GENETIC AND EPIGENETIC ALTERATIONS IN AUTISM

As of today, genetic modifiers, such as copy number variations, single nucleotide polymorphisms, and epigenetic changes, have been extensively studied as possible factors playing role in shaping phenotypes of patients with autism[i] [ii] [iii] [iv] [v] [vi] [vii] [viii] [ix]. Regardless, in most cases, there is no answer to the question of which of these mutations are modifying (i.e., causing phenotypic changes) and which are neutral. Moreover, despite autism is being considered one of the most heritable complex disorders, its genetic etiology is unexplained in about 90% of cases[x], and no potentially ASD-implicated germline mutations are found in copious quantities in autism[xi].  Still, the exact genetic mechanisms are complex and need to be fully understood, even though many genetic changes occurring in the germline, inherited or arising de novo, have been identified[xii].

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Currently, more information is accumulated in the areas of gene expression and transcriptome studies compared to genetic research. For example, the amount of information collected on differentiated gene expression in autism is approximately 12,000 dysregulated genes with dysregulations in the following organs and tissues: about 3500 in the brain, 2600 in cells in the gastrointestinal tract, and 5600 lymphoid lines of cells of the immune system[xiii]. For instance, differential gene expression of the brain’s prefrontal region in ASD revealed that most (239 out of 248) of the differentially expressed genes were upregulated compared to normal controls[xiv]. Many of the discovered dysregulated genes are responsible for numerous crucial functions, including transcription, DNA binding, cell growth, post-synaptic density, and neuroprotection[xv]. However, it was shown that children with ASD are born with aberrant epigenetic changes in the immune system, leading to a chronic inflammatory state. In fact, gene expression studies have 

shown that patients with ASD exhibit significant activation of genes linked to the inflammatory KEGG pathway[i] [ii]. Moreover, the enrichment of histone subunits, crucial to gene expression and epigenetic regulation, confirms the hypothesis that there is an association between epigenetic regulation and inflammation in infection-induced neurodevelopmental diseases, including autism[iii].

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