**6. Duplication of 15q11-13**

It has been estimated that up to ~5% of cases of ASD can be attributed to maternal duplica‐ tion of the genomic region reciprocal to the PWS-AS critical region on chromosome 15q11-13, making it one of the most common chromosomal abnormalities observed in pa‐ tients with ASD [10, 62]. Due to the presence of imprinting at this locus (discussed above), parent-of-origin effects are seen, and, for interstitial duplications, maternal origin confers an increased risk for clinical phenotypes. Paternal duplications are much less common, and do not appear to lead to ASD, as familial cases have been described where a seemingly normal carrier mother transmits a paternally-derived duplication to their child [63]. However, a small number of subjects with paternal duplication of 15q11-13 and various clinical pheno‐ types have been described [64]. Phenotypes are dosage-sensitive at this locus; one extra ma‐ ternal copy of 15q11-13 results in partial autism penetrance, while two extra copies (caused by idic15 or interstitial triplication) result in a much higher penetrance of autism as well as additional phenotypes that are typically more severe than those seen in patients with dupli‐ cations [62]. In the case of triplications, parent-of-origin effects are no longer observed, and both paternal and maternal duplications are associated with poor clinical outcomes [65]. This loss of parent-of-origin effects is interesting, and it may be an indication of the underly‐ ing mechanism that may give rise to a predisposition for these phenotypes. Many heteroge‐ neous and complex phenotypes can be associated with increased copy number of this region including intellectual disability, apraxia, dyslexia, seizures, hypotonia, developmental de‐ lay, gait abnormalities, hyperactivity, schizophrenia, and ASD [66]. Patients with ASD due to duplication of 15q11-13 also display several stereotypic and repetitive behaviors, includ‐ ing rocking, licking, and hand-flapping, among others, that are often directed towards sen‐ sory stimulation, suggesting that the underlying cause of these phenotypes may be due to a disregulation of sensory inputs or signaling [63, 64].

Interestingly, recent post-mortem evaluation of the brains of patients harboring maternal duplication of 15q11-13 suggested that accumulation and deposition of abnormal intracel‐ lular and extracellular amyloid β protein (Aβ) in the specific regions and neuron types in the brains of patients with maternal duplication of 15q11-13 may underlie or contrib‐ ute to some of the neurobehavioral phenotypes associated with ASD [67]. However, fur‐ ther studies are needed to confirm this hypothesis. Several animal models for the CNVbased syndromes associated with chromosome 15q11-13 have been developed to facilitate research into these disorders.
