Some copy number variants associated with autism lead to measurable anatomical defects or exhibit ‘mirrored phenotypes,’ meaning that deletions and duplications of the chromosomal region have opposite anatomical effects. Nicholas Katsanis and his colleagues at Duke University in Durham, North Carolina, are using these observations to investigate which genes within certain copy number variants lead to neurodevelopmental traits.

For example, at chromosomal region 16p11.2, deletions are associated with macrocephaly (abnormally large head) and duplications with microcephaly (abnormally small head). By systematically overexpressing or suppressing each of the 29 genes in the 16p11.2 region, Katsanis and his team have discovered that KCTD13 induces these mirrored phenotypes in a dosage-dependent manner.

The researchers propose to use the same approach to find new genes that drive other autism-related copy number variants. They also plan to generate mutant mice in which KCTD13 is deleted in particular neuronal tissues and compare their anatomy and behavior to those of mice bearing a deletion of the whole 16p11.2 region. In parallel, the researchers plan to cross their mutants with mice bearing a duplication of the 16p region, and test whether this duplication can restore the anatomical and behavioral traits lost when the region is missing.

Katsanis’s team also plans to test two other copy number variants on chromosomes 1 and 3, each of which is associated with autism and, in a manner akin to the dissection of the 16p11.2 region, identify the genes that drive the pathology. These studies could elucidate the biological relevance of these regions in autism and provide a robust method for the systematic identification of dosage-sensitive genes that contribute to cognitive traits.