Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height

Childhood Overgrowth Collaboration; Katrina Tatton-Brown; Sandra Hanks; Elise Ruark; Anna Zachariou; Silvana Del Vecchio Duarte; Emma Ramsay; Katie Snape; Anne Murray; Elizabeth R Perdeaux; Sheila Seal; Chey Loveday; Siddharth Banka; Carol Clericuzio; Frances Flinter; Alex Magee; Vivienne McConnell; Michael Patton; Wolfgang Raith; Julia Rankin; Miranda Splitt; Volker Strenger; Clare Taylor; Patricia Wheeler; Karen I Temple; Trevor Cole; Jenny Douglas; Nazneen Rahman

doi:10.18632/oncotarget.385

Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height

Childhood Overgrowth Collaboration, Katrina Tatton-Brown, Sandra Hanks, Elise Ruark, Anna Zachariou, Silvana Del Vecchio Duarte, Emma Ramsay, Katie Snape, Anne Murray, Elizabeth R Perdeaux, Sheila Seal, Chey Loveday, Siddharth Banka, Carol Clericuzio, Frances Flinter, Alex Magee, Vivienne McConnell, Michael Patton, Wolfgang Raith, Julia RankinMiranda Splitt, Volker Strenger, Clare Taylor, Patricia Wheeler, Karen I Temple, Trevor Cole, Jenny Douglas, Nazneen Rahman

King's College London

Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey, UK.

Research output: Contribution to journal › Article › peer-review

129 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1127-33
Number of pages	7
Journal	Oncotarget
Volume	2
Issue number	12
DOIs	https://doi.org/10.18632/oncotarget.385
Publication status	Published - Dec 2011

Keywords

Abnormalities, Multiple/genetics
Amino Acid Sequence
Body Height
Congenital Hypothyroidism/genetics
Craniofacial Abnormalities/genetics
DNA-Binding Proteins/genetics
Enhancer of Zeste Homolog 2 Protein
Facies
Female
Germ-Line Mutation
Growth Disorders/genetics
Hand Deformities, Congenital/genetics
Histone Methyltransferases
Histone-Lysine N-Methyltransferase/genetics
Histones/genetics
Humans
Male
Polycomb Repressive Complex 2
Sequence Analysis, DNA
Transcription Factors/genetics

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10.18632/oncotarget.385

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Childhood Overgrowth Collaboration, Tatton-Brown, K., Hanks, S., Ruark, E., Zachariou, A., Duarte, S. D. V., Ramsay, E., Snape, K., Murray, A., Perdeaux, E. R., Seal, S., Loveday, C., Banka, S., Clericuzio, C., Flinter, F., Magee, A., McConnell, V., Patton, M., Raith, W., ... Rahman, N. (2011). Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height. Oncotarget, 2(12), 1127-33. https://doi.org/10.18632/oncotarget.385

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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.",

keywords = "Abnormalities, Multiple/genetics, Amino Acid Sequence, Body Height, Congenital Hypothyroidism/genetics, Craniofacial Abnormalities/genetics, DNA-Binding Proteins/genetics, Enhancer of Zeste Homolog 2 Protein, Facies, Female, Germ-Line Mutation, Growth Disorders/genetics, Hand Deformities, Congenital/genetics, Histone Methyltransferases, Histone-Lysine N-Methyltransferase/genetics, Histones/genetics, Humans, Male, Polycomb Repressive Complex 2, Sequence Analysis, DNA, Transcription Factors/genetics",

author = "{Childhood Overgrowth Collaboration} and Katrina Tatton-Brown and Sandra Hanks and Elise Ruark and Anna Zachariou and Duarte, {Silvana Del Vecchio} and Emma Ramsay and Katie Snape and Anne Murray and Perdeaux, {Elizabeth R} and Sheila Seal and Chey Loveday and Siddharth Banka and Carol Clericuzio and Frances Flinter and Alex Magee and Vivienne McConnell and Michael Patton and Wolfgang Raith and Julia Rankin and Miranda Splitt and Volker Strenger and Clare Taylor and Patricia Wheeler and Temple, {Karen I} and Trevor Cole and Jenny Douglas and Nazneen Rahman",

year = "2011",

month = dec,

doi = "10.18632/oncotarget.385",

language = "English",

volume = "2",

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Childhood Overgrowth Collaboration, Tatton-Brown, K, Hanks, S, Ruark, E, Zachariou, A, Duarte, SDV, Ramsay, E, Snape, K, Murray, A, Perdeaux, ER, Seal, S, Loveday, C, Banka, S, Clericuzio, C, Flinter, F, Magee, A, McConnell, V, Patton, M, Raith, W, Rankin, J, Splitt, M, Strenger, V, Taylor, C, Wheeler, P, Temple, KI, Cole, T, Douglas, J & Rahman, N 2011, 'Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height', Oncotarget, vol. 2, no. 12, pp. 1127-33. https://doi.org/10.18632/oncotarget.385

TY - JOUR

T1 - Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height

AU - Childhood Overgrowth Collaboration

AU - Tatton-Brown, Katrina

AU - Hanks, Sandra

AU - Ruark, Elise

AU - Zachariou, Anna

AU - Duarte, Silvana Del Vecchio

AU - Ramsay, Emma

AU - Snape, Katie

AU - Murray, Anne

AU - Perdeaux, Elizabeth R

AU - Seal, Sheila

AU - Loveday, Chey

AU - Banka, Siddharth

AU - Clericuzio, Carol

AU - Flinter, Frances

AU - Magee, Alex

AU - McConnell, Vivienne

AU - Patton, Michael

AU - Raith, Wolfgang

AU - Rankin, Julia

AU - Splitt, Miranda

AU - Strenger, Volker

AU - Taylor, Clare

AU - Wheeler, Patricia

AU - Temple, Karen I

AU - Cole, Trevor

AU - Douglas, Jenny

AU - Rahman, Nazneen

PY - 2011/12

Y1 - 2011/12

N2 - 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.

AB - 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.

KW - Abnormalities, Multiple/genetics

KW - Amino Acid Sequence

KW - Body Height

KW - Congenital Hypothyroidism/genetics

KW - Craniofacial Abnormalities/genetics

KW - DNA-Binding Proteins/genetics

KW - Enhancer of Zeste Homolog 2 Protein

KW - Facies

KW - Female

KW - Germ-Line Mutation

KW - Growth Disorders/genetics

KW - Hand Deformities, Congenital/genetics

KW - Histone Methyltransferases

KW - Histone-Lysine N-Methyltransferase/genetics

KW - Histones/genetics

KW - Humans

KW - Male

KW - Polycomb Repressive Complex 2

KW - Sequence Analysis, DNA

KW - Transcription Factors/genetics

U2 - 10.18632/oncotarget.385

DO - 10.18632/oncotarget.385

M3 - Article

C2 - 22190405

SN - 1949-2553

VL - 2

SP - 1127

EP - 1133

JO - Oncotarget

JF - Oncotarget

IS - 12

ER -

Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height

Abstract

Keywords

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