Characterization of DNA methylation errors in patients with imprinting disorders conceived by assisted reproduction technologies

Hitoshi Hiura, Hiroaki Okae, Naoko Miyauchi, Fumi Sato, Akiko Sato, Mathew Van De Pette, Rosalind M. John, Masayo Kagami, Kunihiko Nakai, Hidenobu Soejima, Tsutomu Ogata, Takahiro Arima

Research output: Contribution to journalArticlepeer-review

81 Citations (Scopus)

Abstract

background: There is an increased incidence of rare imprinting disorders associated with assisted reproduction technologies (ARTs). The identification of epigenetic changes at imprinted loci in ART infants has led to the suggestion that the techniques themselves may predispose embryos to acquire imprinting errors and diseases. However, it is still unknown at what point(s) these imprinting errors arise, or the risk factors. methods: In 2009 we conducted a Japanese nationwide epidemiological study of four well-known imprinting diseases to determine any association with ART. Using bisulfite sequencing, we examine the DNA methylation status of 22 gametic differentially methylated regions (gDMRs) located within the known imprinted loci in patients with Beckwith-Wiedemann syndrome (BWS, n = 1) and also Silver-Russell syndrome (SRS, n = 5) born after ART, and compared these with patients conceived naturally. results: We found a 10-fold increased frequency of BWS and SRS associated with ART. The majority of ART cases showed aberrant DNA methylation patterns at multiple imprinted loci both maternal and paternal gDMRs (5/6), with both hyper- and hypomethylation events (5/6) and also mosaic methylation errors (5/6). Although our study may have been limited by a small sample number, the fact that many of the changes were mosaic suggested that they occurred after fertilization. In contrast, few of the patients who were conceived naturally exhibited a similar pattern of mosaic alterations. The differences in methylation patterns between the patients who were conceived naturally or after ART did not manifest due to the differences in the disease phenotypes in these imprinting disorders. conclusion: A possible association between ART and BWS/SRS was found, and we observed a more widespread disruption of genomic imprints after ART. The increased frequency of imprinting disorders after ART is perhaps not surprising given the major epigenetic events that take place during early development at a time when the epigenome is most vulnerable.

Original languageEnglish
Pages (from-to)2541-2548
Number of pages8
JournalHuman Reproduction
Volume27
Issue number8
DOIs
Publication statusPublished - 2012 Aug

Keywords

  • Assisted reproduction technologies
  • DNA methylation
  • Gametic differentially methylated regions
  • Genomic imprinting
  • Genomic imprinting disorders

ASJC Scopus subject areas

  • Reproductive Medicine
  • Obstetrics and Gynaecology

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