Single-Cell Multiomic Atlas of Human Cortical Development in Down Syndrome - Fetal Cortex Bulk RNA-seq Dataset

Down syndrome, caused by an extra copy of chromosome 21, is the most common genetic form of intellectual disability, which affects up to 1 in 700 live births. Yet, how increased dosage of the ~200 protein-coding genes on human chromosome 21 affects cortical development and function remains unclear. Here we generated a single-cell transcriptome and chromatin accessibility atlas of the human foetal cortex at mid gestation (11-20 weeks after conception), a critical period of cortical development. We uncovered an early global transcriptional network disruption, subtly altering ~1000 genes involved in neural development and function primarily in excitatory neurons. These changes reflected clinical phenotypes like intellectual disability and epilepsy, were accompanied by a significant reduction in layer 4 neurons, and were driven by a network of transcription factors including chromosome 21 genes BACH1, PKNOX1, and GABPA. Finally, a xenograft model replicates key molecular features, offering an experimental platform for validating new therapeutic targets. This resource defines the gene-regulatory landscape of the developing human cortex in Down syndrome, revealing the earliest known molecular and cellular signatures of its neurological manifestations and novel candidate targets for therapeutic interventions.