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

我们建议继续提供数据生成和处理活动，以丰富基因组数据 推动儿科疾病研究的资源。一个成功计划的关键要素将是提供 关于表型良好的患者及其家人的高质量基因组序列数据；收集和 以直观的方式向研究界提供数据；以及将遗传数据与 本程序上下文中的表型信息，并与其他大型数据资源进行比较。这个 最终目标是收集构成结构性出生缺陷和儿科疾病的基因的完整目录。 并能够利用这些信息更好地了解癌症的发病机制、诊断 机会和治疗方向。 我们建议继续作为博德研究所的儿童第一测序中心，就像我们为 在过去的三年里，我们为该计划提供了支持，并支持了其他大型旗舰NIH基因组 项目。我们的中心带来的领域专业知识是高通量数据生成、处理和分析， 和疾病基因发现，以满足儿童优先计划的目标。 我们将在选定的样本上应用深度、高质量的全基因组测序数据。我们将变得灵活 密切合作，满足选定的X01调查人员的需求和兴趣。在接下来的三年里- 一年内，我们可以提供多达25,000个样本，推动新数据类型和更低数据类型的界限 成本。我们对队列类型的混合是灵活的，无论他们是基于三人组(结构性出生缺陷)还是四人组 (癌症研究)。我们将与X01调查人员合作，引入新的数据类型，如RNAseq或Long 适当时阅读排序。我们将参与对这些数据类型及其总体的评估 对该计划的发现和科学产出的影响 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来进行变式评估 以及疾病基因发现，它建立在远大研究人员在统计遗传学方面的世界领先地位的基础上， 功能注释、临床变异解释以及访问外显子和基因组数据 布罗德大学对数十万个样本进行了测序。这使我们能够建立一条系统的管道来 将免费提供给儿童优先计划的基因发现。通过生成和处理数据 以一致的方式，我们可以将儿童优先数据无缝集成到我们的分析框架中。对许多人来说 在儿科研究界针对的疾病中，自信地发现因果基因将需要 世界各地各中心的病例汇聚。我们将与儿童第一数据资源合作 以各种方式居中，确保计划与其他大型资源很好地协调一致 发电项目。有了这一点，我们希望首先作为一个整体支持儿童，并建立数据标准 共享临床基因组学，加快合作，促进强大的疾病基因发现。

We propose to continue to provide data generation and processing activities that will enrich a 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 continue as a Kids First Sequencing Center at the Broad Institute as we have done for the past three years for the program and as we have also 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 Kids First Program. We will apply deep, high-quality whole genome sequencing data on selected samples. We will be flexible to work closely and accommodate the needs and interests of selected X01 Investigators. Over the next three- year period we can provide for as many as 25,000 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 X01 Investigators to introduce new data types such as RNASeq or Long Read Sequencing when appropriate. We will participate in the evaluation of these data types and their overall impact on discovery and scientific output of the program A key feature of our center is our implementation of a robust analytical framework for variant assessment and disease gene discovery, which builds on Broad investigators’ world-leading roles in statistical genetics, functional annotation, and clinical variant interpretation as well as access to exome and genome data from hundreds of thousands of samples sequenced at Broad. This has enabled us to build a systematic pipeline for gene discovery that will be made freely available to the Kids First program. With data produced and processed in a consistent way, we can offer seamless integration of Kids First 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 will partner with the Kids First Data Resource Center in a variety of ways to ensure that the program is well-aligned with other large-scale resource generation projects. With this we hope to support Kids First as a whole and establish standards for data sharing in clinical genomics, accelerating collaboration and facilitating robust disease gene discovery.