Bulk RNA-seq on CTNNB1 mutation CRISPR-corrected ASD iPSC-derived neural progenitor cells as well as one matched control iPSC-derived neural progenitor cells to study the effects of autism genetic background

Alterations in cortical neurogenesis are implicated in neurodevelopmental disorders including autism spectrum disorders (ASDs). Many ASD risk genes have been identified as critical for brain development, but the contribution of genetic backgrounds, although inferred in complex genetic disorders such as ASD, remains unclear. Here, using isogenic induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs) and cortical organoid models, we report that a heterozygous PTEN p.I135L mutation found in an ASD patient with macrocephaly dysregulates cortical neurogenesis in an ASD genetic background-dependent fashion. We found that this PTEN p.I135L mutation led to overproduction of NPC subtypes as well as neuronal subtypes including both deep and upper layer neurons in its ASD background, but not when introduced into a control genetic background. ASD and control background differences in neurogenesis, neural development and synapse signaling were also observed. These findings provide experimental evidence that both a PTEN p.I135L mutation and ASD genetic background contribute to cellular features consistent with ASD associated with macrocephaly. We compared RNA-Seq libraries of neural progenitor cells Arch CTNNB1 WT/WT vs Chap CTNNB1 WT/WT to study the effect of ASD genetic bakcground on gene expression profiles in the neural progenitor cells. Libraries for each genotype include three independent cell culture replicates and three separate passages