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. Overall design: We performed bulk RNA-seq of human brain samples from each 6 fetuses with DS and controls (CON, normal diploid karyotype), from surgical terminations of pregnancy spanning PCW 11 to 14, to complement our single nucleus Multiome (RNA/ATAC sequencing) dataset. One DS sample was excluded from the final analysis, as the data strongly diverged from all other samples, probably due to poor library quality.