**1. Introduction**

Autism Spectrum Disorder (ASD), also currently known as autism, refers to a group of complex behavioral disorders of varying severity, characterized by manifestations noted in early childhood, usually before the age of three and defined as impaired social communication and presence of restricted interests and repetitive behaviors, compromising the entire life of the individual (DSM-5). The etiology is very complex and heterogeneous, with numerous causes described, and includes genetic, epigenetic, or environmental factors in isolation or associated. It aggregates in families with the heritability being estimated at 0.50, but the individual risk and to what extent this is caused by genetic factors or environmental factors remains unre‐ solved. These factors probably interact at least in the majority of cases, and thus the assessment of individuals and genetic counseling is further complicated [124].

Valuable information is been gained through the identification of candidate genes, though case-control and association studies and more recently by comparative genomic hybridization and whole exome and genome sequencing. In the epigenetic area, mechanisms such as genomic imprinting, epimutations and methylation have been identified [133]. Copy number variations (CNVs) have gained prominence on the stage of the discovery of the causes of autism. The *de novo* CNVs have been reported in 7% of simplex families and ~2% in multiplex families. Moreover, hypomorphic alterations in some genes suggest oligogenic inheritance. Recently, discoveries employing large-scale whole exome sequencing (WES) showed that one gene alone is not able to confer significant risk for autism. Instead, the most probable hypoth‐ esis is the contribution of several risk variants that are scattered in hundreds of genes. There

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are approximately 4,000 genes involved in molecular pathways, gene regulation and functional domains that may contribute to neurodevelopmental disorders. It is noteworthy that the same genes can cause different disorders leading to an etiologic overlap [35].

One other issue that has emerged recently is that a significant number of synaptic proteins directly or indirectly affect the structure and function of neurons, dendrites and synapses. Subtle changes in the dendritic and synaptic structures can lead to huge changes in information processing. Dendritic branches and spines are essential for the formation and plasticity of neuronal circuits but are interrupted in many neurologic disorders, such as autism. In many cases the same mutations are observed in unaffected relatives. This suggests the existence of a compensatory mechanism or other genetic or non-genetic causes [140].

New findings on the genetic etiology of autism have pointed to the participation of regulatory regions of transcription factors, the microRNAs (miRNAs), a class of noncoding RNAs of ~22 nucleotides that suppress translation by pairing with miRNA recognition elements present in the 3'untranslated region (3'UTR) of target mRNAs. Candidate genes and sites of miRNA targets have been identified from these. It is known that the expression of many genes involved in autism is regulated by miRNAs. Single nucleotide polymorphisms (SNPs) have been described as modulators or creators of new recognition elements of miRNAs. Therefore, there is a hypothesis that SNPs disrupting the interaction between miRNA and genes can lead to the aberrant expressions of genes implicated in autism, resulting in susceptibility to disease or pathogenesis in at least one subpopulation of affected individuals [149].

Although the involvement of genetic abnormalities in autism is well accepted, recent studies have indicated that there is a similar contribution of environmental factors. However, studies related to the environment, especially those regarding toxic products, have not been system‐ atically reviewed yet, as many studies have limitations, including a lack of reproducibility, small sample size, retrospective design, bias between cases and controls and non-use of an appropriate autism diagnostic tool. Thus, in general, there is a potential involvement of some toxic products in complex genetic-environmental interactions which act synergistically or in parallel on the brain in a way that increases the likelihood of developing autism.

Moreover, although some studies suggest that autistic characteristics are due to central nervous system (CNS) dysfunction, there is evidence of autism-related abnormalities that are not related to the CNS, at least in some individuals. Hence, the metabolic system, immune system dysregulation and oxidative stress have also been implicated in the etiology [107].

Furthermore, other new lines of research also point to the importance of the so-called "braingut axis" revealing the central role of the intestinal microbiota in postnatal development and maturation of the immune and endocrine systems that, in turn, control CNS signaling, brain function and behavior [151]. But studies on this line must be carefully analyzed.

The low recurrence related to any one cause is one of the most intriguing aspects of the etiology, as is the difference in the proportion of affected between the genders, because men are four times more affected by ASD than women [27]. Additionally, there is an association between increased paternal age and risk for ASD. This finding may indicate that *de novo* mutations, which are more common in older men, may play a smaller role in the incidence of autism than the familial genetic load [73].

are approximately 4,000 genes involved in molecular pathways, gene regulation and functional domains that may contribute to neurodevelopmental disorders. It is noteworthy that the same

One other issue that has emerged recently is that a significant number of synaptic proteins directly or indirectly affect the structure and function of neurons, dendrites and synapses. Subtle changes in the dendritic and synaptic structures can lead to huge changes in information processing. Dendritic branches and spines are essential for the formation and plasticity of neuronal circuits but are interrupted in many neurologic disorders, such as autism. In many cases the same mutations are observed in unaffected relatives. This suggests the existence of

New findings on the genetic etiology of autism have pointed to the participation of regulatory regions of transcription factors, the microRNAs (miRNAs), a class of noncoding RNAs of ~22 nucleotides that suppress translation by pairing with miRNA recognition elements present in the 3'untranslated region (3'UTR) of target mRNAs. Candidate genes and sites of miRNA targets have been identified from these. It is known that the expression of many genes involved in autism is regulated by miRNAs. Single nucleotide polymorphisms (SNPs) have been described as modulators or creators of new recognition elements of miRNAs. Therefore, there is a hypothesis that SNPs disrupting the interaction between miRNA and genes can lead to the aberrant expressions of genes implicated in autism, resulting in susceptibility to disease or

Although the involvement of genetic abnormalities in autism is well accepted, recent studies have indicated that there is a similar contribution of environmental factors. However, studies related to the environment, especially those regarding toxic products, have not been system‐ atically reviewed yet, as many studies have limitations, including a lack of reproducibility, small sample size, retrospective design, bias between cases and controls and non-use of an appropriate autism diagnostic tool. Thus, in general, there is a potential involvement of some toxic products in complex genetic-environmental interactions which act synergistically or in

Moreover, although some studies suggest that autistic characteristics are due to central nervous system (CNS) dysfunction, there is evidence of autism-related abnormalities that are not related to the CNS, at least in some individuals. Hence, the metabolic system, immune system dysregulation and oxidative stress have also been implicated in the etiology [107].

Furthermore, other new lines of research also point to the importance of the so-called "braingut axis" revealing the central role of the intestinal microbiota in postnatal development and maturation of the immune and endocrine systems that, in turn, control CNS signaling, brain

The low recurrence related to any one cause is one of the most intriguing aspects of the etiology, as is the difference in the proportion of affected between the genders, because men are four times more affected by ASD than women [27]. Additionally, there is an association between increased paternal age and risk for ASD. This finding may indicate that *de novo* mutations,

genes can cause different disorders leading to an etiologic overlap [35].

316 Autism Spectrum Disorder - Recent Advances

a compensatory mechanism or other genetic or non-genetic causes [140].

pathogenesis in at least one subpopulation of affected individuals [149].

parallel on the brain in a way that increases the likelihood of developing autism.

function and behavior [151]. But studies on this line must be carefully analyzed.

Investigating and understanding the etiology of autism is extremely important for families because it allows a determination of the recurrence risk, the possibility of detecting other associated medical problems, an assessment of the molecular nature and cellular pathophysi‐ ology, and potential therapeutic approaches. In this context, the aim of this chapter is to provide the reader with an overview of these possible causes and others that may contribute to autistic behavior.
