A well-characterized microdeletion in the 22q11.2 chromosomal region is known to be associated with schizophrenia. There is growing evidence that duplications at this locus are also associated with autism. Joseph Gogos and his colleagues at Columbia University in New York have been studying the chain of molecular and cellular events arising from copy number variants (CNVs) at this locus, which may lead to altered brain connectivity.

Behavioral analyses of mice that model deletions at this locus have revealed a unique profile of cognitive impairments. The mice show disruptions in the function of the prefrontal cortex and abnormal connectivity between the prefrontal cortex and other brain structures. In addition, the researchers have identified two genes at this locus, DGCR8 and ZDHHC8, that account for many alterations in local and long-range connectivity. It appears that two molecular pathways are specifically affected: the production of microRNAs, which are involved in gene regulation, and the addition of palmitoyl groups to neuronal proteins, which regulates the function and localization of these proteins within neurons.

These studies have significantly enhanced our understanding of the cognitive, learning and behavioral deficits associated with the 22q11.2 region. The robust association of well-defined genomic imbalances with cognitive and behavioral dysfunction, coupled with the availability of mice that model the disruptions, provides a unique platform for studying this CNV. The work of Gogos and his colleagues may serve as a prototype to guide the analysis of other CNVs linked to autism spectrum disorders.