The social phenotype of Williams syndrome

Williams syndrome (WS) offers an exciting model for social neuroscience because its genetic basis is well-defined, and the unique phenotype reflects dimensions of prosocial behaviors. WS is associated with a strong drive to approach strangers, a gregarious personality, heightened social engagement yet difficult peer interactions, high nonsocial anxiety, unusual bias toward positive affect, and diminished sensitivity to fear. New neurobiological evidence points toward alterations in structure, function, and connectivity of the social brain (amygdala, fusiform face area, orbital-frontal regions). Recent genetic studies implicate gene networks in the WS region with the dysregulation of prosocial neuropeptides. The study of WS has implications for understanding human social development, and may provide insight for translating genetic and neuroendocrine evidence into treatments for disorders of social behavior.

Introduction

Williams syndrome (WS) is a multisystem disorder [1] characterized by a distinctive social profile that holds promise for understanding the underlying neurogenetic systems that provide meaning for human social interaction. Resulting from a hemizygous deletion of ∼25 genes on chromosome 7q11.23 [2^••], a unique and robust behavioral characteristic of WS is an increased social drive particularly toward strangers [3, 4], manifesting as a strength in processing social over nonsocial stimuli, engaging language, increased social gaze, and empathic, friendly, and emotional personality [2••, 5••, 6]. This profile stands against a backdrop of strikingly uneven profile of cognitive functions, with profoundly impaired visual-spatial processing [7] (Figure 1). The neuropsychiatric profile is associated with mean IQ of approximately 50–60, with a typically higher verbal than performance IQ [1, 8]. One fascinating aspect of the WS social phenotype is that, unlike for visual-spatial processing with impaired functions across the board, the haploinsufficiency resulting from the gene deletion leads to a profile characterized by intriguing dissociations, or strengths and weaknesses (e.g. overly friendly with a difficulty in making friends; socially fearless but anxious; positive affect with maladaptive behaviors). In this sense, the WS gene deletion provides a unique model system to begin to relate single/clustered genes to specific alterations at the phenotypic level, with the ultimate potential of advancing our understanding of human social behavior at multiple levels.

This review focuses on capturing the nature of the unique WS social profile by outlining its major features at the level of behavior, followed by recent advances in the study of brain and genes. While the literature on the WS social phenotype has been building up for some time, the syndrome is emerging newly into focus and gaining new interest due to a recent surge of neurobiological evidence suggesting a consistent profile of brain structure and function underlying the social profile. Subsequently, the studies have provided critical new information about the ‘social brain’, paving the way for WS to serve as a ‘prototype model’ of social functioning that will allow new insight into understanding the biological basis of aspects of human social behavior in the future. We finish by addressing entirely new directions in molecular genetics suggesting dysregulation of prosocial neuropeptides in the overly social phenotype of WS, thereby implicating the study of WS prosocial behavior to encompass neuroendocrinology for the first time.