Cited Evidence on Loss of Imprinting (LOI) in Genetic Disorders and Cancer

Mechanisms of Genomic Imprinting

Genomic imprinting is an epigenetic form of gene silencing that occurs during gametogenesis, resulting in parent‑of‑origin‑specific expression of approximately 50–80 genes. 1
Hypermethylation of promoters of tumor‑suppressor genes such as MLH1 and p16 inhibits their expression and can promote tumor progression. 1

In up to 5 % of PWS cases, an imprinting error causes the paternal chromosome 15 to be fully methylated, preventing re‑activation of silenced genes and leading to loss of paternal gene expression; this accounts for <2 % of all PWS cases, while the majority (>70 %) are due to deletions and ~28 % to maternal uniparental disomy. 2

Angelman syndrome can result from loss of the maternal contribution to the 15q11‑q13 region due to an imprinting mutation; when biparental inheritance is confirmed but an imprinting defect is present, this represents a loss‑of‑imprinting mechanism. 3
Additional studies corroborate that imprinting mutations underlie a subset of Angelman syndrome cases, emphasizing the role of LOI in its pathogenesis. 4

Hypermethylation‑mediated silencing of tumor‑suppressor gene promoters (e.g., MLH1, p16) is a mechanistic link between LOI and oncogenesis, supporting the use of LOI as a biomarker for cancer risk and progression. 1

The “imprinting center,” a short DNA sequence, governs the switching and maintenance of parental‑specific methylation patterns that ensure mono‑allelic expression of imprinted genes. 5

In ≤5 % of PWS cases, the paternal chromosome 15 inherited from the father’s mother is fully methylated, preventing re‑activation of silenced genes and leading to loss of paternal gene expression. This imprinting error is described by the American Academy of Pediatrics. [5][6]
The infant receives one copy of chromosome 15 from each parent, but the PWS region is methylated on both copies, resulting in complete silencing of the locus and absence of functional gene products. [7][6]

Angelman syndrome arises from loss of the maternal contribution to the same 15q11‑q13 region, reflecting an imprinting error that silences maternal alleles while paternal alleles remain inactive for the affected genes. [5][8]

Loss of imprinting (LOI) does not involve alterations in the DNA sequence; instead, it reflects abnormal epigenetic marks—primarily DNA methylation—affecting gene regulation, distinguishing it from classic genetic mutations. [5][6]