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

Abstract

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...

The genomic basis of the Williams – Beuren syndrome

“…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). 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].…”

“…So far, only a few cases of duplications have been described in the literature. The clinical presentation associated with reciprocal WBS duplications certainly seems to be milder, and facial features are different and less distinct than those of WBS; thus, presumably more patients exist but remain undiagnosed [103,110,118,119].…”

An atypical 7q11.23 deletion in a normal IQ Williams–Beuren syndrome patient

“…[1][2][3][4] This region frequently undergoes genomic rearrangements due to the presence of low copy repeats flanking the commonly deleted region and results in meiotic nonallelic paralogous recombination. 1 Consistently, along with the 7q11.23 deletion, recent papers reported the reciprocal duplication 5,6 and inversion 7,8 of the region. WBS has a prevalence estimated between 1/7500 and 1/20 000.…”

“…Their phenotypic features vary from isolated SVAS to classic WBS associated with infantile spasms or with autism spectrum behavior. 5,14,15 Genotypephenotype correlation studies of these patients suggested important insights in the genetic causes of some of the typical WBS symptoms. So far, the strongest correlations have been found for some of the facial features and cardiovascular problems linked to elastin haploinsufficiency.…”

Williams–Beuren Syndrome

“…The deletion occurs between proximal and medial LCRs in about 95% of WBS cases, and it occurs between proximal and distal LCRs in the remaining cases. The size of the deletion is approximately 1.55 Mb for the small deletion and approximately 1.84 Mb for the larger one [1][2][3][4][5]. However, the precise size depends upon the exact position of the breakpoints in each block.…”