The epigenetic imprinting defect of Beckwith-Wiedemann patients born following assisted reproductive technology is not restricted to the 11P15 region

Sylvie Rossignol ¹, Virginie Steunou ¹, Celine Chalas ², Antoine Kerjean ², Muriel Rigolet ³, Evani Viegas-Pequignot ³, Pierre Jouannet ², Yves Le Bouc ¹ and Christine Gicquel ^1*

¹ Hopital Trousseau, France
² Hopital Cochin-Port-Royal, France
³ Institut Jacques Monod, France

^* To whom correspondence should be addressed. E-mail: christine.gicquel{at}trs.aphp.fr.

Accepted 5 June 2006

Abstract

Background: Genomic imprinting refers to an epigenetic marking resulting in monoallelic gene expression and plays a critical role in fetal development. Various imprinting diseases have recently been reported in humans and animals born following the use of assisted reproductive technology (ART). All the epimutations implicated involve a loss of methylation of the maternal allele (demethylation of KvDMR1/KCNQ1OT1 in Beckwith-Wiedemann syndrome (BWS), demethylation of SNRPN in Angelman syndrome and demethylation of DMR2/IGF2R in large offspring syndrome), suggesting that ART impairs the acquisition or maintenance of methylation marks on maternal imprinted genes. However, it is unknown whether this epigenetic imprinting error is random or restricted to a specific imprinted domain.

Methods: In this study, we analyzed the methylation status of various imprinted genes (IGF2R gene at 6q26, PEG1/MEST at 7q32, KCNQ1OT1 and H19 at 11p15.5 and SNRPN at 15q11-13) in 40 BWS patients displaying loss of methylation at KCNQ1OT1 (11 BWS patients born after the use of ART and 29 BWS patients conceived naturally).

Results: Three of the 11 ART-conceived patients (27%) and seven of the 29 naturally conceived patients (24%) displayed abnormal methylation at a locus other than KCNQ1OT1.

Conclusion: Some BWS patients display abnormal methylation at loci other than the 11p15 region and the involvement of other loci is not restricted to BWS patients born following the use of ART. Moreover, the mosaic distribution of epimutations suggests that imprinting is lost after fertilization, due to a failure to maintain methylation marks during preimplantation development.

Keywords: Beckwith-Wiedemann syndrome, KCNQ1OT1 gene, assisted reproductive technology, differentially methylated region, genomic imprinting

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