低频/罕见变异在非综合征型唇腭裂发病中的作用研究

非综合征型唇腭裂（NSCL/P）严重影响人类身心健康，由遗传、环境因素共同作用所导致。既往研究发现低频/罕见遗传变异与NSCL/P发病相关。然而，它们（包括基因-基因、基因-环境交互作用）在中国人群NSCL/P发病中的作用仍不清楚。本课题组前期在150对NSCL/P病例和对照的全外显子测序中发现多个与NSCL/P发病相关的低频/罕见遗传变异和基因。接下来，本研究拟：1、采用靶向捕获测序技术在大样本病例-对照和核心家系中进行验证；2、利用流行病学资料和UPLC-MS/MS筛选与NSCL/P发病相关的外环境暴露因素和内环境代谢标志物；3、分析基因-基因、基因-环境交互作用，建立NSCL/P发病风险预测模型，并在大样本的出生队列人群中进行验证；4、对相关位点和基因运用细胞、斑马鱼或小鼠进行功能学研究。本研究旨在揭示低频/罕见遗传变异在中国人群NSCL/P发病中的作用，为其防控提供更多依据。

Non-syndromic cleft lip and palate (NSCL/P) seriously affects human physical and mental health, which is caused by the common effects of genetic and environmental factors. Several studies confirmed that low/rare frequency genetic variants were associated with NSCL/P. However, the role of low/rare frequency genetic variants and its interaction with the environment in the pathogenesis of NSCL/P in Chinese population remains unclear. In our previous study, several low-frequency/rare genetic mutations and genes associated with NSCL/P pathogenesis were found in the whole exon sequencing of 150 NSCL/P cases and 150 controls. Therefore, this study intends to: 1.use target sequencing technology in a large sample of case-control and nuclear family to validate low/rare frequency genetic variants; 2.identify relevant internal and external environmental factors based on UPLC-MS/MS and epidemiological data; 3.evaluate gene-gene and gene-environment interaction, establish the risk prediction model of NSCL/P and test it in a large sample of birth cohort; 4. perform functional studies on variants and genes by experiments in cells, mice or zebrafish. The purpose of this study is to reveal the role of low/rare frequency genetic variants in the development of NSCL/P among Chinese populations, and to provide more evidence for its prevention and control.