Development and Validation of a High Risk and Potential Newborn Screening for Inh

描述（由申请人提供）：儿科医疗保健提供者和家长发现，由于缺乏合适的测试，难以确定在新生儿期可能出现的罕见健康状况。这些情况中有许多是罕见的遗传疾病，通常由于新生儿筛查结果异常、临床症状或有遗传异常史的家庭的关注而被怀疑。例如，脂肪酸氧化障碍（IEM）可能有一般的症状，如嗜睡、呕吐和肝脏异常，这使得很难确定新生儿的病情。在美国，每年有13000名新生儿被怀疑患有不同的先天性代谢错误（IEM）， 3-6%的新生儿患有罕见的遗传综合征。通过单一测试从数千种疾病中精确确定特定疾病是极具挑战性的，特别是在无法获得简单分析物的情况下。对遗传疾病的有效治疗可以预防智力迟钝、脑损伤或猝死等后果。目前的分析物特异性筛选方法不能提供遗传病因学和疾病的全面覆盖。单基因测序方法作为最后的确认手段是昂贵的（200-2000美元）和耗时的（12-16周的周转时间）。这样的DNA测序测试也不切实际，因为它需要大量的血，使婴儿面临失血的风险。我们正在使用大规模平行DNA测序(下一代测序（NGS）方法开发一种针对这些疾病的测试。它可以解决当前检测的缺陷，并作为常规的一级或二级新生儿筛查工具，首先用于高危患者，然后用于症状前患者。准确的症状前诊断是有效预防和管理疾病的先决条件。基于新生儿疾病小组的新生儿综合征筛查和诊断目前无法从一家商业公司获得。这种基于ngs的商业检测可以广泛覆盖这类疾病，可以作为一种服务在全国迅速推广，允许快速诊断决定。利用这一框架，我们可以改善儿童健康，消除长期和昂贵的医疗干预措施，并辨别基因、环境和疾病之间的关键关系。我们的第一个具体目标是通过检查整个基因区域的可变性和开发全血或干血标本的工作流程来使该测试准确。在我们的第二个特定目标中，我们将专注于在单个测试中测试50种不同遗传变异的综合基因面板，并将我们的方法与传统DNA和另一种NGS测序方法进行比较。由此产生的原型将是朝着基于NGS的筛查和诊断测试迈出的有价值的第一步，这将解决这些高风险婴儿的需求。它将帮助医疗保健提供者、患者和家属了解代谢紊乱和遗传综合征的确切原因，并消除不确定性和延误。我们的测试可以同时从单个样本中筛查和诊断数百种遗传疾病，以可承受的价格提供全面的信息。

DESCRIPTION (provided by applicant): Pediatric healthcare providers and parents find it challenging to identify rare health conditions that can present themselves in the neonatal period due to lack of suitable tests. Many of these conditions are rare genetic disorders which are typically suspected due to abnormal newborn screening results, clinical symptoms or as a concern within families with a history of genetic abnormalities. For example fatty acid oxidation disorder (an IEM) may have generic symptoms like lethargy, vomiting, and liver anomalies, which make it very hard to pinpoint the condition in the newborn. Annually, 13,000 neonates in the USA are suspected to be affected by different inborn errors of metabolism (IEM) and 3-6% newborns have rare genetic syndromes. It is extremely challenging to precisely determine by a single test the specific disorder from amongst thousands of disorders, especially where simple analytes are unavailable. Effective treatment of genetic conditions can prevent outcomes such as mental retardation, brain injury, or sudden death. The current approach of analyte specific screening does not provide the genetic etiology and the comprehensive coverage of disorders. The single gene sequencing method used as a last resort for confirming is costly ($200-2000) and time consuming (12-16 weeks turnaround). Such DNA sequencing test is also impractical because it requires significant blood volume that exposes an infant to risk from blood loss. We are developing a test focused on these disorders using massively parallel DNA sequencing (Next Generation Sequencing (NGS) methodology. It can address the deficiencies of current testing and be used as a routine primary or second-tier newborn screening tool, first in high-risk patients and later in pre-symptomatic patients. Accurate pre-symptomatic diagnosis is a prerequisite for effective disease prevention and management. Newborn Disease Panel-based NGS screening and diagnostics is currently unavailable from a commercial company. Such a commercial NGS-based test with broad coverage of such disorders can be rapidly expanded throughout the country as a service, permitting quick diagnostic decisions. Using this framework, we can improve child health, eliminate protracted and costly medical interventions, and discern key relationships between gene, environment and disease. Our first Specific Aim is to make this test accurate by examining variability over an entire genic region and development of workflows on whole or dried blood specimens. In our second Specific Aim, we will focus on a comprehensive gene panel tested on 50 different genetic variations in a single test, and compare our method with conventional DNA and another NGS sequencing method. The resulting prototype will be a valuable first step towards a NGS based screening and diagnostic test that will address the needs of these high-risk infants. It will help healthcare providers, patients, and families to understand the precise cause of metabolic disorders and genetic syndromes, and to remove uncertainty and delay. Our test will simultaneously screen and diagnose hundreds of genetic conditions at once from a single sample, providing comprehensive information at an affordable price.