Copy number variation in regions flanked (or unflanked) by duplicons among patients with developmental delay and/or congenital malformations; detection of reciprocal and partial Williams-Beuren duplications

Kriek, Marjolein; White, Stefan J.; Szuhai, Károly; Knijnenburg, Jeroen; Ommen, Gert‐Jan B. van; Dunnen, Johan T. den; Breuning, Martijn H.

doi:10.1038/sj.ejhg.5201540

Cited by 53 publications

(58 citation statements)

References 30 publications

(19 reference statements)

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“…The underlying genetic bases for the majority of cases of speech/language impairments have been postulated to be complex, involving several loci that interact with each other and the environment to produce an overall susceptibility (Ref. The recent identification of individuals with an exact duplication of the WBS region and severe speech and language delay defines 7q11.23 as a new locus for expressive language disorder and speech impairment (Refs 4,94,95,96,97). Although the common duplication interval spans at least 26 genes, it might be predicted that, as is the case with deletions of the region in WBS, only one or a few of these genes are playing a prominent role in the language-impairment phenotype.…”

Section: Implications For Understanding Speech and Language Developmentmentioning

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.

129

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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...

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Section: Implications For Understanding Speech and Language Developmentmentioning

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.

129

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“…The breakpoints occur within the LCR blocks B cen and B mid with an increased expression of the genes within the single copy region of WBS [110,111]. Smaller and larger duplication sizes have also been reported [111,117,118]. Duplications within the WBS region are supposed to result from the same mechanism of unequal meiotic recombination as the occurrence of deletions in this region.…”

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confidence: 96%

“…In a third of cases, the duplication is inherited from one parent; in a few of the reported families, the chromosome-transmitting parent displayed a mild pattern of WBS-duplication typical symptoms. This observation of only minor symptoms in the duplication-carrying parent could imply that, in addition to gene dosage effects, other mechanisms such as genetic and/or environmental interactions are important in determining the phenotypic outcome of patients with this genetic aberration [109,111,116,118]. Using FISH and quantitative real time PCR, the size of the duplication was calculated generally to be the same size as of the common deletion region in WBS (~1.5 Mb).…”

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confidence: 99%

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The genomic basis of the Williams – Beuren syndrome

Schubert

2008

Cell. Mol. Life Sci.

214

161

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. 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.

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“…Recurrent deletions and reciprocal duplications in 16p13.11 have been previously reported. 14,17 Whereas the deletions have been associated with epilepsy [18][19][20] multiple congenital anomalies and cognitive impairment, 14,17 duplications have been implicated in autism spectrum disorders, intellectual disability 10,17,21,22 and schizophrenia. 23,24 The phenotypes associated with CNVs of 16p13.11 are not consistent and both deletions and duplications of the region have been observed in 'phenotypically normal' individuals.…”

Section: Introductionmentioning

confidence: 99%

Phenotypic manifestations of copy number variation in chromosome 16p13.11

et al. 2010

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The widespread clinical utilization of array comparative genome hybridization, has led to the unraveling of many new copy number variations (CNVs). Although some of these CNVs are clearly pathogenic, the phenotypic consequences of others, such as those in 16p13.11 remain unclear. Whereas deletions of 16p13.11 have been associated with multiple congenital anomalies, the relevance of duplications of the region is still being debated. We report detailed clinical and molecular characterization of 10 patients with duplication and 4 patients with deletion of 16p13.11. We found that patients with duplication of the region have varied clinical features including behavioral abnormalities, cognitive impairment, congenital heart defects and skeletal manifestations, such as hypermobility, craniosynostosis and polydactyly. These features were incompletely penetrant. Patients with deletion of the region presented with microcephaly, developmental delay and behavioral abnormalities as previously described. The CNVs were of varying sizes and were likely mediated by non-allelic homologous recombination between low copy repeats. Our findings expand the repertoire of clinical features observed in patients with CNV in 16p13.11 and strengthen the hypothesis that this is a dosage sensitive region with clinical relevance.

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Copy number variation in regions flanked (or unflanked) by duplicons among patients with developmental delay and/or congenital malformations; detection of reciprocal and partial Williams-Beuren duplications

Cited by 53 publications

References 30 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

Phenotypic manifestations of copy number variation in chromosome 16p13.11

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