Clinical Epigenetics (Aug 2018)

Genetic variation affecting DNA methylation and the human imprinting disorder, Beckwith-Wiedemann syndrome

  • Vinod Dagar,
  • Wendy Hutchison,
  • Andrea Muscat,
  • Anita Krishnan,
  • David Hoke,
  • Ashley Buckle,
  • Priscillia Siswara,
  • David J. Amor,
  • Jeffrey Mann,
  • Jason Pinner,
  • Alison Colley,
  • Meredith Wilson,
  • Rani Sachdev,
  • George McGillivray,
  • Matthew Edwards,
  • Edwin Kirk,
  • Felicity Collins,
  • Kristi Jones,
  • Juliet Taylor,
  • Ian Hayes,
  • Elizabeth Thompson,
  • Christopher Barnett,
  • Eric Haan,
  • Mary-Louise Freckmann,
  • Anne Turner,
  • Susan White,
  • Ben Kamien,
  • Alan Ma,
  • Fiona Mackenzie,
  • Gareth Baynam,
  • Cathy Kiraly-Borri,
  • Michael Field,
  • Tracey Dudding-Byth,
  • Elizabeth M. Algar

DOI
https://doi.org/10.1186/s13148-018-0546-4
Journal volume & issue
Vol. 10, no. 1
pp. 1 – 13

Abstract

Read online

Abstract Background Beckwith-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. Results Single 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 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. Conclusions This 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.

Keywords