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Online mutation report
Partial deletion of the critical 1.5 Mb interval in Williams-Beuren syndrome
  1. R Heller1,2,
  2. A Rauch3,
  3. S Lüttgen2,
  4. B Schröder2,
  5. A Winterpacht2,3
  1. 1Department of Clinical Genetics, Oxford Radcliffe Hospitals NHS Trust, Oxford OX3 7LJ, UK
  2. 2Institute of Human Genetics, University of Hamburg, Butenfeld 42, 22529 Hamburg, Germany
  3. 3Institute of Human Genetics, Friedrich-Alexander-University of Erlangen-Nürnberg, Schwabachanlage 19, 91054 Erlangen, Germany
  1. Correspondence to:
 Dr R Heller, Department of Clinical Genetics, The Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK; 
 heller{at}uke.uni-hamburg.de

https://doi.org/10.1136/jmg.40.8.e99

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    Williams-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 involved7: 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.12

    So far, several cases of either classical WBS or SVAS with or without cognitive deficits have been found to …

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