基于核心家系的全外显子测序鉴定遗传性多发性骨软骨瘤新致病基因

项目名称： 基于核心家系的全外显子测序鉴定遗传性多发性骨软骨瘤新致病基因

项目编号： No.81201353

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 医学四处

项目作者： 王剑

作者单位： 上海交通大学

项目金额： 23万元

中文摘要： 遗传性多发性骨软骨瘤（HME）是一种常染色体显性遗传性骨骼发育异常疾病，属于良性骨肿瘤，但部分患者可恶变为软骨肉瘤。课题组前期建立了已知致病基因EXT1、EXT2的基因突变筛查方法，并成功应用于临床检测。但仍约有9%（4/45）的HME家系在已知致病基因中未找到病理性基因突变位点，提示可能存在新的致病基因。本项目拟以EXT1、EXT2基因突变筛查阴性的HME家系为研究对象，利用序列捕获技术将全基因组外显子区域DNA捕捉、富集后运用Illumina Hiseq测序平台进行高通量测序，并采用基于核心家系的生物信息学分析方法发掘和鉴定新致病基因。从而发现新的检测靶点，进一步完善HME的基因诊断方法。本研究将为HME的分子诊断和遗传咨询提供实验依据，并为进一步阐明分子发病机制及治疗药物的研发奠定基础。

中文关键词： 遗传性多发性骨软骨瘤；致病基因；全外显子组测序；TBXAS1基因；突变

英文摘要： One of the most common hereditary skeletal dysplasias, hereditary multiple exostoses (HME), is an autosomal dominant disorder characterized by the growth of cartilage-capped benign bone tumours around areas of active bone growth. A person with HME has an increased risk of developing a rare form of bone cancer called chondrosarcoma as an adult. In a previous study we developed a method to detect known pathogenic gene (EXT1、EXT2) mutations in HME, and successfully used this in clinical genetic testing. However, these mutations were not detected in approximately 9% (4/45) pedigrees with HME. The results suggested that unknown novel pathogenic gene(s) may be associated with HME. In this study, we will select HME pedigrees with negative EXT1 and EXT2 mutations. We intend to capture and sequence all the coding regions with Agilent SureSelect Human All Exon Kit and Illumina Hiseq sequencing platform. Sequencing data will be analyzed using NextGENe, GATK software and a variety of bioinformatic programs will be used to evaluate the functional significance of identified variants, followed by evaluation of clinical significance according to the phenotypes of family members. The potential list of novel HME genes will be further verified in the other family members and 200 controls, hoping to eventually identify true novel

英文关键词： hereditary multiple exostoses；pathogenic gene；whole exome sequencing；TBXAS1 gene；mutation