Skip to main content Accessibility help

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:


Hide All
1Inoue, K. and Lupski, J.R. (2002) Molecular mechanisms for genomic disorders. Annu Rev Genomics Hum Genet 3, 199-242
2Valero, M.C. et al. (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
3Osborne, L.R. et al. (2001) A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome. Nat Genet 29, 321-325
4Somerville, M.J. et al. (2005) Severe expressive-language delay related to duplication of the Williams-Beuren locus. N Engl J Med 353, 1694-1701
5Bayes, M. et al. (2003) Mutational mechanisms of Williams-Beuren syndrome deletions. Am J Hum Genet 73, 131-151
6Mervis, C.B. and Becerra, A. (2007) Language and communicative development in Williams syndrome. Ment Retard Dev Disabil Res Rev 13, 3-15
7Mervis, C.B. and Klein-Tasman, B.P. (2000) Williams syndrome: cognition, personality, and adaptive behavior. Ment Retard Dev Disabil Res Rev 6, 148-158
8Greenberg, F. (1990) Williams syndrome professional symposium. Am J Med Genet Suppl 6, 85-88
9Strømme, P., Bjørnstad, P.G. and Ramstad, K. (2002) Prevalence estimation of Williams syndrome. J Child Neurol 17, 269-271
10Ewart, A.K. et al. (1993) Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet 5, 11-16
11Dutly, F. and Schinzel, A. (1996) Unequal interchromosomal rearrangements may result in elastin gene deletions causing the Williams-Beuren syndrome. Hum Mol Genet 5, 1893-1898
12Urban, Z. et al. (1996) 7q11.23 deletions in Williams syndrome arise as a consequence of unequal meiotic crossover. Am J Hum Genet 59, 958-962
13Baumer, A. et al. (1998) High level of unequal meiotic crossovers at the origin of the 22q11.2 and 7q11.23 deletions. Hum Mol Genet 7, 887-894
14Osborne, L.R. et al. (1997) PMS2-related genes flank the rearrangement breakpoints associated with Williams syndrome and other diseases on human chromosome 7. Genomics 45, 402-406
15Perez Jurado, L.A. et al. (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
16DeSilva, U. et al. (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
17Pober, B.R. and Dykens, E.M. (1996) Williams syndrome: an overview of medical, cognitive, and behavioral features. Child Adolesc Psych Clinics N Am 5, 929-943
18Morris, C.A. et al. (1988) Natural history of Williams syndrome: physical characteristics. J Pediatr 113, 318-326
19Morris, C.A. (2006) The dysmorphology, genetics, and natural history of Williams-Beuren syndrome. In Williams-Beuren Syndrome: Research, Evaluation, and Treatment (Morris, C.A., Lenhoff, H. and Wang, P., eds), pp. 3-17, Johns Hopkins University Press, Baltimore, MD
20Mervis, C.B. and Morris, C.A. (2007) Williams syndrome. In Neurogenetic Developmental Disorders: Variation of Manifestation in Childhood (Mazzocco, M.M.M. and Ross, J., eds), pp. 199-262, MIT Press, Cambridge, MA
21Mervis, C.B. et al. (2000) The Williams syndrome cognitive profile. Brain Cogn 44, 604-628
22Kaufman, A. and Kaufman, N. (1990) Kaufman Brief Intelligence Test, American Guidance Services, Circle Pines, MN
23Elliott, C. (1990) Differential Ability Scales, Psychological Corporation, San Antonio, TX
24Meyer-Lindenberg, A., Mervis, C.B. and Berman, K.F. (2006) Neural mechanisms in Williams syndrome: a unique window to genetic influences on cognition and behaviour. Nat Rev Neurosci 7, 380-393
25Klein-Tasman, B.P. and Mervis, C.B. (2003) Distinctive personality characteristics of 8-, 9-, and 10-year-olds with Williams syndrome. Dev Neuropsychol 23, 269-290
26American Psychiatric Association (2000) Diagnostic and Statistical Manual for Mental Disorders (4th edn), American Psychiatric Association, Washington, DC
27Leyfer, O.T. et al. (2006) Prevalence of psychiatric disorders in 4 to 16-year-olds with Williams syndrome. Am J Med Genet B Neuropsychiatr Genet 141, 615-622
28Bellugi, U. et al. (1988) Dissociation between language and cognitive functions in Williams syndrome. In Language Development in Exceptional Circumstances (Bishop, D. and Mogford, K., eds), pp. 177-189, Churchill Livingstone, London
29Mervis, C.B. (2003) Williams syndrome: 15 years of psychological research. Dev Neuropsychol 23, 1-12
30Bellugi, U., Wang, P. and Jernigan, T. (1994) Williams syndrome: an unusual neuropsychological profile. In Atypical Cognitive Deficits in Developmental Disorders: Implications for Brain Function (Broman, S. and Grafman, J., eds), pp. 23-56, Erlbaum, Hillsdale, NJ
31Clahsen, H. and Almazan, M. (1998) Syntax and morphology in Williams syndrome. Cognition 68, 167-198
32Bellugi, U. et al. (2000) I. The neurocognitive profile of Williams Syndrome: a complex pattern of strengths and weaknesses. J Cogn Neurosci 12 Suppl 1, 7-29
33Clahsen, H., Ring, M. and Temple, C. (2003) Lexical and morphological skills in English-speaking children with Williams syndrome. Essex Research Reports in Linguistics 43, 1-27
34Masataka, N. (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
35Velleman, S. et al. (2006) Phonological development in Williams syndrome. In Proceedings of the International Clinical Phonetics and Linguistics Association (31 May– 3 June 2006; Dubrovnik, Croatia) (Horga, D. and Mildner, V., eds), 147, FF Press, Zagreb, Croatia
36Nazzi, T., Paterson, S. and Karmiloff-Smith, A. (2003) Early word segmentation by infants and toddlers with Williams syndrome. Infancy 4, 251-271
37Mervis, C.B. and Robinson, B.F. (2000) Expressive vocabulary ability of toddlers with Williams syndrome or Down syndrome: a comparison. Dev Neuropsychol 17, 111-126
38Glenn, S. and Cunningham, C. (2005) Performance of young people with Down syndrome on the Leiter-R and British picture vocabulary scales. J Intellect Disabil Res 49, 239-244
39Klein, B.P. and Mervis, C.B. (1999) Contrasting patterns of cognitive abilities of 9- and 10-year-olds with Williams syndrome or Down syndrome. Dev Neuropsychol 16, 177-196
40Mervis, C.B. (2006) Language ability es in Williams-Beuren syndrome. In Williams-Beuren syndrome: Research, Evaluation, and Treatment (Morris, C.A., Lenhoff, H. and Wang, P., eds) pp. 159-206, Johns Hopkins University Press, Baltimore, MD
41Vicari, S. et al. (2004) Neuropsychological profile of Italians with Williams syndrome: an example of a dissociation between language and cognition? J Int Neuropsychol Soc 10, 862-876
42Udwin, O. and Yule, W. (1990) Expressive language of children with Williams syndrome. Am J Med Genet Suppl 6, 108-114
43Grant, J., Valian, V. and Karmiloff-Smith, A. (2002) A study of relative clauses in Williams syndrome. J Child Lang 29, 403-416
44Zukowski, A. (2004) Investigating knowledge of complex syntax: insights from experimental studies of Williams syndrome. In Developmental Language Disorders: From Phenotypes to Etiologies (Rice, M. and Warren, S., eds), pp. 99-119, MIT Press, Cambridge, MA
45Gosch, A., Stading, G. and Pankau, R. (1994) Linguistic abilities in children with Williams-Beuren syndrome. Am J Med Genet 52, 291-296
46Lukács, Á. (2005) Language Abilities in Williams syndrome, Akadémiai Kiadó, Budapest, Hungary
47Volterra, V. et al. (1996) Linguistic abilities in Italian children with Williams syndrome. Cortex 32, 663-677
48Volterra, V. et al. (2003) Early linguistic abilities of Italian children with Williams syndrome. Dev Neuropsychol 23, 33-58
49Mervis, C.B. et al. (2003) Language abilities of people with Williams syndrome. In International Review of Research in Mental Retardation, (Abbeduto, L., ed.), pp. 35-81, Academic Press, Orlando, FL
50Karmiloff-Smith, A. et al. (1997) Language and Williams syndrome: how intact is “intact”? Child Dev 68, 246-262
51Levy, Y. and Hermon, S. (2003) Morphological abilities of Hebrew-speaking adolescents with Williams syndrome. Dev Neuropsychol 23, 59-83
52Robinson, B.F., Mervis, C.B. and Robinson, B.W. (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
53Laing, E. et al. (2002) Atypical development of language and social communication in toddlers with Williams syndrome. Developmental Science 5, 233-246
54Lord, C. et al. (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
55Klein-Tasman, B.P. et al. Socio-communicative deficits in young children with Williams syndrome: Performance on the Autism Diagnostic Observation Schedule. Child Neuropsychology (in press)
56Bishop, D.V. (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
57Laws, G. and Bishop, D. (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
58Mervis, C.B. (1999) The Williams syndrome cognitive profile: strengths, weaknesses, and interrelations among auditory short term memory, language, and visuospatial constructive cognition. In Ecological Approaches to Cognition: Essays in Honor of Ulric Neisser (Winograd, E., Fivush, R. and Hirst, W., eds), pp. 193-227, Erlbaum, Mahwah, NJ
59Curran, M.E. et al. (1993) The elastin gene is disrupted by a translocation associated with supravalvular aortic stenosis. Cell 73, 159-168
60Li, D.Y. et al. (1997) Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis. Hum Mol Genet 6, 1021-1028
61Tassabehji, M. et al. (1997) Elastin: genomic structure and point mutations in patients with supravalvular aortic stenosis. Hum Mol Genet 6, 1029-1036
62Metcalfe, K. et al. (2000) Elastin: mutational spectrum in supravalvular aortic stenosis. Eur J Hum Genet 8, 955-963
63Botta, A. et al. (1999) Detection of an atypical 7q11.23 deletion in Williams syndrome patients which does not include the STX1A and FZD3 genes. J Med Genet 36, 478-480
64Heller, R. et al. (2003) Partial deletion of the critical 1.5 Mb interval in Williams-Beuren syndrome. J Med Genet 40, e99
65Frangiskakis, J.M. et al. (1996) LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell 86, 59-69
66Tassabehji, M. et al. (1999) Williams syndrome: use of chromosomal microdeletions as a tool to dissect cognitive and physical phenotypes. Am J Hum Genet 64, 118-125
67Gagliardi, C. et al. (2003) Unusual cognitive and behavioural profile in a Williams syndrome patient with atypical 7q11.23 deletion. J Med Genet 40, 526-530
68Hirota, H. et al. (2003) Williams syndrome deficits in visual spatial processing linked to GTF2IRD1 and GTF2I on chromosome 7q11.23. Genet Med 5, 311-321
69Morris, C.A. et al. (2003) GTF2I hemizygosity implicated in mental retardation in Williams syndrome: genotype-phenotype analysis of five families with deletions in the Williams syndrome region. Am J Med Genet A 123, 45-59
70Tassabehji, M. et al. (2005) GTF2IRD1 in craniofacial development of humans and mice. Science 310, 1184-1187
71Howald, C. et al. (2006) Two high throughput technologies to detect segmental aneuploidies identify new Williams-Beuren syndrome patients with atypical deletions. J Med Genet 43, 266-273
72Tassabehji, M. et al. (2006) Gene dosage and Williams syndrome. Presented at the International Congress of Human Genetics (6–10 August 2006; Brisbane, Australia),
73van Hagen, J.M. et al. (2007) Contribution of CYLN2 and GTF2IRD1 to neurological and cognitive symptoms in Williams Syndrome. Neurobiol Dis 26, 112-124
74Edelmann, L. et al. (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
75Li, D.Y. et al. (1998) Novel arterial pathology in mice and humans hemizygous for elastin. J Clin Invest 102, 1783-1787
76Hoogenraad, C.C. et al. (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
77Meng, Y. et al. (2002) Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 35, 121-133
78Meyer-Lindenberg, A. et al. (2004) Neural basis of genetically determined visuospatial construction deficit in Williams syndrome. Neuron 43, 623-631
79Boddaert, N. et al. (2006) Parieto-occipital grey matter abnormalities in children with Williams syndrome. Neuroimage 30, 721-725
80Kippenhan, J.S. et al. (2005) Genetic contributions to human gyrification: sulcal morphometry in Williams syndrome. J Neurosci 25, 7840-7846
81American Academy of pediatrics committee on Genetics D.C., (2004) Towards a quantitative, probabilistic neuroanatomy of cerebral cortex. Cortex 40, 211-212
82Meyer-Lindenberg, A. et al. (2005) Neural correlates of genetically abnormal social cognition in Williams syndrome. Nat Neurosci 8, 991-993
83American Academy of Pediatrics Committee on Genetics (2001) Healthcare supervision for children with Williams syndrome. Pediatrics 107, 1192-1204
84Cherniske, E.M. et al. (2004) Multisystem study of 20 older adults with Williams syndrome. Am J Med Genet A 131, 255-264
85Meyer-Lindenberg, A. et al. (2005) Functional, structural, and metabolic abnormalities of the hippocampal formation in Williams syndrome. J Clin Invest 115, 1888-1895
86Tan-Sindhunata, G. et al. (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
87Velagaleti, G.V. et al. (2002) De novo supernumerary ring chromosome 7: first report of a non-mosaic patient and review of the literature. Clin Genet 61, 202-206
88Chantot-Bastaraud, S. et al. (2004) Clinical findings and cytogenetic analysis of small supernumerary ring chromosomes 7: report of two new cases. Ann Genet 47, 241-249
89Lichtenbelt, K.D. et al. (2005) Supernumerary ring chromosome 7 mosaicism: case report, investigation of the gene content, and delineation of the phenotype. Am J Med Genet A 132, 93-100
90von Beust, G. et al. (2005) Molecular cytogenetic characterization of a de novo supernumerary ring chromosome 7 resulting in partial trisomy, tetrasomy, and hexasomy in a child with dysmorphic signs, congenital heart defect, and developmental delay. Am J Med Genet A 137, 59-64
91Berg, J. et al. (2006) Severe language delay associated with duplication of the Williams-Beuren critical region. Presented at The American Society of Human Genetics (9–13 October 2006; New Orleans, LA, USA), (Program number 86)
92Golden, D. et al. (2006) Array-CGH identifies submicroscopic duplication of common micodeletion regions 7q11.23, 16p13.3, and 22q11.2. Presented at the 31st Annual Meeting of the Association of Genetic Technologists (9–11 June, 2006; Baltimore, MD, USA),
93Jayakar, P. et al. (2006) A female patient with Aicardi syndrome and duplication of Williams syndrome critical region (7q11.23). Presented at The American Society of Human Genetics (9–13 October 2006; New Orleans, LA, USA), (Program number 793)
94Kriek, M. et al. (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
95Kirchhoff, M. et al. (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
96Torniero, C. et al. (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
97Depienne, C. et al. (2007) Autism, language delay and mental retardation in a patient with 7q11 duplication. J Med Genet, Mar 30 [Epub ahead of print]
98Bishop, D.V.M. (1997) Uncommon Understanding: Development and Disorders of Language Comprehension in Children, Psychology Press, Hove, UK
99Dale, P.S. et al. (1998) Genetic influence on language delay in two-year-old children. Nat Neurosci 1, 324-328
100Lewis, B.A. and Thompson, L.A. (1992) A study of developmental speech and language disorders in twins. J Speech Hear Res 35, 1086-1094
101Bishop, D.V., North, T. and Donlan, C. (1995) Genetic basis of specific language impairment: evidence from a twin study. Dev Med Child Neurol 37, 56-71
102Tomblin, J.B. and Buckwalter, P.R. (1998) Heritability of poor language achievement among twins. J Speech Lang Hear Res 41, 188-199
103Fisher, S.E., Lai, C.S. and Monaco, A.P. (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
106Lai, C.S. et al. (2001) A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 413, 519-523
107MacDermot, K.D. et al. (2005) Identification of FOXP2 truncation as a novel cause of developmental speech and language deficits. Am J Hum Genet 76, 1074-1080
108Feuk, L. et al. (2006) Absence of a paternally inherited FOXP2 gene in developmental verbal dyspraxia. Am J Hum Genet 79, 965-972
109Shriberg, L.D. et al. (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
110Zeesman, S. et al. (2006) Speech and language impairment and oromotor dyspraxia due to deletion of 7q31 that involves FOXP2. Am J Med Genet A 140, 509-514
111Lennon, P.A. et al. (2007) Deletion of 7q31.1 supports involvement of FOXP2 in language impairment: Clinical report and review. Am J Med Genet A 143, 791-798
112Shu, W. et al. (2005) Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene. Proc Natl Acad Sci U S A 102, 9643-9648
113Scherer, S.W. and Osborne, L.R. (2007) Williams-Beuren syndrome. In Genomic Disorders: The Genomic Basis of Disease (Stankiewicz, P.T. and Lupski, J.R., eds), pp. 221-236, Humana Press, Totowa, NJ
Somerville, M.J. et al. (2005) Severe expressive-language delay related to duplication of the Williams-Beuren locus. N Engl J Med 353, 1694-1701
Fisher, S.E. (2005) On genes, speech, and language. N Engl J Med. 353, 1655-1657

A database collating clinical information about chromosomal microdeletions/duplications/insertions, translocations and inversion:


Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed