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

项目摘要 该计划提供了一个机会，提供丰富的基因组数据资源，以推动儿科疾病的研究。 一个成功的计划的关键因素将是提供高质量的基因组序列数据， 患者及其家属;以直观的方式收集数据并使其可供研究界使用;以及 在该计划的背景下，遗传数据与表型信息的整合以及与其他大型 数据资源。最终的目标是收集一个完整的基因目录，这些基因是结构性出生缺陷的基础， 儿童癌症，并使这些信息的使用，以更好地了解疾病的机制，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 第一个研究计划，就像我们在支持其他大型旗舰NIH基因组项目中所做的那样。我们的中心带来了 领域专长是高通量数据生成、处理和分析以及疾病基因发现， 达到GMKF计划的目标。 我们将在选定的样本上应用深度，高质量的分阶段全基因组测序数据。我们准备 应用我们久经考验的方法从一系列样本类型中提取DNA，最重要的是唾液样本， 石蜡包埋的材料是儿科和癌症研究的关键。在这三年里，我们将 至少18，000个样本推动了新数据类型和更低成本的边界。我们可以灵活地混合不同的队列类型， 无论它们是基于三重（结构性出生缺陷）还是基于四重（癌症研究）。我们将与研究PI合作， 我们已经证明，从10 X Genomics引入新的数据类型将使变异体分阶段成为不同的单倍型 和结构变异发现。我们还将与调查人员合作，进行随访和功能验证， needed. 我们中心的一个主要特点是我们实施了一个强大的分析框架，用于变异评估和疾病评估。 基因发现，它利用了广泛的研究人员在统计遗传学，功能， 注释和临床变异解释以及访问来自250，000多个参考文献的外显子组和基因组数据 样品这使我们能够建立一个系统的基因发现管道， GMKF计划和合作者。通过以一致的方式生成和处理数据，我们可以提供无缝的 将GMKF数据整合到我们的分析框架中。对于许多儿科研究所针对的疾病， 在社区中，有信心发现致病基因将需要在世界各地的中心聚集病例。我们 通过快速发布遗传和表型数据，为临床基因组学中的数据共享提供新标准， 加速合作并促进强大的疾病基因发现。

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.