**3. ASD associated with CNVs on chromosome 16p11.2**

In recent years, whole genome analyses of cohorts of patients with autism have identified recurrent CNVs on chromosome 16p11.2, effectively linking reciprocal microduplications and microdeletions at this locus with increased susceptibility to ASD [12, 36-39]. Important‐ ly, further studies have revealed that CNVs at this locus are responsible for ~1% of all ASD diagnoses, making it the most common CNV to be associated with ASD identified to date [13]. The 16p11.2 locus is flanked by two directly repeated segmental duplications of ~145 kb, which mediate the NAHR that results in the loss or gain of ~600 kb intermediate region containing ~27 protein-coding genes [9, 12, 40].

ing platforms, have been utilized to detect and analyze CNVs in the genome and to investi‐ gate the mechanism by which these CNVs are generated [34]. CNVs can be formed by several mechanisms, such as non-allelic homologous recombination (NAHR), non-homolo‐ gous end joining (NHEJ), or fork stalling and template switching (FoSTeS) [35]. NAHR, which is often mediated by low copy repeats (LCRs) with high (~95%) sequence similarity flanking the rearranged region, is the most common mechanism by which recurrent CNVs are created. Often this mechanism can result in recurrent genomic rearrangements that are observed in multiple patients with the same disorder, as in Charcot-Marie-Tooth disease type 1A, Prader-Willi syndrome, and Smith-Magenis Syndrome, among many others [32, 33]. The genomic architecture rendering genomic instability at three loci that are enriched

**Figure 2. The genomic structure of loci associated with CNV-based ASD. (A)** Chromosomes 15q11-13, **(B)** 16p11.2, and **(C)** 17p11.2, are enriched for LCRs, or segmental duplications (indicated by red arrows), which facilitate non-allelic homologous recombination (NAHR), resulting in the generation of CNVs (blue and red bars). This figure was generated using the genome browser provided by UCSC (http://genome.ucsc.edu/index.html?org=Hu‐

In recent years, whole genome analyses of cohorts of patients with autism have identified recurrent CNVs on chromosome 16p11.2, effectively linking reciprocal microduplications and microdeletions at this locus with increased susceptibility to ASD [12, 36-39]. Important‐ ly, further studies have revealed that CNVs at this locus are responsible for ~1% of all ASD diagnoses, making it the most common CNV to be associated with ASD identified to date

**3. ASD associated with CNVs on chromosome 16p11.2**

for LCRs are shown in Figure 2.

254 Recent Advances in Autism Spectrum Disorders - Volume I

man&db=hg18&hgsid=289381925].

Interestingly, the microduplication of this region has also been linked to schizophrenia, sug‐ gesting the presence of an underlying biological link between these two disorders [41, 42]. This phenomenon also gives a potential genetic basis for the hypothesis of Crespi et al, which states that autism and schizophrenia represent diametric disorders of the social brain [43]. Thus, schizophrenia and autism might reflect mirror traits of the opposing extremes of behavioral phenotypes reflecting evolution of the social brain [43]. The phenotypes caused by CNV at the 16p11.2 locus are extremely heterogeneous, and, in addition to ASD, they have been reported to include metabolic disorders [44-47], cardiac anomalies [40, 48], de‐ pressive disorder [49], speech delay [50], mental retardation [40, 51, 52], vertebral anomalies [52], syringomyelia [53], abnormal head size [36], and epilepsy [36, 40], as well as other vari‐ ous congenital anomalies and behavioral abnormalities [44]. As the phenotypes of many more patients harboring CNVs in this genomic region are delineated, the full phenotypic spectrum associated with this locus will likely become more well-defined, and the critical genomic interval and dosage-sensitive genes responsible for the phenotypes will be deter‐ mined. Indeed, a more recent study described a patient pedigree for a family with multiple generations of autism or ASD that also carry a smaller-sized deletion within the common deletion of 16p11.2, thereby reducing the "critical" interval for ASD to a 118 kb region con‐ taining only 5 genes: *MVP*, *CDIPT1*, *SEZ6L2*, *ASPHD1*, and *KCTD13 [54]*. To date, none of these genes have been significantly associated with an elevated risk for ASD, which indi‐ cates that the situation is likely much more complex [37, 55]. Furthermore, correlation be‐ tween the phenotypes of patients harboring different- or similar-sized CNVs is confounded by extreme heterogeneity and variability of symptoms. For example, a family with three af‐ fected members harboring identical 16p11.2 deletions was recently described to have mini‐ mal symptom overlap between family members [56]. Subsequent studies have aimed at using model organisms to identify the key dosage-sensitive genes within this region that give rise to the abnormal phenotypes [29, 57, 58]. Among these, chromosome-engineered mouse models harboring reciprocal deletion or duplication of the mouse chromosome syn‐ tenic to human chromosome 16p11.2 have been generated to study the physiological and be‐ havioral phenotypes associated with these chromosome abnormalities [29].
