In order to delineate specific genetic contributions to brain structure, function and clinically relevant behavior and cognition, we have executed an ongoing series of multimodal neuroimaging studies of individuals with copy number variation in the 7q11.23 Williams Syndrome (WS) genomic region. These studies have been responsible for seminal advances in elaborating the neural underpinnings of both visuospatial and socio-emotional aspects of the 7q11.23 phenotype. We have established that the visuospatial construction deficits in WS (hemizygous microdeletion of a contiguous segment of DNA at this locus) are linked to convergent intraparietal sulcus alterations, via multiple neuroimaging techniques, including voxel- and surface-based cortical morphometry, diffusion tensor imaging and functional MRI. Specifically, we have shown that WS individuals harbor disrupted intraparietal sulcal region neural integrity, activation during spatial judgments, gray matter volume, sulcal depth, and associated neural fiber tracts. Likewise, in pursuit of plausible systems-level correlates of the hypersociability and non-social anxiety observed in WS, we have found decreased amygdala activation evoked by fearful face stimuli and conversely, increased amygdala response to non-social frightening stimuli, abnormalities that were linked to altered prefrontal regulation in structural equation models. We have also identified convergent alterations in anterior insula structure, function, and inter-regional connectivity, which predict the characteristic Williams syndrome (WS) personality. Under the auspices of our new longitudinal WS neurodevelopmental study, we have now been able to accelerate collection of these same measurements of visuospatial and socio-emotional systems integrity in a growing cohort of children with and without WS critical region copy number variation (i.e., individuals with one (WS), two (neurotypical), or three (WS region duplication) copies of the WS critical region). Growing this unique dataset will allow understanding of both the developmental trajectory and gene dose-response characteristics of neural abnormalities underlying visuospatial and socio-emotional alterations in this syndrome. Though data accrual will require years of careful and concerted effort to complete, the potential for these studies to shed unprecedented light on genetic contributions to brain development are enormous. In parallel, we have undertaken studies of DNA sequence variation in individuals without WS. This work has yielded remarkable interactions between genotype in the WS-associated GTF2I gene and a measure of trait neuroticism, harm avoidance, in predicting prefrontal response during an emotional face viewing task. In so far as GTF2I sequence variation affects the neural correlates of anxiety-related behavior, this gene may be of particular relevance to the dichotomous anxiety phenotypes present in WS. To the extent that this finding was identified in individuals without WS, such work exemplifies the translational possibilities of WS-directed research benefiting broader scientific understanding of key neural processes in the human brain. This work includes the following studies: NCT01132885, NCT00004571, NCT00001258
