影响心脏发育的关键信号通路基因中非编码功能性多态位点的鉴别及其致病机理研究

Congenital heart disease(CHD) is the most common birth defects and a leading cause of death in the neonatal period and early childhood. Recently，the prevalence of CHD has increased in China. Previous study on genetic mechanism of CHD focused in chromosome aneuploidy and mutations in the handful transcription factors, such as TBX5,GATA-4,NKX2.5 et al. Our previous study in folate metabolism pathway demonstrated that the non-coding region SNPs in key enzyme significantly increased CHD risk(Circulation, 2012，125, 482-490.). In this study, we want to apply this strategy to all the candidate signal pathways affecting cardiac development. We will make use of the pooling target capture sequencing to explore the association between non-coding region SNP and CHD. Furthermore, we will investigate the function of positive SNPs in cardiac development and CHD in vitro and in vivo. This study will deepen our understanding to the etiology of CHD and provide guidance to the prenatal CHD screen and genetic consultant to the patients.

先天性心脏病是我国发病率和死亡率最高的出生缺陷，而且近年来发病率有上升趋势。以往国内外对于先天性心脏病遗传机制的研究主要集中在染色体畸变和少数转录因子编码区点突变中。我们前期在叶酸代谢途径中的研究结果提示关键基因非编码区SNP与中国人群先天性心脏病的发生显著相关（Circulation, 2012，125, 482-490.）。在本研究中试图将此研究策略拓展到心脏发育相关的所有候选信号通路基因中，采用标记样本混合、序列捕获和二代测序技术相结合，系统探索非编码区SNP与先天性心脏病发生的相关性，并对鉴定出的阳性SNP位点从分子、细胞、模式生物等不同层面进行功能分析，阐明其在心脏发育和先天性心脏病发生过程中的作用机制，为先天性心脏病的产前分子筛查和遗传咨询提供指导。