Researchers built the largest brain organoid atlas to date using iPSCs from 352 neurodevelopmental disorder (NDD) patients, studying over 6,000 organoids from 35 patients and 10 healthy controls. Using histology and single-cell RNA sequencing, they found that organoids reliably reproduced disease-specific cellular features. Microcephaly organoids were smaller and showed excessive TTR+ choroid plexus-like cells and cell death. Polymicrogyria organoids had defects in intermediate progenitor cell junctions. Epilepsy organoids showed excessive astrocyte generation and reactive astrogliosis. Intellectual disability organoids also overproduced TTR+ cells. A linear discriminant model classified disease categories from organoid data with up to 93% AUC accuracy, demonstrating that patient-derived brain organoids faithfully capture genotype-to-phenotype relationships across diverse NDDs.
