**2. Common chromosomal alterations: 15q11-q13, 16p11.2 and 22q11.2**

In addition to well-established genic syndromes, a lot of cases of ASD present with numerical or structural chromosomal alterations visible by conventional cytogenetic techniques [164]. Due to the high number of cases and the type and location of the genes described, the associ‐ ation of some chromosomal regions is well established in autism including: 1q21, 2q37, 7q11.23, 15q11-13, 16p11.2, 17p11.2, 22q11.2 and 22q13. Rearrangements involving these regions are detected by GTG banding however more sophisticated molecular techniques are recommend‐ ed. High-resolution whole-genome analysis with array-based technologies have revealed genomic imbalances in at least 10% of cases [170].

Chromosome 15 is reportedly the most common site of autosomal abnormalities in autism with the duplication of 15q11-q13 being the most frequently reported alteration. This region contains at least 30 genes, several of which have been associated to ASD, neurobehavioral disorders, cognitive deficits, hypotonia, language delay and seizures [141, 154].This region, known for its genetic instability, contains many low copy repeats and segmental duplications. It is known as a critical region for Prader-Willi/Angelman syndrome and has a complex pattern of paternal and maternal imprinting; it contains at least five paternally expressed genes (*MKRN3*, *MAGEL2*, *NDN*, *C15orf2*, *snoRNAs* and *SNRPN-SNURF*) and two maternally expressed genes (*UBE3A* and *ATP10A*). Furthermore, epigenetic factors regulating 15q11-13 have been implicated in the presence of autism [6].

The phenotype involving recurrent ∼600 kb microdeletions and microduplications in the 16p11.2 region is characterized by a spectrum of neurodevelopmental impairments including developmental delay and intellectual disability, epilepsy, autism and other psychiatric disorders which are all subject to incomplete penetrance and variable expressivity. This deletion is observed in ~0.5% of autism patients, making this the second most common abnormality in this disorder [48, 156]. Losses in candidate genes in this region, such as *ALDOA*, *DOC2A*, *HIRIP3*, *MAPK3*, *MAZ*, *PPP4C*, SEZ6L2, and *TAOK2*, seem to contribute to the ASD phenotype [171].

The 22q11.2 deletion is one of the most commonly known interstitial deletions identified in humans, and with a frequency of around 1:4,000 live births in the general population, it is related to DiGeorge Sequence/Velocardiofacial syndrome [98, 132]. Recent studies suggest that 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 prenatally and postnatally generated neurons.

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 regions must be evaluated in ASD patients.
