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

## TL;DR

This study uses single-cell analysis to uncover how Down syndrome disrupts brain development, identifying key genes and pathways involved.

## Contribution

The study identifies three dosage-sensitive transcription factors on chromosome 21 that drive neurodevelopmental disruptions in Down syndrome.

## Key findings

- A subtype-specific reduction in RORB- and FOXP1-expressing excitatory neurons was observed in Down syndrome fetal cortices.
- Transcription factors BACH1, PKNOX1, and GABPA were found to regulate genes linked to intellectual disability in Down syndrome.
- Antisense oligonucleotide treatment partially rescued gene expression in human neural progenitors in vitro.

## Abstract

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.

Multiomic single-cell analyses of 15 Down syndrome fetal cortical samples identify widespread disruption of neurodevelopmental transcriptional programs, driven by three dosage-sensitive chromosome 21 transcription factors.