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

Abstract

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 at KCNQ1OT1:TSS DMR (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 patients affected by IC2 LOM. We demonstrate that the IC2 LOM defect can occur in mosaic and non-mosaic patterns, and tissues from the same patient can show variable patterns, which suggests this asymmetric distribution during development. We further suggest that the clinical phenotype in patients 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.