NEW POINTMUTATIONS AND EXON DELETIONS OF THE EP300 GENE IN PATIENTS WITH RUBINSTEIN-TAYBI SYNDROME

Rubinstein-Taybi syndrome (RSTS, #180849, #613684) is a congenital neurodevelopmental disorder characterized by postnatal growth deficiency, characteristic skeletal abnormalities, dysmorphic features and cognitive deficit. Mutations in two genes, CREBBP (16p13.3) and EP300 (22q13.2), have been identified in ~50% and ~3% affected individuals, respectively. CREBBP and EP300 are ubiquitously expressed homologous proteins acting as transcriptional co-activators with intrinsic histone and non-histone acetyltransferase activity. So far, only seven EP300-mutated RSTS patients have been described and other 13 mutations including four exon deletions are reported in the LOVD database. EP300 analysis by DHPLC/directs sequencing and MLPA of 25 CREBBP-negative cases showed four new germ line EP300 alterations including two early inactivating point mutations, an in/del in exon 1 (c.41_51delinsT) and a duplication in exon 2 (c.668dupT) both leading to a frameshift and premature stop codon (p.K14Ifs*31 and p.Q223Sfs*19) and two novel exonic deletions involving exon 12 and both exons 17-18. The transcripts analysis of patient carrying the exon-2point mutation revealed the presence of the aberrant one, but at reduced level, suggesting its possible instability. Accordingto the limited literature about all the four EP300-mutated patients show a convincing RSTS phenotype, but at the mild level with minor skeletal anomalies, a slight cognitive impairment and absence of major malformations. Beyond expanding the RSTS EP300 mutations repertoire, our study points to a contribution of the “minor” gene EP300 less negligible than predicted. Results, implemented by extending the study to our accumulated 52 CREBBP-negative patients, will also help the clinical practice in genotype-phenotype correlation doing.