In Down syndrome, triplication of chromosome 21 (T21) drives changes in brain development that affect cognitive function and brain health across the lifespan; however, the complexity of the disorder and the challenges of studying the prenatal human brain have made it difficult to identify the early developmental events that are disrupted in Down syndrome. Two new papers have now used advanced sequencing techniques to examine the molecular and cellular effects of T21 at key stages of human brain development.

Vuong et al. performed single-nucleus multiomic sequencing on postmortem cortical samples from individuals with Down syndrome and age-matched control individuals during the second trimester of gestation, which corresponds to a critical window for cortical neurogenesis. Gene expression and chromatin accessibility profiling revealed alterations in the cell composition of the Down syndrome samples, including a reduction in the number of radial glial progenitors and altered proportions of deep-layer versus upper-layer excitatory neurons, indicative of an accelerated timeline of neurogenesis. In line with this, systematic analyses of the transcriptional changes revealed dysregulation of molecular pathways and cellular interactions involved in neuronal metabolism, progenitor pool maintenance, neuronal maturation and neuroinflammation. These effects were linked to widespread alterations in chromatin accessibility and changes in specific gene-regulatory networks involved in specifying neuronal identity.