International Meeting for Autism Research (London, May 15-17, 2008): The STX1A, CYLN2, and GTF2i genes in autism-associated 7q11.2 microduplication syndrome as candidate genes for Autism Spectrum Disorders

Friday, May 16, 2008

Champagne Terrace/Bordeaux (Novotel London West)

11:30 AM

P. Malenfant , Department of Physiology, Queen's University, Kingston, ON, Canada

X. Liu , Department of Psychiatry, Queen's University, Kingston, ON, Canada

M. Hudson , Psychiatry, Queen's Univerity, Kingston, ON, Canada

Y. Qiao , Departments of Pathology and Medical Genetics, University of British Columbia, Vancouver, BC, Canada

J. M. Hildebrand , Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada

I. L. Cohen , Psychology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY

A. Chudley , Section of Genetics and Metabolism, University of Manitoba, Winnipeg, MB, Canada

C. Forster-Gibson , Department of Family Medicine, Queen's University, Kingston, ON, Canada

S. M. Lewis , Medical Genetics, University of British Columbia, Vancouver, BC, Canada

E. Rajcan-Separovic , Department of Pathology, University of British Columbia, Vancouver, BC, Canada

J. J. A. Holden , Psychiatry & Physiology, Queen's Univerity, Kingston, ON, Canada

Background: Microdeletions of 7q11.23 are relatively common and associated with the Williams-Beuren Syndrome (WBS), whereas duplications of this region have recently been reported in association with Autism Spectrum Disorders (ASDs) or autistic-like behaviours (Berg et al, 2007).
Objectives: To test candidate genes within 7q11.23 for association with autism using family-based and case-control approaches and to screen a large number of individuals with ASDs for 7q11.23 duplications and deletions.
Methods: Markers within three of the duplicated genes, STX1A, CYLN2, and GTF2i were genotyped using validated custom TaqMan SNP Genotyping Assays on an ABI Prism 7900HT. Both real-time quantitative PCR (RTqPCR) and CGH-array were used to screen for microdeletions/microduplication in more than 900 subjects with ADOS/ADI-R-confirmed ASD. RTqPCR was used to refine the breakpoints in one identified case.
Results: The STX1A, CYLN2, and GTF2i genes were selected based on their function and tested for association with ASDs using 10 SNPs. Haplotype transmission disequilibrium testing revealed a modest over-transmission of one haplotype in each of the three genes tested (P = 0.016, 0.033 and 0.032, respectively) as well as of one 10-marker haplotype (P = 0.032). A single duplication of chromosome 7q11.23 was found in an individual with confirmed ASD, apraxia, intellectual disability and minor craniofacial dysmorphism. The breakpoints (72.37Mb and 73.80Mb) were localized to the flanking low-copy repeats that predispose to the genomic instability characteristic of the 7q11.23 deletion observed in the majority of WBS cases.
Conclusions: Association testing implicates one or more of the genes within the WBS critical region in the etiology of some cases of ASDs. The identification of a single case of the duplication among 913 individuals screened indicates that genomic rearrangements of 7q11.23 are not a common cause of ASDs.

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