A Collaborative search for new genes for non-syndromic deafness

项目摘要： 超过60%的语前聋是遗传性的，其中高达93%是单基因常染色体的 隐性性状某些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。虽然已经在一个基因组中发现了致病突变， 非综合征型常染色体隐性性感音神经性听力损失患者亚组中的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 基因此外，在不同人群中公认的遗传原因的分布以及突变 具体的表型仍然未知。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SNP标记的密集阵列进行基因分型和对大的 人类基因组的片段。土耳其提供了一个非常宝贵的资源， 耳聋的新基因，因为它一直居住在自古以来， 全国大约有4万人口仍然生活在小村庄里，在那里，血缘关系是文化的基础。 norm.在聋人中也有很高的选择性交配，使用手语的历史也很长。 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个近亲繁殖的复合体 常染色体隐性遗传性非综合征性听力损失的土耳其家族。我们将招募超过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 许多常染色体隐性遗传性非综合征性耳聋的基因。在排除共同 我们将有大约150个家族来发现和确认耳聋的新基因。我们将使用基因组 广泛密集的SNP阵列，以寻找新的耳聋基因座，并确定致病突变，无论是传统的或 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， 这是一项战略建议，清楚地表明了这一宝贵资源的效用。仓库将由 完成本提案后，外部调查人员可使用。

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.