Single-cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autism

Yonatan Perez (), Dmitry Velmeshev, Li Wang, Matthew L. White, Clara Siebert, Jennifer Baltazar, Guolong Zuo, Juan Andrés Moriano, Songcang Chen, David M. Steffen, Natalia Garcia Dutton, Shaohui Wang, Brittney Wick, Maximilian Haeussler, Stormy Chamberlain, Arturo Alvarez-Buylla and Arnold Kriegstein ()
Additional contact information
Yonatan Perez: San Francisco
Dmitry Velmeshev: San Francisco
Li Wang: San Francisco
Matthew L. White: San Francisco
Clara Siebert: San Francisco
Jennifer Baltazar: San Francisco
Guolong Zuo: San Francisco
Juan Andrés Moriano: San Francisco
Songcang Chen: San Francisco
David M. Steffen: San Francisco
Natalia Garcia Dutton: San Francisco
Shaohui Wang: San Francisco
Brittney Wick: University of California
Maximilian Haeussler: University of California
Stormy Chamberlain: 400 Farmington Avenue
Arturo Alvarez-Buylla: San Francisco
Arnold Kriegstein: San Francisco

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Duplication 15q (dup15q) syndrome is a leading genetic cause of autism spectrum disorder, offering a key model for studying autism-related mechanisms. Using single-cell and single-nucleus RNA sequencing of cortical organoids from dup15q patient-derived iPSCs and post-mortem brain samples, we identify increased glycolysis, disrupted layer-specific marker expression, and aberrant morphology in deep-layer neurons during fetal-stage organoid development. In adolescent-adult postmortem brains, upper-layer neurons exhibit heightened transcriptional burden related to synaptic signaling, a pattern shared with idiopathic autism. Using spatial transcriptomics, we confirm these cell-type-specific disruptions in brain tissue. By gene co-expression network analysis, we reveal disease-associated modules that are well preserved between postmortem and organoid samples, suggesting metabolic dysregulation that may lead to altered neuron projection, synaptic dysfunction, and neuron hyperexcitability in dup15q syndrome.

Date: 2025
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DOI: 10.1038/s41467-025-61184-4

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