Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1999 Jan;64(1):118–125. doi: 10.1086/302214

Williams syndrome: use of chromosomal microdeletions as a tool to dissect cognitive and physical phenotypes.

M Tassabehji 1, K Metcalfe 1, A Karmiloff-Smith 1, M J Carette 1, J Grant 1, N Dennis 1, W Reardon 1, M Splitt 1, A P Read 1, D Donnai 1
PMCID: PMC1377709  PMID: 9915950

Abstract

In Williams syndrome (WS), a deletion of approximately 1.5 Mb on one copy of chromosome 7 causes specific physical, cognitive, and behavioral abnormalities. Molecular dissection of the phenotype may be a route to identification of genes important in human cognition and behavior. Among the genes known to be deleted in WS are ELN (which encodes elastin), LIMK1 (which encodes a protein tyrosine kinase expressed in the developing brain), STX1A (which encodes a component of the synaptic apparatus), and FZD3. Study of patients with deletions or mutations confined to ELN showed that hemizygosity for elastin is responsible for the cardiological features of WS. LIMK1 and STX1A are good candidates for cognitive or behavioral aspects of WS. Here we describe genetic and psychometric testing of patients who have small deletions within the WS critical region. Our results suggest that neither LIMK1 hemizygosity (contrary to a previous report) nor STX1A hemizygosity is likely to contribute to any part of the WS phenotype, and they emphasize the importance of such patients for dissecting subtle but highly penetrant phenotypes.

Full Text

The Full Text of this article is available as a PDF (445.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arber S., Barbayannis F. A., Hanser H., Schneider C., Stanyon C. A., Bernard O., Caroni P. Regulation of actin dynamics through phosphorylation of cofilin by LIM-kinase. Nature. 1998 Jun 25;393(6687):805–809. doi: 10.1038/31729. [DOI] [PubMed] [Google Scholar]
  2. Baumer A., Dutly F., Balmer D., Riegel M., Tükel T., Krajewska-Walasek M., Schinzel A. A. High level of unequal meiotic crossovers at the origin of the 22q11. 2 and 7q11.23 deletions. Hum Mol Genet. 1998 May;7(5):887–894. doi: 10.1093/hmg/7.5.887. [DOI] [PubMed] [Google Scholar]
  3. Einfeld S. L., Tonge B. J., Florio T. Behavioral and emotional disturbance in individuals with Williams syndrome. Am J Ment Retard. 1997 Jul;102(1):45–53. doi: 10.1352/0895-8017(1997)102<0045:BAEDII>2.0.CO;2. [DOI] [PubMed] [Google Scholar]
  4. Ewart A. K., Morris C. A., Atkinson D., Jin W., Sternes K., Spallone P., Stock A. D., Leppert M., Keating M. T. Hemizygosity at the elastin locus in a developmental disorder, Williams syndrome. Nat Genet. 1993 Sep;5(1):11–16. doi: 10.1038/ng0993-11. [DOI] [PubMed] [Google Scholar]
  5. Ewart A. K., Morris C. A., Ensing G. J., Loker J., Moore C., Leppert M., Keating M. A human vascular disorder, supravalvular aortic stenosis, maps to chromosome 7. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3226–3230. doi: 10.1073/pnas.90.8.3226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Foster K., Ferrell R., King-Underwood L., Povey S., Attwood J., Rennick R., Humphries S. E., Henney A. M. Description of a dinucleotide repeat polymorphism in the human elastin gene and its use to confirm assignment of the gene to chromosome 7. Ann Hum Genet. 1993 May;57(Pt 2):87–96. doi: 10.1111/j.1469-1809.1993.tb00890.x. [DOI] [PubMed] [Google Scholar]
  7. Frangiskakis J. M., Ewart A. K., Morris C. A., Mervis C. B., Bertrand J., Robinson B. F., Klein B. P., Ensing G. J., Everett L. A., Green E. D. LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition. Cell. 1996 Jul 12;86(1):59–69. doi: 10.1016/s0092-8674(00)80077-x. [DOI] [PubMed] [Google Scholar]
  8. Fryssira H., Palmer R., Hallidie-Smith K. A., Taylor J., Donnai D., Reardon W. Fluorescent in situ hybridisation (FISH) for hemizygous deletion at the elastin locus in patients with isolated supravalvular aortic stenosis. J Med Genet. 1997 Apr;34(4):306–308. doi: 10.1136/jmg.34.4.306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Greenberg F., Lewis R. A., Potocki L., Glaze D., Parke J., Killian J., Murphy M. A., Williamson D., Brown F., Dutton R. Multi-disciplinary clinical study of Smith-Magenis syndrome (deletion 17p11.2) Am J Med Genet. 1996 Mar 29;62(3):247–254. doi: 10.1002/(SICI)1096-8628(19960329)62:3<247::AID-AJMG9>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
  10. Gyapay G., Morissette J., Vignal A., Dib C., Fizames C., Millasseau P., Marc S., Bernardi G., Lathrop M., Weissenbach J. The 1993-94 Généthon human genetic linkage map. Nat Genet. 1994 Jun;7(2 Spec No):246–339. doi: 10.1038/ng0694supp-246. [DOI] [PubMed] [Google Scholar]
  11. Jarrold C., Baddeley A. D., Hewes A. K. Verbal and nonverbal abilities in the Williams syndrome phenotype: evidence for diverging developmental trajectories. J Child Psychol Psychiatry. 1998 May;39(4):511–523. [PubMed] [Google Scholar]
  12. Karmiloff-Smith A., Grant J., Berthoud I., Davies M., Howlin P., Udwin O. Language and Williams syndrome: how intact is "intact"? Child Dev. 1997 Apr;68(2):246–262. [PubMed] [Google Scholar]
  13. Li D. Y., Toland A. E., Boak B. B., Atkinson D. L., Ensing G. J., Morris C. A., Keating M. T. Elastin point mutations cause an obstructive vascular disease, supravalvular aortic stenosis. Hum Mol Genet. 1997 Jul;6(7):1021–1028. doi: 10.1093/hmg/6.7.1021. [DOI] [PubMed] [Google Scholar]
  14. Lowery M. C., Morris C. A., Ewart A., Brothman L. J., Zhu X. L., Leonard C. O., Carey J. C., Keating M., Brothman A. R. Strong correlation of elastin deletions, detected by FISH, with Williams syndrome: evaluation of 235 patients. Am J Hum Genet. 1995 Jul;57(1):49–53. [PMC free article] [PubMed] [Google Scholar]
  15. Mari A., Amati F., Conti E., Bengala M., Novelli G., Dallapiccola B. A highly polymorphic CA/GT repeat (LIMK1GT) within the Williams syndrome critical region. Clin Genet. 1998 Mar;53(3):226–227. doi: 10.1111/j.1399-0004.1998.tb02683.x. [DOI] [PubMed] [Google Scholar]
  16. Morris C. A., Demsey S. A., Leonard C. O., Dilts C., Blackburn B. L. Natural history of Williams syndrome: physical characteristics. J Pediatr. 1988 Aug;113(2):318–326. doi: 10.1016/s0022-3476(88)80272-5. [DOI] [PubMed] [Google Scholar]
  17. Nickerson E., Greenberg F., Keating M. T., McCaskill C., Shaffer L. G. Deletions of the elastin gene at 7q11.23 occur in approximately 90% of patients with Williams syndrome. Am J Hum Genet. 1995 May;56(5):1156–1161. [PMC free article] [PubMed] [Google Scholar]
  18. Okano I., Hiraoka J., Otera H., Nunoue K., Ohashi K., Iwashita S., Hirai M., Mizuno K. Identification and characterization of a novel family of serine/threonine kinases containing two N-terminal LIM motifs. J Biol Chem. 1995 Dec 29;270(52):31321–31330. doi: 10.1074/jbc.270.52.31321. [DOI] [PubMed] [Google Scholar]
  19. Osborne L. R., Martindale D., Scherer S. W., Shi X. M., Huizenga J., Heng H. H., Costa T., Pober B., Lew L., Brinkman J. Identification of genes from a 500-kb region at 7q11.23 that is commonly deleted in Williams syndrome patients. Genomics. 1996 Sep 1;36(2):328–336. doi: 10.1006/geno.1996.0469. [DOI] [PubMed] [Google Scholar]
  20. Osborne L. R., Soder S., Shi X. M., Pober B., Costa T., Scherer S. W., Tsui L. C. Hemizygous deletion of the syntaxin 1A gene in individuals with Williams syndrome. Am J Hum Genet. 1997 Aug;61(2):449–452. doi: 10.1086/514850. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Peoples R., Perez-Jurado L., Wang Y. K., Kaplan P., Francke U. The gene for replication factor C subunit 2 (RFC2) is within the 7q11.23 Williams syndrome deletion. Am J Hum Genet. 1996 Jun;58(6):1370–1373. [PMC free article] [PubMed] [Google Scholar]
  22. Read A. P., Newton V. E. Waardenburg syndrome. J Med Genet. 1997 Aug;34(8):656–665. doi: 10.1136/jmg.34.8.656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Ryan A. K., Goodship J. A., Wilson D. I., Philip N., Levy A., Seidel H., Schuffenhauer S., Oechsler H., Belohradsky B., Prieur M. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study. J Med Genet. 1997 Oct;34(10):798–804. doi: 10.1136/jmg.34.10.798. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Sarimski K. Specific eating and sleeping problems in Prader-Willi and Williams-Beuren syndrome. Child Care Health Dev. 1996 May;22(3):143–150. [PubMed] [Google Scholar]
  25. Tassabehji M., Metcalfe K., Donnai D., Hurst J., Reardon W., Burch M., Read A. P. Elastin: genomic structure and point mutations in patients with supravalvular aortic stenosis. Hum Mol Genet. 1997 Jul;6(7):1029–1036. doi: 10.1093/hmg/6.7.1029. [DOI] [PubMed] [Google Scholar]
  26. Tassabehji M., Metcalfe K., Fergusson W. D., Carette M. J., Dore J. K., Donnai D., Read A. P., Pröschel C., Gutowski N. J., Mao X. LIM-kinase deleted in Williams syndrome. Nat Genet. 1996 Jul;13(3):272–273. doi: 10.1038/ng0796-272. [DOI] [PubMed] [Google Scholar]
  27. Udwin O., Yule W. A cognitive and behavioural phenotype in Williams syndrome. J Clin Exp Neuropsychol. 1991 Mar;13(2):232–244. doi: 10.1080/01688639108401040. [DOI] [PubMed] [Google Scholar]
  28. Udwin O., Yule W., Martin N. Cognitive abilities and behavioural characteristics of children with idiopathic infantile hypercalcaemia. J Child Psychol Psychiatry. 1987 Mar;28(2):297–309. doi: 10.1111/j.1469-7610.1987.tb00212.x. [DOI] [PubMed] [Google Scholar]
  29. Wang Y. K., Samos C. H., Peoples R., Pérez-Jurado L. A., Nusse R., Francke U. A novel human homologue of the Drosophila frizzled wnt receptor gene binds wingless protein and is in the Williams syndrome deletion at 7q11.23. Hum Mol Genet. 1997 Mar;6(3):465–472. doi: 10.1093/hmg/6.3.465. [DOI] [PubMed] [Google Scholar]
  30. Yang N., Higuchi O., Ohashi K., Nagata K., Wada A., Kangawa K., Nishida E., Mizuno K. Cofilin phosphorylation by LIM-kinase 1 and its role in Rac-mediated actin reorganization. Nature. 1998 Jun 25;393(6687):809–812. doi: 10.1038/31735. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES