TUBGCP5基因功能缺失导致先天性心脏病的分子机制及其临床诊断价值研究

先天性心脏病（CHD）是我国最常见的出生缺陷，严重影响儿童健康。拷贝数变异是CHD的常见病因之一，但确认其中致病基因仍是亟需解决的问题。我们前期研究发现，15q11.2微缺失在严重CHD表型之一的完全性肺静脉异位引流（TAPVC）患者中显著富集，并在一例TAPVC合并室缺患者中发现15q11.2区域的TUBGCP5基因无义突变；进一步研究表明，在人诱导多能干细胞中敲除TUBGCP5基因导致其不能向心肌细胞正常分化。我们推测TUBGCP5基因可能是15q11.2微缺失中的CHD致病基因。本项目拟分别利用诱导多能干细胞分化模型及Tubgcp5基因敲除小鼠模型，研究TUBGCP5基因在心脏发育中的调控机制，并通过对大样本CHD核心家系全基因组测序数据分析，评价15q11.2微缺失及TUBGCP5基因变异对CHD的诊断效能。本项目将为心脏发育机制的研究提供新的理论基础，发现新的CHD分子标志物。

Congenital heart disease (CHD) is the most common birth defect in our country, which threats children’s heath. Copy number variation (CNV) is one of the common causes of congenital heart disease. However, the identification of causal gene(s) within the interval is still challenging. Our previous studies found that 15q11.2 microdeletion was significantly enriched in total anomalous pulmonary venous connection (TAPVC) patients.We also identified a CHD patient with nonsense mutation in TUBGCP5 gene, which is located in the 15q11.2 locus. Knockout of TUBGCP5 gene significantly affected in vitro cardiomyocyte differentiation from induced pluripotent stem cells (iPSCs). We speculate that TUBGCP5 should be a novel CHD pathogenic gene. Here we plan to use iPSCs differentiation model and Tubgcp5 knockout mouse model to study the molecular mechanism of TUBGCP5 in heart development. Besides, we are going to evaluate the diagnostic efficiency of 15q11.2 microdeletion and TUBGCP5 gene variants in CHD patients through analyzing the available whole genome sequencing data of large cohort of CHD trios. The project will provide a new theoretical basis for the study of cardiac development mechanism and find new biomarker(s) of CHD.