A role for transcription factor GTF2IRD2 in executive function in Williams-Beuren syndrome.

Melanie A Porter,May Tassabehji,Carol Dobson-Stone,John B J Kwok,William Beckett,Peter R Schofield,Allan Siegel

doi:10.1371/journal.pone.0047457

Abstract

Executive functions are amongst the most heritable cognitive traits with twin studies indicating a strong genetic origin. However genes associated with this domain are unknown. Our research into the neurodevelopmental disorder Williams-Beuren syndrome (WBS) has identified a gene within the causative recurrent 1.5/1.6 Mb heterozygous microdeletion on chromosome 7q11.23, which may be involved in executive functioning. Comparative genome array screening of 55 WBS patients revealed a larger ∼1.8 Mb microdeletion in 18% of cases, which results in the loss of an additional gene, the transcription factor GTF2IRD2. The GTF gene family of transcription factors (GTF2I, GTF2IRD1 and GTF2IRD2) are all highly expressed in the brain, and GTF2I and GTF2IRD1 are involved in the pathogenesis of the cognitive and behavioural phenotypes associated with WBS. A multi-level analysis of cognitive, behavioural and psychological functioning in WBS patients showed that those with slightly larger deletions encompassing GTF2IRD2 were significantly more cognitively impaired in the areas of spatial functioning, social reasoning, and cognitive flexibility (a form of executive functioning). They also displayed significantly more obsessions and externalizing behaviours, a likely manifestation of poor cognitive flexibility and executive dysfunction. We provide the first evidence for a role for GTF2IRD2 in higher-level (executive functioning) abilities and highlight the importance of integrating detailed molecular characterisation of patients with comprehensive neuropsychological profiling to uncover additional genotype-phenotype correlations. The identification of specific genes which contribute to executive function has important neuropsychological implications in the treatment of patients with conditions like WBS, and will allow further studies into their mechanism of action.

Highlights

Williams-Beuren Syndrome (WBS) is a neurodevelopmental disorder caused by a hemizygous multi-gene deletion on chromosome 7q11.23
The two FISHnegative WBS patients (WBS023I and WBS425) harboured smaller,0.78 Mb deletions extending from LIMK1 to distal breakpoints within the GTF2IRD2 gene (Figure 1; Table 1)
copy number variants (CNVs) are associated with many neurological syndromes, all patients were screened by genome-wide Array comparative genomic hybridization (aCGH) (Table S2)

Summary

Introduction

Williams-Beuren Syndrome (WBS) is a neurodevelopmental disorder caused by a hemizygous multi-gene deletion on chromosome 7q11.23. Clinical features are multi-systemic and include characteristic craniofacial, cardiovascular, growth and neurological abnormalities [1,2,3,4]. WBS individuals are very friendly, gregarious and empathic, with relatively good emotion recognition abilities. In contrast to their good social perceptual skills, their social reasoning capabilities, such as theory of mind are impaired [5,6]. They display poor impulse control (behavioural disinhibition), a deficit which may underlie their apparent overfriendly personalities and tendency to approach strangers [7,8]

Methods

Results

Discussion

Conclusion