Autism is a severe neurodevelopmental disorder characterized by social interaction and language deficits, and behavior abnormalities, including repetitive or stereotyped actions. Autism is common, affects approximately 2-5/10000 children, and is often seen with accompanying neurological features such as mental retardation and seizures. Autism has a complex etiology, with evidence from pedigree, twin and sibling studies indicating a strong genetic component. Two categories of investigation point to the chromosome 15q11-q13 region deleted in Prader-Willi syndrome and Angelman syndrome (AS) as harboring a locus or loci for autism. Large duplications, affecting maternally-derived chromosomes and resulting in three or four copies of 15q11-q13, are consistently detected in the autistic population; this implies a potential role of genomic imprinting and may indicate that disruption of normal, possibly imprinted , gene dosage of this region can confer susceptibility to autism. Independent studies support linkage of autism in multiplex families to 15q11- q13 and elevated recombination in a 15q11-q13 maternal recombination hotspot, in autism families. DNA marker genotyping for linkage studies reveals null and three allele genotypes at several markers within 15q11-q13, in autism families, suggesting smaller genomic rearrangements. We characterize a 5-kb genomic deletion encompassing one marker as a cause for these results, and this deletion is present at a significantly higher frequency in autism families compared to controls, suggesting an association. This potential susceptibility marker will be explored further for relevance to autism. Maternal-specificity of large duplications may point directly to imprinted, maternally-expressed genes, of which the AS gene termed UBE3A, is an example. The linkage and related data, however, appear to indicate a slightly more telomeric location for an autism locus, within a region containing multiple neurological and positional candidates and unresolved imprinting status. Uniting the duplication and linkage data could involve a possible hypermorphic susceptibility allele. The project will correlate genomic sequence and contigs for the key region, with large duplications and smaller defects, genes, simple-sequence repeat markers, and developing polymorphisms. Genes in the autism candidate region will be analyzed for expression and imprinting in the brain, screened for functional sequence variation, and variants analyzed in simplex and multiplex families to test for involvement in autism.
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