A 2-year-old boy has severe obesity with hyperphagia, hypotonia since infancy, developmental delay, short stature, and small hands and feet. DNA methylation analysis shows absence of the paternal contribution at 15q11-q13. What is the most likely mechanism in a sporadic case?

• A Maternal uniparental disomy of chromosome 15
• B Imprinting centre mutation on the maternally inherited chromosome 15
• C UBE3A mutation inherited from the father
• D Paternal deletion of 15q11-q13 ✓

Explanation

Prader-Willi syndrome arises from loss of expression of paternally expressed genes at 15q11-q13. In sporadic cases about 70 percent have a de novo paternal deletion, roughly 25 percent maternal uniparental disomy, and a small fraction imprinting defects. Maternal uniparental disomy would leave two silent maternal copies but cannot be the mechanism asked when the paternal segment is absent by deletion; UBE3A relates to Angelman syndrome.

Reference: Nelson Textbook of Pediatrics, 21st ed.

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