试图对来自9个中心的BrS数据库进行回顾性分析，每个中心都有>100例不相关的疑似BrS病例的基因分型。对SCN 5A中所有27个翻译外显子进行突变分析。在病例和1,300名表面健康的志愿者中比较了突变频率、类型和定位，这些志愿者包括649名白色受试者和651名非白色受试者（黑人、亚洲人、西班牙人和其他人），这些受试者先前进行了基因分型。共有2，111名无关患者（78%为男性，平均年龄39 ± 15岁）接受了BrS基因检测。BrS病例中罕见突变/变异比对照受试者更常见（438/2，111，21% vs. 11/649，1.7%白色受试者和31/651，4.8%非白色受试者，P <10−53）。BrS 1基因检测的产量范围为11%至28%（P = 0.0017）。总的来说，在SCN 5A中鉴定了293个不同的突变：193个错义，32个无义，38个移码，21个剪接位点和9个框内缺失/插入。4种最常见的BrS 1相关突变为E1784 K（14×）、F861 WfsX 90（11×）、D356 N（8×）和G1408 R（7×）。大多数突变定位于跨膜区域。这个国际BrS基因检测中心联盟已经向公共领域增加了200个新的BrS 1相关突变。总体而言，21%的BrS先证者在SCN 5A中存在突变，而健康对照受试者中报告的罕见变异的背景率为2%至5%。利用本文提供的数据进行的其他研究可能有助于进一步区分致病性突变与病例中发现的类似罕见但无害的突变。
Brugada syndrome (BrS) is a common heritable channelopathy. Mutations in the SCN5A-encoded sodium channel (BrS1) culminate in the most common genotype. This study sought to perform a retrospective analysis of BrS databases from 9 centers that have each genotyped >100 unrelated cases of suspected BrS. Mutational analysis of all 27 translated exons in SCN5A was performed. Mutation frequency, type, and localization were compared among cases and 1,300 ostensibly healthy volunteers including 649 white subjects and 651 nonwhite subjects (blacks, Asians, Hispanics, and others) that were genotyped previously. A total of 2,111 unrelated patients (78% male, mean age 39 ± 15 years) were referred for BrS genetic testing. Rare mutations/variants were more common among BrS cases than control subjects (438/2,111, 21% vs. 11/649, 1.7% white subjects and 31/651, 4.8% nonwhite subjects, respectively, P <10−53). The yield of BrS1 genetic testing ranged from 11% to 28% (P = .0017). Overall, 293 distinct mutations were identified in SCN5A: 193 missense, 32 nonsense, 38 frameshift, 21 splice-site, and 9 in-frame deletions/insertions. The 4 most frequent BrS1-associated mutations were E1784K (14×), F861WfsX90 (11×), D356N (8×), and G1408R (7×). Most mutations localized to the transmembrane-spanning regions. This international consortium of BrS genetic testing centers has added 200 new BrS1-associated mutations to the public domain. Overall, 21% of BrS probands have mutations in SCN5A compared to the 2% to 5% background rate of rare variants reported in healthy control subjects. Additional studies drawing on the data presented here may help further distinguish pathogenic mutations from similarly rare but otherwise innocuous ones found in cases.
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影响因子：
5.5
作者：
Kapplinger, Jamie D.;Tester, David J.;Salisbury, Benjamin A.;Carr, Janet L.;Harris-Kerr, Carole;Pollevick, Guido D.;Wilde, Arthur A. M.;Ackerman, Michael J.
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Ackerman MJ
影响因子：
37.8
作者：
Priori, SG;Napolitano, C;Schwartz, PJ
通讯作者：
Schwartz, PJ
影响因子：
5.5
作者：
Meregalli, Paola G.;Tan, Hanno L.;Wilde, Arthur A. M.
通讯作者：
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