Patient-derived stem cell models capture key features of a rare genetic disorder, offering new insights into its origins and potential treatments
SOURCE: The Institute
September 26, 2025
A team led by Wei-Hsiang Huang, PhD, has created the world's first "mini-brain" models of a rare disease known as Smith-Magenis syndrome. These tiny models, grown from patient stem cells, provide an unprecedented view of how this rare genetic disorder disrupts early brain development. The research, conducted at the Research Institute of the McGill University Health Centre (The Institute) is published in the American Journal of Human Genetics.
Smith-Magenis syndrome (SMS) is a rare genetic disorder often causing intellectual disability, autism spectrum features, sleep disturbance, and seizures. These symptoms are thought to arise from abnormal brain development, but until now scientists have had few ways to study this process directly in human tissue.
By building patient-derived neuronal models, Prof. Huang's team set out to reproduce features of SMS brain development in the lab. Their goal is to understand when and how the disorder begins, and to provide platforms for testing therapies that might one day improve outcomes for patients. This approach may also shed light on other childhood brain disorders with similar structural changes or epilepsy features.
'Mini-brains' are three-dimensional organoids—lab-grown tissues that mimic key features of the developing human cortex. To build them, the team first converted skin cells donated by SMS patients into induced pluripotent stem cells (iPSCs), a type of stem cell that can turn into almost any cell in the body. From these iPSCs, they created both flat layers of neurons (2D cultures) and tiny 3D 'mini-brains' (cortical organoids) that capture early stages of brain development.
When they examined the lab-grown models, the researchers found features that closely mirrored what had been observed in SMS patients through clinical studies. The SMS mini-brains were smaller than controls and showed enlarged cavities resembling ventriculomegaly—a medical condition characterized by the enlargement of the brain's fluid-filled ventricles. SMS-derived neurons also matured faster and fired excessively, reflecting the seizure tendency seen in patients. Further analysis showed that the SMS models had widespread problems in gene regulation, with excitatory neurons more strongly affected than inhibitory ones.
"Seeing patient-like features emerge in a dish was striking—from smaller organoids to overactive neurons," said Yu-Ju Lee, PhD, co–first author and post-doctoral fellow working with Prof. Huang at The Institute.
"These models let us watch disease processes unfold during the exact developmental window when they likely begin," added co-first author Ya-Ting Chang, PhD, also a postdoctoral fellow with Prof Huang. "This gives us concrete targets for future therapies."
Using advanced genomic tools, the team showed that the SMS mutation alters the 3D structure of DNA and disrupts key pathways involved in cell growth, metabolism and brain signaling.
"This is the first time that SMS brain features have ever been modeled in human tissue, and it is the clearest link yet between the genetic defect and the developmental challenges faced by patients," said Prof. Huang. "Our goal is not only to understand how the syndrome develops but also to create platforms for testing therapies that could one day improve patients' lives."
Looking ahead, the group is exploring gene therapy strategies to restore normal gene function and further developing next-generation organoids that better mimic the human brain.
The study was funded by the Canadian Institutes of Health Research and the Smith-Magenis Syndrome Research Foundation.
About the publication
The article "Molecular and developmental deficits in Smith-Magenis syndrome human stem cell-derived cortical neural models" was authored by Yu-Ju Lee, Ya-Ting Chang, Yoobin Cho, Max Kowalczyk, Adrian Dragoiescu, Alain Pacis, Senthilkumar Kailasam, François Lefebvre, Qihuang Zhang, Xiaojing Gao, and Wei-Hsiang Huang, and published in The American Journal of Human Genetics (Oct. 2, 2025).
DOI: https://doi.org/10.1016/j.ajhg.2025.07.020
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