Genetic Mechanisms Emerging from Mouse Models of CNV-Associated Neuropsychiatric Disorders

Many chromosomal deletions and duplications, up to a few million base pairs, are robustly and reproducibly associated with neuropsychiatric disorders. These genomic variants, termed copy number variants (CNVs), confer unprecedented degrees of risk for schizophrenia, autism spectrum disorder, intellectual disability, and attention deficit hyperactivity disorder. These associations spurred the generation of genetic mouse models with construct validity, which in turn provided insights into the mechanisms through which CNV-encoded genes contribute to dimensional features of neuropsychiatric disorders. Evidence suggests that the ultimate phenotypic expression of a gene dose alteration within a CNV is determined by the collective action of multiple, noncontiguously located genes along predetermined developmental trajectories under the modulatory influences of genetic background and environmental factors. Mouse models of CNVs provide opportunities to better understand the genetic origin of neuropsychiatric disorders.