Localization of Nonsyndromic Hearing Impairment Genes

项目摘要 听力障碍（hearing impairment，HI）是世界上最常见的感觉障碍。先天性HI发生在1-2/ 一千个新生儿。了解听力的机制将大大有助于治疗的发展 策略HI。另外，鉴定涉及HI的致病性变体对于治疗HIV感染是非常有益的。 遗传筛查，以便HI可以早期诊断，并在年轻时进行干预， 儿童的认知、社会情感、言语和语言发展。第一步是绘制地图， 确定与非综合征性HI病因有关的基因。虽然NSHI的~160个位点已经被 虽然NSHI基因的定位和90个基因的鉴定，但绝大多数的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，这些过程可能在内部发生故障。 内耳并引起HI表型。鉴定HI相关基因是改善HI的第一步。 听觉过程的知识，这反过来将有助于诊断方式的发展， 治疗干预。为了鉴定新的NSHI基因，分离NSHI的家系正在被建立。 从巴基斯坦和匈牙利（罗姆人）查明。巴基斯坦血统通常是近亲， 大.在进行基因鉴定之前，必须将家系中分离的NSHI基因定位到基因组中， 区域使用基因分型和连锁分析。因此，来自已确定谱系的DNA样本将 使用Illumina Infinium HumanCore BeadChip进行全基因组基因分型， ~ 282，000个标记位点。使用所产生的基因型连锁和单体型分析， 将进行近亲ARNSHI家族纯合性作图，以将NSHI基因座定位到 最小的遗传间隔。与同一遗传区域连锁的多个家庭将是高度危险的。 这是有益的，因为这些家庭可能在同一基因内有变异，并将证明， 该基因可能与NSHI的发病有关。这项研究将提供丰富的资源， 家庭进行NSHI基因鉴定使用外显子组和全基因组下一代测序。

PROJECT SUMMARY Hearing impairment (HI) is the most common sensory deficit in the world. Congenital HI occurs in 1-2 per 1000 newborns. Understanding the mechanism of hearing will greatly aid in the development of treatment strategies for HI. Additionally identification of pathogenic variants involved in HI is highly beneficial for genetic screening so that HI can be diagnosed early and intervention can occur at a young age to maximize the child's cognitive, social-emotional, speech and language development. The first step is to map and identify genes involved in the etiology of nonsyndromic (NS) HI. Although ~160 loci for NSHI have been mapped and 90 genes identified, 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 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. In order to identify new NSHI genes pedigrees segregating NSHI are being ascertained from Pakistan and Hungary (Roma). The Pakistani pedigrees are usually consanguineous and large. Before gene identification the NSHI gene segregating in a family must be mapped to a genomic region using genotyping and linkage analysis. Therefore, DNA samples from the ascertained pedigrees will undergo whole genome genotyping using the Illumina Infinium HumanCore BeadChip which includes ~282,000 marker loci. Using the generated genotypes linkage and haplotype analysis, and for consanguineous ARNSHI families homozygosity mapping, will be performed to localize NSHI loci to the smallest possible genetic intervals. Multiple families with linkage to the same genetic region will be highly beneficial since these families are likely to have variants within the same gene and will demonstrate that an identified gene is likely to be involved in the etiology of NSHI. The study will provide a rich resource of families to carry out NSHI gene identification using exome and whole genome next-generation sequencing.