Copy number aberrations affecting adhesion genes involved in the development of the cerebellar vermis are associated with autism spectrum disorders

We investigated neurodevelopmental dysfunctions in autism spectrum disorders (ASD) by a integrative analysis including the largest genome-wide studies on associations between copy number aberrations (CNA) and ASD, the BioGPS tissue atlas, the Allen-Brain-Atlas, and in situ hybridization histochemistry data from the developing mouse brain. In contrast to the original association studies, we considered "ASD-candidate-genes" each of which is the only CNA-impaired gene in an ASD case, therefore, presumably causing ASD. For extracting ASD-candidate-genes, we developed an analysis pipeline for rare and small CNAs. The independently identified ASD-candidate-genes include neurexins (CNTNAP2, NRXN1), catenin (CTNNA3), cadherin (CDH13), and contactins (CNTN5, CNTN6). Gene set enrichment analysis showed that significant biological processes are all related to cell and synaptic adhesion, postsynaptic density, membrane and synapse. At data from the BioGPS, the Cancer-Genome-Anatomy-Project, and the Allen-Brain-Atlas, ASD-candidate-genes have significantly different variations in their expression values in cerebellum compared to other genes, where at the Allen-Brain-Atlas cerebellar vermis lobes I-II, III, VI, and VIII where most significant. In situ hybridization histochemistry data indicate that ASD-candidate-genes are primarily expressed in the developing mouse cerebellum. Our results, which hint at the vermis as the location of ASD’s pathogenesis, are consistent with pathological studies of ASD cases (90% of the examined brains showed well-defined cerebellar abnormalities). Also studies on children with vermal lesions showed phenotypes similar to autism. The high percentage, 60-80%, of ASD cases showing motoric deficits again hints at the cerebellum. We explain 4:1 male to female ratio in ASD by the regulatory influence of estrogen on the development of the cerebellum.