Identifying Pathogenic Non-Coding Mutations in Rare Mendelian Disease

鉴定罕见孟德尔病的致病性非编码突变

基本信息

  • 批准号:
    9806572
  • 负责人:
  • 金额:
    $ 19.65万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-08-07 至 2021-05-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT Determining new causes for rare and common disease would have major and immediate benefits for patients and their families by improved genetic testing, genetic counseling, insurance reimbursement, and ultimately more effective treatment options. Our long term goal is to disruptively improve and expand genetic testing for rare and common disease. Current diagnostic tests only consider pathogenic variants in protein-coding genes. However, we now have evidence that a substantial fraction of rare disease is due to unknown non-coding genetic variants that influence the regulation of those genes. The goal of this proposal is to identify and quantify the effect of pathogenic non-coding genetic variants on the function and expression of genes that cause rare disease. This initial step will enable treatment early in life when it is still possible to stop the most severe consequences of disease, including death. We will focus on severe early-onset pediatric disorders, including glycogen storage diseases (GSD I, II, III, IV, and IX), and the fatty acid oxidation disorders, very long-chain acyl-CoA dehydrogenase deficiency (VLCAD), and multiple acyl-CoA dehydrogenase deficiency (MADD). To date, genetic tests for these and other diseases are limited to protein-coding mutations. However, our clinical team has collected numerous cases that have a single pathogenic coding variant on only one of the two alleles that must be both affected in these recessive disorders. We also have biochemical and biomarker evidence that supports the diagnosis. Those cases are an ideal opportunity to identify additional disease-causing variants. Our hypothesis is that the genetic causes of recessive disorders include novel genetic variants that can alter either protein sequence (Aim 1), splicing (Aim 2), or gene expression (Aim 3) of disease genes. We have assembled a team of Pediatric clinicians who are experts in GSDs, VLCAD, and MADD, as well as researchers who are experts in genetics, genomics, epigenetic regulation, biomedical engineering, and statistics. This team has obtained patient samples and received Duke IRB approval to begin immediately. We expect this study will identify and validate novel genetic variants that influence disease. While we propose to study a relatively small subset of rare disorders, these strategies will be immediately generalizable to any patient sample with any recessive disorder that has inconclusive genetic testing results. That outcome will provide comprehensive genetic testing, better understanding of disease mechanisms, and ultimately better treatment options.
摘要 确定罕见和常见疾病的新原因将带来重大和直接的好处 通过改进基因检测、遗传咨询、保险等方式, 最后是更有效的治疗方案。我们的长期目标是 颠覆性地改善和扩大罕见和常见疾病的基因检测。电流诊断 测试仅考虑蛋白质编码基因中的致病性变体。但是我们现在有证据表明 很大一部分罕见疾病是由于未知的非编码遗传变异, 影响这些基因的调节。本提案的目标是确定和量化 致病性非编码基因变异对基因功能和表达的影响 导致罕见疾病的基因这一初始步骤将使治疗在生命的早期,当它仍然是 可以阻止疾病最严重的后果,包括死亡。我们将专注于 严重早发性儿科疾病,包括糖原累积病(GSD I、II、III、IV和IV) IX)、脂肪酸氧化障碍、极长链酰基辅酶A脱氢酶缺乏 (VLCAD)和多重酰基辅酶A脱氢酶缺乏症(MADD)。迄今为止, 这些和其它疾病限于蛋白质编码突变。然而,我们的临床团队 我收集了大量病例,这些病例在两个基因中的一个上只有一个致病性编码变异, 在这些隐性疾病中必须同时受到影响的等位基因。我们也有生物化学和 支持诊断的生物标志物证据。这些案件是一个理想的机会, 其他致病变种。我们的假设是隐性遗传的遗传原因 疾病包括新的遗传变异,可以改变蛋白质序列(Aim 1),剪接 (Aim 2),或疾病基因的基因表达(Aim 3)。我们组建了一个儿科团队 GSD、VLCAD和MADD方面的专家临床医生,以及 在遗传学,基因组学,表观遗传调控,生物医学工程和统计学。这支球队 已获得患者样本并获得杜克IRB批准立即开始。我们预计 这项研究将确定和验证影响疾病的新的遗传变异。在我们提议 为了研究一个相对较小的罕见疾病子集,这些策略将立即 可推广到任何患者样本的任何隐性疾病,具有不确定的遗传 测试结果这一结果将提供全面的基因检测,更好地了解 疾病机制,最终更好的治疗方案。

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 }}

GREGORY E CRAWFORD其他文献

GREGORY E CRAWFORD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('GREGORY E CRAWFORD', 18)}}的其他基金

Beyond GWAS: High Throughput Functional Genomics & Epigenome Editing to Elucidate the Effects of Genetic Associations for Schizophrenia
超越 GWAS:高通量功能基因组学
  • 批准号:
    10377555
  • 财政年份:
    2021
  • 资助金额:
    $ 19.65万
  • 项目类别:
Genomics, variation, and evolution of cerebellar circuits linked to higher cognitive functions in humans
与人类高级认知功能相关的小脑回路的基因组学、变异和进化
  • 批准号:
    10375139
  • 财政年份:
    2021
  • 资助金额:
    $ 19.65万
  • 项目类别:
High-Throughput Functional Annotation of Gene Regulatory Elements and Variants Critical to Complex Cellular Phenotypes
对复杂细胞表型至关重要的基因调控元件和变异体的高通量功能注释
  • 批准号:
    10297406
  • 财政年份:
    2021
  • 资助金额:
    $ 19.65万
  • 项目类别:
High-Throughput Functional Annotation of Gene Regulatory Elements and Variants Critical to Complex Cellular Phenotypes
对复杂细胞表型至关重要的基因调控元件和变异体的高通量功能注释
  • 批准号:
    10689190
  • 财政年份:
    2021
  • 资助金额:
    $ 19.65万
  • 项目类别:
Regulatory Mechanisms of CD4+ T Cell Differentiation
CD4 T细胞分化的调控机制
  • 批准号:
    10240966
  • 财政年份:
    2021
  • 资助金额:
    $ 19.65万
  • 项目类别:
Beyond GWAS: High Throughput Functional Genomics & Epigenome Editing to Elucidate the Effects of Genetic Associations for Schizophrenia
超越 GWAS:高通量功能基因组学
  • 批准号:
    10115982
  • 财政年份:
    2021
  • 资助金额:
    $ 19.65万
  • 项目类别:
Genomics, variation, and evolution of cerebellar circuits linked to higher cognitive functions in humans
与人类高级认知功能相关的小脑回路的基因组学、变异和进化
  • 批准号:
    10440526
  • 财政年份:
    2021
  • 资助金额:
    $ 19.65万
  • 项目类别:
High-Throughput Functional Annotation of Gene Regulatory Elements and Variants Critical to Complex Cellular Phenotypes
对复杂细胞表型至关重要的基因调控元件和变异体的高通量功能注释
  • 批准号:
    10475750
  • 财政年份:
    2021
  • 资助金额:
    $ 19.65万
  • 项目类别:
Beyond GWAS: High Throughput Functional Genomics & Epigenome Editing to Elucidate the Effects of Genetic Associations for Schizophrenia
超越 GWAS:高通量功能基因组学
  • 批准号:
    10573335
  • 财政年份:
    2021
  • 资助金额:
    $ 19.65万
  • 项目类别:
3/3 Chromatin regulation during brain development and in ASD
3/3 大脑发育和自闭症谱系障碍中的染色质调节
  • 批准号:
    9727072
  • 财政年份:
    2018
  • 资助金额:
    $ 19.65万
  • 项目类别:

相似海外基金

Linkage of HIV amino acid variants to protective host alleles at CHD1L and HLA class I loci in an African population
非洲人群中 HIV 氨基酸变异与 CHD1L 和 HLA I 类基因座的保护性宿主等位基因的关联
  • 批准号:
    502556
  • 财政年份:
    2024
  • 资助金额:
    $ 19.65万
  • 项目类别:
Olfactory Epithelium Responses to Human APOE Alleles
嗅觉上皮对人类 APOE 等位基因的反应
  • 批准号:
    10659303
  • 财政年份:
    2023
  • 资助金额:
    $ 19.65万
  • 项目类别:
Deeply analyzing MHC class I-restricted peptide presentation mechanistics across alleles, pathways, and disease coupled with TCR discovery/characterization
深入分析跨等位基因、通路和疾病的 MHC I 类限制性肽呈递机制以及 TCR 发现/表征
  • 批准号:
    10674405
  • 财政年份:
    2023
  • 资助金额:
    $ 19.65万
  • 项目类别:
An off-the-shelf tumor cell vaccine with HLA-matching alleles for the personalized treatment of advanced solid tumors
具有 HLA 匹配等位基因的现成肿瘤细胞疫苗,用于晚期实体瘤的个性化治疗
  • 批准号:
    10758772
  • 财政年份:
    2023
  • 资助金额:
    $ 19.65万
  • 项目类别:
Identifying genetic variants that modify the effect size of ApoE alleles on late-onset Alzheimer's disease risk
识别改变 ApoE 等位基因对迟发性阿尔茨海默病风险影响大小的遗传变异
  • 批准号:
    10676499
  • 财政年份:
    2023
  • 资助金额:
    $ 19.65万
  • 项目类别:
New statistical approaches to mapping the functional impact of HLA alleles in multimodal complex disease datasets
绘制多模式复杂疾病数据集中 HLA 等位基因功能影响的新统计方法
  • 批准号:
    2748611
  • 财政年份:
    2022
  • 资助金额:
    $ 19.65万
  • 项目类别:
    Studentship
Genome and epigenome editing of induced pluripotent stem cells for investigating osteoarthritis risk alleles
诱导多能干细胞的基因组和表观基因组编辑用于研究骨关节炎风险等位基因
  • 批准号:
    10532032
  • 财政年份:
    2022
  • 资助金额:
    $ 19.65万
  • 项目类别:
Recessive lethal alleles linked to seed abortion and their effect on fruit development in blueberries
与种子败育相关的隐性致死等位基因及其对蓝莓果实发育的影响
  • 批准号:
    22K05630
  • 财政年份:
    2022
  • 资助金额:
    $ 19.65万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Investigating the Effect of APOE Alleles on Neuro-Immunity of Human Brain Borders in Normal Aging and Alzheimer's Disease Using Single-Cell Multi-Omics and In Vitro Organoids
使用单细胞多组学和体外类器官研究 APOE 等位基因对正常衰老和阿尔茨海默病中人脑边界神经免疫的影响
  • 批准号:
    10525070
  • 财政年份:
    2022
  • 资助金额:
    $ 19.65万
  • 项目类别:
Leveraging the Evolutionary History to Improve Identification of Trait-Associated Alleles and Risk Stratification Models in Native Hawaiians
利用进化历史来改进夏威夷原住民性状相关等位基因的识别和风险分层模型
  • 批准号:
    10689017
  • 财政年份:
    2022
  • 资助金额:
    $ 19.65万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了