中国汉族与世界多种族及地区遗传性耳聋人群致病基因差异性分析研究

Recent advances in the molecular genetics of deafness have vastly improved our ability to identify heritable hearing losses. We have collected a large cohort of probands/families with HHL including a collection of 1297of genetic deafness China Han, South Africa, Nigeria, Tunisia, India, Iran and other ethnic areas (Hearing, loss, HL) through an international collaborative team, established the Miami Otogenetic clinic and research platforms. These interesting preliminary results have thus led us to continue identification of novel genes for deafness and to fully investigate the molecular mechanisms underlying HHL. In this competitive renewal, we will build on these accomplishments and.preliminary data by completing the following specific aims: 1) To screen for known deafness genes using the University of Miami MiamiOt-oGenes panel, analysis of different races, regions of deafness gene responsible and to determine the genetic differences between China deafness and other races. 2) to identify novel deafness-causing genes by performing targeted capture and massively parallel sequen cing of whole exomes (WES) using targeted sequence capture platforms and/or whole exome/genome analysis followed by massively parallel sequencing and data analysis using a customized local pipeline platform. 3) to determine functional consequences of deafness genes with in vitro and in vivo models using innovative approaches. We will perform in vitro studies and animal models for HHL genes identified in our study. Generating these in vitro and in vivo models and linking newly identified genes to cellular pathways and pathophysiology is a necessary step towards developing targeted intervention strategies for deafness. Completion of the proposed aims will not only change the clinical evaluation of deaf and hard-of-hearing persons by making genetic testing an integral piece of the diagnostic evaluation, but will also increase our understanding of the biology of hearing and deafness.

耳聋是常见致残性疾病，是全球重大社会公共问题。初步研究表明世界上不同种族、地区的耳聋致病基因存在差异，仍有大量未知基因有待鉴定。本研究通过国际耳聋家系收集网络，收集了1297个包括中国汉族等世界多种族、地区的遗传性耳聋(Hearing loss，HL)家系，依照不同人种来源分为亚洲黄种人、欧洲白种人、非洲黑色人种及印第安土著人。本项目将在前期家系收集工作及研究的基础上，从已收集的多个种族及地区的遗传性家系中遴选出100个耳聋家系，采用MiamiOtoGenes二代测序试剂盒检测；检测阴性家系采用全外显子测序技术以寻找新的耳聋基因，并对新基因进行功能研究验证其致病性；将各种族的耳聋家系结果汇总分析，探寻中国人群遗传性耳聋致病基因与世界其他种族及地区遗传性耳聋致病基因的异同点，为进一步建立针对中国人群遗传性耳聋诊断技术平台提供重要依据，达到精准医学的精准遗传咨询和精准基因诊断的目的。

耳聋是常见致残性疾病，是全球重大社会公共问题。初步研究表明世界上不同种族、地区的耳聋致病基因存在差异，仍有大量未知基因有待鉴定。.本研究前期通过国际耳聋家系收集网络，收集了1297个包括中国汉族等世界多种族、地区的遗传性耳聋家系。我们首先对前期收集的家系进行已知耳聋基因的突变检测。对检测阴性家系采用我们团队自主研发的“梯级遗传分析法”鉴定新基因，目前已克隆4个耳聋新基因（TMEM43、ABCC1、ELMOD3和PDE1C），是国内克隆耳聋新致病基因最多的团队。并在此基础上，我们通过转基因小鼠模型和细胞模型对这些耳聋新基因进行功能研究验证其致病性。我们提出内耳中发挥外排功能的ABCC1这类蛋白可导致耳聋；TMEM43基因突变可导致听神经病，但其表达在支持细胞，并不直接作用于听觉通路，但是其与CX26和CX30蛋白互作。我们还首次发现ELMOD3基因可以导致常染色体显性耳聋，并通过Elmod3基因敲除小鼠模型，发现该基因缺失在小鼠中同样会引起耳聋。以及首次发现PDE1C基因导致常染色体显性耳聋。.在耳聋家系已知基因鉴定方面：在非综合征耳聋家系中发现TMC1、MYO6、SMPX、P2RX2、DFNA5等耳聋基因的新突变，关于综合征耳聋家系基因鉴定，对收集到的脆骨症、腮耳肾综合征等多种类型家系发现已知基因的新突变。.我们还获得国家发明专利授权1项：新的综合性耳聋相关基因突变检测体系及试剂盒。该试剂盒是针对不同耳聋基因的检测试剂盒，其临床应用将在全国范围内针对特殊耳聋高发群体的基因诊断，用于建立系统的先天性耳聋基因诊断、产前诊断、新生儿听力筛查和干预治疗体系。.培养博士后1人，博士研究生10人，硕士研究生1人。.总体而言，我们对中国与世界其他种族及地区的耳聋致病基因异同点进行总结，为进一步建立针对中国人群遗传性耳聋诊断技术平台提供重要依据。

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