Genomic Rearrangements in Autism Spectrum Disorders: Identification of Novel Candidate Genes

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Malenfant, Patrick
Autism Spectrum Disorders , Genetics , Chromosome abnormalities , Genomic rearrangements , Williams-Beuren Syndrome , Real-time PCR , Microarray , Association testing
There is evidence from family studies for the importance of genetic factors in the development of autism spectrum disorders (ASDs) but the identification of major genes has not been achieved to date. There are several reports of deletions and duplications in individuals with ASDs, some of which are not unique to an individual. In most cases, the frequencies and relevance of these abnormalities are unknown, as they have been identified serendipitously in one or a few individuals. My overall hypothesis was that such rearrangements would facilitate the identification of “culprit” genes associated with ASDs by identifying a small chromosomal region for candidate gene testing. I molecularly characterized two overlapping 2p15-2p16.1 deletions detected in unrelated individuals with confirmed autistic disorder (Subject 1) or autistic features (Subject 2), a 1.4Mb deletion on chromosome Xp22 (Subject 1) and a duplication of chromosome 7q11.23, reciprocal to the Williams-Beuren Syndrome (WBS) deletion, in one individual with an ASD (Subject 3). Using real-time semi-quantitative PCR, I screened a total of 798 individuals with an ASD and 186 healthy controls for the presence of similar abnormalities. No additional cases were identified in either group. Subsequently, I selected 6 genes [Orthodenticle homolog 1 (OTX1), Variable charge, X-linked (VCX), Neuroligin 4, X-linked (NLGN4X), Syntaxin 1A (STX1A), Cytoplasmic linker 2 (CYLN2) and General transcription factor IIi (GTF2i)], based on their function and localization within or in the vicinity of the rearrangements and tested them for association with ASDs. Although there was no evidence for association for any marker or haplotype in most of the genes tested, this was not so for GTF2i. Haplotype transmission disequilibrium testing revealed an increased transmission, from healthy parents to their affected offspring, of the common alleles of one marker and one haplotype in GTF2i (P = 0.0010 and 0.0005, respectively). This gene encodes a brain-expressed transcription factor previously implicated in the mental retardation associated with WBS. Based on these findings, I propose that, although the genomic rearrangements reported herein are not a common cause of ASDs, the GTF2i gene within the WBS critical region is important in the aetiology of autism.
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