A child is born with severe intellectual disability, absent speech, seizures and a happy demeanour with frequent laughter. Methylation analysis of the 15q11-q13 region shows a biparental methylation pattern — both alleles show paternal methylation pattern (no maternal methylation mark). FISH shows intact chromosome 15 on both homologues. What is the molecular diagnosis?

• A Prader-Willi syndrome due to maternal UPD of chromosome 15
• B Angelman syndrome due to a de novo imprinting centre defect silencing the maternal UBE3A without deletion
• C Angelman syndrome due to paternal uniparental disomy (UPD) of chromosome 15 — two paternal copies of 15q11-q13 with silenced UBE3A ✓
• D Prader-Willi syndrome due to imprinting centre defect causing paternal-type methylation of both alleles

Explanation

The methylation analysis showing both alleles carrying paternal methylation pattern (absence of the maternal imprint/maternal unmethylated allele) with intact chromosomes by FISH indicates paternal uniparental disomy (UPD) — two paternal copies and no maternal copy of chromosome 15. In the normal imprinting pattern, the maternal allele expresses UBE3A in neurons (the paternal allele is silenced by an antisense RNA); with two paternal copies (UPD15 paternal), no UBE3A is expressed in neurons, causing Angelman syndrome. Prader-Willi syndrome results from absence of the paternal copy (maternal UPD or deletion of the paternal allele) and involves different imprinted genes (SNRPN, NDN, MAGEL2). The clinical features (intellectual disability, seizures, happy demeanour, absent speech) are those of Angelman syndrome.

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

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Written and medically reviewed by the StethoPrep medical team.