Mutations in Genes Encoding Cardiac Ion Channels Previously Associated With Sudden Infant Death Syndrome (SIDS) Are Present With High Frequency in New Exome Data
Mutations in Genes Encoding Cardiac Ion Channels Previously Associated With Sudden Infant Death Syndrome (SIDS) Are Present With High Frequency in New Exome Data
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DOI：
10.1016/j.cjca.2012.12.002
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发表时间：
2013-09-01
影响因子：
6.2
通讯作者：
Olesen, Morten S.
中科院分区：
文献类型：
--
作者：
Andreasen, Charlotte;Refsgaard, Lena;Olesen, Morten S.
背景：婴儿猝死综合征（SIDS）是工业化国家出生后6个月内死亡的主要原因。SIDS的遗传贡献已被深入研究，迄今为止，14个心脏通道病基因已与SIDS相关。来自国家心脏，肺和血液研究所大机会（NHLBI GO）外显子组测序项目（ESP）的新发表的数据提供了关于背景人群遗传变异的重要知识。我们的目的是确定所有以前与小岛屿发展中国家在ESP的变异，以提高合理的致病突变和变异之间的歧视最有可能是false-positive.Methods：PubMed数据库进行了搜索，以确定小岛屿发展中国家相关的channelopathy变异和这些在ESP人群（6500人）的患病率。在我们自己的对照人群中，将计算机预测工具应用于ESP中存在的变异体和6种SIDS相关变异体（CAV 3 p.C72W，p.T78M; KCNH 2 p.R148W和SCN 5A p.S216L，p.V1951L，p.F2004L）进行基因分型。这对应于ESP群体中1：29个个体是SID相关变体的携带者。在我们自己的控制6 SIDS相关的变异基因分型显示频率与ESP.Conclusions中发现的频率相当：一个非常高的患病率以前SIDS相关的变异体被确定在外显子组数据从人口研究。我们的研究结果表明，建议的致病作用，其中一些变异是值得怀疑的。当在小岛屿发展中国家受害者中发现这些变异时，必须谨慎解释。
Background: Sudden infant death syndrome (SIDS) is the leading cause of death in the first 6 months after birth in the industrialized world. The genetic contribution to SIDS has been investigated intensively and to date, 14 cardiac channelopathy genes have been associated with SIDS. Newly published data from National Heart, Lung, and Blood Institute Grand Opportunity (NHLBI GO) Exome Sequencing Project (ESP) provided important knowledge on genetic variation in the background population. Our aim was to identify all variants previously associated with SIDS in ESP to improve the discrimination between plausible disease-causing mutations and variants most likely to be false-positive.Methods: The PubMed database was searched to identify SIDS-associated channelopathy variants and the prevalence of these in the ESP population (6500 individuals) were obtained. In silico prediction tools were applied to variants present in ESP and 6 SIDS-associated variants (CAV3 p.C72W, p.T78M; KCNH2 p.R148W, and SCN5A p.S216L, p.V1951L, p.F2004L) were genotyped in our own control population.Results: Nineteen different missense variants previously associated with SIDS were identified in ESP affecting 225 of 6424 alleles. This corresponds to 1:29 individuals in the ESP population being carriers of a SIDS-associated variant. Genotyping of 6 SIDS-associated variants in our own controls revealed frequencies comparable with those found in ESP.Conclusions: A very high prevalence of previously SIDS-associated variants was identified in exome data from population studies. Our findings indicate that the suggested disease-causing role of some of these variants is questionable. A cautious interpretation of these variants must be made when found in SIDS victims.