A Collaborative Search for New Genes for Non-Syndromic Deafness

 描述(由申请人提供) 在出生时，每1000名婴儿中至少有1.9人出现临床上严重的听力损失，在他们一生中的某个时候，至少有30%的人受到影响。超过60%的先天性或语前聋是遗传的，其中高达93%是单基因常染色体隐性遗传特征。一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(NSHL)。虽然在常染色体隐性遗传性非霍奇金淋巴瘤(ARNSHL)患者的一个子集的58个不同基因中的一个基因中发现了因果突变，但至少30%的家庭没有可识别的突变。此外，突变特定的音频前庭表型在很大程度上仍不清楚。通过多种国内和国际资源，我们建立了一个储存库，其中包含2060个NSHL家庭的生物样本和临床数据。其中，796个包括至少两个受影响的成员，符合ARNSHL的父母血缘关系，在1,234个家庭中存在。最常见的NSHL形式在所有家庭中都被排除在外。在通过下一代测序基因小组排除所有已知耳聋基因的突变后，我们将使用全外显子组或全基因组测序和微阵列来识别新耳聋基因中的致病单核苷酸、内切和拷贝数变异。大量自交系的可获得性将有助于在纯合子区域内进行分析。为了支持已确定的病理生理学变化的作用，将制作体外和体内模型。小鼠突变将主要用于揭示潜在的病理生理学，而斑马鱼突变将用于那些适合进行药物干预的基因。我们已经成功地应用了这一策略，在这一应用的前一个周期中发现了新的耳聋基因。检测到的变异和相关的音频前庭表型将存储在一个数据库中，外部研究人员可以访问该数据库。这项提议的成果将是耳聋病理生理学中涉及的新基因/途径的发现，聋人病因诊断和咨询的分子诊断测试的基础，以及新干预策略的发展。

 DESCRIPTION (provided by applicant) Clinically significant hearing loss is present in at least 1.9 per 1,000 infants at birth and affecs at least 30% of the population at some time in their lives. More than 60% 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 abnormality (NSHL). While causal mutations have been identified in one of 58 different genes in a subset of patients with autosomal recessive NSHL (ARNSHL), at least 30% of families do not have an identifiable mutation. Moreover, mutation specific audio-vestibular phenotypes remain largely unknown. Through multiple national and international resources we established a repository that contains biological samples and clinical data on 2,060 families with NSHL. Of these, 796 include at least two affected members and are consistent with ARNSHL Parental consanguinity is present in 1,234 families. The most common forms of NSHL have been excluded in all families. After exclusion of mutations in all known deafness genes via a next-generation sequencing gene panel, we will use whole exome or whole genome sequencing and microarrays to identify causative single nucleotide, indel, and copy number variants in novel deafness genes. Availability of a large number of inbred families will facilitate analysis within autozygous region. To support the role of identified changes in pathophysiology, in vitro and in vivo models will be produced. Mouse mutants will be primarily utilized to reveal the underlying pathophysiology, while zebrafish mutants will be used for those genes suitable for pharmacological intervention. We have successfully applied this strategy to discover novel deafness genes during the previous cycle 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 genes/pathways involved in the pathophysiology of deafness, foundation of molecular diagnostic tests for etiological diagnosis and counseling of deaf individuals, and the development of novel interventional strategies.