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Examining the Y-Chromosome in Autism Spectrum Disorder

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There is accumulating evidence that autism spectrum disorder (ASD) is caused by rare inherited or spontaneous genetic mutations, such as copy number changes and single nucleotide alterations. However, the genetic causes that have currently been found only account for about 15% of the cases. Further identification of genetic causes will lead to early diagnosis and aid in the development of interventions for improved outcomes. One striking characteristics of ASD is a strong gender bias, with males four times more likely to be on the spectrum than girls. Recent studies suggest that this gender bias can be caused by genetic mutations found on the sex chromosome. For example, mutations in genes such as PTCHD1, NLGN3 and NLGN4, on chromosome X have been associated with the ASD phenotype. However, the Y chromosome is often disregarded due to its complex and repetitive DNA sequence structure, which makes it difficult to examine comprehensively using conventional genetic technologies. Importantly, chromosome Y contains many genes that are crucial for the brain development and has a high frequency of spontaneous mutations. Moreover, males with abnormal XYY or XXYY karyotypes have increased risk of developing ASD. It is hypothesized that additional genetic mutations involved in ASD can be found on the Y chromosome. The investigators are using the latest genome-sequencing and microarray technologies for discovery of the Y chromosome variants in males associated with autism. Specific aims are to: 1) characterize the DNA sequence and structure of the whole Y chromosome so as to provide a foundation for investigation in this poorly characterized genomic region, 2) identify and validate the candidate autism-associated variants using independent technologies across large case and control cohorts; and 3) Define the effects of mutations on clinical outcomes of the autism individuals and their families. The findings from this project promise to include discovery of novel genetic biomarkers that can be used for early diagnosis and development of novel interventions for autism.