EP300 is located at 22q13.2 and encodes the E1A binding protein p300. It was first reported in relation to autosomal dominant Rubinstein-Taybi syndrome in 2005 (Roelfsema et al., PMID:15706485). Rubinstein-Taybi syndrome is characterized by distinctive facial features, broad and angulated thumbs and halluces, short stature, and intellectual disability. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, distinct molecular mechanisms and phenotypic variability have been described for Rubinstein-Taybi syndrome 2 (OMIM:613684), and Menke-Hennekam syndrome 2 (OMIM:618333). Individuals with Rubinstein-Taybi syndrome typically have characteristic facial features, broad and angulated thumbs and halluces, short stature, and intellectual disability. Menke-Hennekam syndrome presents with impaired intellectual development and dysmorphic facial features, but the patients do not have the distinctive features of those with Rubinstein-Taybi syndrome. Therefore, these disorders have been split into multiple disease entities for consideration. 6 nonsense or frameshift variants, and deletions that have been reported in 6 probands in 3 publications (Foley et al., 2009, PMID: 19353645; Fergelot et al., 2016, PMID: 27648933; PMID: 15706485) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by expression data and an animal model that recapitulates many features of the human disease phenotype (Yao et al., 1998, PMID: 9590171; Viosca et al., 2010, PMID: 19822209). In summary, EP300 is definitively associated with autosomal dominant Rubinstein-Taybi syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 09.01.2021 (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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