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Weaver Syndrome and EZH2 Mutations: Clarifying the Clinical Phenotype

Lookup NU author(s): Dr Sally Lynch, Dr Miranda Splitt

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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 approximate to 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. (c) 2013 Wiley Periodicals, Inc.


Publication metadata

Author(s): Tatton-Brown K, Murray A, Hanks S, Douglas J, Armstrong R, Banka S, Bird LM, Clericuzio CL, Cormier-Daire V, Cushing T, Flinter F, Jacquemont ML, Joss S, Kinning E, Lynch SA, Magee A, McConnell V, Medeira A, Ozono K, Patton M, Rankin J, Shears D, Simon M, Splitt M, Strenger V, Stuurman K, Taylor C, Titheradge H, Van Maldergem L, Temple IK, Cole T, Seal S, Rahman N, Childhood Overgrowth Consortium

Publication type: Article

Publication status: Published

Journal: American Journal of Medical Genetics Part A

Year: 2013

Volume: 161

Issue: 12

Pages: 2972-2980

Print publication date: 01/12/2013

Online publication date: 08/11/2013

Acceptance date: 08/08/2013

ISSN (print): 1552-4825

ISSN (electronic): 1552-4833

Publisher: Wiley-Blackwell

URL: http://dx.doi.org/10.1002/ajmg.a.36229

DOI: 10.1002/ajmg.a.36229

PubMed id: 24214728


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