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

Broadbent et al. Journal of Neurodevelopmental Disorders 2014, 6:18 http://www.jneurodevdisorders.com/content/6/1/18 RESEARCH Open Access Genetic contributions to visuospatial cognition in Williams syndrome: insights from two contrasting partial deletion patients Hannah Broadbent1*, Emily K Farran1, Esther Chin2, Kay Metcalfe3, May Tassabehji3, Peter Turnpenny4,5, Francis Sansbury4,5, Emma Meaburn2 and Annette Karmiloff-Smith2 Abstract Background: Williams syndrome (WS) is a rare neurodevelopmental disorder arising from a hemizygotic deletion of approximately 27 genes on chromosome 7, at locus 7q11.23. WS is characterised by an uneven cognitive profile, with serious deficits in visuospatial tasks in comparison to relatively proficient performance in some other cognitive domains such as language and face processing. Individuals with partial genetic deletions within the WS critical region (WSCR) have provided insights into the contribution of specific genes to this complex phenotype. However, the combinatorial effects of different genes remain elusive. Methods: We report on visuospatial cognition in two individuals with contrasting partial deletions in the WSCR: one female (HR), aged 11 years 9 months, with haploinsufficiency for 24 of the WS genes (up to GTF2IRD1), and one male (JB), aged 14 years 2 months, with the three most telomeric genes within the WSCR deleted, or partially deleted. Results: Our in-depth phenotyping of the visuospatial domain from table-top psychometric, and small- and large-scale experimental tasks reveal a profile in HR in line with typically developing controls, albeit with some atypical features. These data are contrasted with patient JB’s atypical profile of strengths and weaknesses across the visuospatial domain, as well as with more substantial visuospatial deficits in individuals with the full WS deletion. Conclusions: Our findings point to the contribution of specific genes to spatial processing difficulties associated with WS, highlighting the multifaceted nature of spatial cognition and the divergent effects of genetic deletions within the WSCR on different components of visuospatial ability. The importance of general transcription factors at the telomeric end of the WSCR, and their combinatorial effects on the WS visuospatial phenotype are also discussed. Keywords: Williams syndrome, Visuospatial cognition, Navigation, GTF2I, GTF2IRD1, LIMK1 Background Williams syndrome (WS) is a rare autosomal dominant disorder arising from the hemizygotic deletion of approximately 27 genes on chromosome 7, at locus 7q11.23 [1,2]. The deletion occurs spontaneously during meiosis and is due to unequal crossing over at misaligned repeat segments [3]. This typically results in a deletion spanning some 1.55 Mb (approximately 95% of cases) to around 1.84 Mb (approximately 5% of cases) of genomic DNA * Correspondence: 1 Institute of Education, University of London, London, UK Full list of author information is available at the end of the article [4-8]. However, a number of individuals with partial deletions within the WS critical region (WSCR) of chromosome 7 have also been identified [for examples, 9,10]. Such cases can provide important insights into the contribution of specific genes to the phenotypic outcome of WS. Given the uneven cognitive profile characteristic of WS, particularly the contrast between poor non-verbal abilities relative to verbal cognition [for example, 11], research into individuals with partial deletions has sought to identify candidate genes responsible for deficits in domains such as global intellectual difficulties [10], social cognition [12], and spatial cognition [13-15]. © 2014 Broadbent et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Broadbent et al. Journal of Neurodevelopmental Disorders 2014, 6:18 http://www.jneurodevdisorders.com/content/6/1/18 In the case of individuals with the full WS deletion, spatial deficits have been well documented, with poor performance reported on visuospatial construction tasks, [16,17], mental imagery [18,19], and the use of spatial frames of reference [20,21]. More recently, deficits in large-scale spatial navigation have also been identified in WS [22,23]. But which genes contribute to these smallscale and large-scale spatial impairments remains a topic of debate. One study that examined two families with a partial WS phenotype, including supravalvular aortic stenosis (SVAS) and deficits in visuospatial construction, found that affected family members were hemizygous for the elastin (ELN) and LIM-Kinase1 (LIMK1) genes [13], which lie within the WSCR. Given that ELN is not expressed in the brain and mutations of which are not associated with spatial deficits but with cardiovascular abnormalities, it was concluded that it must be the other deleted gene, LIMK1, that plays an important role in the phenotypic expression of impaired spatial cognition in WS. Indeed, in vivo, Limk1 knockout mice have impaired spatial learning performance when tested on reversal learning in the Morris water maze [24]. They also present with abnormal synaptic structure and neuronal spine morphology, as well as altered hippocampal long-term potentiation. The role of LIMK1, however, has remained inconclusive, with other studies of patients with partial deletions that include LIMK1 suggesting that hemizygosity for this gene does not in itself result in deficits in visuospatial cognition [for examples., 9,15]. Using a large battery of perceptual and visuospatial tasks, Gray and colleagues [15] report a very detailed assessment of two patients with deletions of only ELN and LIMK1, compared with two adults with full WS matched on verbal ability. A profile of normal spatial performance emerged from the two partial deletion patients compared to those with the full deletion, suggesting that LIMK1 alone did not explain spatial deficits in WS. In addition, the successful performance of these same two partial deletion patients on a large-scale spatial task indicated that the hemizygotic deletion of LIMK1 was also insufficient to result in the poor large-scale search strategies identified in individuals with full WS on the same task [14]. These findings concur to indicate that the sole deletion of LIMK1 is not sufficient to result in deficits in any form of spatial cognition. Instead, the authors suggest that LIMK1 may play a role in the spatial cognitive profile in WS only when deleted alongside other genes, particularly those at the telomeric end of the WSCR. It is these latter (...truncated)