Bartsch Oliver, Schmidt Stefanie, Richter Marion, Morlot Susanne, Seemanová Eva, Wiebe Glenis, Rasi Sasan
Institut für Humangenetik, Klinikum, Universität Mainz, 55101, Mainz, Germany.
Hum Genet. 2005 Sep;117(5):485-93. doi: 10.1007/s00439-005-1331-y. Epub 2005 Jul 14.
Rubinstein-Taybi syndrome (RSTS) is a distinct dominant disorder characterized by short stature, typical face, broad angulated thumbs and halluces, and mental retardation. The RSTS can be caused by chromosomal microdeletions and molecular mutations in the CREBBP gene; however, relatively few mutations have been reported to date. Here, we aimed to determine the rate of point mutations and other small molecular lesions in true RSTS and possible mild variants, by using genomic DNA sequencing. A consecutive series of patients including 17 patients from our previous study was investigated. We identified 19 causative mutations of CREBBP in a total of 45 patients representing three different diagnostic groups: (a) 17 mutations in 30 patients with unequivocal RSTS (detection rate 56.6%), (b) two mutations in eight patients with features suggestive of RSTS ("moderate or incomplete RSTS", detection rate 25%), and (c) no mutation in seven patients with undiagnosed syndromes and isolated features of RSTS. In general, the mutations were distributed without hot spots and most were unique; however, three recurrent mutations (R370X, R1664H, and N1978S) were identified. Furthermore, we detected 15 different intragenic polymorphisms, including two non-synonymous coding polymorphisms, L551I and Q2208H. We report not only the highest detection rate (56.6%) of CREBBP mutations in patients with RSTS to date, but also the second missense mutation (N1978S) in a patient with moderate or incomplete RSTS. Previous studies have identified cytogenetic deletions in the CREBBP gene in eight to 12% of patients and very recently, Roelfsema et al. reported EP300 gene mutations in three of 92 (3.3%) patients with either true RSTS or different syndromes resembling RSTS. Our 56.6% detection rate of molecular mutations in CREBBP in patients with unequivocal RSTS supports the new concept that RSTS is a genetically heterogeneous disorder and furthermore, indicates that RSTS may be caused by gene/s other than CREBBP in up to 30% of cases.
鲁宾斯坦-泰比综合征（RSTS）是一种独特的显性疾病，其特征为身材矮小、典型面容、宽阔且呈角状的拇指和拇趾以及智力发育迟缓。RSTS可由CREBBP基因的染色体微缺失和分子突变引起；然而，迄今为止报道的突变相对较少。在此，我们旨在通过基因组DNA测序确定真正的RSTS患者以及可能的轻度变异患者中的点突变率和其他小分子病变情况。我们对包括之前研究中的17名患者在内的一系列连续患者进行了调查。我们在总共45名代表三个不同诊断组的患者中鉴定出19个CREBBP致病突变：（a）30名明确诊断为RSTS的患者中有17个突变（检出率56.6%），（b）8名具有RSTS特征（“中度或不完全RSTS”）的患者中有2个突变（检出率25%），（c）7名未确诊综合征且仅有RSTS孤立特征的患者中未检测到突变。总体而言，突变分布无热点且大多数是独特的；然而，鉴定出了三个复发性突变（R370X、R1664H和N1978S）。此外，我们检测到15种不同的基因内多态性，包括两种非同义编码多态性，L551I和Q2208H。我们不仅报告了迄今为止RSTS患者中CREBBP突变的最高检出率（56.6%），还报告了一名中度或不完全RSTS患者中的第二个错义突变（N1978S）。先前的研究在8%至12%的患者中鉴定出CREBBP基因的细胞遗传学缺失，最近，Roelfsema等人报告在92名真正的RSTS患者或类似RSTS的不同综合征患者中有3名（3.3%）存在EP300基因突变。我们在明确诊断为RSTS的患者中CREBBP分子突变的56.6%检出率支持了RSTS是一种基因异质性疾病的新概念，此外，表明在高达30%的病例中，RSTS可能由CREBBP以外的其他基因引起。
