Identification of Nonsyndromic Hearing Impairment Genes

描述(申请人提供)：听力障碍对受影响的个人有重大影响。它可以深刻地影响交流、语言习得、言语、认知技能和心理社会发展。超过60%的深度早发性耳聋是由遗传因素引起的，在大多数情况下，这是由于单基因突变造成的。非综合征性听力障碍(NSHI)是已知的最具异质性的特征。到目前为止，已有90多个基因定位于NSHL，35个基因已被鉴定。 该项目的目标是继续开发NSHL家系资源，定位新的NSHL基因座，完善已知NSHL基因座的遗传区域，并鉴定新的NSHL基因。 遇难者家属来自瑞士、约旦、土耳其、巴基斯坦和美国。目前，巴基斯坦、约旦和美国正在确定更多的家庭。对于已经确定的家系，进行基因组扫描和精细作图，以建立连锁并将家系中分离的基因定位到尽可能小的遗传区域。低频率NSHI(WFS1)和一种高频NSHI(ACTG1)基因已在两个美国家系中被鉴定。本研究还发现了一些新的基因座(DFNA23、DFNA24、DFNB35、DFNB38、DFNB39、DFNB42、DFNB43、DFNB44和DFNB45)。此外，对于其他家系，已建立了连锁关系，并缩小了已知NSHI基因座的遗传区域(如DFNB13、DFNB19)，这些基因尚未被鉴定。基因鉴定是通过筛选映射到与NSHI感兴趣基因相同的物理区域的基因，在迄今尚未鉴定出基因的区域进行的。将首先对那些被认为是最强有力的候选基因进行测序。如果一个基因属于一类以前被认为与听力障碍表型有关的基因，具有潜在的听力功能，和/或根据RT-PCR实验和公共数据库中的信息在耳蜗内表达，那么它将被认为是一个很好的候选基因。为了发展表型/基因型关系，强调了获得良好的临床数据的重要性。这项研究还将提供有关不同人群中某些基因/突变对公众健康影响的重要信息。贝勒人类基因组测序中心已经开发了一种技术，以便于以成本和时间高效的方式对大量基因进行测序，并已在本研究中实施。NSHI新基因的识别将有助于理解控制听力机制的基因的功能，这将有助于未来制定预防和治疗听力障碍的干预策略。

DESCRIPTION (provided by applicant): Hearing impairment has a major impact on affected individuals. It can profoundly influence communication, language acquisition, speech, cognitive skills and psychosocial development. More than 60 percent of the cases of profound early-onset deafness are caused by genetic factors, which in most cases are due to single gene mutations. Nonsyndromic hearing impairment (NSHI) is the most heterogeneous trait known. Thus far, over 90 genes have been localized for NSHL and 35 genes have been identified. The goals of this project are to continue to develop a resource of families with NSHL, map novel NSHL loci, refine the genetic regions for known NSHL loci and identify novel NSHL genes. Families have been ascertained from Switzerland, Jordan, Turkey, Pakistan and the United States. Currently, additional families are being ascertained in Pakistan, Jordan and the USA. For the families that have been ascertained, genome scans and fine mapping is carried to establish linkage and map the locus segregating in the family to the smallest possible genetic region. The genes responsible for low frequency NSHI (WFS1) and a form of high frequency NSHI (ACTG1) have been identified in two of the USA families. This study has also identified a number of novel loci (DFNA23, DFNA24, DFNB35, DFNB38, DFNB39, DFNB42, DFNB43, DFNB44 and DFNB45) for which the genes are currently unknown. In addition, for other families linkage has been established and the genetic region has been reduced (e.g. DFNB13, DFNB19) for known NSHI loci where the gene has not yet been identified. Gene identification is conducted in regions where a gene has not been identified to date by screening genes that map to the same physical region as the NSHI locus of interest. Sequencing will first be performed on those genes that are believed to be the strongest candidates. A gene will be considered a good candidate if it belongs to a class of genes that have previously been implicated in the hearing impairment phenotype, has a potential function in the role of hearing and/or is expressed within the cochlea based upon RT-PCR experiments and from information available in public databases. The importance of obtaining good clinical data is stressed in order to develop phenotype/genotype relationships. The study will also yield important information on the public health impact of certain genes/mutations within various populations. Technology has been developed at the Baylor Human Genome Sequencing Center to facilitate the sequencing of a large number of genes in a cost- and time-efficient manner and has been implemented in this study. Identification of novel genes for NSHI will aid in understanding the function of genes controlling the mechanism of hearing, which will in the future facilitate the development of intervention strategies to prevent and treat hearing impairment.