Association of four imprinting disorders and ART

Hiromitsu Hattori,Norio Kobayashi,Hiroaki Okae,Tsutomu Ogata,Koichi Kyono,Naoko Miyauchi,Hitoshi Hiura,Masayo Kagami,Takahiro Arima,Souta Takahashi,Akane Kitamura

doi:10.1186/s13148-019-0623-3

Abstract

BackgroundHuman-assisted reproductive technologies (ART) are a widely accepted treatment for infertile couples. At the same time, many studies have suggested the correlation between ART and increased incidences of normally rare imprinting disorders such as Beckwith-Wiedemann syndrome (BWS), Angelman syndrome (AS), Prader-Willi syndrome (PWS), and Silver-Russell syndrome (SRS). Major methylation dynamics take place during cell development and the preimplantation stages of embryonic development. ART may prevent the proper erasure, establishment, and maintenance of DNA methylation. However, the causes and ART risk factors for these disorders are not well understood.ResultsA nationwide epidemiological study in Japan in 2015 in which 2777 pediatrics departments were contacted and a total of 931 patients with imprinting disorders including 117 BWS, 227 AS, 520 PWS, and 67 SRS patients, were recruited. We found 4.46- and 8.91-fold increased frequencies of BWS and SRS associated with ART, respectively. Most of these patients were conceived via in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and showed aberrant imprinted DNA methylation. We also found that ART-conceived SRS (ART-SRS) patients had incomplete and more widespread DNA methylation variations than spontaneously conceived SRS patients, especially in sperm-specific methylated regions using reduced representation bisulfite sequencing to compare DNA methylomes. In addition, we found that the ART patients with one of three imprinting disorders, PWS, AS, and SRS, displayed additional minor phenotypes and lack of the phenotypes. The frequency of ART-conceived Prader-Willi syndrome (ART-PWS) was 3.44-fold higher than anticipated. When maternal age was 37 years or less, the rate of DNA methylation errors in ART-PWS patients was significantly increased compared with spontaneously conceived PWS patients.ConclusionsWe reconfirmed the association between ART and imprinting disorders. In addition, we found unique methylation patterns in ART-SRS patients, therefore, concluded that the imprinting disorders related to ART might tend to take place just after fertilization at a time when the epigenome is most vulnerable and might be affected by the techniques of manipulation used for IVF or ICSI and the culture medium of the fertilized egg.

Highlights

Human-assisted reproductive technologies (ART) are a widely accepted treatment for infertile couples
We inquired about detailed clinical information and examined the relationship with ART using a second-stage survey ensuring the exclusion of duplicates and a total of 931 patients with imprinting disorders were recruited
We ascertained the frequencies of ART-Beckwith-Wiedemann syndrome (BWS), ART-Angelman syndrome (AS), ART-Prader-Willi syndrome (PWS), and ART-Silver-Russell syndrome (SRS) via a questionnaire sent to doctors (Table 1)

Summary

Introduction

Human-assisted reproductive technologies (ART) are a widely accepted treatment for infertile couples. Many studies have suggested the correlation between ART and increased incidences of normally rare imprinting disorders such as Beckwith-Wiedemann syndrome (BWS), Angelman syndrome (AS), Prader-Willi syndrome (PWS), and Silver-Russell syndrome (SRS). The majority of studies published previously have suggested that babies conceived after ART have increased incidences of normally rare imprinting disorders such as Beckwith-Wiedemann syndrome (BWS), Angelman syndrome (AS), PraderWilli syndrome (PWS), and Silver-Russell syndrome (SRS) [2,3,4,5,6,7]. Many studies have suggested that ovarian stimulation, culture media used for gametes and early embryos, in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) manipulations, and the freezing and thawing of embryos may prevent the proper establishment and maintenance of genomic imprinting and cause imprinting disorders [11, 12]

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