**4. Genetic anticipation**

Genetic anticipation studies are fundamental in the elucidation of inheritance mechanisms for any genetically influenced condition, because, in addition to the clinical importance and guidance in genetic counseling, these investigations can assist in the elucidation of the recur‐ rence risks in future generations (Constantino et al., 2010).

much and is referred to in the literature either as an association or as comorbidity. Probably the truth is, that in most cases, the different manifestations result from the same causal fac‐

Genetic Etiology of Autism http://dx.doi.org/10.5772/53106 219

Monozygotic and dizygotic twin studies indicate a variety of neuropsychiatric diagnoses as‐ sociated with ASD, including attention deficit and hyperactivity disorder (ADHD) and anxi‐ ety disorder (Lichtenstein et al., 2010). High frequencies of these diseases have been reported in children with autism, as has bipolar disorder in adolescents and young adults (Munesue et al., 2008; Simonoff et al., 2008). The wide range of clinical behavioral symptoms among carriers may be justified and be a good argument to consider the diagnosis of ASD alone, with all the possible manifestations expected in the spectrum, as no individual is ex‐ actly like another. In this way, families would be less anxious and confused on receiving

There are a number of diseases associated with autism, whose genetic etiology is well estab‐ lished, i.e. autistic behavior is one of the possible manifestations. The most common is Frag‐ ile X syndrome (FRAXA). This is the most frequent form of inherited mental retardation and is considered a monogenic cause of ASD. Symptoms include neurodevelopmental delay, anxiety, hyperactivity, and autistic-like behavior, which are accompanied by macroorchid‐ ism and distinct facial morphology. It is caused by the expansion of the CGG trinucleotide repeat in the 5' untranslated region of the fragile X mental retardation 1 (*FMR1*) gene result‐ ing in loss of the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein abundant in the brain and gonads of affected men. FMRP has multiple functions in the RNA metabolism, including mRNA decay, dendritic targeting of mRNAs and protein synthesis. In neurons lacking FMRP, a wide array of mRNAs encoding proteins involved in synaptic structure and function are altered. As a result of this complex dysregulation, in the absence of FMRP, spine morphology and functioning is impaired (De Rubeis et al., 2012). Frequen‐ cies of between 2% and 3% of FRAXA have been observed in studies on boys with ASD, while in boys with FRAXA, the frequencies of ASD range from 20% to 40% (Kaufmann et al., 2004; Shibayama et al., 2004). Tuberous Sclerosis, another monogenic disease that results from mutations in the *TSC1* and *TSC2* genes, is observed in about 1% of individuals with ASD and is regarded as the second most common genetic cause of the autistic phenotype

The list of medical conditions associated with the autistic phenotype, including genetic syn‐ dromes, is growing. Examples of genetic conditions associated with autism and the gene re‐ gions involved are: Angelman Syndrome (*UBE3A*), Rett syndrome (*MECP2*), neurofibromatosis (*NF1*), Timothy syndrome (*CACNA1C*), Smith-Lemli-Opitz syndrome (*DHCR7*), CHARGE (*CHD7*), Cohen syndrome (*VPS13B*), Noonan syndrome (*PTPN11*), 2q37 deletion syndrome, Cornelia de Lange syndrome (*NIPBL, SMC1A* and *SMC3*), DiGeorge/ Velocardiofacial syndrome (22q11), Smith-Magenis (*RAI1*), Williams-Beuren syndrome (7q11.23) and Phelan-McDermid syndrome (22q13.3) (Berg et al.,2007; Phelan, 2008; Dela‐

Many inborn errors of metabolism also seem to contribute to at least 5% of ASD cases as the de‐ ficiency of certain enzymes in metabolic diseases can result in the accumulation of substances

haye et al., 2009; Van der Aa et al., 2009; Laje et al., 2010; Betancour, 2011).

tor, which suggests the term "association" is more appropriate than "comorbidity".

three or four diagnoses for the same child.

(Smalley, 1998).

Following a promising approach in the investigation of complex disease etiologies, studies on endophenotypes ("intermediate phenotypes") may be used to direct the search for the etiology of ASD (Weinberger et al., 2001). Manifestations related to autistic behavior are of‐ ten observed in varying degrees of severity in unaffected individuals of previous genera‐ tions in the same family, thereby characterizing the phenomenon of genetic anticipation in ASD (Losh et al., 2008).

A Swedish study reported that the existence of individuals with schizophrenia and bipolar dis‐ order in the family is a risk factor for the occurrence of autism. The authors found an association between schizophrenic parents or siblings with increased risk of ASD. Bipolar disorder also proved to be a risk factor, but not as strong as schizophrenia (Sullivan et al., 2012).

Studies of autistic families have also shown a significant increase in the recurrence of ASD in first-degree relatives of carriers. For example, siblings of individuals with ASD have a 22- to 25 fold higher risk of having the disorder (Lauritsen et al., 2005; Abrahams & Geschwind, 2008). There are significantly higher risks of ASD in offspring of parents with ASD and those with fam‐ ilial history of psychiatric problems. Depression and personality disorders have been reported to be more common in mothers of children diagnosed with ASD than in mothers of children with normal development (Daniels et al., 2008; Constantino et al., 2010). Even some non-affect‐ ed individuals of different generations in the same family may show subtle impairment in cog‐ nitive development, language changes or in social interaction; this is termed the *broad autism phenotype*. This phenotypic diversity of autistic behavior and psychiatric manifestations in fam‐ ilies of the patients indicate that the genetic factors that influence ASD may be composed of dis‐ tinct elements that manifest differently between affected and non-affected family members *(*Pickles et al., 2000; Szatmari et al., 2000; Goldberg et al., 2005).

In the molecular field, studies on genealogies with multiple affected family members and studies on twins suggest that allelic variations are associated with increased susceptibility to ASD and that there are etiological factors common to both ASD and milder autistic pheno‐ types (Lundstrom et al., 2010; Arking et al., 2008; Wang et al., 2009). Hence, epidemiological studies have been developed with families in an attempt to clarify the relative proportions of cases of autism and *broad autism phenotypes* in the population that might explain these complex mechanisms of genetic transmission.
