A Collaborative search for new genes for non-syndromic deafness

描述（申请人提供）：超过60%的语前聋是遗传性的，其中高达93%是单基因常染色体隐性遗传。某些形式的遗传性耳聋可以通过其相关的综合征特征来识别，但在大多数情况下，听力损失是唯一的异常。虽然在非综合征型常染色体隐性性感音神经性听力损失患者的一个子集中，已在31个不同基因中的一个中鉴定出因果突变，但至少40%的家庭没有可鉴定的突变，也没有证明与任何已知基因的联系。此外，不同人群中公认的遗传原因的分布以及突变特异性表型仍然未知。分子技术的最新进展为在整个基因组中对SNP标记的密集阵列进行基因分型以及轻松地对人类基因组的大片段进行测序提供了前所未有的机会。土耳其为鉴定耳聋的新基因提供了非常宝贵的资源，因为土耳其自古以来就有人居住，大部分人口仍然生活在全国约40 000个小村庄中，在那里，血缘关系是文化规范。在土耳其的一些特定地区，聋人之间也有很高程度的自愿性交配，使用手语的历史也很长。所有这些因素都对耳聋新突变的生存、表达和传播有着深远的影响。我们已经确定了247个常染色体隐性遗传非综合征性听力损失的近交系多重土耳其家庭。我们将招募超过100个具有相同特征的额外家族，这将导致创建一个优秀的库，可用于识别常染色体隐性遗传非综合征性耳聋的许多剩余基因。在排除常见的已知基因后，我们将有大约150个家庭发现和确认新的耳聋基因。我们将使用全基因组密集SNP阵列来寻找耳聋的新位点，并通过传统或下一代测序来鉴定致病突变。我们已经在一个家庭中发现了一个新的耳聋基因，使用所提出的策略，清楚地表明了这种宝贵资源的效用。在完成本提案后，将向外部调查人员提供储存库。 公共卫生相关性：该项目是一项涉及美国和土耳其调查人员的遗传性耳聋合作研究。该项目的目标是确定非综合征性耳聋的新基因位点和新基因，并建立遗传性耳聋研究资源，包括土耳其大量家庭的生物样本和临床数据。这项提案的结果将扩大遗传性耳聋基因组基础的科学知识。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This project is a collaborative study of genetic deafness involving investigators from the United States and Turkey. The goals of the project are to identify new loci and new genes for non-syndromic deafness and to establish a resource for research on genetic deafness including biological samples and clinical data from large numbers of families in Turkey. The outcome of this proposal will expand the scientific knowledge on the genomic basis of hereditary deafness.