A Collaborative Search for New Genes for Non-Syndromic Deafness

项目总监/首席调查员(最后、第一、中间)： 项目摘要 在出生时，每1000名婴儿中至少有1.9人出现临床上显著的听力损失，并影响到近一半的 人口在他们生命中的某个时候。近70%的先天性或语前聋是遗传性耳聋， 其中高达93%为单基因常染色体隐性性状。某些形式的遗传性耳聋可能是 但在大多数情况下，听力损失是唯一的发现(NSHL)。 目前公认的耳聋基因中的DNA变异在超过三分之一的受影响人群中没有检测到 患有常染色体隐性遗传性非霍奇金淋巴瘤的个体，使得大量家庭没有分子诊断。 我们建立了一个储存库，其中包含了大约3000个家庭的生物样本和临床数据 与NSHL合作。其中，超过1000人包括至少两名受影响的成员，并符合 常染色体隐性遗传NSHL。最常见的非霍奇金淋巴瘤在所有家庭中都被排除在外；都知道 在400多个家庭中排除了耳聋基因。我们将使用基因组测序来识别 常染色体隐性遗传性NSHL家系中未解决的潜在编码和非编码变体 我们的储存库。大量近交系的可获得性将有助于在纯合子内进行分析 地区。为了支持已确定的变异在病理生理学中的作用，我们将进行功能实验 利用体外和小鼠模型。我们已经成功地将这一策略应用于发现新的耳聋 基因在这一应用的前几个周期中。检测到的变异和相关的音频-前庭 表型将被存储在一个外部研究人员可以访问的数据库中。这样做的结果是 提案将是在基因和途径中发现新的编码和非编码变体 耳聋的病理生理学，病因诊断的分子诊断试验的基础，咨询，和 对受影响个体进行分子治疗的候选资格。 OMB编号0925-0001/0002(08/12版批准至2015年8月31日)页面续格式页面

Program Director/Principal Investigator (Last, First, Middle): Project Summary Clinically significant hearing loss is present in at least 1.9 per 1,000 infants at birth and affects nearly half of the population at some time in their lives. Nearly 70% of congenital or prelingual deafness is genetic in origin, and of these up to 93% are monogenic autosomal recessive traits. Some forms of genetic deafness can be recognized by their associated syndromic features, but in most cases, hearing loss is the only finding (NSHL). DNA variants in currently recognized deafness genes are not detected in more than one-third of affected individuals with autosomal recessive NSHL, leaving large number of families without a molecular diagnosis. We established a repository that contains biological samples and clinical data on about three thousand families with NSHL. Of these, over a thousand include at least two affected members and are consistent with autosomal recessive NSHL. The most common forms of NSHL have been excluded in all families; all known deafness genes were excluded in over four hundred families. We will use genome sequencing to identify underlying coding and non-coding variants in families with autosomal recessive NSHL that remain unsolved in our Repository. Availability of a large number of inbred families will facilitate analysis within autozygous regions. To support the role of identified variants in pathophysiology, we will perform functional experiments utilizing in vitro and mouse models. We have successfully applied this strategy to discover novel deafness genes during the previous cycles of this application. Detected variants and associated audio-vestibular phenotypes will be stored in a database that will be accessible by outside researchers. The outcomes of this proposal will be discoveries of novel coding and non-coding variants in genes and pathways involved in the pathophysiology of deafness, foundation of molecular diagnostic tests for etiological diagnosis, counseling, and candidacy for molecular treatments of affected individuals. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page