Hum. Reprod. Advance Access originally published online on December 10, 2008
Human Reproduction 2009 24(3):741-747; doi:10.1093/humrep/den406
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Clinical and molecular genetic features of Beckwith–Wiedemann syndrome associated with assisted reproductive technologies
1 Department of Medical and Molecular Genetics, University of Birmingham School of Medicine, Institute of Biomedical Research, Birmingham B15 2TT, UK 2 West Midlands Regional Genetics Service, Birmingham Women's Hospital, Edgbaston, Birmingham B15 2TG, UK 3 Department of Clinical Genetics, Churchill Hospital, Old Road Headington, Oxford OX3 7LJ, UK 4 Department of Clinical Genetics, Royal Liverpool Children's Hospital, Liverpool L12 2AP, UK 5 South East of Scotland Clinical Genetics Service, Edinburgh, UK 6 Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge CB2 4AT, UK
7 Correspondence address. Tel: +44-121-627-2741; Fax: +44-121-414-2538; E-mail: e.r.maher{at}bham.ac.uk
BACKGROUND: Beckwith–Wiedemann syndrome (BWS) is a model imprinting disorder resulting from mutations or epigenetic events affecting imprinted genes at 11p15.5. Most BWS cases are sporadic and result from imprinting errors (epimutations) involving either of the two 11p15.5 imprinting control regions (IC1 and IC2). Previously, we and other reported an association between sporadic BWS and assisted reproductive technologies (ARTs).
METHODS: In this study, we compared the clinical phenotype and molecular features of ART (IVF and ICSI) and non-ART children with sporadic BWS. A total of 25 patients with post-ART BWS were ascertained (12 after IVF and 13 after ICSI).
RESULTS: Molecular genetic analysis revealed an IC2 epimutations (KvDMR1 loss of methylation) in 24 of the 25 children tested. Comparison of clinical features of children with post-ART BWS to those with non-ART BWS and IC2 defects revealed a lower frequency of exomphalos (43 versus 69%, P = 0.029) and a higher risk of neoplasia (two cases, P = 0.0014). As loss of methylation at imprinting control regions other than 11p15.5 might modify the phenotype of BWS patients with IC2 epimutations, we investigated differentially methylated regions (DMRs) at 6q24, 7q32 and 15q13 in post-ART and non-ART BWS IC2 cases (n = 55). Loss of maternal allele methylation at these DMRs occurred in 37.5% of ART and 6.4% of non-ART BWS IC2 defect cases. Thus, more generalized DMR hypomethylation is more frequent, but not exclusive to post-ART BWS.
CONCLUSIONS: These findings provide further evidence that ART may be associated with disturbed normal genomic imprinting in a subset of children.
Key words: Beckwith–Wiedemann syndrome/imprinting disorder/assisted reproductive technologies/epimutations/loss of methylation
Submitted on April 15, 2008; resubmitted on October 8, 2008; accepted on October 17, 2008.
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