Publication date: Jul 04, 2025
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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Semantics
| Type | Source | Name |
|---|---|---|
| disease | MESH | syndrome |
| disease | MESH | autism |
| disease | MESH | Duplication 15q |
| disease | MESH | autism spectrum disorder |
| pathway | REACTOME | Glycolysis |
| drug | DRUGBANK | Trestolone |
| drug | DRUGBANK | Sucrose |
| drug | DRUGBANK | Flunarizine |
| drug | DRUGBANK | Pentaerythritol tetranitrate |
| drug | DRUGBANK | Aspartame |
| drug | DRUGBANK | Coenzyme M |
| pathway | REACTOME | Axon guidance |
| drug | DRUGBANK | Dextrose unspecified form |
| pathway | REACTOME | Metabolism |
| disease | MESH | intellectual disability |
| disease | MESH | epilepsy |
| drug | DRUGBANK | Glycine |
| disease | MESH | anomalies |
| drug | DRUGBANK | Proline |
| disease | MESH | Chromosome Aberrations |
| disease | MESH | Chromosome Disorders |
| disease | MESH | Chromosome Duplication |