Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant disorder 
characterised by facial dysmorphisms, growth and psychomotor development delay, 
and skeletal defects. The known genetic causes are point mutations or deletions 
of the CREBBP (50-60%) and EP300 (5%) genes. To detect chromosomal 
rearrangements indicating novel positional candidate RSTS genes, we used a-CGH 
to study 26 patients fulfilling the diagnostic criteria for RSTS who were 
negative at fluorescence in situ hybridisation analyses of the CREBBP and EP300 
regions, and direct sequencing analyses of the CREBBP gene. We found seven 
imbalances (27%): four de novo and three inherited rearrangements not reported 
among the copy number variants. A de novo 7p21.1 deletion of 500 kb included the 
TWIST1 gene, a suggested candidate for RSTS that is responsible for the 
Saethre-Chotzen syndrome, an entity that enters in differential diagnosis with 
RSTS. A similar issue of differential diagnosis was raised by a large 4.3 Mb 
2q22.3q23.1 deletion encompassing ZEB2, the gene responsible for the 
Mowat-Wilson syndrome, whose signs may overlap with RSTS. Positional candidate 
genes could not be sought in the remaining pathogenetic imbalances, because of 
the size of the involved region (a 9 Mb 2q24.3q31.1 deletion) and/or the 
relative paucity of suitable genes (a 5 Mb 3p13p12.3 duplication). One of the 
inherited rearrangements, the 17q11.2 379Kb duplication, represents the 
reciprocal event of the deletion underlying an overgrowth syndrome, both being 
mediated by the NF1-REP-P1 and REP-P2 sub-duplicons. The contribution of this 
and the other detected CNVs to the clinical RSTS phenotype is difficult to 
assess.