15q11.2 Duplication Encompassing Only theUBE3AGene Is Associated with Developmental Delay and Neuropsychiatric Phenotypes

Abstract

Duplications of chromosome region 15q11-q13 with the maternal imprint are associated with a wide spectrum of neuropsychiatric disorders, including autism spectrum disorders, developmental delay, learning difficulties, schizophrenia, and seizures. These observations suggest there is a dosage-sensitive imprinted gene or genes within this region that explains the increased risk for neuropsychiatric phenotypes. We present a female patient with developmental delay in whom we identified a maternally inherited 129-Kb duplication in chromosome region 15q11.2 encompassing only the UBE3A gene. Expression analysis in cultured fibroblasts confirmed overexpression of UBE3A in the proband, compared with age- and sex-matched controls. We further tested segregation of this duplication in four generations and found it segregated with neuropsychiatric phenotypes. Our study shows for the first time clinical features associated with overexpression of UBE3A in humans and underscores the significance of this gene in the phenotype of individuals with 15q11-q13 duplication.

New Perspectives on Genomic Imprinting, an Essential and Multifaceted Mode of Epigenetic Control in the Developing and Adult Brain

“…In addition, triplications of Ube3a normal expression in mice causes autism-like phenotypes, including reduced social recognition and interactions and abnormal USVs during social interactions, whereas doubling Ube3a ’s dosage impairs these behaviors mildly (Smith et al 2011). This is consistent with more pronounced autistic features observed in humans with 15q11–13 maternal triplications than duplications, suggesting that the brain is highly sensitive to UBE3A dosage (Hogart et al 2010, Noor et al 2015). Recently, a mutation enhancing UBE3A ubiquitin ligase activity has been implicated in autism (Yi et al 2015).…”

An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A

“…Moreover, our work provides further evidence that excess UBE3A activity in the brain increases risk for autism. Future studies will be needed to assess phenotypic similarities between this genetically precise T485A point mutation that hyperactivates UBE3A, 15q11-13 duplication that elevates UBE3A and other genes, and a recently identified family with a 15q11.2 duplication that encompasses only UBE3A and that segregates with autistic features, developmental delay, depression and schizophrenia (Noor et al, 2015). …”

Epigenetic Regulation of UBE3A and Roles in Human Neurodevelopmental Disorders

“…Interestingly, a recent family was described in which the proband had developmental delay and a maternally inherited small (129 kb) duplication encompassing only UBE3A that segregated with neuropsychiatric phenotypes across three prior generations [96]. Evidence implicating increased maternal copies of UBE3A is strongest for ASD phenotypes in patients with large interstitial duplications.…”