Summary Williams syndrome (WS) 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 WS lack precisely the same set of genes, with breakpoints in chromosome band 7q11.231–5. The contribution of specific genes to the neuroanatomical and functional alterations, leading to behavioral pathologies in humans, remains largely unexplored. Here, we investigate neural progenitor cells (NPCs) and cortical neurons derived from WS and typically developing (TD) induced pluripotent stem cells (iPSCs). WS NPCs have an increased doubling time and apoptosis compared to TD NPCs. Using an atypical WS subject6, 7, we narrowed this cellular phenotype to a single gene candidate, FZD9. At the neuronal stage, WS-derived layers V/VI cortical neurons were characterized by longer total dendrites, increased numbers of spines and synapses, aberrant calcium oscillation and altered network connectivity. Morphometric alterations observed in WS neurons were validated after Golgi staining of postmortem layers V/VI cortical neurons. This human iPSC model8 fills in the current knowledge gap in WS cellular biology and could lead to further insights into the molecular mechanism underlying the disorder and the human social brain.

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 ~1.5 Mb region of ~25 genes deleted in >98% 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 72.32-72.38Mb and the telomeric breakpoint to 72.66 Mb, 10kb downstream of GTF2IRD1. Cognitive testing (WPPSI-R, K-BIT, and PLS-3) deomstrated 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.

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.

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