Submission Details

Angelman syndrome (AS) is caused by loss-of-function of the maternally-inherited copy of UBE3A by a variety of genetic mechanisms. The paternal copy of the gene is imprinted in the brain, so variants on the paternal allele do not manifest as AS in the individual. Angelman syndrome is characterized by severe developmental delay and intellectual disability, speech impairment, gait ataxia, trembling of limbs, microcephaly, seizures, and happy demeanor. About 70% of AS is caused by microdeletions of 15q11-13, about 7% by uniparental disomy, 3% by imprinting center defects, 10% by variants in the UBE3A gene, and the remaining 10% are unknown (see Fang et al. 1999 for review of UBE3A variant spectrum). Variants can arise de novo or be inherited from the patient's mother. Mouse models with maternally-derived null alleles recapitulate many of the phenotypic features of AS, and unsilencing of paternal wild-type UBE3A expression in mice ameliorated many of the phenotypic defects seen in the mouse model (Jiang et al. 1998, Miura et al. 2002, Meng et al. 2013). In summary, the UBE3A gene is definitively associated with AS. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. More information can be found at GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1144/).