神经管畸形是一组基因型和表型高度异质性的出生缺陷，致病基因不明。胚胎发育早期的神经上皮细胞具有极性，包括细胞平面极性(PCP)和顶底端极性(ABP)，这些细胞极性正常形成和维持是初级神经胚发育的基础。近来研究人员在人NTDs患者发现各种PCP基因罕见变异，证实PCP基因突变是人NTDs的遗传基础；我们前期研究发现ABP基因（PARD3）多态性和人NTDs相关，且在人NTD患者中发现ABP基因拷贝数变异。本项目利用二代测序技术对人NTDs患者开展ABP通路基因的高通量筛查，分析ABP基因罕见变异与人NTDs的相关性，获得人NTDs特异性ABP基因罕见变异的负荷量、变异图谱；利用293HEK细胞、极性细胞3D培养下体外过表达体系分析ABP基因变异细胞内核心ABP、PCP蛋白表达以及共定位和相互作用；利用慢病毒RNAi技术i建立ABP基因沉默鸡胚模型，分析ABP基因沉默后鸡胚发育表型、神经上皮形态学。

Neural tube defects (NTDs) are a group of birth defects with highly genotypic and phenotypic heterogeneity.Their pathogenic genes remain unknown.Epitheliuml cell has polarity in the early embrogenesis,including planner cell polarity (PCP) and apical basal polarity (ABP),which both play a key role in establishing and maintaining cell polarity and is required for normal primary neurulation development. Recently a variety of rare variants in PCP genes have been identifed in human NTDs,confirming mutations of PCP pathway are the genetic basis of human NTDs. Our previous studies have showed that the polymorphisms of ABP gene (PARD3) are related with human NTDs,and copy number variants of ABP genes were identifed in human NTDs. In this project, we will perform high-throughout variant screening of ABP genes in NTD case using next-generation sequencing technology (NGS). The association between rare variants of ABP genes and human NTDs, the genomic burden and spectrum of human NTD-specific rare genetic variant will be analyzed. Furthermore, in vitro overexpression in 293HEK cell and polar cells (MDCK cell) in 3D culture will be applied to study the co-localization, expression and interaction of core ABP/PCP proteins in mutated cell. RNAi lentiviral injection in chick ovo will be applied to explore the developmental phenotyps of chick embryo, the morphology of neurepithelium in ABP gene knocked-down chick embryo model.