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2023 ACMG Annual Clinical Genetics Meeting Digital ...
Correlating UBE3A enzyme activity with clinical se ...
Correlating UBE3A enzyme activity with clinical severity in Angelman syndrome
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Pdf Summary
Angelman syndrome (AS) is a rare genetic disorder characterized by intellectual disability, speech impairment, ataxia, seizures, microcephaly, sleep disturbance, and excitable behavior. It is caused by the loss of the UBE3A gene on chromosome 15 in neurons. This study aimed to correlate the enzyme activity of UBE3A with the clinical severity of AS in individuals with UBE3A mutations. The goal is to develop an assay that can classify UBE3A variants as pathogenic or benign.<br /><br />The study included 71 individuals with UBE3A variants enrolled in the Angelman syndrome natural history study. Clinical severity was measured using cognitive ability, age of seizure onset, head circumference, and disordered sleep. Enzyme activity of UBE3A variants was measured using a functional assay that reports the activity as a percentage of wild-type UBE3A activity.<br /><br />Higher UBE3A activity (>20%) was correlated with milder clinical severity, particularly in cognitive ability. Lower UBE3A activity (<20%) showed a wide range in clinical severity. It was found that UBE3A activity may not be the sole determinant of clinical severity in AS, and other factors may contribute. Additionally, siblings with the same UBE3A variant showed a higher correlation in clinical severity than unrelated individuals with the same variant, suggesting that environmental or nurturing factors may play a role in phenotypic differences.<br /><br />Furthermore, individuals with missense variants of UBE3A scored higher on cognitive ability compared to those with null variants. This indicates that individuals with missense variants tend to be less severely affected. However, this correlation was not significant in other domains.<br /><br />In conclusion, this study found that UBE3A enzyme activity is correlated with the clinical severity of AS. Higher UBE3A activity is associated with milder clinical severity, while lower activity corresponds to a wider range in severity. Factors other than UBE3A activity and genetic variants may contribute to the phenotypic presentation of AS.
Asset Subtitle
Presenting Author - Bhavana Ambil, BS; Co-Author - Jalin Stelzer, BS; Co-Author - Wen-Hann Tan, BMBS; Co-Author - Jason Yi, PhD; Co-Author - Elizabeth R. Jalazo, MD;
Meta Tag
Brain/Nervous System
Chromosomal Abnormalities
Chromosome Structure/Function
Cognitive Disorders
Etiology
Gene Localization
Genome sequencing
Genotype-Phenotype Correlations
Inheritance Patterns
Intellectual disability
Pathogenesis
Structure/Function
Variant Detection
Co-Author
Jalin Stelzer, BS
Co-Author
Wen-Hann Tan, BMBS
Co-Author
Jason Yi, PhD
Co-Author
Elizabeth R. Jalazo, MD
Presenting Author
Bhavana Ambil, BS
Keywords
Angelman syndrome
genetic disorder
intellectual disability
speech impairment
seizures
microcephaly
UBE3A gene
clinical severity
enzyme activity
missense variants
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