Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect.
Exome sequencing identifies rare variants in multiple genes in atrioventricular septal defect.
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DOI：
10.1038/gim.2015.60
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发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
Mital S
中科院分区：
文献类型：
--
作者：
D'Alessandro LC;Al Turki S;Manickaraj AK;Manase D;Mulder BJ;Bergin L;Rosenberg HC;Mondal T;Gordon E;Lougheed J;Smythe J;Devriendt K;Bhattacharya S;Watkins H;Bentham J;Bowdin S;Hurles ME;Mital S
40%的房室间隔缺损（AVSD）的遗传病因不明。传统的测序和阵列已经确定了病因，只有少数的非综合征的个人与AVSD。在81名与AVSD无关的先证者中进行全外显子组测序，以确定与AVSD具有强生物学相关性的112个基因的综合组中的潜在因果变异。与对照组相比，在基因集中鉴定出罕见和罕见/损伤性变体的显著富集（比值比1.52，95%置信区间1.35-1.71，p = 4.8 x 10-11）。与法洛四联症非AVSD队列相比，富集特异于AVSD先证者（优势比2.25，95%置信区间1.84-2.76，p = 2.2 x 10-16）。与对照组相比，6个基因（NIPBL，CHD 7，CEP 152，BMPR 1a，ZFPM 2和MDM 4）在AVSD中富集了罕见变异，包括3个综合征相关基因（NIPBL，CHD 7，CEP 152）。研究结果在81名房室传导阻滞先证者的重复队列中得到证实。与AVSD具有强烈生物学相关性的基因突变，包括综合征相关基因，即使在孤立的心脏病患者中也可能导致AVSD。与AVSD相关的基因集的鉴定将有助于在该队列中进行靶向遗传筛查。
The genetic etiology of atrioventricular septal defect (AVSD) is unknown in 40% cases. Conventional sequencing and arrays have identified the etiology in only a minority of non-syndromic individuals with AVSD. Whole exome sequencing was performed in 81 unrelated probands with AVSD to identify potentially causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD. A significant enrichment of rare and rare/damaging variants was identified in the gene set, compared with controls (odds ratio 1.52, 95% confidence interval 1.35–1.71, p = 4.8 x 10-11). The enrichment was specific to AVSD probands compared with a non-AVSD cohort with tetralogy of Fallot (odds ratio 2.25, 95% confidence interval 1.84-2.76, p = 2.2 x 10-16). Six genes (NIPBL, CHD7, CEP152, BMPR1a, ZFPM2 and MDM4) were enriched for rare variants in AVSD compared to controls, including three syndrome-associated genes (NIPBL, CHD7, CEP152). The findings were confirmed in a replication cohort of 81 AVSD probands. Mutations in genes with strong biological relevance to AVSD, including syndrome-associated genes, can contribute to AVSD even in those with isolated heart disease. The identification of a gene set associated with AVSD will facilitate targeted genetic screening in this cohort.
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