中国一万例耳聋样本大规模平行测序数据分析及三个新致聋基因的鉴定与致病机理研究

The prevention and cost-effective treatment of sensorineural hearing loss has been unrealized for many years in otorhinolaryngology clinic. China hosts the most massive deaf population in the world. The effective strategy of diminishing the incidence of sensorineural hearing loss is to reduce the birth defect of hearing loss based on the accurate and reliable prenatal diagnosis and genetic counseling. The identification of the genes underlying hereditary hearing loss and to decipher its pathological mechanism will provide accurate molecular targets for the clinical genetic diagnosis of hearing loss. In the previous study, our group has collaborated with other groups of Chinese Hearing Loss Genetic Consortium (CHLGC), finishing the sample collection of 16052 cases with hearing loss from 28 provinces and autonomous regions nationwide. We have completed the massively parallel sequencing (MPS) of 620 genes potentially related to hearing loss in 10000 cases with hearing loss （pre-excluded GJB2 and SLC26A4 positive cases）. This project is designed to carry out the bioinformatics analysis of MPS big data to establish a large genetic variation database of 620 genes potentially related to hearing loss in 16,052 Chinese cases with hearing loss. We will conduct the comprehensive functional study for the newly identified WYF1, DFNB105 and DFNB109 to clarify their important roles in the development of the auditory mechanisms and to decipher the pathological mechanism. The aim of this project is to provide reliable methods for clinical genetic diagnosis and biological treatment for these types of hearing loss.

感音神经性耳聋的有效预防和低成本治疗是耳鼻咽喉科多年未解的临床难题。我国拥有世界上最为庞大的耳聋人群，降低耳聋发病率最有效的策略是基于准确可靠的产前诊断控制耳聋患儿的出生，耳聋致病基因和发病机制研究可为临床耳聋基因诊断提供准确的分子靶标。在前期工作中，本课题组与“中国遗传性耳聋基因研究战略联盟”各研究团队合作，在全国二十八个省市自治区采集了16052例耳聋样本，完成了一万例耳聋样本（已排除GJB2和SLC26A4突变致聋）620个潜在的耳聋相关基因大规模平行测序（MPS）。本申请项目拟对所产生的MPS大数据进行系统地生物信息学分析和验证，绘制16052例耳聋样本的遗传变异图谱，并就发现的一个DFNA和二个DFNB候选新致聋基因在蛋白水平、细胞水平及果蝇、斑马鱼、小鼠等模式动物水平开展深入的功能研究，系统阐述候选新基因的致聋机制，为三型耳聋的临床基因诊断和生物学治疗奠定基础。

遗传性耳聋为全球高发的出生缺陷，感音神经性耳聋的有效预防和低成本治疗是耳鼻咽喉科多年未解的临床难题。我国拥有世界上最为庞大的耳聋人群，降低耳聋发病率最有效的策略是基于准确可靠的产前诊断控制耳聋患儿的出生，耳聋致病基因和发病机制研究可为临床耳聋基因诊断提供准确的分子靶标。依托我国丰富的遗传资源，本团队联合国内听觉研究领域的50多个基础研究及临床专业团队采集了覆盖中国大陆地区31个省市自治区42个民族的两万多例耳聋样本，基于中国全地域多民族的遗传性耳聋病例基因检测，汇集生物信息、遗传诊断和分子遗传学研究力量，完成了从测序数据分析、变异鉴定注释到基因诊断遗传咨询等工作，为一万多个耳聋家庭明确了分子病因。基于CDGC海量数据资源，系统开发了国际上最大的耳聋遗传变异数据库（http://cdgc.eargene.org/），开发了国际上首个耳聋基因变异功能预测模型（DVPred），研发了遗传变异致病证据注释和解读支持系统（DVInt），提出了隐性基因型网络模型等原创算法及全新的致病性判断证据法则，为国内外耳聋临床和基础科研团队的研究及临床实践提供了大型专病数据库知识库支持。在新基因功能研究方面，我们发现slc4a2b功能的丧失导致斑马鱼神经母细胞中毛细胞凋亡增加数量减少，slc4a2b在斑马鱼HCs的发育中起着关键作用。本研究构建了DFNB105基因敲除果蝇幼虫模型，电生理检测提示有明确的听觉功能异常。通过系统阐述候选新基因的致聋机制，为遗传性耳聋的临床基因诊断和生物学治疗奠定了基础。