AbstractFamilial Rubinstein–Taybi syndrome (RTS) is very rare. Here we report on the 6th and 7th case of inherited RTS. Family 1 presents with incomplete or mild RTS over three generations; a 13‐year‐old girl (proband 1) with mild but typical facial features and learning disabilities, her very mildly affected mother (proband 2), and the maternal grandmother (proband 3). Family 2 includes three females with classical RTS (probands 4–6) and their father (proband 7) with broad thumbs and halluces. Proband 5 also had a brain tumor (ganglioglioma) at the age of 3 years. In probands 1–3, direct sequencing identified a novel CREBBP missense mutation, c.2728A > G (predicting p.Thr910Ala), that was absent in non‐affected family members. The p.Thr910Ala variant is outside the crucial histone acetyltransferase domain, and this may explain the mild and variable phenotype. In probands 4–7 we identified another novel CREBBP mutation, c.4134G > T, which alters the consensus splice sequence at position 1 of exon 25. The c.4134G > T mutation was transmitted from the very mildly affected father who displayed somatic mosaicism (with 38% mutated alleles in blood and 31% in buccal smear DNA) to his three daughters. Our findings emphasize that variable expression (family 1) and somatic mosaicism (family 2) contribute to the phenotypic variability of RTS. Somatic mosaicism may be more frequent in RTS than previously assumed. Accumulating data suggest a recurrence risk of approximately 0.5–1% for parents of a child with RTS, exceeding the so far estimated risk of ∼0.1% for siblings. © 2010 Wiley‐Liss, Inc.