Human Genetics

, Volume 128, Issue 1, pp 3–26 | Cite as

Copy number variants at Williams–Beuren syndrome 7q11.23 region

  • Giuseppe MerlaEmail author
  • Nicola Brunetti-Pierri
  • Lucia Micale
  • Carmela Fusco
Review Article


Copy number variants (CNVs) of the Williams–Beuren syndrome (WBS) 7q11.23 region are responsible for neurodevelopmental disorders with multi-system involvement and variable expressivity. Typical features of WBS microdeletion comprise a recognizable pattern of facial dysmorphisms, supravalvular aortic stenosis, connective tissue abnormalities, hypercalcemia, and a distinctive neurobehavioral phenotype. Conversely, the phenotype of patients carrying the 7q11.23 reciprocal duplications includes less distinctive facial dysmorphisms and prominent speech delay. The common deletion/duplication ranges in size from 1.5 to 1.8 Mb and encompasses approximately 28 genes. This region is flanked by low copy repeats (LCRs) with greater than ~97% identity, which can mediate non-allelic homologous recombination resulting from misalignment of LCRs during meiosis. A clear genotype–phenotype correlation has been established in WBS only for the elastin gene, which is responsible for the vascular and connective tissue abnormalities. The molecular substrates underlying the other clinical features of 7q11.23 CNVs, including the neurocognitive phenotypes, are still debated. Recent studies suggest that besides the role of the genes in the deleted/duplicated interval, multiple factors such as regulatory sequences, epigenetic mechanisms, parental origin of the CNV, and nucleotide variations in the non-deleted/duplicated allele may be important in determining the variable expressivity of 7q11.23 CNV phenotypes. Here, we review the clinical and molecular findings and the recent insights on genomic disorders associated with CNVs involving the 7q11.23 region.


Autism Spectrum Disorder Attention Deficit Hyperactivity Disorder Proliferate Cell Nuclear Antigen Supravalvular Aortic Stenosis Duplication Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank members of Drs. Merla and Brunetti-Pierri’s laboratories for helpful discussion. We are grateful to Dr. Savino Calvano for providing with FISH picture, Massimo Carella and Orazio Palmieri for aCGH analysis. This work was in part supported by grants from the Jérôme Lejeune Foundation, the Italian Ministry of Health (Ricerca Corrente 2008-10), the Fondazione Banca del Monte di Foggia “Domenico Siniscalco Ceci”, the Italian Telethon Foundation (Grant No. GGP06122), and with the contribution of Ministero degli Affari Esteri, Direzione Generale per la Promozione e la Cooperazione Culturale (2009–2010) to GM. NBP is supported by grant of the Italian Telethon Foundation (Grant No. TCBP37TELC).


  1. American Academy of Pediatrics Committee on Genetics (2001) Health care supervision for children with Williams syndrome. Pediatrics 107:1192–1204Google Scholar
  2. Amenta S, Sofocleous C, Kolialexi A, Thomaidis L, Giouroukos S, Karavitakis E, Mavrou A, Kitsiou S, Kanavakis E, Fryssira H (2005) Clinical manifestations and molecular investigation of 50 patients with Williams syndrome in the Greek population. Pediatr Res 57:789–795CrossRefPubMedGoogle Scholar
  3. Antonell A, de Luis O, Domingo-Roura X, Perez-Jurado LA (2005) Evolutionary mechanisms shaping the genomic structure of the Williams-Beuren syndrome chromosomal region at human 7q11.23. Genome Res 15:1179–1188CrossRefPubMedGoogle Scholar
  4. Antonell A, Del Campo M, Magano LF, Kaufmann L, Martinez de la Iglesia J, Gallastegui F, Flores R, Schweigmann U, Fauth C, Kotzot D, Perez-Jurado LA (2010) Partial 7q11.23 deletions further implicate GTF2I and GTF2IRD1 as the main genes responsible for the Williams-Beuren syndrome neurocognitive profile. J Med Genet. doi: 10.1136/jmg.2009.071712
  5. Axelsson S, Bjornland T, Kjaer I, Heiberg A, Storhaug K (2003) Dental characteristics in Williams syndrome: a clinical and radiographic evaluation. Acta Odontol Scand 61:129–136CrossRefPubMedGoogle Scholar
  6. Bailey JA, Gu Z, Clark RA, Reinert K, Samonte RV, Schwartz S, Adams MD, Myers EW, Li PW, Eichler EE (2002) Recent segmental duplications in the human genome. Science 297:1003–1007CrossRefPubMedGoogle Scholar
  7. Bayarsaihan D, Dunai J, Greally JM, Kawasaki K, Sumiyama K, Enkhmandakh B, Shimizu N, Ruddle FH (2002) Genomic organization of the genes Gtf2ird1, Gtf2i, and Ncf1 at the mouse chromosome 5 region syntenic to the human chromosome 7q11.23 Williams syndrome critical region. Genomics 79:137–143CrossRefPubMedGoogle Scholar
  8. Bayes M, Magano LF, Rivera N, Flores R, Perez Jurado LA (2003) Mutational mechanisms of Williams-Beuren syndrome deletions. Am J Hum Genet 73:131–151CrossRefPubMedGoogle Scholar
  9. Beckmann JS, Estivill X, Antonarakis SE (2007) Copy number variants and genetic traits: closer to the resolution of phenotypic to genotypic variability. Nat Rev Genet 8:639–646CrossRefPubMedGoogle Scholar
  10. Bellugi U, Bihrle A, Jernigan T, Trauner D, Doherty S (1990) Neuropsychological, neurological, and neuroanatomical profile of Williams syndrome. Am J Med Genet Suppl 6:115–125CrossRefPubMedGoogle Scholar
  11. Berg JS, Brunetti-Pierri N, Peters SU, Kang SH, Fong CT, Salamone J, Freedenberg D, Hannig VL, Prock LA, Miller DT, Raffalli P, Harris DJ, Erickson RP, Cunniff C, Clark GD, Blazo MA, Peiffer DA, Gunderson KL, Sahoo T, Patel A, Lupski JR, Beaudet AL, Cheung SW (2007) Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams-Beuren syndrome region. Genet Med 9:427–441CrossRefPubMedGoogle Scholar
  12. Beunders G, van de Kamp JM, Veenhoven RM, van Hagen JM, Nieuwint AW, Sistermans EA (2010) A triplication of the Williams Beuren Syndrome region in a patient with mental retardation, a severe expressive language delay, behavioural problems and dysmorfisms. J Med Genet 47:271–275Google Scholar
  13. Beuren AJ, Apitz J, Harmjanz D (1962) Supravalvular aortic stenosis in association with mental retardation and a certain facial appearance. Circulation 26:1235–1240PubMedGoogle Scholar
  14. Bird LM, Billman GF, Lacro RV, Spicer RL, Jariwala LK, Hoyme HE, Zamora-Salinas R, Morris C, Viskochil D, Frikke MJ, Jones MC (1996) Sudden death in Williams syndrome: report of ten cases. J Pediatr 129:926–931CrossRefPubMedGoogle Scholar
  15. Black JA, Carter RE (1963) Association between aortic stenosis and facies of severe infantile hypercalcaemia. Lancet 2:745–749CrossRefPubMedGoogle Scholar
  16. Botta A, Novelli G, Mari A, Novelli A, Sabani M, Korenberg J, Osborne LR, Digilio MC, Giannotti A, Dallapiccola B (1999) Detection of an atypical 7q11.23 deletion in Williams syndrome patients which does not include the STX1A and FZD3 genes. J Med Genet 36:478–480PubMedGoogle Scholar
  17. Bouchireb K, Boyer O, Bonnet D, Brunelle F, Decramer S, Landthaler G, Liutkus A, Niaudet P, Salomon R (2010) Clinical features and management of arterial hypertension in children with Williams-Beuren syndrome. Nephrol Dial Transplant 25(2):434–438Google Scholar
  18. Broder K, Reinhardt E, Ahern J, Lifton R, Tamborlane W, Pober B (1999) Elevated ambulatory blood pressure in 20 subjects with Williams syndrome. Am J Med Genet 83:356–360CrossRefPubMedGoogle Scholar
  19. Brunetti-Pierri N, Berg JS, Scaglia F, Belmont J, Bacino CA, Sahoo T, Lalani SR, Graham B, Lee B, Shinawi M, Shen J, Kang SH, Pursley A, Lotze T, Kennedy G, Lansky-Shafer S, Weaver C, Roeder ER, Grebe TA, Arnold GL, Hutchison T, Reimschisel T, Amato S, Geragthy MT, Innis JW, Obersztyn E, Nowakowska B, Rosengren SS, Bader PI, Grange DK, Naqvi S, Garnica AD, Bernes SM, Fong CT, Summers A, Walters WD, Lupski JR, Stankiewicz P, Cheung SW, Patel A (2008) Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet 40:1466–1471CrossRefPubMedGoogle Scholar
  20. Bultman S, Gebuhr T, Yee D, La Mantia C, Nicholson J, Gilliam A, Randazzo F, Metzger D, Chambon P, Crabtree G, Magnuson T (2000) A Brg1 null mutation in the mouse reveals functional differences among mammalian SWI/SNF complexes. Mol Cell 6:1287–1295CrossRefPubMedGoogle Scholar
  21. Cairo S, Merla G, Urbinati F, Ballabio A, Reymond A (2001) WBSCR14, a gene mapping to the Williams–Beuren syndrome deleted region, is a new member of the Mlx transcription factor network. Hum Mol Genet 10:617–627CrossRefPubMedGoogle Scholar
  22. Cambiaso P, Orazi C, Digilio MC, Loche S, Capolino R, Tozzi A, Faedda A, Cappa M (2007) Thyroid morphology and subclinical hypothyroidism in children and adolescents with Williams syndrome. J Pediatr 150:62–65CrossRefPubMedGoogle Scholar
  23. Chapman CA, du Plessis A, Pober BR (1996) Neurologic findings in children and adults with Williams syndrome. J Child Neurol 11:63–65CrossRefPubMedGoogle Scholar
  24. Cherniske EM, Carpenter TO, Klaiman C, Young E, Bregman J, Insogna K, Schultz RT, Pober BR (2004) Multisystem study of 20 older adults with Williams syndrome. Am J Med Genet A 131:255–264CrossRefPubMedGoogle Scholar
  25. Collette JC, Chen XN, Mills DL, Galaburda AM, Reiss AL, Bellugi U, Korenberg JR (2009) William’s syndrome: gene expression is related to parental origin and regional coordinate control. J Hum Genet 54:193–198CrossRefPubMedGoogle Scholar
  26. Crackower MA, Kolas NK, Noguchi J, Sarao R, Kikuchi K, Kaneko H, Kobayashi E, Kawai Y, Kozieradzki I, Landers R, Mo R, Hui CC, Nieves E, Cohen PE, Osborne LR, Wada T, Kunieda T, Moens PB, Penninger JM (2003) Essential role of Fkbp6 in male fertility and homologous chromosome pairing in meiosis. Science 300:1291–1295CrossRefPubMedGoogle Scholar
  27. Curran ME, Atkinson DL, Ewart AK, Morris CA, Leppert MF, Keating MT (1993) The elastin gene is disrupted by a translocation associated with supravalvular aortic stenosis. Cell 73:159–168CrossRefPubMedGoogle Scholar
  28. Cusco I, Corominas R, Bayes M, Flores R, Rivera-Brugues N, Campuzano V, Perez-Jurado LA (2008) Copy number variation at the 7q11.23 segmental duplications is a susceptibility factor for the Williams-Beuren syndrome deletion. Genome Res 18:683–694CrossRefPubMedGoogle Scholar
  29. Dai L, Bellugi U, Chen XN, Pulst-Korenberg AM, Jarvinen-Pasley A, Tirosh-Wagner T, Eis PS, Graham J, Mills D, Searcy Y, Korenberg JR (2009) Is it Williams syndrome? GTF2IRD1 implicated in visual-spatial construction and GTF2I in sociability revealed by high resolution arrays. Am J Med Genet A 149A:302–314CrossRefPubMedGoogle Scholar
  30. de la Serna IL, Ohkawa Y, Imbalzano AN (2006) Chromatin remodelling in mammalian differentiation: lessons from ATP-dependent remodellers. Nat Rev Genet 7:461–473CrossRefGoogle Scholar
  31. De Zeeuw CI, Hoogenraad CC, Goedknegt E, Hertzberg E, Neubauer A, Grosveld F, Galjart N (1997) CLIP-115, a novel brain-specific cytoplasmic linker protein, mediates the localization of dendritic lamellar bodies. Neuron 19:1187–1199CrossRefPubMedGoogle Scholar
  32. Del Campo M, Antonell A, Magano LF, Munoz FJ, Flores R, Bayes M, Perez Jurado LA (2006) Hemizygosity at the NCF1 gene in patients with Williams-Beuren syndrome decreases their risk of hypertension. Am J Hum Genet 78:533–542CrossRefPubMedGoogle Scholar
  33. Del Pasqua A, Rinelli G, Toscano A, Iacobelli R, Digilio C, Marino B, Saffirio C, Mondillo S, Pasquini L, Sanders SP, de Zorzi A (2009) New findings concerning cardiovascular manifestations emerging from long-term follow-up of 150 patients with the Williams-Beuren-Beuren syndrome. Cardiol Young 19:563–567CrossRefPubMedGoogle Scholar
  34. Depienne C, Heron D, Betancur C, Benyahia B, Trouillard O, Bouteiller D, Verloes A, LeGuern E, Leboyer M, Brice A (2007) Autism, language delay and mental retardation in a patient with 7q11 duplication. J Med Genet 44:452–458CrossRefPubMedGoogle Scholar
  35. Doll A, Grzeschik KH (2001) Characterization of two novel genes, WBSCR20 and WBSCR22, deleted in Williams-Beuren syndrome. Cytogenet Cell Genet 95:20–27CrossRefPubMedGoogle Scholar
  36. Dykens EM (2003) Anxiety, fears, and phobias in persons with Williams syndrome. Dev Neuropsychol 23:291–316CrossRefPubMedGoogle Scholar
  37. Eckert MA, Hu D, Eliez S, Bellugi U, Galaburda A, Korenberg J, Mills D, Reiss AL (2005) Evidence for superior parietal impairment in Williams syndrome. Neurology 64:152–153PubMedGoogle Scholar
  38. Edelmann L, Prosnitz A, Pardo S, Bhatt J, Cohen N, Lauriat T, Ouchanov L, Gonzalez PJ, Manghi ER, Bondy P, Esquivel M, Monge S, Delgado MF, Splendore A, Francke U, Burton BK, McInnes LA (2007) An atypical deletion of the Williams-Beuren syndrome interval implicates genes associated with defective visuospatial processing and autism. J Med Genet 44:136–143CrossRefPubMedGoogle Scholar
  39. Einfeld SL, Tonge BJ, Florio T (1997) Behavioral and emotional disturbance in individuals with Williams syndrome. Am J Ment Retard 102:45–53CrossRefPubMedGoogle Scholar
  40. Enkhmandakh B, Makeyev AV, Erdenechimeg L, Ruddle FH, Chimge NO, Tussie-Luna MI, Roy AL, Bayarsaihan D (2009) Essential functions of the Williams-Beuren syndrome-associated TFII-I genes in embryonic development. Proc Natl Acad Sci USA 106:181–186CrossRefPubMedGoogle Scholar
  41. Ensenauer RE, Adeyinka A, Flynn HC, Michels VV, Lindor NM, Dawson DB, Thorland EC, Lorentz CP, Goldstein JL, McDonald MT, Smith WE, Simon-Fayard E, Alexander AA, Kulharya AS, Ketterling RP, Clark RD, Jalal SM (2003) Microduplication 22q11.2, an emerging syndrome: clinical, cytogenetic, and molecular analysis of thirteen patients. Am J Hum Genet 73:1027–1040CrossRefPubMedGoogle Scholar
  42. Eronen M, Peippo M, Hiippala A, Raatikka M, Arvio M, Johansson R, Kahkonen M (2002) Cardiovascular manifestations in 75 patients with Williams syndrome. J Med Genet 39:554–558CrossRefPubMedGoogle Scholar
  43. Ewart AK, Morris CA, Atkinson D, Jin W, Sternes K, Spallone P, Stock AD, Leppert M, Keating MT (1993) Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet 5:11–16CrossRefPubMedGoogle Scholar
  44. Ferrero GB, Biamino E, Sorasio L, Banaudi E, Peruzzi L, Forzano S, di Cantogno LV, Silengo MC (2007) Presenting phenotype and clinical evaluation in a cohort of 22 Williams-Beuren syndrome patients. Eur J Med Genet 50:327–337CrossRefPubMedGoogle Scholar
  45. Ferrero GB, Howald C, Micale L, Biamino E, Augello B, Fusco C, Turturo MG, Forzano S, Reymond A, Merla G (2010) An atypical 7q11.23 deletion in a normal IQ Williams-Beuren syndrome patient. Eur J Hum Genet 18:33–38CrossRefPubMedGoogle Scholar
  46. Francke U (1999) Williams-Beuren syndrome: genes and mechanisms. Hum Mol Genet 8:1947–1954CrossRefPubMedGoogle Scholar
  47. Frangiskakis JM, Ewart AK, Morris CA, Mervis CB, Bertrand J, Robinson BF, Klein BP, Ensing GJ, Everett LA, Green ED, Proschel C, Gutowski NJ, Noble M, Atkinson DL, Odelberg SJ, Keating MT (1996) LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell 86:59–69CrossRefPubMedGoogle Scholar
  48. Fujiwara T, Mishima T, Kofuji T, Chiba T, Tanaka K, Yamamoto A, Akagawa K (2006) Analysis of knock-out mice to determine the role of HPC-1/syntaxin 1A in expressing synaptic plasticity. J Neurosci 26:5767–5776CrossRefPubMedGoogle Scholar
  49. Funakoshi T, Maeshima K, Yahata K, Sugano S, Imamoto F, Imamoto N (2007) Two distinct human POM121 genes: requirement for the formation of nuclear pore complexes. FEBS Lett 581:4910–4916CrossRefPubMedGoogle Scholar
  50. Gagliardi C, Bonaglia MC, Selicorni A, Borgatti R, Giorda R (2003a) Unusual cognitive and behavioural profile in a Williams syndrome patient with atypical 7q11.23 deletion. J Med Genet 40:526–530CrossRefPubMedGoogle Scholar
  51. Gagliardi C, Frigerio E, Burt DM, Cazzaniga I, Perrett DI, Borgatti R (2003b) Facial expression recognition in Williams syndrome. Neuropsychologia 41:733–738CrossRefPubMedGoogle Scholar
  52. Giannotti A, Tiberio G, Castro M, Virgilii F, Colistro F, Ferretti F, Digilio MC, Gambarara M, Dallapiccola B (2001) Coeliac disease in Williams syndrome. J Med Genet 38:767–768CrossRefPubMedGoogle Scholar
  53. Gillberg C, Rasmussen P (1994) Brief report: four case histories and a literature review of Williams syndrome and autistic behavior. J Autism Dev Disord 24:381–393CrossRefPubMedGoogle Scholar
  54. Giordano U, Turchetta A, Giannotti A, Digilio MC, Virgilii F, Calzolari A (2001) Exercise testing and 24-hour ambulatory blood pressure monitoring in children with Williams syndrome. Pediatr Cardiol 22:509–511CrossRefPubMedGoogle Scholar
  55. Glessner JT, Wang K, Cai G, Korvatska O, Kim CE, Wood S, Zhang H, Estes A, Brune CW, Bradfield JP, Imielinski M, Frackelton EC, Reichert J, Crawford EL, Munson J, Sleiman PM, Chiavacci R, Annaiah K, Thomas K, Hou C, Glaberson W, Flory J, Otieno F, Garris M, Soorya L, Klei L, Piven J, Meyer KJ, Anagnostou E, Sakurai T, Game RM, Rudd DS, Zurawiecki D, McDougle CJ, Davis LK, Miller J, Posey DJ, Michaels S, Kolevzon A, Silverman JM, Bernier R, Levy SE, Schultz RT, Dawson G, Owley T, McMahon WM, Wassink TH, Sweeney JA, Nurnberger JI, Coon H, Sutcliffe JS, Minshew NJ, Grant SF, Bucan M, Cook EH, Buxbaum JD, Devlin B, Schellenberg GD, Hakonarson H (2009) Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. Nature 459:569–573CrossRefPubMedGoogle Scholar
  56. Gorlach A, Lee PL, Roesler J, Hopkins PJ, Christensen B, Green ED, Chanock SJ, Curnutte JT (1997) A p47-phox pseudogene carries the most common mutation causing p47-phox-deficient chronic granulomatous disease. J Clin Invest 100:1907–1918CrossRefPubMedGoogle Scholar
  57. Greenberg F, Lewis RA (1988) The Williams syndrome. Spectrum and significance of ocular features. Ophthalmology 95:1608–1612PubMedGoogle Scholar
  58. Hannes FD, Sharp AJ, Mefford HC, de Ravel T, Ruivenkamp CA, Breuning MH, Fryns JP, Devriendt K, Van Buggenhout G, Vogels A, Stewart H, Hennekam RC, Cooper GM, Regan R, Knight SJ, Eichler EE, Vermeesch JR (2009) Recurrent reciprocal deletions and duplications of 16p13.11: the deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. J Med Genet 46:223–232CrossRefPubMedGoogle Scholar
  59. Henrichsen CN, Chaignat E, Reymond A (2009a) Copy number variants, diseases and gene expression. Hum Mol Genet 18:R1–R8CrossRefPubMedGoogle Scholar
  60. Henrichsen CN, Vinckenbosch N, Zollner S, Chaignat E, Pradervand S, Schutz F, Ruedi M, Kaessmann H, Reymond A (2009b) Segmental copy number variation shapes tissue transcriptomes. Nat Genet 41:424–429CrossRefPubMedGoogle Scholar
  61. Herguner S, Mukaddes NM (2006) Autism and Williams syndrome: a case report. World J Biol Psychiatry 7:186–188CrossRefPubMedGoogle Scholar
  62. Heyting C (1996) Synaptonemal complexes: structure and function. Curr Opin Cell Biol 8:389–396CrossRefPubMedGoogle Scholar
  63. Hill ID, Dirks MH, Liptak GS, Colletti RB, Fasano A, Guandalini S, Hoffenberg EJ, Horvath K, Murray JA, Pivor M, Seidman EG (2005) Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 40:1–19CrossRefPubMedGoogle Scholar
  64. Hillier LW, Fulton RS, Fulton LA, Graves TA, Pepin KH, Wagner-McPherson C, Layman D, Maas J, Jaeger S, Walker R, Wylie K, Sekhon M, Becker MC, O’Laughlin MD, Schaller ME, Fewell GA, Delehaunty KD, Miner TL, Nash WE, Cordes M, Du H, Sun H, Edwards J, Bradshaw-Cordum H, Ali J, Andrews S, Isak A, Vanbrunt A, Nguyen C, Du F, Lamar B, Courtney L, Kalicki J, Ozersky P, Bielicki L, Scott K, Holmes A, Harkins R, Harris A, Strong CM, Hou S, Tomlinson C, Dauphin-Kohlberg S, Kozlowicz-Reilly A, Leonard S, Rohlfing T, Rock SM, Tin-Wollam AM, Abbott A, Minx P, Maupin R, Strowmatt C, Latreille P, Miller N, Johnson D, Murray J, Woessner JP, Wendl MC, Yang SP, Schultz BR, Wallis JW, Spieth J, Bieri TA, Nelson JO, Berkowicz N, Wohldmann PE, Cook LL, Hickenbotham MT, Eldred J, Williams D, Bedell JA, Mardis ER, Clifton SW, Chissoe SL, Marra MA, Raymond C, Haugen E, Gillett W, Zhou Y, James R, Phelps K, Iadanoto S, Bubb K, Simms E, Levy R, Clendenning J, Kaul R, Kent WJ, Furey TS, Baertsch RA, Brent MR, Keibler E, Flicek P, Bork P, Suyama M, Bailey JA, Portnoy ME, Torrents D, Chinwalla AT, Gish WR et al (2003) The DNA sequence of human chromosome 7. Nature 424:157–164CrossRefPubMedGoogle Scholar
  65. Hinsley TA, Cunliffe P, Tipney HJ, Brass A, Tassabehji M (2004) Comparison of TFII-I gene family members deleted in Williams-Beuren syndrome. Protein Sci 13:2588–2599CrossRefPubMedGoogle Scholar
  66. Hirota H, Matsuoka R, Chen XN, Salandanan LS, Lincoln A, Rose FE, Sunahara M, Osawa M, Bellugi U, Korenberg JR (2003) Williams syndrome deficits in visual spatial processing linked to GTF2IRD1 and GTF2I on chromosome 7q11.23. Genet Med 5:311–321CrossRefPubMedGoogle Scholar
  67. Hoogenraad CC, Koekkoek B, Akhmanova A, Krugers H, Dortland B, Miedema M, van Alphen A, Kistler WM, Jaegle M, Koutsourakis M, Van Camp N, Verhoye M, van der Linden A, Kaverina I, Grosveld F, De Zeeuw CI, Galjart N (2002) Targeted mutation of Cyln2 in the Williams syndrome critical region links CLIP-115 haploinsufficiency to neurodevelopmental abnormalities in mice. Nat Genet 32:116–127CrossRefPubMedGoogle Scholar
  68. Howald C, Merla G, Digilio MC, Amenta S, Lyle R, Deutsch S, Choudhury U, Bottani A, Antonarakis SE, Fryssira H, Dallapiccola B, Reymond A (2006) Two high throughput technologies to detect segmental aneuploidies identify new Williams-Beuren syndrome patients with atypical deletions. J Med Genet 43:266–273CrossRefPubMedGoogle Scholar
  69. Huang YH, Bao Y, Peng W, Goldberg M, Love K, Bumcrot DA, Cole G, Langer R, Anderson DG, Sawicki JA (2009) Claudin-3 gene silencing with siRNA suppresses ovarian tumor growth and metastasis. Proc Natl Acad Sci USA 106:3426–3430CrossRefPubMedGoogle Scholar
  70. Huelsken J, Vogel R, Brinkmann V, Erdmann B, Birchmeier C, Birchmeier W (2000) Requirement for beta-catenin in anterior-posterior axis formation in mice. J Cell Biol 148:567–578CrossRefPubMedGoogle Scholar
  71. Huelsken J, Vogel R, Erdmann B, Cotsarelis G, Birchmeier W (2001) beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105:533–545CrossRefPubMedGoogle Scholar
  72. Iafrate AJ, Feuk L, Rivera MN, Listewnik ML, Donahoe PK, Qi Y, Scherer SW, Lee C (2004) Detection of large-scale variation in the human genome. Nat Genet 36:949–951CrossRefPubMedGoogle Scholar
  73. Iizuka K, Horikawa Y (2008) ChREBP: a glucose-activated transcription factor involved in the development of metabolic syndrome. Endocr J 55:617–624CrossRefPubMedGoogle Scholar
  74. Iizuka K, Bruick RK, Liang G, Horton JD, Uyeda K (2004) Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc Natl Acad Sci USA 101:7281–7286CrossRefPubMedGoogle Scholar
  75. Ino T, Nishimoto K, Iwahara M, Akimoto K, Boku H, Kaneko K, Tokita A, Yabuta K, Tanaka J (1988) Progressive vascular lesions in Williams-Beuren syndrome. Pediatr Cardiol 9:55–58CrossRefPubMedGoogle Scholar
  76. Iwaki S, Jensen BM, Gilfillan AM (2007) Ntal/Lab/Lat2. Int J Biochem Cell Biol 39:868–873CrossRefPubMedGoogle Scholar
  77. Jernigan TL, Bellugi U (1990) Anomalous brain morphology on magnetic resonance images in Williams syndrome and Down syndrome. Arch Neurol 47:529–533PubMedGoogle Scholar
  78. Jernigan TL, Bellugi U, Sowell E, Doherty S, Hesselink JR (1993) Cerebral morphologic distinctions between Williams and Down syndromes. Arch Neurol 50:186–191PubMedGoogle Scholar
  79. Jones KL, Smith DW (1975) The Williams elfin facies syndrome. A new perspective. J Pediatr 86:718–723CrossRefPubMedGoogle Scholar
  80. Kabashima T, Kawaguchi T, Wadzinski BE, Uyeda K (2003) Xylulose 5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated protein phosphatase in rat liver. Proc Natl Acad Sci USA 100:5107–5112CrossRefPubMedGoogle Scholar
  81. Kaplan P, Kirschner M, Watters G, Costa MT (1989) Contractures in patients with Williams syndrome. Pediatrics 84:895–899PubMedGoogle Scholar
  82. Kapp ME, von Noorden GK, Jenkins R (1995) Strabismus in Williams syndrome. Am J Ophthalmol 119:355–360PubMedGoogle Scholar
  83. Karmiloff-Smith A, Grant J, Ewing S, Carette MJ, Metcalfe K, Donnai D, Read AP, Tassabehji M (2003) Using case study comparisons to explore genotype-phenotype correlations in Williams-Beuren syndrome. J Med Genet 40:136–140CrossRefPubMedGoogle Scholar
  84. Karnik SK, Brooke BS, Bayes-Genis A, Sorensen L, Wythe JD, Schwartz RS, Keating MT, Li DY (2003) A critical role for elastin signaling in vascular morphogenesis and disease. Development 130:411–423CrossRefPubMedGoogle Scholar
  85. Kawaguchi T, Takenoshita M, Kabashima T, Uyeda K (2001) Glucose and cAMP regulate the L-type pyruvate kinase gene by phosphorylation/dephosphorylation of the carbohydrate response element binding protein. Proc Natl Acad Sci USA 98:13710–13715CrossRefPubMedGoogle Scholar
  86. Kerzendorfer C, O’Driscoll M (2009) Human DNA damage response and repair deficiency syndromes: linking genomic instability and cell cycle checkpoint proficiency. DNA Repair 8:1139–1152CrossRefPubMedGoogle Scholar
  87. Kirchhoff M, Bisgaard AM, Bryndorf T, Gerdes T (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 50:33–42CrossRefPubMedGoogle Scholar
  88. Kitagawa H, Fujiki R, Yoshimura K, Mezaki Y, Uematsu Y, Matsui D, Ogawa S, Unno K, Okubo M, Tokita A, Nakagawa T, Ito T, Ishimi Y, Nagasawa H, Matsumoto T, Yanagisawa J, Kato S (2003) The chromatin-remodeling complex WINAC targets a nuclear receptor to promoters and is impaired in Williams syndrome. Cell 113:905–917CrossRefPubMedGoogle Scholar
  89. Klein-Tasman BP, Mervis CB (2003) Distinctive personality characteristics of 8-, 9-, and 10-year-olds with Williams syndrome. Dev Neuropsychol 23:269–290CrossRefPubMedGoogle Scholar
  90. Korenberg JR, Chen XN, Hirota H, Lai Z, Bellugi U, Burian D, Roe B, Matsuoka R (2000) VI. Genome structure and cognitive map of Williams syndrome. J Cogn Neurosci 12(Suppl 1):89–107Google Scholar
  91. Korinek V, Barker N, Willert K, Molenaar M, Roose J, Wagenaar G, Markman M, Lamers W, Destree O, Clevers H (1998) Two members of the Tcf family implicated in Wnt/beta-catenin signaling during embryogenesis in the mouse. Mol Cell Biol 18:1248–1256PubMedGoogle Scholar
  92. Kriek M, White SJ, Szuhai K, Knijnenburg J, van Ommen GJ, den Dunnen JT, Breuning MH (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 14:180–189CrossRefPubMedGoogle Scholar
  93. Lai CS, Fisher SE, Hurst JA, Vargha-Khadem F, Monaco AP (2001) A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 413:519–523CrossRefPubMedGoogle Scholar
  94. Lakusta L, Dessalegn B, Landau B (2010) Impaired geometric reorientation caused by genetic defect. Proc Natl Acad Sci USA 107(7):2813–2817Google Scholar
  95. Lam PP, Leung YM, Sheu L, Ellis J, Tsushima RG, Osborne LR, Gaisano HY (2005) Transgenic mouse overexpressing syntaxin-1A as a diabetes model. Diabetes 54:2744–2754CrossRefPubMedGoogle Scholar
  96. Lazebnik MB, Tussie-Luna MI, Hinds PW, Roy AL (2009) Williams-Beuren syndrome-associated transcription factor TFII-I regulates osteogenic marker genes. J Biol Chem 284:36234–36239CrossRefPubMedGoogle Scholar
  97. Lee JA, Carvalho CM, Lupski JR (2007) A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell 131:1235–1247CrossRefPubMedGoogle Scholar
  98. Levitin DJ (2005) Musical behavior in a neurogenetic developmental disorder: evidence from Williams Syndrome. Ann N Y Acad Sci 1060:325–334CrossRefPubMedGoogle Scholar
  99. Levitin DJ, Cole K, Chiles M, Lai Z, Lincoln A, Bellugi U (2004) Characterizing the musical phenotype in individuals with Williams Syndrome. Child Neuropsychol 10:223–247PubMedGoogle Scholar
  100. Levitin DJ, Cole K, Lincoln A, Bellugi U (2005) Aversion, awareness, and attraction: investigating claims of hyperacusis in the Williams syndrome phenotype. J Child Psychol Psychiatry 46:514–523CrossRefPubMedGoogle Scholar
  101. Leyfer OT, Woodruff-Borden J, Klein-Tasman BP, Fricke JS, Mervis CB (2006) Prevalence of psychiatric disorders in 4 to 16-year-olds with Williams syndrome. Am J Med Genet B Neuropsychiatr Genet 141B:615–622CrossRefPubMedGoogle Scholar
  102. Li DY, Faury G, Taylor DG, Davis EC, Boyle WA, Mecham RP, Stenzel P, Boak B, Keating MT (1998) Novel arterial pathology in mice and humans hemizygous for elastin. J Clin Invest 102:1783–1787CrossRefPubMedGoogle Scholar
  103. Li HH, Roy M, Kuscuoglu U, Spencer CM, Halm B, Harrison KC, Bayle JH, Splendore A, Ding F, Meltzer LA, Wright E, Paylor R, Deisseroth K, Francke U (2009) Induced chromosome deletions cause hypersociability and other features of Williams-Beuren syndrome in mice. EMBO Mol Med 1:50–65CrossRefPubMedGoogle Scholar
  104. Lupski JR (1998) Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet 14:417–422CrossRefPubMedGoogle Scholar
  105. Lupski JR (2009) Genomic disorders ten years on. Genome Med 1:42CrossRefPubMedGoogle Scholar
  106. Majka J, Burgers PM (2004) The PCNA-RFC families of DNA clamps and clamp loaders. Prog Nucleic Acid Res Mol Biol 78:227–260CrossRefPubMedGoogle Scholar
  107. Makeyev AV, Erdenechimeg L, Mungunsukh O, Roth JJ, Enkhmandakh B, Ruddle FH, Bayarsaihan D (2004) GTF2IRD2 is located in the Williams-Beuren syndrome critical region 7q11.23 and encodes a protein with two TFII-I-like helix-loop-helix repeats. Proc Natl Acad Sci USA 101:11052–11057CrossRefPubMedGoogle Scholar
  108. Marler JA, Elfenbein JL, Ryals BM, Urban Z, Netzloff ML (2005) Sensorineural hearing loss in children and adults with Williams syndrome. Am J Med Genet A 138:318–327PubMedGoogle Scholar
  109. Martindale DW, Wilson MD, Wang D, Burke RD, Chen X, Duronio V, Koop BF (2000) Comparative genomic sequence analysis of the Williams syndrome region (LIMK1-RFC2) of human chromosome 7q11.23. Mamm Genome 11:890–898CrossRefPubMedGoogle Scholar
  110. McCarroll SA, Kuruvilla FG, Korn JM, Cawley S, Nemesh J, Wysoker A, Shapero MH, de Bakker PI, Maller JB, Kirby A, Elliott AL, Parkin M, Hubbell E, Webster T, Mei R, Veitch J, Collins PJ, Handsaker R, Lincoln S, Nizzari M, Blume J, Jones KW, Rava R, Daly MJ, Gabriel SB, Altshuler D (2008) Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet 40:1166–1174CrossRefPubMedGoogle Scholar
  111. McRory JE, Rehak R, Simms B, Doering CJ, Chen L, Hermosilla T, Duke C, Dyck R, Zamponi GW (2008) Syntaxin 1A is required for normal in utero development. Biochem Biophys Res Commun 375:372–377CrossRefPubMedGoogle Scholar
  112. Meng X, Lu X, Morris CA, Keating MT (1998) A novel human gene FKBP6 is deleted in Williams syndrome. Genomics 52:130–137CrossRefPubMedGoogle Scholar
  113. Meng Y, Zhang Y, Tregoubov V, Janus C, Cruz L, Jackson M, Lu WY, MacDonald JF, Wang JY, Falls DL, Jia Z (2002) Abnormal spine morphology and enhanced LTP in LIMK-1 knockout mice. Neuron 35:121–133CrossRefPubMedGoogle Scholar
  114. Mercuri E, Atkinson J, Braddick O, Rutherford MA, Cowan FM, Counsell SJ, Dubowitz LM, Bydder G (1997) Chiari I malformation in asymptomatic young children with Williams syndrome: clinical and MRI study. Eur J Paediatr Neurol 1:177–181PubMedGoogle Scholar
  115. Merla G, Ucla C, Guipponi M, Reymond A (2002) Identification of additional transcripts in the Williams-Beuren syndrome critical region. Hum Genet 110:429–438CrossRefPubMedGoogle Scholar
  116. Merla G, Howald C, Antonarakis SE, Reymond A (2004) The subcellular localization of the ChoRE-binding protein, encoded by the Williams-Beuren syndrome critical region gene 14, is regulated by 14–3-3. Hum Mol Genet 13:1505–1514CrossRefPubMedGoogle Scholar
  117. Merla G, Howald C, Henrichsen CN, Lyle R, Wyss C, Zabot MT, Antonarakis SE, Reymond A (2006) Submicroscopic deletion in patients with Williams-Beuren syndrome influences expression levels of the nonhemizygous flanking genes. Am J Hum Genet 79:332–341CrossRefPubMedGoogle Scholar
  118. Merritt JL, Lindor NM (2008) Further clinical description of duplication of Williams-Beuren region presenting with congenital glaucoma and brachycephaly. Am J Med Genet A 146A:1055–1058CrossRefPubMedGoogle Scholar
  119. Mervis CB (2006) Williams-Beuren syndrome: research, evaluation, and treatment. Johns Hopkins University Press, BaltimoreGoogle Scholar
  120. Mervis CB, Klein-Tasman BP (2000) Williams syndrome: cognition, personality, and adaptive behavior. Ment Retard Dev Disabil Res Rev 6:148–158CrossRefPubMedGoogle Scholar
  121. Mervis CB, Robinson BF, Bertrand J, Morris CA, Klein-Tasman BP, Armstrong SC (2000) The Williams syndrome cognitive profile. Brain Cogn 44:604–628CrossRefPubMedGoogle Scholar
  122. Metcalfe K, Rucka AK, Smoot L, Hofstadler G, Tuzler G, McKeown P, Siu V, Rauch A, Dean J, Dennis N, Ellis I, Reardon W, Cytrynbaum C, Osborne L, Yates JR, Read AP, Donnai D, Tassabehji M (2000) Elastin: mutational spectrum in supravalvular aortic stenosis. Eur J Hum Genet 8:955–963CrossRefPubMedGoogle Scholar
  123. Micale L, Fusco C, Augello B, Napolitano LM, Dermitzakis ET, Meroni G, Merla G, Reymond A (2008) Williams-Beuren syndrome TRIM50 encodes an E3 ubiquitin ligase. Eur J Hum Genet 16(9):1038–1049Google Scholar
  124. Mizugishi K, Yamanaka K, Kuwajima K, Kondo I (1998) Interstitial deletion of chromosome 7q in a patient with Williams syndrome and infantile spasms. J Hum Genet 43:178–181CrossRefPubMedGoogle Scholar
  125. Morimoto M, An B, Ogami A, Shin N, Sugino Y, Sawai Y, Usuku T, Tanaka M, Hirai K, Nishimura A, Hasegawa K, Sugimoto T (2003) Infantile spasms in a patient with Williams syndrome and craniosynostosis. Epilepsia 44:1459–1462CrossRefPubMedGoogle Scholar
  126. Morin PJ (2005) Claudin proteins in human cancer: promising new targets for diagnosis and therapy. Cancer Res 65:9603–9606CrossRefPubMedGoogle Scholar
  127. Morris CA, Carey JC (1990) Three diagnostic signs in Williams syndrome. Am J Med Genet Suppl 6:100–101CrossRefPubMedGoogle Scholar
  128. Morris CA, Demsey SA, Leonard CO, Dilts C, Blackburn BL (1988) Natural history of Williams syndrome: physical characteristics. J Pediatr 113:318–326CrossRefPubMedGoogle Scholar
  129. Morris CA, Leonard CO, Dilts C, Demsey SA (1990) Adults with Williams syndrome. Am J Med Genet Suppl 6:102–107CrossRefPubMedGoogle Scholar
  130. Morris CA, Thomas IT, Greenberg F (1993) Williams syndrome: autosomal dominant inheritance. Am J Med Genet 47:478–481CrossRefPubMedGoogle Scholar
  131. Morris CA, Mervis CB, Hobart HH, Gregg RG, Bertrand J, Ensing GJ, Sommer A, Moore CA, Hopkin RJ, Spallone PA, Keating MT, Osborne L, Kimberley KW, Stock AD (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 123:45–59CrossRefGoogle Scholar
  132. Nakamoto S, Saga T, Shinohara T (2003) Williams syndrome associated with complete atrioventricular septal defect. Heart 89:e15CrossRefPubMedGoogle Scholar
  133. Nicolaides NC, Kinzler KW, Vogelstein B (1995) Analysis of the 5′ region of PMS2 reveals heterogeneous transcripts and a novel overlapping gene. Genomics 29:329–334CrossRefPubMedGoogle Scholar
  134. Nimchinsky EA, Sabatini BL, Svoboda K (2002) Structure and function of dendritic spines. Annu Rev Physiol 64:313–353CrossRefPubMedGoogle Scholar
  135. O’Driscoll M, Dobyns WB, van Hagen JM, Jeggo PA (2007) Cellular and clinical impact of haploinsufficiency for genes involved in ATR signaling. Am J Hum Genet 81:77–86CrossRefPubMedGoogle Scholar
  136. Ohazama A, Sharpe PT (2007) TFII-I gene family during tooth development: candidate genes for tooth anomalies in Williams syndrome. Dev Dyn 236:2884–2888CrossRefPubMedGoogle Scholar
  137. Orellana C, Bernabeu J, Monfort S, Rosello M, Oltra S, Ferrer I, Quiroga R, Martinez-Garay I, Martinez F (2008) Duplication of the Williams-Beuren critical region: case report and further delineation of the phenotypic spectrum. J Med Genet 45:187–189CrossRefPubMedGoogle Scholar
  138. Osborne LR, Herbrick JA, Greavette T, Heng HH, Tsui LC, Scherer SW (1997) PMS2-related genes flank the rearrangement breakpoints associated with Williams syndrome and other diseases on human chromosome 7. Genomics 45:402–406CrossRefPubMedGoogle Scholar
  139. Osborne LR, Li M, Pober B, Chitayat D, Bodurtha J, Mandel A, Costa T, Grebe T, Cox S, Tsui LC, Scherer SW (2001) A 1.5 million-base pair inversion polymorphism in families with Williams-Beuren syndrome. Nat Genet 29:321–325CrossRefPubMedGoogle Scholar
  140. Ou Z, Berg JS, Yonath H, Enciso VB, Miller DT, Picker J, Lenzi T, Keegan CE, Sutton VR, Belmont J, Chinault AC, Lupski JR, Cheung SW, Roeder E, Patel A (2008) Microduplications of 22q11.2 are frequently inherited and are associated with variable phenotypes. Genet Med 10:267–277CrossRefPubMedGoogle Scholar
  141. Ounap K, Laidre P, Bartsch O, Rein R, Lipping-Sitska M (1998) Familial Williams-Beuren syndrome. Am J Med Genet 80:491–493CrossRefPubMedGoogle Scholar
  142. Palmer SJ, Tay ES, Santucci N, Cuc Bach TT, Hook J, Lemckert FA, Jamieson RV, Gunnning PW, Hardeman EC (2007) Expression of Gtf2ird1, the Williams syndrome-associated gene, during mouse development. Gene Expr Patterns 7:396–404CrossRefPubMedGoogle Scholar
  143. Palmer SJ, Santucci N, Widagdo J, Bontempo SJ, Tay ES, Hook J, Lemckert F, Gunning PW, Hardeman EC (2009) Negative auto-regulation of GTF2IRD1 in Williams-Beuren syndrome via a novel DNA binding mechanism. J Biol Chem 285(7):4715–4724Google Scholar
  144. Pankau R, Partsch CJ, Gosch A, Oppermann HC, Wessel A (1992) Statural growth in Williams-Beuren syndrome. Eur J Pediatr 151:751–755CrossRefPubMedGoogle Scholar
  145. Pankau R, Gosch A, Wessel A (1993) Radioulnar synostosis in Williams-Beuren syndrome: a component manifestation. Am J Med Genet 45:783CrossRefPubMedGoogle Scholar
  146. Pankau R, Partsch CJ, Winter M, Gosch A, Wessel A (1996) Incidence and spectrum of renal abnormalities in Williams-Beuren syndrome. Am J Med Genet 63:301–304CrossRefPubMedGoogle Scholar
  147. Pankau R, Siebert R, Kautza M, Schneppenheim R, Gosch A, Wessel A, Partsch CJ (2001) Familial Williams-Beuren syndrome showing varying clinical expression. Am J Med Genet 98:324–329CrossRefPubMedGoogle Scholar
  148. Partsch CJ, Dreyer G, Gosch A, Winter M, Schneppenheim R, Wessel A, Pankau R (1999) Longitudinal evaluation of growth, puberty, and bone maturation in children with Williams syndrome. J Pediatr 134:82–89CrossRefPubMedGoogle Scholar
  149. Partsch CJ, Japing I, Siebert R, Gosch A, Wessel A, Sippell WG, Pankau R (2002) Central precocious puberty in girls with Williams syndrome. J Pediatr 141:441–444CrossRefPubMedGoogle Scholar
  150. Partsch CJ, Siebert R, Caliebe A, Gosch A, Wessel A, Pankau R (2005) Sigmoid diverticulitis in patients with Williams-Beuren syndrome: relatively high prevalence and high complication rate in young adults with the syndrome. Am J Med Genet A 137:52–54PubMedGoogle Scholar
  151. Peoples R, Perez-Jurado L, Wang YK, Kaplan P, Francke U (1996) The gene for replication factor C subunit 2 (RFC2) is within the 7q11.23 Williams syndrome deletion. Am J Hum Genet 58:1370–1373PubMedGoogle Scholar
  152. Perez Jurado LA, Li X, Francke U (1995) The human calcitonin receptor gene (CALCR) at 7q21.3 is outside the deletion associated with the Williams syndrome. Cytogenet Cell Genet 70:246–249CrossRefPubMedGoogle Scholar
  153. Perez Jurado LA, Wang YK, Peoples R, Coloma A, Cruces J, Francke U (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 7:325–334CrossRefPubMedGoogle Scholar
  154. Perez Jurado LA, Wang YK, Francke U, Cruces J (1999) TBL2, a novel transducin family member in the WBS deletion: characterization of the complete sequence, genomic structure, transcriptional variants and the mouse ortholog. Cytogenet Cell Genet 86:277–284CrossRefPubMedGoogle Scholar
  155. Pernot C, Worms AM, Marcon F, Admant P (1984) Williams-Beuren facies with mental retardation and tetralogy of Fallot. Pediatrie 39:53–58PubMedGoogle Scholar
  156. Pezzi N, Prieto I, Kremer L, Perez Jurado LA, Valero C, Del Mazo J, Martinez AC, Barbero JL (2000) STAG3, a novel gene encoding a protein involved in meiotic chromosome pairing and location of STAG3-related genes flanking the Williams-Beuren syndrome deletion. FASEB J 14:581–592PubMedGoogle Scholar
  157. Pittschieler K, Morini G, Crepaz R (1993) Williams syndrome and coeliac disease. Acta Paediatr 82:ivGoogle Scholar
  158. Pober BR (2010) Williams-Beuren syndrome. N Engl J Med 362:239–252CrossRefPubMedGoogle Scholar
  159. Pober BR, Filiano JJ (1995) Association of Chiari I malformation and Williams syndrome. Pediatr Neurol 12:84–88CrossRefPubMedGoogle Scholar
  160. Pober BR, Morris CA (2007) Diagnosis and management of medical problems in adults with Williams-Beuren syndrome. Am J Med Genet C Semin Med Genet 145C:280–290CrossRefPubMedGoogle Scholar
  161. Pober BR, Lacro RV, Rice C, Mandell V, Teele RL (1993) Renal findings in 40 individuals with Williams syndrome. Am J Med Genet 46:271–274CrossRefPubMedGoogle Scholar
  162. Potocki L, Bi W, Treadwell-Deering D, Carvalho CM, Eifert A, Friedman EM, Glaze D, Krull K, Lee JA, Lewis RA, Mendoza-Londono R, Robbins-Furman P, Shaw C, Shi X, Weissenberger G, Withers M, Yatsenko SA, Zackai EH, Stankiewicz P, Lupski JR (2007) Characterization of Potocki-Lupski syndrome (dup(17)(p11.2p11.2)) and delineation of a dosage-sensitive critical interval that can convey an autism phenotype. Am J Hum Genet 80:633–649CrossRefPubMedGoogle Scholar
  163. Potter N, Karakoula A, Phipps KP, Harkness W, Hayward R, Thompson DN, Jacques TS, Harding B, Thomas DG, Palmer RW, Rees J, Darling J, Warr TJ (2008) Genomic deletions correlate with underexpression of novel candidate genes at six loci in pediatric pilocytic astrocytoma. Neoplasia 10:757–772PubMedGoogle Scholar
  164. Prescott J, Jariwala U, Jia L, Cogan JP, Barski A, Pregizer S, Shen HC, Arasheben A, Neilson JJ, Frenkel B, Coetzee GA (2007) Androgen receptor-mediated repression of novel target genes. Prostate 67:1371–1383CrossRefPubMedGoogle Scholar
  165. Prieto I, Suja JA, Pezzi N, Kremer L, Martinez AC, Rufas JS, Barbero JL (2001) Mammalian STAG3 is a cohesin specific to sister chromatid arms in meiosis I. Nat Cell Biol 3:761–766CrossRefPubMedGoogle Scholar
  166. Proschel C, Blouin MJ, Gutowski NJ, Ludwig R, Noble M (1995) Limk1 is predominantly expressed in neural tissues and phosphorylates serine, threonine and tyrosine residues in vitro. Oncogene 11:1271–1281PubMedGoogle Scholar
  167. Raiborg C, Stenmark H (2009) The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature 458:445–452CrossRefPubMedGoogle Scholar
  168. Ranheim EA, Kwan HC, Reya T, Wang YK, Weissman IL, Francke U (2005) Frizzled 9 knock-out mice have abnormal B-cell development. Blood 105:2487–2494CrossRefPubMedGoogle Scholar
  169. Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, Gonzalez JR, Gratacos M, Huang J, Kalaitzopoulos D, Komura D, MacDonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW, Hurles ME (2006) Global variation in copy number in the human genome. Nature 444:444–454CrossRefPubMedGoogle Scholar
  170. Richter NJ, Rogers GW Jr, Hensold JO, Merrick WC (1999) Further biochemical and kinetic characterization of human eukaryotic initiation factor 4H. J Biol Chem 274:35415–35424CrossRefPubMedGoogle Scholar
  171. Rose C, Wessel A, Pankau R, Partsch CJ, Bursch J (2001) Anomalies of the abdominal aorta in Williams-Beuren syndrome—another cause of arterial hypertension. Eur J Pediatr 160:655–658PubMedGoogle Scholar
  172. Roy AL, Du H, Gregor PD, Novina CD, Martinez E, Roeder RG (1997) Cloning of an inr- and E-box-binding protein, TFII-I, that interacts physically and functionally with USF1. EMBO J 16:7091–7104CrossRefPubMedGoogle Scholar
  173. Sadler LS, Robinson LK, Verdaasdonk KR, Gingell R (1993) The Williams syndrome: evidence for possible autosomal dominant inheritance. Am J Med Genet 47:468–470CrossRefPubMedGoogle Scholar
  174. Santer R, Pankau R, Schaub J, Burgin-Wolff A (1996) Williams-Beuren syndrome and celiac disease. J Pediatr Gastroenterol Nutr 23:339–340PubMedGoogle Scholar
  175. Santos A, Silva C, Rosset D, Deruelle C (2010) Just another face in the crowd: Evidence for decreased detection of angry faces in children with Williams syndrome. Neuropsychologia 48(4):1071–1078Google Scholar
  176. Sarimski K (1996) Specific eating and sleeping problems in Prader-Willi and Williams-Beuren syndrome. Child Care Health Dev 22:143–150CrossRefPubMedGoogle Scholar
  177. Scherer SW, Gripp KW, Lucena J, Nicholson L, Bonnefont JP, Perez-Jurado LA, Osborne LR (2005) Observation of a parental inversion variant in a rare Williams-Beuren syndrome family with two affected children. Hum Genet 117:383–388CrossRefPubMedGoogle Scholar
  178. Schlesinger BE, Butler NR, Black JA (1956) Severe type of infantile hypercalcaemia. Br Med J 1:127–134CrossRefPubMedGoogle Scholar
  179. Schmitt JE, Eliez S, Warsofsky IS, Bellugi U, Reiss AL (2001) Corpus callosum morphology of Williams syndrome: relation to genetics and behavior. Dev Med Child Neurol 43:155–159PubMedGoogle Scholar
  180. Schubert C (2009) The genomic basis of the Williams-Beuren syndrome. Cell Mol Life Sci 66:1178–1197CrossRefPubMedGoogle Scholar
  181. Schubert C, Laccone F (2006) Williams-Beuren syndrome: determination of deletion size using quantitative real-time PCR. Int J Mol Med 18:799–806PubMedGoogle Scholar
  182. Scott RW, Olson MF (2007) LIM kinases: function, regulation and association with human disease. J Mol Med 85:555–568CrossRefPubMedGoogle Scholar
  183. Sebat J, Lakshmi B, Troge J, Alexander J, Young J, Lundin P, Maner S, Massa H, Walker M, Chi M, Navin N, Lucito R, Healy J, Hicks J, Ye K, Reiner A, Gilliam TC, Trask B, Patterson N, Zetterberg A, Wigler M (2004) Large-scale copy number polymorphism in the human genome. Science 305:525–528CrossRefPubMedGoogle Scholar
  184. Sellner LN, Taylor GR (2004) MLPA and MAPH: new techniques for detection of gene deletions. Hum Mutat 23:413–419CrossRefPubMedGoogle Scholar
  185. Sforzini C, Milani D, Fossali E, Barbato A, Grumieri G, Bianchetti MG, Selicorni A (2002) Renal tract ultrasonography and calcium homeostasis in Williams-Beuren syndrome. Pediatr Nephrol 17:899–902CrossRefPubMedGoogle Scholar
  186. Shaffer LG, Kennedy GM, Spikes AS, Lupski JR (1997) Diagnosis of CMT1A duplications and HNPP deletions by interphase FISH: implications for testing in the cytogenetics laboratory. Am J Med Genet 69:325–331CrossRefPubMedGoogle Scholar
  187. Sharp AJ, Mefford HC, Li K, Baker C, Skinner C, Stevenson RE, Schroer RJ, Novara F, De Gregori M, Ciccone R, Broomer A, Casuga I, Wang Y, Xiao C, Barbacioru C, Gimelli G, Bernardina BD, Torniero C, Giorda R, Regan R, Murday V, Mansour S, Fichera M, Castiglia L, Failla P, Ventura M, Jiang Z, Cooper GM, Knight SJ, Romano C, Zuffardi O, Chen C, Schwartz CE, Eichler EE (2008) A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet 40:322–328CrossRefPubMedGoogle Scholar
  188. Smith AD, Gilchrist ID, Hood B, Tassabehji M, Karmiloff-Smith A (2009) Inefficient search of large-scale space in Williams syndrome: further insights on the role of LIMK1 deletion in deficits of spatial cognition. Perception 38:694–701CrossRefPubMedGoogle Scholar
  189. Somerville MJ, Mervis CB, Young EJ, Seo EJ, del Campo M, Bamforth S, Peregrine E, Loo W, Lilley M, Perez-Jurado LA, Morris CA, Scherer SW, Osborne LR (2005) Severe expressive-language delay related to duplication of the Williams-Beuren locus. N Engl J Med 353:1694–1701CrossRefPubMedGoogle Scholar
  190. Stagi S, Bindi G, Neri AS, Lapi E, Losi S, Jenuso R, Salti R, Chiarelli F (2005) Thyroid function and morphology in patients affected by Williams syndrome. Clin Endocrinol 63:456–460CrossRefGoogle Scholar
  191. Stankiewicz P, Lupski JR (2002) Genome architecture, rearrangements and genomic disorders. Trends Genet 18:74–82CrossRefPubMedGoogle Scholar
  192. Stinton C, Elison S, Howlin P (2010) Mental health problems in adults with Williams syndrome. Am J Intellect Dev Disabil 115:3–18CrossRefPubMedGoogle Scholar
  193. Stromme P, Bjornstad PG, Ramstad K (2002) Prevalence estimation of Williams syndrome. J Child Neurol 17:269–271CrossRefPubMedGoogle Scholar
  194. Tam E, Young EJ, Morris CA, Marshall CR, Loo W, Scherer SW, Mervis CB, Osborne LR (2008) The common inversion of the Williams-Beuren syndrome region at 7q11.23 does not cause clinical symptoms. Am J Med Genet A 146A:1797–1806CrossRefPubMedGoogle Scholar
  195. Tassabehji M (2003) Williams-Beuren syndrome: a challenge for genotype-phenotype correlations. Hum Mol Genet 12(Spec No 2):R229–R237Google Scholar
  196. Tassabehji M, Metcalfe K, Karmiloff-Smith A, Carette MJ, Grant J, Dennis N, Reardon W, Splitt M, Read AP, Donnai D (1999) Williams syndrome: use of chromosomal microdeletions as a tool to dissect cognitive and physical phenotypes. Am J Hum Genet 64:118–125CrossRefPubMedGoogle Scholar
  197. Tassabehji M, Hammond P, Karmiloff-Smith A, Thompson P, Thorgeirsson SS, Durkin ME, Popescu NC, Hutton T, Metcalfe K, Rucka A, Stewart H, Read AP, Maconochie M, Donnai D (2005) GTF2IRD1 in craniofacial development of humans and mice. Science 310:1184–1187CrossRefPubMedGoogle Scholar
  198. Thompson PD, Webb M, Beckett W, Hinsley T, Jowitt T, Sharrocks AD, Tassabehji M (2007) GTF2IRD1 regulates transcription by binding an evolutionarily conserved DNA motif ‘GUCE’. FEBS Lett 581:1233–1242CrossRefPubMedGoogle Scholar
  199. Tipney HJ, Hinsley TA, Brass A, Metcalfe K, Donnai D, Tassabehji M (2004) Isolation and characterisation of GTF2IRD2, a novel fusion gene and member of the TFII-I family of transcription factors, deleted in Williams-Beuren syndrome. Eur J Hum Genet 12:551–560CrossRefPubMedGoogle Scholar
  200. Tomaiuolo F, Di Paola M, Caravale B, Vicari S, Petrides M, Caltagirone C (2002) Morphology and morphometry of the corpus callosum in Williams syndrome: a T1-weighted MRI study. Neuroreport 13:2281–2284CrossRefPubMedGoogle Scholar
  201. Tomida J, Masuda Y, Hiroaki H, Ishikawa T, Song I, Tsurimoto T, Tateishi S, Shiomi T, Kamei Y, Kim J, Kamiya K, Vaziri C, Ohmori H, Todo T (2008) DNA damage-induced ubiquitylation of RFC2 subunit of replication factor C complex. J Biol Chem 283:9071–9079CrossRefPubMedGoogle Scholar
  202. Torniero C, dalla Bernardina B, Novara F, Vetro A, Ricca I, Darra F, Pramparo T, Guerrini R, Zuffardi O (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 15:62–67CrossRefPubMedGoogle Scholar
  203. Torniero C, Dalla Bernardina B, Novara F, Cerini R, Bonaglia C, Pramparo T, Ciccone R, Guerrini R, Zuffardi O (2008) Dysmorphic features, simplified gyral pattern and 7q11.23 duplication reciprocal to the Williams-Beuren deletion. Eur J Hum Genet 16:880–887CrossRefPubMedGoogle Scholar
  204. Trauner DA, Bellugi U, Chase C (1989) Neurologic features of Williams and Down syndromes. Pediatr Neurol 5:166–168CrossRefPubMedGoogle Scholar
  205. Tsao CY, Westman JA (1997) Infantile spasms in two children with Williams syndrome. Am J Med Genet 71:54–56CrossRefPubMedGoogle Scholar
  206. Turner DJ, Miretti M, Rajan D, Fiegler H, Carter NP, Blayney ML, Beck S, Hurles ME (2008) Germline rates of de novo meiotic deletions and duplications causing several genomic disorders. Nat Genet 40:90–95CrossRefPubMedGoogle Scholar
  207. Udwin O, Yule W (1991) A cognitive and behavioural phenotype in Williams syndrome. J Clin Exp Neuropsychol 13:232–244CrossRefPubMedGoogle Scholar
  208. Urban Z, Helms C, Fekete G, Csiszar K, Bonnet D, Munnich A, Donis-Keller H, Boyd CD (1996) 7q11.23 deletions in Williams syndrome arise as a consequence of unequal meiotic crossover. Am J Hum Genet 59:958–962PubMedGoogle Scholar
  209. Urban Z, Michels VV, Thibodeau SN, Davis EC, Bonnefont JP, Munnich A, Eyskens B, Gewillig M, Devriendt K, Boyd CD (2000) Isolated supravalvular aortic stenosis: functional haploinsufficiency of the elastin gene as a result of nonsense-mediated decay. Hum Genet 106:577–588CrossRefPubMedGoogle Scholar
  210. Urban Z, Riazi S, Seidl TL, Katahira J, Smoot LB, Chitayat D, Boyd CD, Hinek A (2002) Connection between elastin haploinsufficiency and increased cell proliferation in patients with supravalvular aortic stenosis and Williams-Beuren syndrome. Am J Hum Genet 71:30–44CrossRefPubMedGoogle Scholar
  211. Uyeda K, Yamashita H, Kawaguchi T (2002) Carbohydrate responsive element-binding protein (ChREBP): a key regulator of glucose metabolism and fat storage. Biochem Pharmacol 63:2075–2080CrossRefPubMedGoogle Scholar
  212. Valero MC, de Luis O, Cruces J, Perez Jurado LA (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 69:1–13CrossRefPubMedGoogle Scholar
  213. Van der Aa N, Rooms L, Vandeweyer G, van den Ende J, Reyniers E, Fichera M, Romano C, Delle Chiaie B, Mortier G, Menten B, Destree A, Maystadt I, Mannik K, Kurg A, Reimand T, McMullan D, Oley C, Brueton L, Bongers EM, van Bon BW, Pfund R, Jacquemont S, Ferrarini A, Martinet D, Schrander-Stumpel C, Stegmann AP, Frints SG, de Vries BB, Ceulemans B, Kooy RF (2009) Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome. Eur J Med Genet 52:94–100CrossRefPubMedGoogle Scholar
  214. van Hagen JM, van der Geest JN, van der Giessen RS, Lagers-van Haselen GC, Eussen HJ, Gille JJ, Govaerts LC, Wouters CH, de Coo IF, Hoogenraad CC, Koekkoek SK, Frens MA, van Camp N, van der Linden A, Jansweijer MC, Thorgeirsson SS, De Zeeuw CI (2007) Contribution of CYLN2 and GTF2IRD1 to neurological and cognitive symptoms in Williams Syndrome. Neurobiol Dis 26:112–124CrossRefPubMedGoogle Scholar
  215. Wain LV, Armour JA, Tobin MD (2009) Genomic copy number variation, human health, and disease. Lancet 374:340–350CrossRefPubMedGoogle Scholar
  216. Wang PP, Jernigan TL (1994) Morphometric studies using neuroimaging. Neurol Clin 12:789–802PubMedGoogle Scholar
  217. Wang PP, Hesselink JR, Jernigan TL, Doherty S, Bellugi U (1992) Specific neurobehavioral profile of Williams’ syndrome is associated with neocerebellar hemispheric preservation. Neurology 42:1999–2002PubMedGoogle Scholar
  218. Wang PP, Doherty S, Rourke SB, Bellugi U (1995) Unique profile of visuo-perceptual skills in a genetic syndrome. Brain Cogn 29:54–65CrossRefPubMedGoogle Scholar
  219. Wang YK, Perez-Jurado LA, Francke U (1998) A mouse single-copy gene, Gtf2i, the homolog of human GTF2I, that is duplicated in the Williams-Beuren syndrome deletion region. Genomics 48:163–170CrossRefPubMedGoogle Scholar
  220. Wessel A, Gravenhorst V, Buchhorn R, Gosch A, Partsch CJ, Pankau R (2004) Risk of sudden death in the Williams-Beuren syndrome. Am J Med Genet A 127A:234–237CrossRefPubMedGoogle Scholar
  221. Williams JC, Barratt-Boyes BG, Lowe JB (1961) Supravalvular aortic stenosis. Circulation 24:1311–1318PubMedGoogle Scholar
  222. Wilson DI, Goodship JA, Burn J, Cross IE, Scambler PJ (1992) Deletions within chromosome 22q11 in familial congenital heart disease. Lancet 340:573–575CrossRefPubMedGoogle Scholar
  223. Winter M, Pankau R, Amm M, Gosch A, Wessel A (1996) The spectrum of ocular features in the Williams-Beuren syndrome. Clin Genet 49:28–31PubMedCrossRefGoogle Scholar
  224. Wren C, Oslizlok P, Bull C (1990) Natural history of supravalvular aortic stenosis and pulmonary artery stenosis. J Am Coll Cardiol 15:1625–1630PubMedCrossRefGoogle Scholar
  225. Yamashita H, Takenoshita M, Sakurai M, Bruick RK, Henzel WJ, Shillinglaw W, Arnot D, Uyeda K (2001) A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver. Proc Natl Acad Sci USA 98:9116–9121CrossRefPubMedGoogle Scholar
  226. Yoshimura K, Kitagawa H, Fujiki R, Tanabe M, Takezawa S, Takada I, Yamaoka I, Yonezawa M, Kondo T, Furutani Y, Yagi H, Yoshinaga S, Masuda T, Fukuda T, Yamamoto Y, Ebihara K, Li DY, Matsuoka R, Takeuchi JK, Matsumoto T, Kato S (2009) Distinct function of 2 chromatin remodeling complexes that share a common subunit, Williams syndrome transcription factor (WSTF). Proc Natl Acad Sci USA 106:9280–9285CrossRefPubMedGoogle Scholar
  227. Zani VJ, Asou N, Jadayel D, Heward JM, Shipley J, Nacheva E, Takasuki K, Catovsky D, Dyer MJ (1996) Molecular cloning of complex chromosomal translocation t(8;14;12)(q24.1;q32.3;q24.1) in a Burkitt lymphoma cell line defines a new gene (BCL7A) with homology to caldesmon. Blood 87:3124–3134PubMedGoogle Scholar
  228. Zhang F, Gu W, Hurles ME, Lupski JR (2009) Copy number variation in human health, disease, and evolution. Annu Rev Genomics Hum Genet 10:451–481CrossRefPubMedGoogle Scholar
  229. Zhao C, Pleasure SJ (2004) Frizzled-9 promoter drives expression of transgenes in the medial wall of the cortex and its chief derivative the hippocampus. Genesis 40:32–39CrossRefPubMedGoogle Scholar
  230. Zhao C, Pleasure SJ (2005) Frizzled9 protein is regionally expressed in the developing medial cortical wall and the cells derived from this region. Brain Res Dev Brain Res 157:93–97CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Giuseppe Merla
    • 1
    Email author
  • Nicola Brunetti-Pierri
    • 2
    • 3
    • 4
  • Lucia Micale
    • 1
  • Carmela Fusco
    • 1
  1. 1.Laboratory of Medical GeneticsIRCCS Casa Sollievo Della Sofferenza HospitalSan Giovanni RotondoItaly
  2. 2.Telethon Institute of Genetics and MedicineNaplesItaly
  3. 3.Department of PediatricsFederico II University of NaplesNaplesItaly
  4. 4.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA

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