Two children carry the same deletion at 15q11-q13 confirmed by methylation analysis. One has hypotonia, hyperphagia, obesity and small hands and feet. The other has severe intellectual disability, ataxia, bursts of inappropriate laughter and seizures. What explains the different phenotypes?

• A Mitochondrial heteroplasmy affecting penetrance differently in each child
• B Uniparental disomy versus triplet repeat expansion at the same locus
• C Random X-inactivation skewing modifying expression of genes within the deletion
• D Genomic imprinting: loss of paternal expression causes Prader-Willi, loss of maternal UBE3A expression causes Angelman ✓

Explanation

15q11-q13 is an imprinted region. Genes in the Prader-Willi critical region are expressed only from the paternal allele, so paternal deletion causes Prader-Willi syndrome. UBE3A is expressed mainly from the maternal allele in brain, so maternal deletion causes Angelman syndrome. The same cytogenetic deletion therefore produces two distinct diseases depending on the parent of origin. Heteroplasmy, repeat expansion and X-inactivation are unrelated mechanisms here.

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

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Written and medically reviewed by the StethoPrep medical team.