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

Osborne, Lucy R.; Li, Martin; Pober, Barbara R.; Chitayat, David; Bodurtha, Joann; Mandel, Ariane; Costa, Teresa; Grebe, Theresa A.; Cox, Sarah; Tsui, Lap Chee; Scherer, Stephen W.

doi:10.1038/ng753

Cited by 299 publications

(278 citation statements)

References 27 publications

Supporting

Mentioning

256

Contrasting

Unclassified

Order By: Relevance

“…This 1.5 million base pair region has been shown to commonly undergo deletion, duplication or inversion through unequal meiotic recombination between highly similar flanking segments of DNA (Refs 2,3,4 …”

Section: Introductionmentioning

confidence: 99%

Rearrangements of the Williams–Beuren syndrome locus: molecular basis and implications for speech and language development

Osborne

Mervis

2007

Expert Rev. Mol. Med.

Self Cite

126

View full text Add to dashboard Cite

The Williams-Beuren syndrome (WBS) locus on human chromosome 7q11.23 is flanked by complex chromosome-specific low-copy repeats that mediate recurrent genomic rearrangements of the region. Common genomic rearrangements arise through unequal meiotic recombination and result in complex but distinct behavioural and cognitive phenotypes. Deletion of 7q11.23 results in WBS, which is characterised by mild to moderate intellectual disability or learning difficulties, with relative cognitive strengths in verbal short-term memory and in language and extreme weakness in visuospatial construction, as well as anxiety, attention-deficit hyperactivity disorder and overfriendliness. By contrast, duplication results in severely delayed speech and expressive language, with relative strength in visuospatial construction. Although deletion and duplication of the WBS region have very different effects, both cause forms of language impairment and suggest that dosage-sensitive genes within the region are important for the proper development of human speech and language. The spectrum and frequency of genomic rearrangements at 7q11.23 presents an exceptional opportunity to identify gene(s) directly involved in human speech and language development.Although childhood disorders of cognition, language and behaviour are extremely common (WHO: http://www.who.int/en/), causative genes have remained particularly refractory to traditional genetic approaches since the disorders themselves are often sporadic in nature and their causes complex and both genetically and environmentally heterogeneous. Genomic disorders, caused by the gain, loss or inversion of specific chromosome regions, are often characterised by neurodevelopmental phenotypes and present a unique opportunity to identify genes and pathways that are necessary for proper brain development and function (Ref. 1).One such region that is prone to genomic rearrangement is the Williams-Beuren syndrome (WBS) locus at chromosome 7q11.23. This 1.5 million base pair region has been shown to commonly undergo deletion, duplication or inversion through unequal meiotic recombination between highly similar flanking segments of DNA (Refs 2,3,4 CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptthe region is not associated with any clinical features, but can predispose the chromosome to subsequent unequal recombination during the next round of meiosis. The inversion is estimated to be present at a frequency of 1 in 20, but there is a fivefold increase in carrier frequency in the parents of children with the WBS deletion (Refs 3,5). Deletion and duplication of 7q11.23 result in distinct patterns of cognitive impairment, both of which impact on language and speech abilities, albeit in very different ways (Refs 4, 6, 7). The WBS deletion has an estimated frequency of between 1 in 7500 and 1 in 20 000 (Refs 8, 9). As a result of the mechanism of genomic rearrangement, duplication should occur at a similar frequency; however, owing to its very recent discovery, the population fre...

show abstract

Section: Introductionmentioning

confidence: 99%

Rearrangements of the Williams–Beuren syndrome locus: molecular basis and implications for speech and language development

Osborne

Mervis

2007

Expert Rev. Mol. Med.

Self Cite

126

View full text Add to dashboard Cite

show abstract

“…An inhibited formation of chiasmata during meiosis because of the inverted WBS region could further raise the risk of misalignment between nonallelic LCR blocks; thus, individuals carrying the inversion are of higher susceptibility to deletion or duplication during meiosis [101,107]. The presence of this inversion has also been reported for patients displaying symptoms of WBS [104]. However, in a recent study on expression level of genes within the WBS single-copy region revealed no significant differences in gene expression level between individuals without the inversion and healthy inversion-carriers, except for a 1.2-fold elevated STX1A expression in inversion carrier.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

“…In the population of WBS patients, about 30 % of the chromosome-transmitting parents are carriers of a paracentric inversion of the WBS locus on chromosome 7 with breakpoints external to the WBS single copy gene region, which does not disrupt any actively expressed genes [78,104]. In the non-WBS population, this inversion is present in about 5 % [104,105]. The inversion is generated by meiotic or mitotic intrachromatid misalignment between the inverted homologous centromeric and telomeric LCR blocks, resulting in a non-allelic homologous recombination between the paired LCR blocks.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The genomic basis of the Williams – Beuren syndrome

Schubert

2008

Cell. Mol. Life Sci.

180

161

View full text Add to dashboard Cite

. The Williams-Beuren syndrome is a genomic disorder (prevalence: 1/7,500 to 1/20,000), caused by a hemizygous contiguous gene deletion on chromosome 7q11.23. Typical symptoms comprise supravalvular aortic stenosis, mental retardation, overfriendliness and visuospatial impairment. The common deletion sizes range of 1.5–1.8 mega base pairs (Mb), encompassing app. 28 genes. For a few genes, a genotype-phenotype correlation has been established. The best-explored gene within this region is the elastin gene; its haploinsufficiency causes arterial stenosis. The region of the Williams-Beuren syndrome consists of a single copy gene region (~1.2 Mb) flanked by repetitive sequences – Low Copy Repeats (LCR). The deletions arise as a consequence of misalignment of these repetitive sequences during meiosis and a following unequal crossing over due to high similarity of LCRs. This review presents an overview of the Williams-Beuren syndrome region considering the genomic assembly, chromosomal rearrangements and their mechanisms (i.e. deletions, duplications, inversions) and evolutionary and historical aspects.

show abstract

“…Additionally we used BAC CTA-208H19 and PAC RO5-1186P10 from within the common WBS-deletion interval and the flanking BACs RP11-815K3 (centromeric) and CTB-139P11 (telomeric) to detect possible inversion of the WBS region. 21 The clones were biotin-or digoxigenin-labelled by nick translation. Chromosomal in situ suppression hybridisation and detection of the biotinylated probe was carried out as described.…”

Section: Chromosome Analysismentioning

confidence: 99%

The elastin gene is disrupted in a family with a balanced translocation t(7;16)(q11.23;q13) associated with a variable expression of the Williams-Beuren syndrome

et al. 2002

View full text Add to dashboard Cite

The Williams-Beuren syndrome (WBS) is a complex developmental disorder with multisystemic manifestations including supravalvular aortic stenosis (SVAS), a so-called elfin face, a hoarse voice, and a specific cognitive phenotype. Most WBS patients have a 41 Mb deletion on one of their chromosomes 7 in q11 but except for elastin, whose haploinsufficiency causes the cardiovascular malformations, it is unknown which genes in the deletion area contribute to the phenotype. We have investigated a family with a cytogenetically balanced translocation t(7;16)(q11.23;q13) in which affected individuals manifested a broad spectrum of clinical phenotypes ranging from a hoarse voice as the only feature to the full WBS phenotype. Molecular cytogenetic and DNA sequence analyses of the translocation breakpoint showed that the cytogenetic rearrangement disrupts the elastin gene locus within intron 5 in the exact same manner in all translocation carriers. The recently described large inversion of the 7q11.23 region was not present in this family. Our data demonstrate that disruption of the elastin gene by a translocation breakpoint may cause classical WBS, atypical WBS, SVAS, or no recognisable phenotype, and provide a clear example for extensive phenotypic variability associated with a position effect in humans.

show abstract

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

Cited by 299 publications

References 27 publications

Rearrangements of the Williams–Beuren syndrome locus: molecular basis and implications for speech and language development

Rearrangements of the Williams–Beuren syndrome locus: molecular basis and implications for speech and language development

The genomic basis of the Williams – Beuren syndrome

The elastin gene is disrupted in a family with a balanced translocation t(7;16)(q11.23;q13) associated with a variable expression of the Williams-Beuren syndrome

Contact Info

Product

Resources

About