Skip to main content

Advertisement

Log in

Association of GTF2i in the Williams-Beuren Syndrome Critical Region with Autism Spectrum Disorders

  • Original Paper
  • Published:
Journal of Autism and Developmental Disorders Aims and scope Submit manuscript

Abstract

Duplications of 7q11.23, deleted in Williams-Beuren Syndrome, have been implicated in autism spectrum disorders (ASDs). A 1.5 Mb duplication was identified in one girl with severe expressive language deficits and anxiety among 1,142 ASD individuals screened for this duplication. Family-based association studies of Tag-SNPs in three genes (STX1A , CYLN2 and GTF2i) in two multiplex autism family cohorts revealed strong association of two GTF2i SNPs and their haplotype in Cohort 1 and the combined families. The risk alleles and haplotype were associated with severe problems in social interaction and excessive repetitive behaviors. Our findings suggest the GTF2i gene is important in the etiology of autism in individuals with this duplication and in non-duplication cases with severe social interaction problems and repetitive behaviors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  • American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders: DSM-IV) (4th ed.). Washington, DC: American Psychiatric Association.

    Google Scholar 

  • Beckman, M. L., Bernstein, E. M., & Quick, M. W. (1998). Protein kinase C regulates the interaction between a GABA transporter and syntaxin 1A. The Journal of Neuroscience, 18, 6103–6112.

    PubMed  Google Scholar 

  • Benjamini, Y., & Hochberg, Y. (1995). Controlling the false discovery rate: A practical and powerful approach to multiple testing. Journal of the Royal Statistical Society, Series B (Methodological), 57, 289–300.

    Google Scholar 

  • Berg, J. S., Brunetti-Pierri, N., Peters, S. U., Kang, S. H., Fong, C. T., Salamone, J., et al. (2007). Speech delay and autism spectrum behaviors are frequently associated with duplication of the 7q11.23 Williams-Beuren syndrome region. Genetics in Medicine, 9, 427–441.

    Article  PubMed  Google Scholar 

  • Beunders, G., van de Kamp, J. M., Veenhoven, R. H., van Hagen, J. M., Nieuwint, A. W., & Sistermans, E. A. (2010). A triplication of the Williams-Beuren syndrome region in a patient with mental retardation, a severe expressive language delay, behavioural problems and dysmorphisms. Journal of Medical Genetics, 47, 271–275.

    Article  PubMed  Google Scholar 

  • Bragina, L., Giovedi, S., Barbaresi, P., Benfenati, F., & Conti, F. (2010). Heterogeneity of glutamatergic and GABAergic release machinery in cerebral cortex: analysis of synaptogyrin, vesicle-associated membrane protein, and syntaxin. Neuroscience, 165, 934–943.

    Article  PubMed  Google Scholar 

  • Brock, J. (2007). Language abilities in Williams syndrome: A critical review. Development and Psychopathology, 19, 97–127.

    Article  PubMed  Google Scholar 

  • Cohen, I. L. (2003). Criterion-related validity of the PDD Behavior Inventory. Journal of Autism Developmental Disorder, 33, 47–53.

    Article  Google Scholar 

  • Cohen, I. L., Schmidt-Lackner, S., Romanczyk, R., & Sudhalter, V. (2003). The PDD behavior inventory: A rating scale for assessing response to intervention in children with pervasive developmental disorder. Journal of Autism Developmental Disorder, 33, 31–45.

    Article  Google Scholar 

  • Dai, L., Bellugi, U., Chen, X. N., Pulst-Korenberg, A. M., Jarvinen-Pasley, A., Tirosh-Wagner, T., et al. (2009). Is it Williams syndrome? GTF2IRD1 implicated in visual-spatial construction and GTF2I in sociability revealed by high resolution arrays. American Journal of Medical Genetics Part A, 149A, 302–314.

    Article  PubMed  Google Scholar 

  • Depienne, C., Heron, D., Betancur, C., Benyahia, B., Trouillard, O., Bouteiller, D., et al. (2007). Autism, language delay and mental retardation in a patient with 7q11 duplication. Journal of Medical Genetics, 44, 452–458.

    Article  PubMed  Google Scholar 

  • Durand, C. M., Betancur, C., Boeckers, T. M., Bockmann, J., Chaste, P., Fauchereau, F., et al. (2007). Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nature Genetics, 39, 25–27.

    Article  PubMed  Google Scholar 

  • Edelman, E. A., Girirajan, S., Finucane, B., Patel, P. I., Lupski, J. R., Smith, A. C., et al. (2007). Gender, genotype, and phenotype differences in Smith-Magenis syndrome: A meta-analysis of 105 cases. Clinical Genetics, 71, 540–550.

    Article  PubMed  Google Scholar 

  • Edelmann, L., Prosnitz, A., Pardo, S., Bhatt, J., Cohen, N., Lauriat, T., et al. (2007). An atypical deletion of the Williams-Beuren syndrome interval implicates genes associated with defective visuospatial processing and autism. Journal of Medical Genetics, 44, 136–143.

    Article  PubMed  Google Scholar 

  • Francke, U. (1999). Williams-Beuren syndrome: genes and mechanisms. Human Molecular Genetics, 8, 1947–1954.

    Article  PubMed  Google Scholar 

  • Geschwind, D. H., Sowinski, J., Lord, C., Iversen, P., Shestack, J., Jones, P., et al. (2001). The autism genetic resource exchange: a resource for the study of autism and related neuropsychiatric conditions. American Journal of Human Genetics, 69, 463–466.

    Article  PubMed  Google Scholar 

  • Hakimi, M. A., Dong, Y., Lane, W. S., Speicher, D. W., & Shiekhattar, R. (2003). A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes. Journal of Biological Chemistry, 278, 7234–7239.

    Article  PubMed  Google Scholar 

  • Hakre, S., Tussie-Luna, M. I., Ashworth, T., Novina, C. D., Settleman, J., Sharp, P. A., et al. (2006). Opposing functions of TFII-I spliced isoforms in growth factor-induced gene expression. Molecular Cell, 24, 301–308.

    Article  PubMed  Google Scholar 

  • Hamdan, F. F., Piton, A., Gauthier, J., Lortie, A., Dubeau, F., Dobrzeniecka, S., et al. (2009). De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy. Ann.Neurol., 65, 748–753.

    Article  PubMed  Google Scholar 

  • Jacquemont, M. L., Sanlaville, D., Redon, R., Raoul, O., Cormier-Daire, V., Lyonnet, S., et al. (2006). Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. Journal of Medical Genetics, 43, 843–849.

    Article  PubMed  Google Scholar 

  • Jones, W., Bellugi, U., Lai, Z., Chiles, M., Reilly, J., Lincoln, A., et al. (2000). II. Hypersociability in Williams syndrome. Journal of Cognitive Neuroscience, 12(Suppl 1), 30–46.

    Article  PubMed  Google Scholar 

  • Kirchhoff, M., Bisgaard, A. M., 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. European Journal of Medical Genetics, 50, 33–42.

    Article  PubMed  Google Scholar 

  • Kriek, M., White, S. J., Szuhai, K., Knijnenburg, J., van Ommen, G. J., den Dunnen, J. T., 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. European Journal of Human Genetics, 14, 180–189.

    Article  PubMed  Google Scholar 

  • Laird, N. M., Horvath, S., & Xu, X. (2000). Implementing a unified approach to family-based tests of association. Genetic Epidemiology, 19(Suppl 1), S36–S42.

    Article  PubMed  Google Scholar 

  • Levitin, D. J., Cole, K., Lincoln, A., & Bellugi, U. (2005). Aversion, awareness, and attraction: investigating claims of hyperacusis in the Williams syndrome phenotype. Journal of Child Psychology and Psychiatry, 46, 514–523.

    Article  PubMed  Google Scholar 

  • Liu, X., Novosedlik, N., Wang, A., Hudson, M. L., Cohen, I. L., Chudley, A. E., et al. (2009). The DLX1and DLX2 genes and susceptibility to autism spectrum disorders. European Journal of Human Genetics, 17, 228–235.

    Article  PubMed  Google Scholar 

  • Lord, C., Rutter, M., & Le, C. A. (1994). Autism diagnostic interview-revised: A revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. Journal of Autism Developmental Disorder, 24, 659–685.

    Article  Google Scholar 

  • Lord, C., Risi, S., Lambrecht, L., Cook, E. H., Jr., Leventhal, B. L., DiLavore, P. C., et al. (2000). The autism diagnostic observation schedule-generic: A standard measure of social and communication deficits associated with the spectrum of autism. Journal of Autism Developmental Disorder, 30, 205–223.

    Article  Google Scholar 

  • Makeyev, A. V., & Bayarsaihan, D. (2009). Alternative splicing and promoter use in TFII-I genes. Gene, 433, 16–25.

    Article  PubMed  Google Scholar 

  • McDougle, C. J., Erickson, C. A., Stigler, K. A., & Posey, D. J. (2005). Neurochemistry in the pathophysiology of autism. Journal of Clinical Psychiatry, 66(Suppl 10), 9–18.

    PubMed  Google Scholar 

  • Merla, G., Brunetti-Pierri, N., Micale, L., & Fusco, C. (2010). Copy number variants at Williams-Beuren syndrome 7q11.23 region. Human Genetics, 128, 3–26.

    Article  PubMed  Google Scholar 

  • Merritt, J. L., & Lindor, N. M. (2008). Further clinical description of duplication of Williams-Beuren region presenting with congenital glaucoma and brachycephaly. American Journal of Medical Genetics, 146A, 1055–1058.

    Article  PubMed  Google Scholar 

  • Orellana, C., Bernabeu, J., Monfort, S., Rosello, M., Oltra, S., Ferrer, I., et al. (2008). Duplication of the Williams-Beuren critical region: Case report and further delineation of the phenotypic spectrum. Journal of Medical Genetics, 45, 187–189.

    Article  PubMed  Google Scholar 

  • Osborne, L. R., & Mervis, C. B. (2007). Rearrangements of the Williams-Beuren syndrome locus: molecular basis and implications for speech and language development. Expert Reviews in Molecular Medicine, 9, 1–16.

    Article  PubMed  Google Scholar 

  • Ott, J. (1999). Methods of analysis and resources available for genetic trait mapping. Journal of Heredity, 90, 68–70.

    Article  PubMed  Google Scholar 

  • Perez Jurado, L. A., Peoples, R., Kaplan, P., Hamel, B. C., & Francke, U. (1996). Molecular definition of the chromosome 7 deletion in Williams syndrome and parent-of-origin effects on growth. American Journal of Human Genetics, 59, 781–792.

    PubMed  Google Scholar 

  • Rajcan-Separovic, E., Harvard, C., Liu, X., McGillivray, B., Hall, J. G., Qiao, Y., et al. (2007). Clinical and molecular cytogenetic characterisation of a newly recognised microdeletion syndrome involving 2p15–16.1. Journal of Medical Genetics, 44, 269–276.

    Article  PubMed  Google Scholar 

  • Schuyler, S. C., & Pellman, D. (2001). Microtubule “plus-end-tracking proteins”: The end is just the beginning. Cell, 105, 421–424.

    Article  PubMed  Google Scholar 

  • Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., et al. (2007). Strong association of de novo copy number mutations with autism. Science, 316, 445–449.

    Article  PubMed  Google Scholar 

  • Somerville, M. J., Mervis, C. B., Young, E. J., Seo, E. J., del Campo, M., Bamforth, S., et al. (2005). Severe expressive-language delay related to duplication of the Williams-Beuren locus. New England Journal of Medicine, 353, 1694–1701.

    Article  PubMed  Google Scholar 

  • Stein, A., Weber, G., Wahl, M. C., & Jahn, R. (2009). Helical extension of the neuronal SNARE complex into the membrane. Nature, 460, 525–528.

    PubMed  Google Scholar 

  • Sudhof, T. C. (2000). The synaptic vesicle cycle revisited. Neuron, 28, 317–320.

    Article  PubMed  Google Scholar 

  • Torniero, C., B. B., dalla., Novara, F., Vetro, F., Ricco, I., Darra, F., 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. European Journal of Human Genetics, 15, 62–67.

    Article  PubMed  Google Scholar 

  • Torniero, C., dalla, B. B., Novara, F., Cerini, R., Bonaglia, C., Pramparo, T., et al. (2008). Dysmorphic features, simplified gyral pattern and 7q11.23 duplication reciprocal to the Williams-Beuren deletion. European Journal of Human Genetics, 16, 880–887.

    Article  PubMed  Google Scholar 

  • Tyson, C., Harvard, C., Locker, R., Friedman, J. M., Langlois, S., Lewis, M. E., et al. (2005). Submicroscopic deletions and duplications in individuals with intellectual disability detected by array-CGH. American Journal of Medical Genetics Part A, 139, 173–185.

    Article  PubMed  Google Scholar 

  • Van der Aa, N., Rooms, L., Vandeweyer, G., van den Ende, J., Reyniers, E., Fichera, M., et al. (2009). Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome. European Journal of Medical Genetics, 52, 94–100.

    Article  PubMed  Google Scholar 

  • Vorstman, J. A., Staal, W. G., van Daalen E., van Engeland, H., Hochstenbach, P. F., & Franke, L. (2006). Identification of novel autism candidate regions through analysis of reported cytogenetic abnormalities associated with autism. Molecular Psychiatry, 11(1), 1–18, 28.

    Google Scholar 

  • Yu, Y. X., Shen, L., Xia, P., Tang, Y. W., Bao, L., & Pei, G. (2006). Syntaxin 1A promotes the endocytic sorting of EAAC1 leading to inhibition of glutamate transport. Journal of Cell Science, 119, 3776–3787.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by an OMHF grant (PI: JJAH), a CIHR-IHRT grant (#43820) to JJAH (PI) and ASD-CARC (http://www.AutismResearch.com), CIHR grants (RT-64217: MESL, PI; MOP 74502: ERS, PI), Michael Smith Foundation for Health Research (MESL and ERS), on-going support from Ongwanada, and an OMHF studentship to PM. PM, YQ and NR are trainees with the CIHR/NAAR STIHR Inter-Institute ASDs Training Program (PI: JJAH) (http://www.AutismTraining.ca). This research was also supported, in part, by funds from the New York State Office of Mental Retardation and Developmental Disabilities. The authors are very grateful to the families who participated in this research through ASD-CARC (http://www.AutismResearch.com), and acknowledge the resources provided by the AGRE (Autism Genetics Resource Exchange) consortium and the participating AGRE families. AGRE is a program of Cure Autism Now and supported, in part, by grant MH64547 from the NIMH to Daniel H. Geschwind (PI). We thank Chris Hall for her excellent work managing our DNA Bank and preparing samples for these studies.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jeanette J. A. Holden.

Additional information

Patrick Malenfant and Xudong Liu contributed equally to the work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Malenfant, P., Liu, X., Hudson, M.L. et al. Association of GTF2i in the Williams-Beuren Syndrome Critical Region with Autism Spectrum Disorders. J Autism Dev Disord 42, 1459–1469 (2012). https://doi.org/10.1007/s10803-011-1389-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10803-011-1389-4

Keywords

Navigation