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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·Arnold Kriegstein
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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.

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HumansSingle-Cell AnalysisNeuronsOrganoidsInduced Pluripotent Stem CellsChromosomes, Human, Pair 15Autistic DisorderBrainAdolescentChromosome DisordersTranscriptomeAutism Spectrum DisorderMaleFemaleGene Expression ProfilingGene Regulatory NetworksGlycolysisAdultChromosome DuplicationChromosome AberrationsIntellectual DisabilityJournal Article

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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, Arnold Kriegstein. 2025-07-04. Single-cell analysis of dup15q syndrome reveals developmental and postnatal molecular changes in autism.. https://doi.org/10.1038/s41467-025-61184-4

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