Genome-wide Studies of Copy Number Variation and Exome Sequencing Identify Rare Variants in BAG3 as a Cause of Dilated Cardiomyopathy
Genome-wide Studies of Copy Number Variation and Exome Sequencing Identify Rare Variants in BAG3 as a Cause of Dilated Cardiomyopathy
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DOI：
10.1016/j.ajhg.2011.01.016
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发表时间：
2011-03-11
影响因子：
9.8
通讯作者：
Hershberger, Ray E.
中科院分区：
文献类型：
--
作者：
Norton, Nadine;Li, Duanxiang;Hershberger, Ray E.
扩张型心肌病通常导致心力衰竭，是心脏移植最常见的诱发原因。家族性扩张型心肌病已被证明是由30多个基因的罕见变异突变引起的，但主要通过基于连锁或候选基因发现方法，仅确定了其遗传原因的35%。在一个常染色体显性遗传的多代家庭中，我们对先证者及其三个受影响的家庭成员进行了全外显子组测序，并对先证者及其受影响的父亲和未受影响的母亲进行了全基因组拷贝数变异。外显子组测序鉴定出428个单点变异，导致错义、无义或剪接位点改变。全基因组拷贝数分析发现51个插入缺失和440个拷贝数变异> 1kb。其中，在7名受影响的家庭成员中发现了8733 bp的缺失，该缺失包括热休克蛋白合作伙伴bcl2相关的无氧基因3 （BAG3）的外显子4，而在355名对照组中没有缺失。为了确定这类蛋白变体与遗传DCM的相关性，我们在311个其他不相关的DCM先显子中对BAG3的编码外显子进行了测序，并在355个对照dna中发现了1个移码、2个无义和4个错义罕见变体，其中4个是家族性的，与疾病分离。在斑马鱼模型中敲低bag3重现DCM和心力衰竭。我们得出结论，新的综合基因组方法已经确定了BAG3的罕见变异是DCM的病因。
Dilated cardiomyopathy commonly causes heart failure and is the most frequent precipitating cause of heart transplantation. Familial dilated cardiomyopathy has been shown to be caused by rare variant mutations in more than 30 genes but only similar to 35% of its genetic cause has been identified, principally by using linkage-based or candidate gene discovery approaches. In a multigenerational family with autosomal dominant transmission, we employed whole-exome sequencing in a proband and three of his affected family members, and genome-wide copy number variation in the proband and his affected father and unaffected mother. Exome sequencing identified 428 single point variants resulting in missense, nonsense, or splice site changes. Genome-wide copy number analysis identified 51 insertion deletions and 440 copy number variants > 1 kb. Of these, a 8733 bp deletion, encompassing exon 4 of the heat shock protein cochaperone BCL2-associated athanogene 3 (BAG3), was found in seven affected family members and was absent in 355 controls. To establish the relevance of variants in this protein class in genetic DCM, we sequenced the coding exons in BAG3 in 311 other unrelated DCM probands and identified one frameshift, two nonsense, and four missense rare variants absent in 355 control DNAs, four of which were familial and segregated with disease. Knockdown of bag3 in a zebrafish model recapitulated DCM and heart failure. We conclude that new comprehensive genomic approaches have identified rare variants in BAG3 as causative of DCM.