Dimensional Deconstruction and Reconstruction of CNV-Associated Neuropsychiatric Disorders

Rare genomic variants, termed copy number variants (CNVs), confer unprecedented degrees of risk for schizophrenia, autism spectrum disorders, intellectual disability, and attention deficit hyperactivity disorder. The pleiotropic actions of CNVs on seemingly diverse clinical diagnoses raise the tantalizing possibility that many clinically defined neuropsychiatric disorders share common genetic, molecular, and neuronal mechanisms, but their ultimate phenotypic features diverge under the modulatory influence of factors other than copy number variants. Mouse models of CNVs are being developed, and these studies have provided insights into the precise manner through which CNV-encoded genes contribute to dimensional features of neuropsychiatric disorders. Evidence suggests that individual genes encoded in contiguous deletion or duplication cause quantitative dimensional shifts in cognitive, socioemotional, and motivational domains in a non-contiguous manner and that the phenotypic targets of individual contributory genes are not identical. Thus, quantitative, dimensional profiling of CNV mouse models is a sound alternative to a disease-specific modeling.