Identification of rare variants in novel candidate genes in pulmonary atresia patients by next generation sequencing
Identification of rare variants in novel candidate genes in pulmonary atresia patients by next generation sequencing
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通过下一代测序鉴定肺闭锁患者新候选基因中的罕见变异
DOI：
10.1016/j.csbj.2020.01.011
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发表时间：
2020-01-01
影响因子：
6
通讯作者：
Sun, Kun
中科院分区：
文献类型：
--
作者：
Shi, Xin;Zhang, Li;Sun, Kun
肺闭锁(PA)是一种罕见的先天性心脏病，临床表现复杂，死亡率高。由于PA发病机制中的遗传决定因素仍不清楚，通过全外显子组测序(WES)彻底识别遗传因素将为PA的潜在发病机制提供新的见解。我们收集了来自PA/VSD(n=60)、PA/IVS(n=20)、TOF/PA(n=20)和100名健康对照的WES数据。通过基于变异的关联和基于基因的负荷分析，确定了罕见的变异和新基因。然后，我们探索了我们的候选基因在内皮细胞系、肺动脉组织和胚胎心脏中的表达模式。首次证实了7个新候选基因(DNAH10、DST、FAT1、HMCN1、HNRNPC、TEP1和TYK2)的56个罕见损伤变异体在PA发病中起作用。在本研究中，PA/VSD、PA/IVS和TOF/PA的遗传模式不同。综上所述，我们的发现为这种罕见的先天性出生缺陷的分子基础提供了新的见解。(C)2020作者。由Elsevier B.V.代表计算和结构生物技术研究网络出版。
Pulmonary atresia (PA) is a rare congenital heart defect (CHD) with complex manifestations and a high mortality rate. Since the genetic determinants in the pathogenesis of PA remain elusive, a thorough identification of the genetic factors through whole exome sequencing (WES) will provide novel insights into underlying mechanisms of PA. We performed WES data from PA/VSD (n = 60), PA/IVS (n = 20), TOF/PA (n = 20) and 100 healthy controls. Rare variants and novel genes were identified using variant-based association and gene-based burden analysis. Then we explored the expression pattern of our candidate genes in endothelium cell lines, pulmonary artery tissues, and embryonic hearts. 56 rare damage variants of 7 novel candidate genes (DNAH10, DST, FAT1, HMCN1, HNRNPC, TEP1, and TYK2) were certified to have function in PA pathogenesis for the first time. In our research, the genetic pattern among PA/VSD, PA/IVS and TOF/PA were different to some degree. Taken together, our findings contribute new insights into the molecular basis of this rare congenital birth defect. (C) 2020 The Authors. Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.