Single-cell atlas of the developing Down syndrome brain cortex

  • Nat Med. 2026 Mar;32(3):1061-1072. doi: 10.1038/s41591-026-04211-1.
Michael Lattke  1 ,  Wee Leng Tan  2 ,  Salil Kalarikkal Sukumaran  2 ,  Kagistia Hana Utami  2 ,  Marcos Sintes  3  2 ,  Srinivasan Sakthivel  2 ,  Jonathan Tan  2 ,  Auriel Lim  2 ,  Vibhavari Aysha Bansal  2 ,  Katerina Rekopoulou  4 ,  Nik Matthews  4 ,  Ivan Alić  5  6 ,  Željka Krsnik  7 ,  Dean Nižetić  5 ,  Boaz P Levi  8 ,  Vincenzo De Paola  9  10
Affiliations
  • 1. Department of Brain Sciences, Imperial College London, London, UK. [email protected].
  • 2. Duke-NUS Medical School, Singapore, Singapore.
  • 3. Department of Brain Sciences, Imperial College London, London, UK.
  • 4. NIHR Imperial BRC Genomics Facility, Imperial College London, London, UK.
  • 5. The Blizard Institute, Queen Mary University of London, London, UK.
  • 6. Department of Anatomy, Histology and Embryology, University of Zagreb, Zagreb, Croatia.
  • 7. Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.
  • 8. Allen Institute for Brain Science, Seattle, WA, USA.
  • 9. Department of Brain Sciences, Imperial College London, London, UK. [email protected].
  • 10. Duke-NUS Medical School, Singapore, Singapore. [email protected].
PMID: 41545595 DOI: 10.1038/s41591-026-04211-1
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.