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Advanced Parental Age and Autism: The role of aneuploidy and uniparental disomy in ASD pathogenesis

State/Province Full: 
New York
United States

Numerous studies have demonstrated that rates of autism spectrum disorders (ASDs) rise with older ages of the parents. Researchers are currently investigating the ways an aging paternal germline can contribute to Autism Spectrum Disorders (ASDs), namely through increased rates of mutation of the DNA sequence. Although the effects of paternal age, namely higher rates of mutation and copy number variation in offspring, have indeed been linked to ASDs, no study has determined the potential role of maternal age. We propose that maternal nondisjunction and resulting aneuploidy could cause ASDs and remain undetected. Since most aneuploidies are lethal embryonically, surviving offspring often undergo a "rescue" event that restores normal chromosome number. Depending on when an aneuploidy rescue occurs and which chromosome is lost, offspring exhibit either covert mosaic aneuploidy in sub-populations of cells or heterodisomic uniparental disomy (UPD). These defects have been implicated in other genetic disorders and may contribute to the molecular basis of ASDs, but are, surprisingly, unlikely to have been detected by current approaches that utilize cultured blood, a tissue that demonstrates low or absent levels of aneuploidy in mosaic individuals. In this study, we will perform comprehensive analysis of the genomes of children with ASD born to parents of advanced age, employing DNA isolated from buccal epithelium. By comparing children's genotypes with their parents and applying computational analysis on SNP array signal intensities, this study has the potential to identify the prevalence of covert mosaicism and heterodisomic UPD in children with ASDs.