Clinical Diagnostic Sequencing of Structural Variation

结构变异的临床诊断测序

基本信息

  • 批准号:
    9230412
  • 负责人:
  • 金额:
    $ 71.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-04-01 至 2020-02-29
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): This project proposes an innovative, low-cost whole-genome sequencing (WGS) test for the genome-wide delineation of structural variation (SV) to capture the full spectrum of pathogenic variation that is currently detected by two lower-resolution methods. Genome-wide SV studies are the ACMG recommended first-tier diagnostic screen for a myriad of congenital anomalies, including autism spectrum disorder. Diagnostic SV screening relies on karyotyping or chromosomal microarray (CMA). Karyotyping can detect balanced chromosomal rearrangements (BCRs) at microscopic resolution but is insensitive to smaller alterations, whereas CMA can detect copy number variants (CNVs) but not BCRs. At present, no validated genome-wide method can identify both BCRs and CMA-resolution CNVs in a single diagnostic test, leaving inevitable blind spots depending on the technology chosen. Moreover, submicroscopic, or `cryptic', BCRs are intractable to all conventional diagnostics and represent one of the last unexplored spaces of genomic variation. We have shown that large-insert WGS, or `jumping' libraries, can delineate both BCRs and CNVs in a research capacity. We have also recently demonstrated its clinical potential by providing an in utero prenatal diagnosis (Talkowski et al., 2012, N Engl J Med). In a paper published back-to-back with our prenatal sequencing, Co-I Wapner and colleagues validated CMA as the preferred method for prenatal diagnostics through an NICHD consortium of 4,340 prenatal samples with both karyotyping and CMA (Wapner et al., 2012, N Engl J Med). Here, we propose to validate jumping library sequencing for routine SV detection in these well-characterized prenatal samples. We will perform a critical validation in Aim 1 to determine the sensitivity of our sequencing method to capture all pathogenic SVs detected by karyotyping and CMA, with the benefit of precise sequence resolution for gene discovery. In Aim 2, we will calibrate the added diagnostic value of cryptic SVs in at least 400 trios from the highest yield diagnostic cohort (ultrasound defects) for which conventional methods failed to detect a causative mutation. Our preliminary data suggest that cryptic SVs account for 5.3-9.4% of pathogenic mutations; an important component of the diagnostic yield that is presently uncharacterized. In Aim 3, we will integrate CMA data from a consortium of academic and commercial diagnostic sites with the exome aggregation project at the Broad Institute, which will collectively represent an amalgamation of >200,000 subjects. We will compare diagnostic yield from conventional criteria to a quantitative risk score based on the convergence of genomics datasets. The final product will be the validation of a single sequencing platform to overcome the limitations of two lower-resolution methods, the determination of clinical yield from a currently uncharacterized class of genomic variation, and the creation of a publicly accessible genome annotation resource. This project could have an immediate and transformative impact on genetic diagnostic practice.
 描述(由申请人提供):该项目提出了一种创新的、低成本的全基因组测序(WGS)测试,用于全基因组范围内的结构变异(SV)描绘,以捕获目前通过两种较低分辨率方法检测到的致病性变异的全谱。全基因组SV研究是ACMG推荐的用于无数先天性异常(包括自闭症谱系障碍)的第一级诊断筛查。诊断性SV筛查依赖于核型分析或染色体微阵列(CMA)。核型分析可以在显微镜分辨率下检测平衡染色体重排(BCR),但对较小的改变不敏感,而CMA可以检测拷贝数变异(CNV),但不能检测BCR。目前,还没有经过验证的全基因组方法可以在单一诊断测试中识别BCR和CMA分辨率CNV,根据所选择的技术留下不可避免的盲点。此外,亚微观或“神秘”的BCR对所有常规诊断都是难以处理的,并且代表了基因组变异的最后未开发空间之一。我们已经表明,大插入WGS,或'跳跃'库,可以描绘BCR和CNV的研究能力。我们最近还通过提供子宫内产前诊断证明了其临床潜力(Talkowski等人,2012,N Engl J Med)。在与我们的产前测序背靠背发表的一篇论文中,Co-I Wapner及其同事通过具有核型分析和CMA的4,340个产前样本的NICHD联盟验证了CMA是产前诊断的优选方法(Wapner et al.,2012,N Engl J Med)。在这里,我们建议验证跳跃文库测序常规SV检测在这些良好的特点产前样本。我们将在目标1中进行关键验证,以确定我们的测序方法捕获通过核型分析和CMA检测到的所有致病性SV的灵敏度,并受益于基因发现的精确序列分辨率。在目标2中,我们将在来自最高产量诊断队列(超声缺陷)的至少400个trios中校准隐藏SV的附加诊断价值,对于这些trios,常规方法未能检测到致病突变。我们的初步数据表明,隐性SV占致病性突变的5.3-9.4%,是目前尚未表征的诊断率的重要组成部分。在目标3中,我们将整合来自学术和商业诊断网站联盟的CMA数据与布罗德研究所的外显子组聚合项目,这将共同代表超过200,000名受试者的合并。我们将比较常规标准的诊断率与基于基因组学数据集收敛的定量风险评分。最终产品将是一个单一测序平台的验证,以克服两种低分辨率方法的局限性,从目前未表征的一类基因组变异中确定临床产量,并创建一个可公开访问的基因组注释资源。该项目可能对遗传诊断实践产生直接和变革性的影响。

项目成果

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MICHAEL E TALKOWSKI其他文献

MICHAEL E TALKOWSKI的其他文献

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{{ truncateString('MICHAEL E TALKOWSKI', 18)}}的其他基金

The Genomic Architecture of Pregnancy Loss
流产的基因组结构
  • 批准号:
    10705318
  • 财政年份:
    2021
  • 资助金额:
    $ 71.51万
  • 项目类别:
Core B - Technical Services
核心 B - 技术服务
  • 批准号:
    10613364
  • 财政年份:
    2021
  • 资助金额:
    $ 71.51万
  • 项目类别:
The Genomic Architecture of Pregnancy Loss
流产的基因组结构
  • 批准号:
    10226655
  • 财政年份:
    2021
  • 资助金额:
    $ 71.51万
  • 项目类别:
Core B - Technical Services
核心 B - 技术服务
  • 批准号:
    10463548
  • 财政年份:
    2021
  • 资助金额:
    $ 71.51万
  • 项目类别:
Scalable tool and comprehensive maps to interpret structural variation across the neuropsychiatric spectrum
可扩展的工具和综合图谱可解释整个神经精神谱系的结构变化
  • 批准号:
    10162661
  • 财政年份:
    2019
  • 资助金额:
    $ 71.51万
  • 项目类别:
Exploring the genetic architecture of structural birth defects
探索结构性出生缺陷的遗传结构
  • 批准号:
    9809586
  • 财政年份:
    2019
  • 资助金额:
    $ 71.51万
  • 项目类别:
Scalable tool and comprehensive maps to interpret structural variation across the neuropsychiatric spectrum
可扩展的工具和综合图谱可解释整个神经精神谱系的结构变化
  • 批准号:
    10414009
  • 财政年份:
    2019
  • 资助金额:
    $ 71.51万
  • 项目类别:
Exploring the genetic architecture of structural birth defects
探索结构性出生缺陷的遗传结构
  • 批准号:
    10004116
  • 财政年份:
    2019
  • 资助金额:
    $ 71.51万
  • 项目类别:
Molecular mechanisms and genetic drivers of reciprocal genomic disorders
相互基因组疾病的分子机制和遗传驱动因素
  • 批准号:
    9982392
  • 财政年份:
    2018
  • 资助金额:
    $ 71.51万
  • 项目类别:
Molecular mechanisms and genetic drivers of reciprocal genomic disorders
相互基因组疾病的分子机制和遗传驱动因素
  • 批准号:
    10224767
  • 财政年份:
    2018
  • 资助金额:
    $ 71.51万
  • 项目类别:

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