先天性心脏病（CHD）是我国最常见的出生缺陷，致病基因突变是导致其发生的重要因素，然而目前已知的基因突变仅能解释少数CHD病例，新的致病基因的发现及机制研究对CHD的早期防控极为重要。我们在前期研究中，通过对300例CHD患者样本进行靶向测序分析，发现PTCH1功能缺失变异在CHD组中显著富集；小鼠模型实验进一步证实PTCH1缺失可导致心脏流出道发育障碍，提示PTCH1是新的CHD致病基因，但具体致病机制不明。本项目拟通过基因敲除小鼠模型及体外心肌细胞诱导分化模型，借助原位杂交、免疫组化及细胞转录组测序等手段，研究PTCH1缺失对心肌细胞分化、凋亡和迁移等过程的影响，揭示PTCH1功能缺失导致心脏流出道发育障碍的分子机制；并利用高通量测序技术分析我国CHD患者PTCH1基因突变谱，探讨该基因作为分子标志物在CHD诊断中的应用价值。本项目将为CHD发病机制的阐明及分子诊断提供新的理论依据。

Congenital heart disease (CHD) is the most common birth defect in China, and pathogenic gene mutations are one of the major causing reasons. However, only a small proportion of CHD cases could be diagnosed and explained by using currently known gene mutations. Therefore, identifying novel CHD pathogenic genes and exploring their roles in CHD would be critical for early diagnosis and prevention of CHD. In our previous studies through high throughput sequencing of 300 CHD cases and mouse model validation, we have identified PTCH1 as a novel CHD pathogenic gene whose defects could cause outflow tract defects, but the underlying mechanism is unknown. In the present project, we will investigate the molecular basis that how defective PTCH1 affects cell differentiation, proliferation, apoptosis, and migration in heart outflow tract development thus leads to CHD phenotype by using in vitro cardiomyocyte differentiation model and PTCH1 knockout mice; we will also characterize the mutational spectrum of PTCH1 in Chinese CHD patients using high throughput sequencing. Our project would provide novel theoretical basis for pathogenesis and molecular diagnosis of CHD, which would help to improve early diagnosis and prevention of birth defects in China.