利用外显子组测序技术识别房间隔缺损新基因

Congenital heart disease (CHD) is the most common birth defect. Atrial septal defects (ASD) is one of the major subtypes of CHD. ASD has high heritability, but few ASD-related genes have been identified. Our group has collected a ASD family in previous studies and ruled out eight known ASD-causing genes and two potentially related genes.On this basis, this study intends to screen out ASD-causing genes in this family, using the whole exome sequencing technology. Screened-out genes are then verified in a large sample of sporadic ASD cases to evaluate their contribution to the ASD development..This study is expected to identify new causal genes of ASD from the genome-wide level and thus lay groundwork for the description of ASD pathogenesis and early clinical diagnosis and treatment..

先天性心脏病（先心病）是我国围产期排首位的出生缺陷。房间隔缺损(atrial septal defects, ASD)，是先心病常见的几种主要亚型之一。ASD的遗传度较高；而目前已识别的ASD相关基因相对较少。本课题组在前期研究工作中收集了一个单纯性ASD家系，并排除了已知的8个ASD明确致病基因和2个潜在相关基因。.在此基础上，本研究计划利用全外显子组测序技术对该家系进行致病基因筛选。对筛选到的相关基因在散发ASD样本中进行验证，获得其对ASD发病的遗传贡献度。.本研究有望从全基因组水平识别和鉴定出ASD新致病基因，为阐述ASD发病机制和早期临床诊治提供支持。

房间隔缺损（ASD）是世界上最常见的心脏畸形之一。本研究在前期家系样本的基础上，识别鉴定房间隔缺损（ASDII）的致病基因。课题执行期内，我们通过全外显子组测序，初步识别鉴定了家系致病基因，LBX2基因。随后，通过CRISPR / Cas9技术敲除斑马鱼lbx2基因。通过对lbx2敲除斑马鱼的心房和心室进行染色，与野生型相比，纯合子中心肌细胞的不紧密分布现象更为严重；对crip2基因进行原位杂交，发现在纯合体中神经嵴细胞的迁移明显延迟。因此，我们认为LBX2为ASDII的潜在致病基因，可能通过影响神经嵴细胞的迁移及心脏分离的过程而引起心脏的异常发育。