Duplication of the Williams-Beuren critical region: case report and further delineation of the phenotypic spectrum

Abstract

Only 12 patients with a duplication of the Williams-Beuren critical region (WBCR) have been reported to date, with variable developmental, psychomotor and language delay, in the absence of marked dysmorphic features. In this paper we present a new WBCR microduplication case, which supports the wide variability displayed by this duplication in the phenotype. The WBCR microduplication may be associated with autistic spectrum disorder, but most reported cases do not show this behavioral disorder, or may even show a hypersociable personality, as with our patient. From the present case and a review of the 12 previously described,1(-)6 we conclude that the phenotype associated with duplication of WBCR can affect the same domains as WBCR deletion, but that they cluster near the polar ends of social relationship (autism-like v hypersociability), language (expressive language impairment v "cocktail party" speech), visuospatial (severe v normal), mental retardation (severe v mild) and dysmorphic (severe v mild) features.

Genomic duplication resulting in increased copy number of genes encoding the sister chromatid cohesion complex conveys clinical consequences distinct from Cornelia de Lange

“…Reciprocal duplication and deletion of the PMP22 gene result in CMT1A and HNPP, respectively,4 5 6 both are inherited neuropathies but with distinct clinical presentations. Williams–Beuren syndrome (WBS) and its reciprocal duplication syndrome are the results of deletion and duplication of a region on 7q11.23 45 46 47 48. WBS is featured by cognitive deficiency with relative preservation of linguistic abilities, neurobehavioral problems, recognisable facial dysmorphism, and cardiac and ophthalmologic abnormalities.…”

Molecular and clinical characterization of de novo and familial cases with microduplication 3q29: guidelines for copy number variation case reporting

“…Although these rearrangements can both arise from a common mechanism involving nonallelic homologous recombination with region-specific low copy repeats (Lupski, 2004), microduplication syndromes are usually less commonly recognized, possibly due to ascertainment bias, milder and more variable phenotype, and technical limitations of cytogenetics and fluorescent in situ hybridization (FISH). Well characterized chromosomal regions shown to involve these reciprocal duplication and deletion events include duplication of 17p11.2 causing a phenotype associated with moderate mental retardation and behavioural disturbances (Potocki et al, 2000), with the reciprocal microdeletion resulting in Smith-Magenis syndrome; microduplication of 22q11.2 (Ensenauer et al, 2003) having a somewhat variable phenotype with cardiac malformation and features similar to the classical microdeletion 22q11.2 syndrome; microduplication of 15q11 ] q13 characterized by developmental delay and autism, reciprocal to deletions causing Prader-Willi/ Angelman syndromes (Dimitropoulos and Schultz, 2007), and microduplication of 7q11.23, which has been related to severe expressive language delay (Somerville et al ., 2005;Merritt and Lindor, 2008;Orellana et al ., 2008;Torniero et al ., 2008), while the corresponding deletion causes Williams-Beuren syndrome (Osborne et al ., 1996). Most recently, copy number variations (CNVs) in the form of microdeletions and microduplications of chromosome 16p11.2 have also been observed in autism spectrum disorder (Kumar et al ., 2008;Marshall et al ., 2008;Weiss et al ., 2008).…”

CNV and nervous system diseases – what’s new?

“…The most significant phenotypic component observed in almost all dup(7)(q11.23) patients is their moderate to severe language delay, paired with normal to only mildly impaired nonverbal and visuospatial skills (Somerville et al, 2005;Kriek et al, 2006;Berg et al, 2007;Depienne et al, 2007;Kirchhoff et al, 2007a;Torniero et al, 2007Torniero et al, , 2008Merritt and Lindor, 2008;Orellana et al, 2008). This pattern is the opposite of the typical WBS patients who display fluent expressive language alongside poor visuospatial skills (Mervis BCSTR1 BCSTR1 BBSTR1 BBSTR1 BBSTR1 BBSTR2 BBSTR2 BBSTR2 CR16T WS10 D7S1870 Cusco et al (2008).…”

“…1 ); these two duplications are thus the bona fide reciprocal duplications of the 1.55 Mb WBS common recurrent deletion. The breakpoints of the duplications described in Kriek et al (2006), Berg et al (2007), Depienne et al (2007), Kirchhoff et al (2007a), Merritt and Lindor (2008), Orellana et al (2008) and Torniero et al (2008) were not exactly mapped. They could be in any LCR or in the non-duplicated region between the LCRs Am and Bt; the duplications could thus be reciprocal to the common recurrent deletion, uncommon recurrent deletion (if the breakpoints are in Ac and Am), or perhaps some may represent nonrecurrent duplications.…”

“…WBS patients have a distinctive and characteristic facial phenotype, whereas the dup(7)(q11.23) patients, though having some mild dysmorphology, do not share a common gestalt (Somerville et al, 2005;Kriek et al, 2006;Berg et al, 2007;Depienne et al, 2007;Kirchhoff et al, 2007a;Torniero et al, 2007Torniero et al, , 2008Merritt and Lindor, 2008;Orellana et al, 2008). Most WBS patients display cardiovascular and connective tissue anomalies (the most common form being supravalcular aortic stenosis SVAS) resulting from haploinsufficiency of the ELN gene inside WBCR ( Fig.…”