先天性心脏病（CHD）是最常见的出生缺陷之一，导致该病的原因多样化，而其发病的遗传机制并未完全明确。已知16p11.2微缺失可导致CHD，但前期研究显示，仅部分携带该缺失的胎儿会患CHD，其外显不全的分子机制尚不清楚。以往研究表明，基因组中的低频/罕见变异可调控16p11.2微缺失相关表型（如神经发育障碍表型）的外显率。因此，存在于16p11.2区域内或外的基因低频/罕见变异（单核苷酸变异/小片段插入或缺失），可能是CHD外显不全的重要调控因素。本项目拟采用全外显子组测序技术对携带16p11.2微缺失的CHD核心家系进行低频/罕见变异的筛选与鉴定，前期已在其中两个家系分别获得NCOR2和HDAC5基因新发的、罕见的有害变异，后续将在CHD病例-对照队列中进行目的基因的验证分析，以确定CHD候选基因。最后，在细胞模型和斑马鱼模型中进行候选基因功能学研究，初步阐述其调控CHD的分子机制。

Congenital heart disease (CHD) is one of the most common birth defects. Various causes are considered to lead to CHD, but the genetic mechanism of CHD remains unclear. It is known that 16p11.2 microdeletion can cause CHD, but previous studies have shown that only part of the fetus carrying the deletion will develop CHD, and the molecular mechanism of its incomplete penetrance is unclear. Previous studies have shown that low-frequency/rare variants in the genome can regulate the penetrance of 16p11.2 microdeletion-related phenotypes, such as the neurodevelopmental disorder phenotype. Therefore, low-frequency/rare variants of genes within or outside the 16p11.2 region may be an important regulatory factor for CHD incomplete penetrance. This project intends to use whole-exome sequencing to screen and identify low frequency/rare variants in CHD families carrying 16p11.2 microdeletion. Our previous research has identified two rare de-novo deleterious variants in NCOR2 and HDAC5, respectively. Subsequently, these two genes and/or other genes functionally related with CHD will be validated in CHD case-control cohorts for further determining candidate gene(s). Finally, functional studies of candidate genes will be performed in cell models and zebrafish models, and their molecular mechanisms for regulating CHD will be preliminarily explained.