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

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 t he WBS deletion is thought to be unequal meiotic recombination, probably me diated by the highly homologous DNA that flanks the commonly deleted region (3). Here, we report the use of interphase fluorescence in situ hybridizati on (FISH) and pulsed-field gel electrophoresis (PFGE) to identify a genomic polymorphism in families with WBS, consisting of an inversion of the WBS r egion. We have observed that the inversion is hemizygous in 3 of 11 (27%) a typical affected individuals who show a subset of the WBS phenotypic spectr um 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 invers ion exclusively in the parent transmitting the disease-related chromosome. These results suggest the presence of a newly identified genomic variant wi thin the population that may be associated with the disease. It may result in predisposition to primarily WBS-causing microdeletions, but may also cau se translocations and inversions.