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, Hennekam Raoul C
Department of Genetics, and INSERM U1211, University Hospital of Bordeaux, Bordeaux, France.
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Am J Med Genet A. 2016 Dec;170(12):3069-3082. doi: 10.1002/ajmg.a.37940. Epub 2016 Sep 20.
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 Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients.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.
鲁宾斯坦-泰比综合征（RSTS）是一种发育障碍，其特征为典型面容、远端肢体异常、智力残疾以及大量其他特征。已知有两个基因可导致RSTS，在临床诊断病例中，60%由CREBBP基因引起，8 - 10%由EP300基因引起。这两个旁系同源基因均参与染色质重塑，并编码与400多种蛋白质相互作用的转录共激活因子。截至目前，已发表了26例携带EP300突变的个体。在此，我们描述了42例未发表的携带EP300突变和基因内缺失的RSTS患者的表型和基因型，并提供了另外10例患者的最新情况。我们将这些数据与308例携带CREBBP突变的个体进行了比较。我们证明，EP300突变导致的表型在很大程度上通常类似于由CREBBP突变引起的经典RSTS表型，尽管除了悬垂的小柱外，大多数面部体征不那么明显。肢体异常与CREBBP突变个体更相似，除了拇指和拇趾成角在EP300突变个体中非常罕见。智力残疾程度不一，但通常不那么明显，而小头畸形更常见。各种类型的突变均有发生，但截断突变和小的重排最为常见（86%）。HAT结构域中的错义突变与经典RSTS表型相关，但未检测到其他基因型-表型相关性。12/52例EP300突变个体的母亲发生了先兆子痫，而CREBBP突变个体的母亲中这一比例为2/59，这使得怀有EP300突变胎儿成为已知最强的先兆子痫预测指标。© 2016威利期刊公司
