Rubinstein-Taybi syndrome due to EP300 haploinsufficiency

Summary

Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (MONDO:0013364) is a disease caused by EP300 (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: EP300 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 1,425
• Phenotypes (HPO): 123

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		34	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

123 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000218	High palate	Very frequent (80-99%)
HP:0000273	Facial grimacing	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000369	Low-set ears	Very frequent (80-99%)
HP:0000494	Downslanted palpebral fissures	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0001999	Abnormal facial shape	Very frequent (80-99%)
HP:0002553	Highly arched eyebrow	Very frequent (80-99%)
HP:0005322	Prominent nasal septum	Very frequent (80-99%)
HP:0005484	Secondary microcephaly	Very frequent (80-99%)
HP:0006200	Widened distal phalanges	Very frequent (80-99%)
HP:0008897	Postnatal growth retardation	Very frequent (80-99%)
HP:0010055	Broad hallux	Very frequent (80-99%)
HP:0011304	Broad thumb	Very frequent (80-99%)
HP:0012758	Neurodevelopmental delay	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000077	Abnormality of the kidney	Frequent (30-79%)
HP:0000119	Abnormality of the genitourinary system	Frequent (30-79%)
HP:0000189	Narrow palate	Frequent (30-79%)
HP:0000444	Convex nasal ridge	Frequent (30-79%)
HP:0000478	Abnormality of the eye	Frequent (30-79%)
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000712	Emotional lability	Frequent (30-79%)
HP:0000722	Compulsive behaviors	Frequent (30-79%)
HP:0000733	Abnormal repetitive mannerisms	Frequent (30-79%)
HP:0000756	Agoraphobia	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0001513	Obesity	Frequent (30-79%)
HP:0001627	Abnormal heart morphology	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002205	Recurrent respiratory infections	Frequent (30-79%)
HP:0002870	Obstructive sleep apnea	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0007086	Social and occupational deterioration	Frequent (30-79%)
HP:0008752	Laryngeal cartilage malformation	Frequent (30-79%)
HP:0008872	Feeding difficulties in infancy	Frequent (30-79%)
HP:0009765	Low hanging columella	Frequent (30-79%)
HP:0009834	Abnormal proximal phalanx morphology of the hand	Frequent (30-79%)
HP:0009836	Broad distal phalanx of finger	Frequent (30-79%)
HP:0011087	Talon cusp	Frequent (30-79%)
HP:0012760	Reduced social responsiveness	Frequent (30-79%)
HP:0025269	Panic attack	Frequent (30-79%)
HP:0030680	Abnormal cardiovascular system morphology	Frequent (30-79%)
HP:0100710	Impulsivity	Frequent (30-79%)
HP:0100852	Abnormal fear/anxiety-related behavior	Frequent (30-79%)
HP:0410263	Brain imaging abnormality	Frequent (30-79%)
HP:0000010	Recurrent urinary tract infections	Occasional (5-29%)
HP:0000034	Hydrocele testis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Rubinstein-Taybi syndrome due to EP300 haploinsufficiency
Mondo ID	MONDO:0013364
OMIM	613684
Orphanet	353284
NCIT	C153291
UMLS	C3150941
MedGen	462291
GARD	0017535
Is cancer (heuristic)	no

Also known as: EP300 Rubinstein-Taybi syndrome · RSTS2 · Rubinstein-Taybi syndrome 2 · Rubinstein-Taybi syndrome caused by mutation in EP300 · Rubinstein-Taybi syndrome due to EP300 haploinsufficiency · Rubinstein-Taybi syndrome type 2

Data availability: 1,425 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › Rubinstein-Taybi syndrome › Rubinstein-Taybi syndrome due to EP300 haploinsufficiency

Related subtypes (2): Rubinstein-Taybi syndrome due to CREBBP mutations, chromosome 16p13.3 deletion syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

168 likely benign, 160 uncertain significance, 83 benign, 70 benign/likely benign, 61 conflicting classifications of pathogenicity, 39 pathogenic, 15 likely pathogenic, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2424165	NC_000022.10:g.(?41074407)(41489122_?)del	DNAJB7	Pathogenic	criteria provided, single submitter
1030396	NM_001429.4(EP300):c.2225del (p.Pro742fs)	EP300	Pathogenic	criteria provided, multiple submitters, no conflicts
1068928	NM_001429.4(EP300):c.4216_4219dup (p.Lys1407delinsThrTer)	EP300	Pathogenic	criteria provided, single submitter
1072487	NM_001429.4(EP300):c.650dup (p.Asn217fs)	EP300	Pathogenic	criteria provided, single submitter
1173071	NM_001429.3:c.4271_4367del	EP300	Pathogenic	criteria provided, single submitter
1174646	NM_001429.4(EP300):c.3671+1G>A	EP300	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1320123	NM_001429.4(EP300):c.3826_3827dup (p.Leu1276fs)	EP300	Pathogenic	criteria provided, single submitter
1322823	NM_001429.4(EP300):c.2333dup (p.Asn779fs)	EP300	Pathogenic	criteria provided, multiple submitters, no conflicts
1326926	NM_001429.4(EP300):c.1423dup (p.Tyr475fs)	EP300	Pathogenic	no assertion criteria provided
1333868	NM_001429.4(EP300):c.6101del (p.Gly2034fs)	EP300	Pathogenic	criteria provided, single submitter
1365909	NM_001429.4(EP300):c.4065C>G (p.Tyr1355Ter)	EP300	Pathogenic	criteria provided, single submitter
1370430	NM_001429.4(EP300):c.3684del (p.Glu1229fs)	EP300	Pathogenic	criteria provided, single submitter
1371078	NM_001429.4(EP300):c.4873del (p.Asp1625fs)	EP300	Pathogenic	criteria provided, single submitter
137620	NM_001429.4(EP300):c.104_107del (p.Ser35fs)	EP300	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1426847	NM_001429.4(EP300):c.4785del (p.Phe1596fs)	EP300	Pathogenic	criteria provided, single submitter
1427007	NM_001429.4(EP300):c.4826_4833dup (p.Ile1612fs)	EP300	Pathogenic	criteria provided, single submitter
1459685	NC_000022.10:g.(?41553153)(41554524_?)del	EP300	Pathogenic	criteria provided, single submitter
1698627	NM_001429.4(EP300):c.598C>T (p.Arg200Ter)	EP300	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1708228	NM_001429.4(EP300):c.6323del (p.Gln2108fs)	EP300	Pathogenic	criteria provided, single submitter
1708232	NM_001429.4(EP300):c.108_111del (p.Phe37fs)	EP300	Pathogenic	criteria provided, single submitter
1710191	NM_001429.4(EP300):c.2734C>T (p.Gln912Ter)	EP300	Pathogenic	no assertion criteria provided
183678	NM_001429.4(EP300):c.4933C>T (p.Arg1645Ter)	EP300	Pathogenic	criteria provided, multiple submitters, no conflicts
2013506	NM_001429.4(EP300):c.4595del (p.Asn1532fs)	EP300	Pathogenic	criteria provided, single submitter
2030508	NM_001429.4(EP300):c.6739dup (p.Gln2247fs)	EP300	Pathogenic	criteria provided, single submitter
2035946	NM_001429.4(EP300):c.4947dup (p.Ser1650fs)	EP300	Pathogenic	criteria provided, single submitter
2060293	NM_001429.4(EP300):c.3672_3673dup (p.Thr1225fs)	EP300	Pathogenic	criteria provided, single submitter
210940	NM_001429.4(EP300):c.4836dup (p.Val1613fs)	EP300	Pathogenic	criteria provided, single submitter
210941	NM_001429.4(EP300):c.6915_6918del (p.Asn2305fs)	EP300	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2126804	NM_001429.4(EP300):c.5880dup (p.Pro1961fs)	EP300	Pathogenic	criteria provided, single submitter
2135640	NM_001429.4(EP300):c.4444_4445dup (p.Asp1482fs)	EP300	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
EP300	Definitive	Autosomal dominant	Rubinstein-Taybi syndrome due to EP300 haploinsufficiency	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EP300	Orphanet:353284	Rubinstein-Taybi syndrome due to EP300 haploinsufficiency
ACO2	Orphanet:313850	Infantile cerebellar-retinal degeneration
ACO2	Orphanet:98676	Autosomal recessive isolated optic atrophy
PANK2	Orphanet:216866	Classic pantothenate kinase-associated neurodegeneration
PANK2	Orphanet:216873	Atypical pantothenate kinase-associated neurodegeneration

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EP300	HGNC:3373	ENSG00000100393	Q09472	Histone acetyltransferase p300	gencc,clinvar
ACO2	HGNC:118	ENSG00000100412	Q99798	Aconitate hydratase, mitochondrial	clinvar
PANK2	HGNC:15894	ENSG00000125779	Q9BZ23	Pantothenate kinase 2, mitochondrial	clinvar
DNAJB7	HGNC:24986	ENSG00000172404	Q7Z6W7	DnaJ homolog subfamily B member 7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
EP300	Histone acetyltransferase p300	Functions as a histone acetyltransferase and regulates transcription via chromatin remodeling.
ACO2	Aconitate hydratase, mitochondrial	Catalyzes the isomerization of citrate to isocitrate via cis-aconitate.
PANK2	Pantothenate kinase 2, mitochondrial	Mitochondrial isoform that catalyzes the phosphorylation of pantothenate to generate 4’-phosphopantothenate in the first and rate-determining step of coenzyme A (CoA) synthesis.
DNAJB7	DnaJ homolog subfamily B member 7	Probably acts as a co-chaperone.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	2	6.0×	0.112
Transcription factor	1	2.1×	0.605
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EP300	Transcription factor	no	2.3.1.48	Znf_TAZ, Znf_ZZ, Bromodomain
ACO2	Enzyme (other)	yes	4.2.1.3	AconitaseA/IPMdHydase_ssu_swvl, Acoase/IPM_deHydtase_lsu_aba, Aconitase_mito-like
PANK2	Enzyme (other)	yes	2.7.1.33	Type_II_PanK, ATPase_NBD
DNAJB7	Other/Unknown	no		DnaJ_domain, DnaJ_domain_CS, J_dom_sf

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adrenal tissue	1
bone marrow cell	1
colonic epithelium	1
apex of heart	1
heart right ventricle	1
left ventricle myocardium	1
endothelial cell	1
monocyte	1
stromal cell of endometrium	1
left testis	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EP300	292	ubiquitous	marker	colonic epithelium, adrenal tissue, bone marrow cell
ACO2	291	ubiquitous	marker	heart right ventricle, apex of heart, left ventricle myocardium
PANK2	282	ubiquitous	marker	endothelial cell, stromal cell of endometrium, monocyte
DNAJB7	127	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, right testis, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EP300	10,122
ACO2	4,776
DNAJB7	2,183
PANK2	1,312

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EP300	Q09472	60
PANK2	Q9BZ23	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACO2	Q99798	95.44
DNAJB7	Q7Z6W7	59.38

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 71. Enrichment computed across 4 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production	1	761.3×	0.014	EP300
NFE2L2 regulating inflammation associated genes	1	761.3×	0.014	EP300
NFE2L2 regulating ER-stress associated genes	1	761.3×	0.014	EP300
Coenzyme A biosynthesis	1	475.8×	0.014	PANK2
NFE2L2 regulates pentose phosphate pathway genes	1	475.8×	0.014	EP300
NFE2L2 regulating MDR associated enzymes	1	475.8×	0.014	EP300
Regulation of NFE2L2 gene expression	1	475.8×	0.014	EP300
PI5P Regulates TP53 Acetylation	1	423.0×	0.014	EP300
RUNX3 regulates p14-ARF	1	380.7×	0.014	EP300
Regulation of FOXO transcriptional activity by acetylation	1	380.7×	0.014	EP300
STAT3 nuclear events downstream of ALK signaling	1	346.1×	0.014	EP300
Regulation of gene expression by Hypoxia-inducible Factor	1	317.2×	0.014	EP300
NOTCH2 intracellular domain regulates transcription	1	317.2×	0.014	EP300
Activation of the TFAP2 (AP-2) family of transcription factors	1	317.2×	0.014	EP300
NFE2L2 regulating tumorigenic genes	1	317.2×	0.014	EP300
RUNX3 regulates NOTCH signaling	1	271.9×	0.014	EP300
TRAF3-dependent IRF activation pathway	1	253.8×	0.014	EP300
Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells	1	237.9×	0.014	EP300
FOXO-mediated transcription of cell death genes	1	237.9×	0.014	EP300
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	1	223.9×	0.014	EP300
Zygotic genome activation (ZGA)	1	223.9×	0.014	EP300
Polo-like kinase mediated events	1	211.5×	0.014	EP300
TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest	1	200.3×	0.014	EP300
NOTCH4 Intracellular Domain Regulates Transcription	1	190.3×	0.014	EP300
Maturation of TCA enzymes and regulation of TCA cycle	1	190.3×	0.014	ACO2
Regulation of TP53 Activity through Methylation	1	181.3×	0.014	EP300
NFE2L2 regulating anti-oxidant/detoxification enzymes	1	181.3×	0.014	EP300
CD209 (DC-SIGN) signaling	1	173.0×	0.015	EP300
Regulation of TP53 Activity through Acetylation	1	152.3×	0.015	EP300
TGFBR3 expression	1	152.3×	0.015	EP300

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
behavioral defense response	1	5617.3×	0.002	EP300
negative regulation of protein oligomerization	1	5617.3×	0.002	EP300
swimming	1	5617.3×	0.002	EP300
peptidyl-lysine propionylation	1	5617.3×	0.002	EP300
regulation of tubulin deacetylation	1	5617.3×	0.002	EP300
peptidyl-lysine crotonylation	1	5617.3×	0.002	EP300
peptidyl-lysine butyrylation	1	5617.3×	0.002	EP300
internal protein amino acid acetylation	1	2808.7×	0.003	EP300
N-terminal peptidyl-lysine acetylation	1	1872.4×	0.004	EP300
obsolete regulation of bile acid metabolic process	1	1872.4×	0.004	PANK2
thigmotaxis	1	1404.3×	0.004	EP300
citrate metabolic process	1	1404.3×	0.004	ACO2
negative regulation of chromosome condensation	1	1404.3×	0.004	EP300
internal peptidyl-lysine acetylation	1	1123.5×	0.005	EP300
negative regulation of brown fat cell differentiation	1	936.2×	0.005	EP300
pantothenate metabolic process	1	702.2×	0.006	PANK2
regulation of triglyceride metabolic process	1	702.2×	0.006	PANK2
positive regulation of TORC2 signaling	1	702.2×	0.006	EP300
positive regulation of T-helper 17 cell lineage commitment	1	702.2×	0.006	EP300
regulation of fatty acid metabolic process	1	624.1×	0.006	PANK2
coenzyme A biosynthetic process	1	510.7×	0.007	PANK2
protein acetylation	1	468.1×	0.007	EP300
cellular response to L-leucine	1	468.1×	0.007	EP300
regulation of glycolytic process	1	401.2×	0.008	EP300
regulation of cellular response to heat	1	351.1×	0.009	EP300
regulation of androgen receptor signaling pathway	1	330.4×	0.009	EP300
host-mediated activation of viral transcription	1	295.6×	0.010	EP300
regulation of mitochondrion organization	1	280.9×	0.010	EP300
negative regulation of gluconeogenesis	1	267.5×	0.010	EP300
stimulatory C-type lectin receptor signaling pathway	1	244.2×	0.010	EP300

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 3

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EP300	9	3
ACO2	0	0
PANK2	0	0
DNAJB7	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COENZYME_A	3	EP300
CURCUMIN	3	EP300
EPIGALOCATECHIN GALLATE	3	EP300
MOLIBRESIB	2	EP300
MIVEBRESIB	2	EP300
STREPTONIGRIN	2	EP300
BERBERINE CHLORIDE	1	EP300
PLUMBAGIN	1	EP300
INOBRODIB	1	EP300

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
EP300	767	Binding:763, Functional:3, ADMET:1
PANK2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EP300	2.3.1.48	histone acetyltransferase
ACO2	4.2.1.3	aconitate hydratase
PANK2	2.7.1.33	pantothenate kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
EP300	767

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

9 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
COENZYME_A	3	EP300
CURCUMIN	3	EP300
EPIGALOCATECHIN GALLATE	3	EP300
MOLIBRESIB	2	EP300
MIVEBRESIB	2	EP300
STREPTONIGRIN	2	EP300
BERBERINE CHLORIDE	1	EP300
PLUMBAGIN	1	EP300
INOBRODIB	1	EP300

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	EP300
C	Druggable family + PDB, no drug	1	PANK2
D	Druggable family + AlphaFold only, no drug	1	ACO2
E	Difficult family or no structure, no drug	1	DNAJB7

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ACO2	0	—
PANK2	1	—
DNAJB7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.