Unusual cognitive and behavioural profile in a Williams syndrome patient with atypical 7q11.23 deletion

Abstract

C olorectal cancer (CRC) is the third most common cancer diagnosed in both men and women, and the second most common cause of cancer deaths in the United States. There were approximately 150 000 new cases resulting in 57 000 deaths in 2002.1 CRC is one of the most studied cancer types and its underlying aetiology best elucidated. Colorectal tumorigenesis involves a multistep process including genetic and epigenetic alterations of numerous CRC related genes that may act as either oncogenes or tumour suppressor genes. [2][3][4][5] The majority of sporadic CRCs are characterised by deletions of large chromosomal segments, which are thought to represent the loss of wild type tumour suppressor genes.6 7 About 15% of sporadic CRCs, on the other hand, show microsatellite instability (MSI), characterised by the insertion and/or deletion of simple repeat sequences and indicative of the involvement of defective mismatch repair. Birt-Hogg-Dubé syndrome (BHD, OMIM 135150) is an inherited autosomal dominant syndrome characterised by a triad of cutaneous lesions consisting of fibrofolliculomas, trichodiscomas, and acrochordons. 10 A wide spectrum of neoplastic and non-neoplastic features has been described in BHD patients, 11 including diverse types of kidney tumours 12-17 and spontaneous pneumothorax.12-16 18 BHD has also been reported to be associated with colonic polyposis and colorectal neoplasia, 13 19-22 although a large study of 223 patients from 33 BHD families could not establish such a relation. 23 We recently reported a high incidence of colorectal polyps and carcinomas in patients with confirmed BHD germline mutations, indicating that the BHD gene may be involved in colorectal tumorigenesis. 13 The BHD gene has been mapped to chromosome subband 17p11.2 12 14 and recently identified to encode a novel protein named follicullin. 15 Based on the presence of inactivating BHD mutations in BHD patients, and the detection of LOH in a significant proportion of BHD related tumours, the BHD gene was considered to be a tumour suppressor gene. A 44% frequency of frameshift mutations within a mononucleotide (C) 8 tract (nt 1733-1740) has been detected in BHD patients, 15 and this repeat tract represents a BHD mutational hot spot.13 15 Other studies have reported the presence of frameshift mutations within intragenic mononucleotide tracts of the TGFBR2 and BAX genes in CRC cell lines and tumours with high level MSI.24 25 The poly C tract of the BHD gene may therefore be a potential site of mutation in CRC characterised by MSI.We have evaluated the role of the BHD gene in 47 unselected colorectal tumours (10 polyps and 37 carcinomas) by screening all coding exons of the BHD gene for mutations and analysing 46 of the tumours for LOH in the chromosome region surrounding the BHD locus. Furthermore, alterations in BHD promoter methylation profiles were determined in 23 cases of matched normal/carcinoma tissues where a sufficient quantity of DNA was available. We report the detection of two novel somatic missense mutations of ...

The subcellular localization of the ChoRE-binding protein, encoded by the Williams–Beuren syndrome critical region gene 14, is regulated by 14-3-3

“…ELN haploinsufficiency has been linked to supravalvular aortic and other stenoses (21,36,37), whereas a mouse model suggests that CYLN2 hemizygosity might contribute to the WBS cognitive profile (38). Furthermore, the study of WBS patients with atypical deletion suggests that GTF2IRD1, GTF2I and CYLN2 genes might contribute to the visual spatial processing deficits harbored by WBS patients (39,40). However, the gene(s) responsible for the IGT and silent diabetes reported in the majority of the WBS patients remains to be determined.…”

Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits

“…However, the location of the breakpoints in nonhomologous or with low similarity sequences suggests that the most likely mechanism leading to this atypical rearrangements may be nonhomologous end joining or other processes that do not required high homology at the breakpoint, and support the proposal that other mechanisms predisposes to genomic instability of the WBS region 31 This study underscores the importance to map precisely the WBS deletion boundaries to revaluate the significance of the WBS genes hemizygosity in the pathogenesis of epilepsy, facial features, and neurological phenotypes. [32][33][34][35][36][37][38][39][40] CONFLICT OF INTEREST All patients and/or their parents gave written consent for the study, for genetic testing some gave consent for publication of photos. Ethics Committee approval was not required as this was not a specific study but a report of clinical investigation undertaken for four WBS patients, as part of their standard clinical care.…”

An atypical 7q11.23 deletion in a normal IQ Williams–Beuren syndrome patient

“…The detection of a normal full-scale IQ in our patient supports the previous assumptions that GTF2IRD1 and GTF2I genes are crucial for WBS cognitive features. 19,22,[27][28][29][30][31] Nevertheless, we have to emphasize that our patient exhibits a peculiar discrepancy between verbal IQ and performance IQ, resembling the PIQ/VIQ ratio that has been reported in typical WBS patients. 19,32,33 This finding seems contrary to previous reports of absent or minor visuospatial deficit in atypical WBS patients keeping GTF2IRD1 and GTF2I genes.…”

“…27 Other reports suggested that the GTF2I and GTF2IRD1 genes have dosagedependent influences on craniofacial and neurological development and that hemizygosity for these genes appears to be associated with the general intellectual disability/mental retardation 22 and/or visuospatial construction difficulties. 19,21,24,[28][29][30] Finally, further insights into genotype-phenotype correlations come from an intriguing report of an individual without the abnormal motor behavior and the specific spatial and impaired visual-spatial capacities. Genetic analysis showed that this patient had a deletion that excluded the genes RFC2, CLIP2, GTF2IRD1 and GTF2I.…”

“…19,32,33 This finding seems contrary to previous reports of absent or minor visuospatial deficit in atypical WBS patients keeping GTF2IRD1 and GTF2I genes. 19,28,31 Nonetheless, WBS207 scores on performance subtests were heterogeneous because he exhibited difficulties in geometric designs but not in picture completion, even if both investigate VSC, and in object assembly and in block design, but not in mazes, even if all investigate visual-motor integration. Therefore, the low result of PIQ could be related to the ocular anomalies (hypermetropic astigmatism associated with convergent strabismus) in association to some hampering of his fine motricity.…”