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

2.50
Hdl Handle:
http://hdl.handle.net/11287/620030
Title:
Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations.
Authors:
Fergelot, P.; Van Belzen, M.; Van Gils, J.; Afenjar, A.; Armour, C. M.; Arveiler, B.; Beets, L.; Burglen, L.; Busa, T.; Collet, M.; Deforges, J.; de Vries, B. B. A.; Dominguez Garrido, E.; Dorison, N.; Dupont, J.; Francannet, C.; Garciá-Minaúr, S.; Gabau Vila, E.; Gebre-Medhin, S.; Gener Querol, B.; Geneviève, D.; Gérard, M.; Gervasini, C. G.; Goldenberg, A.; Josifova, D.; Lachlan, K. L.; Maas, S.; Maranda, B.; Moilanen, J. L.; Nordgren, A.; Parent, P.; Rankin, Julia; Reardon, W.; Rio, M.; Roume, J.; Shaw, A.; Smigiel, R.; Sojo, A.; Solomon, B.; Stembalska, A.; Stumpel, C.; Suarez, F.; Terhal, P.; Thomas, S.; Touraine, R.; Verloes, A.; Vincent-Delorme, C.; Wincent, J.; Peters, D. J. M.; Bartsch, O.; Larizza, L.; Lacombe, D.; Hennekam, R. C.
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 Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients.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. © 2016 Wiley Periodicals, Inc.
Citation:
Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations. 2016 Dec;170(12):3069-3082 Am. J. Med. Genet. A
Publisher:
Wiley
Journal:
American journal of medical genetics. Part A
Issue Date:
20-Sep-2016
URI:
http://hdl.handle.net/11287/620030
DOI:
10.1002/ajmg.a.37940
PubMed ID:
27648933
Additional Links:
http://dx.doi.org/10.1002/ajmg.a.37940
Type:
Journal Article
Language:
en
ISSN:
1552-4833
Appears in Collections:
Clinical Genetics (Peninsula Genetics); 2016 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorFergelot, P.en
dc.contributor.authorVan Belzen, M.en
dc.contributor.authorVan Gils, J.en
dc.contributor.authorAfenjar, A.en
dc.contributor.authorArmour, C. M.en
dc.contributor.authorArveiler, B.en
dc.contributor.authorBeets, L.en
dc.contributor.authorBurglen, L.en
dc.contributor.authorBusa, T.en
dc.contributor.authorCollet, M.en
dc.contributor.authorDeforges, J.en
dc.contributor.authorde Vries, B. B. A.en
dc.contributor.authorDominguez Garrido, E.en
dc.contributor.authorDorison, N.en
dc.contributor.authorDupont, J.en
dc.contributor.authorFrancannet, C.en
dc.contributor.authorGarciá-Minaúr, S.en
dc.contributor.authorGabau Vila, E.en
dc.contributor.authorGebre-Medhin, S.en
dc.contributor.authorGener Querol, B.en
dc.contributor.authorGeneviève, D.en
dc.contributor.authorGérard, M.en
dc.contributor.authorGervasini, C. G.en
dc.contributor.authorGoldenberg, A.en
dc.contributor.authorJosifova, D.en
dc.contributor.authorLachlan, K. L.en
dc.contributor.authorMaas, S.en
dc.contributor.authorMaranda, B.en
dc.contributor.authorMoilanen, J. L.en
dc.contributor.authorNordgren, A.en
dc.contributor.authorParent, P.en
dc.contributor.authorRankin, Juliaen
dc.contributor.authorReardon, W.en
dc.contributor.authorRio, M.en
dc.contributor.authorRoume, J.en
dc.contributor.authorShaw, A.en
dc.contributor.authorSmigiel, R.en
dc.contributor.authorSojo, A.en
dc.contributor.authorSolomon, B.en
dc.contributor.authorStembalska, A.en
dc.contributor.authorStumpel, C.en
dc.contributor.authorSuarez, F.en
dc.contributor.authorTerhal, P.en
dc.contributor.authorThomas, S.en
dc.contributor.authorTouraine, R.en
dc.contributor.authorVerloes, A.en
dc.contributor.authorVincent-Delorme, C.en
dc.contributor.authorWincent, J.en
dc.contributor.authorPeters, D. J. M.en
dc.contributor.authorBartsch, O.en
dc.contributor.authorLarizza, L.en
dc.contributor.authorLacombe, D.en
dc.contributor.authorHennekam, R. C.en
dc.date.accessioned2016-09-29T14:09:10Z-
dc.date.available2016-09-29T14:09:10Z-
dc.date.issued2016-09-20-
dc.identifier.citationPhenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations. 2016 Dec;170(12):3069-3082 Am. J. Med. Genet. Aen
dc.identifier.issn1552-4833-
dc.identifier.pmid27648933-
dc.identifier.doi10.1002/ajmg.a.37940-
dc.identifier.urihttp://hdl.handle.net/11287/620030-
dc.description.abstractRubinstein-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. © 2016 Wiley Periodicals, Inc.en
dc.languageENG-
dc.language.isoenen
dc.publisherWileyen
dc.relation.urlhttp://dx.doi.org/10.1002/ajmg.a.37940en
dc.rightsArchived with thanks to American journal of medical genetics. Part Aen
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titlePhenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations.en
dc.typeJournal Articleen
dc.identifier.journalAmerican journal of medical genetics. Part Aen
dc.type.versionIn press (epub ahead of print)en

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