Prader-Willi syndrome (PWS) and Angelman syndrome (AS) both result from loss of function of genes on chromosome 15q11-q13, yet they produce entirely different phenotypes. The molecular mechanism underlying this parent-of-origin difference is:

• A X-linked recessive inheritance with variable penetrance
• B Trinucleotide repeat expansion in the same gene causing different disease based on parent of origin
• C Genomic imprinting: PWS results from loss of paternal 15q11-q13 (paternal genes silenced by maternal imprint are absent), and AS from loss of maternal 15q11-q13 (UBE3A only expressed from maternal allele) ✓
• D Mitochondrial inheritance with heteroplasmy

Explanation

Chromosome 15q11-q13 is subject to genomic imprinting. In PWS, the deletion or uniparental disomy affects the PATERNAL chromosome, eliminating SNRPN, NDN, MAGEL2, and other paternally-expressed genes that are silenced on the maternal chromosome — causing hypotonia, hyperphagia, obesity, and hypogonadism. In AS, the deletion or uniparental disomy affects the MATERNAL chromosome, silencing UBE3A (ubiquitin ligase) which is only expressed from the maternal allele in neurons (paternal UBE3A is imprinted/silenced in brain) — causing intellectual disability, ataxia, seizures, and happy demeanor. Both can result from deletion (70%), uniparental disomy, or imprinting center mutations.

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

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Written and medically reviewed by the StethoPrep medical team.