Variegated overexpression of chromosome 21 genes reveals molecular and immune subtypes of Down syndrome

Micah G. Donovan, Neetha P. Eduthan, Keith P. Smith, Eleanor C. Britton, Hannah R. Lyford, Paula Araya, Ross E. Granrath, Katherine A. Waugh, Belinda Enriquez Estrada, Angela L. Rachubinski, Kelly D. Sullivan, Matthew D. Galbraith () and Joaquin M. Espinosa ()
Additional contact information
Micah G. Donovan: University of Colorado Anschutz Medical Campus
Neetha P. Eduthan: University of Colorado Anschutz Medical Campus
Keith P. Smith: University of Colorado Anschutz Medical Campus
Eleanor C. Britton: University of Colorado Anschutz Medical Campus
Hannah R. Lyford: University of Colorado Anschutz Medical Campus
Paula Araya: University of Colorado Anschutz Medical Campus
Ross E. Granrath: University of Colorado Anschutz Medical Campus
Katherine A. Waugh: University of Colorado Anschutz Medical Campus
Belinda Enriquez Estrada: University of Colorado Anschutz Medical Campus
Angela L. Rachubinski: University of Colorado Anschutz Medical Campus
Kelly D. Sullivan: University of Colorado Anschutz Medical Campus
Matthew D. Galbraith: University of Colorado Anschutz Medical Campus
Joaquin M. Espinosa: University of Colorado Anschutz Medical Campus

Nature Communications, 2024, vol. 15, issue 1, 1-22

Abstract: Abstract Individuals with Down syndrome, the genetic condition caused by trisomy 21, exhibit strong inter-individual variability in terms of developmental phenotypes and diagnosis of co-occurring conditions. The mechanisms underlying this variable developmental and clinical presentation await elucidation. We report an investigation of human chromosome 21 gene overexpression in hundreds of research participants with Down syndrome, which led to the identification of two major subsets of co-expressed genes. Using clustering analyses, we identified three main molecular subtypes of trisomy 21, based on differential overexpression patterns of chromosome 21 genes. We subsequently performed multiomics comparative analyses among subtypes using whole blood transcriptomes, plasma proteomes and metabolomes, and immune cell profiles. These efforts revealed strong heterogeneity in dysregulation of key pathophysiological processes across the three subtypes, underscored by differential multiomics signatures related to inflammation, immunity, cell growth and proliferation, and metabolism. We also observed distinct patterns of immune cell changes across subtypes. These findings provide insights into the molecular heterogeneity of trisomy 21 and lay the foundation for the development of personalized medicine approaches for the clinical management of Down syndrome.

Date: 2024
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DOI: 10.1038/s41467-024-49781-1

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