Mutation Update for UBE3A Variants in Angelman Syndrome


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Abstract

Angelman syndrome is a neurodevelopmental disorder caused by a deficiency of the imprinted and maternally expressedUBE3Agene. Although de novo genetic and epigenetic imprinting defects ofUBE3Agenomic locus account for majority of Angelman diagnoses, approximately 10% of individuals affected with Angelman syndrome are a result of UBE3A loss-of-function mutations occurring on the expressed maternal chromosome. The variants described in this manuscript represent the analysis of 2,515 patients referred forUBE3Agene sequencing at our institution, along with a comprehensive review of theUBE3Amutation literature. Of these, 267 (10.62%) patients had a report issued for detection of aUBE3Agene nucleotide variant, which in many cases involved family studies resulting in reclassification of variants of unknown clinical significance (VUS). Overall, 111 (4.41%) probands had a nucleotide change classified as pathogenic or strongly favored to be pathogenic, 29 (1.15%) had a VUS, and 126 (5.0%) had a nucleotide change classified as benign or strongly favored to be benign. All variants and their clinical interpretations are submitted to NCBI ClinVar, a freely accessible human variation and phenotype database.

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