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

• 批准号: 8663586
• 负责人: MUSTAFA TEKIN
• 金额: $ 65.08万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8663586
• 关键词: Affect; Area; Biological; Biological Assay; Blood capillaries; Candidate Disease Gene; Characteristics; Child; Chromosome Mapping; Clinical; Clinical Data; Communication; Communities; Computer Simulation; Consanguinity; Country; Custom; DNA; Data; Defect; Detection; Diagnosis; Dideoxy Chain Termination DNA Sequencing; Disease; Exclusion; Exons; Family; Family Sizes; Future; Gene Pool; Genes; Genetic; Genetic Counseling; Genome; Genomics; Genotype; Goals; Hearing Impaired Persons; Human Genome; Inbreeding; Individual; Inherited; Knowledge; Lead; Left; Life; Link; Maps; Meleagris gallopavo; Molecular; Molecular Diagnostic Testing; Mutation; Outcome; Parents; Partner in relationship; Patients; Phenotype; Population; Prevention; Recording of previous events; Recruitment Activity; Research Personnel; Resources; Sampling; Sensorineural Hearing Loss; Sign Language; Stable Populations; Technology; Time; United States; Variant; autosomal recessive trait; base; capillary; deafness; empowered; exome; gene discovery; genetic linkage analysis; genetic pedigree; genome-wide; hearing impairment; improved; member; next generation; next generation sequencing; novel; repository; reproductive; screening

Project Summary: More than 60% of 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 abnormality. While causal mutations have been identified in one of 31 different genes in a subset of patients with non-syndromic autosomal recessive sensorineural hearing loss, at least 40% of families do not have an identifiable mutation nor do they demonstrate linkage to any known gene. Moreover, the distribution of recognized genetic causes in different populations as well as mutation specific phenotypes remains unknown. Recent advances in molecular technologies provide unprecedented opportunities to genotype dense arrays of SNP markers throughout the genome and to sequence large segments of the human genome with ease. Turkey provides a very valuable resource for the identification of new genes for deafness because it has been continually inhabited since ancient times and much of the population still lives in about 40,000 small villages throughout the country, where consanguinity is the cultural norm. There is also a high level of assortative mating among the deaf and a very long history of the use of sign language in specific areas of Turkey. All of these factors are known to have a profound influence on the survival, expression and spread of new mutations for deafness. We have ascertained 247 inbred multiplex Turkish families with autosomal recessive non-syndromic hearing loss. We will recruit >100 additional families with the same characteristics which will lead to creation of an excellent repository that can be used to identify many of the remaining genes for autosomal recessive non-syndromic deafness. After exclusion of common known genes, we will have ~150 families to discover and confirm new genes for deafness. We will use genome wide dense SNP arrays to find new loci for deafness and identify causative mutations with either traditional or next-generation sequencing. We have already discovered a new deafness gene in one family using the proposed strategy, clearly demonstrating the utility of this invaluable resource. The Repository will be made available to external investigators upon completion of this proposal.

项目摘要： 超过60％的初步耳聋的起源是遗传的，其中93％是单基染色体的 隐性特征。某些形式的遗传性耳聋可以通过其相关综合症特征来识别 但是在大多数情况下，听力损失是唯一的异常。虽然在其中一个中发现了因果突变 31个非综合常染色体隐性接触性听力损失的患者子集中的31种不同基因 至少有40％的家庭没有可识别的突变，也没有证明与任何已知的联系 基因。此外，在不同人群中公认的遗传原因的分布以及突变 具体表型仍然未知。分子技术的最新进展提供了前所未有的 整个基因组中基因型密集的SNP标记阵列的机会，并对大序列进行序列 人类基因组的段轻松。土耳其为识别提供了非常宝贵的资源 新基因的耳聋基因，因为它从远古时代开始一直居住 人口仍然生活在全国大约40,000个小村庄中 规范。聋人之间还有高水平的交配，并且使用符号的历史很长 土耳其特定领域的语言。所有这些因素都对 新突变的生存，表达和聋哑的传播。我们已经确定了247个近近近百货 具有常染色体隐性非混合性听力损失的土耳其家庭。我们将招募>另外100个家庭 具有相同的特征，这将导致创建出色的存储库，可用于识别 常染色体隐性非综合性耳聋的剩余基因。排除共同 已知的基因，我们将拥有约150个家庭来发现并确认新基因的耳聋。我们将使用基因组 宽阔的SNP阵列可找到新的基因座，并以传统或 下一代测序。我们已经在一个家庭中发现了一个新的耳聋基因 拟议的策略清楚地证明了这一宝贵资源的实用性。存储库将制作 该提案完成后，外部调查人员可用于外部调查人员。