NC NEXUS, North Carolina Newborn Exome Sequencing for Universal Screening

描述(申请人提供)：自20世纪60年代开始新生儿筛查以来，技术的进步使其在越来越多的疾病中得到应用。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。在基因组规模测序的临床应用和为婴儿和儿童获得实际好处方面出现了许多挑战。它在国家统计局中的有效性尚未得到证实，它在儿科人群中的应用需要特殊检查，不仅是为了潜在的临床好处，也是因为它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、面对和克服必须应对的主要挑战，以便实施深度测序技术，以加强目前在多样化儿科人群中的新生儿筛查。总体目标1将评估WES作为一种诊断工具的效用，以扩展当前NBS的效用。使用通过国家统计局确定的已知疾病的婴儿和幼儿的不同队列，我们将检验WES的敏感性和特异性。我们还将在目前未经筛查的已知疾病儿童队列中使用WES作为未来国家统计局的潜在候选者。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开发和评估分析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被发现，同时也尊重父母的利益和权利。总体目标3将探讨知情决策涉及的伦理、法律和社会问题(ELSL)，并制定关于测试后返回结果的最佳做法。我们将开发新的决策支持工具，评估它们在父母决策中的有效性，并研究这项新技术在新生儿及其家人的脆弱和特殊人群中部署时给临床医生带来的负担。

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.