Summary Down syndrome (DS) leads to a significant risk for structural birth defects and health conditions, all presenting with substantial variability in severity. We have obtained whole genome sequencing (WGS) on approximately 1700 probands with Down syndrome (DS) via three service awards. In this R03, we request funds to enrich the available phenotype data on this established DS-WGS cohort (KF-X01-DS-CHD dbGaP accession number phs002330) and harmonize these data with other resources to ensure maximum impact of this first-of-its kind genotype/phenotype investment in DS research. These samples were contributed by four research groups, with Emory’s DS360 study contributing the largest cohort. For most participants, phenotype evaluation was done at one time point only, although we do have substantial information provided by our interviews around the time of birth with mothers of the probands. We propose two aims to expand, enrich and harmonize this first-of- its-kind WGS resource for the DS research community. We will expand medical phenotyping data on participants from Emory’s DS360 program on whom WGS is available. We will recontact participants where we have WGS data to complete an updated medical history questionnaire. These data will be used as a guide for subsequent medical record collection. Caregiver report data may be the sole source of information; thus, these reports are vital to identify presence of birth defects along with later-onset disorders. Where caregivers have indicated medical conditions in the medical history questionnaire, we will attempt to obtain medical records from those providers. These medical records will be abstracted into a standardized medical record summary form. We will curate existing phenotype and maternal environmental variables on participants in DS360 on whom WGS is available and map diagnoses to ontology terms to expand potential identification of DS- associated genetic and environmental risk factors. We have extensive questionnaire data from interviews conducted with mothers of probands with DS. We will work with the data coordinating centers of Kids First and INCLUDE to harmonize these comprehensive data and map them onto standard ontology terms to promote cross-disease analyses in the Kids First large set of cohorts and to allow new genotype/phenotype studies in the DS research community. The proposed new data collection, along with our existing data that include clinical and environmental variables, will be curated, harmonized and shared. This expanded data will enhance research on DS as well as promote cross-disease analyses.

Project Narrative Down syndrome (DS) leads to a significant risk for structural birth defects and health conditions, all presenting with substantial variability in severity. We have obtained whole genome sequencing (WGS) on approximately 1700 probands with Down syndrome (DS) via three service awards. In this R03, we request funds to enrich the available phenotype data on this established DS-WGS cohort (KF-X01-DS-CHD dbGaP accession number phs002330) and harmonize these data with other resources to ensure maximum impact of this first-of-its kind genotype/phenotype investment in DS research.