Precision Medicine in the Diagnosis of Genetic Disorders in Neonates

精准医学在新生儿遗传性疾病诊断中的应用

• 批准号: 10460478
• 负责人: Jonathan M. Davis
• 金额: $ 164.57万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10460478
• 关键词: Admission activity; Adopted; Adult; Affect; Birth Weight; Blood; Caring; Child; Clinical; Clinical Management; Clinical Trials; Computerized Medical Record; Congenital Abnormality; Copy Number Polymorphism; Data; Data Analyses; Detection; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic tests; Diet; Disease; Documentation; Economics; Emerging Technologies; Enrollment; Ethics; Etiology; Fathers; Foundations; Genes; Genetic; Genetic Diseases; Genome; Genomics; Genotype; Goals; Guidelines; Health; Health Insurance Portability and Accountability Act; Health Personnel; Hereditary Disease; Hospital Costs; Hospitals; Incidence; Industry; Infant; Infant Mortality; Infrastructure; Intervention; Investigation; Length of Stay; Life Cycle Stages; Measures; Medical; Medicine; Mendelian disorder; Methodology; Modality; Modeling; Molecular Diagnosis; Morbidity - disease rate; Mothers; Neonatal; Neonatal Intensive Care Units; Neonatal Mortality; Neonatal Screening; North Carolina; Notification; Onset of illness; Operative Surgical Procedures; Outcome; Palliative Care; Patients; Pharmaceutical Preparations; Phenotype; Philosophy; Population; Pregnancy; Prospective Studies; Provider; Reflex action; Repetitive Sequence; Signs and Symptoms; Site; Spottings; Support Groups; Technology; Testing; Therapeutic; Time; Translations; Universities; Update; Variant; base; care costs; clinically relevant; comparative; cost; cost effective; diagnostic accuracy; diagnostic value; direct application; economic evaluation; economic impact; exome; exome sequencing; experimental study; functional disability; gene panel; genetic disorder diagnosis; genome sequencing; genome-wide; high risk; high risk infant; improved; improved outcome; infant morbidity/mortality; models and simulation; mortality; neonatal care; neonatal morbidity; neonatal period; neonate; next generation sequencing; novel strategies; precision medicine; proband; programs; prospective; provider portal; public-private partnership; research clinical testing; sequencing platform; standard of care; targeted treatment; tool; treatment planning; user-friendly; variant of unknown significance; web portal; whole genome

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.

抽象的： 先天畸形和遗传疾病是美国婴儿死亡的主要原因1。尽管 新生儿筛查 (NBS) 显着降低了某些遗传性疾病的婴儿发病率和死亡率， 这些改进并未对新生儿重症监护病房 (NICU) 产生重大影响，其中 10 - 25% 的新生儿重症监护病房 (NICU) 入院婴儿因遗传病而住院 比没有遗传条件的人长约 40%。由于很多人的表述不够具体 对于这些遗传性疾病，许多婴儿没有及时得到明确的诊断（如果有的话）。大的， 确定新生儿群体遗传病总体发病率的综合研究 缺乏，直到最近随着下一代测序方法的出现才成为可能，例如 如外显子组和全基因组测序（WGS）。需要精确快速的分子诊断来优化 临床结果，同时降低死亡率和发病率。为了避免道德、财务和技术方面的问题 在外显子组和基因组测序方面，我们正在推出快速、有针对性的下一代测序 (TNGS) 小组，询问标准干血斑中与影响表型的基因相匹配的基因 新生儿人群，有潜力检测 > 98% 的孟德尔临床相关序列变异 发病率和死亡率最高的遗传性疾病。在这里，我们将进行多中心前瞻性试验 检查精准新生儿医学的诊断功效、临床效用和经济影响 通过六个领先的 CTSA 站点和行业之间的公私合作伙伴关系，进一步发展 TNGS 方法。我们将描述诊断时间、开始适当治疗的时间 （或姑息治疗），以及 400 名具有与遗传一致的体征/症状的高危新生儿的总费用 疾病，将标准诊断程序与 TNGS 和 WGS 进行比较。本研究的目的是： 1) 评估 多重（多基因）诊断测试（TNGS、WGS）对入院婴儿的功效和临床实用性 新生儿重症监护室； 2) 比较临床多重测序对高危新生儿的经济影响 符合当前的护理诊断测试标准； 3) 开发并评估电子设备的使用 加速结果返回的机制（包括现有治疗的任何支持文件和 开放临床试验）。该提案的总体目标是检查临床效用和 高危新生儿新生儿基因组的运营基础设施，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 护理或 WGS，为 CTSA 范围内的新生儿精准医学计划奠定了基础。

项目成果

2022: a pivotal year for diagnosis and treatment of rare genetic diseases.

• DOI: 10.1101/mcs.a006204
• 发表时间: 2022-03
• 期刊: Cold Spring Harbor molecular case studies
• 影响因子: 1.8
• 作者: Kingsmore SF

An automated 13.5 hour system for scalable diagnosis and acute management guidance for genetic diseases.

• DOI: 10.1038/s41467-022-31446-6
• 发表时间: 2022-07-26
• 期刊: Nature communications
• 影响因子: 16.6

Diagnosis of genetic diseases in seriously ill children by rapid whole-genome sequencing and automated phenotyping and interpretation.

• DOI: 10.1126/scitranslmed.aat6177
• 发表时间: 2019-04-24
• 期刊: Science translational medicine
• 影响因子: 17.1

The Role of Genome Sequencing in Neonatal Intensive Care Units.

• DOI: 10.1146/annurev-genom-120921-103442
• 发表时间: 2022-08-31
• 期刊: Annual review of genomics and human genetics
• 影响因子: 8.7

Rapid Whole-Genomic Sequencing and a Targeted Neonatal Gene Panel in Infants With a Suspected Genetic Disorder.

对疑似遗传性疾病婴儿进行快速全基因组测序和靶向新生儿基因组。

• DOI: 10.1001/jama.2023.9350
• 发表时间: 2023
• 期刊: JAMA
• 作者: Maron,JillL;Kingsmore,Stephen;Gelb,BruceD;Vockley,Jerry;Wigby,Kristen;Bragg,Jennifer;Stroustrup,Annemarie;Poindexter,Brenda;Suhrie,Kristen;Kim,JaeH;Diacovo,Thomas;Powell,CynthiaM;Trembath,Andrea;Guidugli,Lucia;Ellsworth,Ka
• 通讯作者: Ellsworth,Ka