OAVS致病基因鉴定及其生物学作用网络构建

眼-耳-脊柱序列征（OAVS）是临床较为常见的出生缺陷，其遗传基础已被公认，但致病基因远未明确。课题组目前已收集816例OAVS样本，其中包括罕见的多患者家系，是非常珍贵的遗传资源。前期研究积累了210例OAVS患者的外显子组测序数据，并通过综合分析和动物模型锁定FOXI3为OAVS的致病基因之一。基于OAVS的高度异质性，本项目拟以FOXI3为线索，通过差异表达分析、神经嵴细胞迁移/增殖实验、蛋白质相互作用研究、基因双敲小鼠模型等明确FOXI3的致病机制及其调控的下游基因；然后以FOXI3的下游基因为对象，通过高级生物信息学分析，在OAVS患者外显子组测序数据库中搜寻新的候选致病基因，并进行相应功能研究以验证。通过如此系统地研究，有望鉴定多个OAVS致病基因并构建其生物学作用网络，可为阐明OAVS的发病机制及建立其防治方法奠定基础。

Oculo-auriculo-vertebral spectrum (OAVS) is one of common birth defects. So far, it has been confirmed that OAVS is a genetic disease. However, the pathogenic genes of OAVS are far from clear. We have collected 816 cases of OAVS samples, including rare multi-patients families which are a very valuable for genetic studies. In the previous study, we have accumulated 210 cases exome sequencing data, and identified FOXI3 as one of the pathogenic genes of OAVS through comprehensive analysis and animal model study. Consider heterogeneity, we will clarify the pathogenic mechanism and downstream genes of FOXI3 through analysis of gene expression differences, neural crest cell migration/proliferation, protein-protein interactions, double knockout mouse model in this project. And then taking the downstream genes of FOXI3 as the subject, we will search new candidate genes for OAVS in exome sequencing data through advanced bioinformatics analysis and confirmed the function by cell and animal model studies. Depend on these studies, it is very promising to identify multiple pathogenic genes for OAVS and construct their biological action network, which will promote us to illuminate the pathogenesis of OAVS and lay the foundation for prenatal diagnosis of OAVS.