**Possible Endophenotypes in the Search for Genetic Risk Factors in Autism Spectrum Disorders**

Adriana Díaz-Anzaldúa, Rigoberto Rosendo Gutiérrez, Alejandro Díaz-Anzaldúa and José Octavio Hernández Lagunas

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/60039

**1. Introduction**

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Autism Spectrum Disorders (ASD) are complex neuropsychiatric conditions characterized by stereotypic behaviors and conspicuous deficits in social communication. It has been demon‐ strated that there is genetic and clinical heterogeneity in these disorders. Inherited and/or de novo genetic factors, as well as environmental and epigenetic components have been shown to be involved in the etiology of ASD. Among the common comorbity are epilepsy and seizures, gastrointestinal problems, depression, anxiety, hyperactivity (including ADHD), Tourette syndrome, phobias, dysmorphic features, and psychotic disorders [1-5].

The etiological role of genetic factors in ASD has been evaluated by twin studies; the concord‐ ance found in monozygotic pairs is higher than the concordance in dizygotic twins (36 to 91% versus less than 32% [6]). Concordance estimates for both types of twins have been reported to be higher if the analyzed phenotype is ASD as opposed to narrow phenotypes [7].

Heritability of ASD has been estimated to be as high as 90%, although a more recent report suggests that it may be about 19-35% in males and 50-63% in females [8]. While some cases are considered sporadic and have been associated with mutations, others are familial and may tend to be associated with relatively common genetic variation [9].

Genes related with synaptic development, signaling, chromatin remodeling, transcrip‐ tion, methylation, neurotropism, and neuroptrotection are probably involved in ASD. These genes may include some that code for neurexins, neuroligins, shanks, reelin,

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integrins, cadherins, contactins, and neutrophins. Linkage and association with ASD have been described in different regions of autosomes that harbor candidate genes (Table 1, figure 1) [10-17]. In addition, as table 2 shows, the X chromosome has also been implicated in ASD (Table 2, figure 1) [18-20].


**Table 1.** Genes frequently linked or associated with ASD in autosomes


**Table 2.** Genes frequently linked or associated with ASD in the X chromosome

Besides Fragile-X syndrome, other single-gene disorders are sometimes associated with ASD. Rett syndrome (MECP2 gene) is an autism-related condition. Tuberous sclerosis (TSC1 and TSC2 genes) may account for 1 out of 10 cases of ASD. Furthermore, 50% of individuals with Smith-Lemli-Opitz syndrome (DHCR7 gene) and 10% of those with phenylketonuria (PAH gene) may have ASD; in addition, adenylosuccinase deficiency, characterized by psychomotor delay, is often comorbid with epilepsy and autistic features [17, 21-23]. As described earlier, epilepsy is a common comorbidity in patients with ASD, and it has also been associated with region 15q11.1–q13.3 (ubiquitin-protein ligase E3A gene,UBE3A), TSC1 and TSC2 genes, MeCP2, CNTNAP2, SYN1, Fragile X syndrome, 1q21.1, 7q11.23, 16p11.2, 18q12.1, 22q11.2, and 22q13.3 (SHANK 3 gene).

**Figure 1.** Chromosomal regions frequently linked or associated with ASD

integrins, cadherins, contactins, and neutrophins. Linkage and association with ASD have been described in different regions of autosomes that harbor candidate genes (Table 1, figure 1) [10-17]. In addition, as table 2 shows, the X chromosome has also

been implicated in ASD (Table 2, figure 1) [18-20].

352 Autism Spectrum Disorder - Recent Advances

**Gene symbol Product**

RELN Reelin

EN2 Engrailed 2

**Table 1.** Genes frequently linked or associated with ASD in autosomes

**Gene symbol Product** NLGN4 Neuroligin 4 NLGN3 Neuroligin 3

OXTR Oxytocin receptor

MET MET protooncogene FOXP2 Forkhead box P2

SLC25A12 Solute carrier family 25 member 12

CNTNAP2 Contactin-associated protein-like 2 BDNF Brain derived neurotrophic factor SLC6A4 Solute carrier family 25 member 4

FMR1 Fragile X mental retardation protein MECP2 Methyl CpG binding protein 2

Besides Fragile-X syndrome, other single-gene disorders are sometimes associated with ASD. Rett syndrome (MECP2 gene) is an autism-related condition. Tuberous sclerosis (TSC1 and TSC2 genes) may account for 1 out of 10 cases of ASD. Furthermore, 50% of individuals with Smith-Lemli-Opitz syndrome (DHCR7 gene) and 10% of those with phenylketonuria (PAH gene) may have ASD; in addition, adenylosuccinase deficiency, characterized by psychomotor delay, is often comorbid with epilepsy and autistic features [17, 21-23]. As described earlier, epilepsy is a common comorbidity in patients with ASD, and it has also been associated with region 15q11.1–q13.3 (ubiquitin-protein ligase E3A gene,UBE3A), TSC1 and TSC2 genes, MeCP2, CNTNAP2, SYN1, Fragile X syndrome, 1q21.1, 7q11.23, 16p11.2, 18q12.1, 22q11.2, and

**Table 2.** Genes frequently linked or associated with ASD in the X chromosome

22q13.3 (SHANK 3 gene).

GRIK2 Glutamate receptor ionotropic kainate 2

CADPS2 Calcium dependent activator protein for secretion 2

Chromosomal anomalies such as deletions, duplications, inversions, balanced and unbalanced translocations, and aneuploidies have been described in some children with ASD [24]. For example, deletions on region 22q11-q13, which is associated with velo-cardiofacial syndrome, have been identified in about 1% of children with ASD; besides SHANK3, this region harbors two genes that have been associated with ASD, that code for proline dehydrogenase (PRODH) and catechol-o-methyltransferase (COMT) [25]. According to a meta-analysis, copy-number variants and truncating mutations in SHANK genes may be present in almost 1% of patients with ASD (SHANK1 in 0.04%, SHANK2 in 0.17%, and SHANK3 mutations in 0.69%) [26].

De novo chromosomal deletions or duplications have been identified in about 7 to 10% of patients. The 15q11-q13 chromosomal region, that includes a locus for the Prader-Willi/ Angelman syndrome, is affected in 1% to 4% of children with ASD. Moreover, the phenotype of a supernumerary chromosome 15 includes autistic features such as develop‐ mental delay, mental retardation, neurological signs and behavioral disturbances. A 3.7 megabase deletion (Smith Magenis Syndrome) or duplication (Potocki-Lupski syndrome) on the 17p11.2 region is also associated with ASD [27]. Likewise, deletions on the short arm of chromosome X (NLGN4 gene) and an inversion on 7q (at common fragile sites) have been implicated in ASD [28].

Specific environmental and epigenetic factors have also been associated with ASD. For example, advanced paternal age at conception of the child, especially in non-familial cases, could impact the vulnerability to these disorders with de novo mutations [29, 30]. In addition, errors in DNA methylation during spermatogenesis may affect the next generations. Recently, it was found in a mouse model that older fathers had a significant decrease in methylation in genomic regions associated with the control of transcription. Indeed, the expression of developmental genes implicated in ASD was dysregulated in the offspring of old fathers [31].

Other non genetic factors that have been associated with ASD include maternal use of certain substances during pregnancy, such as valproic acid, ethanol, thalidomide or misoprostol; low birth weight (or intrauterine growth retardation), congenital rubella and other infections, as well as cerebral palsy [32-38]. Environmental insults may increase the risk to ASD in genetically sensitive individuals, possibly by promoting cellular oxidative stress, and adaptive responses that could include reduced methylation activity, which is the most common epigenetic mechanism. Interestingly, the 15q11-q13 chromosomal region is subject to methylationdependent genomic imprinting [39]; in addition, GABAergic genes in the same region, GABRB3, GABRA5, and GABRG3, were found to be epigenetically dysregulated in a subset of ASD patients [40].
