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

描述（由申请人提供）：普遍新生儿听力筛查是一项广泛采用的临床实践，并在美国法律强制执行。目前基于生理学的听力筛查方案产生高假阳性率，无法发现早发性听力损失并提供明确潜在病因的诊断。研究表明先天性听力损失的主要诊断是耳聋基因突变和巨细胞病毒感染。大规模平行测序技术的最新进展使得常规分析总计数百万碱基对的人类基因目标组成为可能。然而，这项新技术还没有在耳聋基因上得到验证。更重要的是，捕获目标耳聋基因的高成本使得这些技术进步不太可能转化为广泛采用的临床工具。该项目的R21阶段将测试和验证一种低成本方法的核心技术，以有效捕获大多数常见耳聋基因的外显子，并通过大规模并行测序仪与各种类型的下游测序应用相结合，以检测基因突变。在R33阶段，我们将扩大我们的定制基因芯片的捕获范围，包括所有确认的耳聋基因和耳聋基因候选。该项目的总体目标是为基于dna的听力筛查方法提供一个具有成本竞争力和成熟的实施方案，这将大大增强当前普遍的新生儿听力筛查计划。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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 and 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. This project will test and validate the core technology for a low-cost approach to efficiently capture exons of all confirmed deafness genes and deafness gene candidates. The overall goal of the project is to provide a DNA-based hearing screening method that will significantly enhance the current universal newborn hearing screening program.