Abstract
Beckwith-Wiedemann syndrome (BWS) is a representative imprinting disorder. Gain of methylation at imprinting control region 1 (ICR1-GOM), leading to the biallelic expression of IGF2 and silencing of H19, is one of the causative alterations in BWS. Twenty percent of BWS patients with ICR1-GOM have genetic defects in ICR1. Evidence of methylation anticipation in familial BWS patients with ICR1 genetic defects has been reported. However, the precise methylation pattern and extent of anticipation in these patients remain elusive. In addition, although age-related IGF2-DMR0 hypomethylation has been reported in the normal population, the period of its occurrence is unknown. In this study, we analyzed 10 sites (IGF2-DMR0, IGF2-DMR2, CTCF binding sites 1–7, and the H19 promoter) within the IGF2/H19 domain in familial BWS patients harboring a pathogenic variant in ICR1. We found that sites near the variant had relatively higher methylation in the first affected generation and observed methylation anticipation through maternal transmission in the next generation. The extent of anticipation was greater at sites far from the variant than nearby sites. The extended and severe GOM might be due to the insufficient erasure/demethylation of pre-acquired ICR1-GOM in primordial germ cells or during the preimplantation stage. In the normal population, age-related IGF2-DMR0 hypomethylation occurred; it became established by young adulthood and continued to old age. Further studies are needed to clarify (1) the precise mechanism of anticipation in patients with familial BWS and (2) the mechanism and biological significance of constitutive hypomethylation of IGF2-DMR0 and/or other imprinted differentially methylated regions.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Soejima H, Higashimoto K. Epigenetic and genetic alterations of the imprinting disorder Beckwith-Wiedemann syndrome and related disorders. J Hum Genet. 2013;58:402–9.
Brioude F, Kalish JM, Mussa A, Foster AC, Bliek J, Ferrero GB, et al. Expert consensus document: clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement. Nat Rev Endocrinol. 2018;14:229–49.
Thorburn MJ, Wright ES, Miller CG, Smith-Read EH. Exomphalos-macroglossia-gigantism syndrome in Jamaican infants. Am J Dis Child. 1970;119:316–21.
Mussa A, Russo S, De Crescenzo A, Chiesa N, Molinatto C, Selicorni A, et al. Prevalence of Beckwith-Wiedemann syndrome in North West of Italy. Am J Med Genet A. 2013;161A:2481–6.
Uyar A, Seli E. The impact of assisted reproductive technologies on genomic imprinting and imprinting disorders. Curr Opin Obstet Gynecol. 2014;26:210–21.
Lazaraviciute G, Kauser M, Bhattacharya S, Haggarty P, Bhattacharya S. A systematic review and meta-analysis of DNA methylation levels and imprinting disorders in children conceived by IVF/ICSI compared with children conceived spontaneously. Hum Reprod Update. 2014;20:840–52.
Mussa A, Molinatto C, Cerrato F, Palumbo O, Carella M, Baldassarre G, et al. Assisted reproductive techniques and risk of Beckwith-Wiedemann syndrome. Pediatrics. 2017;140:e20164311.
Eggermann T, Algar E, Lapunzina P, Mackay D, Maher ER, Mannens M, et al. Clinical utility gene card for: Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2014. https://www.nature.com/articles/ejhg2013132
Sparago A, Cerrato F, Vernucci M, Ferrero GB, Silengo MC, Riccio A. Microdeletions in the human H19 DMR result in loss of IGF2 imprinting and Beckwith-Wiedemann syndrome. Nat Genet. 2004;36:958–60.
Prawitt D, Enklaar T, Gartner-Rupprecht B, Spangenberg C, Oswald M, Lausch E, et al. Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms’ tumor. Proc Natl Acad Sci USA. 2005;102:4085–90.
Sparago A, Russo S, Cerrato F, Ferraiuolo S, Castorina P, Selicorni A, et al. Mechanisms causing imprinting defects in familial Beckwith-Wiedemann syndrome with Wilms’ tumour. Hum Mol Genet. 2007;16:254–64.
Demars J, Shmela ME, Rossignol S, Okabe J, Netchine I, Azzi S, et al. Analysis of the IGF2/H19 imprinting control region uncovers new genetic defects, including mutations of OCT-binding sequences, in patients with 11p15 fetal growth disorders. Hum Mol Genet. 2010;19:803–14.
Poole RL, Leith DJ, Docherty LE, Shmela ME, Gicquel C, Splitt M, et al. Beckwith-Wiedemann syndrome caused by maternally inherited mutation of an OCT-binding motif in the IGF2/H19-imprinting control region, ICR1. Eur J Hum Genet. 2012;20:240–3.
Higashimoto K, Jozaki K, Kosho T, Matsubara K, Fuke T, Yamada D, et al. A novel de novo point mutation of the OCT-binding site in the IGF2/H19-imprinting control region in a Beckwith-Wiedemann syndrome patient. Clin Genet. 2013;86:539–44.
Abi Habib W, Azzi S, Brioude F, Steunou V, Thibaud N, Das Neves C, et al. Extensive investigation of the IGF2/H19 imprinting control region reveals novel OCT4/SOX2 binding site defects associated with specific methylation patterns in Beckwith-Wiedemann syndrome. Hum Mol Genet. 2014;23:5763–73.
Weth O, Renkawitz R. CTCF function is modulated by neighboring DNA binding factors. Biochem Cell Biol. 2011;89:459–68.
Berland S, Appelbäck M, Bruland O, Beygo J, Buiting K, Mackay DJ, et al. Evidence for anticipation in Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2013;21:1344–8.
Murrell A, Ito Y, Verde G, Huddleston J, Woodfine K, Silengo MC, et al. Distinct methylation changes at the IGF2-H19 locus in congenital growth disorders and cancer. PLoS ONE. 2008;3:e1849.
Sullivan MJ, Taniguchi T, Jhee A, Kerr N, Reeve AE. Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation. Oncogene. 1999;18:7527–34.
Cui H, Onyango P, Brandenburg S, Wu Y, Hsieh CL, Feinberg AP. Loss of imprinting in colorectal cancer linked to hypomethylation of H19 and IGF2. Cancer Res. 2002;62:6442–6.
Hidaka H, Higashimoto K, Aoki S, Mishima H, Hayashida C, Maeda T, et al. Comprehensive methylation analysis of imprinting-associated differentially methylated regions in colorectal cancer. Clin Epigenetics. 2018;10:150.
Ito Y, Koessler T, Ibrahim AE, Rai S, Vowler SL, Abu-Amero S, et al. Somatically acquired hypomethylation of IGF2 in breast and colorectal cancer. Hum Mol Genet. 2008;17:2633–43.
Elliott M, Bayly R, Cole T, Temple IK, Maher ER. Clinical features and natural history of Beckwith-Wiedemann syndrome: presentation of 74 new cases. Clin Genet. 1994;46:168–74.
DeBaun MR, Tucker MA. Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry. J Pedia. 1998;132(3 Pt 1):398–400.
Weksberg R, Shuman C, Beckwith JB. Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2010;18:8–14.
Higashimoto K, Nakabayashi K, Yatsuki H, Yoshinaga H, Jozaki K, Okada J, et al. Aberrant methylation of H19-DMR acquired after implantation was dissimilar in soma versus placenta of patients with Beckwith-Wiedemann syndrome. Am J Med Genet A. 2012;158A:1670–5.
Hori N, Nakano H, Takeuchi T, Kato H, Hamaguchi S, Oshimura M, et al. A dyad oct-binding sequence functions as a maintenance sequence for the unmethylated state within the H19/Igf2-imprinted control region. J Biol Chem. 2002;277:27960–7.
Hori N, Yamane M, Kouno K, Sato K. Induction of DNA demethylation depending on two sets of Sox2 and adjacent Oct3/4 binding sites (Sox-Oct motifs) within the mouse H19/insulin-like growth factor 2 (Igf2) imprinted control region. J Biol Chem. 2012;287:44006–16.
Zimmerman DL, Boddy CS, Schoenherr CS. Oct4/Sox2 binding sites contribute to maintaining hypomethylation of the maternal igf2/h19 imprinting control region. PLoS ONE. 2013;8:e81962.
Mussa A, Molinatto C, Baldassarre G, Riberi E, Russo S, Larizza L, et al. Cancer risk in Beckwith-Wiedemann syndrome: a systematic review and meta-analysis outlining a novel (epi)genotype specific histotype targeted screening protocol. J Pedia. 2016;176:e1.
Maas SM, Vansenne F, Kadouch DJ, Ibrahim A, Bliek J, Hopman S, et al. Phenotype, cancer risk, and surveillance in Beckwith-Wiedemann syndrome depending on molecular genetic subgroups. Am J Med Genet A. 2016;170:2248–60.
Acknowledgements
We thank the Analytical Research Center for Experimental Sciences, Saga University, for their experimental support. This study was supported by the following: grants from the Grant-in-Aid for Scientific Research (C) program of the Japan Society for the Promotion of Science [16K09970, awarded to KH; 17K08687, awarded to HS], grants for Practical Research Projects for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED) [17ek0109280h0001, 17ek0109234h0001, and 17ek0109205h0001, awarded to HS], a grant for Child Health and Development research from the National Center for Child Health and Development [26–13, awarded to HS], a grant for Research on Intractable Diseases from the Ministry of Health, Labor, and Welfare [H29-nanchitou(nan)-ippan-025, awarded to HS], a grant from the Joint Research Program of the Institute for Molecular and Cellular Regulation at Gunma University [16029, awarded to KH], and a grant from the 2018 Liaoning Provincial Natural Science Key Project of China [no. 20180530064, awarded to FS].
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Sun, F., Higashimoto, K., Awaji, A. et al. The extent of DNA methylation anticipation due to a genetic defect in ICR1 in Beckwith-Wiedemann syndrome. J Hum Genet 64, 937–943 (2019). https://doi.org/10.1038/s10038-019-0634-0
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s10038-019-0634-0
This article is cited by
-
Thirteen cases support the clinical significance of imprinting center 1 (IC1) microdeletions in Beckwith–Wiedemann syndrome
Clinical Epigenetics (2025)
-
Identification of responsible sequences which mutations cause maternal H19-ICR hypermethylation with Beckwith–Wiedemann syndrome-like overgrowth
Communications Biology (2024)
