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Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations

Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations
Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations
Rubinstein–Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8–10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype–phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia
1552-4825
3069-3082
Fergelot, Patricia
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Van Belzen, Martine
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Van Gils, Julien
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Armour, Christine M.
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Beets, Lex
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Busa, Tiffany
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Collet, Marie
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Deforges, Julie
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Gebre-Medhin, Samuel
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Gérard, Marion
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Josifova, Dragana
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Reardon, Willie
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Sojo, Amaia
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Bartsch, Oliver
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Larizza, Lidia
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Lacombe, Didier
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Hennekam, Raoul C.
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Fergelot, Patricia, Van Belzen, Martine, Van Gils, Julien, Afenjar, Alexandra, Armour, Christine M., Arveiler, Benoit, Beets, Lex, Burglen, Lydie, Busa, Tiffany, Collet, Marie, Deforges, Julie, de Vries, Bert B.A., Dominguez Garrido, Elena, Dorison, Nathalie, Dupont, Juliette, Francannet, Christine, Garciá-Minaúr, Sixto, Gabau Vila, Elisabeth, Gebre-Medhin, Samuel, Gener Querol, Blanca, Geneviève, David, Gérard, Marion, Gervasini, Cristina Giovanna, Goldenberg, Alice, Josifova, Dragana, Lachlan, Katherine, Maas, Saskia, Maranda, Bruno, Moilanen, Jukka S., Nordgren, Ann, Parent, Philippe, Rankin, Julia, Reardon, Willie, Rio, Marlène, Roume, Joëlle, Shaw, Adam, Smigiel, Robert, Sojo, Amaia, Solomon, Benjamin, Stembalska, Agnieszka, Stumpel, Constance, Suarez, Francisco, Terhal, Paulien, Thomas, Simon, Touraine, Renaud, Verloes, Alain, Vincent-Delorme, Catherine, Wincent, Josephine, Peters, Dorien J.M., Bartsch, Oliver, Larizza, Lidia, Lacombe, Didier and Hennekam, Raoul C. (2016) Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations. American Journal of Medical Genetics part A, 170 (12), 3069-3082. (doi:10.1002/ajmg.a.37940).

Record type: Article

Abstract

Rubinstein–Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8–10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype–phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia

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Accepted/In Press date: 7 August 2016
e-pub ahead of print date: 20 September 2016
Published date: December 2016
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 402669
URI: http://eprints.soton.ac.uk/id/eprint/402669
ISSN: 1552-4825
PURE UUID: cdf19f48-acf5-4852-b32a-1f0b17929ff4

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Date deposited: 14 Nov 2016 12:52
Last modified: 06 Oct 2020 19:31

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Contributors

Author: Patricia Fergelot
Author: Martine Van Belzen
Author: Julien Van Gils
Author: Alexandra Afenjar
Author: Christine M. Armour
Author: Benoit Arveiler
Author: Lex Beets
Author: Lydie Burglen
Author: Tiffany Busa
Author: Marie Collet
Author: Julie Deforges
Author: Bert B.A. de Vries
Author: Elena Dominguez Garrido
Author: Nathalie Dorison
Author: Juliette Dupont
Author: Christine Francannet
Author: Sixto Garciá-Minaúr
Author: Elisabeth Gabau Vila
Author: Samuel Gebre-Medhin
Author: Blanca Gener Querol
Author: David Geneviève
Author: Marion Gérard
Author: Cristina Giovanna Gervasini
Author: Alice Goldenberg
Author: Dragana Josifova
Author: Katherine Lachlan
Author: Saskia Maas
Author: Bruno Maranda
Author: Jukka S. Moilanen
Author: Ann Nordgren
Author: Philippe Parent
Author: Julia Rankin
Author: Willie Reardon
Author: Marlène Rio
Author: Joëlle Roume
Author: Adam Shaw
Author: Robert Smigiel
Author: Amaia Sojo
Author: Benjamin Solomon
Author: Agnieszka Stembalska
Author: Constance Stumpel
Author: Francisco Suarez
Author: Paulien Terhal
Author: Simon Thomas
Author: Renaud Touraine
Author: Alain Verloes
Author: Catherine Vincent-Delorme
Author: Josephine Wincent
Author: Dorien J.M. Peters
Author: Oliver Bartsch
Author: Lidia Larizza
Author: Didier Lacombe
Author: Raoul C. Hennekam

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