EP300 – EP300-related Rubinstein-Taybi Syndrome

Rubinstein-Taybi syndrome (RSTS) is a rare autosomal dominant neurodevelopmental disorder characterized by broad thumbs and halluces, distinctive craniofacial features, growth retardation, and intellectual disability. While loss-of-function variants in the CREBBP gene account for ~60% of RSTS cases, heterozygous pathogenic variants in EP300 underlie approximately 5–10% of patients, designated RSTS type 2. The EP300 gene encodes the p300 histone acetyltransferase, a key chromatin regulator and transcriptional coactivator (PMID:15706485).

Genetic studies have identified over 50 unrelated RSTS patients harboring EP300 variants, including frameshift, nonsense, splice-site, and missense changes, with most arising de novo. Truncating mutations causing haploinsufficiency predominate, and missense variants within the HAT domain recapitulate classic RSTS features. Comprehensive cohort analyses confirm a consistent genotype–phenotype correlation, with 90% of variants occurring de novo and 5% inherited in a familial case demonstrating autosomal dominant transmission (PMID:27648933; PMID:27964710).

Segregation data include a multi-generation pedigree in which a mother and daughter both carry the same heterozygous frameshift EP300 variant, confirming autosomal dominant inheritance and variable expressivity. De novo occurrence is supported by trio sequencing in multiple cases, and one report of germline mosaicism underscores the importance of parental testing (PMID:27964710).

Functional characterization demonstrates that EP300 variants impair p300-mediated histone acetyltransferase activity, leading to global deficits in histone H2A and H2B acetylation in patient-derived lymphoblastoid cells. Patient iPSC lines harboring the p.Lys1277Ter variant display reduced p300 protein levels and altered differentiation potential, consistent with haploinsufficiency as the primary pathogenic mechanism (PMID:21984751; PMID:29944992).

No major conflicting evidence has been published. A handful of RSTS-like patients negative for EP300 sequencing likely harbor intronic or regulatory variants beyond current detection limits, but these do not dispute the EP300–RSTS association.

In summary, strong clinical validity is supported by >50 unrelated probands with EP300 loss-of-function variants, de novo occurrence, limited familial segregation, and concordant functional assays demonstrating p300 haploinsufficiency. Key take-home: EP300 genetic testing is essential for accurate diagnosis and management of RSTS2 and informs genetic counseling and surveillance strategies.

References

• American Journal of Human Genetics • 2005 • Genetic heterogeneity in Rubinstein-Taybi syndrome: mutations in both the CBP and EP300 genes cause disease. PMID:15706485
• American Journal of Medical Genetics Part A • 2016 • Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations. PMID:27648933
• BMC Medical Genetics • 2016 • First case report of inherited Rubinstein-Taybi syndrome associated with a novel EP300 variant. PMID:27964710
• Journal of Medical Genetics • 2012 • Histone acetylation deficits in lymphoblastoid cell lines from patients with Rubinstein-Taybi syndrome. PMID:21984751
• Stem Cell Research • 2018 • Generation of the Rubinstein-Taybi syndrome type 2 patient-derived induced pluripotent stem cell line (IAIi001-A) carrying the EP300 exon 23 stop mutation c.3829A>T, p.Lys1277.* PMID:29944992

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