Clinical and molecular genetic features of Beckwith–Wiedemann syndrome associated with assisted reproductive technologies

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...

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Bibliographic Details
Published in:Human reproduction (Oxford) 2009-03, Vol.24 (3), p.741-747
Main Authors: Lim, Derek, Bowdin, Sarah C., Tee, Louise, Kirby, Gail A., Blair, Edward, Fryer, Alan, Lam, Wayne, Oley, Christine, Cole, Trevor, Brueton, Louise A., Reik, Wolf, Macdonald, Fiona, Maher, Eamonn R.
Format: Article
Language:English
Subjects:
Alleles
assisted reproductive technologies
Beckwith-Wiedemann Syndrome - diagnosis
Beckwith-Wiedemann Syndrome - genetics
Beckwith–Wiedemann syndrome
Biological and medical sciences
Child
Child, Preschool
DNA Methylation
Epigenesis, Genetic
epimutations
Female
Fertilization in Vitro - methods
Genomic Imprinting
Genomics
Gynecology. Andrology. Obstetrics
Humans
imprinting disorder
loss of methylation
Male
Medical sciences
Mutation
Reproductive Techniques, Assisted - adverse effects
Sperm Injections, Intracytoplasmic - methods
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Summary: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.
ISSN:0268-1161
1460-2350
DOI:10.1093/humrep/den406