Ebstein anomaly

Summary

Ebstein anomaly (MONDO:0009144) is a disease with 3 cohort genes and 3 clinical trials.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 4
• Phenotypes (HPO): 27
• Clinical trials: 3

Clinical features

Epidemiology

Prevalence records

22 prevalence record(s), Orphanet, top 20 (validated / broadest geography first):

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1.25	Europe	Validated
Prevalence at birth	1-9 / 100 000	3.5	Europe	Validated
Prevalence at birth	1-9 / 100 000	7.8	France	Validated
Prevalence at birth	1-5 / 10 000	19.5	Austria	Validated
Prevalence at birth	1-9 / 100 000	3.1	Belgium	Validated
Prevalence at birth	1-5 / 10 000	16.5	Croatia	Validated
Prevalence at birth	1-5 / 10 000	18.2	Denmark	Validated
Prevalence at birth	1-5 / 10 000	11.6	Germany	Validated
Prevalence at birth	1-9 / 100 000	1.1	Hungary	Validated
Prevalence at birth	1-9 / 100 000	3.6	Ireland	Validated
Prevalence at birth	1-9 / 100 000	4.1	Italy	Validated
Prevalence at birth	1-5 / 10 000	24.1	Malta	Validated
Prevalence at birth	1-9 / 100 000	5.7	Netherlands	Validated
Prevalence at birth	1-9 / 100 000	1	Poland	Validated
Prevalence at birth	1-9 / 1 000 000	0.6	Spain	Validated
Prevalence at birth	1-5 / 10 000	27.2	Switzerland	Validated
Prevalence at birth	1-9 / 100 000	3.5	United Kingdom	Validated
Prevalence at birth	1-9 / 100 000	6.5	Ukraine	Validated
Prevalence at birth	1-9 / 100 000	4.7	Taiwan, Province of China	Validated
Prevalence at birth	1-9 / 100 000	6.6	Specific population	Validated

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0001622	Premature birth	Very frequent (80-99%)
HP:0001631	Atrial septal defect	Very frequent (80-99%)
HP:0002093	Respiratory insufficiency	Very frequent (80-99%)
HP:0010316	Ebstein anomaly of the tricuspid valve	Very frequent (80-99%)
HP:0011575	Imperforate tricuspid valve	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0030680	Abnormal cardiovascular system morphology	Very frequent (80-99%)
HP:0000961	Cyanosis	Frequent (30-79%)
HP:0001643	Patent ductus arteriosus	Frequent (30-79%)
HP:0001671	Abnormal cardiac septum morphology	Frequent (30-79%)
HP:0001962	Palpitations	Frequent (30-79%)
HP:0005110	Atrial fibrillation	Frequent (30-79%)
HP:0005180	Tricuspid regurgitation	Frequent (30-79%)
HP:0011675	Arrhythmia	Frequent (30-79%)
HP:0011712	Right bundle branch block	Frequent (30-79%)
HP:0031667	Holosystolic murmur	Frequent (30-79%)
HP:0100749	Chest pain	Frequent (30-79%)
HP:0001635	Congestive heart failure	Occasional (5-29%)
HP:0001645	Sudden cardiac death	Occasional (5-29%)
HP:0002094	Dyspnea	Occasional (5-29%)
HP:0002637	Cerebral ischemia	Occasional (5-29%)
HP:0004306	Abnormality of the endocardium	Occasional (5-29%)
HP:0004420	Arterial thrombosis	Occasional (5-29%)
HP:0010741	Pedal edema	Occasional (5-29%)
HP:0012418	Hypoxemia	Occasional (5-29%)
HP:0001297	Stroke	Very rare (<1-4%)
HP:0001658	Myocardial infarction	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Ebstein anomaly
Mondo ID	MONDO:0009144
EFO	EFO:0007244
MeSH	D004437
OMIM	224700
Orphanet	1880
DOID	DOID:14289
ICD-10-CM	Q22.5
ICD-11	307157712
NCIT	C84681
UMLS	C0013481
MedGen	4435
GARD	0006313
MedDRA	10014075
Is cancer (heuristic)	no

Also known as: Ebstein anomaly · Ebstein anomaly (disease) · Ebstein anomaly of the tricuspid valve · Ebstein’s anomaly · Ebstein’s anomaly (disorder) [ambiguous] · Ebstein’s anomaly of tricuspid valve · Ebstein’s malformation

Data availability: 4 ClinVar variants · 1 ClinGen variant curation · 1 GenCC gene-disease record · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart valve disorder › tricuspid valve disorder › congenital tricuspid malformation › Ebstein anomaly

Related subtypes (9): tricuspid valve prolapse, cardiac valvular dysplasia, X-linked, tricuspid atresia, tricuspid valve agenesis, congenital tricuspid stenosis, straddling or overriding tricuspid valve, accessory tricuspid valve tissue, anomaly of the tricuspid valve chordae, parachute tricuspid valve

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

4 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
631491	NM_001260.3(CDK8):c.185C>A (p.Ser62Ter)	CDK8	Pathogenic	criteria provided, single submitter
268042	46;XY;t(18;20)(q21.1;p11.23)dn		Uncertain significance	criteria provided, single submitter
559395	Single allele	CEP85L	Uncertain significance	no assertion criteria provided
42968	NM_000257.4(MYH7):c.3658_3660del (p.Glu1220del)	MYH7	Uncertain significance	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 9 · 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
MYH7	Supportive	Autosomal dominant	Ebstein anomaly	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYH7	Orphanet:154	Familial isolated dilated cardiomyopathy
MYH7	Orphanet:1880	Ebstein malformation of the tricuspid valve
MYH7	Orphanet:324604	Classic multiminicore myopathy
MYH7	Orphanet:54260	Left ventricular noncompaction
MYH7	Orphanet:59135	Laing distal myopathy
MYH7	Orphanet:636965	Autosomal dominant myosin storage myopathy
MYH7	Orphanet:636970	Autosomal recessive myosin storage myopathy
CDK8	Orphanet:528084	Non-specific syndromic intellectual disability
CEP85L	Orphanet:572013	Posterior-predominant lissencephaly-broad flat pons and medulla-midline crossing defects syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MYH7	HGNC:7577	ENSG00000092054	P12883	Myosin-7	gencc,clinvar
CDK8	HGNC:1779	ENSG00000132964	P49336	Cyclin-dependent kinase 8	clinvar
CEP85L	HGNC:21638	ENSG00000111860	Q5SZL2	Centrosomal protein of 85 kDa-like	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYH7	Myosin-7	Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction.
CDK8	Cyclin-dependent kinase 8	Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes.
CEP85L	Centrosomal protein of 85 kDa-like	Plays an essential role in neuronal cell migration.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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
Kinase	1	9.2×	0.246
Scaffold/PPI	1	5.8×	0.246
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYH7	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
CDK8	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
CEP85L	Other/Unknown	no		Cep85/Cep85L, CC4_CEP85

Expression context

Cohort genes with no expression data: 0.

2 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
hindlimb stylopod muscle	1
skeletal muscle tissue of biceps brachii	1
adrenal tissue	1
buccal mucosa cell	1
secondary oocyte	1
pylorus	1
thymus	1
tibialis anterior	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYH7	167	tissue_specific	marker	apex of heart, hindlimb stylopod muscle, skeletal muscle tissue of biceps brachii
CDK8	289	ubiquitous	yes	adrenal tissue, buccal mucosa cell, secondary oocyte
CEP85L	248	ubiquitous	marker	thymus, tibialis anterior, pylorus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CDK8	2,827
MYH7	2,744
CEP85L	581

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYH7	P12883	43
CDK8	P49336	36

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CEP85L	Q5SZL2	64.98

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 34. Enrichment computed across 3 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	407.9×	0.013	CDK8
Signaling by NOTCH1 in Cancer	1	407.9×	0.013	CDK8
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	407.9×	0.013	CDK8
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1	368.4×	0.013	CDK8
Signaling by NOTCH1	1	356.9×	0.013	CDK8
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	1	308.6×	0.013	CDK8
NOTCH1 Intracellular Domain Regulates Transcription	1	237.9×	0.013	CDK8
Epigenetic regulation of adipogenesis genes by MLL3 and MLL4 complexes	1	215.5×	0.013	CDK8
Signaling by TGF-beta Receptor Complex	1	200.3×	0.013	CDK8
Constitutive Signaling by NOTCH1 PEST Domain Mutants	1	196.9×	0.013	CDK8
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants	1	196.9×	0.013	CDK8
Epigenetic regulation of gene expression by MLL3 and MLL4 complexes	1	196.9×	0.013	CDK8
Respiratory Syncytial Virus Infection Pathway	1	196.9×	0.013	CDK8
Signaling by NOTCH	1	175.7×	0.013	CDK8
RSV-host interactions	1	156.4×	0.013	CDK8
Adipogenesis	1	156.4×	0.013	CDK8
Epigenetic regulation by WDR5-containing histone modifying complexes	1	154.3×	0.013	CDK8
Regulation of lipid metabolism by PPARalpha	1	141.0×	0.013	CDK8
Transcriptional regulation of white adipocyte differentiation	1	129.8×	0.014	CDK8
Signaling by TGFB family members	1	115.3×	0.015	CDK8
PPARA activates gene expression	1	94.4×	0.017	CDK8
MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis	1	82.8×	0.019	CDK8
Epigenetic regulation of gene expression	1	71.4×	0.021	CDK8
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.025	CDK8
Metabolism of lipids	1	31.6×	0.042	CDK8
Viral Infection Pathways	1	30.8×	0.042	CDK8
Infectious disease	1	24.8×	0.051	CDK8
RNA Polymerase II Transcription	1	22.5×	0.054	CDK8
Gene expression (Transcription)	1	17.8×	0.066	CDK8
Generic Transcription Pathway	1	15.1×	0.075	CDK8

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
regulation of slow-twitch skeletal muscle fiber contraction	1	2808.7×	0.004	MYH7
regulation of the force of skeletal muscle contraction	1	1872.4×	0.004	MYH7
transition between fast and slow fiber	1	802.5×	0.007	MYH7
adult heart development	1	401.2×	0.007	MYH7
cardiac muscle hypertrophy in response to stress	1	351.1×	0.007	MYH7
muscle filament sliding	1	351.1×	0.007	MYH7
regulation of the force of heart contraction	1	330.4×	0.007	MYH7
striated muscle contraction	1	280.9×	0.007	MYH7
ventricular cardiac muscle tissue morphogenesis	1	234.1×	0.008	MYH7
skeletal muscle contraction	1	170.2×	0.009	MYH7
regulation of heart rate	1	156.0×	0.009	MYH7
ATP metabolic process	1	156.0×	0.009	MYH7
cardiac muscle contraction	1	133.8×	0.009	MYH7
muscle contraction	1	69.3×	0.016	MYH7
neuron migration	1	44.6×	0.024	CEP85L
positive regulation of transcription by RNA polymerase II	1	5.0×	0.188	CDK8

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CDK8	SORAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDK8	23	4
MYH7	0	0
CEP85L	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SORAFENIB	4	CDK8
PONATINIB	4	CDK8
QUIZARTINIB	4	CDK8
VATALANIB	3	CDK8
DINACICLIB	3	CDK8
LINIFANIB	3	CDK8
FASUDIL	3	CDK8
ALVOCIDIB	3	CDK8
ALISERTIB	3	CDK8
LESTAURTINIB	3	CDK8
INDIRUBIN	2	CDK8
DORAMAPIMOD	2	CDK8
FORETINIB	2	CDK8
ILORASERTIB	2	CDK8
VORUCICLIB	2	CDK8
CT-7001	2	CDK8
CP-724714	2	CDK8
SENEXIN B	1	CDK8
SEL-120 FREE BASE	1	CDK8
BMS-387032	1	CDK8
SEL-120	1	CDK8
SNS-314	1	CDK8
AST-487	1	CDK8

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CDK8	509	Binding:499, Functional:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CDK8	2.7.11.22, 2.7.11.23	cyclin-dependent kinase, [RNA-polymerase]-subunit kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CDK8	509

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

23 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)
SORAFENIB	4	CDK8
PONATINIB	4	CDK8
QUIZARTINIB	4	CDK8
VATALANIB	3	CDK8
DINACICLIB	3	CDK8
LINIFANIB	3	CDK8
FASUDIL	3	CDK8
ALVOCIDIB	3	CDK8
ALISERTIB	3	CDK8
LESTAURTINIB	3	CDK8
INDIRUBIN	2	CDK8
DORAMAPIMOD	2	CDK8
FORETINIB	2	CDK8
ILORASERTIB	2	CDK8
VORUCICLIB	2	CDK8
CT-7001	2	CDK8
CP-724714	2	CDK8
SENEXIN B	1	CDK8
SEL-120 FREE BASE	1	CDK8
BMS-387032	1	CDK8
SEL-120	1	CDK8
SNS-314	1	CDK8
AST-487	1	CDK8

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CDK8
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MYH7, CEP85L

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MYH7	0	—
CEP85L	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02914171	PHASE1	COMPLETED	Study of Autologous Bone Marrow Derived Mononuclear Cells for Treatment of Ebstein Anomaly
NCT05225311	Not specified	RECRUITING	Fetal Ebstein Anomaly and Tricuspid Valve Dysplasia Registry
NCT01907971	Not specified	COMPLETED	Assessment of Left and Right Ventricular Function in Patients With Ebstein Anomaly With Different Echocardiographic Methods