Genomic Imprinting

Genomic imprinting is an epigenetic phenomenon in which gene expression depends on the parent of origin. Imprinted genes are silenced on one parental allele through DNA methylation and histone modification, so only the allele from one specific parent is expressed. Disruption of imprinting (through deletion, uniparental disomy, or imprinting center defects) causes distinct clinical syndromes.

• Parent-of-origin expression: Imprinted genes are monoallelically expressed. Some are expressed only from the paternal allele (e.g., IGF2) and others only from the maternal allele (e.g., H19, UBE3A in brain).
• Imprinting centers (ICs): Regulatory regions that control the methylation status of imprinted gene clusters. Mutations or epimutations at the IC can disrupt imprinting of multiple genes.
• DNA methylation: The primary mechanism of imprinting. Methylation marks are erased in primordial germ cells and re-established according to the sex of the transmitting parent.
• Uniparental disomy (UPD): Inheritance of both copies of a chromosome (or segment) from one parent. Isodisomy = two copies of one homolog; heterodisomy = one copy of each homolog from the same parent. UPD can cause disease if it involves an imprinted region.
• Imprinting clusters: Imprinted genes occur in clusters, not scattered randomly. Major clusters include 15q11.2-q13 (Prader-Willi/Angelman), 11p15.5 (Beckwith-Wiedemann/Silver-Russell), and 14q32.

• Prader-Willi syndrome (PWS): Loss of paternally expressed genes at 15q11.2-q13 (SNRPN cluster). Causes include ~70% paternal deletion, ~25% maternal UPD 15, ~2-5% imprinting defect. Features: neonatal hypotonia, childhood-onset hyperphagia/obesity, intellectual disability, hypogonadism.
• Angelman syndrome (AS): Loss of maternally expressed UBE3A at 15q11.2-q13. Causes include ~70% maternal deletion, ~3-7% paternal UPD 15, ~3% imprinting defect, ~10% UBE3A point mutations. Features: severe intellectual disability, absent speech, seizures, ataxic gait, happy demeanor.
• Beckwith-Wiedemann syndrome (BWS): Imprinting defects at 11p15.5 involving IGF2 (paternally expressed growth factor) and CDKN1C (maternally expressed growth suppressor). Features: macrosomia, macroglossia, omphalocele, hemihyperplasia, and increased embryonal tumor risk (Wilms tumor, hepatoblastoma).
• Silver-Russell syndrome: Often involves hypomethylation at 11p15.5 (H19/IGF2 locus) or maternal UPD 7. Features: intrauterine and postnatal growth restriction, relative macrocephaly, body asymmetry.