Confirmatory Screening for Congenital Non-Syndromic Genetic Hearing Loss Using Ta

描述(由申请人提供)：美国每年约有8000名儿童出生时患有某种形式的听力损失，严重到需要特殊服务。其中一半是遗传的，覆盖了基因组中数百个不同的突变影响听力过程的区域。遗传易感性的一个例子是，一些人在服用某些抗生素药物后更有可能患上听力损失。婴儿出生时也可能因怀孕期间感染的巨细胞病毒(CMV)等病毒感染而导致听力损失。新生儿重症监护病房中的新生儿更有可能因为经常使用的抗生素的毒副作用而患上听力损失。了解这种疾病的病因及其治疗是非常具有挑战性的，但也是极其重要的。目前的听力筛查方法不能提供遗传病因，而用于补充这一点的单基因测序方法成本高、耗时长且不切实际，需要大量血液样本，而婴儿不容易安全地获取血样。我们正在开发一种使用大规模并行DNA测序[下一代测序(NGS)]方法的测试，该测试可以解决当前测试的不足，并用作当前听力筛查确定的高危患者的常规二线新生儿筛查工具。该测试还可用于舌后听力损失患者的诊断，以确定致病基因。这种基于NGS测序面板的筛查和诊断方法目前无法从商业公司获得，也无法满足新生儿的需求。这种基于NGS的商业诊断方法可以作为一项服务在全国范围内迅速推广，允许做出快速诊断决定，并有可能通过避免诊断延迟来降低医疗成本。目前使用的新生儿听力筛查方案可能会导致一半以上未通过筛查测试的新生儿失去后续行动，也不能解决导致听力丧失的先天性感染问题。我们的第一个具体目标是使这项测试准确和适合新生儿，因此我们将专注于正确的标本收集策略，从而达到最高的敏感性和特异性。在我们的第二个具体目标中，我们将重点放在一个全面的基因小组上，在一个单一的测试中解决所有相关的遗传位点和CMV特异性小组，并使其强大和准确。由此产生的原型将是一个有价值的第二级筛查和诊断工具，将导致一项满足这些高危婴儿需求的测试。它将帮助医疗保健提供者、患者和他们的家人了解听力损失的确切原因，并制定相应的计划。我们的测试的独特之处在于，它可以同时从单个样本中同时筛查和/或诊断数百种此类疾病，为家庭及其医生提供更全面的信息，同时又负担得起，并提供对相关数据的访问。

DESCRIPTION (provided by applicant): Approximately 8,000 children in the USA are born each year with some form of hearing loss severe enough to require special services. Half of these are genetic in origin covering several hundred different regions in the genome where mutations affect the hearing process. One example of genetic predisposition makes some people more likely to develop hearing loss after taking certain antibiotic medications. Infants may also be born with hearing loss caused by a viral infection like cytomegalovirus (CMV) that was acquired during pregnancy. Newborns in the neonatal intensive care units are more likely to suffer from hearing loss as a toxic side effect of the antibiotics which are frequently administered. It is very challenging, while extremely important, to understand the cause of the disease and its treatment. The current approach of audiometric screening doesn't provide the genetic etiology, and the single gene sequencing method used to compliment this is costly, time consuming and impractical, requiring a large blood sample that cannot be easily obtained safely from an infant. We are developing a test using massively parallel DNA sequencing [Next Generation Sequencing (NGS)] methodology that can address the deficiencies of current testing and be used as a routine second-tier newborn screening tool in high-risk patients identified by current audiometric hearing screening. The test can also be used as a diagnostic for individuals with post lingual hearing loss for the identification of disease-causing loci. Such NGS sequencing panel-based screening and diagnostic methodologies are currently not available from a commercial company or for addressing the needs of newborns. Such commercial NGS-based diagnostic methods can be rapidly expanded throughout the country as a service, permitting quick diagnostic decisions, and have the potential to reduce healthcare costs by avoiding diagnostic delays. The newborn hearing screening protocols that are currently in use can result in over half of newborns who fail the screening test to be lost to follow-up and do not address the problem of congenital infections that cause hearing loss. Our first Specific Aim is to make this test accurate and appropriate for newborns and therefore we will focus on the right specimen collection strategy so the highest sensitivity and specificity is reached. In our second Specific Aim we will focus on a comprehensive gene panel addressing all relevant genetic loci and CMV specific panel in a single test and make it robust and accurate. The resulting prototype will be a valuable second tier-screening and diagnostic tool that will lead to a test that will address the needs of these high-risk infants. It will help healthcare providers, patients, and thei families to understand the precise cause of the hearing loss, and to plan accordingly. Our test is unique in that it simultaneously screens and/or diagnoses hundreds of these conditions at once from a single sample, providing more comprehensive information to families and their physicians and yet affordable and provide access to the associated data.