From Genes to Neural Circuits to Behavior & Back Again: Neurogenetic Mechanisms in Williams Syndrome

Individuals with Williams syndrome, a fascinating and rare neurogenetic, developmental condition, have only one copy of approximately 25 genes on chromosome 7, instead of the typical, expected two copies (i.e., a “hemideletion”). People with Williams syndrome have a unique profile of striking behavioral features: remarkable hypersociability combined with differential impact on cognitive functions—some mildly affected while others, particularly visuospatial construction, are severely impaired. More recently, individuals with a “duplication” of these same genes, yielding three gene copies, have been studied as well. Interestingly, in contrast people with the Williams syndrome hemideltion, individuals with the Duplication syndrome show a behavioral picture that is in many ways the opposite of that of Williams syndrome itself. In particular, these individuals often have autistic, rather than hypersocial, traits or even autism per se, and many have relative strengths in visuospatial processing. Because the genes involved are known, studying persons with Williams syndrome, along with those with the Duplication syndrome, affords a privileged setting for investigating how genes are translated in the brain to produce cognitive and behavioral features. We have used multimodal brain imaging to identify several fundamental aspects of the brain phenotype in Williams syndrome and the Duplication syndrome that are related to their hallmark behavioral features. We are combining these results with our knowledge of the special genetic characteristic of these populations to test for associations of brain structure and function with “gene-dosage” (one copy of affected genes (i.e., in Williams syndrome) versus two copies (i.e., in the general “control” population) versus three copies. We also test for effects of variation in these chromosome 7 genes in the general population, and we are carrying out longitudinal studies of children with both syndromes in order to understand how brains develop over time in the face of these particular genetic landscapes. More generally, by understanding neurogenetic mechanisms of behavior in the special context of these genetic architectures, information may be obtained about how genetic variation is transduced in the brain to produce the extraordinarily wide range of human variability.