The extent of DNA methylation anticipation due to a genetic defect in ICR1 in Beckwith-Wiedemann syndrome
2019
Beckwith-Wiedemann syndrome (BWS) is a representative imprinting disorder. Gain of methylation at imprinting control region 1 (ICR1-GOM), leading to the biallelic expression of IGF2 and silencing of H19, is one of the causative alterations in BWS. Twenty percent of BWS patients with ICR1-GOM have genetic defects in ICR1. Evidence of methylation anticipation in familial BWS patients with ICR1 genetic defects has been reported. However, the precise methylation pattern and extent of anticipation in these patients remain elusive. In addition, although age-related IGF2-DMR0 hypomethylation has been reported in the normal population, the period of its occurrence is unknown. In this study, we analyzed 10 sites (IGF2-DMR0, IGF2-DMR2, CTCF binding sites 1–7, and the H19 promoter) within the IGF2/H19 domain in familial BWS patients harboring a pathogenic variant in ICR1. We found that sites near the variant had relatively higher methylation in the first affected generation and observed methylation anticipation through maternal transmission in the next generation. The extent of anticipation was greater at sites far from the variant than nearby sites. The extended and severe GOM might be due to the insufficient erasure/demethylation of pre-acquired ICR1-GOM in primordial germ cells or during the preimplantation stage. In the normal population, age-related IGF2-DMR0 hypomethylation occurred; it became established by young adulthood and continued to old age. Further studies are needed to clarify (1) the precise mechanism of anticipation in patients with familial BWS and (2) the mechanism and biological significance of constitutive hypomethylation of IGF2-DMR0 and/or other imprinted differentially methylated regions.
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