A Collaborative Search for New Genes for Non-Syndromic Deafness

合作寻找非综合征性耳聋的新基因

基本信息

批准号：
10396975
负责人：
MUSTAFA TEKIN
金额：
$ 64.43万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10396975
关键词：
ATAC-seq Affect Bioinformatics Biological Birth CRISPR interference CRISPR/Cas technology Candidate Disease Gene Cell physiology Cells Child Chromatin Chromosome 8 Clinic Clinical Data Clinical Management Cochlea Code Consanguinity Counseling DNA Data Databases Diagnosis Enhancers Etiology FRAP1 gene Family Foundations Functional disorder Gene Expression Genes Genetic Genetic Counseling Genetic Transcription Genomics Goals Hearing Human Human Cell Line In Vitro Inbreeding Individual Infant Integral Membrane Protein International Knock-in Mouse Knock-out Knowledge Link Mediating Modeling Molecular Molecular Diagnosis Molecular Diagnostic Testing Morphology Mus Mutant Strains Mice Mutate Mutation Newborn Infant Nucleic Acid Regulatory Sequences Outcome Parents Pathway interactions Persons Pharmaceutical Preparations Phenotype Population Principal Investigator Regulatory Element Research Personnel Role Sampling Signal Transduction Site Syndrome Testing Therapeutic Therapeutic Intervention Time Translating Universities Untranslated RNA Variant analysis pipeline autosomal recessive trait base causal variant clinical translation clinically significant deaf deafness diagnostic tool exome sequencing experimental study gene discovery gene therapy genetic deafness genetic testing genetic variant genome analysis genome sequencing growth differentiation factor 6 hearing impairment improved in vitro Model loss of function member molecular diagnostics mouse genome mouse model mutant normal hearing notch protein novel precursor cell programs progressive hearing loss repository reproductive single-cell RNA sequencing standard of care success

项目摘要

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

项目主任/首席研究员（最后、第一、中间）：项目概要每 1,000 名婴儿中至少有 1.9 名婴儿在出生时出现具有临床意义的听力损失，影响了近一半的婴儿。他们生命中某个时期的人口。近 70% 的先天性或语前性耳聋是遗传性的，并且其中高达 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其相关症状特征可识别，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者中未检测到患有常染色体隐性遗传性 NSHL 的个体，导致大量家庭无法进行分子诊断。我们建立了一个存储库，其中包含约三千个家庭的生物样本和临床数据与 NSHL。其中，超过一千人包括至少两名受影响的成员，并且与常染色体隐性遗传性非霍奇金淋巴瘤。所有家庭均排除了最常见的 NSHL 形式；众所周知超过四百个家族的耳聋基因被排除。我们将使用基因组测序来识别常染色体隐性遗传 NSHL 家族中的潜在编码和非编码变异尚未解决我们的存储库。大量近交系的可用性将有助于自合子内的分析地区。为了支持已识别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。我们已经成功应用这一策略来发现新的耳聋该应用程序的先前周期中的基因。检测到的变异和相关的音频前庭表型将存储在外部研究人员可以访问的数据库中。这样做的结果该提案将发现涉及基因和通路的新编码和非编码变体耳聋的病理生理学、病因诊断、咨询和分子诊断测试的基础对受影响个体进行分子治疗的候选资格。 OMB 编号 0925-0001/0002（修订版 08/12 已批准至 8/31/2015）页面延续格式页面