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定位非综合征性听力障碍（NSHI）是已知的最异质性的性状，有>40个定位位点和>50个已确定的基因。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不同的过程可能发生故障并导致听力障碍（HI）表型。识别与HI相关的基因是提高听觉过程知识的第一步，这反过来将有助于诊断方式和治疗干预的发展，并有助于通过遗传筛查进行早期诊断。为了绘制和细化新的NSHI位点和具有未知基因的NSHI位点的间隔，正在从整个巴基斯坦确定分离NSHI的家系。这些家系通常都是近亲，可以独立地建立联系。由于NSHI基因座的极端异质性，重要的是利用可以单独建立连锁的家族来定位基因座。近亲家系是绘制常染色体隐性（AR） NSHI的理想方法，因为可以进行纯合子作图，而且与没有近亲交配的家系不同，它们可以提供足够的信息来建立联系。使用来自确定谱系的DNA样本，将使用Illumina Infinium HumanLinkage-12面板进行全基因组基因分型。连锁分析和单倍型分析，以及近亲家族纯合性定位，将用于定位NSHI位点到尽可能小的遗传间隔。在可能的情况下，将使用来自多个与同一遗传区域建立联系的家族的信息来优化区间。该研究将为利用下一代测序技术进行NSHI基因鉴定提供丰富的家族资源。目标：绘制NSHI基因座，并利用大量具有良好特征的NSHI家族资源将其细化到尽可能小的区域。

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.