Molecular genetics of non-syndromic hearing loss (NSHL)

描述(由申请人提供)： 摘要：听力损失是影响2800多万美国人的最常见的感觉障碍。尽管遗传因素在HL的病因中起着重要的作用，并且在鉴定大约70个非综合征性听力损失(NSHL)基因方面取得了惊人的成功，但对于参与听力过程的基因以及这些基因缺陷引起的疾病的分子机制仍有许多了解。我们的长期目标是更好地了解遗传性耳聋的遗传和分子基础，以便开发有效的遗传咨询和成功的治疗策略。鉴于许多耳聋家系仍然没有显示出与任何已知基因座的连锁，而且 NSHL患者所有已知基因的突变频率仍有待确定，因此，继续寻找新的人类耳聋基因，完成NSHL所有已知基因的突变筛查是非常重要的。最近在“靶浓缩”方法和下一代测序(NGS)方面的技术进步为突破基因阵列施加的限制提供了一个独特的机会，现在可以对所有已知的导致耳聋的基因进行完整的分析。NGS的应用将大大加快疾病基因发现的步伐，现在首次使遗传性耳聋的分子流行病学研究成为可能。有趣的是，正如我们的初步报告所显示的那样 研究中，我们收集了分离常染色体显性或隐性耳聋的一组独特的大家系，证实了NSHL在这些家系中的进一步异质性，成功地利用NGS技术鉴定了两个新的基因，定位了新的基因座，并建立了已知NSHL基因的突变筛选方案。因此，这些有趣的初步结果引导我们继续鉴定NSHL的新基因，并全面研究NSHL的分子机制。总体而言，拟议目标的完成不仅将增加我们对听力和耳聋生物学的理解，而且将通过改善NSHL的临床诊断和患者护理而具有高度的翻译性。我们在这次竞争更新中的具体目标是：1.识别NSHL的新基因。1A.利用传统和创新技术鉴定常染色体显性NSHL(ADNSHL)的新基因；利用传统和创新技术，在收集的近亲家系和具有广泛NSHL家族史但已知没有任何已知耳聋基因突变的聋人×聋人交配家系中，鉴定常染色体隐性NSHL(ARNSHL)的新基因。2.已知NSHL基因致聋突变的完整突变筛查。2A。确定已知NSHL基因中导致耳聋的突变的流行率。2B。在我们的大型数据库中搜索临床相关的基因-表型相关性。

DESCRIPTION (provided by applicant): Abstract: Hearing loss (HL) is the most common sensory disorder affecting more than 28 million Americans. Despite the significant role of genetic factors in the etiology of HL, and astonishing success that has been achieved in the identification of approximately 70 genes for non-syndromic hearing loss (NSHL), much remains to be known about genes involved in the hearing process and the molecular mechanisms of disorders due to defects of these genes. Our long-range goal is to better understand the genetic and molecular basis of hereditary deafness so that effective genetic counseling and successful treatment strategies can be developed. Given the facts that many deafness pedigrees still fail to show linkage to any of the known loci and that mutation frequencies in all the known genes in persons with NSHL remains to be determined, it is therefore important for us to continue identifying new human deafness genes and to complete mutation screening of all known genes for NSHL. The recent technological advances in "target- enrichment" methods and next generation sequencing (NGS) offers a unique opportunity to break through the barriers of limitations imposed by gene arrays and now allows for the complete analysis of all known deafness-causing genes. The application of NGS will greatly accelerate the pace of disease gene discovery and is now making molecular epidemiological studies of genetic deafness possible for the first time. Interestingly, as shown in our preliminary studies, we have collected a unique group of large families segregating autosomal dominant or recessive deafness, confirmed further heterogeneity of NSHL in these families, successfully identified two new genes using NGS, mapped new loci, and established mutation screening protocol for known NSHL genes. These interesting preliminary results have thus led us to continue identification of novel genes for NSHL and to fully investigate the molecular mechanisms underlying NSHL. Overall, completion of the proposed aims will not only increase our understanding of the biology of hearing and deafness, but will be highly translational by improving the clinical diagnosis of NSHL and patient care. Our Specific Aims in this competitive renewal are: 1. Identify new genes for NSHL. 1a. Identify new genes for autosomal dominant NSHL (ADNSHL) using traditional and innovative technologies; 1b. Identify new genes for autosomal recessive NSHL (ARNSHL) using traditional and innovative technologies in the collected consanguineous families and in the selected probands from deaf x deaf mating families with extensive family histories of NSHL but known not to carry mutations in any known deafness gene. 2. Complete mutation screening of deafness-causing mutations in known NSHL genes. 2a. Determine the prevalence of deafness-causing mutations in known NSHL genes. 2b. Search for clinically relevant genotype- phenotype correlations in our large database.