01985nas a2200325   4500000000100000008004100001260001500042653001500057653001100072653001900083653001300102653001300115653003300128653002300161653001700184653001100201653001300212653001900225653001400244100001200258700002800270700001800298700002200316245007000338856007200408300001200480490000700492520114600499022001401645       2023                            d  c2023-04-0110aAssembloid10aAutism10abrain organoid10aDominant10aepilepsy10aGene-environment-interaction10aGenotype-phenotype10aMicrocephaly10aMosaic10aMutation10aNeural rosette10aRecessive1 aLu Wang1 aCharlotte Owusu-Hammond1 aDavid Sievert1 aJoseph G. Gleeson00aStem Cell–Based Organoid Models of Neurodevelopmental Disorders  uhttps://www.sciencedirect.com/science/article/pii/S0006322323000392  a622-6310 v933 aThe past decade has seen an explosion in the identification of genetic causes of neurodevelopmental disorders, including Mendelian, de novo, and somatic factors. These discoveries provide opportunities to understand cellular and molecular mechanisms as well as potential gene-gene and gene-environment interactions to support novel therapies. Stem cell–based models, particularly human brain organoids, can capture disease-associated alleles in the context of the human genome, engineered to mirror disease-relevant aspects of cellular complexity and developmental timing. These models have brought key insights into neurodevelopmental disorders as diverse as microcephaly, autism, and focal epilepsy. However, intrinsic organoid-to-organoid variability, low levels of certain brain-resident cell types, and long culture times required to reach maturity can impede progress. Several recent advances incorporate specific morphogen gradients, mixtures of diverse brain cell types, and organoid engraftment into animal models. Together with nonhuman primate organoid comparisons, mechanisms of human neurodevelopmental disorders are emerging.  a0006-3223