Molecular and clinical correlation study of Williams-Beuren syndrome: No evidence of molecular factors in the deletion region or imprinting affecting clinical outcome

Wang, Michael S.; Schinzel, Albert; Kotzot, Dieter; Balmer, Damina; Casey, Robin; Chodirker, B. N.; Gyftodimou, Jolanda; Petersen, Michael B.; Lopez-Rangel, Elena; Robinson, Wendy P.

doi:10.1002/(sici)1096-8628(19990903)86:1<34::aid-ajmg7>3.0.co;2-4

Cited by 34 publications

(17 citation statements)

References 48 publications

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“…When the third marker, D7S489, was included informative detection increased to almost 99%. To increase the detection closer to 100%, additional useful markers will need to be chosen 27,23,35-37. …”

Section: Discussionmentioning

confidence: 99%

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Detection of deletions at 7q11.23 in Williams-Beuren syndrome by polymorphic markers

Dutra

Pieri

Teixeira

et al. 2011

Clinics

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INTRODUCTION:Williams-Beuren syndrome (WBS; OMIM 194050) is caused by a hemizygous contiguous gene microdeletion at 7q11.23. Supravalvular aortic stenosis, mental retardation, overfriendliness, and ocular and renal abnormalities comprise typical symptoms in WBS. Although fluorescence in situ hybridization is widely used for diagnostic confirmation, microsatellite DNA markers are considered highly informative and easily manageable.OBJECTIVES:This study aimed to test the microsatellite markers for the diagnosis of Williams-Beuren syndrome, to determine the size and parental origin of microdeletion, compare the clinical characteristics between patients with different sizes of the deletion and parental origin.METHODS:We studied 97 patients with clinical diagnosis of Williams-Beuren syndrome using five microsatellite markers: D7S1870, D7S489, D7S613, D7S2476 and D7S489_A.RESULTS AND DISCUSSION:Using five markers together, the result was informative in all patients. The most informative marker was D7S1870 (78.4%), followed by D7S613 (75.3%), D7S489 (70.1%) and D7S2476 (62.9%). The microdeletion was present in 84 (86.6%) patients and absent in 13 (13.4%) patients. Maternal deletions were found in 52.4% of patients and paternal deletions in 47.6% of patients. The observed size of deletions was 1.55 Mb in 76/84 patients (90.5%) and 1.84 Mb in 8/84 patients (9.5%). SVAS as well as ocular and urinary abnormalities were more frequent in the patients with a deletion. There were no clinical differences in relation to either the size or parental origin of the deletion.CONCLUSION:Using these five selected microsatellite markers was informative in all patients, thus can be considered an alternative method for molecular diagnosis in Williams-Beuren syndrome.

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Section: Discussionmentioning

confidence: 99%

“…The origin of deletion occurs at the same frequency, and there is no clear-cut clinical association between parental imprinting and phenotype differences, except for hypertension and some aspects of growth, such as height, weight and head circumference 17,13,23,24. …”

Section: Introductionmentioning

confidence: 99%

Detection of deletions at 7q11.23 in Williams-Beuren syndrome by polymorphic markers

Dutra

Pieri

Teixeira

et al. 2011

Clinics

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“…The prevalence of WBS is 1–2 in 20,000 [16], and most cases are sporadic [17]–[18] arising from instability at the 7q11.23 locus, which contains highly repetitive segmental duplications. These low copy repeats (LCRs) make the region prone to chromosome rearrangements through a mechanism of non-allelic homologous recombination [19].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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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.

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“…Other frequent features are growth and psychomotor retardation with muscular hypotonia, limited visuospatial cognition, and specific language as well as behavioural abnormalities (overfriendliness and anxiety disorders, hypersensitivity to sounds). [3][4][5] Endocrine and metabolic disturbances (infantile hypercalcaemia) may occur.…”

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confidence: 99%

Partial deletion of the critical 1.5 Mb interval in Williams-Beuren syndrome

Heller

Rauch²,

Lüttgen³

et al. 2003

Journal of Medical Genetics

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W illiams-Beuren syndrome (WBS, OMIM 194050) is a microdeletion syndrome caused by hemizygosity for multiple genes in 7q11.23 including the elastin locus (ELN).1 2 The classical WBS phenotype comprises elastin arteriopathy (supravalvular aortic stenosis and/or peripheral pulmonary stenosis), connective tissue abnormalities (for example, abnormal joint mobility, hernia and diverticula, hoarse voice), and a particular facial appearance (supraorbital fullness, stellate pattern of the iris, short nose with long philtrum, full lips, and wide mouth). Other frequent features are growth and psychomotor retardation with muscular hypotonia, limited visuospatial cognition, and specific language as well as behavioural abnormalities (overfriendliness and anxiety disorders, hypersensitivity to sounds).3-5 Endocrine and metabolic disturbances (infantile hypercalcaemia) may occur.Despite at least 21 genes having been identified in the common 1.5 Mb deletion interval in humans, 6 their individual contribution to the multisystem phenotype of WBS is unclear. So far, only the gene coding for elastin (ELN) has been proven to be causally involved 7 : ELN is deleted in all WBS patients with a microdeletion 7q11.23 who have been reported to date. However, hemizygosity for ELN alone does not cause WBS, but isolated supravalvular aortic stenosis (SVAS).8 Hence, haploinsufficiency for ELN is necessary but not sufficient for WBS.Molecular dissection of the WBS phenotype is hindered by the fact that over 95% of patients with the classical phenotype carry an apparently identical ∼1.5 Mb deletion interval.9-11 This constant size is explained by non allelic-homologous recombination between duplicons flanking the deletion interval.12 The presence of these direct repeats is assumed to be a predisposing factor for the WBS microdeletion that occurs with a frequency of approximately 1 in 20 000 liveborn children. 12So far, several cases of either classical WBS or SVAS with or without cognitive deficits have been found to be associated with a smaller deletion. In seven of these cases an alternative proximal breakpoint was involved, and an eighth case featured an alternative distal breakpoint [13][14][15][16] (reviewed in Osborne 2 ). We present a further independent case with an atypical deletion but with the classical WBS phenotype. Together, these cases indicate that the critical WBS region is smaller than 1.5 Mb. CASE REPORT AND METHODSThe patient and his healthy twin sister were born to non-consanguineous parents (maternal age 26, paternal age 41) after an uneventful pregnancy. Birth weight, height, and head circumference were within the normal range for twins. The constellation of supravalvular aortic stenosis, pulmonary Key points• We present the case of a patient with the classical phenotype of Williams-Beuren syndrome who has only a partial deletion of the common 1.5 Mb deletion interval at 7q11.23.• Fluorescence in situ hybridisation (FISH) with the commercial WBSCR probe (from Appligene/Oncor) showed two specific signals in each metaphas...

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Molecular and clinical correlation study of Williams-Beuren syndrome: No evidence of molecular factors in the deletion region or imprinting affecting clinical outcome

Cited by 34 publications

References 48 publications

Detection of deletions at 7q11.23 in Williams-Beuren syndrome by polymorphic markers

Detection of deletions at 7q11.23 in Williams-Beuren syndrome by polymorphic markers

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

Partial deletion of the critical 1.5 Mb interval in Williams-Beuren syndrome

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