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

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.

Yonatan Perez, PhD

Postdoctoral Scholar

Li Wang, PhD

Postdoctoral Scholar

Clara Siebert

PhD Candidate

Jennifer Baltazar

Master’s Student

Guolong Zuo, PhD

Postdoctoral Scholar

Juan Moriano, PhD

Postdoctoral Scholar

Songcang Chen, MD

Senior Scientist

Shaohui Wang

Specialist