16p11.2微缺失是一种再发性、致儿童精神发育异常的基因组微失衡。携带者具有高度精神发育表型异质性，原因不明。国外和我们前期的研究提示16p11.2区域外的精神发育相关基因变异、16p11.2区域内精神发育相关基因的半合子型（比如KCTD13基因单体型）可能是16p11.2微缺失的表型修饰基因，但以上研究需要更多16p11.2微缺失携带者进行验证。本项目建立16p11.2微缺失携带者队列，根据详尽精神发育问卷进行分组评分，根据携带者类型（家族性和散发，患者和对照）开展全基因组测序、神经干细胞系的RNA-Seq、16p11.2区域重测序，系统遗传学方法寻找参与携带者精神发育的修饰基因型，然后在体外瞬时表达系统，携带者iPS细胞分化形成的神经干细胞中开展功能研究，验证16p11.2微缺失联合某修饰基因型对神经干细胞形态和发育的作用，明确16p11.2微缺失致病的的遗传、神经生理基础。

As a recurrent CNV, 16p11.2 microdeletion is recognized as improtant pathogenic risk for children's neuro-developmental disorders. The observation of high heterogeneity of neuro-developmental phenotypes in 16p11.2 microdeletion implied other modifier genes co-exist. But the potential genetic mechanism is unknown yet. Previous study and our preliminary result suggested that either the genomic/genic variant ourside 16p11.2 region, or the the founder hemizygous genic variant (such as KCTD13 haplotype) inside 16p11.2 region could contribute to the phenotypic heterogeneity of 16p11.2 microdeletion. Above hypothesis needs a 16p11.2 carrier cohort to validate. In this project, we will recruit carriers and perform whole 16p11.2 target sequencing, whole genome sequencing and RNA-Seq on neural progenitor cells (NPc) for these 16p11.2 carriers according their categories (sporadic or familiar, case or control), to distinguish the modifier genes of neuo-developmental phenotype using the systemic genetics analysis. The function experiment will designed in the in vitro transient expression cells and the 16p11.2 NPc which is differentiated from the carriers' induced pluripotent stem cells, to confirm the morphological and developmental character of NPc due to 16p11.2 deletion and particular modifier genotype. The aim of our project is to illuminate the genetic and neurophysical basis of 16p11.2 deletion involved in neuro-developmental disorders.