An apparently de novo UBE3A missense variant p.(Tyr777Cys) in the HECT domain in a child with an atypical early childhood phenotype suggestive of Angelman syndrome: a case report and focused literature review
Year: 2026
Type: article
Study design: Case Report
Abstract: Background Angelman syndrome (AS) is a neurodevelopmental disorder associated with loss of maternal UBE3A function in neurons. Interpreting rare UBE3A missense variants can be challenging, particularly when parental origin and functional effects have not been established. Case Presentation We report a 30-month-old Chinese boy with global developmental delay, motor impairment, and severe expressive language impairment, without clinically observed seizures during the available follow-up. Genetic evaluation, including trio whole-exome sequencing and proband whole-genome sequencing, identified an apparently de novo heterozygous UBE3A missense variant, NM_130839.5:c.2330A>G, p. (Tyr777Cys), within the homologous to the E6AP carboxyl terminus (HECT) domain. Copy-number analysis did not identify a large deletion involving 15q11.2-q13. Electroencephalography (EEG) showed paroxysmal high-amplitude 2–3 Hz spike-slow and sharp-slow complexes, and the magnetic resonance imaging (MRI) report suggested delayed white-matter myelination. The variant was classified as a variant of uncertain significance (VUS) in the laboratory report and remained a VUS following reassessment using the UBE3A-specific ClinGen Variant Curation Expert Panel (VCEP) specifications. Its maternal or paternal allelic origin remains undetermined, and its functional effects have not been experimentally assessed. Conclusion This report documents the rare, apparently de novo UBE3A HECT-domain variant p. (Tyr777Cys), together with detailed early developmental and electrophysiological findings. Substantial motor and expressive language impairment accompanied by EEG abnormalities suggestive of AS, despite no clinically observed seizures by 30 months, highlights the importance of considering AS during the evaluation of unexplained developmental delay. Integrated clinical assessment, EEG, and family-based genetic testing help identify candidate variants and guide further investigation. Although p. (Tyr777Cys) remains a VUS, the documented phenotype provides a reference for future case comparisons, parent-of-origin studies, and functional investigations.
Source: Frontiers in Genetics
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7225593671