2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Looking locally for answers: A case report highlighting cellular localization assays of <em>UBE3A</em> to demonstrate pathogenicity in Angelman syndrome

Pdf Summary

This case presentation discusses a 10-year-old male with global developmental delays, hyperactive behaviors, and seizure-like episodes. The individual was initially diagnosed with Angelman syndrome (AS) due to the lack of speech, intellectual disability, motor impairment, unique behaviors, and seizures. Fragile X, Microarray, and Angelman/Prader Willi methylation analysis all yielded normal results. However, targeted UBE3A sequence analysis followed by whole exome sequencing revealed a de novo p.A289V variant in UBE3A. This variant was initially classified as of uncertain significance but was later reclassified as likely pathogenic.<br /><br />Functional assays conducted in two laboratories demonstrated that the A289V variant retained approximately 80% of wild-type UBE3A catalytic activity. However, localization studies showed that UBE3A was largely localized in the cytosol, supporting the pathogenicity of this variant. The individual also underwent an EEG, which showed characteristic notched-delta findings associated with Angelman syndrome. Vineland Adaptive Behavior Scales scores indicated higher-than-expected scores for a typical child with Angelman syndrome, confirming the intellectual disability diagnosis.<br /><br />The case highlights the importance of scalable functional characterization assays and cellular localization assays in characterizing variants of uncertain significance in Angelman syndrome. Molecular confirmation of diagnosis is increasingly critical, especially with multiple therapeutics in late-stage clinical development for Angelman syndrome. Additionally, determining the phase of the variant (maternal or paternal allele) is crucial in understanding pathogenicity in disorders with parent-of-origin pathophysiology.<br /><br />References:<br />- Weston KP, Gao X, Zhao J, et al. Identification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis. Nat Commun. 2021;12(1):6809. <br />- Bossuyt SNV, Punt AM, de Graaf IJ, et al. Loss of nuclear UBE3A activity is the predominant cause of Angelman syndrome in individuals carrying UBE3A missense mutations. Hum Mol Genet. 2021;30(6):430-442.

Asset Subtitle

Presenting Author - Liz Jalazo, MD; Co-Author - Jennifer M. R. Mathews, MS, CGC; Co-Author - Jalin Stelzer, BS; Co-Author - Mattijs Punt, BS; Co-Author - Jason Yi, PhD; Co-Author - Ype Elgersma, PhD; Co-Author - Elizabeth R. Jalazo, MD;

Meta Tag

Epigenetics

Gene Localization

Imprinting

Inheritance Patterns

NextGen Sequencing

Co-Author Jennifer M. R. Mathews, MS, CGC

Co-Author Jalin Stelzer, BS

Co-Author Mattijs Punt, BS

Co-Author Jason Yi, PhD

Co-Author Ype Elgersma, PhD

Co-Author Elizabeth R. Jalazo, MD

Presenting Author Liz Jalazo, MD

Keywords

developmental delays

hyperactive behaviors

seizure-like episodes

Angelman syndrome

UBE3A variant

pathogenicity

functional assays

diagnosis confirmation

therapeutics development

parent-of-origin pathophysiology