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

  • Lucy R. Osborne (a1) and Carolyn B. Mervis (a2)

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.

Corresponding author
*Corresponding author: Lucy R. Osborne, Department of Medicine, University of Toronto, 7360 Medical Sciences Bldg, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada. Tel: +1 416 946 5804; Fax: +1 416 978 8765; E-mail:
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1K. Inoue and J.R. Lupski (2002) Molecular mechanisms for genomic disorders. Annu Rev Genomics Hum Genet 3, 199-242

2M.C. Valero (2000) Fine-scale comparative mapping of the human 7q11.23 region and the orthologous region on mouse chromosome 5G: the low-copy repeats that flank the Williams-Beuren syndrome deletion arose at breakpoint sites of an evolutionary inversion(s). Genomics 69, 1-13

3L.R. Osborne (2001) A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome. Nat Genet 29, 321-325

4M.J. Somerville (2005) Severe expressive-language delay related to duplication of the Williams-Beuren locus. N Engl J Med 353, 1694-1701

5M. Bayes (2003) Mutational mechanisms of Williams-Beuren syndrome deletions. Am J Hum Genet 73, 131-151

6C.B. Mervis and A. Becerra (2007) Language and communicative development in Williams syndrome. Ment Retard Dev Disabil Res Rev 13, 3-15

7C.B. Mervis and B.P. Klein-Tasman (2000) Williams syndrome: cognition, personality, and adaptive behavior. Ment Retard Dev Disabil Res Rev 6, 148-158

9P. Strømme , P.G. Bjørnstad and K. Ramstad (2002) Prevalence estimation of Williams syndrome. J Child Neurol 17, 269-271

10A.K. Ewart (1993) Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet 5, 11-16

11F. Dutly and A. Schinzel (1996) Unequal interchromosomal rearrangements may result in elastin gene deletions causing the Williams-Beuren syndrome. Hum Mol Genet 5, 1893-1898

13A. Baumer (1998) High level of unequal meiotic crossovers at the origin of the 22q11.2 and 7q11.23 deletions. Hum Mol Genet 7, 887-894

14L.R. Osborne (1997) PMS2-related genes flank the rearrangement breakpoints associated with Williams syndrome and other diseases on human chromosome 7. Genomics 45, 402-406

15L.A. Perez Jurado (1998) A duplicated gene in the breakpoint regions of the 7q11.23 Williams-Beuren syndrome deletion encodes the initiator binding protein TFII-I and BAP-135, a phosphorylation target of BTK. Hum Mol Genet 7, 325-334

16U. DeSilva (2000) Molecular characterization of the mouse p47-phox (Ncf1) gene and comparative analysis of the mouse p47-phox (Ncf1) gene to the human NCF1 gene. Mol Cell Biol Res Commun 3, 224-230

18C.A. Morris (1988) Natural history of Williams syndrome: physical characteristics. J Pediatr 113, 318-326

24A. Meyer-Lindenberg , C.B. Mervis and K.F. Berman (2006) Neural mechanisms in Williams syndrome: a unique window to genetic influences on cognition and behaviour. Nat Rev Neurosci 7, 380-393

25B.P. Klein-Tasman and C.B. Mervis (2003) Distinctive personality characteristics of 8-, 9-, and 10-year-olds with Williams syndrome. Dev Neuropsychol 23, 269-290

29C.B. Mervis (2003) Williams syndrome: 15 years of psychological research. Dev Neuropsychol 23, 1-12

31H. Clahsen and M. Almazan (1998) Syntax and morphology in Williams syndrome. Cognition 68, 167-198

34N. Masataka (2001) Why early linguistic milestones are delayed in children with Williams syndrome: late onset of hand banging as a possible rate-limiting constraint on the emergence of canonical babbling. Developmental Science 4, 158-164

36T. Nazzi , S. Paterson and A. Karmiloff-Smith (2003) Early word segmentation by infants and toddlers with Williams syndrome. Infancy 4, 251-271

37C.B. Mervis and B.F. Robinson (2000) Expressive vocabulary ability of toddlers with Williams syndrome or Down syndrome: a comparison. Dev Neuropsychol 17, 111-126

38S. Glenn and C. Cunningham (2005) Performance of young people with Down syndrome on the Leiter-R and British picture vocabulary scales. J Intellect Disabil Res 49, 239-244

39B.P. Klein and C.B. Mervis (1999) Contrasting patterns of cognitive abilities of 9- and 10-year-olds with Williams syndrome or Down syndrome. Dev Neuropsychol 16, 177-196

41S. Vicari (2004) Neuropsychological profile of Italians with Williams syndrome: an example of a dissociation between language and cognition? J Int Neuropsychol Soc 10, 862-876

43J. Grant , V. Valian and A. Karmiloff-Smith (2002) A study of relative clauses in Williams syndrome. J Child Lang 29, 403-416

45A. Gosch , G. Stading and R. Pankau (1994) Linguistic abilities in children with Williams-Beuren syndrome. Am J Med Genet 52, 291-296

47V. Volterra (1996) Linguistic abilities in Italian children with Williams syndrome. Cortex 32, 663-677

48V. Volterra (2003) Early linguistic abilities of Italian children with Williams syndrome. Dev Neuropsychol 23, 33-58

49C.B. Mervis (2003) Language abilities of people with Williams syndrome. In International Review of Research in Mental Retardation, (L. Abbeduto , ed.), pp. 35-81, Academic Press, Orlando, FL

50A. Karmiloff-Smith (1997) Language and Williams syndrome: how intact is “intact”? Child Dev 68, 246-262

51Y. Levy and S. Hermon (2003) Morphological abilities of Hebrew-speaking adolescents with Williams syndrome. Dev Neuropsychol 23, 59-83

52B.F. Robinson , C.B. Mervis and B.W. Robinson (2003) The roles of verbal short-term memory and working memory in the acquisition of grammar by children with Williams syndrome. Dev Neuropsychol 23, 13-31

53E. Laing (2002) Atypical development of language and social communication in toddlers with Williams syndrome. Developmental Science 5, 233-246

54C. Lord (2000) The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Dev Disord 30, 205-223

56D.V. Bishop (1998) Development of the Children's Communication Checklist (CCC): a method for assessing qualitative aspects of communicative impairment in children. J Child Psychol Psychiatry 39, 879-891

57G. Laws and D. Bishop (2004) Pragmatic language impairment and social deficits in Williams syndrome: a comparison with Down's syndrome and specific language impairment. Int J Lang Commun Disord 39, 45-64

21C.B. Mervis (2000) The Williams syndrome cognitive profile. Brain Cogn 44, 604-628

59M.E. Curran (1993) The elastin gene is disrupted by a translocation associated with supravalvular aortic stenosis. Cell 73, 159-168

60D.Y. Li (1997) Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis. Hum Mol Genet 6, 1021-1028

61M. Tassabehji (1997) Elastin: genomic structure and point mutations in patients with supravalvular aortic stenosis. Hum Mol Genet 6, 1029-1036

62K. Metcalfe (2000) Elastin: mutational spectrum in supravalvular aortic stenosis. Eur J Hum Genet 8, 955-963

64R. Heller (2003) Partial deletion of the critical 1.5 Mb interval in Williams-Beuren syndrome. J Med Genet 40, e99

65J.M. Frangiskakis (1996) LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell 86, 59-69

66M. Tassabehji (1999) Williams syndrome: use of chromosomal microdeletions as a tool to dissect cognitive and physical phenotypes. Am J Hum Genet 64, 118-125

67C. Gagliardi (2003) Unusual cognitive and behavioural profile in a Williams syndrome patient with atypical 7q11.23 deletion. J Med Genet 40, 526-530

68H. Hirota (2003) Williams syndrome deficits in visual spatial processing linked to GTF2IRD1 and GTF2I on chromosome 7q11.23. Genet Med 5, 311-321

70M. Tassabehji (2005) GTF2IRD1 in craniofacial development of humans and mice. Science 310, 1184-1187

71C. Howald (2006) Two high throughput technologies to detect segmental aneuploidies identify new Williams-Beuren syndrome patients with atypical deletions. J Med Genet 43, 266-273

73J.M. van Hagen (2007) Contribution of CYLN2 and GTF2IRD1 to neurological and cognitive symptoms in Williams Syndrome. Neurobiol Dis 26, 112-124

74L. Edelmann (2007) An atypical deletion of the Williams-Beuren Syndrome interval implicates genes associated with defective visuospatial processing and autism. J Med Genet 44, 136-143

75D.Y. Li (1998) Novel arterial pathology in mice and humans hemizygous for elastin. J Clin Invest 102, 1783-1787

76C.C. Hoogenraad (2002) Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice. Nat Genet 32, 116-127

77Y. Meng (2002) Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 35, 121-133

78A. Meyer-Lindenberg (2004) Neural basis of genetically determined visuospatial construction deficit in Williams syndrome. Neuron 43, 623-631

79N. Boddaert (2006) Parieto-occipital grey matter abnormalities in children with Williams syndrome. Neuroimage 30, 721-725

80J.S. Kippenhan (2005) Genetic contributions to human gyrification: sulcal morphometry in Williams syndrome. J Neurosci 25, 7840-7846

82A. Meyer-Lindenberg (2005) Neural correlates of genetically abnormal social cognition in Williams syndrome. Nat Neurosci 8, 991-993

85A. Meyer-Lindenberg (2005) Functional, structural, and metabolic abnormalities of the hippocampal formation in Williams syndrome. J Clin Invest 115, 1888-1895

86G. Tan-Sindhunata (2000) Molecular cytogenetic characterization of a small, familial supernumerary ring chromosome 7 associated with mental retardation and an abnormal phenotype. Am J Med Genet 92, 147-152

87G.V. Velagaleti (2002) De novo supernumerary ring chromosome 7: first report of a non-mosaic patient and review of the literature. Clin Genet 61, 202-206

88S. Chantot-Bastaraud (2004) Clinical findings and cytogenetic analysis of small supernumerary ring chromosomes 7: report of two new cases. Ann Genet 47, 241-249

94M. Kriek (2006) Copy number variation in regions flanked (or unflanked) by duplicons among patients with developmental delay and/or congenital malformations; detection of reciprocal and partial Williams-Beuren duplications. Eur J Hum Genet 14, 180-189

95M. Kirchhoff (2007) 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. Eur J Med Genet 50, 33-42

96C. Torniero (2007) Cortical dysplasia of the left temporal lobe might explain severe expressive-language delay in patients with duplication of the Williams-Beuren locus. Eur J Hum Genet 15, 62-67

100B.A. Lewis and L.A. Thompson (1992) A study of developmental speech and language disorders in twins. J Speech Hear Res 35, 1086-1094

101D.V. Bishop , T. North and C. Donlan (1995) Genetic basis of specific language impairment: evidence from a twin study. Dev Med Child Neurol 37, 56-71

102J.B. Tomblin and P.R. Buckwalter (1998) Heritability of poor language achievement among twins. J Speech Lang Hear Res 41, 188-199

103S.E. Fisher , C.S. Lai and A.P. Monaco (2003) Deciphering the genetic basis of speech and language disorders. Annu Rev Neurosci 26, 57-80

104SLI Consortium (2002) A genomewide scan identifies two novel loci involved in specific language impairment. Am J Hum Genet 70, 384-398

105SLI Consortium (2004) Highly significant linkage to the SLI1 locus in an expanded sample of individuals affected by specific language impairment. Am J Hum Genet 74, 1225-1238

106C.S. Lai (2001) A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 413, 519-523

107K.D. MacDermot (2005) Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. Am J Hum Genet 76, 1074-1080

108L. Feuk (2006) Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia. Am J Hum Genet 79, 965-972

109L.D. Shriberg (2006) Speech, prosody, and voice characteristics of a mother and daughter with a 7;13 translocation affecting FOXP2. J Speech Lang Hear Res 49, 500-525

112W. Shu (2005) Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene. Proc Natl Acad Sci U S A 102, 9643-9648

S.E. Fisher (2005) On genes, speech, and language. N Engl J Med. 353, 1655-1657This is an informative editorial discussing the genetic basis of speech and language in relation to chromosome 7.

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Expert Reviews in Molecular Medicine
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