Epigenetic mosaicism and cell burden in Beckwith-Wiedemann syndrome due to loss of methylation at imprinting control region 2

Beckwith-Wiedemann syndrome (BWS) is a rare overgrowth disorder caused by epigenetic alterations on Chromosome 11p15.5. Most molecular changes are sporadic and are thought to occur in a mosaic pattern. Thereby, the distribution of affected cells differs between tissues for each individual, which can...

Full description

Saved in:
Bibliographic Details
Published in:Cold Spring Harbor molecular case studies 2021-12, Vol.7 (6), p.a006115
Main Authors: Duffy, Kelly A, Hathaway, Evan R, Klein, Steven D, Ganguly, Arupa, Kalish, Jennifer M
Format: Article
Language:English
Subjects:
Beckwith-Wiedemann Syndrome - genetics
Chromosome 11
DNA Methylation
Embryogenesis
Embryonic growth stage
Epigenetics
Female
Genomic Imprinting
Genotypes
Humans
KCNQ1OT1 protein
Methylation
Mosaicism
Mosaics
Pathogenesis
Phenotype
Phenotypes
Potassium channels (voltage-gated)
Pregnancy
Skewed distributions
Tissues
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Beckwith-Wiedemann syndrome (BWS) is a rare overgrowth disorder caused by epigenetic alterations on Chromosome 11p15.5. Most molecular changes are sporadic and are thought to occur in a mosaic pattern. Thereby, the distribution of affected cells differs between tissues for each individual, which can complicate genotype-phenotype correlations. In two of the BWS molecular subtypes, tissue mosaicism has been demonstrated; however, mosaicism has not been specifically studied in the most common cause of BWS, loss of methylation (LOM) at TSS differentially methylated region (DMR) imprinting center 2 (IC2) LOM. The increased prevalence of twinning associated with the IC2 LOM subtype and the discordant phenotypes between the twins previously led to the proposal of diffused epigenetic mosaicism, leading to asymmetric distribution of affected cells during embryonic development. In this study, we evaluated the level of methylation detected in 64 samples collected from 30 individuals with IC2 LOM. We demonstrate that the IC2 LOM defect can occur in mosaic and nonmosaic patterns, and tissues from the same individual can show variable patterns, which suggests that this asymmetric distribution occurs during development. We further suggest that the clinical phenotype in individuals with BWS IC2 LOM is correlated with the epigenetic burden of affected cells in each tissue type. This series is the first report to demonstrate tissue mosaicism within the IC2 LOM epigenotype, and consideration of this mosaicism is necessary to understanding the pathogenesis of BWS.
ISSN:2373-2865
2373-2873
DOI:10.1101/mcs.a006115