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

项目摘要/摘要我们建议继续提供数据生成和处理活动，这些活动将丰富基因组数据资源，以推动儿科疾病研究，特别是支持INCLUDE(研究生命周期中的共生情况以了解唐氏综合症)。成功的关键因素将是提供关于表型良好的唐氏综合症患者及其家人的高质量基因组序列数据；以直观的方式收集数据并向研究界提供数据；在该计划的背景下将遗传数据与表型信息相结合，并与其他大型数据资源进行比较。我们的中心带来了高通量数据生成、处理和分析以及疾病基因发现方面的领域专业知识，以满足儿童优先和包括计划的目标。我们将在研究唐氏综合症相关并发症的研究人员提供的样本上应用深度、高质量的全基因组测序和RNA测序数据。我们将灵活地密切合作，并满足选定的包括X01调查人员的需求和兴趣。我们将参与对这些数据类型及其对该计划的发现和科学产出的整体影响的评估。我们中心的一个主要特点是我们为变异评估和疾病基因发现实施了一个强大的分析框架，该框架建立在远大研究人员在统计遗传学、功能注释和临床变异解释方面的世界领先地位的基础上，以及从远大测序的数十万个样本中获取外显子组和基因组数据。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INCLUDE计划。通过以一致的方式生成和处理数据，我们可以将Include数据无缝集成到我们的分析框架中。对于唐氏综合症研究界针对的许多并存疾病来说，要有信心地发现因果基因，就需要收集世界各地各个中心的病例。我们将与INCLUDE数据协调中心合作，使INCLUDE项目能够向从事唐氏综合症相关研究的研究人员提供数据。通过这一项目，我们希望作为一个整体支持INCLUDE项目和唐氏综合症研究，并为临床基因组学中的数据共享建立标准，加快合作，促进唐氏综合症并存的强大基因发现。

Project Summary/Abstract We propose to continue to provide data generation and processing activities that will enrich a genomic data resource to propel pediatric disease research and in particular for support of INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) with this supplement proposal. Key elements for success will be the provision of high quality genome sequence data on well-phenotyped Down syndrome 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. Our center brings the domain expertise in high throughput data generation, processing and analysis, and disease gene discovery required to meet the objectives of both the Kids First and INCLUDE programs. We will apply deep, high-quality whole genome sequencing and RNA sequencing data on samples to be provided by investigators studying the co-morbidities associated with Down syndrome. We will be flexible to work closely and accommodate the needs and interests of selected INCLUDE X01 Investigators. 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 INCLUDE program. With data produced and processed in a consistent way, we can offer seamless integration of INCLUDE data into our analytic framework. For many of the co-morbidities targeted by the Down syndrome research community, confident discovery of causal genes will require aggregation of cases across centers around the world. We will partner with the INCLUDE Data Coordinating Center to enable the INCLUDE Project to make the data available to investigators pursuing Down syndrome-related research. With this we hope to support the INCLUDE Project and Down syndrome research as a whole and establish standards for data sharing in clinical genomics, accelerating collaboration and facilitating robust gene discovery for Down syndrome co-morbidities.