脊髓血管畸形是导致青壮年严重残疾的一类神经系统疾病，与脑血管畸形一样被认为是一种先天性疾病，目前尚无其遗传背景的研究。我们前期研究中采用基于核心家系的全外显子测序和筛选策略，发现了新发突变基因CEACAM5和SETD6。迄今文献报道CEACAM5和SETD6均与肿瘤相关，前者可诱导血管新生，后者是细胞抗氧化应激的重要调节因子，这些也是血管畸形发生的关键机制。因此我们推测他们可能与脊髓血管畸形致病相关。本研究拟利用大样本的患者和健康对照队列对上述基因进行关联分析，以验证其与脊髓血管畸形的相关性；同时拟使用CEACAM5和SETD6突变患者的畸形团内皮细胞构建细胞模型，通过分析突变对mRNA和蛋白表达水平、内皮血管新生功能、抗氧化应激能力的影响，来阐明CEACAM5和SETD6介导脊髓血管畸形发生的机制，将为研究血管畸形提供新思路。

Spinal arteriovenous malformation (SAVM) is a complicated sort of neurological disease that causes severe disability in young adults, which is considered as a congenital disease as well as cerebral arteriovenous malformation. As a sporadic disease, there is no genetic study of this disease yet. Based on the whole exon sequencing and screening strategy of the core families, the de novo mutant genes CEACAM5 and SETD6 were found in our previous study. According to the literatures reported before, both of them were associated with tumor. The CEACAM5 has ability to induce angiogenesis and the SETD6 is an important regulator of cell antioxidation. The biological functions of CEACAM5 and SETD6 are also the key mechanisms for the development of vascular malformation. We thus speculate that the CEACAM5 and SETD6 may be associated with the onset of SAVM. In this study, a larger number of patients and paired control subjects will be sequenced to establish the association between the mutations of CEACAM5 and SETD6 and the SAVM. In addition, the endothelial cells will be primarily cultured from patients with the mutations of CEACAM5 and SETD6 as the in vitro experimental model. Using these cultured cells, the mechanism of CEACAM5 and SETD6 in regulating the pathogenesis of SAVM will be elucidated by determining the expression level of mRNA and protein, the endothelial cell proliferation, migration and VEGF reaction, the ROS and oxidative damage effect markers. The current investigation will fill the gaps between CEACAM5 and SETD6 mutation and SAVM, which provides insights into the mechanisms of SAVM for combating the disease.