Human Gene Module / Chromosome 22 / EP300

EP300E1A binding protein p300

Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
4 / 18
Rare Variants / Common Variants
33 / 0
Aliases
EP300, RP1-85F18.1,  KAT3B,  RSTS2,  p300
Associated Syndromes
Rubinstein-Taybi syndrome-2
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
22q13.2
Associated Disorders
ASD, DD/NDD, ID
Relevance to Autism

A rare mutation in the EP300 gene has been identified in a patient with ASD (Vaags et al., 2012).

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.

Reports related to EP300 (18 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Genetic heterogeneity in Rubinstein-Taybi syndrome: mutations in both the CBP and EP300 genes cause disease Roelfsema JH , et al. (2005) No -
2 Support Confirmation of EP300 gene mutations as a rare cause of Rubinstein-Taybi syndrome Zimmermann N , et al. (2007) No -
3 Support Further case of Rubinstein-Taybi syndrome due to a deletion in EP300 Foley P , et al. (2009) No -
4 Primary Rare deletions at the neurexin 3 locus in autism spectrum disorder Vaags AK , et al. (2012) Yes -
5 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
6 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
7 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No Microcephaly, growth retardation
8 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
9 Support CREBBP and EP300 mutational spectrum and clinical presentations in a cohort of Swedish patients with Rubinstein-Taybi syndrome Wincent J , et al. (2016) No ID, ASD
10 Support Identification of Intellectual Disability Genes in Female Patients with a Skewed X-Inactivation Pattern Fieremans N , et al. (2016) No -
11 Recent Recommendation Rubinstein-Taybi syndrome type 2: report of nine new cases that extend the phenotypic and genotypic spectrum Hamilton MJ , et al. (2016) No ID, ASD
12 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
13 Support Phenotype and genotype in 52 patients with Rubinstein-Taybi syndrome caused by EP300 mutations Fergelot P , et al. (2016) No -
14 Support Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands Jin SC , et al. (2017) No Neurodevelopmental disorders (NDD)
15 Support Further delineation of an entity caused by CREBBP and EP300 mutations but not resembling Rubinstein-Taybi syndrome Menke LA , et al. (2018) No DD, ID, ASD
16 Support Rubinstein-Taybi 2 associated to novel EP300 mutations: deepening the clinical and genetic spectrum Lpez M , et al. (2018) No -
17 Support Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants Lecoquierre F , et al. (2019) No -
18 Support - Hiraide T et al. (2021) No -
Rare Variants   (33)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss Unknown - - 29506490 Lpez M , et al. (2018)
c.3163C>T p.Arg1055Ter stop_gained Unknown - - 29506490 Lpez M , et al. (2018)
c.3728+5G>C - splice_site_variant De novo NA - 29506490 Lpez M , et al. (2018)
c.4172+2dup - frameshift_variant De novo NA - 25363760 De Rubeis S , et al. (2014)
c.1833T>G p.Tyr611Ter stop_gained De novo NA - 27465822 Hamilton MJ , et al. (2016)
c.1876C>T p.Arg626Ter stop_gained De novo NA - 27479843 Lelieveld SH et al. (2016)
c.4511T>G p.Phe1504Cys missense_variant De novo NA - 29506490 Lpez M , et al. (2018)
c.4066C>T p.Arg1356Ter stop_gained De novo NA - 27465822 Hamilton MJ , et al. (2016)
c.3857A>G p.Asn1286Ser missense_variant De novo NA - 27465822 Hamilton MJ , et al. (2016)
c.4783T>G p.Phe1595Val missense_variant De novo NA - 27465822 Hamilton MJ , et al. (2016)
c.5471A>C p.Gln1824Pro missense_variant De novo NA - 27465822 Hamilton MJ , et al. (2016)
c.5492_5494del p.Arg1831del inframe_deletion De novo NA - 29460469 Menke LA , et al. (2018)
c.3912del p.Arg1305ValfsTer2 frameshift_variant De novo NA - 28991257 Jin SC , et al. (2017)
c.70_71del p.Ser24GlyfsTer14 frameshift_variant De novo NA - 29506490 Lpez M , et al. (2018)
c.3857A>G p.Asn1286Ser missense_variant De novo NA Simplex 33644862 Hiraide T et al. (2021)
c.4879C>T p.Arg1627Trp missense_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.3661del p.Gln1221SerfsTer6 frameshift_variant De novo NA - 27465822 Hamilton MJ , et al. (2016)
c.5873del p.Pro1958ArgfsTer2 frameshift_variant De novo NA - 27465822 Hamilton MJ , et al. (2016)
c.4954_4957dup p.Cys1653TyrfsTer21 frameshift_variant De novo NA - 29506490 Lpez M , et al. (2018)
c.631G>A p.Gly211Ser missense_variant Familial Paternal Simplex 22209245 Vaags AK , et al. (2012)
c.104_107del p.Ser35TyrfsTer12 frameshift_variant De novo NA - 27465822 Hamilton MJ , et al. (2016)
c.6574_6585del p.Gln2192_Gln2195del inframe_deletion Unknown - - 27159028 Fieremans N , et al. (2016)
c.4705_4706del p.Phe1569LeufsTer19 frameshift_variant De novo NA - 26788536 Wincent J , et al. (2016)
c.6627_6638del p.Asn2209_Gln2213delinsLys inframe_deletion De novo NA - 29506490 Lpez M , et al. (2018)
c.3671+5G>A - splice_site_variant De novo NA - 25533962 Deciphering Developmental Disorders Study (2014)
c.4783T>G p.Phe1595Val missense_variant Familial Paternal Simplex 31036916 Lecoquierre F , et al. (2019)
TCAGAGAGCAGC>TC - frameshift_variant De novo NA - 25533962 Deciphering Developmental Disorders Study (2014)
c.659_662del p.Thr220SerfsTer16 frameshift_variant De novo NA Simplex 27465822 Hamilton MJ , et al. (2016)
c.5824A>T p.Met1942Leu missense_variant Familial Paternal Multi-generational 26788536 Wincent J , et al. (2016)
c.5581C>T p.Gln1861Ter stop_gained De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.7222_7223del p.Gln2408GlufsTer39 frameshift_variant Familial Maternal Multi-generational 29506490 Lpez M , et al. (2018)
c.3661del p.Gln1221SerfsTer6 frameshift_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.4912dup p.His1638ProfsTer35 frameshift_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

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). De novo loss-of-function variants in EP300 have also been identified in individuals from the Deciphering Developmental Disorders study (Fitzgerald et al., 2015).

Score Delta: Score remained at 4S

1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

1/1/2021
4S
icon
4S

Score remained at 4S

Description

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). De novo loss-of-function variants in EP300 have also been identified in individuals from the Deciphering Developmental Disorders study (Fitzgerald et al., 2015).

10/1/2019
4S
icon
1

Decreased from 4S to 1

New Scoring Scheme
Description

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). De novo loss-of-function variants in EP300 have also been identified in individuals from the Deciphering Developmental Disorders study (Fitzgerald et al., 2015).

Reports Added
[New Scoring Scheme]
7/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

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). De novo loss-of-function variants in EP300 have also been identified in individuals from the Deciphering Developmental Disorders study (Fitzgerald et al., 2015).

10/1/2017
4S
icon
4S

Decreased from 4S to 4S

Description

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). De novo loss-of-function variants in EP300 have also been identified in individuals from the Deciphering Developmental Disorders study (Fitzgerald et al., 2015).

10/1/2016
4S
icon
4S

Decreased from 4S to 4S

Description

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). De novo loss-of-function variants in EP300 have also been identified in individuals from the Deciphering Developmental Disorders study (Fitzgerald et al., 2015).

7/1/2016
icon
4S

Increased from to 4S

Description

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). 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). De novo loss-of-function variants in EP300 have also been identified in individuals from the Deciphering Developmental Disorders study (Fitzgerald et al., 2015).

Krishnan Probability Score

Score 0.56512301512648

Ranking 1256/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.99999999999948

Ranking 38/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Iossifov Probability Score

Score 0.958

Ranking 75/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.44926919010066

Ranking 351/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 0

Ranking 443/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
STAT6 signal transducer and activator of transcription 6, interleukin-4 induced Human Protein Binding 6778 P42226
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