A Role for Transcription Factor GTF2IRD2 in Executive Function in Williams-Beuren Syndrome

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.

Genetic contributions to visuospatial cognition in Williams syndrome: insights from two contrasting partial deletion patients

“…Initially, the examination of visuospatial performance by HR and JB seems indicative of the additive effect of deleting each of the GTF2I family genes on the severity of cognitive impairment, and is in line with other findings in individuals with extended deletions (approximately 1.8 Mb) that encompass GTF2IRD2 , who present with significantly greater neurological impairments than individuals with shorter deletions typical of WS [59]. However, although we cannot dismiss the effects of other deleted genes in JB that extend beyond the WSCR on cognitive functioning, JB’s high level of performance on small-scale mental rotation and VPT rules out the conclusion of a general deficit, and excludes the role of genes telomeric to GTF2I in these specific small-scale spatial abilities.…”

Differing Microdeletion Sizes and Breakpoints in Chromosome 7q11.23 in Williams-Beuren Syndrome Detected by Chromosomal Microarray Analysis

“…Compared to WBS patients with a typical 1.5-Mb deletion, only 2 additional genes, NCF1 and GTF2IRD2 , are deleted in those with a larger 1.8-Mb size deletion. After analyzing cognitive, behavioral and psychological functioning in 55 WBS patients, Porter et al [2012] showed that those with 1.8-Mb deletions encompassing GTF2IRD2 had significantly poorer cognitive functions including spatial functioning, social reasoning, and executive function. The GTF2IRD1 and GTF2I are the transcription factor TFII-I family members encoding BEN and TFII-I proteins, respectively.…”

Verbal labels increase the salience of novel objects for preschoolers with typical development and Williams syndrome, but not in autism

“…Exclusion criteria included the presence of uncorrected hearing or vision impairment and the presence of major medical problems. All participants with WS had their diagnosis confirmed with the positive fluorescent in situ hybridization (FISH) test and displayed the typical ~1.6 Mb heterozygous microdeletion at 7q11.23 [51]. …”