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.