Next-generation sequencing identifies novel genes with rare variants in total anomalous pulmonary venous connection.
Next-generation sequencing identifies novel genes with rare variants in total anomalous pulmonary venous connection.
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下一代测序鉴定出肺静脉连接异常中具有罕见变异的新基因
DOI：
10.1016/j.ebiom.2018.11.008
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发表时间：
2018-12
期刊：
影响因子：
11.1
通讯作者：
Yu Y
中科院分区：
文献类型：
--
作者：
Shi X;Huang T;Wang J;Liang Y;Gu C;Xu Y;Sun J;Lu Y;Sun K;Chen S;Yu Y
完全性肺静脉异位引流(TAPVC)是一种罕见的先天性心脏病(CHD)。TAPVC患者死亡率高达80%左右，其存活率和预后并不令人满意。然而，TAPVC的遗传病因和发病机制仍不清楚。本研究旨在通过下一代测序(NGS)研究TAPVC潜在的基因组风险。通过对78例散发性TAPVC患者和100例健康对照进行全外显子组测序，采用Fisher‘s精确检验和基因负荷检验，发现罕见变异。然后，我们检测了细胞、肺静脉组织和胚胎中的候选基因表达模式。最后，我们在另外100例TAPVC病例中使用靶序列(TS)验证了这些基因。在TAPVC患者中发现了7个基因(CLTCL1、CST3、GXYLT1、HMGA2、SNAI1、VAV2、ZDHHC8)的42个罕见变异。这些基因在人脐静脉内皮细胞、小鼠肺静脉和人胚胎心脏中高表达。人类肺静脉样本中这些基因的mRNA水平在病例组和对照组之间有显著差异。通过网络分析和在斑马鱼胚胎中的表达谱分析，我们发现SNAI1、HMGA2和VAV2是TAPVC最重要的基因。我们的研究发现了可能与TAPVC相关的新的候选基因，并阐明了这种罕见的先天性出生缺陷的可能分子发病机制。此外，SNAI1、HMGA2和VAV2是新的TAPVC候选基因，在人类和动物中都没有报道。中国国家自然科学基金。
Total anomalous pulmonary venous connection (TAPVC) is recognized as a rare congenital heart defect (CHD). With a high mortality rate of approximately 80%, the survival rate and outcomes of TAPVC patients are not satisfactory. However, the genetic aetiology and mechanism of TAPVC remain elusive. This study aimed to investigate the underlying genomic risks of TAPVC through next-generation sequencing (NGS). Rare variants were identified through whole exome sequencing (WES) of 78 sporadic TAPVC cases and 100 healthy controls using Fisher's exact test and gene-based burden test. We then detected candidate gene expression patterns in cells, pulmonary vein tissues, and embryos. Finally, we validated these genes using target sequencing (TS) in another 100 TAPVC cases. We identified 42 rare variants of 7 genes (CLTCL1, CST3, GXYLT1, HMGA2, SNAI1, VAV2, ZDHHC8) in TAPVC cases compared with controls. These genes were highly expressed in human umbilical vein endothelial cells (HUVECs), mouse pulmonary veins and human embryonic hearts. mRNA levels of these genes in human pulmonary vein samples were significantly different between cases and controls. Through network analysis and expression patterns in zebrafish embryos, we revealed that SNAI1, HMGA2 and VAV2 are the most important genes for TAPVC. Our study identifies novel candidate genes potentially related to TAPVC and elucidates the possible molecular pathogenesis of this rare congenital birth defect. Furthermore, SNAI1, HMGA2 and VAV2 are novel TAPVC candidate genes that have not been reported previously in either humans or animals. National Natural Science Foundation of China.
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影响因子：
4.6
作者：
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通讯作者：
Martin, James F.
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作者：
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Acquatil, Francesco
影响因子：
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作者：
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Seidman CE
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影响因子：
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作者：
通讯作者：
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影响因子：
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作者：
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通讯作者：
Agarwal R