Precision Medicine in the Diagnosis of Genetic Disorders in Neonates

摘要： 先天畸形和遗传疾病是美国婴儿死亡的主要原因。而当 新生儿筛查(NBS)极大地降低了一些遗传性疾病的婴儿发病率和死亡率， 这些改进并没有对新生儿重症监护病房(NICU)产生重大影响，那里有10- 所有NICU入院的婴儿中有25%是遗传疾病的结果，这些婴儿留在医院 大约比那些没有遗传疾病的人长40%。由于许多项目的非具体介绍 在这些遗传性疾病中，许多婴儿没有得到及时的明确诊断，如果真的有的话。大的， 确定新生儿总体遗传性疾病发病率的综合研究是 缺乏而且直到最近才有可能随着下一代测序方法的出现 作为外显子组和全基因组测序(WGS)。需要精确和快速的分子诊断来优化 在减少死亡率和发病率的同时，提高临床效果。为了避免道德、财务和技术上的 在外显子组和基因组测序方面，我们正在引入一种快速的、有针对性的下一代测序 (TNGS)小组，询问标准干血点是否有与影响表型的基因匹配 新生儿群体，并有可能检测出孟德尔病毒98%的临床相关序列变异 遗传性疾病的发病率和死亡率最高。在这里，我们将进行一项多中心的前瞻性试验 检验一种精密新生儿药物的诊断效果、临床实用性和经济影响。 通过六个领先的CTSA站点和行业的公私合作伙伴关系进一步发展 TNG方法论。我们将确定诊断时间、开始适当治疗的时间 (或姑息治疗)，以及400名体征/症状与基因一致的高危新生儿的总费用 将标准诊断程序与TNG和WGS进行比较。本研究旨在：1)评估 多重(多基因)诊断试验(TNGs、WGS)对入院婴儿的疗效和临床应用 NICU；2)比较临床多重测序对高危新生儿的经济影响 符合当前护理诊断测试标准；以及3)开发和评估电子设备的使用 加速结果返回机制(包括现有治疗和 公开临床试验)。这项建议的首要目标是检查临床效用和 对高危新生儿进行新生儿基因分析的操作基础设施，以确定是否会 以比标准诊断低得多的成本提供更及时的诊断和更好的护理 CARE或WGS，为CTSA广泛的新生儿精准医学计划奠定了基础。

Abstract: Congenital abnormalities and genetic diseases are a leading cause of infant mortality in the US1. While newborn screening (NBS) has dramatically reduced infant morbidity and mortality for some genetic disorders, these improvements have not had a significant impact in Neonatal Intensive Care Units (NICU) where 10 - 25% of all NICU admissions are the result of a genetic disease, with these infants staying in the hospital approximately 40% longer than those without genetic conditions. Due to the non-specific presentation of many of these genetic disorders, many infants do not receive a definitive diagnosis in a timely fashion, if at all. Large, comprehensive studies to determine the overall incidence of genetic disease in the neonatal population are lacking and have only recently been possible with the advent of next generation sequencing methodology such as exome and whole genome sequencing (WGS). Precise and rapid molecular diagnosis is needed to optimize clinical outcomes while reducing mortality and morbidity. In order to avoid the ethical, financial and technical aspects of exome and genome sequencing, we are introducing a rapid, targeted, next-generation sequencing (TNGS) panel that interrogates standard dried blood spots for genes matched to phenotypes affecting the neonatal population and has the potential to detect >98% of clinically relevant sequence variants for Mendelian inherited disorders with the highest morbidity and mortality. Here, we will conduct a multicenter prospective trial to examine the diagnostic efficacy, clinical utility and economic impact of a precision neonatal medicine approach through a public-private partnership among six leading CTSA sites and industry to further develop the TNGS methodology. We will characterize the time to diagnosis, time to initiation of appropriate treatment (or palliative care), and total costs in 400 high-risk neonates with signs/symptoms consistent with a genetic disorder, comparing standard diagnostic procedures to TNGS and WGS. This study aims to: 1) Assess the efficacy and the clinical utility of multiplexed (multi-gene) diagnostic tests (TNGS, WGS) for infants admitted to the NICU; 2) Examine the economic impact of clinical multiplexed sequencing in high-risk neonates compared with current standard of care diagnostic testing; and 3) Develop and evaluate the use of an electronic mechanism for accelerated results return (including any supporting documentation of existing treatments and open clinical trials). The overarching goal of this proposal is to examine the clinical utility and operational infrastructure of a neonatal gene panel in high-risk neonates in order to determine if it will provide a more timely diagnosis and better care at significantly lower cost than standard diagnostic care or WGS, establishing the foundation for a CTSA wide Neonatal Precision Medicine Program.