New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants.
New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants.
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新的基于人群的外来数据正在质疑以前与心肌病相关的遗传变异的致病性。
DOI：
10.1038/ejhg.2012.283
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发表时间：
2013-09
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心肌病是一组具有不同病因的异质性疾病。我们重点研究了三种由基因决定的心肌病：肥厚型(HCM)、扩张型(DCM)和致心律失常的右室心肌病(ARVC)。到目前为止，已有84个基因与这些心肌病有关，但已报道的变异的致病作用往往令人怀疑。为了确定可能的假阳性变异，我们在最近发表的外显组数据中调查了以前报道的心肌病相关变异的流行率。我们搜索了NHLBI-GO外显子组测序项目(ESP)中报告的错义和无义变体，该项目包含6500个个体的外显子组数据。在ESP中，我们在之前与HCM相关的687个变异体中发现了94个(14%)，在与DCM相关的337个变异体中发现了58个(17%)，在与ARVC相关的209个变异体中发现了38个变异体(18%)。这些发现对应于HCM的1：4、DCM的1：6和ARVC的1：5的基因型患病率。PolyPhen-2预测是在所有先前发表的与心肌病相关的错义变体上进行的。我们发现，与那些不存在的变异体相比，在ESP中存在的变异体被预测为良性的变异体的显著过度表达。为了验证我们的发现，在对照人群中对7个与心肌病相关的变异进行了基因分型，结果显示频率与ESP中发现的频率相当。总而言之，我们从普通人群中的表型流行率(HCM 1：500、DCM 1：2500和ARVC 1：5000)中发现了比预期高出1000多倍的基因型流行率，我们的数据表明，大量这些变异不是心肌病的单基因原因。
Cardiomyopathies are a heterogeneous group of diseases with various etiologies. We focused on three genetically determined cardiomyopathies: hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC). Eighty-four genes have so far been associated with these cardiomyopathies, but the disease-causing effect of reported variants is often dubious. In order to identify possible false-positive variants, we investigated the prevalence of previously reported cardiomyopathy-associated variants in recently published exome data. We searched for reported missense and nonsense variants in the NHLBI-Go Exome Sequencing Project (ESP) containing exome data from 6500 individuals. In ESP, we identified 94 variants out of 687 (14%) variants previously associated with HCM, 58 out of 337 (17%) variants associated with DCM, and 38 variants out of 209 (18%) associated with ARVC. These findings correspond to a genotype prevalence of 1:4 for HCM, 1:6 for DCM, and 1:5 for ARVC. PolyPhen-2 predictions were conducted on all previously published cardiomyopathy-associated missense variants. We found significant overrepresentation of variants predicted as being benign among those present in ESP compared with the ones not present. In order to validate our findings, seven variants associated with cardiomyopathy were genotyped in a control population and this revealed frequencies comparable with the ones found in ESP. In conclusion, we identified genotype prevalences up to more than one thousand times higher than expected from the phenotype prevalences in the general population (HCM 1:500, DCM 1:2500, and ARVC 1:5000) and our data suggest that a high number of these variants are not monogenic causes of cardiomyopathy.
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