Genetic hearing screening and diagnosis facilitated by using a combined low-cost

项目摘要/摘要 普遍的新生儿听力筛查是一种被广泛采用的临床实践，并由法律强制在 美国。现有的基于生理的听力筛查方法存在较高的假阳性率，无法满足听力筛查的需要 以检测早发性听力损失，并提供确定潜在病因的诊断。研究表明， 先天性耳聋的主要诊断问题是耳聋基因的遗传突变和感染 携带巨细胞病毒。大规模并行测序技术的最新进展使其有可能 例行公事地分析总计数百万个碱基对的目标人类基因集。然而，新技术并没有 被证实有耳聋基因。更重要的是，与捕获靶向耳聋相关的高昂成本 基因使这些技术进步不太可能转化为广泛采用的临床工具。 项目的R21阶段将测试和验证核心技术，以实现高效的低成本方法 最常见耳聋基因外显子的捕获及其与不同类型下游基因偶联的适应性 大规模并行测序仪在基因突变检测中的测序应用。在R33阶段 我们将扩大我们定制基因芯片的捕获范围，以包括所有确诊的耳聋基因和 耳聋基因候选。该项目的总体目标是提供一个具有成本竞争力和成熟的 基于DNA的听力筛查方法的实施方案将显著增强当前的 普及新生儿听力筛查计划。

Project summary/abstract Universal newborn hearing screening is a widely-adopted clinical practice and mandated by law in the United States. Current physiology-based hearing screening protocol generates high false positive rate and is unable to detect early-onset hearing loss and provide a diagnosis that defines underlying etiology. Studies have indicated that the primary diagnostic concern in congenital hearing loss is genetic mutations in deafness genes and infections with cytomegalovirus. Recent advances in massively-parallel sequencing technologies have made it possible to routinely analyze targeted sets of human genes totaling millions of base pairs. However, the new technology has not been validated with deafness genes. More importantly, the high cost associated with capturing targeted deafness genes makes it unlikely that these technological advances will be translated into a widely-adopted clinical tool. The R21 phase of the project will test and validate the core technology for a low-cost approach to efficiently capture exons of most common deafness genes and its suitability for coupling with various types of downstream sequencing applications by massively parallel sequencers for the detection of genetic mutations. In the R33 phase we will expand the capturing coverage of our custom genechips to include all confirmed deafness genes and deafness gene candidates. The overall goal of the project is to provide a cost-competitive and mature implementation protocol for a DNA-based approach for hearing screening that will significantly enhance the current universal newborn hearing screening program.