title: 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 region. 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.
authors.affiliation: Department of Medicine, The University of Toronto, 1 King's College Circle, Toronto, Ontario, Canada.
authors.forename: L R
authors.initials: LR
authors.lastname: Osborne
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.forename: B
authors.initials: B
authors.lastname: Pober
authors.forename: D
authors.initials: D
authors.lastname: Chitayat
authors.forename: J
authors.initials: J
authors.lastname: Bodurtha
authors.forename: A
authors.initials: A
authors.lastname: Mandel
authors.forename: T
authors.initials: T
authors.lastname: Costa
authors.forename: T
authors.initials: T
authors.lastname: Grebe
authors.forename: S
authors.initials: S
authors.lastname: Cox
authors.forename: L C
authors.initials: LC
authors.lastname: Tsui
authors.forename: S W
authors.initials: SW
authors.lastname: Scherer
mesh_terms: D000293:Adolescent; D007446:Chromosome Inversion; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D016521:Electrophoresis, Gel, Pulsed-Field; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D020161:Physical Chromosome Mapping; D011110:Polymorphism, Genetic / Q000235:genetics*; D018980:Williams Syndrome / Q000235:genetics*
chemical_list: D005819:Genetic Markers