A 3-year-old boy with an 'angelman-like' phenotype (seizures, intellectual disability, happy demeanor) is found NOT to have a deletion at 15q11-q13 on FISH. Methylation analysis shows two copies of paternal methylation pattern at the SNRPN locus. What is the diagnosis?

• A Angelman syndrome caused by paternal uniparental disomy of chromosome 15 ✓
• B Prader-Willi syndrome caused by maternal uniparental disomy of chromosome 15
• C Angelman syndrome caused by imprinting center mutation affecting UBE3A expression on maternal chromosome
• D Prader-Willi syndrome caused by paternal deletion at 15q11-q13

Explanation

Angelman syndrome (AS) requires loss of maternally derived UBE3A expression in the brain (UBE3A is maternally imprinted — only the maternal allele is expressed in neurons). The causes include: maternal deletion 15q11-q13 (~70%), paternal UPD15 (~7%, both chromosomes from father = no maternal UBE3A), imprinting center defect (~3%), UBE3A mutation (~11%), and unknown (~10%). When methylation analysis shows two copies of paternal methylation pattern at SNRPN, it indicates paternal uniparental disomy — both chromosomes are of paternal origin, thus lacking maternal UBE3A expression, causing AS. UPD of paternal origin causes AS; UPD of maternal origin at chromosome 15 causes Prader-Willi syndrome.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.