Prader-Willi syndrome results from loss of paternal chromosome 15q11–q13 (deletion or maternal uniparental disomy). The key concept explaining why maternal UPD causes the same phenotype as paternal deletion is:

• A Maternal chromosome 15q11–q13 genes are normally active, but paternal genes are imprinted (silenced)
• B Paternal chromosome 15q11–q13 genes are expressed, but maternal genes are imprinted (silenced); loss of paternal copies has the same effect as having two silenced maternal copies ✓
• C Both copies of 15q11–q13 are required for normal dosage, regardless of parental origin
• D UPD causes recessive mutations to become homozygous, revealing hidden recessive alleles from the mother

Explanation

In the 15q11–q13 region, paternal alleles are expressed while maternal alleles are imprinted (epigenetically silenced). Loss of the expressed paternal copies — whether by deletion of the paternal chromosome or by inheritance of two maternal (silenced) copies (maternal UPD) — results in absence of the paternal gene products (SNRPN, NDN, snoRNAs), causing Prader-Willi syndrome. Angelman syndrome results from loss of the maternal allele (UBE3A is maternally expressed).

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

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Written and medically reviewed by the StethoPrep medical team.