POSTER NO: 450

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

¹S.W. Scherer, ¹M. Li, ²B. Pober, ¹D. Chitayat, ³J. Bodurtha, ⁴A. Mandel, ⁵T. Costa, ⁶T. Grebe, ⁶S. Cox, ¹L.C. Tsui, ⁴L.R. Osborne
¹Hospital for Sick Children, Toronto, Canada, ²Yale Department of Genetics, New Haven, USA, ³Virginia Commonwealth University, Richmond, USA, ⁴University of Toronto, Toronto, Canada, ⁵Department of Pediatrics, Halifax, Canada, ⁶University of Arizona, Phoenix, USA

Williams-Beuren syndrome (WBS) is most often caused by hemizygous deletion of a 1.5 million base pair (Mb) interval encompassing at least 20 genes at 7q11.23. As in many other haploinsufficiency diseases, the mechanism underlying the WBS deletion is unequal meiotic recombination, most likely mediated by highly homologous DNA (>300 kb in size) that flanks the commonly deleted region. Our study, used interphase fluorescence in situ hybridization (FISH) and pulsed-field gel electrophoresis, to identify a genomic polymorphism in WBS families consisting of an inversion of the WBS region (Nature Genetics, 29: 321-325, 2001). The inversion was found to be present hemizygously in 3 of 11 (27%) atypical patients whom exhibit a subset of the WBS phenotypic spectrum, but do not carry the typical WBS microdeletion. Two of these children also had a parent who carried the inversion. Moreover, in 4 of 12 (33%) families examined with a proband carrying the WBS deletion, the inversion was observed exclusively in the parent transmitting the disease-related chromosome. We have also recently identified families having more than one affected sibling to also carry the WBS inversion. These results suggest the presence of a newly identified genomic variant within the population that may be associated with the disease. It could cause a predisposition to primarily WBS-causing microdeletions, but also translocations and inversions. Our findings also support the idea that genomic polymorphism may be an important contributor in other disease-associated recurrent chromosomal rearrangements that were previously thought to be stochastic in nature. Therefore, we are currently investigating if inversion polymorphism might be involved in other diseases.