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A 1.5 million–base pair inversion polymorphism in families with Williams-Beuren syndrome

Abstract

Williams-Beuren syndrome (WBS) is most often caused by hemizygous deletion of a 1.5-Mb interval encompassing at least 17 genes at 7q11.23 (refs. 1,2). As with many other haploinsufficiency diseases, the mechanism underlying the WBS deletion is thought to be unequal meiotic recombination, probably mediated by the highly homologous DNA that flanks the commonly deleted region3. Here, we report the use of interphase fluorescence in situ hybridization (FISH) and pulsed-field gel electrophoresis (PFGE) to identify a genomic polymorphism in families with WBS, consisting of an inversion of the WBS region. We have observed that the inversion is hemizygous in 3 of 11 (27%) atypical affected individuals who show a subset of the WBS phenotypic spectrum but do not carry the typical WBS microdeletion. Two of these individuals also have a parent who carries the inversion. In addition, in 4 of 12 (33%) families with a proband carrying the WBS deletion, we observed the inversion exclusively in the parent transmitting the disease-related chromosome. These results suggest the presence of a newly identified genomic variant within the population that may be associated with the disease. It may result in predisposition to primarily WBS-causing microdeletions, but may also cause translocations and inversions.

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Figure 1: The WBS region at 7q11.23.
Figure 2: Detection and characterization of the 1.5-Mb inversion in families with WBS by three-color interphase FISH.
Figure 3: Individual with atypical WBS (11719) with a t(6;7)(q27;q11.23) translocation also carried the WBS inversion.
Figure 4: Polymorphic DNA marker analysis in families with WBS.
Figure 5: A new NotI–PFGE restriction fragment in individuals carrying the WBS inversion.

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Acknowledgements

We thank the affected families and their clinical support staff for continued assistance on this project, as well as The Centre for Applied Genomics at the Hospital for Sick Children in Toronto, the Canadian Genetic Diseases Network, and P. Marsden for technical support. The work is sponsored by the Canadian Institutes for Health Research (CIHR). L.C.T. is a Distinguished Scientist of the CIHR and Seller Chair of Cystic Fibrosis Research; L.R.O. and S.W.S. are Scholars of the CIHR.

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Correspondence to Stephen W. Scherer.

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Osborne, L., Li, M., Pober, B. et al. A 1.5 million–base pair inversion polymorphism in families with Williams-Beuren syndrome. Nat Genet 29, 321–325 (2001). https://doi.org/10.1038/ng753

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