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Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype

Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype
Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype
Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve.
ezh2, weaver syndrome, histone methyl transferases
1552-4825
2972-2980
Tatton-Brown, Katrina
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Murray, Anne
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Hanks, Sandra
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Douglas, Jenny
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Armstrong, Ruth
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Banka, Siddharth
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Bird, Lynne M.
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Clericuzio, Carol L.
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Cormier-Daire, Valerie
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Cushing, Tom
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Flinter, Frances
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Jacquemont, Marie-Line
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Joss, Shelagh
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Kinning, Esther
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Lynch, Sally Ann
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Magee, Alex
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McConnell, Vivienne
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Medeira, Ana
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Ozono, Keiichi
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Patton, Michael
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Rankin, Julia
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Shears, Debbie
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Simon, Marleen
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Splitt, Miranda
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Strenger, Volker
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Stuurman, Kyra
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Taylor, Clare
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Titheradge, Hannah
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Van Maldergem, Lionel
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Temple, I. Karen
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Cole, Trevor
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Seal, Sheila
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Rahman, Nazneen
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Tatton-Brown, Katrina
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Murray, Anne
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Hanks, Sandra
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Douglas, Jenny
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Armstrong, Ruth
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Banka, Siddharth
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Bird, Lynne M.
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Clericuzio, Carol L.
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Cormier-Daire, Valerie
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Cushing, Tom
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Flinter, Frances
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Jacquemont, Marie-Line
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Joss, Shelagh
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Kinning, Esther
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Lynch, Sally Ann
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Magee, Alex
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McConnell, Vivienne
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Medeira, Ana
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Ozono, Keiichi
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Patton, Michael
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Rankin, Julia
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Shears, Debbie
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Simon, Marleen
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Splitt, Miranda
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Strenger, Volker
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Stuurman, Kyra
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Taylor, Clare
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Titheradge, Hannah
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Van Maldergem, Lionel
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Temple, I. Karen
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Cole, Trevor
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Seal, Sheila
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Rahman, Nazneen
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Tatton-Brown, Katrina, Murray, Anne, Hanks, Sandra, Douglas, Jenny, Armstrong, Ruth, Banka, Siddharth, Bird, Lynne M., Clericuzio, Carol L., Cormier-Daire, Valerie, Cushing, Tom, Flinter, Frances, Jacquemont, Marie-Line, Joss, Shelagh, Kinning, Esther, Lynch, Sally Ann, Magee, Alex, McConnell, Vivienne, Medeira, Ana, Ozono, Keiichi, Patton, Michael, Rankin, Julia, Shears, Debbie, Simon, Marleen, Splitt, Miranda, Strenger, Volker, Stuurman, Kyra, Taylor, Clare, Titheradge, Hannah, Van Maldergem, Lionel, Temple, I. Karen, Cole, Trevor, Seal, Sheila and Rahman, Nazneen (2013) Weaver syndrome and EZH2 mutations: Clarifying the clinical phenotype. American Journal of Medical Genetics part A, 161 (12), 2972-2980. (doi:10.1002/ajmg.a.36229).

Record type: Article

Abstract

Weaver syndrome, first described in 1974, is characterized by tall stature, a typical facial appearance, and variable intellectual disability. In 2011, mutations in the histone methyltransferase, EZH2, were shown to cause Weaver syndrome. To date, we have identified 48 individuals with EZH2 mutations. The mutations were primarily missense mutations occurring throughout the gene, with some clustering in the SET domain (12/48). Truncating mutations were uncommon (4/48) and only identified in the final exon, after the SET domain. Through analyses of clinical data and facial photographs of EZH2 mutation-positive individuals, we have shown that the facial features can be subtle and the clinical diagnosis of Weaver syndrome is thus challenging, especially in older individuals. However, tall stature is very common, reported in >90% of affected individuals. Intellectual disability is also common, present in ~80%, but is highly variable and frequently mild. Additional clinical features which may help in stratifying individuals to EZH2 mutation testing include camptodactyly, soft, doughy skin, umbilical hernia, and a low, hoarse cry. Considerable phenotypic overlap between Sotos and Weaver syndromes is also evident. The identification of an EZH2 mutation can therefore provide an objective means of confirming a subtle presentation of Weaver syndrome and/or distinguishing Weaver and Sotos syndromes. As mutation testing becomes increasingly accessible and larger numbers of EZH2 mutation-positive individuals are identified, knowledge of the clinical spectrum and prognostic implications of EZH2 mutations should improve.

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More information

e-pub ahead of print date: 6 November 2013
Published date: December 2013
Keywords: ezh2, weaver syndrome, histone methyl transferases
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 359986
URI: http://eprints.soton.ac.uk/id/eprint/359986
ISSN: 1552-4825
PURE UUID: acf804af-3452-46fd-b192-019512733d38
ORCID for I. Karen Temple: ORCID iD orcid.org/0000-0002-6045-1781

Catalogue record

Date deposited: 19 Nov 2013 16:12
Last modified: 09 Jan 2022 02:58

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Contributors

Author: Katrina Tatton-Brown
Author: Anne Murray
Author: Sandra Hanks
Author: Jenny Douglas
Author: Ruth Armstrong
Author: Siddharth Banka
Author: Lynne M. Bird
Author: Carol L. Clericuzio
Author: Valerie Cormier-Daire
Author: Tom Cushing
Author: Frances Flinter
Author: Marie-Line Jacquemont
Author: Shelagh Joss
Author: Esther Kinning
Author: Sally Ann Lynch
Author: Alex Magee
Author: Vivienne McConnell
Author: Ana Medeira
Author: Keiichi Ozono
Author: Michael Patton
Author: Julia Rankin
Author: Debbie Shears
Author: Marleen Simon
Author: Miranda Splitt
Author: Volker Strenger
Author: Kyra Stuurman
Author: Clare Taylor
Author: Hannah Titheradge
Author: Lionel Van Maldergem
Author: I. Karen Temple ORCID iD
Author: Trevor Cole
Author: Sheila Seal
Author: Nazneen Rahman

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