ArticleClinical epigenetics2018
Genetic variation affecting DNA methylation and the human imprinting disorder, Beckwith-Wiedemann syndrome.
Article in Clinical epigenetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8 citing papers in PubMed, 23 citations in OpenAlex.
- Multi-omic analysis identifies a multi-step pathology in a case of multiple chorangioma syndrome in monochorionic twins.Orphanet journal of rare diseases · 2026Article
- Review
- Rescuing DNMT1 fails to fully reverse the molecular and functional repercussions of its loss in mouse embryonic stem cells.Nucleic acids research · 2025Article
- Identification of differentially methylated regions in rare diseases from a single-patient perspective.Clinical epigenetics · 2022Article
- Sparse principal component analysis based on genome network for correcting cell type heterogeneity in epigenome-wide association studies.Medical & biological engineering & computing · 2022Article
- Current views in chronic obstructive pulmonary disease pathogenesis and management.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2021Review
- Genomic imprinting disorders: lessons on how genome, epigenome and environment interact.Nature reviews. Genetics · 2019Review
- Crosstalk of Genetic Variants, Allele-Specific DNA Methylation, and Environmental Factors for Complex Disease Risk.Frontiers in genetics · 2018Review
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34 authors at 18 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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