RTS is subdivided into type 1 and type 2 associated with pathogenic variants or re-arrangements in the CREBBP and EP300 genes respectively, typically leading to haploinsufficiency.
These two genes are paralogs and code for CBP and p300, respectively. These proteins are transcriptional coactivators that possess a catalytic lysine acetyl transferase (KAT) domain involved in the acetylation of lysine residues of histones but also other proteins. CBP and p300 promote transcription by creating a chromatin environment that is favorable for gene expression and by linking different transcription factors to each other. They thus orchestrate the regulation of the transcription machinery, from the basal promoter to the enhancers of the target genes.
Pathogenic variants in CREBBP and EP300 have been identified in respectively 55-75% and 8-11% of clinically RTS diagnosed cases.
To date, over 500 CREBBP and over 120 EP300 pathogenic variants have been reported, distributed along all 31 exons.
CREBBP