A 14-month-old boy has severe intellectual disability, absent speech, inappropriate happy demeanor with frequent laughter, characteristic puppet-like ataxic gait, seizures with a characteristic EEG pattern, and hypopigmentation compared to siblings. Molecular testing reveals absence of maternal UBE3A expression. What is the epigenetic mechanism in the majority of cases?

• A Maternal deletion of chromosome 15q11-q13 (genomic imprinting) ✓
• B Gain-of-function mutation in paternal UBE3A allele
• C Uniparental disomy of paternal chromosome 15
• D Trinucleotide repeat expansion in UBE3A promoter

Explanation

Angelman syndrome is caused by loss of maternally expressed UBE3A in the brain. The most common mechanism (70–75% of cases) is a de novo maternal deletion of 15q11-q13. In the brain, UBE3A is imprinted (the paternal copy is silenced), so deletion of the maternal copy results in complete absence of UBE3A expression. Uniparental disomy (paternal UPD, ~5–7%) and imprinting center defects (~3%) are less common. This contrasts with Prader-Willi syndrome, which results from loss of paternal 15q11-q13 expression. Both are classic examples of genomic imprinting disorders.

Reference: Ghai Essential Pediatrics, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.