Autism spectrum disorder (ASD) is a complex of neurodevelopmental disorders which characterized by language deficits and pervasive behavioural regressions, including social interaction impairments and stereotyped restrictive behaviours. Regarding to the statistical report of (X) the prevalence of autism has raised over the last (X years/decades) into (X – XX) individuals. REF In accordance with this progressive increase of ASD cases, and lack of efficient diagnosis and treatment, moreover, the difficulties on the society and families of autistic children, the investigation of ASD biomarkers became a fundamental priority.
There have been numerous studies designed to demonstrate autism aetiology through genetic mutations. Recently, the link between ASD and environmental factors have been widely investigated. Regarding to many studies, genetic and environmental factors are both involved in autism pathogenesis.(Weiss et al., 2009, Hogg et al., 2014, Karimi et al., 2017) Any alterations in the gene expression patterns by affect the quality and quantity of gene expression without changes in the genomic DNA sequence refer to be epigenetic modification, including DNA methylation, histone modifications such as acetylation or methylation of histone tails, or non-coding RNAs such as microRNAs. These alterations presented as the most significant mediator in the genome and environmental interactions, however, it can be inherited and manipulated by different environmental factors, including nutrition, chemical exposures and lifestyle.
Epigenetics and ASD:
Genome abnormalities estimated to be only 10-20% of all ASD patients, whereas many epigenetics modifications demonstrate the aetiology and contribute in the emergence and susceptibility to ASD.(Schaefer and Mendelsohn, 2008) Largest population-based twin study has done on 192 twin pairs with ASD attempted to explain and provide rigorous quantitative estimates of genetic heritability of autism and the effects of shared environment, shows that environmental factors explain about 55% of the liability to autism. Although that the genetic factors also play an important role.(Hallmayer et al., 2011) Interpregnancy Interval (IPI) time between two pregnancies were studied to evaluate the association between IPI and risk of ASD in second-born children. This association was not explained by antidepressant drugs used before pregnancy, maternal BMI, or unfavorable events during the first or second pregnancy.(Zerbo et al., 2015) This study has not dealt with the other potential explanatory factors such as infertility, data of maternal nutritional status, including folate and iron, in order to explain the association between ASD and IPI. Dysregulated Homer1a gene expression was found to be induced and contributed with ASD pathology by studied the Basal and lateral nucleus of the amygdala (BLA) from valproic acid-exposed animals.(Banerjee et al., 2016) This finding is fascinating and provides a novel interesting information for the ASD researchers to be further investigated. Due to Homer1a impact on the functioning of metabotropic glutamate receptors (mGluR5), Homer1 and Shank3, which have previously been correlated with ASD.
Methylation and expression levels with ASD:
One of the most common epigenetic mechanisms is the DNA methylation which generally regulate the transcriptional process by adding a methyl group to the cytosine from S-adenosyl-methionine (SAM) by DNA methyltransferases (DNMT). A strong relationship between ASD and methylation has been investigated and reported in several studies. The expression of FOXP1 gene is regulated by methylation, cis-acting SNPs, and microRNA. A study used comparative gene expression profiling analysis of lymphoblastoid cell lines (LCL) discovered that Increasing of FOXP1 expression level is associated with the pathogenesis of ASD.(Wei-Hsien Chien1, 2013) Since FOXP1 gene is regulated by several mechanisms it would be interesting to determine the exact underlying mechanisms that implicated in the increased expression levels of the FOXP1 gene in ASD. Another study of a neuron-specific gene ENO2, were found to be hypermethylated in the promoter region in about 14.5% of the autistic compared with the control age-/sex-matched of ASD samples, this suggests that downregulation of ENO2 expression could be a biomarker for autistic children.(Wang et al., 2014) However, several questions remain unanswered whether the ENO2 gene is differentially expressed in the embryo or fetal tissues at early stages of gestation, and if it is a key component in brain development. Recent study of RELN gene methylation patterns has used post-mortem neocortical tissue of post-puberal among autistic and control individuals, reported an upstream methylated promoter region in autistic brains, whereas a methylated downstream region was only found in controls. This methylation patterns differences associated with decreased RELN gene expression among autistic compared to controls.(Lintas et al., 2016)
Collectively, the previous-mentioned studies have provide support for the potential role of DNA methylation in autism which attracted our attention to identify innovative differentially expressed genes associated with methylation level of autistic children comparing to healthy ones in our population using comparative gene expression of …GENE… and analysis its relation to the methylation level.