A single-cell multiomic analysis identifies molecular and gene-regulatory mechanisms dysregulated in developing Down syndrome neocortex
Summary
Down syndrome (DS) is the most common genetic cause of intellectual disability, yet the cellular and molecular mechanisms driving this developmental disorder remain unclear. In this study, we profiled human mid-gestation neocortex with snMultiomics across 26 donors. We observed a reduction in neural progenitors and corticothalamic neurons and an increase of intratelencephalic neurons, accompanied by accelerated neuronal specification. We uncovered widespread changes in gene expression, chr
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# A single-cell multiomic analysis identifies molecular and gene-regulatory mechanisms dysregulated in developing Down syndrome neocortex
*Published: 2026 Apr 23*
Down syndrome (DS) is the most common genetic cause of intellectual disability,
yet the cellular and molecular mechanisms driving this developmental disorder
remain unclear. In this study, we profiled human mid-gestation neocortex with
snMultiomics across 26 donors. We observed a reduction in neural progenitors and
corticothalamic neurons and an increase of intratelencephalic neurons,
accompanied by accelerated neuronal specification. We uncovered widespread
changes in gene expression, chromatin accessibility, and cell interaction
networks affecting neurogenesis, specification, and maturation; and in
gene-regulatory networks directing these processes, including those downstream
of human chromosome 21 (HSA21)-encoded genes. We identified cell-specific
molecular pathways shared with other neurodevelopmental disorders and enrichment
of genome-wide association study signals in DS-altered chromatin. Together, our
data revealed a cascade of molecular dysregulation outlining the earliest steps
in DS, providing a foundation for future therapeutic targets.
DOI: 10.1126/science.aea1259