Convergent Pathways in Idiopathic Autism Revealed by Time Course Transcriptomic Analysis of Patient-Derived Neurons

Purpose: The transcriptional differences between iPSC-derived cortical neurons from patients with idiopathic ASD and unaffected controls was examined over a 135-day course of neuronal differentiation using RNAseq analysis Methods: Induced pluripotent stem cells (5 control iPSC and 6 ASD-specific iPSC) were differentiated into cortical neurons and RNA samples were obtained at two different time points day 35 post differentiation and day 135 post differentiation. RNAseq was performed from the RNA isolated at the different time points and the differentially expressed genes identified. Pathway analysis for gene ontology and biological processes, as well as, weighted gene co-expression network analysis was performed. Results: The results of this analysis show ASD-specific misregulation of genes involved in neuronal differentiation, axon guidance, cell migration, DNA and RNA metabolism, and neural region patterning. Furthermore, functional analysis revealed defects in neuronal migration and electrophysiological activity, providing compelling support for the transcriptome analysis data. Conclusions: Transcriptional analyses of the ASD and control neurons showed ASD-specific molecular phenotypes affecting networks involved in neuronal differentiation, the cytoskeletal matrix structure formation, patterning, DNA and RNA metabolism. Transcriptome analysis was performed on cortical neurons derived from induced pluripotent stem cells from individuals with autism and cognitively normal control individuals. Transcriptome analysis was performed by next generation sequencing (RNAseq) and the genes that were differentially expressed between the control iPSC-derived neurons and the Autism-specific iPSC-derived neurons. Transcriptome analysis was performed at day 35 post differentiation and day 135 post differentiation.