In genomic imprinting disorders, Prader-Willi syndrome (PWS) and Angelman syndrome (AS) both involve chromosome 15q11-q13 but differ in parent-of-origin of deletion. The molecular basis for the parent-of-origin specificity is:

• A Differential X-inactivation patterns in the 15q region cause sex-specific penetrance of the deletion
• B Anticipation due to trinucleotide repeat expansion differs between maternal and paternal transmission at 15q
• C Mitochondrial inheritance ensures maternal transmission of the disease-causing mutation in Angelman syndrome
• D Differential methylation of CpG islands at 15q11-q13 imprinting control region (IC) epigenetically silences maternal genes (SNRPN/NDN) on the maternal chromosome and paternal UBE3A on the paternal chromosome; only the active allele from the affected parent's chromosome matters ✓

Explanation

Chromosome 15q11-q13 is subject to genomic imprinting, where gene expression is determined by parent of origin. The imprinting control center (IC) uses differential DNA methylation to silence specific genes. PWS arises from loss of the paternally expressed genes in this region (SNRPN, NDN/Necdin, and SNORD snoRNA clusters), which occurs via paternal deletion (70%), maternal uniparental disomy (25%), or IC defects (5%). AS arises from loss of UBE3A (E6-AP ubiquitin ligase), which is maternally expressed in neurons (biallelically in other tissues), through maternal deletion, paternal UPD, IC defects, or UBE3A mutation. In neurons, the paternal UBE3A allele is silenced by a long antisense RNA (UBE3A-ATS) whose transcription is driven from the paternal IC. Thus, the same chromosomal region causes entirely different syndromes depending on which parental chromosome is affected.

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

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Written and medically reviewed by the StethoPrep medical team.