The University of Southampton
University of Southampton Institutional Repository

Evidence for anticipation in Beckwith–Wiedemann syndrome

Evidence for anticipation in Beckwith–Wiedemann syndrome
Evidence for anticipation in Beckwith–Wiedemann syndrome
Classical Beckwith–Wiedemann syndrome (BWS) was diagnosed in two sisters and their male cousin. The children’s mothers and a third sister were tall statured (178, 185 and 187?cm) and one had mild BWS features as a child. Their parents had average heights of 173?cm (mother) and 180?cm (father). This second generation tall stature and third generation BWS correlated with increased methylation of the maternal H19/IGF2-locus. The results were obtained by bisulphite treatment and subclone Sanger sequencing or next generation sequencing to quantitate the degree of CpG-methylation on three locations: the H19 promoter region and two CTCF binding sites in the H19 imprinting control region (ICR1), specifically in ICR1 repeats B1 and B7. Upon ICR1 copy number analysis and sequencing, the same maternal point variant NCBI36:11:g.1979595T>C that had been described previously as a cause of BWS in three brothers, was found. As expected, this point variant was on the paternal allele in the non-affected grandmother. This nucleotide variant has been shown to affect OCTamer-binding transcription factor-4 (OCT4) binding, which may be necessary for maintaining the unmethylated state of the maternal allele. Our data extend these findings by showing that the OCT4 binding site mutation caused incomplete switching from paternal to maternal ICR1 methylation imprint, and that upon further maternal transmission, methylation of the incompletely demethylated variant ICR1 allele was further increased. This suggests that maternal and paternal ICR1 alleles are treated differentially in the female germline, and only the paternal allele appears to be capable of demethylation.
beckwith–wiedemann syndrome, anticipation, imprinting, H19, IGF2
1018-4813
1344-1348
Berland, Siren
ea95fe59-84f4-48be-a444-0910df383621
Appelbäck, Mia
cb9f83b0-3ebf-4b9a-900e-5f26737a8272
Bruland, Ove
48c91647-0533-4e59-b36e-837f5e438f85
Beygo, Jasmin
7d5384e5-392a-456b-a8f8-858dd6259da2
Buiting, Karin
30a70db4-a859-42fc-8d10-8a6db0ff0d71
Mackay, Deborah J.G.
588a653e-9785-4a00-be71-4e547850ee4a
Karen Temple, I.
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Houge, Gunnar
ba43cb7c-6e94-4642-9f08-bfa4d826a8fd
Berland, Siren
ea95fe59-84f4-48be-a444-0910df383621
Appelbäck, Mia
cb9f83b0-3ebf-4b9a-900e-5f26737a8272
Bruland, Ove
48c91647-0533-4e59-b36e-837f5e438f85
Beygo, Jasmin
7d5384e5-392a-456b-a8f8-858dd6259da2
Buiting, Karin
30a70db4-a859-42fc-8d10-8a6db0ff0d71
Mackay, Deborah J.G.
588a653e-9785-4a00-be71-4e547850ee4a
Karen Temple, I.
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Houge, Gunnar
ba43cb7c-6e94-4642-9f08-bfa4d826a8fd

Berland, Siren, Appelbäck, Mia, Bruland, Ove, Beygo, Jasmin, Buiting, Karin, Mackay, Deborah J.G., Karen Temple, I. and Houge, Gunnar (2013) Evidence for anticipation in Beckwith–Wiedemann syndrome. European Journal of Human Genetics, 21 (12), 1344-1348. (doi:10.1038/ejhg.2013.71). (PMID:23572028)

Record type: Article

Abstract

Classical Beckwith–Wiedemann syndrome (BWS) was diagnosed in two sisters and their male cousin. The children’s mothers and a third sister were tall statured (178, 185 and 187?cm) and one had mild BWS features as a child. Their parents had average heights of 173?cm (mother) and 180?cm (father). This second generation tall stature and third generation BWS correlated with increased methylation of the maternal H19/IGF2-locus. The results were obtained by bisulphite treatment and subclone Sanger sequencing or next generation sequencing to quantitate the degree of CpG-methylation on three locations: the H19 promoter region and two CTCF binding sites in the H19 imprinting control region (ICR1), specifically in ICR1 repeats B1 and B7. Upon ICR1 copy number analysis and sequencing, the same maternal point variant NCBI36:11:g.1979595T>C that had been described previously as a cause of BWS in three brothers, was found. As expected, this point variant was on the paternal allele in the non-affected grandmother. This nucleotide variant has been shown to affect OCTamer-binding transcription factor-4 (OCT4) binding, which may be necessary for maintaining the unmethylated state of the maternal allele. Our data extend these findings by showing that the OCT4 binding site mutation caused incomplete switching from paternal to maternal ICR1 methylation imprint, and that upon further maternal transmission, methylation of the incompletely demethylated variant ICR1 allele was further increased. This suggests that maternal and paternal ICR1 alleles are treated differentially in the female germline, and only the paternal allele appears to be capable of demethylation.

Text
berland13bws.pdf - Version of Record
Available under License Other.
Download (824kB)

More information

e-pub ahead of print date: 10 April 2013
Published date: December 2013
Keywords: beckwith–wiedemann syndrome, anticipation, imprinting, H19, IGF2
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 350959
URI: http://eprints.soton.ac.uk/id/eprint/350959
ISSN: 1018-4813
PURE UUID: 06fcd313-a602-4179-9f8e-cde14ce1808e
ORCID for Deborah J.G. Mackay: ORCID iD orcid.org/0000-0003-3088-4401
ORCID for I. Karen Temple: ORCID iD orcid.org/0000-0002-6045-1781

Catalogue record

Date deposited: 11 Apr 2013 13:25
Last modified: 28 Oct 2023 01:44

Export record

Altmetrics

Contributors

Author: Siren Berland
Author: Mia Appelbäck
Author: Ove Bruland
Author: Jasmin Beygo
Author: Karin Buiting
Author: I. Karen Temple ORCID iD
Author: Gunnar Houge

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×