Mutational mechanisms of Williams-Beuren syndrome deletions

被引:259
作者
Bayés, M [1 ]
Magano, LF [1 ]
Rivera, N [1 ]
Flores, R [1 ]
Jurado, LAP [1 ]
机构
[1] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Unitat Genet, Barcelona 08003, Spain
关键词
D O I
10.1086/376565
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Williams-Beuren syndrome (WBS) is a segmental aneusomy syndrome that results from a heterozygous deletion of contiguous genes at 7q11.23. Three large region-specific low-copy repeat elements (LCRs), composed of different blocks (A, B, and C), flank the WBS deletion interval and are thought to predispose to misalignment and unequal crossing-over, causing the deletions. In this study, we have determined the exact deletion size and LCR copy number in 74 patients with WBS, as well as precisely defined deletion breakpoints in 30 of them, using LCR-specific nucleotide differences. Most patients (95%) exhibit a 1.55-Mb deletion caused by recombination between centromeric and medial block B copies, which share similar to99.6% sequence identity along 105 - 143 kb. In these cases, deletion breakpoints were mapped at several sites within the recombinant block B, with a cluster (>27%) occurring at a 12 kb region within the GTF2I/GTF2IP1 gene. Almost one-third (28%) of the transmitting progenitors were found to be heterozygous for an inversion between centromeric and telomeric LCRs. All deletion breakpoints in the patients with the inversion occurred in the distal 38-kb block B region only present in the telomeric and medial copies. Finally, only four patients (5%) displayed a larger deletion (similar to1.84 Mb) caused by recombination between centromeric and medial block A copies. We propose models for the specific pairing and precise aberrant recombination leading to each of the different germline rearrangements that occur in this region, including inversions and deletions associated with WBS. Chromosomal instability at 7q11.23 is directly related to the genomic structure of the region.
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页码:131 / 151
页数:21
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