**4. Cellular adhesion molecules (CAMs)**

the high prevalence of autistic behaviors in children with 22q11.2 deletions should not be viewed only as ASD but as prodromal symptoms preceding the onset of schizophrenia [9, 132, 153]. Individuals with hemizygosity of the 22q11.2 deletion represent genetically identifiable cases of ASD. However, the 22q11.2 gene(s) responsible for ASD have not been identified yet. *Tbx1* is one of the candidate genes, possibly through its role in diverse cell types, including

Several large chromosomal microarray studies have reported the prevalence of CNV variants in people with particular features (e.g., autism, schizophrenia, and epilepsy) but few studies have investigated the prevalence in the general population. In a screening of 6,813 consecutive cord blood samples from a predominantly French–Canadian population to assess genomic CNVs, 23 children were identified with alterations in 15q11-q13, 16p11.2 or 22q11.2. Longitu‐ dinal follow-up studies are needed to determine the clinical consequences of CNVs identified at birth [146]. Anyway, considering the important implications for genetic counseling, these

Dysregulation of gene expression of several genes/loci converging on the same networks (overlay) and/or combinatorial effects of different deleterious genetic variations appear to exceed a threshold and result in the autistic phenotype. In support of these ideas, strategies based on bioinformatics have identified many candidate genes, showing that ASD can be triggered by different types of genetic variations in many different genes, a phenomenon known as non-allelic genetic heterogeneity [74, 138, 105]. This model is more accepted; combines both common and rare variations posing risk for ASD, particularly those involving synaptic genes and genes involved in neurogenesis [138]. Thus it is assumed that people with ASD have a set of genetic variants that predispose them to abnormal development of brain structures involved in processing social information (the "social brain"). But it is known that there is no common pathophysiology in ASD. This may result from mutations in many different genes involved in different functions [138]. The kinds of variants that incline to autism

CNVs are microduplications or microdeletions resulting from insertions, deletions or trans‐ locations in the human genome that are observed in the general population and commonly found in genic regions in individuals with neuropsychiatric disorders. They can be inherited or *de novo*, frequent or rare with a frequency of less than 1% of the population. A substantial portion of autism cases appears to result from rare CNVs with variations larger than 100kb; they are more common in individuals with ASD than in the general population [33, 83, 118]. *De novo* CNVs have been reported in 5-10% of cases of idiopathic ASD. Many studies have revealed that some CNVs occur at significantly higher frequencies than others and some are exclusively observed subjects and not found in normal controls. This has allowed the identi‐ fication of new candidate genes which have not yet been described in the Autism Chromosome Rearrangement Database, such as *GABRA5, GABRA3, GABRG3, UBE3A, E2F1, PLCB1, PMP22,*

prenatally and postnatally generated neurons.

318 Autism Spectrum Disorder - Recent Advances

regions must be evaluated in ASD patients.

**3. Copy number variations (CNVs)**

and can involve several genes at the same time are the CNVs.

While the majority of genetic mutations currently linked to autism are rare variants that change the protein-coding sequence of synaptic candidate genes, regulatory polymorphisms affecting constitutive and alternative splicing have emerged as risk factors in other diseases, accounting for an estimated 40-60% of general disease risk [131].

Neurons communicate via synapses, mainly mediated by precisely controlled intercellular interactions. Interactions between presynaptic and postsynaptic cellular adhesion molecules (CAMs) drive synapse maturation during development. CAMs provide "bridges", that is, cellto-cell connectivity between pre and postsynaptic sites. These transsynaptic interactions are regulated by alternative splicing of CAMs RNAs, which ultimately determines neurotrans‐ mitter phenotype. Failure to generate the appropriate CAMs can result in loss of activitydependent neuronal plasticity, and risk for developmental disorders, including autism. However, it remains unclear as to how many and which proteins are involved in the synap‐ togenesis process [161]. The postsynaptic proteome of excitatory synapses of a mammalian brain contains over 1,000 proteins, indicating complex protein-protein interactions that occur both within and between synapses [15, 30, 32, 47].

Typically, CAMs are located at the center of synapse and contain three domains: an intracel‐ lular domain that interacts with the intracellular scaffolding protein, a transmembrane domain and an extracellular domain which interacts with other CAMs [101]. Intercellular interactions in synapses mediated by protein-protein CAMs are involved in recognition and alignment of pre and postsynaptic sites, transsynaptic signaling, the exact location of neurotransmitter receptors and release of synaptic vesicles. There are several families of CAMs that have already been recognized, including neurexins (Nrxs) and neuroligins (NLS), neuronal transmembrane proteins rich in leucine (LRRTMs), N-cadherin/β-catenin, ephrins and Eph, SynCAM receptors and integrins [161].

The Nrxs and NLS contain an extracellular domain that participates in the pre and postsynaptic interaction and an intracellular domain that is involved in multiple functional interactions and regulatory processes. They interact with high affinity via their extracellular regions [135, 136]. Nrxs create extracellular protein-protein interactions with the intracellular signaling cascade. NLS binds to areas of postsynaptic density (PSD), proteins which are supported by glutama‐ tergic synapses. In postsynaptic sites, the NLS/Nrxs interactions cause an increase in the PSD agglomeration recruitment of postsynaptic N-methyl-D-aspartate (NMDA) and α-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Thus, the binding of Nrxs and NLS helps to align presynaptic and postsynaptic receptor release (Budreck et al., 2013; Mondin, Tessier, Thoumine, 2013).

LRRTMproteins are a groupoftype Itransmembraneproteins containing extracellularleucinerich repeats and a short cytoplasmic tail. They play a key role in the development and matura‐ tion of synapses, but are also directly involved in synaptic transmission and more complex behavior [87]. Contactins (CNTNs) provide a set of glycan phosphatidyl-inositol (GPI) Ig-CAM links containing six N-terminal Ig-like domains and four Fibronectin Type III domains. CNTNs play an important role in the formation of axon connections in the developing nervous system. For example, Cntn-1 and Cntn-2 are involvedin axon growth andguidance, and Cntn-6 is expressed in the presynaptic region in the developing nervous system [169].

As most neurological diseases originate as a dysfunction of neural circuits whose function is highly dependent on the accuracy of cell-cell adhesions, there is increasing evidence connect‐ ing several neurological disorders with mutations or altered expressions of CAMs. For example, mutations in the *NLS* and *Nrxs* genes are found in patients with autism [136]. Therefore, research on the role of CAMs will help provide a better understanding of the underlying mechanisms of pathogenic neurological disorders [172].
