Several disorders caused by single-gene mutations, such as Fragile X syndrome, Rett syndrome and Angelman syndrome, are associated with autism. In these disorders, a substantial proportion of affected individuals meet diagnostic criteria for autism spectrum disorders, reflecting a greatly increased risk of autism conferred by the mutations. Although these monogenic disorders collectively only account for a minority of autism cases (10-15%), the molecular alterations in these disorders could reveal common pathogenic pathways shared by ASDs. Recent studies have demonstrated the presence of 5-hydroxymethylcytosine (5hmC), the 6th nucleotide in the genome. Unlike 5-methylcytosine (5mC) that has been implicated in the repression of gene expression, 5-hmC has been proposed to play significant role(s) in gene reactivation, which would be important for proper neuronal functions. We have found that the alteration of 5hmC at specific loci could be a common epigenetic alteration associated with autism-linked monogenic disorders. In this proposal, we will explore the role of 5hmC-mediated epigenetic modulation in ASD-linked monogenic disorders as well as autism in general. Our study could contribute to the identification of autism genetic/epigenetic risk factors, and will provide insight into the molecular pathogenesis of autisms.