**3. Overlapping genetic etiologies**

Although many environmental factors are related to the pathogenesis of autism, such as the ru‐ bella virus whose disruptive effects in the brain may result in autistic behavior, the participa‐ tion of genetic components is certain. The estimated concordance rate for identical twins ranges from 60 to 90%, while among dizygotic twins and non-twin siblings the rate is from 5 to 31% (Bailey, et al., 1995; Rosenberg et al., 2009; Hallmayer et al., 2011). Based on studies of twins, her‐ itability was estimated to be between 60 and 80% (Geschwind, 2011; Hallmayer et al., 2011).

In up to 10% of ASD cases it is possible to identify etiological, genetic or environmental fac‐ tors (syndromic autism). Thus, in about 90% of the cases there is no known cause (non-syn‐ dromic autism). A multifactorial etiology can be assigned to these idiopathic cases after the exclusion of environmental and genetic causes, and using specific evaluations (Veenstra-Vanderweele et al., 2004). Scientific discoveries until now have shown that there are multi‐ ple genetic factors (polygenes) involved in the predisposition to ASD which, associated with an external trigger (environmental factor), would result in the behavioral framework for au‐ tism. However, these factors alone also result in changes in the brain that lead to autistic be‐ havior. Thus, the same factors may be present in two children with one having autism and the other not. There is no doubt that science has elucidated many biological mysteries about

Prenatal or perinatal infections by viral agents such as rubella and cytomegalovirus, as well as exposure to toxic agents, such as thalidomide, valproic acid and alcohol, are some of the best-known environmental causes of ASD (Chess et al., 1978; Christianson et al., 1994).

'Allergenic' environmental factors and autoimmune problems during pregnancy may also be involved in the etiology of autism. The presence of circulating maternal antibodies against fetal brain proteins suggests the possibility of their transposition in the blood-brainbarrier. Studies have demonstrated the presence of pro-inflammatory cytokines in the fetal brain, such as TNF (tumor necrosis factor) which is preformed in maternal mast cells (Vojda‐

Even premature birth has been implicated as a cause of ASD. Babies from gestations of less than 28 weeks have a high risk of neurological problems. A study in Atlanta, USA, showed that children born in the 33rd gestational week have a greater risk for autistic characteristics

There is a link between oxidative stress and immune response (Viora et al., 2001). There are suggestions that environmental factors trigger oxidative stress in individuals genetically susceptible to autism, which would lead to losses in methylation and secondary neurologic deficits (Dardeno et al., 2010). Increased levels of oxidative stress markers have already been described in the cord blood of mothers who had premature births compared to those of

autism, yet for every issue clarified, another, even more complex, appears.

**2. Environmental etiology**

216 Recent Advances in Autism Spectrum Disorders - Volume I

ni, 2008; Angelidou et al., 2012).

(Limperopoulos et al., 2008).

mothers who had full term births (Joshi et al., 2008).

Many genomic regions, with genes implicated as candidates, have been associated to the eti‐ ology of autistic behavior, although the results of some studies have not been replicated. Even so, it is estimated that all proposed regions together would be involved in the etiology of less than 1% of cases. In addition, scientific evidence shows that changes in regions re‐ ported in ASD have also been described in other neuropsychiatric diseases, which suggests that there is an etiological connection with phenotypes attributed to other neurodevelop‐ ment abnormalities (Griswold et al., 2012). For example, some rare mutations associated with increased risk for ASD and schizophrenia have already been reported in 15q13.3, 16p11.2 and 22q11.21 and in the *NRXN1* gene (Weiss et al., 2008; Levinson et al., 2011; Sand‐ ers et al., 2011).

Moreover, many genes involved in nonsyndromic intellectual disabilities (ID) and in epilep‐ sy have also been implicated in the etiology of nonsyndromic ASD. These genes probably belong to a continuum of neurodevelopment disorders that manifest in different manners depending on associated genetic and environmental factors. The identification of changes is crucial for patients and for counseling of families, as well as for the identification or exclu‐ sion of the presence of specific genetic diseases in patients with ASD (Betancour, 2011).

Many patients with chromosomal or monogenic diseases have autistic behavior as one phe‐ notypic manifestation of the disease. A scientific enigma to be elucidated refers to the possi‐ ble causes of the varying severity of symptoms or the presence/absence of manifestations in carriers in the same family. They are not free from rare or common mutations associated with behavioral phenotype in isolation. Thus, in autism, studies on gene interactions are fundamental and what is called overlapped etiology can be an additive effect between dif‐ ferent genes, some of them more significants.
