Relevance to Autism

Heterozygous variants in the EP300 gene are responsible for Rubinstein-Taybi syndrome 2 (OMIM 613684), a multiple congenital anomaly syndrome characterized by intellectual disability, postnatal growth deficiency, microcephaly, broad thumbs and halluces, and dysmorphic facial features (Roelfsema et al., 2005; Zimmermann et al., 2007; Foley et al., 2009). A patient with a de novo EP300 frameshift variant and a clinical diagnosis of Rubinstein-Taybi syndrome 2 also presented with autism (Wincent et al., 2015). A report describing nine new cases with Rubinstein-Taybi syndrome type 2 identified three cases with a diagnosis of autism spectrum disorder (Hamilton et al., 2016). Phenotypic characterization of 52 patients with Rubinstein-Taybi syndrome 2, 42 of whom were previously unpublished, found that 12 out of 49 cases (25%) presented with autism or autistic behavior (Fergelot et al., 2016). A de novo frameshift variant in EP300 and a de novo damaging missense variant in EP300 were identified in ASD probands from the Autism Sequencing Consortium and the Simons Simplex Collection, respectively (De Rubeis et al., 2014; Iossifov et al., 2014). Additional de novo loss-of-function and missense variants in the EP300 gene were reported in ASD probands from the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in the same report identified EP300 as a gene reaching exome-wide significance (P < 2.5E-06).De novo loss-of-function variants in EP300 have also been identified in individuals from the Deciphering Developmental Disorders study (Fitzgerald et al., 2015).

Molecular Function

This gene encodes the adenovirus E1A-associated cellular p300 transcriptional co-activator protein. It functions as a histone acetyltransferase that regulates transcription via chromatin remodeling and is important in the processes of cell proliferation and differentiation. It mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. This gene has also been identified as a co-activator of HIF1A (hypoxia-inducible factor 1 alpha), and thus plays a role in the stimulation of hypoxia-induced genes such as VEGF. Defects in this gene are a cause of Rubinstein-Taybi syndrome and may also play a role in epithelial cancer.

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