A Collaborative Search for New Genes for Non-Syndromic Deafness

 描述（由申请人提供） 每1，000名婴儿中至少有1.9名在出生时存在临床显著的听力损失，并且在他们生命中的某个时候影响至少30%的人口。超过60%的先天性或语前聋是遗传性的，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（NSHL）。虽然在常染色体隐性遗传性NSHL（ARNSHL）患者的58个不同基因中的一个中已经确定了因果突变，但至少30%的家庭没有可识别的突变。此外，突变特异性听觉前庭表型仍然在很大程度上未知。通过多种国家和国际资源，我们建立了一个储存库，其中包含2，060个NSHL家庭的生物样本和临床数据。其中，796个家庭至少有两名受影响的成员，与ARNSHL一致。最常见的NSHL形式已被排除在所有家庭。在通过下一代测序基因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鉴定新耳聋基因中的致病性单核苷酸、插入缺失和拷贝数变异。大量近交系的可用性将有助于在纯合区域内进行分析。为了支持已确定的病理生理学变化的作用，将建立体外和体内模型。小鼠突变体将主要用于揭示潜在的病理生理学，而斑马鱼突变体将用于那些适合于药物干预的基因。在本申请的前一个周期中，我们已经成功地应用这种策略发现了新的耳聋基因。检测到的变异和相关的听觉前庭表型将被存储在一个数据库中，外部研究人员可以访问。该提案的成果将是发现参与耳聋病理生理学的新基因/途径，为耳聋个体的病因诊断和咨询奠定分子诊断测试的基础，以及开发新的干预策略。

 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.