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个州的一项基本公共卫生计划。全基因组/外显子组测序成本的下降提供了一个机会，人们可以问，全基因组分析(WGA)是否可以作为一种针对任何和每种疾病的具有成本效益的新生儿筛查方法。我们将解决将这项技术应用于国家统计局所提出的某些关键问题。我们将在1620个与新生儿临床数据相关的新生儿血点中使用完整外显子组测序(WES)作为一种经济有效的WGA方法。然后，我们将测试WES作为新陈代谢和免疫紊乱的NBS工具。这些数据将被用来1)比较突变数据与生化测试的敏感性和特异性，2)识别预测 患有某些代谢紊乱的儿童有更大的代谢失代偿风险，3)识别导致那些初级免疫缺陷的基因突变，这些突变是当前用于严重联合免疫缺陷筛查的T细胞受体切除环试验没有检测到的，以及4)扫描9个基因的变异，这些变异对药物代谢具有临床重要性，如果WES被用作NBS方法，将是典型的“二次发现”。我们还将制定在新生儿期进行WGA的参与者保护框架，确定关键利益相关者对使用WGA的看法、观点和价值偏好，与加州大学黑斯廷斯大学法律、科学和卫生政策联盟合作，确定使用WGA和纳入WGA的法律和宪法问题 将PGX纳入国家统计局方案，并根据WGA为扩大的国家统计局方案制定和传播政策建议。 相关性：我们计划测试一种全基因组分析方法的使用，即全外显子组测序，作为目前正在筛查的疾病和其他目前新生儿筛查遗漏但可能适合新生儿筛查的疾病的新生儿筛查的唯一方法。这将为新生儿提供实质性的公共卫生好处，否则他们可能会在发生严重甚至不可逆转的损害时得不到诊断和治疗。同样重要的是，我们将探索家长对偶然发现的兴趣，并制定适当的 法律框架，以确保WGA的NBS可以在道德上进行。

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. RELEVANCE: We plan to test the use of one method of whole genome analysis, whole exome sequencing, as the sole method of newborn screening for disorders currently being screened for and others that are missed by current newborn screening but for which newborn screening might be appropriate. This would provide substantial public health benefit for newborns who might otherwise go undiagnosed and untreated while serious, even irreversible, damage occurs. Equally important, we will explore parents' interest in incidental findings and develop appropriate legal frameworks to make sure NBS by WGA can be done ethically.