A child is born with hypotonia, feeding difficulty, and almond-shaped eyes. At age 5, obesity and hyperphagia develop. Molecular testing shows maternal uniparental disomy (UPD) of chromosome 15 with two copies of maternal chromosome 15 and no paternal copy. Which syndrome results, and what is the critical imprinted region involved?

• A Angelman syndrome — normally maternally expressed UBE3A in 15q11-q13 is absent when maternal 15 is missing
• B Beckwith-Wiedemann syndrome — loss of maternal imprinting at 11p15.5 affecting IGF2 expression
• C Prader-Willi syndrome — normally paternally expressed genes in 15q11-q13 (SNRPN, NDN) are absent when paternal 15 is missing ✓
• D Silver-Russell syndrome — hypomethylation of H19/IGF2 imprinting control region 1 on 11p15.5

Explanation

Maternal UPD of chromosome 15 (both chromosomes 15 are maternal, no paternal copy) causes Prader-Willi syndrome (PWS). The PWS critical region 15q11-q13 normally expresses paternally inherited genes — SNRPN (small nuclear ribonucleoprotein N), NECDIN (NDN), and MAGEL2. The maternal alleles of these genes are silenced by methylation (imprinted). With no paternal chromosome 15, these genes are absent → PWS. Angelman syndrome occurs with absence of the maternal copy (loss of maternal UBE3A expression), which may result from paternal UPD or maternal deletion. Beckwith-Wiedemann and Silver-Russell involve 11p15.5.

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

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Written and medically reviewed by the StethoPrep medical team.