Abstract
BackgroundAutism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Although numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders.MethodsWe describe the use of high-resolution genome-wide tilepath microarrays and comparative genomic hybridization to identify copy number variants within 119 probands from multiplex autism families. We next carried out DNA methylation analysis by bisulfite sequencing in a proband and his family, expanding this analysis to methylation analysis of peripheral blood and temporal cortex DNA of autism cases and matched controls from independent datasets. We also assessed oxytocin receptor (OXTR) gene expression within the temporal cortex tissue by quantitative real-time polymerase chain reaction (PCR).ResultsOur analysis revealed a genomic deletion containing the oxytocin receptor gene, OXTR (MIM accession no.: 167055), previously implicated in autism, was present in an autism proband and his mother who exhibits symptoms of obsessive-compulsive disorder. The proband's affected sibling did not harbor this deletion but instead may exhibit epigenetic misregulation of this gene through aberrant gene silencing by DNA methylation. Further DNA methylation analysis of the CpG island known to regulate OXTR expression identified several CpG dinucleotides that show independent statistically significant increases in the DNA methylation status in the peripheral blood cells and temporal cortex in independent datasets of individuals with autism as compared to control samples. Associated with the increase in methylation of these CpG dinucleotides is our finding that OXTR mRNA showed decreased expression in the temporal cortex tissue of autism cases matched for age and sex compared to controls.ConclusionTogether, these data provide further evidence for the role of OXTR and the oxytocin signaling pathway in the etiology of autism and, for the first time, implicate the epigenetic regulation of OXTR in the development of the disorder.See the related commentary by Gurrieri and Neri:
Highlights
Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable
10 copy number variants (CNVs) were contained within previously published CNVs from the database of genomic variants [28], while 2 CNVs extended the size of the known CNV regions (Additional file 3)
We chose to focus on 19 of the 113 putative deletions or duplications identified in the first screen to validate by array comparative genomic hybridization (CGH) dye swap experiments using select individuals (Additional file 3, top) or, in the case of the oxytocin receptor (OXTR) deletion described below, by microsatellite and quantitative real-time polymerase chain reaction (PCR) analysis
Summary
Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders. Classic autism comprises a spectrum of behavioral and cognitive disturbances of childhood development. The core autism phenotype includes deficits in social interaction, language development and patterns of repetitive behaviors and/or restricted interests. The population prevalence of the spectrum of autism disorders is estimated to range between 1/300 [1] to 1/100 http://www.nsch data.org/, with a male: female ratio of 4:1 [2,3]. Numerous approaches including genetic linkage, genome-wide association, candidate gene association and gene expression analysis have been used to identify the additional genes implicated in the development of autism [7,8]. The heterogeneous nature of autism and autism spectrum disorders has limited their success
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