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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月4日

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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

摘要

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.