Administrative Supplement for Leigh Syndrome Spectrum Expert Panel Curation

利氏综合征谱专家小组管理的行政补充

基本信息

  • 批准号:
    10225911
  • 负责人:
  • 金额:
    $ 7.8万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-08-01 至 2021-05-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY. Mitochondrial disease is a highly phenotypically and genetically heterogeneous group of progressive, multi-system disorders affecting 1 in 4,300 people due to impaired cellular energy metabolism. Many mitochondrial disorders fall within the NICHD high priority clinical domain, which involves a broad spectrum of neurodevelopmental disabilities including autism. The common pediatric mitochondrial disease presentations termed Leigh syndrome (LS) or Leigh-like syndrome (LLS), which can be caused by mutations in approximately 90 genes across both nuclear and mitochondrial genomes, are linked with intellectual and neurodevelopmental disabilities, infection susceptibility that often precipitates neurodevelopmental regression, metabolic strokes in basal ganglia and deep brain structures at any point in childhood including, in some cases, in the newborn period that is associated with primary lactic acidosis from birth and early demise, with an overall 35% mortality in childhood. Establishing an accurate genetic diagnosis of these diverse pediatric mitochondrial encephalopathy syndromes is critically important, as an increasing number have clinical actionability involving initiation or avoidance of specific medications, cofactors, or diets. Accurate diagnosis currently remains challenging, as there is no expertly-curated and comprehensive catalogue of pathogenic LS, LLS, and other gene mutations to guide diagnosis and clinical actionability. Since 2012, the project PIs have co-led the international Mitochondrial Disease Sequence Data Resource (MSeqDR) consortium to organize and curate mitochondrial disease genomic knowledge, analysis and sharing tools, and phenotypes. This organized MSeqDR community structure and committed international expertise is now poised to collaboratively curate genes and variants relevant to the most prevalent and treatable mitochondrial LS and LLS pediatric encephalopathy syndromes using ClinGen resources and curation tools. Aim 1. To complete gene-disease association expert curation for all pediatric mitochondrial encephalopathy syndromes with neurodevelopmental disability in the Leigh and Leigh-like spectrum. We will utilize the ClinGen gene curation tools and frameworks to review the gene-disease relationship for approximately 90 genes that cause LS, LLS, and other pediatric mitochondrial encephalopathy syndromes. We have brought together 32 leading international experts from 11 countries to collaboratively analyze all relevant data and achieve consensus in this important gene-disease curation effort. Aim 2. To expertly curate variants in the most prevalent and treatable pediatric-onset mitochondrial encephalopathy nuclear and mtDNA genes. Nuclear genes causing the most prevalent (SURF1, POLG, FBXL4) and treatable (SLC19A3, BTD, PDSS2, PDHA1, TPK1, ACAD9, ETHE1, HIBCH) pediatric-onset LS and LLS will be prioritized. In addition, our global network of leading mtDNA disease experts will evaluate the mtDNA variant pathogenicity assertions for mtDNA- associated pediatric LS and LLS genes, starting with the 3 most common causes (ATP6, ND5, MT-TL).
项目摘要。线粒体疾病是一个高度表型和遗传异质性的群体 由于细胞能量代谢受损,4,300人中有1人患有进行性多系统疾病。 许多线粒体疾病属于NICHD高优先级临床领域,其涉及广泛的 包括自闭症在内的神经发育障碍。常见的小儿线粒体疾病 Leigh综合征(LS)或Leigh样综合征(LLS),可由以下突变引起: 大约90个基因在核和线粒体基因组中,与智力和 神经发育障碍,感染易感性,往往沉淀神经发育退化, 在儿童期的任何时候,基底神经节和深部脑结构中的代谢性中风, 例,在新生儿期,与原发性乳酸酸中毒从出生和早期死亡, 儿童死亡率为35%。对这些不同的儿科疾病建立准确的基因诊断 线粒体脑病综合征是至关重要的,因为越来越多的临床 涉及开始或避免特定药物、辅助因子或饮食的可作用性。准确诊断 目前仍然具有挑战性,因为没有专门策划和全面的致病LS目录, LLS和其他基因突变,以指导诊断和临床可行性。自2012年以来,项目PI 共同领导国际线粒体疾病序列数据资源(MSeqDR)联盟, 和策划线粒体疾病基因组知识,分析和共享工具,和表型。这 有组织的MSeqDR社区结构和承诺的国际专业知识现在准备合作, 筛选与最常见和可治疗的线粒体LS和LLS儿科相关的基因和变异 使用ClinGen资源和治疗工具。目标1。完成基因-疾病 所有儿童线粒体脑病综合征的协会专家策展, 神经发育障碍的症状我们将利用ClinGen基因 策展工具和框架,以审查约90个基因的基因-疾病关系,导致 LS、LLS和其他儿科线粒体脑病综合征。我们召集了32个领先的 来自11个国家的国际专家合作分析所有相关数据,并达成共识, 这个重要的基因疾病治疗项目目标2.为了熟练地策划最流行的变体, 可治疗的小儿线粒体脑病核和mtDNA基因。核基因 引起最普遍的(SURF 1,POLG,FBXL 4)和可治疗的(SLC 19 A3,BTD,PDSS 2,PDHA 1,TPK 1, ACAD 9、ETHE 1、HIBCH)儿科发作LS和LLS将优先考虑。此外,我们的全球网络 领先的mtDNA疾病专家将评估mtDNA变异致病性断言, 相关的儿科LS和LLS基因,从3个最常见的原因(ATP 6,ND 5,MT-TL)开始。

项目成果

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MARNI J FALK其他文献

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{{ truncateString('MARNI J FALK', 18)}}的其他基金

Genomics & Data Integration Core
基因组学
  • 批准号:
    10450696
  • 财政年份:
    2021
  • 资助金额:
    $ 7.8万
  • 项目类别:
Genomics & Data Integration Core
基因组学
  • 批准号:
    10240002
  • 财政年份:
    2021
  • 资助金额:
    $ 7.8万
  • 项目类别:
Genomics & Data Integration Core
基因组学
  • 批准号:
    10678899
  • 财政年份:
    2021
  • 资助金额:
    $ 7.8万
  • 项目类别:
Administrative Supplement - Mitochondrial respiratory chain disease mechanistic and therapeutic modeling
行政补充-线粒体呼吸链疾病机制和治疗模型
  • 批准号:
    10798475
  • 财政年份:
    2020
  • 资助金额:
    $ 7.8万
  • 项目类别:
Mitochondrial respiratory chain disease mechanistic and therapeutic modeling
线粒体呼吸链疾病机制和治疗模型
  • 批准号:
    10569023
  • 财政年份:
    2020
  • 资助金额:
    $ 7.8万
  • 项目类别:
Mitochondrial respiratory chain disease mechanistic and therapeutic modeling
线粒体呼吸链疾病机制和治疗模型
  • 批准号:
    10343742
  • 财政年份:
    2020
  • 资助金额:
    $ 7.8万
  • 项目类别:
Administrative Supplement (Undergraduate Summer Research Experiences) - Mitochondrial respiratory chain disease mechanistic and therapeutic modeling
行政补充(本科生暑期研究经历)-线粒体呼吸链疾病机制和治疗模型
  • 批准号:
    10809930
  • 财政年份:
    2020
  • 资助金额:
    $ 7.8万
  • 项目类别:
Primary Mitochondrial Disease Expert Curation Panel
原发性线粒体疾病专家小组
  • 批准号:
    10696934
  • 财政年份:
    2017
  • 资助金额:
    $ 7.8万
  • 项目类别:
Primary Mitochondrial Disease Expert Curation Panel
原发性线粒体疾病专家小组
  • 批准号:
    10173437
  • 财政年份:
    2017
  • 资助金额:
    $ 7.8万
  • 项目类别:
Primary Mitochondrial Disease Expert Curation Panel
原发性线粒体疾病专家小组
  • 批准号:
    10480773
  • 财政年份:
    2017
  • 资助金额:
    $ 7.8万
  • 项目类别:

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