Molecular genetics of non-syndromic hearing loss (NSHL)

描述（由申请人提供）： 翻译后摘要：听力损失（HL）是最常见的感觉障碍影响超过28万美国人。尽管遗传因素在HL的病因学中起着重要作用，并且在鉴定非综合征性听力损失（NSHL）的大约70个基因方面取得了惊人的成功，但关于参与听力过程的基因以及由于这些基因缺陷而导致的疾病的分子机制仍有很多东西有待了解。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，以便制定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未能显示与任何已知基因座的连锁， NSHL患者所有已知基因的突变频率仍有待确定，因此，我们必须继续鉴定新的人类耳聋基因，并完成所有已知NSHL基因的突变筛查。最近在“靶富集”方法和下一代测序（NGS）方面的技术进步提供了突破基因阵列所施加的限制的障碍的独特机会，并且现在允许对所有已知的致突变基因进行完整分析。NGS的应用将大大加快疾病基因发现的步伐，并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，正如我们的初步研究所示， 研究中，我们收集了一组独特的分离常染色体显性或隐性耳聋的大家庭，证实了这些家庭中NSHL的进一步异质性，成功地利用NGS鉴定了两个新基因，定位了新的位点，并建立了已知NSHL基因的突变筛查方案。因此，这些有趣的初步结果，使我们继续确定新的基因为NSHL，并充分研究NSHL的分子机制。总的来说，完成拟议的目标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来实现高度转化。我们在这次竞争性更新中的具体目标是：1。识别NSHL的新基因。1a.使用传统和创新技术鉴定常染色体显性NSHL（ADNSHL）的新基因; 1b.使用传统和创新技术，在收集的近亲家庭和选择的先证者中识别常染色体隐性NSHL（ARNSHL）的新基因，这些先证者来自具有广泛NSHL家族史但已知未携带任何已知耳聋基因突变的耳聋x耳聋交配家庭。2.已知NSHL基因中致突变突变的完整突变筛查。2a.确定已知NSHL基因中致孕突变的患病率。2b.在我们的大型数据库中搜索临床相关的基因型-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.