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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 (LOM) at KCNQ1OT1: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.

SUBMITTER: Duffy KA

PROVIDER: S-EPMC8751414 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBeckwith-Wiedemann syndrome (BWS) is an imprinting disorder with a population frequency of approximately 1 in 10,000. The most common epigenetic defect in BWS is a loss of methylation (LOM) at the 11p15.5 imprinting centre, KCNQ1OT1 TSS-DMR, and affects 50% of cases. We hypothesised that genetic factors linked to folate metabolism may play a role in BWS predisposition via effects on methylation maintenance at KCNQ1OT1 TSS-DMR.ResultsSingle nucleotide variants (SNVs) in the folate pathway affecting methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), 5-methyltetrahydrofolate-homocysteine S-methyltransferase (MTR), cystathionine beta-synthase (CBS) and methionine adenosyltransferase (MAT1A) were examined in 55 BWS patients with KCNQ1OT1 TSS-DMR LOM and in 100 unaffected cases. MTHFR rs1801133: C>T was more prevalent in BWS with KCNQ1OT1 TSS-DMR LOM (p < 0.017); however, the relationship was not significant when the Bonferroni correction for multiple testing was applied (significance, p = 0.0036). None of the remaining 13 SNVs were significantly different in the two populations tested. The DNMT1 locus was screened in 53 BWS cases, and three rare missense variants were identified in each of three patients: rs138841970: C>T, rs150331990: A>G and rs757460628: G>A encoding NP_001124295 p.Arg136Cys, p.His1118Arg and p.Arg1223His, respectively. These variants have population frequencies of less than 1 in 1000 and were absent from 100 control cases. Functional characterization using a hemimethylated DNA trapping assay revealed a reduced methyltransferase activity relative to wild-type DNMT1 for each variant ranging from 40 to 70% reduction in activity.ConclusionsThis study is the first to examine folate pathway genetics in BWS and to identify rare DNMT1 missense variants in affected individuals. Our data suggests that reduced DNMT1 activity could affect maintenance of methylation at KCNQ1OT1 TSS-DMR in some cases of BWS, possibly via a maternal effect in the early embryo. Larger cohort studies are warranted to further interrogate the relationship between impaired MTHFR enzymatic activity attributable to MTHFR rs1801133: C>T, dietary folate intake and BWS.

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

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