**11. Epigenetic in autism**

Particularly in light of recent findings on mutations in the genes that encode synaptic mole‐ cules associated with the communication between neurons, genetic factors are considered to be the most important contributors to the pathogenesis of autism. Epigenetic mechanisms, such as DNA methylation and modifications to histone proteins, regulate DNA structure and gene expression, but without changing DNA sequence. Epigenetic abnormalities are as‐ sociated with several neurodevelopmental diseases. Many features of autism are consistent with an epigenetic dysregulation, such as discordance of monozygotic twins, parental origin and the gender-dependent effects of some alterations. Since epigenetic modifications are known to be affected by environmental factors such as nutrition, drugs and mental stress, ASD are not only caused by congenital genetic defects, but may also be caused by environ‐ mental factors via an epigenetic mechanism.

of twins seems to increase with advancing paternal age. It was suggested that this result may be related to factors such as *de novo* mutations in germ lines, exposure to toxic agents during life and epigenetic alterations (Lundstrom et al., 2010; Hultman et al., 2011). Advanc‐ ing maternal age was also reported as a risk factor for autism (Parner et al., 2012). However,

Genetic Etiology of Autism http://dx.doi.org/10.5772/53106 229

The development of the next generation sequencing has radically modified the scientific landscape, making it possible to sequence all exomes of any person. The power of this ap‐ proach has been demonstrated by a number of studies which have identified pathogenic mutations in diseases that have been difficult to make by traditional genetic mapping.

Exons are coding regions of the genome responsible for the development of functional ele‐ ments of the body, such as proteins. It has become clear that exome sequencing has great potential with respect to sporadic diseases and the identification of *de novo* mutations. Whole-exome sequencing (WES) of patient-parent trios has proven to be a successful screen‐ ing tool for the identification of candidate genes causing complex phenotypes such as in ASD, learning disability, and schizophrenia (Choi et al., 2009; Bilguvar et al., 2010; Vissers et

O´Roak et al. (2012) studied all coding regions of the genome for parent-child trios exhibit‐ ing sporadic ASD, under the hypothesis that *de novo* mutations underlie a substantial frac‐ tion of the risk for developing ASD in families with no previous history of ASD or related phenotypes (simplex families). They observed that these mutations are overwhelmingly pa‐ ternal in origin and positively correlated with paternal age, consistent with the modest in‐ creased risk for children of older fathers. It was also possible to estimate 384-821 loci which

The analysis the homozygosity is used to define loci that may be involved in recessive ho‐ mozygous mutations that cause diseases characterized by genetic heterogeneity (Lencz et al., 2007; Nalls et al., 2009). Starting from this concept, Chahrour et al. (2012) used homo‐ zygosity analysis to identify probands from non-consanguineous families that showed evi‐ dence of distant shared ancestry, suggesting potentially recessive mutations. The WES of 16 probands revealed validated homozygous, potentially pathogenic, recessive mutations that segregated perfectly the disease in 4 of 16 families. The candidate genes that were found, *UBE3B, CLTCL1, NCKAP5L,* and *ZNF18,* encode proteins involved in neuronal activities.

Neale et al. (2012) studied 175 trios to assess *de novo* mutations. They found strong evidence that *CHD8* and *KATNAL2* are genuine autism risk factors. However, the small increase in the rate of *de novo* events, when taken together with the protein interaction results, were con‐ sistent with an important but limited role for these mutations in ASD, similar to that docu‐ mented for *de novo* CNVs. According the authors, the data indicated that most of the observed *de novo* events are unconnected to ASD; those that do confer risk are distributed

al., 2010; Gilman et al., 2011; Pagnamenta et al., 2012; Sanders et al., 2012).

the explanations for these phenomena are still only speculative.

**12. Exome sequencing**

could be considered pathogenic.

An example of this phenomenon in ASD is the mechanism of action of the *SHANK3* gene. *SHANK3* is strongly suspected of being involved in the etiology of ASD since several muta‐ tions have been identified in a particular phenotypic group of patients with ASD. SHANK3 (also known as *ProSAP2*) regulates the structural organization of dendritic spines and is a binding partner of neuroligins; genes encoding neuroligins are mutated in autism and As‐ perger's syndrome (Durand et al., 2007). It codes a synaptic scaffolding protein enriched in the postsynaptic density of excitatory synapses and plays important roles in the formation, maturation and maintenance of synapses. Haploinsufficiency of the *SHANK3* gene causes a developmental disorder, 22q13.3 deletion syndrome (known as Phelan-McDermid syn‐ drome), which is characterized by severe language and speech delay, hypotonia, global de‐ velopmental delay and autistic behavior. Five CpG-islands have been identified in the gene, and tissue-specific expression is epigenetically regulated by DNA methylation. Cumulative evidence in animal models has shown that several *SHANK3* variants are expressed in the developing rodent brain with their expression being regulated by the DNA methylation of intragenic promoters (Uchino et al., 2006).

Additionally, oxidative stress in brain cells occurs due to environmental and genetic causes and leads to decreased activity of the methionine synthase enzyme, which participates in DNA methylation processes. So, when the activity of this enzyme is impaired, affected indi‐ viduals can exhibit attention deficits and other signs, including autistic symptoms, due to defects in the expression of genes that are controlled by this epigenetic mechanism (Na‐ viaux, 2008; Dhillon et al., 2011).Therefore, environmental factors may activate intracellular pathways during embryonic development thereby causing epigenetic changes in neural function that would explain the relationship between environmental signals and genome in the regulation of individual differences in behavior (Zhang & Meaney, 2010).

Studies carried out in Sweden involving 208 autistic children with Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) and Asperger's syndrome (AS) obtained in‐ teresting results. The authors observed that advancing paternal age is associated with an in‐ creasing risk for ASD in offspring, that autistic-like traits in the normal population are affected by both young and advancing paternal age and that autistic similarity within pairs of twins seems to increase with advancing paternal age. It was suggested that this result may be related to factors such as *de novo* mutations in germ lines, exposure to toxic agents during life and epigenetic alterations (Lundstrom et al., 2010; Hultman et al., 2011). Advanc‐ ing maternal age was also reported as a risk factor for autism (Parner et al., 2012). However, the explanations for these phenomena are still only speculative.
