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.
Division of Genetics & Epidemiology, Institute of Cancer Research, Sutton, UK.
Katrina
K
Tatton-Brown
Anne
A
Murray
Sandra
S
Hanks
Jenny
J
Douglas
Ruth
R
Armstrong
Siddharth
S
Banka
Lynne M
LM
Bird
Carol L
CL
Clericuzio
Valerie
V
Cormier-Daire
Tom
T
Cushing
Frances
F
Flinter
Marie-Line
ML
Jacquemont
Shelagh
S
Joss
Esther
E
Kinning
Sally Ann
SA
Lynch
Alex
A
Magee
Vivienne
V
McConnell
Ana
A
Medeira
Keiichi
K
Ozono
Michael
M
Patton
Julia
J
Rankin
Debbie
D
Shears
Marleen
M
Simon
Miranda
M
Splitt
Volker
V
Strenger
Kyra
K
Stuurman
Clare
C
Taylor
Hannah
H
Titheradge
Lionel
L
Van Maldergem
I Karen
IK
Temple
Trevor
T
Cole
Sheila
S
Seal
Nazneen
N
Rahman
D000015:Abnormalities, Multiple / Q000235:genetics* / Q000503:physiopathology; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D003409:Congenital Hypothyroidism / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D019465:Craniofacial Abnormalities / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D002658:Developmental Disabilities; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D006130:Growth Disorders / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D006228:Hand Deformities, Congenital / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008607:Intellectual Disability / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation; D010641:Phenotype; D063151:Polycomb Repressive Complex 2 / Q000235:genetics*; D058495:Sotos Syndrome / Q000235:genetics / Q000503:physiopathology
C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2
EZH2; Weaver syndrome; histone methyl transferases