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，这将丰富基因组数据资源，以推动儿科疾病研究，特别是支持包括（调查一生共发疾病以了解唐氏综合症）。成功的关键因素将是提供表型良好的唐氏综合征患者及其家庭的高质量基因组序列数据；以直观的方式向研究界收集和获取数据；并将遗传数据与表型信息在本项目背景下进行整合，并与其他大型数据资源进行比较。我们的中心在高通量数据生成、处理和分析以及疾病基因发现方面拥有专业知识，以满足“儿童优先”和“包括”项目的目标。我们将对研究唐氏综合症相关合并症的研究人员提供的样本应用深度、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INCLUDE X01调查员的需求和兴趣。我们将参与评估这些数据类型及其对项目发现和科学产出的总体影响。我们中心的一个关键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基因发现，这建立在Broad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，以及从Broad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，它将免费提供给INCLUDE程序。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所针对的许多合并症，有信心地发现致病基因将需要汇集世界各地中心的病例。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征相关研究的研究者提供数据。我们希望以此支持INCLUDE项目和整个唐氏综合征研究，并建立临床基因组学数据共享标准，加速合作并促进唐氏综合征合并症的强大基因发现。

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.