MLPA analysis for a panel of syndromes with mental retardation reveals imbalances in 5.8% of patients with mental retardation and dysmorphic features, including duplications of the Sotos syndrome and Williams–Beuren syndrome regions

Kirchhoff, Maria; Bisgaard, Anne‐Marie; Bryndorf, Thue; Gerdes, Tommy

doi:10.1016/j.ejmg.2006.10.002

Cited by 90 publications

(94 citation statements)

References 22 publications

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“…20 A patient with a smaller (520-650 kb) duplication within the Sotos syndrome critical region, also encompassing the NSD1 gene but not reciprocal to the common deletion (Figure 1e, top), had microcephaly and short stature in addition to mild facial dysmorphism. 21 This suggests that the gene dosage effect that seems to be responsible for this phenotype is limited to a region smaller than the 1.1 Mb minimum-duplicated fragment found in our patients, and that it is likely to involve the NSD1 gene.…”

Section: Discussionmentioning

confidence: 92%

“…A large duplication including this and adjacent regions, detected by fluorescence in situ hybridization (FISH), 20 and a small duplication contained within the region, detected by multiplex ligationdependent probe amplification (MLPA), 21 have been reported. However, the duplication reciprocal to the common deletion of the Sotos critical region predicted by nonallelic homologous recombination at the flanking LCRs has not been described to date, and its phenotypic consequences in humans are not known.…”

Section: Introductionmentioning

confidence: 99%

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A syndrome of short stature, microcephaly and speech delay is associated with duplications reciprocal to the common Sotos syndrome deletion

et al. 2009

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Genomic rearrangements are an increasingly recognized mechanism of human phenotypic variation and susceptibility to disease. Sotos syndrome is characterized by overgrowth, macrocephaly, developmental delay and advanced osseous maturation. Haploinsufficiency of NSD1, caused by inactivating point mutations or deletion copy number variants, is the only known cause of Sotos syndrome. A recurrent 2 Mb deletion has been described with variable frequency in different populations. In this study, we report two individuals of different ethnic and geographical backgrounds, with duplications reciprocal to the common Sotos syndrome deletion. Our findings provide evidence for the existence of a novel syndrome of short stature, microcephaly, delayed bone development, speech delay and mild or absent facial dysmorphism. The phenotype is remarkably opposite to that of Sotos syndrome, suggesting a role for NSD1 in the regulation of somatic growth in humans.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

A syndrome of short stature, microcephaly and speech delay is associated with duplications reciprocal to the common Sotos syndrome deletion

et al. 2009

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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.

128

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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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“…The low detection rate of P096 kit observed in this study might be explained by the fact that the frequency of the syndromes covered is lower compared to those detected by P064 kit (except for Down syndrome, but the patients with phenotype suggestive of trisomy 21 were not included in this study). Other studies that have used MLPA P064 kit had detection rates of 5.8-9.2% when patients were selected based on the presence of ID and/or multiple congenital anomalies (6, 7), and of 14,1%, when patients were selected based on phenotype suggestive of a microdeletion syndrome (6). All these data emphasize the fact that submicroscopic anomalies are involved in a large number of cases with ID/multiple congenital anomalies, and consequently the selection of patients based on clinical suspicion of microdeletion syndrome may increase the detection rate.…”

Section: Discussionmentioning

confidence: 99%

Detection of chromosomal imbalances using combined MLPA kits in patients with syndromic intellectual disability

Sireteanu¹,

Popescu²,

Braha³

et al. 2014

Romanian Review of Laboratory Medicine

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MLPA analysis for a panel of syndromes with mental retardation reveals imbalances in 5.8% of patients with mental retardation and dysmorphic features, including duplications of the Sotos syndrome and Williams–Beuren syndrome regions

Cited by 90 publications

References 22 publications

A syndrome of short stature, microcephaly and speech delay is associated with duplications reciprocal to the common Sotos syndrome deletion

A syndrome of short stature, microcephaly and speech delay is associated with duplications reciprocal to the common Sotos syndrome deletion

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

Detection of chromosomal imbalances using combined MLPA kits in patients with syndromic intellectual disability

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