Genome Sequencing in support of the Gabriella Miller Kids First Pediatric Research Program

项目摘要摘要 这一计划提供了机会，提供丰富的基因组数据资源，推动儿科疾病研究。 一个成功的计划的关键要素将是提供高质量的表型良好的基因组序列数据 患者及其家属；以直观的方式收集数据并向研究界提供数据；以及 将遗传数据与表型信息在该计划的背景下进行整合，并与其他大型 数据资源。最终目标是收集导致结构性出生缺陷的完整基因目录，并 并使儿科癌症能够利用这些信息更好地了解疾病的发病机制、诊断 机会和治疗方向。 我们建议在布罗德研究所建立一个测序中心，为加布里埃拉·米勒的孩子们提供资源 第一研究计划，正如我们在支持其他大型旗舰NIH基因组计划时所做的那样。我们的中心带来了 领域专业知识是高通量数据生成、处理和分析以及疾病基因发现所需的 达到GMKF计划的目标。 我们将在选定的样本上应用深度、高质量的阶段性全基因组测序数据。我们准备好了 应用我们经过良好测试的方法从一系列样本类型中提取DNA，最重要的是唾液样本和 石蜡包埋材料是儿科和癌症研究的关键。在三年时间里，我们将处理 至少18,000个样本突破了新数据类型和更低成本的界限。我们可以灵活地混合使用不同的队列类型， 无论它们是基于三联体(对于结构性出生缺陷)还是四联体(在癌症研究中)。我们将与研究PI合作，以 从10X基因组学引入新的数据类型，我们已经展示了这些数据类型将使变异分阶段形成不同的单倍型 和结构变异的发现。我们还将与调查人员合作，进行后续和功能验证，如 需要的。 我们中心的一个主要特点是我们为变异评估和疾病实施了一个强大的分析框架 基因发现，它利用了远大研究人员在统计遗传学、功能性和功能性研究领域的世界领先地位 注释、临床变异解释以及从超过250,000篇参考文献中获取外显子组和基因组数据 样本。这使我们能够建立一个系统的基因发现管道，将免费提供给 GMKF计划和合作者。通过以一致的方式生产和处理数据，我们可以提供无缝 将GMKF数据集成到我们的分析框架中。对于儿科研究针对的许多疾病 在社区，对因果基因的自信发现将需要世界各地中心的病例汇总。我们 提出通过快速发布遗传和表型数据来实现临床基因组学数据共享的新标准， 加快合作，促进强有力的疾病基因发现。

Project Summary Abstract This program presents the opportunity to provide a rich genomic data resource to propel pediatric disease research. Key elements to a successful program will be the provision of high quality genome sequence data on well-phenotyped patients and their families; the collection and accessibility of data to the research community in an intuitive manner; and the integration of genetic data with phenotypic information in the context of this program and comparison to other large data resources. The ultimate goal is to assemble a complete catalogue of genes that underlie structural birth defects and pediatric cancer and to enable the use of this information to better understand disease mechanism, diagnostic opportunities and therapeutic direction. We propose to establish a sequencing center at the Broad Institute to serve a resource for the Gabriella Miller Kids First Research Program, as we have done in support of other large flagship NIH genome projects. Our center brings the domain expertise is high throughput data generation, processing and analysis and disease gene discovery required to meet the objectives of the GMKF Program. We will apply deep, high-quality phased whole genome sequencing data on selected samples. We are prepared to apply our well-tested methods for extraction of DNA from a range of sample types, most importantly saliva samples and paraffin-embedded material which are key to pediatric and cancer research. Over the three years period we will process at least 18,000 samples pushing the boundary on new data types and lower cost. We are flexible to a mix of cohort types, whether they are trio based (for structural birth defects) or quads (in cancer studies). We will work with study PIs to introduce new data types from 10X Genomics that we have shown will enable phasing of variants into distinct haplotypes and structural variation discovery. We will also work with investigators to perform follow up and functional validation as needed. A key feature of our center is our implementation of a robust analytical framework for variant assessment and disease gene discovery, which takes advantage of Broad investigators' world-leading roles in statistical genetics, functional annotation, and clinical variant interpretation as well as access to exome and genome data from over 250,000 reference samples. This has enabled us to build a systematic pipeline for gene discovery that will be made freely available to the GMKF program and collaborators. With data produce and processed in a consistent way, we can offer seamless integration of GMKF data into our analytic framework. For many of the diseases targeted by pediatric research community, confident discovery of causal genes will require aggregation of cases across centers around the world. We offer to enable a new standard for data sharing in clinical genomics by rapidly releasing genetic and phenotype data, accelerating collaboration and facilitating robust disease gene discovery.