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Williams Syndrome (WS) is a rare genetic disorder with unique behavioral features. Yet the rareness of WS has limited the number and type of studies that can be conducted in which inferences are made about how neuroanatomical abnormalities mediate behaviors. In this study, we extracted a WS-specific neuroanatomical profile from structural magnetic resonance imaging (MRI) measurements and tested its association with behavioral features of WS. Using a WS adult cohort (22 WS, 16 healthy controls), we modeled a sparse representation of a WS-specific neuroanatomical profile. The predictive performances are robust within the training cohort (10-fold cross-validation, AUC = 1.0) and accurately identify all WS individuals in an independent child WS cohort (seven WS, 59 children with diverse developmental status, AUC = 1.0). The WS-specific neuroanatomical profile includes measurements in the orbitofrontal cortex, superior parietal cortex, Sylvian fissures, and basal ganglia, and variability within these areas related to the underlying size of hemizygous deletion in patients with partial deletions. The profile intensity mediated the overall cognitive impairment as well as personality features related to hypersociability. Our results imply that the unique behaviors in WS were mediated through the constellation of abnormalities in cortical-subcortical circuitry consistent in child WS and adult WS. The robustness of the derived WS-specific neuroanatomical profile also demonstrates the potential utility of our approach in both clinical and research applications., Highlights • A Williams Syndrome Specific neuroanatomical profile is extracted to provide both explanatory power and clinical utilities • Multidimensional features of MRI are summarized into one single score to depict the morphological differences across groups • The model robustly identify Williams Syndrome individuals despite age differences • The selected features indicate the mediation paths from brain to cognition

Williams syndrome (WS) is associated with deficits in adaptive behavior and an uneven adaptive profile. This study investigated the association of intelligence, visual-motor functioning, and personality characteristics with the adaptive behavior in individuals with WS. One hundred individuals with WS and 25 individuals with developmental disabilities of other etiologies were included in this study. This study found that IQ and visual-motor functioning significantly predicted adaptive behavior in individuals of WS. Visual-motor functioning especially predicted the most amount of unique variance in overall adaptive behavior and contributed to the variance above and beyond that of IQ. Present study highlights the need for interventions that address visual-motor and motor functioning in individuals with WS.

© 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. Williams syndrome is a genetic neurodevelopmental disorder characterized by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities. Nearly all clinically diagnosed individuals with Williams syndrome lack precisely the same set of genes, with breakpoints in chromosome band 7q11.23 (refs 1, 2, 3, 4, 5). The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioural pathologies in humans, remains largely unexplored. Here we investigate neural progenitor cells and cortical neurons derived from Williams syndrome and typically developing induced pluripotent stem cells. Neural progenitor cells in Williams syndrome have an increased doubling time and apoptosis compared with typically developing neural progenitor cells. Using an individual with atypical Williams syndrome, we narrowed this cellular phenotype to a single gene candidate, frizzled 9 (FZD9). At the neuronal stage, layer V/VI cortical neurons derived from Williams syndrome were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in neurons from Williams syndrome were validated after Golgi staining of post-mortem layer V/VI cortical neurons. This model of human induced pluripotent stem cells fills the current knowledge gap in the cellular biology of Williams syndrome and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.

Williams syndrome (WS) is a genetic condition often paired with abnormal social functioning and behavior. In particular, those with WS are characterized as being relatively hypersocial, overly emotional/empathic, and socially uninhibited or fearless. In addition, WS is associated with abnormal amygdala structure and function. Very little is known however about the relationship between specific social behaviors and altered amygdala function in WS. This study was designed to compare three models that relate abnormal social behavior with amygdala function in WS (indiscriminate sociability, emotional and empathic sociability and social fearlessness). We used a social behavior assessment procedure (Salk Institute Sociability Questionnaire), functional magnetic resonance imaging and an implicit emotion face processing task to test these models. Our findings provide support for a model of abnormal social fearlessness by showing that in WS, abnormal amygdala response to fear is paired with an increased tendency to approach strangers. Specifically, individuals with WS that exhibited less amygdala response to fearful facial expressions (compared to neutral) also exhibited an increased tendency to approach strangers. These findings contribute to our understanding of social and emotional functioning in neurodevelopmental conditions and provide evidence that in WS, amygdala response to fear modulates social behavior.

Previous studies of children with Williams syndrome (WS) have found a specific deficit in dorsal cortical stream function, indicated by poor performance in coherence thresholds for motion compared to form. Here we investigated whether this is a transient developmental feature or a persisting aspect of cerebral organization in WS. Motion and form coherence thresholds were tested in a group of 45 WS individuals aged 16-42 years, and 19 normal adult controls.Although there was considerable variation in the coherence thresholds across individuals with WS, the WS group showed overall worse performance than controls. A significant group x threshold condition interaction showed a substantially greater performance deficit for motion than for form coherence in the WS group relative to controls. This result suggests that the motion deficit is an enduring feature in WS and is a marker for one aspect of dorsal-stream vulnerability. (c) 2005 Elsevier Ltd. All rights reserved.

Most descriptions of callitrichid antipredator behavior have come from observations of visual encounters with predators, but there is also anecdotal evidence suggesting that callitrichids may use auditory cues associated with raptors for the early detection of potential danger. In the present study, Geoffroy’s marmosets consistently reacted to the tape-recorded calls of a red-tailed hawk (Buteo jamaicensis) with high-intensity antipredator behaviors. Compared to the taped calls of a raven (Corvus corax) and the taped sound of a power drill, the hawk calls elicited more startle reactions, more alarm calls, longer freeze times, increased use of safe areas of their enclosure and greater disruption in ongoing behavior. Once in a relatively safe location in the enclosure, the marmosets visually monitored the site of origin of the calls for 10 min and minimized locomotion for 30 min, but resumed baseline levels of other activities that had been disrupted by the hawk calls. Marmosets may use the auditory cues associated with predators for early detection, and subsequent avoidance, of a potential predator in the vicinity.

Genetic contributions to human cognition and behavior are clear but difficult to define. Williams syndrome (WS) provides a unique model for relating single genes to visual-spatial cognition and social behavior. We defined a approximately 1.5 Mb region of approximately 25 genes deleted in98% of typical WS and then rare small deletions, showing that visual-spatial construction (VSC) in WS was associated with the genes GTF2IRD1 and GTF2I. To distinguish the roles of GTF2IRD1 and GTF2I in VSC and social behavior, we utilized multiple genomic methods (custom high resolution oligonucleotide microarray, multicolor FISH and somatic cell hybrids analyzed by PCR) to identify individuals deleted for either gene but not both. We analyzed genetic, cognitive and social behavior in a unique individual with WS features (heart defects, small size, facies), but with an atypical deletion of a set of genes that includes GTF2IRD1, but not GTF2I. The centromeric breakpoint localized to the region 72.32-72.38 Mb and the telomeric breakpoint to 72.66 Mb, 10 kb downstream of GTF2IRD1. Cognitive testing (WPPSI-R, K-BIT, and PLS-3) demonstrated striking deficits in VSC (Block Design, Object Assembly) but overall performance 1.5-3 SD above WS means. We have now integrated the genetic, clinical and cognitive data with previous reports of social behavior in this subject. These results combine with previous data from small deletions to suggest the gene GTF2IRD1 is associated with WS facies and VSC, and that GTF2I may contribute to WS social behaviors including increased gaze and attention to strangers.

Williams syndrome is a neurogenetic disorder resulting from a hemizygous microdeletion at band 7q11.23. It is characterized by aberrant development of the brain and a unique profile of cognitive and behavioral features. We sought to identify the neuroanatomical abnormalities that are most strongly associated with Williams syndrome employing signal detection methodology. Once identified with a Quality Receiver Operating Characteristic Curve, we hypothesized those brain regions distinguishing subjects with Williams syndrome from controls would be linked to the social phenotype of individuals with this disorder. Thirty-nine adolescents and young adults with Williams syndrome and 40 typically developing controls matched for age and gender were studied. The Quality Receiver Operating Characteristic Curve identified a combination of an enlarged ventral anterior prefrontal cortex and large bending angle of the corpus callosum to distinguish between Williams syndrome and controls with a sensitivity of 85.4% and specificity of 75.0%. Within the Williams syndrome group, bending angle significantly correlated with ventral anterior prefrontal cortex size but not with other morphometric brain measures. Ventral anterior prefrontal size in subjects with Williams syndrome was positively associated with the use of social engagement devices in a narrative task assessing the use of social and affective language. Our findings suggest that aberrant morphology of the ventral anterior prefrontal cortex is a pivotal contributing factor to the abnormal size and shape of the cerebral cortex and to the social-affective language use typical of individuals with Williams Syndrome.

Objective Autistic disorder (AD) and Williams syndrome (WS) are neurodevelopmental disorders characterized by contrasting abnormal social behavior (the former, socially avoidant; the latter, outwardly social); nonetheless, there are individuals with WS who display some behaviors that are characteristic of AD. We quantified the extent to which autism spectrum disorder (ASD) behaviors were present in children with WS. Method Twenty children with WS (27-58 months) and 26 age- and IQ-equivalent children with AD were administered the Autism Diagnostic Observation Schedule (ADOS). ADOS behaviors were compared between groups. Results Two children with WS met DSM-IV criteria for AD, one of whom was also classified as having AD by the ADOS algorithm. Discriminant analysis of ADOS behaviors indicated that gesture, showing, and quality of social overtures best discriminated the groups. Conclusions Although some children with WS demonstrated some ASD behaviors, and a minority of children with WS had coexisting AD, the symptom profile in WS was different from AD. Despite some deficits in communication behaviors, showing, and initiating joint attention, children with WS made social overtures and efforts to engage others, whereas children with AD tended not to do so.

We sought to clarify the nature of the face processing strength commonly observed in individuals with Williams syndrome (WS) by comparing the face recognition ability of persons with WS to that of persons with autism and to healthy controls under three conditions: Upright faces with neutral expressions, upright faces with varying affective expressions, and inverted faces with neutral expressions. No differences were observed under the upright/neutral expression condition. However, the WS group was more accurate than the autism group when discriminating upright faces with varying affective expressions, whereas the opposite pattern emerged when discriminating inverted faces. We interpret these differences as a reflection of the contrasting social features of the two syndromes.

The relationship between age and IQ was evaluated in a cross-sectional sample of 80 individuals with Williams syndrome (17 to 52 years). The relationship between age and WAIS-R subtest scores was such that increases and decreases in raw scores occurred at a rate sufficient to maintain stability of age-corrected scaled scores, indicating a developmental trajectory similar to that of the WAIS-R normative sample. Despite stability of age- corrected scaled scores with age, increased age was related to higher Performance IQ. This disparity, which occurs during the conversion of sums of scaled scores to IQs, may be unique to the WAIS-R. Although Performance IQ increased with age, results imply that the overall IQ of an adult with Williams syndrome will likely remain stable.

The relationship between age and IQ was evaluated in a cross-sectional sample of 80 individuals with Williams syndrome (17 to 52 years). The relationship between age and WAIS-R subtest scores was such that increases and decreases in raw scores occurred at a rate sufficient to maintain stability of age-corrected scaled scores, indicating a developmental trajectory similar to that of the WAIS-R normative sample. Despite stability of age- corrected scaled scores with age, increased age was related to higher Performance IQ. This disparity, which occurs during the conversion of sums of scaled scores to IQs, may be unique to the WAIS-R. Although Performance IQ increased with age, results imply that the overall IQ of an adult with Williams syndrome will likely remain stable.