Exome analysis of a family with Wolff-Parkinson-White syndrome identifies a novel disease locus.
Exome analysis of a family with Wolff-Parkinson-White syndrome identifies a novel disease locus.
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沃尔夫 - 帕金森 - 白综合症家庭的外显子分析确定了一个新型疾病基因座。
DOI：
10.1002/ajmg.a.37297
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发表时间：
2015-12
期刊：
影响因子：
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通讯作者：
Baylor Hopkins Centers for Mendelian Genomics
中科院分区：
文献类型：
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作者：
Bowles NE;Jou CJ;Arrington CB;Kennedy BJ;Earl A;Matsunami N;Meyers LL;Etheridge SP;Saarel EV;Bleyl SB;Yost HJ;Yandell M;Leppert MF;Tristani-Firouzi M;Gruber PJ;Baylor Hopkins Centers for Mendelian Genomics
预激综合征（WPW）是室上性心动过速的常见原因，具有心源性猝死的风险。迄今为止，只有一个基因PRKAG 2（编码5' -AMP-活化蛋白激酶亚基γ-2）中的突变已被鉴定为WPW的病因。通过外显子组测序分析来自WPW家族的五名成员的DNA样品。我们应用了最近设计的优先级排序策略（VAAST/谱系VAAST）以及基于本体的算法（Phevor），将潜在破坏性变体的数量减少到10个：还确定了先前与长QT综合征相关的KCNE 2变体。在这11个变异体中，只有MYH 6 p.E1885K在所有受影响的个体中与WPW表型分离，并且在10个未受影响的家族成员中不存在。通过计算机模拟方法预测该变体具有破坏性，并且在1，000个基因组和NHLBI外显子组测序项目数据库中不存在。对47名不相关WPW患者的重复队列进行筛查，未发现PRKAG 2或MYH 6中其他可能的致病变异。MYH 6变体已在患有房间隔缺损、心肌病和病窦综合征的患者中被鉴定。我们的数据突出了与该基因缺陷相关的表型的多效性。
Wolff–Parkinson–White (WPW) syndrome is a common cause of supraventricular tachycardia that carries a risk of sudden cardiac death. To date, mutations in only one gene, PRKAG2, which encodes the 5’ -AMP-activated protein kinase subunit γ-2, have been identified as causative for WPW. DNA samples from five members of a family with WPW were analyzed by exome sequencing. We applied recently designed prioritization strategies (VAAST/pedigree VAAST) coupled with an ontology-based algorithm (Phevor) that reduced the number of potentially damaging variants to 10: a variant in KCNE2 previously associated with Long QT syndrome was also identified. Of these 11 variants, only MYH6 p.E1885K segregated with the WPW phenotype in all affected individuals and was absent in 10 unaffected family members. This variant was predicted to be damaging by in silico methods and is not present in the 1,000 genome and NHLBI exome sequencing project databases. Screening of a replication cohort of 47 unrelated WPW patients did not identify other likely causative variants in PRKAG2 or MYH6. MYH6 variants have been identified in patients with atrial septal defects, cardiomyopathies, and sick sinus syndrome. Our data highlight the pleiotropic nature of phenotypes associated with defects in this gene.