imprinting

Genomic imprinting occurs through differential DNA methylation of CpG islands during gametogenesis, silencing one parental allele so that gene expression depends on which parent contributed the allele, not on classic Mendelian dominance. This is established in the germline and maintained through mitotic divisions in somatic cells, then erased and reset each generation during gamete formation.

The most tested example involves chromosome 15q11-13: - Prader-Willi syndrome: occurs when the paternal copy of the region is deleted (or maternal uniparental disomy occurs), since the paternal allele is normally the only one expressed (maternal allele is imprinted/silenced). Presents with hyperphagia/obesity, hypotonia, intellectual disability, and hypogonadism. - Angelman syndrome: occurs when the maternal copy is deleted (or paternal uniparental disomy occurs), since the maternal allele is normally the only one expressed. Presents with ataxia, seizures, inappropriate laughter ("happy puppet" syndrome), and severe intellectual disability.

Other imprinted genes include IGF2 (paternally expressed; associated with Beckwith-Wiedemann syndrome when biallelically expressed, and Silver-Russell syndrome when both alleles are silenced) and H19 (maternally expressed, functions as a tumor suppressor/growth regulator).

Clinical significance: Imprinting disorders illustrate that phenotype can depend on parental origin of a mutation, not just presence of a mutant allele. This concept is important for understanding uniparental disomy, epigenetic silencing, and why genetic counseling must consider the parental origin of chromosomal abnormalities. It also explains why some conditions are more severe when inherited from a specific parent (e.g., certain repeat expansion diseases like Huntington's show anticipation more from paternal inheritance).