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Epigenetic characterization of discordant twins with Beckwith Wiedemann syndrome, with clinical findings at birth and neurodevelopmental follow-up
Introduction: Beckwith-Wiedemann syndrome (BWS) is one of the most frequent congenital disorders that is predominantly caused by epigenetic defects. Monozygotic discordant twins are ideal to study those defects since they are, by conventional genetics, identical. Case: The monochorial, biamniotic twin pregnancy of this GIIPI mother was complicated by discordant growth of the twins, and feto-fetal transfusion. Upon their preterm birth at 31+1 weeks gestation, the male twins were found discordant also for BWS by clinical criteria: among other findings, the blood-receiving LGA twin had macroglossia.
With informed parental consent, a genetic work-up using conventional genetic and epigenetic methods was pursued in the entire family. Extensive fotodocumentation of the twins' clinical findings is available, as are data about growth and psychomotor development up to the age of 6 years.
Methods: DNA methylation was studied on 4 different DMRs (differenzially methylated domains) within the BWS region that were shown to be most reponsible for phenotypic alterations, like KvDMR1 and H19/IGF2 DMR. In addition, we also analyzed other imprinted domains/genes that are thought to be involved in embryonic growth, like GRB10, SNRPN, MEST, GNAS and DLK1/MEG3 IG-DMR, within the BWS region on 11p15.5. Results: We found the KvDMR1 to be hypomethylated in blood of the affected and unaffected twin, while in fibroblasts, buccal swab and saliva, the region revealed epigenetical discordance. The IGF2/H19 DMRs showed no significant differences between the twins. Interestingly, in the IGF2 DMR2 we observed an epigenetical similarity of the affected twin to the older sister, who had had slight hypertrophy at birth but is otherwise normal. Looking at other imprinted loci which are involved in prenatal growth, we did not detect any significant alterations in DNA methylation between the family members. Conclusion: For the BWS-affected twin, the results point to an almost exclusive role of the KvDMR1– methylation for the development of the phenotype.
Annotation: This report is dedicated to Prof. F.C. Sitzmann.