A phenotypic brain organoid atlas and biobank for neurodevelopmental disorders

Lu Wang¹, Yuji Nakamura², Junhao Li³, David Sievert², Yang Liu⁴, Toan Nguyen², Prudhvi Sai Jetti², Ethan Thai⁵, Rachel Yibei Zhou², Jiaming Weng⁶, Naomi Meave², Manya Yadavilli², Robyn Howarth², Kevin Camey⁴, Niyati Banka², Charlotte Owusu-Hammond², Chelsea Barrows², Stephen F Kingsmore⁷, Maha S Zaki⁸, Eran Mukamel³, Joseph G Gleeson⁹

Affiliations

¹ Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA; Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA; Department of Physiology and Neuroscience, University of Southern California, Los Angeles, CA 90033, USA; USC Neuroscience Graduate Program, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: lwang419@usc.edu.
² Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA.
³ Department of Cognitive Science, University of California, San Diego, La Jolla, CA 92037, USA.
⁴ Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA; Department of Physiology and Neuroscience, University of Southern California, Los Angeles, CA 90033, USA; USC Neuroscience Graduate Program, University of Southern California, Los Angeles, CA 90089, USA.
⁵ Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA; Department of Physiology and Neuroscience, University of Southern California, Los Angeles, CA 90033, USA; USC Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA.
⁶ Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA; Program in Bioinformatics and Systems Biology, University of California, San Diego, La Jolla, CA 92093, USA.
⁷ Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA.
⁸ Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12311, Egypt.
⁹ Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA. Electronic address: jogleeson@health.ucsd.edu.

PMID: 41187745
DOI: 10.1016/j.stem.2025.10.006

A phenotypic brain organoid atlas and biobank for neurodevelopmental disorders

Lu Wang et al. Cell Stem Cell. 2025.

. 2025 Dec 4;32(12):1923-1940.e7.

doi: 10.1016/j.stem.2025.10.006. Epub 2025 Nov 3.

Authors

Affiliations

¹ Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA; Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA; Department of Physiology and Neuroscience, University of Southern California, Los Angeles, CA 90033, USA; USC Neuroscience Graduate Program, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: lwang419@usc.edu.
² Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA.
³ Department of Cognitive Science, University of California, San Diego, La Jolla, CA 92037, USA.
⁴ Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA; Department of Physiology and Neuroscience, University of Southern California, Los Angeles, CA 90033, USA; USC Neuroscience Graduate Program, University of Southern California, Los Angeles, CA 90089, USA.
⁵ Center for Craniofacial Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA; Department of Physiology and Neuroscience, University of Southern California, Los Angeles, CA 90033, USA; USC Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA.
⁶ Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA; Program in Bioinformatics and Systems Biology, University of California, San Diego, La Jolla, CA 92093, USA.
⁷ Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA.
⁸ Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo 12311, Egypt.
⁹ Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA. Electronic address: jogleeson@health.ucsd.edu.

PMID: 41187745
DOI: 10.1016/j.stem.2025.10.006

Abstract

Thousands of genes are associated with neurodevelopmental disorders (NDDs), yet mechanisms and targeted treatments remain elusive. To fill these gaps, we present a California Institute of Regenerative Medicine (CIRM)-initiated NDD biobank of 352 publicly available genetically diverse patient-derived induced pluripotent stem cells (iPSCs), along with clinical details, brain imaging, and genomic data, representing four major categories of disease: microcephaly (MIC), polymicrogyria (PMG), epilepsy (EPI), and intellectual disability (ID). From 35 representative patients, we studied over 6,000 brain organoids for histology and single-cell transcriptomics. Compared with an organoid library from ten neurotypicals, patients showed distinct cellular defects linked to underlying clinical disease categories. MIC showed defects in cell survival and excessive TTR+ cells, PMG showed intermediate progenitor cell junction defects, EPI showed excessive astrogliosis, and ID showed excessive generation of TTR+ cells. Our organoid atlas demonstrates both conserved and divergent NDD category-specific phenotypes, bridging genotype and phenotype. This NDD iPSC biobank can support future disease modeling and therapeutic approaches.

Keywords: brain organoids; epilepsy; intellectual disability; microcephaly; neurodevelopmental disease; polymicrogyria; single-cell sequencing.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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A phenotypic brain organoid atlas and biobank for neurodevelopmental disorders

Affiliations

A phenotypic brain organoid atlas and biobank for neurodevelopmental disorders

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

LinkOut - more resources

Full Text Sources

Research Materials

Miscellaneous