Williams syndrome (WMS) is a most compelling model of human cognition, of human genome organization, and of evolution. Due to a deletion in chromosome band 7q11.23, subjects have cardiovascular, connective tissue, and neurode-velopmental deficits. Given the striking peaks and valleys in neurocognition including deficits in visual-spatial and global processing, preserved language and face processing, hypersociability, and heightened affect, the goal of this work has been to identify the genes that are responsible, the cause of the deletion, and its origin in primate evolution. To do this, we have generated an integrated physical, genetic, and transcriptional map of the WMS and flanking regions using multicolor metaphase and interphase fluorescence in situ hybridization (FISH) of bacterial artificial chromosomes (BACs) and P1 artificial chromosomes (PACs), BAC end sequencing, PCR gene marker and microsatellite, large-scale sequencing, cDNA library, and database analyses. The results indicate the genomic organization of the WMS region as two nested duplicated regions flanking a largely single-copy region. There are at least two common deletion breakpoints, one in the centromeric and at least two in the telomeric repeated regions. Clones anchoring the unique to the repeated regions are defined along with three new pseudogene families. Primate studies indicate an evolutionary hot spot for chromosomal inversion in the WMS region. A cognitive phenotypic map of WMS is presented, which combines previous data with five further WMS subjects and three atypical WMS subjects with deletions; two larger (deleted for D7S489L) and one smaller, deleted for genes telomeric to FZD9 , through LIMK1 , but not WSCR1 or telomeric. The results establish regions and consequent gene candidates for WMS features including mental retardation, hypersociability, and facial features. The approach provides the basis for defining pathways linking genetic underpinnings with the neuroanatomical, functional, and behavioral consequences that result in human cognition.

Williams syndrome (WMS), a genetic condition resulting from a contiguous deletion on the long arm of chromosome 7, is associated with a relatively consistent profile of neurocognitive and neurobehavioral features. The distinctiveness and regularity of the profile of learning and behavioral characteristics in this genetic condition suggests that underlying neurobiological correlates may be identifiable. In this initial study, we report findings derived from a high-resolution neuroimaging study of 14 young adult subjects with WMS and an individually matched normal control group. Compared to controls, subjects with WMS were noted to have decreased overall brain and cerebral volumes, relative preservation of cerebellar and superior temporal gyrus (STG) volumes, and disproportionate volume reduction of the brainstem. Analyses also suggested that the pattern of cerebral lobe proportions in WMS may be altered compared to normal controls with a greater ratio of frontal to posterior (parietal+occipital) tissue. Assessment of tissue composition indicated that, relative to controls, individuals with WMS have relative preservation of cerebral gray matter volume and disproportionate reduction in cerebral white matter volume. However, within the cerebral gray matter tissue compartment, the right occipital lobe was noted to have excess volume loss. Combined with our growing knowledge of the function of genes in the commonly deleted region for WMS, more detailed information regarding the structure and function of the WMS brain will provide a unique opportunity for elucidating meaningful correlations amongst genetic, neurobiological, and neurobehavioral factors in humans.

The rare, genetically based disorder, Williams syndrome (WMS), produces a constellation of distinctive cognitive, neuroanatomical, and electrophysiological features which we explore through the series of studies reported here. In this paper, we focus primarily on the cognitive characteristics of WMS and begin to forge links among these characteristics, the brain, and the genetic basis of the disorder. The distinctive cognitive profile of individuals with WMS includes relative strengths in language and facial processing and profound impairment in spatial cognition. The cognitive profile of abilities, including what is ‘typical’ for individuals with WMS is discussed, but we also highlight areas of variability across the group of individuals with WMS that we have studied. Although the overall cognitive abilities (IQs) of individuals with WMS are typically in the mild-to-moderate range of mental retardation, the peaks and valleys within different cognitive domains make this syndrome especially intriguing to study across levels. Understanding the brain basis (and ultimately the genetic basis) for higher cognitive functioning is the goal we have begun to undertake with this line of interdisciplinary research.

Studies of abnormal populations provide a rare opportunity for examining relationships between cognition, genotype and brain neurobiology, permitting comparisons across these different levels of analysis. In our studies, we investigate individuals with a rare, genetically based disorder called Williams syndrome (WMS) to draw links among these levels. A critical component of such a cross-domain undertaking is the clear delineation of the phenotype of the disorder in question. Of special interest in this paper is a relatively unexplored unusual social phenotype in WMS that includes an overfriendly and engaging personality. Four studies measuring distinct aspects of hypersocial behavior in WMS are presented, each probing specific aspects in WMS infants, toddlers, school age children, and adults. The abnormal profile of excessively social behavior represents an important component of the phenotype that may distinguish WMS from other developmental disorders. Furthermore, the studies show that the profile is observed across a wide range of ages, and emerges consistently across multiple experimental paradigms. These studies of hypersocial behavior in WMS promise to provide the ground-work for crossdisciplinary analyses of gene-brain-behavior relationships.