Bioinformatic approaches have been extensively applied in genetic and genomic studies of autism spectrum disorders (ASD). However, since this disorder has a distinct albeit complex genetic etiology, these studies have generated data sets requiring additional empirical and theoretical evaluations of molecular and cellular pathway. Additionally, genetic-environmental interactions in ASD are poorly understood. To prioritize genomic variations, molecular/cellular processes and environmental factors, systems biology approaches should be applied. Here, we present a molecular cytogenomic and somatic genomic view on a possible "ASD pathway" to address genetic-environmental interactions in ASD. Taking into account the relevance of these considerations for brain diseases, as a whole, we propose a multi-hit hypothesis to explain the complex nature of interactions between germline mutations, somatic genomic variations (i.e. aneuploidy, genome and chromosome instability) and environment in neuropsychiatric disorders. Using different bioinformatic methods for gene prioritization and analyzing candidate processes for brain dysfunction, it becomes possible to place personalized genomic data in a systems (neuro)biology context. Multidimensional omics data is, therefore, a target for advanced bioinformatics studies, which are able to clarify the biological mechanisms of specific genetic changes in ASD and to enhance the potential for new therapeutic concepts.