Sequencing of Newborn Blood Spot DNA to Improve and Expand Newborn Screening

描述（由申请人提供）：新生儿筛查（NBS）是所有50个州的基本公共卫生计划。全基因组/外显子组测序成本的下降提供了一个机会，让我们思考全基因组分析（WGA）是否可以作为一种具有成本效益的新生儿筛查方法。我们将解决这项技术应用于国家统计局所提出的一些关键问题。我们将使用全外显子组测序（WES）作为WGA的一种具有成本效益的方法，用于与新生儿临床数据相关的1620个新生儿血点。然后，我们将测试WES作为代谢和免疫疾病的NBS工具。这些数据将用于1）比较突变数据与生化检测的敏感性和特异性，2）识别预测哪些突变的基因变异。 患有某些代谢紊乱的儿童处于代谢失代偿的更大风险中，3）鉴定导致那些原发性免疫缺陷的基因中的突变，所述突变不能通过用于严重联合免疫缺陷筛查的当前T细胞受体切除环测定检测到，和4）扫描9个基因的变异，这些变异在临床上对药物代谢很重要，并且是典型的“次要发现”如果WES被用作NBS方法。我们还将制定一个参与者保护框架，用于在新生儿期进行WGA，确定关键利益相关者对使用WGA进行NBS的观点、观点和价值偏好，与加州大学黑斯廷斯分校法律、科学和卫生政策联盟合作，确定使用WGA的法律的和宪法问题，并将其纳入 PGx纳入国家统计局计划，并根据WGA制定和传播扩大国家统计局计划的政策建议。

DESCRIPTION (provided by applicant): Newborn screening (NBS) is an essential public health program in all 50 states. The falling cost of whole genome/ exome sequencing provides an opportunity to ask whether whole genome analysis (WGA) might serve as a method of cost-effective newborn screening for any and every condition. We will address certain critical questions raised by the application of this technology to NBS. We will use Whole Exome Sequencing (WES) as a cost-effective method of WGA in 1620 newborn blood spots that are linked to the clinical data of the newborns. We will then test WES as a NBS Tool for metabolic and immunological disorders. These data will be used to 1) compare the sensitivity and specificity of mutation data with biochemical testing, 2) identify gene variants that predict which children with certain metabolic disorders are at greater risk for metabolic decompensation, 3) identify mutations in genes responsible for those primary immunodeficiencies that are not detected by the current T-Cell receptor excision circle assay used for severe combined immunodeficiency screening, and 4) scan 9 genes for variants that are clinically important for drug metabolism and would be typical "secondary findings" if WES were to be used as a NBS method. We will also develop a participant protection framework for conducting WGA during the neonatal period, determine the views, perspectives, and value preferences of key stakeholders about using WGA for NBS, collaborate with the UC Hastings Consortium on Law, Science and Health Policy, to identify the legal and constitutional issues for using WGA, and for incorporating PGx into NBS programs, and develop and disseminate policy recommendations for expanded NBS programs based on WGA.