The Rubinstein-Taybi syndrome (RSTS, MIM 180849), a dominant Mendelian disorder with typical face, short stature, skeletal abnormalities, and mental retardation, is usually caused by heterozygous mutations of the CREBBP gene, but recently, EP300 gene mutations were reported in three individuals. Using quantitative PCR (for the CREBBP and EP300 genes) and genomic sequencing (for the EP300 gene), we studied here 13 patients who had shown no mutation after genomic sequencing of the CREBBP gene in a previous investigation. Two new disease-causing mutations were identified, including a partial deletion of CREBBP and a 1-bp deletion in EP300, c.7100delC (p.P2366fsX2401). The 1-bp deletion represents the fourth EP300 mutation reported to date and was identified in a patient with non-classical RSTS. Based on the very similar structure of the CREBBP and EP300 genes and the higher rate of single-nucleotide polymorphisms in EP300 (2.23 per individual) as compared to CREBBP (0.71 per individual) (P>0.001, Wilcoxon test), it may be assumed that EP300 gene mutations should be as frequent as CREBBP gene mutations. Based on the location of the EP300 gene mutations identified so far (outside the histone acetyl transferase domain) and the observed (although not very striking) phenotypical differences with the EP300 mutations, we propose that most EP300 mutations could be associated with other phenotypes, not classical RSTS.