A Collaborative Search for New Genes for Non-Syndromic Deafness

项目负责人/主要研究者（最后一名、第一名、中间名）： 项目摘要 每1，000名婴儿中至少有1.9名在出生时就患有临床上显著的听力损失， 在他们生命中的某个时刻。近70%的先天性或语前耳聋是遗传性的， 其中高达93%是单基因常染色体隐性性状。某些形式的遗传性耳聋可能是 通过其相关的综合征特征识别，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未被检测到 常染色体隐性遗传NSHL的个体，留下大量的家庭没有分子诊断。 我们建立了一个储存库，其中包含约3000个家庭的生物样本和临床数据 关于NSHL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NSHL。最常见的NSHL形式已被排除在所有家庭;所有已知的 在400多个家系中排除了耳聋基因。我们将使用基因组测序来识别 常染色体隐性NSHL家族中的潜在编码和非编码变异， 我们的仓库。大量近交系的可用性将有助于分析纯合子中的 地区为了支持已鉴定的变异体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。我们已经成功地应用这种策略来发现新的耳聋 基因在本申请的前几个周期中。检测到的变体和相关的听觉-前庭 表型将储存在一个数据库中，外部研究人员可以访问。这个结果 这项提案将是发现新的编码和非编码变异的基因和途径，涉及 耳聋的病理生理学，病因诊断的分子诊断测试的基础，咨询， 受影响个体的分子治疗的候选人资格。 OMB编号0925-0001/0002（2012年8月批准至2015年8月31日修订版）页码续页格式页码

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