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 mutation...

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Published in:American journal of medical genetics. Part A 2013-12, Vol.161A (12), p.2972-2980
Main Authors: 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, Rahman, Nazneen
Format: Article
Language:English
Subjects:
Abnormalities, Multiple - genetics
Abnormalities, Multiple - physiopathology
Adolescent
Camptodactyly
Child
Child, Preschool
Chromosome Deletion
Congenital Hypothyroidism - complications
Congenital Hypothyroidism - genetics
Congenital Hypothyroidism - physiopathology
Craniofacial Abnormalities - complications
Craniofacial Abnormalities - genetics
Craniofacial Abnormalities - physiopathology
Data processing
Developmental Disabilities
Enhancer of Zeste Homolog 2 Protein
EZH2
Female
Growth Disorders - complications
Growth Disorders - genetics
Growth Disorders - physiopathology
Hand Deformities, Congenital - complications
Hand Deformities, Congenital - genetics
Hand Deformities, Congenital - physiopathology
Hernia
histone methyl transferases
Histone methyltransferase
Humans
Intellectual disabilities
Intellectual Disability - complications
Intellectual Disability - genetics
Intellectual Disability - physiopathology
Male
Missense mutation
Mutation
Phenotype
Phenotypes
Polycomb Repressive Complex 2 - genetics
Skin
Sotos Syndrome - genetics
Sotos Syndrome - physiopathology
Weaver syndrome
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Summary: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. © 2013 Wiley Periodicals, Inc.
ISSN:1552-4825
1552-4833
DOI:10.1002/ajmg.a.36229