基因组拷贝数变异致听觉前庭功能异常的发生机制及干预研究

Genetic factors are the main causes of hearing impairment and vestibular dysfunction. At present, there are still some patients cannot identify the molecular causes. So, it may be the key to solve this problem to find the new pathogenic form of auditory vestibular genome, such as copy number (CNVs). Based on the large-scale genetic resource bank and our research about CNVs, through gene whole sequence capture (including exons and introns) and next generation sequencing, extending from single gene research model to genome model, this study is going to detect and identify the CNVs in auditory vestibular genome in a large sample. First, the analysis of SLC26A4 will be performed to identify the pathogenic CNVs in patients with the enlarged vestibular aqueduct syndrome. Then, it will be extended to study the molecular epidemiology of CNVs in relevant genome for the patients with unknown etiology and obvious phenotypic characteristics of the auditory vestibular disease, to study the CNVs molecular epidemiology of auditory vestibular genome, and draw the detailed CNVs mutation spectrum. Through the auditory vestibular genomic structure analysis to explore the mechanism of CNVs and regional laws, through the construction of animal model and the function research to study the pathogenic mechanisms, through the break point analysis and statistical copy number coefficient to establish the intervention strategies.

遗传因素是导致听觉前庭功能障碍的主要病因，目前仍有相当比例患者分子病因不明，鉴定听觉前庭基因组致病拷贝数变异（CNVs）可能是提高分子确诊率的关键之一。本课题以前期建立的16456例听觉前庭疾病遗传资源库为基础，利用基因全序列（外显子和内含子）捕获、二代测序技术，由单基因研究模式拓展至基因组研究模式，在大样本中实现听觉前庭基因组CNVs的检测及鉴定。课题首先对不能明确分子病因的大前庭水管综合征病例进行SLC26A4基因全序列检测，计算拷贝数系数分析断裂点，鉴定致病CNVs，总结其系统研究策略；进而推广至病因不明、表型特征明显的听觉前庭疾病患者群进行相关基因组分析，研究听觉前庭基因组CNVs分子流行病学，绘制详细的突变谱。对重要的CNVs构建模式动物并进行功能研究，通过基因组结构区域分析探索CNVs发生机制，全面阐述中国人群听觉前庭基因组CNVs致病机制并建立预防干预策略。

遗传因素是导致听觉前庭功能障碍的主要病因，目前仍有相当比例患者分子病因不明，鉴定听觉前庭基因组致病拷贝数变异（CNVs）可能是提高分子确诊率的关键之一。本课题以前期建立的16456例听觉前庭疾病遗传资源库为基础，利用基因全序列（外显子和内含子）捕获、二代测序技术，由单基因研究模式拓展至基因组研究模式，在大样本中实现听觉前庭基因组CNVs的检测及鉴定。课题首先对不能明确分子病因的大前庭水管综合征病例进行SLC26A4基因全序列检测，计算拷贝数系数分析断裂点，鉴定致病CNVs，总结其系统研究策略；进而推广至病因不明、表型特征明显的听觉前庭疾病患者群进行相关基因组分析，研究听觉前庭基因组CNVs分子流行病学，绘制详细的突变谱。对重要的CNVs构建模式动物并进行功能研究，通过基因组结构区域分析探索CNVs发生机制，全面阐述中国人群听觉前庭基因组CNVs致病机制并建立预防干预策略。

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