Autism Spectrum Disorder (ASD) is a common pediatric neurobiological disorder with up to 80% of genetic etiologies. Systems biology approaches may make it possible to test novel therapeutic strategies targeting molecular pathways to alleviate ASD symptoms. A clinical database of autism subjects was queried for individuals with a copy number variation (CNV) on microarray, Vineland, and Parent Concern Questionnaire scores. Pathway analyses of genes from pathogenic CNVs yielded 659 genes whose protein–protein interactions and mRNA expression mapped 121 genes with maximal antenatal expression in 12 brain regions. A Research Domain Criteria (RDoC)-derived neural circuits map revealed significant differences in anxiety, motor, and activities of daily living skills scores between altered CNV genes and normal microarrays subjects, involving Positive Valence (reward), Cognition (IQ), and Social Processes. Vascular signaling was identified as a biological process that may influence these neural circuits. Neuroinflammation, microglial activation, iNOS and 3-nitrotyrosine increase in the brain of Semaphorin 3F- Neuropilin 2 (Sema 3F-NRP2) KO, an ASD mouse model, agree with previous reports in the brain of ASD individuals. Signs of platelet deposition, activation, release of serotonin, and albumin leakage in ASD-relevant brain regions suggest possible blood brain barrier (BBB) deficits. Disruption of neurovascular signaling and BBB with neuroinflammation may mediate causative pathophysiology in some ASD subgroups. Although preliminary, these data demonstrate the potential for developing novel therapeutic strategies based on clinically derived data, genomics, cognitive neuroscience, and basic neuroscience methods.