EP300 – Rubinstein-Taybi syndrome 2

Rubinstein-Taybi syndrome type 2 (RSTS2) is an autosomal dominant neurodevelopmental disorder caused by haploinsufficient variants in EP300 leading to Rubinstein-Taybi syndrome due to EP300 haploinsufficiency. Two unrelated Chinese boys (0.7 and 10.4 years old) presented with classical features including microcephaly, growth delay, intellectual disability, speech delay, congenital heart defect, immunodeficiency, and adrenal insufficiency ([PMID:37162176]). Both harbored novel de novo heterozygous EP300 variants: c.3750C>A (p.Cys1250Ter) and c.1889T>G (p.Tyr630Cys), predicted to truncate or destabilize the histone acetyltransferase domain, consistent with loss-of-function mechanism.

EP300 encodes a transcriptional coactivator with intrinsic histone acetyltransferase activity critical for chromatin remodeling. Haploinsufficiency is established by truncating and disruptive missense variants leading to reduced acetyltransferase activity and downstream dysregulation of developmental gene expression. Although only two RSTS2 probands have been reported, the phenotype mirrors that of CREBBP-related RSTS, supporting a shared pathomechanism. Genetic testing for EP300 should be integrated into diagnostic panels for RSTS and related neurodevelopmental disorders to guide management and genetic counseling.

References

• Molecular genetics & genomic medicine • 2023 • Novel heterozygous variants in the EP300 gene cause Rubinstein-Taybi syndrome 2: Reports from two Chinese children. PMID:37162176

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