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Lessons from BWS twins: complex maternal and paternal hypomethylation and a common source of haematopoietic stem cells

Lessons from BWS twins: complex maternal and paternal hypomethylation and a common source of haematopoietic stem cells
Lessons from BWS twins: complex maternal and paternal hypomethylation and a common source of haematopoietic stem cells
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
twinning, beckwith–wiedemann syndrome, methylation defect, chromosome 11p15, hypomethylation of imprinted loci, vascular connections
1018-4813
1625-1634
Bliek, Jet
71a7b9b1-a591-491d-832a-9b670ef05195
Alders, Marielle
bb9f98b8-4d54-40ba-9d69-1e17008bb599
Maas, Saskia M.
5c29928c-22b8-4d42-8a5a-831ba536d809
Oostra, Roelof-Jan
75b92f45-0040-445e-bc9d-45ad1f7bcce2
Mackay, Deborah M.
588a653e-9785-4a00-be71-4e547850ee4a
van der Lip, Karin
8e893e9a-4bad-4009-b9ca-1d4142cfa37c
Callaway, Johnatan L.
77d4a46a-e0f1-4d7d-8883-b533a77b712d
Brooks, Alice
737906da-9d68-47c6-9825-f3acc22b3987
van 't Padje, Sandra
32571555-4b3e-4b6c-a777-686232ca3f64
Westerveld, Andries
a46f0038-5e3f-4c9a-997e-244795aa1aa8
Leschot, Nico J.
5460e8b7-6cb2-47fe-a2ac-57cff7801a69
Mannens, Marcel M.A.M.
bb288561-4e69-4243-956b-894269170cd1
Bliek, Jet
71a7b9b1-a591-491d-832a-9b670ef05195
Alders, Marielle
bb9f98b8-4d54-40ba-9d69-1e17008bb599
Maas, Saskia M.
5c29928c-22b8-4d42-8a5a-831ba536d809
Oostra, Roelof-Jan
75b92f45-0040-445e-bc9d-45ad1f7bcce2
Mackay, Deborah M.
588a653e-9785-4a00-be71-4e547850ee4a
van der Lip, Karin
8e893e9a-4bad-4009-b9ca-1d4142cfa37c
Callaway, Johnatan L.
77d4a46a-e0f1-4d7d-8883-b533a77b712d
Brooks, Alice
737906da-9d68-47c6-9825-f3acc22b3987
van 't Padje, Sandra
32571555-4b3e-4b6c-a777-686232ca3f64
Westerveld, Andries
a46f0038-5e3f-4c9a-997e-244795aa1aa8
Leschot, Nico J.
5460e8b7-6cb2-47fe-a2ac-57cff7801a69
Mannens, Marcel M.A.M.
bb288561-4e69-4243-956b-894269170cd1

Bliek, Jet, Alders, Marielle, Maas, Saskia M., Oostra, Roelof-Jan, Mackay, Deborah M., van der Lip, Karin, Callaway, Johnatan L., Brooks, Alice, van 't Padje, Sandra, Westerveld, Andries, Leschot, Nico J. and Mannens, Marcel M.A.M. (2009) Lessons from BWS twins: complex maternal and paternal hypomethylation and a common source of haematopoietic stem cells. European Journal of Human Genetics, 17 (12), 1625-1634. (doi:10.1038/ejhg.2009.77).

Record type: Article

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

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More information

Published date: December 2009
Keywords: twinning, beckwith–wiedemann syndrome, methylation defect, chromosome 11p15, hypomethylation of imprinted loci, vascular connections

Identifiers

Local EPrints ID: 72386
URI: https://eprints.soton.ac.uk/id/eprint/72386
ISSN: 1018-4813
PURE UUID: 147cfa7d-31ee-4d1b-96d8-5fd36d48a0de
ORCID for Deborah M. Mackay: ORCID iD orcid.org/0000-0003-3088-4401

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Date deposited: 11 Feb 2010
Last modified: 19 Nov 2019 01:53

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Contributors

Author: Jet Bliek
Author: Marielle Alders
Author: Saskia M. Maas
Author: Roelof-Jan Oostra
Author: Karin van der Lip
Author: Johnatan L. Callaway
Author: Alice Brooks
Author: Sandra van 't Padje
Author: Andries Westerveld
Author: Nico J. Leschot
Author: Marcel M.A.M. Mannens

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