Role of epigenomic misregulation in the etiology of autism spectrum disorders – EPI-ASD

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. Although ASD was found to be the most heritable of all the psychiatric disorders based upon twin and family studies, neither single gene nor consensus gene combination has been shown to be frequently linked to idiopathic autism. Genetic susceptibility loci have been identified on virtually every chromosome by a combination of whole genome scans, cytogenetics, and genetic linkage/association analyses. Genes encoding proteins involved in synapse formation and function such as glutamate receptors or neuroligins and proteins involved in axon guidance such as SHANK3 have been linked to ASD. Finally, cytogenetic studies demonstrated that copy number variants (both inherited and de novo) are 10 times more frequent in the autistic population than in the general population. Altogether, around 103 genes and 44 genomic loci have been reported in ASD with considerable overlap with other disorders such as intellectual deficiency, epilepsy, schizophrenia and attention deficit hyperactivity disorder (ADHD). These data suggest that ASD is not a single-gene disorder with Mendelian inheritance but rather a complex disorder resulting from simultaneous genetic variations in multiple genes as well as complex interactions between genetic, epigenetic and environmental factors.
Epigenetic control of autism susceptibility is a recent concept and most certainly a topic of great interest in the field. Involvement of epigenetic regulatory mechanisms in the pathogenesis of ASD has been suggested by gene expression profiling of monozygotic twins discordant in diagnosis of autism that identified differentially expressed, neurologically relevant genes. ,This hypothesis is also supported by the observation that the most common recurrent cytogenetic abnormalities in ASD involve maternally derived duplications of the imprinted domain on chromosome 15q11–13. Finally, abnormal methylation patterns have been detected at several candidate genes in ASD patients. Together with the occurrence of ASD in patients with disorders arising from epigenetic mutations (fragile X syndrome) or that involve key epigenetic regulatory factors (Rett syndrome) these studies collectively support the hypothesis that a mixed epigenetic and genetic mode of inheritance could be relevant to ASD. The aim of our study is to develop an original project based on genome-wide approaches using multipotent stem cells analyses to investigate whether pathogenic epigenomic variations may account for some cases of idiopathic ASD. We will focus in particular on chromatin modifications and miRNA expression. Expected results should provide new insights into the molecular and cellular bases of ASD. Novel findings in the miRNA field may demonstrate the value of miRNA signatures in ASD diagnosis and prognosis. Ultimately, our data may pave the way to novel therapeutic trials aiming at restoring epigenetic failures that contribute to ASD.