Mutation Update for UBE3A variants in Angelman syndrome

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Molecular Biology

Background:

• Angelman syndrome is a rare neurodevelopmental disorder.
• It results from the loss of function of the UBE3A gene, which is imprinted and maternally expressed.
• While most cases stem from genetic or epigenetic defects in the UBE3A locus, about 10% are due to UBE3A loss-of-function mutations.

Purpose of the Study:

• To analyze UBE3A gene variants in a large cohort of patients with suspected Angelman syndrome.
• To review and classify UBE3A mutations from existing literature.
• To contribute findings to the NCBI ClinVar database for broader accessibility.

Main Methods:

• Analysis of UBE3A gene sequencing data from 2,515 referred patients.
• Comprehensive literature review of UBE3A mutations.
• Classification of identified nucleotide variants as pathogenic, benign, or variants of unknown clinical significance (VUS), often involving family studies.

Main Results:

• A total of 267 patients (10.62%) had a reported UBE3A gene nucleotide variant.
• 111 probands (4.41%) had pathogenic or strongly pathogenic variants.
• 29 variants (1.15%) were classified as VUS, and 126 (5.0%) were benign or strongly benign.

Conclusions:

• UBE3A gene sequencing and variant analysis are crucial for diagnosing Angelman syndrome.
• This study identified a significant proportion of pathogenic UBE3A variants, contributing to the understanding of the genetic landscape of the disorder.
• All identified variants and their clinical interpretations are submitted to ClinVar, enhancing data sharing and research.