**1. Introduction**

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214 Recent Advances in Autism Spectrum Disorders - Volume I

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Autism Spectrum Disorders (ASD) are severe neurodevelopment disorders characterized by impairment in social interaction and communication, and repetitive and stereotyped behav‐ iors. Motor deficits, aggressive behavior, abnormal sleep patterns, gastrointestinal problems, epilepsy and intellectual disability are also observed. Manifestations are observed before three years of age with early stimulation being recommended (Baird et al., 2006; Faras et al., 2010; Bronsard et al., 2011; Miles, 2011; Angelidou et al., 2012). Due to the great phenotypic variability of carriers and the subjectivity of the differential diagnostic criteria of "Pervasive Developmental Disorders" (American Psychiatric Association, 2000), ASD is today consid‐ ered the most appropriate denomination. The general term, autism, is often used as a syno‐ nym for ASD.

ASD were described more than seven decades ago (Sanders, 2009) and many neurobiologi‐ cal changes have been illustrated in carriers, yet the diagnosis is still based on behavioral aspects using diagnostic scales. However, even though there is a detailed "checklist" made up of several scales, most are not translated and validated in different countries, which hin‐ ders standardized and efficacious diagnosis (Marteleto et al., 2008; Rapin & Goldman, 2008; Sato et al., 2009; Biederman et al., 2010).

The prevalence of ASD varies by region, but it is believed to be around 1:150 individuals. However, higher prevalences of up to 1:88 children have been described (Currenti, 2010; An‐ gelidou et al., 2012). The tentatives to explain such high prevalence rates involve changes in diagnostic criteria, greater knowledge of the general population and the exposure of the ge‐ netic material of fetus to internal and external toxic agents (King & Bearman, 2009; Lintas & Persico, 2009; Avchen et al., 2011).

© 2013 Fett-Conte et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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).

Premature birth is associated with the formation of reactive oxygen species (Davis & Auten, 2010). Stress typically results in the release of corticotropin-releasing hormone (CRH) with elevated levels of this hormone in plasma being associated with premature births (Warren et al., 1992; Chrousos, 1995). CRH may stimulate the release of a cytokine, interleukin-6 (IL-6), by mast cells, which are part of the immune system. IL-6, by injuring the blood-brain barrier due to stress related to CRH and mast cells, increases its permeability (Esposito et al., 2001). With the increased permeability, neurotoxic molecules can reach the brain and cause an in‐ flammatory process that contributes to the pathogenesis of ASD (Theoharides, 2008; Valent

Genetic Etiology of Autism http://dx.doi.org/10.5772/53106 217

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‐

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‐

Genetic anticipation studies are fundamental in the elucidation of inheritance mechanisms for any genetically influenced condition, because, in addition to the clinical importance and

et al., 2012). This process has suggested a new possibility for the etiology of ASD.

**3. Overlapping genetic etiologies**

ferent genes, some of them more significants.

**4. Genetic anticipation**

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