Despite extensive research efforts, the etiopathogenesis of ASD thus far remains elusive. To date ASD remains a behaviorally defined spectrum with no known biological markers suitable to support diagnosis or subgroup categorization 
The genetic architecture of ASD is highly heterogeneous 
, and only about 10–20% of individuals with ASD have an identified genetic etiology 
. The transmission pattern is complex in most families and is not compatible with simple Mendelian inheritance 
, suggesting that protein-coding genes are responsible for only part of the ASD etiology. Growing evidence supports the involvement of epigenetic regulatory mechanisms in the pathogenesis of ASD 
, with a contribution of DNA methylation, genomic imprinting, chromatin modifications and non coding RNA 
As for other complex diseases, the full etiology most probably relies on a complex interplay between genes, the genome organization and the environment. A well-understood example of such interplay comes from studies of the Rett syndrome. It is worth recalling that LINE-1 elements, a retrotransposon family accounting for 17% of the human genome, play fundamental roles in neurogenesis by altering the expression of neuronal genes, which, in turn, influence neuronal cell fate 
. Rett syndrome patients have recently been found to display an increased susceptibility to LINE-1 retrotransposition, dependent on the abnormal methylation status of the overall genome due to mutation of the DNA methyl-binding protein, MeCP2 
, which is regarded as the causative alteration of the Rett disease.
Importantly, growing evidence links germline hypomethylation and genomic instability. Structural mutations in individuals with schizophrenia, bipolar disorder, developmental retardation and autism are significantly more concentrated within hypomethylated regions, suggesting a connection between the methylation status of genomic DNA and human disease 
Here we have tested the hypothesis that HERVs - a component of human mobile retrotransposon families 
- play roles in the onset or progression of the disease. Based on their ability to be mobilized under specific stimuli, HERVs might actually be considered as emerging pathogens and can be seen as spanning the bridge between genetic predisposition and environmental factors. Their responsiveness to environmental conditions is an intrinsic property that places them at the frontline of the gene-environment interaction. HERVs are also formidable evolutionary forces that have shaped the architecture of the genomes of higher organisms, with some conserving the ability to induce new integrants within their host's genome 
. Recent studies have disclosed unsuspected effects of retroelements in genome-wide modulation of the transcriptome 
in fundamental processes such as embryogenesis 
and in a variety of pathologies 
, including complex brain disorders, eg, schizophrenia 
We have studied four HERV families in PBMCs in an attempt to identify molecular signatures of ASD that may be easily detected in peripheral samples. An increasing number of molecular studies indeed indicate the importance of differential expression of ASD-associated genes in peripheral tissues, as well as in postmortem brains, from ASD subjects 
. In particular, monozygotic twins, discordant for diagnosis of autism, were reported to show differential gene expression in lymphoblastoid cell lines 
The data presented here indicate that the percentage of HERV-H and HERV-W positive samples, evaluated in fresh and in culture stimulated PBMCs by qualitative RT-PCR, is higher in cases compared to controls, while HERV-K shows only minimal differences and HERV-E was virtually absent. When considering all positive samples in either condition (fresh or stimulated), the differences were significant for HERV-H, but not for the other HERV families analyzed. Quantitative determination of HERVs in PBMCs showed that HERV-H expression, indeed, was statistically significantly higher in ASD, and, conversely, HERV-W was higher in healthy controls.
Furthermore, HERV-H expression negatively correlated with age only in ASD patients. Based on the evidence that HERV-H is expressed in high levels selectively in ASDs, the correlation with age might be viewed as a disease-dependent feature not present in HCs.
Interestingly, high expression of HERV-H was also associated with “severe” score in Communication and Motor Psychoeducational Profile-3.
To the best of our knowledge, this is the first evidence linking retrotransposon activity and ASD. Notwithstanding the relatively small size of the samples tested in this work, the statistical significance of the present findings supports the hypothesis that HERV-H overexpression might be regarded as a potential early marker detectable in ASD patients. The analysis of individual patients and controls also suggests an increased intrinsic predisposition of the PBMCs from ASD patients to express HERV-H in response to mitogenic stimulation in culture. HERV-H overexpression might be of help to differentiate young ASD children from age-matched controls. Because detecting autism at the earliest possible age is of outmost importance to optimize outcomes for children with the disorder, identifying the presence of HERV-H in PBMCs of young children could be useful for this purpose. Furthermore, because autism remains a behaviorally defined disorder, the identification of a biological marker could also be of support for a confident diagnosis. The identification of a reliable biomarker for ASD could supplement and validate existing clinical methods; in particular, a biomarker that is expressed at, or even before, the onset of symptoms might obviate the need to wait for behavioral criteria to be met before beginning treatment.
Larger number of ASD patients and follow-up data will be needed to further substantiate the present results. Yet, as the first comparative analysis of ASD patients and controls focusing on HERV families, we believe that the present findings are well worth pursuing in future research. More generally, the quantitative differences in HERV-H and HERV-W env expression between ASD patients and controls suggest a contribution of a “non-coding” fraction of the genome to ASD.