Autism is a neuropsychiatric disorder exhibiting a complex genetic etiology with significant clinical and locus heterogeneity. Duplications affecting chromosome 15q11-q13 are the most common cytogenetic abnormality in autism, and linkage and association studies indicate that this region is involved in inherited susceptibility for autism in chromosomally normal families. We propose dissecting the genetic basis for inherited risk associated with 15q11-q13 in autism by (1) employing a thoroughly phenotyped dataset of 365 parent-child trios and 330 multiplex families; (2) characterization of duplicon-mediated rearrangements and potential epigenetic effects; (3) identifying genetically more homogeneous subgroups with which to detect and characterize genetic effects; and (4) performing high-resolution linkage disequilibrium mapping using single nucleotide polymorphisms (SNPs) to define haplotypes for use in analysis of allelic effects in these families. Our goal will be accomplished through five specific aims. (1) Recruitment and detailed clinical assessment of singleton families using a standardized panel of diagnostic instruments and algorithms. (2) Characterization of chromosomal rearrangements involving 15q and examination of potential epigenetic dysregulation of imprinted expression. (3) Construction of a complete haplotype map for the 15q11-q13 candidate region and identification of a reduced set of SNPs for discrimination of all common (>5%) haplotypes. (4) Application of individual markers and multi-marker haplotypes to characterize allelic and epistatic effects in these autism families. (5) Identification of 15q11-q13 allelic variants in autism and preliminary characterization of the functional effect of those variations. Associated haplotype blocks and/or functionally-significant regions within candidate genes will be screened to identify likely functional variants. We will evaluate the significance of any genetic findings by examination of independent datasets through collaboration with other groups. The result of these efforts will be an understanding of how 15q11-q13 contributes to inherited susceptibility in autism and the broader autism spectrum. ? ?
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