Localization of nonsyndromic hearing impairment genes

描述(由申请人提供)：非综合征性听力障碍基因的定位非综合征性听力障碍(NSHI)是已知的最具异质性的性状，有&gt；140个定位的基因座和&gt；50个识别的基因。然而，绝大多数NSHI基因既没有定位，也没有鉴定。NSHI的极端遗传异质性是由于内耳内的不同过程导致听力障碍(HI)表型。识别与HI有关的基因是提高对听觉过程的了解的第一步，这反过来将有助于开发诊断模式和治疗干预措施，并通过基因筛查帮助早期诊断。为了定位和完善新的NSHI基因座和未知基因的NSHI基因座的间隔，正在从巴基斯坦全国范围内确定分离NSHI的家系。这些家系通常既有血缘关系，又能独立建立连锁关系。由于NSHI具有极强的基因座异质性，因此利用能单独建立连锁关系的家系来定位基因座是很重要的。血缘家系是定位常染色体隐性(AR)NSHI的理想家系，因为可以进行纯合作图，而且与没有血缘匹配的家系不同，它们可以提供足够的信息来建立连锁。使用来自已确定的家系的DNA样本，将使用Illumina Infinium Human Linkage-12面板进行全基因组基因分型。对于有血缘关系的ARNSHI家系，将使用连锁和单倍型分析以及纯合子作图，将NSHI基因座定位到尽可能小的遗传间隔。尽可能利用与同一基因区域有关联的多个家系提供的信息来细化间隔。这项研究将为利用下一代测序进行NSHI基因鉴定提供丰富的家系资源。目标：利用具有良好特征的NSHI家系的大量资源，定位NSHI基因座并将其提炼到尽可能小的区域。 公共卫生相关性：巴基斯坦将确定患有非综合征性听力障碍(NSHI)的大型近亲家庭。为了定位NSHI基因座，将使用SNP阵列产生的基因数据进行连锁分析。完成这项建议的目标将提供一个资源，以确定新的基因座以及基因未知的已知NSHI基因座的基因。

DESCRIPTION (provided by applicant): Localization of Nonsyndromic Hearing Impairment Genes Non-syndromic hearing impairment (NSHI) is the most heterogeneous trait known, with > 140 mapped loci and >50 identified genes. However, the vast majority of NSHI genes have neither been localized nor identified. The extreme genetic heterogeneity of NSHI is due to the different processes which can malfunction within the inner ear and cause the hearing impairment (HI) phenotype. Identification of genes involved in HI is the first step in improving knowledge of the auditory process which in turn will aid in the development of diagnostic modalities and therapeutic interventions, and additionally aid in early diagnosis through genetic screening. In order to map and refine the interval for novel NSHI loci and NSHI loci with unknown genes, pedigrees segregating NSHI are being ascertained from throughout Pakistan. These pedigrees are usually both consanguineous and can independently establish linkage. Due to extreme locus heterogeneity of NSHI it is important that loci be mapped using families which can individually establish linkage. Consanguineous pedigrees are ideal for mapping autosomal recessive (AR) NSHI since homozygosity mapping can be performed, and unlike pedigrees without consanguineous matings, they can be sufficiently informative to establish linkage. Using DNA samples from the ascertained pedigrees, whole genome genotyping will be carried out using the Illumina Infinium HumanLinkage-12 panel. Linkage and haplotype analysis, and for consanguineous ARNSHI families homozygosity mapping, will be used to localize NSHI loci to the smallest possible genetic intervals. Information from multiple families with established linkage to the same genetic region will be used to refine the interval whenever possible. The study will provide a rich resource of families to carry out NSHI gene identification using next generation sequencing. Goal: To map NSHI loci and refine them to the smallest possible region using a large resource of well characterized families with NSHI. PUBLIC HEALTH RELEVANCE: Large consanguineous families with nonsyndromic hearing impairment (NSHI) will be ascertained from Pakistan. In order to map NSHI loci, linkage analysis will be carried using genotype data generated from SNP arrays. Completion of the aims of this proposal will provide a resource to identify genes for novel loci as well as for known NSHI loci for which the gene is unknown.