胎儿超声心动图联合基因测定对家族性先天性心脏病复杂畸形发病机制的研究

Congenital heart disease (CHD) rate among all cases of birth defects in the first place, CHD is familial incidence, with a certain genetic background, their characters most cases are isolated cardiac anomalies, rather than genetic syndromes of multiple system diseases involved in cardiac anomalies. We found that many family CHD cases are complex even lethal cardiac malformations diagnosed by fetal echocardiography in early previous study. The prognosis of these fetuses is very poor; they often die shortly after birth or died in womb because they have to depend on the special fetal blood circulation to survive. Fetal echocardiography is the only way to detect fetal heart malformations; adoption of a high-build up a family fortune, the collection of genetic factors is more "homogeneous" cases contribute to studies on the etiology of CHD. We suspect that: gene research in fetal cardiac malformation detected by fetal echocardiography is scientific, familial genetic sequencing analysis for complex cardiac malformation is easy to find a gene mutation. This project aims to find the relationship between CHD detected by echocardiography with gene abnormality from the perspective of family research, expect to find disease-causing genes, and to discover new genes, in order to further clarify the molecular mechanisms of pathogenesis of family CHD.

先天性心脏病（CHD）发生率位居所有出生缺陷病例首位，CHD可呈家族性发病，有一定遗传背景，其发病特点多为单纯性心脏畸形，而不是遗传综合征中多系统病变累及的心脏畸形。本课题组前期工作应用胎儿超声心动图检查发现家族性CHD常为复杂致死性心脏畸形，此类胎儿预后极差，常依赖于胎儿特有的血液循环模式才能存活，出生后很快死亡或胎死宫内。而胎儿超声心动图是检测胎儿心脏畸形的唯一方法；采用高发家系、收集遗传因子较为"同质"的病例有助于对CHD进行病因学研究。故提出假设：对胎儿超声心动图诊断的胎儿心脏畸形进行基因水平研究是最科学的，对家族性复杂心脏畸形进行基因测序易于寻找基因突变位点。本课题拟从家系的角度探讨胎儿超声心动图检测的复杂CHD与基因异常的关系，期望寻找到相关的致病基因，并能发现新的致病基因，为进一步阐明CHD家系发病的分子机理提供新的实验依据。

先天性心脏病（CHD）发生率位居所有出生缺陷病例首位， CHD可呈家族性发病，有一定遗传背景，其发病特点多为单纯性心脏畸形，而不是遗传综合征中多系统病变累及的心脏畸形。采用高发家系、收集遗传因子较为“同质”的病例有助于对CHD进行病因学研究。. 本项目对检测出的复杂畸形进行家系调查，选择家系里有两例或者两例以上CHD患者的高发家系为研究对象。复杂心脏畸形引产后，采集胎儿的脐带血，心脏病变组织及胎盘组织标本；收集病理解剖大体标本；继续妊娠生产的采集新生儿外周血，采集父母亲外周血，建立生物样本库，同时所有超声测量参数及血流存储，建立胎儿超声心动图影像数据库。收集的心脏畸形胎儿的脐带血、心脏病变组织、胎盘组织标本、父母亲外周血标本，使用二代DNA基因测序技术，对比对胎儿及其父母的基因检测结果，寻找家族性胎儿复杂性心脏畸形的致病基因。. 2014年1月至2016年12月课题组共完成胎儿超声心动图检查6579例，复杂性家族性先天性心脏畸形共5例，胎儿心脏横纹肌瘤15例，家族性发病7例。发现NM_018670.3(MESP1): c.526A>T (p.T176S)杂合突变，TSC已知致病基因4例，新发突变3例，包括TSC2：c.4813C>T，c.682C>T，c.5228G>T，c.2125G>T，c.1939G>A，c.2251C>T，c.1139T＞C。对于这些基因的检出，新发现的基因填补了基因空白，而且家系基因的遗传特性将会对孕妇再次妊娠提供指导及遗传学检测。

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