Recent discoveries of contrasting phenotypes caused by deletion vs. duplication events within the same genetic locus suggest that investigation of gene dosage effects may provide valuable clues into how copy number variations (CNVs), or duplications or deletions of stretches of DNA, disrupt the brain and ultimately contribute to disease pathogenesis. However, almost nothing is known about the consequences of such reciprocal imbalances on brain function or behavior.

Carrie Bearden and her colleagues at the University of California, Los Angeles have collected extensive clinical, behavioral and brain imaging data from a large cohort of children with deletion of the 22q11.2 chromosomal region. The data reveal structural and functional disruptions of neural circuits relevant to language and social communication. Bearden plans to obtain comparable structural and functional brain anatomic data in a cohort of children with gain-of-function mutations (duplications of genetic material) in the same gene location.

Preliminary data from Bearden’s group indicate robust dose-dependent effects in brain regions critical for social processes. The researchers aim to use a novel artificial-language-learning paradigm that has revealed disruption of language-relevant neural circuits in both individuals with 22q11.2 deletions and children with idiopathic autism (autism of unknown cause). Extensive data from individuals with 22q11.2 deletions, typically developing children and children with idiopathic autism may allow for key comparisons across neural and behavioral levels of analysis.

The investigators hope to use this ‘genetics-first’ approach to investigate whether brain structure and language-related neural circuitry, along with associated clinical phenotypes, differ meaningfully as a function of gene dosage. This information may reveal whether treatments are best tailored to a specific genetic event, or may be generalizable to those with autism of other or unknown etiologies.