Single-cell atlas of the developing Down syndrome brain cortex.

Nature medicine 2026

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.

15 Figures Extracted

Fig. 1

A single-cell gene expression and chromatin accessibility atlas of the human fetal cortex in DS. a , Stages of cortical development covered by fetal t...

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Quality control and identification of non-cortical samples in the fetal brain single-cell multiomic atlas. a , Immunostaining for markers of the corti...

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Characterization of cell populations in the fetal brain single-cell multiomic atlas. a , Cell type marker gene expression projected on UMAP dimensiona...

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Expression changes in the complete dataset comprising all cell populations and gene ontology (GO) terms enriched for differential genes. a , Number of...

Fig. 2

Gene expression changes mainly affect excitatory neurons and are linked to neural development and function. a , Cell populations of the subsetted and ...

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Subsetting of excitatory lineage cells from complete dataset (PCW10-20) or samples from early (PCW11 to PCW13) or late stages (PCW16 to PCW20) separat...

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Validation of differentially expressed genes with alternative analysis approach and published data. a , Number of differentially expressed genes betwe...

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Expression changes in early and late excitatory lineage (PCW11-13 / PCW16-20). a , Number of genes differentially expressed between DS and CON samples...

Fig. 3

Integrated gene-regulatory network analysis predicts key mediators contributing to the deregulation of transcriptional programs downstream of Chr. 21 ...

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Validation of predicted TF binding to cis-regulatory elements and prediction of early and late-stage TF networks. a , Fraction of predicted TF-cis-reg...

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Prediction of Chr21 genes regulating network TFs via protein-protein-interactions from BioGRID database. a , Interactions of Chr21 proteins with netwo...

Fig. 4

Altered transcriptional programs and predicted Chr. 21 TF targets in the developing DS cortex are partially recapitulated in vitro and rescued by TF m...

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Characterization of iPSC-derived neural cells in vitro and validation of antisense oligonucleotide (ASO) mediated reduction of Chr21 TF expression. a ...

Fig. 5

Transplanted human neural cells reveal DS molecular and cellular phenotypes not recapitulated in vitro and emerging at later stages of fetal developme...

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Comparison of molecular phenotypes in iPSC-derived neural cells from transplants and in vitro with fetal DS cortex. a , Mapping transcriptomes of al...