The Comorbidity of Autism with the Genomic Disorders of Chromosome 15q11.2-q13

Department of Medical Microbiology and Immunology, University of California, Davis, CA 95616, USA.
Neurobiology of Disease (Impact Factor: 5.08). 10/2008; 38(2):181-91. DOI: 10.1016/j.nbd.2008.08.011
Source: PubMed


A cluster of low copy repeats on the proximal long arm of chromosome 15 mediates various forms of stereotyped deletions and duplication events that cause a group of neurodevelopmental disorders that are associated with autism or autism spectrum disorders (ASD). The region is subject to genomic imprinting and the behavioral phenotypes associated with the chromosome 15q11.2-q13 disorders show a parent-of-origin specific effect that suggests that an increased copy number of maternally derived alleles contributes to autism susceptibility. Notably, nonimprinted, biallelically expressed genes within the interval also have been shown to be misexpressed in brains of patients with chromosome 15q11.2-q13 genomic disorders, indicating that they also likely play a role in the phenotypic outcome. This review provides an overview of the phenotypes of these disorders and their relationships with ASD and outlines the regional genes that may contribute to the autism susceptibility imparted by copy number variation of the region.

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Available from: Janine M Lasalle, Dec 17, 2013
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    • "Chromosome 15q duplication syndrome occurs in 0.5 to 3% of all ASD cases [11]. High pain tolerance in individuals with Dup15q remains poorly characterized [12]. There is limited evidence of high pain tolerance within specific genetic populations. "
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    ABSTRACT: Parents of children with chromosome 15q duplication syndrome (Dup15q) have anecdotally reported high pain threshold as a feature of the disorder. The purpose of this study was to document parental-reported estimates of the frequency of high pain tolerance and the stimuli that fail to evoke a normal pain response. We sent an online survey to 840 families with children with Dup15q to explore the frequency and clinical manifestations of high pain threshold. There were 216 respondents (25.7%). A high pain threshold was reported in 87% of children at some time. There was a trend (p = 0.06) for high pain threshold to be more commonly observed among children with the isodicentric (85.6%) and other genetic variants (95%) than interstitial (69.6%) duplications. There was no association between reports of high pain threshold and reports of an intellectual disability (91% of cases), autism spectrum disorder (83% of cases), or self-injurious behavior (40% of cases). Reports included many dramatic cases such as severe burns, broken bones, and electrical traumas, which were associated with little or no evidence of a painful stimulus. A high pain threshold is reported in other disorders associated with intellectual disability and autism; the underlying mechanism in Dup15q and other disorders remains undefined.
    Full-text · Article · Feb 2016 · Epilepsy & Behavior
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    • "Duplication or triplication of maternally inherited 15q11-13, the chromosomal location where UBE3A resides, is one of the most common cytogenetic events associated with autism (Glessner et al., 2009; Hogart et al., 2010). Individuals with one extra maternal copy of 15q11-13 display partial autism penetrance, whereas individuals with two extra copies display almost complete penetrance (Hogart et al., 2010; Urraca et al., 2013). UBE3A is the only gene in this region that is consistently expressed from the maternal, but not paternal, allele in mature neurons (Albrecht et al., 1997; Rougeulle et al., 1997; Vu and Hoffman, 1997), suggesting that abnormally elevated levels of UBE3A contribute to autism in 15q11-13 duplication syndrome. "
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    ABSTRACT: Deletion of UBE3A causes the neurodevelopmental disorder Angelman syndrome (AS), while duplication or triplication of UBE3A is linked to autism. These genetic findings suggest that the ubiquitin ligase activity of UBE3A must be tightly maintained to promote normal brain development. Here, we found that protein kinase A (PKA) phosphorylates UBE3A in a region outside of the catalytic domain at residue T485 and inhibits UBE3A activity toward itself and other substrates. A de novo autism-linked missense mutation disrupts this phosphorylation site, causing enhanced UBE3A activity in vitro, enhanced substrate turnover in patient-derived cells, and excessive dendritic spine development in the brain. Our study identifies PKA as an upstream regulator of UBE3A activity and shows that an autism-linked mutation disrupts this phosphorylation control. Moreover, our findings implicate excessive UBE3A activity and the resulting synaptic dysfunction to autism pathogenesis. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Cell
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    • "Various studies have linked ASD with the maternally but not paternally derived duplication of the PWS 15q11–13 critical region with duplications of the 15q11–13 region occurring in 3–5 % of cases with idiopathic autism (Hogart et al. 2010; Veltman et al. 2004). Based on these findings, it is evident that the mUPD subtype of PWS shares a genetic similarity with ASD, in that both may show increased maternal expression of the 15q11–13 region (Hogart et al. 2010; Veltman et al. 2004). In relation to this genetic similarity, current research has found that individuals with PWS, and the mUPD subtype, have an increased risk for developing autistic-like symptoms and express similar patterns of repetitive behaviors and social competency deficits as those with ASD (Descheemaeker et al. 2006; Dimitropoulos et al. 2012; Dykens et al. 2011). "
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    ABSTRACT: Children with Prader-Willi syndrome (PWS) are at risk for autism spectrum disorder (ASD), including pervasive social deficits. While play impairments in ASD are well documented, play abilities in PWS have not been evaluated. Fourteen children with PWS and ten children with ASD were administered the Autism Diagnostic Observation Schedule (ADOS) (Lord et al. in Autism Diagnostic Observation Schedule manual. Western Psychological Services, Los Angeles, 2006) as part of a larger project. A modified Affect in Play Scale (APS; Russ in Play in child development and psychotherapy: toward empirically supported practice. Lawrence Erlbaum Associates Publishers, Mahwah, 2004; Pretend play in childhood: foundation of adult creativity. APA Books, Washington, 2014) was used to score ADOS play activities. Results indicate both groups scored below normative data on measures of imagination, organization, and affective expression during individual play. In addition, the inclusion of a play partner in both groups increased all scaled scores on the APS. These findings suggest children with PWS show impaired pretend play abilities similar to ASD. Further research is warranted and should focus on constructing and validating programs aimed at improving symbolic and functional play abilities within these populations.
    Full-text · Article · Sep 2014 · Journal of Autism and Developmental Disorders
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