Single-cell atlas of the developing Down syndrome brain cortex
Summary
Down syndrome (DS), caused by trisomy of chromosome 21, is the leading genetic cause of intellectual disability, yet the mechanisms disrupting fetal brain development remain unclear. We performed single-cell transcriptomic and chromatin accessibility profiling of approximately 250,000 cells from 15 DS and 15 control human fetal cortices (10-20 weeks postconception). Our analysis revealed a subtype-specific reduction in RORB- and FOXP1-expressing excitatory neurons and widespread disruption
Content
# Single-cell atlas of the developing Down syndrome brain cortex
*Published: 2026 Mar*
Down syndrome (DS), caused by trisomy of chromosome 21, is the leading genetic
cause of intellectual disability, yet the mechanisms disrupting fetal brain
development remain unclear. We performed single-cell transcriptomic and
chromatin accessibility profiling of approximately 250,000 cells from 15 DS and
15 control human fetal cortices (10-20 weeks postconception). Our analysis
revealed a subtype-specific reduction in RORB- and FOXP1-expressing excitatory
neurons and widespread disruption of neurodevelopmental transcriptional
programs. Chromosome 21 transcription factors BACH1, PKNOX1 and GABPA emerged as
dosage-sensitive hubs regulating genes linked to intellectual disability.
Antisense oligonucleotide-mediated normalization of these transcription factors
in human neural progenitors in vitro partially rescued target gene expression.
Benchmarking a humanized in vivo model captured additional molecular and
cellular signatures of DS, complementing the in vitro model. Together, we
present a resource defining the gene-regulatory landscape underlying cortical
development in DS and highlight molecular pathways for further investigation.
DOI: 10.1038/s41591-026-04211-1