A child is born with hypotonia, intellectual disability, and short stature. Methylation-specific PCR of the 15q11-q13 region shows normal maternal methylation pattern but absence of the paternal unmethylated allele. FISH shows no deletion. What is the most likely mechanism and diagnosis?

• A De novo deletion of paternal 15q11-q13 causing Angelman syndrome due to absent maternal UBE3A expression
• B Paternal uniparental disomy for chromosome 15 causing Angelman syndrome via silencing of maternal UBE3A
• C Maternal uniparental disomy (mUPD) for chromosome 15 — both copies of 15q11-q13 come from the mother; since the paternal allele is normally unmethylated and expressed (SNRPN, MKRN3, MAGEL2), its absence causes Prader-Willi syndrome ✓
• D Gain-of-function mutation in MECP2 causing overexpression of maternal-pattern genes on both copies of chromosome 15

Explanation

The methylation-specific PCR shows absence of the paternal unmethylated allele at 15q11-q13, without FISH deletion. This pattern is consistent with maternal uniparental disomy (mUPD) — both chromosome 15s were inherited from the mother, leaving no paternal-origin 15q11-q13 alleles. Prader-Willi syndrome (PWS) results from absence of paternally expressed, maternally imprinted genes in this region (SNRPN, MKRN3, NDN, MAGEL2). This contrasts with Angelman syndrome (absence of maternally expressed UBE3A, due to either paternal UPD, maternal deletion, or UBE3A mutation). PWS presents with neonatal hypotonia, failure to thrive, then later hyperphagia, obesity, and intellectual disability.

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

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Written and medically reviewed by the StethoPrep medical team.