title: Lessons from BWS twins: complex maternal and paternal hypomethylation and a common source of haematopoietic stem cells.
abstract: The Beckwith-Wiedemann syndrome (BWS) is a growth disorder for which an increased frequency of monozygotic (MZ) twinning has been reported. With few exceptions, these twins are discordant for BWS and for females. Here, we describe the molecular and phenotypic analysis of 12 BWS twins and a triplet; seven twins are MZ, monochorionic and diamniotic, three twins are MZ, dichorionic and diamniotic and three twins are dizygotic. Twelve twins are female. In the majority of the twin pairs (11 of 13), the defect on chromosome 11p15 was hypomethylation of the paternal allele of DMR2. In 5 of 10 twins, there was additional hypomethylation of imprinted loci; in most cases, the loci affected were maternally methylated, but in two cases, hypomethylation of the paternally methylated DLK1 and H19 DMRs was detected, a novel finding in BWS. In buccal swabs of the MZ twins who share a placenta, the defect was present only in the affected twin; comparable hypomethylation in lymphocytes was detected in both the twins. The level of hypomethylation reached levels below 25%. The exchange of blood cells through vascular connections cannot fully explain the degree of hypomethylation found in the blood cell of the non-affected twin. We propose an additional mechanism through which sharing of aberrant methylation patterns in discordant twins, limited to blood cells, might occur. In a BWS-discordant MZ triplet, an intermediate level of demethylation was found in one of the non-affected sibs; this child showed mild signs of BWS. This finding supports the theory that a methylation error proceeds and possibly triggers the twinning process.
authors.affiliation: Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands. j.bliek@amc.uva.nl
authors.forename: Jet
authors.initials: J
authors.lastname: Bliek
authors.forename: Marielle
authors.initials: M
authors.lastname: Alders
authors.forename: Saskia M
authors.initials: SM
authors.lastname: Maas
authors.forename: Roelof-Jan
authors.initials: RJ
authors.lastname: Oostra
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Mackay
authors.forename: Karin
authors.initials: K
authors.lastname: van der Lip
authors.forename: Johnatan L
authors.initials: JL
authors.lastname: Callaway
authors.forename: Alice
authors.initials: A
authors.lastname: Brooks
authors.forename: Sandra
authors.initials: S
authors.lastname: van 't Padje
authors.forename: Andries
authors.initials: A
authors.lastname: Westerveld
authors.forename: Nico J
authors.initials: NJ
authors.lastname: Leschot
authors.forename: Marcel M A M
authors.initials: MM
authors.lastname: Mannens
mesh_terms: D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D005220:Fathers; D005260:Female; D018392:Genomic Imprinting; D005838:Genotype; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D008297:Male; D009035:Mothers; D010641:Phenotype; D010929:Placentation / Q000235:genetics; D011247:Pregnancy; D014427:Twins / Q000235:genetics; D014429:Twins, Dizygotic / Q000235:genetics; D014430:Twins, Monozygotic / Q000235:genetics