Genetic causes of hearing loss from the population to the molecular level

描述(申请人提供)：感音神经性听力损失(SNHL)是最常见的先天性感觉障碍。在超过50%的病例中，病因是遗传的。基因检测在SNHL患者的护理中发挥着重要作用，因为早期干预计划可以显著改善发育和生活质量。已有超过的基因被认为与SNHL有因果关系，但没有其他缺陷，称为非综合征性听力损失。目前，基因检测只专注于检测这些基因中的一小部分，因此在许多情况下，遗传原因永远无法确定。基因测试中的这种差距是三个因素的结果：1)这些基因对美国耳聋的相对贡献尚不清楚；2)大量的“耳聋”基因尚未被发现；3)直到最近，测序技术一直过于昂贵和耗时，无法在每个人的基础上进行大量基因的突变筛查。在这项研究中，我们建议解决这些问题，从而改进NSHL的基因检测。为了满足对高效和全面的NSHL基因测试平台的需求，我们正在开发一个低成本的诊断平台，其中高通量基因组浓缩与下一代测序相结合，以询问SNHL患者中与NSHL有关的所有基因。除了满足临床需求外，该平台还将提供目前无法获得的美国遗传性耳聋的流行病学数据。为了提高在听力和耳聋生物学中重要的新基因的发现速度，我们将把诊断平台与基于发束蛋白质表达数据的基因发现平台联系起来。此外，我们建议使用功能研究来更好地了解已知的耳聋基因TECTA。我们将使用Audiogene音频分析来进一步定义DFNA8/12中的基因-表型相关性，并确定这种类型的耳聋在美国人群中是否常见。我们将部分阐明1-tectorin与其相互作用伙伴之一CEACAM16的功能关系，以加深我们对耳聋分子机制的理解。该项目目标的完成将改善遗传性听力损失的诊断，并提供对涉及听力的基因的更多了解。

DESCRIPTION (provided by applicant): Sensorineural hearing loss (SNHL) is the most prevalent congenital sensory deficit. In over 50% of cases, the cause is genetic. Genetic testing plays an important role in caring for patients with SNHL, as early intervention programs can significantly improve development and quality of life. More than 64 genes have been causally implicated in SNHL without other defects, termed non-syndromic hearing loss (NSHL). Genetic testing currently focuses on testing only a few of these genes and so in many cases, the genetic cause is never determined. This gap in genetic testing is a result of three factors: 1) the relative contribution of these genes to deafness in the United States is not known; 2) a large number of 'deafness' genes have not yet been discovered; 3) until recently, sequencing technology has been too costly and time-consuming to permit mutation screening of large numbers of genes on a per-person basis. In this study, we propose to address these issues, thereby improving genetic testing for NSHL. In order to address the need for an efficient and comprehensive genetic testing platform for NSHL we are developing a low-cost diagnostic platform in which high-throughput genomic enrichment is paired with next-generation sequencing to interrogate all genes implicated in NSHL in persons with SNHL. In additional to filling a clinical need, this platform will provide epidemiological data on genetic deafness in the USA, which is currently not available. To increase the rate of discovery of new genes important in the biology of hearing and deafness, we will link the diagnostic platform with a gene discovery platform based on protein expression data from hair bundles. In addition, we propose to use functional studies to gain a better understanding of a known deafness gene, TECTA. We will use AudioGene audio profiling to further define genotype-phenotype correlations in DFNA8/12 and determine if this type of deafness is common in the US population. We will clarify, in part, the functional relationship of 1-tectorin with one of its interacting partners, CEACAM16, to improve our understanding of the molecular mechanisms underlying deafness. Completion of the goals of this project will improve the diagnosis for hereditary hearing loss and provide a greater understanding of the genes involved in hearing.