Localization of Nonsyndromic Hearing Impairment Genes

项目总结 听力障碍是世界上最常见的感觉障碍。先天性HI的发生率为1-2% 1000个新生儿。了解听力的机制将极大地帮助治疗的发展 针对HI的策略。此外，识别与HI有关的致病变异对 基因筛查，以便早期诊断HI，并在年轻时进行干预，以最大限度地提高 儿童的认知、社会情感、言语和语言发展。第一步是绘制地图和 确定与非综合征(NS)HI病因学相关的基因。尽管NSHI的大约160个基因座 定位和鉴定了90个基因，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不同的过程，这些过程可以在 并引起内耳的HI表型。识别与HI有关的基因是改进的第一步 对听觉过程的了解，这反过来将有助于诊断模式的发展和 治疗性干预。为了鉴定新的NSHI基因，分离NSHI的家系正在进行 来自巴基斯坦和匈牙利(罗马)。巴基斯坦血统通常是血缘关系密切的， 大号的。在基因鉴定之前，在一个家族中分离的NSHI基因必须被定位到一个基因组上 使用基因分型和连锁分析。因此，来自已确定的家系的DNA样本将 使用Illumina Infinium人核珠芯片进行全基因组基因分型，该芯片包括 282,000个标记基因座。使用生成的基因类型连锁和单倍型分析，并用于 血缘关系ARNSHI家系纯合子作图，将NSHI基因座定位到 最小可能的遗传间隔。与同一基因区域连锁的多个家系将高度 有益的，因为这些家族很可能在同一基因内有变异，并将证明 发现的基因可能与NSHI的病因学有关。这项研究将提供丰富的资源 利用外显子组和全基因组下一代测序进行NSHI基因鉴定。

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.