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Using case study comparisons to explore genotype-phenotype correlations in Williams-Beuren syndrome
  1. A Karmiloff-Smith1,
  2. J Grant1,
  3. S Ewing1,
  4. M J Carette2,
  5. K Metcalfe2,
  6. D Donnai2,
  7. A P Read2,
  8. M Tassabehji2
  1. 1Neurocognitive Development Unit, Institute of Child Health, London, UK
  2. 2Department of Medical Genetics, St Mary’s Hospital, Manchester M13 0JH, UK
  1. Correspondence to:
 Dr M Tassabehji, Department of Medical Genetics, St Mary’s Hospital, Hathersage Road, Manchester M13 0JH, UK;

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Williams-Beuren syndrome (WBS, MIM 194050) is a rare condition, with striking physical and behavioural features,1–3 which occurs in 1/20 000-1/50 000 live births. Cases are generally sporadic; however, familial cases with an autosomal dominant mode of inheritance have been reported. It results in a complex phenotype with physical, cognitive, and behavioural aspects that include an uneven cognitive profile (WBSCP), with verbal tasks outstripping spatial tasks, and overall IQs in the 50-60 range. Physically, WBS phenotypes include a dysmorphic face, congenital heart disease (typically supravalvular aortic stenosis (SVAS)), growth retardation, hyperacusis, premature ageing, and often infantile hypercalcaemia. These features are caused by deletion of the Williams-Beuren syndrome critical region (WBSCR) at chromosomal position 7q11.23 on either the maternal or paternal chromosome 7. The deletion is thought to arise from recombination between misaligned repeat sequences flanking the WBSCR during meiosis. The breakpoints cluster within these repeat regions, so that most WBS patients have similar deletions of approximately 1.5 Mb. A few WBS patients have, however, been reported with smaller deletions (<1 Mb).3,4 Patients with partial deletions of the WBSCR (that include the elastin gene) and SVAS as the only resulting phenotype have also been described.5 No credible cases of WBS without the deletion have so far been reported, suggesting that haploinsufficiency for a single gene will not explain the phenotype. Nineteen genes have so far been described in the WBSCR, yet only elastin hemizygosity has been confidently associated with any aspect of the WBS phenotype, namely SVAS, hernias, and possibly premature ageing. It would therefore appear that, alone or in combination, some of the remaining genes in the deleted region are responsible for the other features of WBS.

Relations between genotype and phenotype in WBS are mainly studied at the group level with rather gross measures of …

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