A transcriptomic analysis of the autistic brain reveals convergent molecular pathology. The study identifies consistent differences in transcriptome organization between autistic and normal brain tissues, with regional patterns of gene expression typically distinguishing frontal and temporal cortex significantly attenuated in the autistic brain, suggesting abnormalities in cortical patterning. Two distinct modules of co-expressed genes associated with autism were identified: a neuronal module enriched for known autism susceptibility genes, including the neuronal-specific splicing factor A2BP1/FOX1, and an immune-glial module enriched for immune genes and glial markers. High-throughput RNA sequencing demonstrated dysregulated splicing of A2BP1-dependent alternative exons in the autistic brain. The neuronal module was enriched for genetically associated variants, supporting the causal involvement of these genes in autism, while the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic etiology. These results provide strong evidence for convergent molecular abnormalities in ASD, implicating transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction. The study analyzed post-mortem brain tissue samples from 19 autism cases and 17 controls using Illumina microarrays, identifying 444 genes showing significant expression changes in the autistic cortex. Supervised hierarchical clustering showed distinct clustering of most autism cortex samples, with one case having a 15q duplication. Gene ontology analysis revealed that downregulated genes in the autistic cortex were enriched for synaptic function, while upregulated genes were enriched for immune and inflammatory response. Further validation using RNA sequencing confirmed differential splicing of A2BP1-dependent exons in the autistic brain. The study also identified two co-expression modules, M12 and M16, with M12 enriched for neuronal markers and M16 enriched for astrocyte and microglial markers. M12 showed significant enrichment for known autism susceptibility genes, while M16 showed no enrichment for autism GWAS signals. The results suggest that the observed molecular abnormalities in the autistic brain are convergent and may be related to abnormal developmental patterning. The study provides a molecular neuropathological basis for ASD, highlighting the role of transcriptional and alternative-splicing abnormalities in the synaptic and signaling pathogenesis of ASD. The findings suggest that immune changes have a less pronounced genetic component and may be secondary phenomena or caused by environmental factors. The study also identifies alterations in differential splicing associated with A2BP1/FOX1 levels in the autistic brain, with many affected exons belonging to genes involved in synaptic function. The results provide a new pathway-based framework for assessing the enrichment of genetic association signals in other psychiatric disorders.A transcriptomic analysis of the autistic brain reveals convergent molecular pathology. The study identifies consistent differences in transcriptome organization between autistic and normal brain tissues, with regional patterns of gene expression typically distinguishing frontal and temporal cortex significantly attenuated in the autistic brain, suggesting abnormalities in cortical patterning. Two distinct modules of co-expressed genes associated with autism were identified: a neuronal module enriched for known autism susceptibility genes, including the neuronal-specific splicing factor A2BP1/FOX1, and an immune-glial module enriched for immune genes and glial markers. High-throughput RNA sequencing demonstrated dysregulated splicing of A2BP1-dependent alternative exons in the autistic brain. The neuronal module was enriched for genetically associated variants, supporting the causal involvement of these genes in autism, while the immune-glial module showed no enrichment for autism GWAS signals, indicating a non-genetic etiology. These results provide strong evidence for convergent molecular abnormalities in ASD, implicating transcriptional and splicing dysregulation as underlying mechanisms of neuronal dysfunction. The study analyzed post-mortem brain tissue samples from 19 autism cases and 17 controls using Illumina microarrays, identifying 444 genes showing significant expression changes in the autistic cortex. Supervised hierarchical clustering showed distinct clustering of most autism cortex samples, with one case having a 15q duplication. Gene ontology analysis revealed that downregulated genes in the autistic cortex were enriched for synaptic function, while upregulated genes were enriched for immune and inflammatory response. Further validation using RNA sequencing confirmed differential splicing of A2BP1-dependent exons in the autistic brain. The study also identified two co-expression modules, M12 and M16, with M12 enriched for neuronal markers and M16 enriched for astrocyte and microglial markers. M12 showed significant enrichment for known autism susceptibility genes, while M16 showed no enrichment for autism GWAS signals. The results suggest that the observed molecular abnormalities in the autistic brain are convergent and may be related to abnormal developmental patterning. The study provides a molecular neuropathological basis for ASD, highlighting the role of transcriptional and alternative-splicing abnormalities in the synaptic and signaling pathogenesis of ASD. The findings suggest that immune changes have a less pronounced genetic component and may be secondary phenomena or caused by environmental factors. The study also identifies alterations in differential splicing associated with A2BP1/FOX1 levels in the autistic brain, with many affected exons belonging to genes involved in synaptic function. The results provide a new pathway-based framework for assessing the enrichment of genetic association signals in other psychiatric disorders.