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

Fergelot, Patricia; Van Belzen, Martine; Van Gils, Julien; Afenjar, Alexandra; Armour, Christine M.; Arveiler, Benoit; Beets, Lex; Burglen, Lydie; Busa, Tiffany and Collet, Marie, et al. (2016) In American Journal of Medical Genetics, Part A 170(12). p.3069-3082
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 Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients.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... (More)

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 Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients.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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published
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keywords
EP300, genotype, phenotype, pre-eclampsia, Rubinstein–Taybi syndrome
in
American Journal of Medical Genetics, Part A
volume
170
issue
12
pages
14 pages
publisher
John Wiley & Sons
external identifiers
  • scopus:84988447945
  • wos:000388199100004
ISSN
1552-4825
DOI
10.1002/ajmg.a.37940
language
English
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yes
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4e61efe1-552e-4e1b-9031-e8dd396122fe
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2016-12-08 09:47:57
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2017-10-22 05:23:26
@article{4e61efe1-552e-4e1b-9031-e8dd396122fe,
  abstract     = {<p>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 &gt;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.</p>},
  author       = {Fergelot, Patricia and Van Belzen, Martine and Van Gils, Julien and Afenjar, Alexandra and Armour, Christine M. and Arveiler, Benoit and Beets, Lex and Burglen, Lydie and Busa, Tiffany and Collet, Marie and Deforges, Julie and de Vries, Bert B A and Dominguez Garrido, Elena and Dorison, Nathalie and Dupont, Juliette and Francannet, Christine and Garciá-Minaúr, Sixto and Gabau Vila, Elisabeth and Gebre-Medhin, Samuel and Gener Querol, Blanca and Geneviève, David and Gérard, Marion and Gervasini, Cristina Giovanna and Goldenberg, Alice and Josifova, Dragana and Lachlan, Katherine and Maas, Saskia and Maranda, Bruno and Moilanen, Jukka S. and Nordgren, Ann and Parent, Philippe and Rankin, Julia and Reardon, Willie and Rio, Marlène and Roume, Joëlle and Shaw, Adam and Smigiel, Robert and Sojo, Amaia and Solomon, Benjamin and Stembalska, Agnieszka and Stumpel, Constance and Suarez, Francisco and Terhal, Paulien and Thomas, Simon and Touraine, Renaud and Verloes, Alain and Vincent-Delorme, Catherine and Wincent, Josephine and Peters, Dorien J M and Bartsch, Oliver and Larizza, Lidia and Lacombe, Didier and Hennekam, Raoul C.},
  issn         = {1552-4825},
  keyword      = {EP300,genotype,phenotype,pre-eclampsia,Rubinstein–Taybi syndrome},
  language     = {eng},
  month        = {12},
  number       = {12},
  pages        = {3069--3082},
  publisher    = {John Wiley & Sons},
  series       = {American Journal of Medical Genetics, Part A},
  title        = {Phenotype and genotype in 52 patients with Rubinstein–Taybi syndrome caused by EP300 mutations},
  url          = {http://dx.doi.org/10.1002/ajmg.a.37940},
  volume       = {170},
  year         = {2016},
}