Association of GTF2i in the Williams-Beuren Syndrome Critical Region with Autism Spectrum Disorders
- 696 Downloads
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.
KeywordsAutism Spectrum Disorders (ASDs) Gene association GTF2i gene 7q11.23 duplication Williams-Beuren Syndrome (WBS)
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.
- American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders: DSM-IV) (4th ed.). Washington, DC: American Psychiatric Association.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
- 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.CrossRefGoogle 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.PubMedCrossRefGoogle 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