We describe a syndrome that is associated with a reciprocal duplication of the WBS microdeletion region. Patient 1 has intellectual strengths and weaknesses that are in direct contrast to those of children with WBS. Expressive language, especially syntax and phonology, is the area of greatest weakness for Patient 1, whereas for children with WBS, expressive language is a relative strength.2
When Patient 1 had difficulty making himself understood, he often successfully resorted to drawing what he was trying to express. Visuospatial construction (including drawing) is the area of greatest weakness for children with WBS, and most children with WBS who are Patient 1’s age are able to draw only a few recognizable objects.15
Previous descriptions of persons with larger duplications of the region (supernumerary ring chromosome 7) have noted delay in expressive language or impairment accompanied by articulation problems, but none of these reports contain standardized assessment results or comparative data on expressive and receptive language.16
Karyotypes were derived from G-banding, not from molecular analysis, so the extent of each duplication remains unknown. Our findings specify the expressive-language phenotype associated with dup7q11.23 and define the precise region of chromosome 7 contributing to it as the 1.5-Mb interval commonly deleted in WBS.
There appears to be a subtle but recognizable facial phenotype that is shared by both Patient 1 and previously described persons with supernumerary ring chromosome 7, one that consists of a high and broad nose, posteriorly rotated ears, a high-arched palate, and a short philtrum.16–18
When accompanied by delay in expressive language, this gestalt warrants testing for duplication of the WBS critical region.
Although there is a strong genetic component to language impairment, so far only the transcription factor FOXP2 has been implicated as a cause of the problem, and only in a few cases.19
Disruption of FOXP2 results in reduced functional dosage and leads to deficits in both expressive and receptive language, in addition to orofacial dyspraxia that impairs the coordination of complex fine-motor movements of the lower face.19,20
The remaining cases of language impairment were predicted to involve complex causes.1
The identification of a second locus associated with language impairment is therefore unexpected and opens up the possibility of linking the expressive-language phenotype to a specific gene or genes from within the WBS region.
The contrast between phenotypes associated with deletion and those associated with duplication of the WBS region, as well as the accompanying changes in gene expression, suggests that genes within this region are dosage sensitive. These observations also suggests that perturbation can have a dramatic, negative effect on both language development and visuospatial construction ability.
The duplication or deletion encompasses 26 to 27 genes, many of which can be ruled out as important contributors to the WBS phenotype on the basis of the correlation of genotype with phenotype in persons with atypical deletions.21–24
The minimal critical interval that must be deleted in classic WBS spans the region between the gene encoding elastin and the common distal breakpoint and encompasses just nine genes. Included within the WBS minimal critical interval are three general transcription factor 2 I (GTF2I
) genes, encoding a family of proteins that are predicted to possess some functional redundancy.25
In a simple or more complex model, alteration of expression of a single gene — or in the case of the GTF2I
family, possibly a combination of genes — might lead to a distinctive language-impairment phenotype that overlaps with that observed in Patient 1. Our discovery of the WBS duplication provides both the long-sought-after reference case for ascertainment of other patients and an entry point toward the discovery of new genes required for the normal acquisition and expression of language. The association between expressive-language delay and duplication of the WBS region also has implications for the molecular diagnosis of language delay.