A phenotypic brain organoid atlas for neurodevelopmental disorders

Thousands of genes are associated with neurodevelopmental disorders (NDDs), yet mechanisms and targeted treatments remain elusive. To fill these gaps, we present a CIRM-funded NDD biobank of 352 publicly-available genetically-diverse patient-derived 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 36 representative patients, we studied 5182 brain organoids (hBOs) for histology and transcriptomics differences at the single-cell level. Compared with a library of hBOs from ten neurotypicals, patient hBOs showed distinct cellular defects linked to underlying clinical disease categories. MIC shows defects in cell survival, PMG shows intermediate progenitor cell junction defects, EPI shows excessive generation of astroglia, and ID shows excessive generation of cortical hem cells. Our hBOs atlas demonstrates both conserved and divergent NDD category-specific phenotypes, bridging genotype and phenotype. The NDD iPSC biobank can support future disease modeling and therapeutic approaches.