NC NEXUS, North Carolina Newborn Exome Sequencing for Universal Screening

描述（由申请人提供）： 自20世纪60年代新生儿筛查（NBS）开始以来，技术进步已导致其在越来越多的疾病中使用。全基因组测序及其更简单的推论全外显子组测序（WES）的最新发展现在提供了以快速和负担得起的方式全面定义个体基因组内的变异的机会。随着基因组规模测序的临床应用以及对婴儿和儿童的实际益处，出现了许多挑战。其在NBS中的效用尚未得到证实，其在儿科人群中的应用需要特殊的检查，不仅是为了潜在的临床益处，而且还为了它所带来的独特的伦理挑战。在这份提案中，我们概述了一种高度跨学科的方法， 确定，面对和克服必须满足的主要挑战，以实施深度测序技术，以加强目前在不同儿科人群中的新生儿筛查。总体目标1将评价水环境统计作为诊断工具的效用，以扩大目前国家统计局的效用。使用不同的队列的婴儿和幼儿与已知的条件，通过NBS确定，我们将检查的敏感性和特异性WES。我们还将利用WES在目前尚未筛选为NBS潜在候选人的已知条件的儿童队列中。总体目标2将根据伦理学和循证医学的原则，在临床导向的框架内制定和评估分析WES的框架。我们将制定战略，指导临床医生，临床实验室和患者/家庭就不可避免的偶然发现做出决定，这些发现将以尊重儿童和保护其未来自主权的方式进行检测，同时也尊重父母的利益和权利。总体目标3将探讨知情决策中涉及的伦理、法律的和社会问题，并制定有关检测后返回结果的最佳做法。我们将开发新的决策支持工具，并评估其在父母决策中的有用性，并检查临床医生的负担，因为这项新技术被部署在新生儿及其家庭的脆弱和特殊人群中。 相关性：基因组医学通过促进更准确的诊断、更深入地了解疾病机制以及针对性的预防和治疗，在改善儿童健康方面具有巨大的潜力。这一建议与公共卫生有关，因为在基因组医学在新生儿筛查中广泛应用之前，仍需解决关键挑战。

DESCRIPTION (provided by applicant): Since newborn screening (NBS) began in the 1960's, technological advances have resulted in its use in an increasing number of disorders. Recent developments in whole genome sequencing and its simpler corollary, whole exome sequencing (WES), now afford the opportunity to comprehensively define the variation within an individual's genome in a rapid and affordable manner. Many challenges arise with the clinical application of genome-scale sequencing and in deriving practical benefit to infants and children. Its utility in NBS has yet to be demonstrated and its application in the pediatric population requires special examination, not only for potential clinical benefits, but also for the unique ethical challenges it presents. In this proposal, we outline a highly interdisciplinary approach to identifying, confronting and overcoming the major challenges that must be met in order to implement deep sequencing technology to enhance current newborn screening in a diverse pediatric population. Overarching Aim 1 will evaluate the utility of WES as a diagnostic tool to extend the utility of current NBS. Using diverse cohorts of infants and young children with known conditions identified through NBS, we will examine the sensitivity and specificity of WES. We will also utilize WES in cohorts of children with known conditions not currently screened for as potential candidates for NBS in the future. Overarching Aim 2 will develop and assess a framework for analyzing WES in a clinically oriented framework based on principles of ethics and evidence-based medicine. We will develop strategies to guide clinicians, clinical laboratories and patients/families in their decisions regarding the inevitable incidental findings that will be detected in ways that respect the child and protect his/her future autonomy, while also respecting parental interests and rights. Overarching Aim 3 will explore ethical, legal and social issues (ELSl) involved in informed decision-making and develop best practices regarding return of results after testing. We will develop novel decision support tools and evaluate their usefulness in parental decision making, and examine the burdens placed on clinicians as this new technology is deployed in the vulnerable and special population that are newborns and their families. RELEVANCE: Genomic medicine has tremendous potential to improve the health of children by facilitating more accurate diagnosis, deeper insight into mechanisms of disease, and individually targeted prevention and treatment. This proposal is relevant to public health because critical challenges remain to be addressed before genomic medicine can be broadly implemented in the newborn screening context.