A Collaborative search for new genes for non-syndromic deafness

项目总结： 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 隐性性状。某些形式的遗传性耳聋可以通过其相关的症状特征来识别， 但在大多数情况下，听力损失是唯一的异常。虽然已经在其中一种情况下发现了因果突变 非综合征型常染色体隐性遗传性感音神经性聋患者亚群中的31个不同基因， 至少40%的家庭没有可识别的突变，也没有表现出与任何已知的连锁 吉恩。此外，公认的遗传原因在不同人群中的分布以及突变 具体的表型尚不清楚。分子技术的最新进展提供了前所未有的 在整个基因组中对密集的SNP标记阵列进行基因分型和对大片段进行测序的机会 轻松获得人类基因组的片段。土耳其提供了非常宝贵的资源来确定 耳聋的新基因，因为它自古以来就一直存在，而且许多 人口仍然生活在全国大约40,000个小村庄里，那里的血缘关系是文化 诺曼。聋人之间也有很高的分类交配水平，使用手势的历史也很长 土耳其特定地区的语言。众所周知，所有这些因素都对 耳聋新突变的存活、表达和传播。我们已经确定了247个近亲交配的复合体 常染色体隐性遗传性非综合征性耳聋土耳其家系。我们将再招募100个家庭 具有相同的特征，这将导致创建一个优秀的存储库，可用于识别 常染色体隐性遗传性非综合征性耳聋的许多剩余基因。在排除公共后 在已知基因的情况下，我们将有大约150个家庭来发现和确认新的耳聋基因。我们将使用基因组 广泛密集的SNP阵列，寻找耳聋的新基因座，并识别与传统或 下一代测序。我们已经在一个家庭中发现了一种新的耳聋基因 提出的战略，清楚地表明了这一宝贵资源的效用。将创建存储库 在完成本提案后，可供外部调查人员使用。

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.