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.

Figure 1. The Williams–Beuren syndrome region on chromosome 7q11.23

Genes within the 1.55 Mb commonly deleted/duplicated region at 7q11.23 are represented by green arrows indicating the direction of transcription. ELN (elastin), LIMK (LIM domain kinase 1) and GTF2I (general transcription factor II, I) all of which have been linked to phenotypic aspects of Williams–Beuren syndrome, are highlighted in red. The two genes that are variably deleted/duplicated, depending upon the location of the telomeric breakpoint, are represented by blue arrows. WBSCR16, which lies outside the commonly deleted/duplicated region, is represented by a brown arrow. The flanking low-copy repeats (LCRs), which mediate meiotic rearrangement of the region, are represented by cream-coloured boxes. Each LCR is expanded beneath to show its composition of blocks of homology designated A, B and C. Approximately 95% of deletions occur between the highly similar B-blocks in the centromeric and medial LCRs, as indicated by the dotted red lines. Pseudogenes are indicated by an asterisk. For full versions of gene names see the HUGO Gene Nomenclature Committee website (http://www.gene.ucl.ac.uk/nomenclature/index.html). The figure was adapted from Ref. , with permission from Humana Press.