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 I I pI5.5. Most BWS cases are sporadic and result from imprinting errors (epimutations) involving either of the two I I p 15.5 imprinting control regions (IC I 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 (KvDMRI 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 I I p 15.5 might modify the phenotype of BWS patients with IC2 epimutations, we investigated differentially methylated regions (DMRs) at 6q24, 7q32 and I5qI3 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.