先天性脊柱侧凸高致病性拷贝数变异的发现及机制研究

Congenital scoliosis (CS) is a severe congenital malformation of spine. Some CS patients are accompanied with multi-systemic abnormal, which not only cause psychophysical problems but also bring high burden to families and society. Due to lack of early prediction methods, most patients were found in their late phase. Therefore, it is important to develop new diagnostic method and therapeutic target. Based on previous study, we found the surprising phenomenon that some highly causative copy number variations (CNV) existed in sporadic CS patients. Furthermore, we hypothesized that 'In the early development of embryo, some somatic related CNVs may contribute to the occurrence of CS'. In this project, we plan to identify de novo CNVs of CS patients in whole genome region using array-based comparative genomes hybridization with the strategy of trio pedigrees combining with sporadic cases. And the pathogenicity of these CNVs will be confirmed by case-control study， cellular functional study and zebrafish model genome-edited a CRISPR-Cas9 system. This will certainly provide theoretical foundation of genetic and biomolecular etiology for CS, and new clinical/genetics typing system will also be explored.

先天性脊柱侧凸（Congenital Scoliosis，CS）是一种严重致残性疾病，可伴多系统异常，导致严重的身体和心理问题，给家庭和社会造成极大负担。因缺乏早期预测手段，CS多在出现脊柱畸形才被发现，因而探索早期诊断方法和病因治疗靶点是当前 CS 的研究热点。在前期研究基础上，课题组发现了散发CS患者存在高致病性CNV这一独特现象，并由此提出"在胚胎发育时期，某些与体节发育相关的拷贝数变异（CNV）可能导致CS发病"这一科学假说。本项目拟采用微阵列比较基因组杂交技术，通过核心家系结合散发病例的研究策略，在全基因组水平检测与CS相关CNV，并通过大样本人群验证、细胞功能试验以及基于CRISPR/Cas9基因编辑技术建立的动物模型验证其致病性及可能机制，为预测疾病发展和指导临床早期干预时机提供理论依据。

先天性脊柱侧凸（Congenital Scoliosis，CS）是一种严重致残性疾病，可伴多系统异常，导致严重的身体和心理问题，给家庭和社会造成极大负担。因缺乏早期预测手段，CS多在出现脊柱畸形才被发现，因而探索早期诊断方法和病因治疗靶点是当前CS的研究热点。在前期研究基础上，课题组发现了散发CS患者存在高致病性CNV这一独特现象，并由此提出"在胚胎发育时期，某些与体节发育相关的拷贝数变异（CNV）可能导致CS发病"这一科学假说。本项目采用了微阵列比较基因组杂交技术，通过核心家系结合散发病例的研究策略，在全基因组水平检测与CS相关的CNV，并通过大样本人群验证、细胞功能试验以及基于CRISPR/Cas9基因编辑技术建立的TBX6 KO的小鼠模型动物模型来验证其致病性及探究可能机制，为预测疾病发展和指导临床早期干预时机提供理论依据。探索新的CS临床/遗传学分型，探寻CS的个体化早期诊断和治疗措施。