A novel UBE3A sequence variant identified in eight related individuals with neurodevelopmental delay, results in a phenotype which does not match the clinical criteria of Angelman syndrome

• Published in: Molecular genetics & genomic medicine 2020-11, Vol.8 (11), p.e1481-n/a
• Main Authors: Geerts‐Haages, Amber, Bossuyt, Stijn N. V., Besten, Inge, Bruggenwirth, Hennie, Burgt, Ineke, Yntema, Helger G., Punt, A. Mattijs, Brooks, Alice, Elgersma, Ype, Distel, Ben, Valstar, Marlies
• Format: Article
• Language: English
• Subjects: Adult; Amino acids; Angelman syndrome; Angelman Syndrome - diagnosis; Angelman Syndrome - genetics; Angelman's syndrome; Animals; Ataxia; Behavior; Criteria; Developmental Disabilities - diagnosis; Developmental Disabilities - genetics; Diagnosis, Differential; E3 protein ubiquitin ligase; Enzyme Stability; Epilepsy; Families & family life; Female; Functional analysis; Gene Deletion; Genetic analysis; Genetic diversity; Genomes; Genotype & phenotype; HEK293 Cells; Humans; Intellectual disabilities; intellectual disability; Localization; Male; Mice; Missense mutation; missense variant; Mutants; Mutation; Neurodevelopmental disorders; Original; Parents & parenting; Pedigree; Phenotype; Phenotypes; Protein Transport; Proteins; Questionnaires; Sleep; Stability analysis; UBE3A; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.1481

Background Loss of functional UBE3A, an E3 protein ubiquitin ligase, causes Angelman syndrome (AS), a neurodevelopmental disorder characterized by severe developmental delay, speech impairment, epilepsy, movement or balance disorder, and a characteristic behavioral pattern. We identified a novel UBE3A sequence variant in a large family with eight affected individuals, who did not meet the clinical AS criteria. Methods Detailed clinical examination and genetic analysis was performed to establish the phenotypic diversity and the genetic cause. The function of the mutant UBE3A protein was assessed with respect to its subcellular localization, stability, and E3 ubiquitin ligase activity. Results All eight affected individuals showed the presence of a novel maternally inherited UBE3A sequence variant (NM_130838.4(UBE3A):c.1018‐1020del, p.(Asn340del), which is in line with a genetic AS diagnosis. Although they presented with moderate to severe intellectual disability, the phenotype did not match the clinical criteria for AS. In line with this, functional analysis of the UBE3A p.Asn340del mutant protein revealed no major deficits in UBE3A protein localization, stability, or E3 ubiquitin ligase activity. Conclusion The p.(Asn340del) mutant protein behaves distinctly different from previously described AS‐linked missense mutations in UBE3A, and causes a phenotype that is markedly different from AS. This study further extends the range of phenotypes that are associated with UBE3A loss, duplication, or mutation. We report on the clinical phenotype and functional characterization of a novel maternally‐inherited UBE3A sequence variant, p.Asn340del, that was identified in a large family with eight affected individuals. We show that the p.Asn340del mutant protein behaves distinctly different from previously described Angelman syndrome (AS)‐linked missense mutations in UBE3A, and causes a phenotype that does not match the clinical criteria for AS. This study further extends the range of phenotypes that are associated with UBE3A loss, duplication or mutation.