Syndromes caused by imprinting disorders: Prader-Willi syndrome and Angelman syndrome.
Genomic imprinting is an epigenetic mechanism in which only one parental copy of a gene is expressed, while the other is silenced by DNA methylation. This parent-of-origin–specific expression is established during gametogenesis and maintained throughout life.
As a result:
- loss of the active allele causes disease,
- loss of the imprinted (silenced) allele has no effect.
Imprinting disorders typically involve:
- microdeletions,
- uniparental disomy (UPD),
- imprinting center defects.
Key Concepts in Imprinting Disorders
Parental Origin Matters
- The same chromosomal region, if lost from mother vs father, can cause different syndromes.
- Best example: chromosome 15q11–q13.
I. PRADER–WILLI SYNDROME (PWS)
Prader–Willi syndrome is a genomic imprinting disorder caused by loss of paternally expressed genes in the 15q11–q13 region, leading to hypotonia, hyperphagia, obesity, hypogonadism, and intellectual disability.
Genetic and Molecular Basis
Critical Region
- Chromosome: 15q11–q13
- Normal situation:
- Paternal allele → active
- Maternal allele → imprinted (silenced)
Pathophysiology
- Loss of paternally expressed genes in 15q11–q13.
- Dysfunction of hypothalamic regulation.
- Impaired satiety control → hyperphagia.
- Reduced growth hormone and gonadotropin secretion.
- Developmental delay and cognitive impairment.