D. J. Hedges
,
Miami Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL
H. N. Cukier
,
Miami Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL
D. Q. MA
,
Miami Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL
J. M. Jaworski
,
Miami Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL
P. L. Whitehead
,
Miami Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL
H. H. Wright
,
Neuropsychiatry and Behavioral Sciences, University of South Carolina School of Medicine, Columbia, SC
R. K. Abramson
,
Neuropsychiatry and Behavioral Sciences, University of South Carolina School of Medicine, Columbia, SC
S. E. Echandia
,
Miami Institute for Human Genomics, University of Miami, Miami, FL
Z. M. Kozhekbaeva
,
Miami Institute for Human Genomics, University of Miami, Miami, FL
L. Nathanson
,
Miami Institute for Human Genomics, University of Miami, Miami, FL
J. P. Hussman
,
Hussman Foundation, Ellicott City, MD
J. Haines
,
Center for Human Genetics Research, Vanderbilt University, Nashville, TN
M. L. Cuccaro
,
Miami Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL
J. R. Gilbert
,
Miami Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL
M. A. Pericak-Vance
,
Miami Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL
Background:
Autism has a strong genetic component, but studies over the past decade have demonstrated that the underlying genetics are complex. Previous research suggests an important role for copy number variants (CNVs) in autism risk and indicates a strong association of CNVs with the autistic phenotype. Gamma-aminobutyric acidGABA) is the primary inhibitory neurotransmitter in the adult human brain. The chromosome 4 GABR cluster has previously been implicated in autistic disorder through both cytogenetic alterations as well as association with SNPs in the gene. Consequently, genes encoding for proteins involved in the GABA network represent excellent candidates for possible involvement in autism.
Objectives: While several studies have now conducted whole-genome surveys of structural variation in autistic individuals, we sought to achieve a significantly higher resolution analysis by employing a candidate gene strategy, primarily focused on GABA related genes. Using this approach, we have the ability to detect smaller scale structural variants that remain undetectable using standard whole genome CGH arrays.
Methods: Custom 1x244k Agilent comparative genomic hybridization (CGH) arrays were designed covering GABA related genes, as well as 28 additional autism candidate genes, including Neurexins 1-3 and Neuroligins 1-4, and SHANK3. Collectively, our probes spanned a total of 15 Mb with a density of approximately 1 probe every 150 nucleotides. 250 autism cases and 250 control individuals are currently being evaluated by aCGH. All experimental and control samples were hybridized vs. a single reference sample. Putative CNVs detected via aCGH will subsequently be validated using either standard PCR followed by gel electrophoresis or real-time quantitative PCR, depending upon the predicted size of the event.
Results: Preliminary results indicate putative CNVs in two autism candidates.
Conclusions: Pending validation of CNV events and additional analyses.
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