Autism spectrum disorder (ASD), affecting 1 in 68 children in the U.S., is a significant unresolved public health concern. The clinical presentations of ASD can be quite broad, and recent evidence points to many different genetic causes. This heterogeneity could lead to a scientific and clinical impasse; each cause of ASD has its own disrupted mechanisms and requires its own unique treatment. However, a more optimistic interpretation, for which there is now accumulating evidence, is that many different primary causes of ASD actually converge on a limited subset of biochemical pathways in nerve cells that mediate cell growth and function. Demonstrating that such a mechanistic convergence exists would be a significant step forward for the field.

Elliott Sherr and his team at the University of California, San Francisco propose that changes in both structural and functional brain imaging correlate with the severity of cognitive-behavioral impairment in individuals with ASD, and that these changes are linked to changes in RAS-ERK and AKT/PI3K intracellular signaling pathways that can be measured in white blood cells taken from those with ASD. Previously, Sherr and his collaborators demonstrated that ASD individuals with 16p11.2 copy number variants (CNVs) exhibit a number of structural and functional changes in their brains¹, ². They have also demonstrated that biochemical changes in the ERK signaling pathway are correlated with social impairments in a mouse model³.

In the current study, Sherr and his team will perform structural and functional imaging on individuals with idiopathic ASD and macrocephaly, and who show biochemical alterations in RAS-ERK and AKT/PI3K signaling pathways in their blood cells. These imaging results will be compared with data from healthy controls and from the 16p11.2 CNV individuals previously tested. The team will also assess whether structural and functional changes in the ASD brain correlate with impairments in cognition and behavior relative to the matched control cohort. The team hypothesizes that the two ASD cohorts will show similar brain imaging changes. If verified, this would be the first time brain imaging findings have been linked to ASD biology — an important step toward using imaging as a marker for defining ASD subclasses and for measuring responses to treatment.