U01.01.047 Disorders of imprinting

Imprinting refers to a genetic phenomenon where one gene copy is silenced through methylation, resulting in the expression of only the other copy. These disorders are characterized by parent-of-origin effects, meaning the clinical manifestations depend on whether the mutation or deletion occurs on the maternally or paternally inherited chromosome.

Key Imprinting Disorders

Disorder	Silenced Gene	Affected Allele	Key Chromosomal Locus	Notes
Prader-Willi Syndrome	Maternally derived genes	Paternal allele deleted/mutated	Chromosome 15 (paternal origin)	25% cases due to maternal uniparental disomy.
Angelman Syndrome	Paternally derived UBE3A	Maternal allele deleted/mutated	UBE3A on maternal copy of chromosome 15	5% cases due to paternal uniparental disomy.

Prader-Willi Syndrome

Gene Silence: Maternally derived genes.
Mechanism: Disease arises when the paternal allele is deleted or mutated.
Clinical Features:
- Hyperphagia
- Obesity
- Intellectual disability
- Hypogonadism
- Hypotonia
Mnemonic: “Prader has no Dad” → Indicates paternal deletion.

Angelman Syndrome

Gene Silence: Paternally derived UBE3A.
Mechanism: Disease arises when the maternal allele is deleted or mutated.
Clinical Features:
- Seizures
- Ataxia
- Severe intellectual disability
- Inappropriate laughter (“happy puppet” appearance)
Mnemonic: “MDs are Angels” → Maternal deletion causes Angelman syndrome.

Points to Remember

Chromosome Involved: Both disorders involve defects on chromosome 15.
Uniparental Disomy:
- In Prader-Willi Syndrome, 25% of cases result from maternal uniparental disomy (inheritance of two maternal copies).
- In Angelman Syndrome, 5% of cases result from paternal uniparental disomy (inheritance of two paternal copies).
Mnemonic Guide:
- Prader-Willi Syndrome: Paternal deletion → no dad.
- Angelman Syndrome: Maternal deletion → “MDs are angels.”
Symptoms are highly distinctive, aiding in diagnosis:
- Prader-Willi: Obesity and hypotonia.
- Angelman: Laughter, seizures, and severe intellectual disability.

References

First Aid for the USMLE Step 1.
Genetics and Genomics in Medicine.
NCBI Gene Reviews.

USMLE Step 1 Review Series

Curriculum