Localization of nonsyndromic hearing impairment genes

非综合征性听力损伤（NSHI）是已知的最异质的性状，具有> 140个定位的基因座和>50个鉴定的基因。然而，绝大多数NSHI基因既没有被定位也没有被鉴定。NSHI的极端遗传异质性是由于不同的过程，这些过程可以在内耳内发生故障并导致听力障碍（HI）表型。识别HI相关基因是提高听觉过程知识的第一步，这反过来将有助于开发诊断模式和治疗干预措施，并通过遗传筛查辅助早期诊断。为了绘制和完善新的NSHI基因座和NSHI基因座与未知基因的间隔，谱系分离NSHI正在确定从整个巴基斯坦。这些家系通常都是近亲，并能独立建立连锁。由于NSHI的极端位点异质性，重要的是使用可以单独建立连锁的家系来定位位点。血缘家系是理想的常染色体隐性遗传（AR）NSHI定位，因为纯合性定位可以进行，不像没有血缘交配的家系，他们可以有足够的信息建立连锁。使用来自已确定谱系的DNA样本，使用Illumina Infinium HumanLinkage-12面板进行全基因组基因分型。连锁和单倍型分析，并为近亲ARNSHI家庭纯合性定位，将被用来定位NSHI基因座的最小可能的遗传间隔。在可能的情况下，将使用与同一遗传区域建立连锁关系的多个家庭的信息来细化间隔。本研究为利用下一代测序技术进行NSHI基因鉴定提供了丰富的家系资源。 目的：利用大量的NSHI家族的特征，绘制NSHI基因座，并将其细化到尽可能小的区域。 公共卫生相关性：将从巴基斯坦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，将使用从SNP阵列产生的基因型数据进行连锁分析。完成这项建议的目的将提供一个资源，以确定新的基因座以及已知的NSHI基因座的基因是未知的。

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.