title: Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height.
abstract: The biological processes controlling human growth are diverse, complex and poorly understood. Genetic factors are important and human height has been shown to be a highly polygenic trait to which common and rare genetic variation contributes. Weaver syndrome is a human overgrowth condition characterised by tall stature, dysmorphic facial features, learning disability and variable additional features. We performed exome sequencing in four individuals with Weaver syndrome, identifying a mutation in the histone methyltransferase, EZH2, in each case. Sequencing of EZH2 in additional individuals with overgrowth identified a further 15 mutations. The EZH2 mutation spectrum in Weaver syndrome shows considerable overlap with the inactivating somatic EZH2 mutations recently reported in myeloid malignancies. Our data establish EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth.
authors.affiliation: Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, UK.
authors.forename: Katrina
authors.initials: K
authors.lastname: Tatton-Brown
authors.forename: Sandra
authors.initials: S
authors.lastname: Hanks
authors.forename: Elise
authors.initials: E
authors.lastname: Ruark
authors.forename: Anna
authors.initials: A
authors.lastname: Zachariou
authors.forename: Silvana Del Vecchio
authors.initials: Sdel V
authors.lastname: Duarte
authors.forename: Emma
authors.initials: E
authors.lastname: Ramsay
authors.forename: Katie
authors.initials: K
authors.lastname: Snape
authors.forename: Anne
authors.initials: A
authors.lastname: Murray
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Perdeaux
authors.forename: Sheila
authors.initials: S
authors.lastname: Seal
authors.forename: Chey
authors.initials: C
authors.lastname: Loveday
authors.forename: Siddharth
authors.initials: S
authors.lastname: Banka
authors.forename: Carol
authors.initials: C
authors.lastname: Clericuzio
authors.forename: Frances
authors.initials: F
authors.lastname: Flinter
authors.forename: Alex
authors.initials: A
authors.lastname: Magee
authors.forename: Vivienne
authors.initials: V
authors.lastname: McConnell
authors.forename: Michael
authors.initials: M
authors.lastname: Patton
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Raith
authors.forename: Julia
authors.initials: J
authors.lastname: Rankin
authors.forename: Miranda
authors.initials: M
authors.lastname: Splitt
authors.forename: Volker
authors.initials: V
authors.lastname: Strenger
authors.forename: Clare
authors.initials: C
authors.lastname: Taylor
authors.forename: Patricia
authors.initials: P
authors.lastname: Wheeler
authors.forename: Karen I
authors.initials: KI
authors.lastname: Temple
authors.forename: Trevor
authors.initials: T
authors.lastname: Cole
authors.forename: Jenny
authors.initials: J
authors.lastname: Douglas
authors.forename: Nazneen
authors.initials: N
authors.lastname: Rahman
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000595:Amino Acid Sequence; D001827:Body Height; D003409:Congenital Hypothyroidism / Q000235:genetics*; D019465:Craniofacial Abnormalities / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein; D019066:Facies; D005260:Female; D018095:Germ-Line Mutation; D006130:Growth Disorders / Q000235:genetics; D006228:Hand Deformities, Congenital / Q000235:genetics*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006657:Histones / Q000235:genetics; D006801:Humans; D008297:Male; D063151:Polycomb Repressive Complex 2; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D014157:Transcription Factors; D000076983:Histone Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2