Technology development for rapid detection and diagnosis of metabolic disorders

快速检测和诊断代谢紊乱的技术开发

基本信息

  • 批准号:
    8767347
  • 负责人:
  • 金额:
    $ 8.42万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-07-10 至 2015-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION: Inborn errors of metabolism are detected at birth through public newborn screening (NBS) programs using tandem mass spectrometry (MS/MS), with early and definitive diagnosis critical to patient outcomes. However, a number of obstacles contribute to the delayed diagnosis of many diseases, including high rates of false positive screening results, the inability to differentiate disease subtypes, and biochemical heterogeneity leading to discrepancies in test results. Additionally, some disorders are not included in current NBS panels. Here we propose to investigate whether the combination of genetic and metabolite technologies established in our laboratories - based on targeted next-generation sequencing (NGS) and liquid chromatography tandem mass spectrometry (LC-MS/MS) - can shorten the time to diagnosis following an abnormal NBS result, as well as facilitate detection of additional disorders. We will focus on five disorders, three that exemplify the diagnostic challenges described above (VLCADD - very long-chain acyl-CoA dehydrogenase deficiency, GA1 - glutaric acidemia type I, and MMA - methylmalonic acidemia), and two that are not currently screened (OTCD - ornithine transcarbamoylase deficiency, and CPSD - carbamoylphosphate synthetase I deficiency). These disorders are all caused by mitochondrial enzyme defects that impact the homeostasis of a variety of pathways (e.g. amino acid and organic acid metabolism). Our genetic approach of the responsible disease genes utilizes complementary long padlock probes (cLPPs) for multiplex target capture and NGS, which will identify mutations and copy-number variations (CNVs) at clinical-grade accuracy and completeness and at very low cost. The metabolite approach involves a LC-MS/MS multiplex-marker panel combining both the standard NBS panel and additional markers (e.g. small molecule intermediates of energy metabolism). This strategy is based on the finding that metabolic changes detectable on the mitochondria-systems level, which are secondary to the primary enzyme defect identified in NBS, may play a role in the expression of the disease phenotype. Accordingly, our NGS panel of 524 genes not only contains the primary disease-causing genes but also functionally related candidate genes, which we have prioritized using a gene-network analysis of mitochondrial protein-protein interaction data. We will evaluate the performance of the two technologies using whole blood samples from children with confirmed disease and their parents, as well as archived dried blood spot (DBS) specimens from the patients collected at birth and obtained from the California Newborn Screening Program. Data analysis will utilize a new family-based, statistical sequence analysis to eliminate false-negative DNA variants, individual and combined metabolic marker analysis, and a systematic patient disease-phenotype analysis. In collaboration with the California NBS program, our results will contribute to the description and implementation of novel metabolic and genetic markers for screening of inherited metabolic conditions.
产品说明:先天性代谢缺陷在出生时通过公共新生儿筛查(NBS)计划使用串联质谱(MS/MS)检测,早期和明确的诊断对患者的预后至关重要。然而,一些障碍导致许多疾病的延迟诊断,包括高假阳性率的筛查结果,无法进行诊断,以及无法进行诊断。 以区分疾病亚型和生化异质性,导致测试结果的差异。此外,一些疾病不包括在目前的NBS面板。在这里,我们建议研究我们实验室建立的遗传和代谢物技术的组合-基于靶向下一代测序(NGS)和液相色谱串联质谱(LC-MS/MS)-是否可以缩短NBS结果异常后的诊断时间,以及促进其他疾病的检测。我们将着力把握好五个 这些疾病中的三种是上述诊断挑战的疾病(VLCADD -极长链酰基-CoA脱氢酶缺乏症、GA 1-I型谷氨酸血症和MMA -甲基丙二酸血症),两种是目前未筛选的疾病(OTCD -鸟氨酸转氨甲酰酶缺乏症和CPSD -氨甲酰磷酸合成酶I缺乏症)。这些疾病都是由线粒体酶缺陷引起的,线粒体酶缺陷影响各种途径(例如氨基酸和有机酸代谢)的稳态。我们的遗传学方法的责任疾病基因利用互补长锁探针(cLPP)的多重目标捕获和NGS,这将确定突变和拷贝数变异(CNV)在临床级的准确性和完整性,并在非常低的成本。代谢物方法涉及LC-MS/MS多重标记物组,其结合了标准NBS组和其他标记物(例如能量代谢的小分子中间体)。这种策略是基于这样的发现,即在NBS中鉴定的主要酶缺陷的继发性代谢系统水平上可检测到的代谢变化可能在疾病表型的表达中起作用。因此,我们的524个基因的NGS面板不仅包含主要致病基因,而且还包含功能相关的候选基因,我们使用线粒体蛋白质-蛋白质相互作用数据的基因网络分析对其进行了优先排序。我们将使用确诊疾病儿童及其父母的全血样本以及出生时采集的患者存档干血斑(DBS)标本和从加州新生儿筛查项目中获得的标本来评估这两种技术的性能。数据分析将利用新的基于家族的统计序列分析来消除假阴性DNA变异、个体和组合代谢标志物分析以及系统的患者疾病表型分析。在与加州国家统计局计划合作,我们的研究结果将有助于描述和实施新的代谢和遗传标记筛选遗传代谢条件。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Curt Scharfe其他文献

Curt Scharfe的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Curt Scharfe', 18)}}的其他基金

Multiplex gene sequencing and metabolomics analysis from newborn dried blood spots to improve screening and diagnosis of metabolic disorders.
对新生儿干血斑进行多重基因测序和代谢组学分析,以改善代谢性疾病的筛查和诊断。
  • 批准号:
    10881231
  • 财政年份:
    2020
  • 资助金额:
    $ 8.42万
  • 项目类别:
Multiplex gene sequencing and metabolomics analysis from newborn dried blood spots to improve screening and diagnosis of metabolic disorders.
对新生儿干血斑进行多重基因测序和代谢组学分析,以改善代谢性疾病的筛查和诊断。
  • 批准号:
    10033377
  • 财政年份:
    2020
  • 资助金额:
    $ 8.42万
  • 项目类别:
Multiplex gene sequencing and metabolomics analysis from newborn dried blood spots to improve screening and diagnosis of metabolic disorders.
对新生儿干血斑进行多重基因测序和代谢组学分析,以改善代谢性疾病的筛查和诊断。
  • 批准号:
    10413215
  • 财政年份:
    2020
  • 资助金额:
    $ 8.42万
  • 项目类别:
Multiplex gene sequencing and metabolomics analysis from newborn dried blood spots to improve screening and diagnosis of metabolic disorders.
对新生儿干血斑进行多重基因测序和代谢组学分析,以改善代谢性疾病的筛查和诊断。
  • 批准号:
    10665559
  • 财政年份:
    2020
  • 资助金额:
    $ 8.42万
  • 项目类别:
Multiplex gene sequencing and metabolomics analysis from newborn dried blood spots to improve screening and diagnosis of metabolic disorders.
对新生儿干血斑进行多重基因测序和代谢组学分析,以改善代谢性疾病的筛查和诊断。
  • 批准号:
    10251254
  • 财政年份:
    2020
  • 资助金额:
    $ 8.42万
  • 项目类别:
Technology development for rapid detection and diagnosis of metabolic disorders
快速检测和诊断代谢紊乱的技术开发
  • 批准号:
    9066438
  • 财政年份:
    2014
  • 资助金额:
    $ 8.42万
  • 项目类别:

相似海外基金

Sediment Drilling Facility for environmental and genetic archives
环境和遗传档案沉积物钻探设施
  • 批准号:
    LE240100064
  • 财政年份:
    2024
  • 资助金额:
    $ 8.42万
  • 项目类别:
    Linkage Infrastructure, Equipment and Facilities
Aerial Archives of Race and American-Occupied Japan
种族和美国占领的日本的航空档案
  • 批准号:
    24K03721
  • 财政年份:
    2024
  • 资助金额:
    $ 8.42万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
CAREER: Understanding biosphere-geosphere coevolution through carbonate-associated phosphate, community archives, and open-access education in rural schools
职业:通过碳酸盐相关磷酸盐、社区档案和农村学校的开放教育了解生物圈-地圈协同进化
  • 批准号:
    2338055
  • 财政年份:
    2024
  • 资助金额:
    $ 8.42万
  • 项目类别:
    Continuing Grant
Designing a Bridging Model Using Learning Content Information LOD to Link School Education and Digital Archives
使用学习内容信息 LOD 设计桥接模型来链接学校教育和数字档案
  • 批准号:
    23H03695
  • 财政年份:
    2023
  • 资助金额:
    $ 8.42万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Doris Lessing's Archives: Communism, Decolonisation and Literary Practice
多丽丝·莱辛档案:共产主义、非殖民化和文学实践
  • 批准号:
    2888789
  • 财政年份:
    2023
  • 资助金额:
    $ 8.42万
  • 项目类别:
    Studentship
Building a sustainable future for anthropology's archives: Researching primary source data lifecycles, infrastructures, and reuse
为人类学档案构建可持续的未来:研究主要源数据生命周期、基础设施和重用
  • 批准号:
    2314762
  • 财政年份:
    2023
  • 资助金额:
    $ 8.42万
  • 项目类别:
    Standard Grant
Reading Writing Lives: Publishing & Preserving Australian Literary Archives
阅读写作生活:出版
  • 批准号:
    DP230101797
  • 财政年份:
    2023
  • 资助金额:
    $ 8.42万
  • 项目类别:
    Discovery Projects
Integrated High-Definition Visualization of Digital Archives for Borobudur Temple
婆罗浮屠寺数字档案集成高清可视化
  • 批准号:
    22KJ3026
  • 财政年份:
    2023
  • 资助金额:
    $ 8.42万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Research on multilingual data integration for digital archives of Japanese culture
日本文化数字档案多语言数据集成研究
  • 批准号:
    23K11780
  • 财政年份:
    2023
  • 资助金额:
    $ 8.42万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
A Preliminary Study for Constructing International Network of Image Archives on Afghan Cultural Heritages
构建阿富汗文化遗产国际图像档案网络的初步研究
  • 批准号:
    23K00915
  • 财政年份:
    2023
  • 资助金额:
    $ 8.42万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了