? Overall. Individuals with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), are predisposed to a spectrum of heterogeneous diseases while simultaneously protected from developing other pathogenic conditions relative to the typical population. In ways still poorly defined, T21 protects individuals from most solid malignancies while strongly predisposing them to Alzheimer?s disease, congenital heart disease, leukemias, autoimmune disorders, and diverse neurological conditions. However, little is known about the mechanisms underlying this differential clinical profile or the relationship between these conditions in the context of DS versus when occurring in the general population. Moreover, individuals with DS display a large degree of phenotypic variation suggesting the existence of modulating factors that affect how T21 manifests at the individual level, including genetic variation, epigenetic modifiers, varying endotypes modulating the transcriptome, proteome and metabolome, lifestyle and environmental factors, or even perhaps the microbiome. Therefore, elucidating the mechanisms driving and modulating DS comorbidities will serve not only the six million people worldwide with DS alive today, but also millions of individuals affected by these comorbidities in the typical population. The importance of this fact has been acknowledged by NIH through the launching of the INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Project. Within this framework, the INCLUDE Project has recognized the strategic importance of a large cohort study of individuals with DS to accelerate research in this area, with the goal of enabling a precision medicine approach to DS via novel diagnostics and therapeutic tools. Therefore, the mission of this DCC team is to create a world- class resource and associated platforms for empowered data sharing, data access, and integrative analysis that will enable novel investigations into all DS comorbidities across the lifespan. To achieve this goal, the proposed DCC will create a real-time, integrated data ecosystem that will catalyze innovation, collaboration, and transformative discoveries by engaging and empowering a diverse community of stakeholders to drive collaborative, accelerated discovery on behalf of transformative action and impact from bench to bedside and beyond. Altogether, the efforts underpinning the proposed efforts will serve first and foremost people with DS by accelerating research into DS comorbidities, but will also elevate our understanding of human biology across diverse scientific disciplines.
? Overall. People with Down syndrome are strongly predisposed to develop a wide range of comorbidities that shorten their lifespan and decrease their quality of life, such as Alzheimer?s disease, congenital heart disease, leukemias, autoimmune disorders, and diverse neurological conditions. The proposed activities under this project seek to create a world-class resource for collaborative discovery, data sharing, data access, and integrative analysis that would enable novel investigations into all DS comorbidities across the lifespan and further integrating across datasets for related diseases occurring in the general population, thus paving the way for a precision medicine approach to DS. Furthermore, this resource and associated platforms will also have broader impacts by empowering physicians, educators, government officials, and advocates with the tools required to elicit evidence- based transformative action in the clinic, the classroom, the government, and society at large.
