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Inheritance

1

Autosomal dominant MYH7-associated subtype HP:0000006

Most Ebstein anomaly is sporadic and genetically unexplained. A minority is Mendelian: the MYH7-associated subtype that co-segregates with left ventricular noncompaction is autosomal dominant with variable penetrance and variable expressivity, so a relative carrying the same variant may manifest isolated noncompaction, isolated Ebstein anomaly, or both. Chromosomal microdeletions at 1p36 and 8p23.1 account for a further syndromic fraction.

Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE

Show evidence (2 references)

PMID:23794396 SUPPORT Human Clinical

"which seems to represent a subtype of Ebstein anomaly with autosomal dominant inheritance and variable penetrance"

Establishes autosomal dominant inheritance with variable penetrance for the MYH7-associated subtype.

PMID:38884760 SUPPORT Human Clinical

"the studies summarized here provide, in aggregate, evidence for monogenic and oligogenic factors driving pathogenesis"

Review concluding that both monogenic and oligogenic contributions operate, consistent with a predominantly non-Mendelian disease containing a Mendelian minority.

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Subtypes

1

MYH7-associated Ebstein anomaly with left ventricular noncompaction

MYH7 hgnc:7577

The Mendelian minority of Ebstein anomaly: a heterozygous MYH7 sarcomeric variant co-segregating with left ventricular noncompaction, transmitted autosomal dominantly with variable penetrance and variable expressivity, so a relative carrying the same variant may manifest isolated noncompaction, isolated Ebstein anomaly, or both. It accounted for 8 of 141 unselected probands, and noncompaction was confined almost entirely to this group. This subtype is the reason genetic testing and cascade family evaluation are recommended when Ebstein anomaly presents alongside noncompaction. Note this is a *genetic* subtype; the Carpentier A-D anatomic grading and the Celermajer severity index are severity scales rather than subtypes and are curated under `diagnosis` instead.

Show evidence (2 references)

PMID:21127202 SUPPORT Human Clinical

"Among 8 mutation-positive probands, 6 had LVNC, whereas among 133 mutation-negative probands, none had LVNC."

Establishes the subtype boundary, since noncompaction is essentially confined to the MYH7-mutation-positive group.

PMID:23794396 SUPPORT Human Clinical

"which seems to represent a subtype of Ebstein anomaly with autosomal dominant inheritance and variable penetrance"

The source itself frames this constellation as a subtype of Ebstein anomaly, which is the basis for modeling it as one here.

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Discussions and Knowledge Gaps

1

How does a sarcomeric beta-myosin heavy chain defect produce a tricuspid valve delamination phenotype?

KNOWLEDGE GAP OPEN myh7_sarcomere_to_valve_mechanism

Attached to

pathophysiology#Failure of tricuspid leaflet delamination

MYH7 encodes a contractile protein of the cardiomyocyte sarcomere, yet MYH7 variants cause a valve morphogenesis defect. The intervening steps, whether altered myocardial mechanics during the valvulogenic window perturb the apoptotic and matrix-remodelling programme that delaminates the leaflets or some other route operates, are not established. The absence of an animal model reproducing the full Ebstein phenotype is the main barrier to resolving this.

Proposed experiments

Conditional Ebstein-associated MYH7 variant in developing right ventricular myocardium

exp_ebstein_myh7_delamination_model

Express an Ebstein-associated MYH7 missense variant conditionally in the developing right ventricular myocardium and quantify, across the valvulogenic window, leaflet delamination extent, the position of the functional tricuspid hinge relative to the true annulus, and apoptosis in the myocardium underlying the septal and inferior leaflet primordia.

Decision criterion

Reproduction of apical hinge displacement with retained leaflet-myocardial adherence would establish that a sarcomeric defect is sufficient to cause the delamination phenotype.

Single-cell transcriptomic profiling of the developing atrioventricular junction

exp_ebstein_av_junction_single_cell

Profile the developing atrioventricular junction in an MYH7-variant model versus wild type at successive timepoints spanning the delamination window, to identify which cell populations and programmes diverge before the anatomic lesion is established.

Show evidence (1 reference)

PMID:38884760 SUPPORT Human Clinical

"Although Ebstein's anomaly remains one of the least understood cardiac malformations to date"

Authoritative review stating that the disease mechanism remains among the least understood in structural cardiac malformation.

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Pathophysiology

10

Failure of tricuspid leaflet delamination

During normal atrioventricular valvulogenesis the tricuspid leaflets are excavated from the inner layer of the right ventricular myocardium by an undermining and delamination process involving localized apoptosis and extracellular matrix remodelling of the developing valve primordium. In Ebstein anomaly this delamination is incomplete, so the septal and posteroinferior leaflets remain adherent to the underlying ventricular myocardium and interventricular septum rather than forming discrete, freely mobile, chordally tethered structures. This is the primary developmental lesion from which every downstream feature of the disease follows.

Cardiac valve cell CL:1000147 Endocardial cell CL:0002350

Tricuspid valve morphogenesis GO:0003186 ⚠ ABNORMAL Atrioventricular valve morphogenesis GO:0003181 ⚠ ABNORMAL

Tricuspid valve UBERON:0002134 Tricuspid valve leaflet UBERON:0005484

Downstream

Apical displacement of the functional tricuspid orifice Because the leaflets remain attached to myocardium instead of hinging at the true atrioventricular junction, the effective valve orifice comes to lie apically within the right ventricle.

Accessory atrioventricular pathway substrate Downward displacement of the septal leaflet is associated with discontinuity of the central fibrous body and septal atrioventricular ring, leaving direct atrioventricular muscular connections.

Show evidence (3 references)

PMID:26357983 SUPPORT Human Clinical

"It is a right ventricular myopathy with failure of tricuspid valve delamination and highly variable tricuspid valve morphology that usually results in severe regurgitation."

Mayo Clinic review establishing failure of delamination plus right ventricular myopathy as the defining lesion.

PMID:23269033 SUPPORT Human Clinical

"The current opinion among authors is that it is a genetically heterogeneous condition caused by failure of delamination of the TV leaflets from the underlying myocardium and the interventricular septum."

Review stating the delamination-failure mechanism and adherence to both myocardium and interventricular septum.

PMID:21127202 SUPPORT Human Clinical

"Ebstein anomaly is a rare congenital heart malformation characterized by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium."

Independent characterization of leaflet adherence to underlying myocardium as the anatomic hallmark.

Apical displacement of the functional tricuspid orifice

The functional tricuspid annulus is displaced downward (apically) into the right ventricle, well below the true anatomic atrioventricular junction. Echocardiography demonstrates apical displacement of the septal leaflet with variable tethering of leaflet tissue to the right ventricular myocardium, and in many hearts the valve is additionally rotated towards the right ventricular outflow tract.

Tricuspid valve anulus UBERON:0005997

Downstream

Atrialization of the right ventricle The myocardium interposed between the true annulus and the displaced functional orifice is incorporated into the right atrial chamber.

Tricuspid regurgitation (haemodynamic lesion) Displaced, tethered and rotated leaflets cannot appose during systole.

Show evidence (2 references)

PMID:32622490 SUPPORT Human Clinical

"Echocardiography is diagnostic in most patients and demonstrates apical displacement of the septal leaflet and variable tethering of leaflet tissue to the right ventricular myocardium."

Mayo Clinic review describing apical displacement and leaflet tethering as the diagnostic anatomic finding.

PMID:36151322 SUPPORT Human Clinical

"The tricuspid valve is abnormal with different degrees of displacement of the septal leaflet and abnormal rotation of the valve towards the right ventricular outflow tract."

Imaging review documenting both the graded septal-leaflet displacement and the rotational component of the deformity.

Anterosuperior leaflet redundancy and abnormal tethering

The anterosuperior leaflet is usually not displaced but is enlarged, redundant, and frequently fenestrated, with abnormal chordal and direct muscular attachments to the right ventricular free wall. This sail-like leaflet is the tissue that cone reconstruction mobilizes and rotates to build a competent neo-valve, so its morphology determines repairability. Multiple valve orifices, and the absence of the severe inferior leaflet displacement or extreme valve rotation that liberate spare tissue, are the intraoperative features that predict a need for pericardial patch augmentation of a deficient septal leaflet.

Tricuspid valve leaflet UBERON:0005484

Downstream

Tricuspid regurgitation (haemodynamic lesion) Tethering and fenestration of the redundant anterosuperior leaflet compound the coaptation defect produced by apical displacement of the other leaflets.

Show evidence (2 references)

PMID:41819162 SUPPORT Human Clinical

"Intraoperative factors associated with patch use were multiple TV orifices"

Single-centre surgical series identifying multiple tricuspid valve orifices as an intraoperative feature that leaves insufficient native tissue for a patch-free cone repair.

PMID:41819162 SUPPORT Human Clinical

"absence of severe inferior leaflet displacement (OR, 3.24; 95% CI, 1.11-9.47; P = .03), and absence of extreme TV rotation (OR, 3.19; 95% CI, 1.21-8.41; P = .02)"

The same series showing that hearts without severe inferior leaflet displacement or extreme valve rotation more often needed patch augmentation, quantifying how leaflet morphology governs repairability.

Atrialization of the right ventricle

The segment of right ventricular myocardium lying between the true anatomic tricuspid annulus and the displaced functional orifice becomes thin-walled and dyskinetic, and contracts in phase with the right atrium rather than the ventricle. Three morphologic components are therefore recognisable within the right heart: the right atrium proper, the atrialized right ventricle, and a reduced functional right ventricle. The loss of effective ventricular volume, compounded by an intrinsic right ventricular myopathy, limits antegrade pulmonary blood flow.

Cardiac muscle cell CL:0000746

Right ventricle UBERON:0002080 Right atrium UBERON:0002078

Downstream

Right heart volume overload and progressive dilation A dyskinetic atrialized segment and a small functional ventricle reduce forward stroke volume and amplify chamber dilation.

Show evidence (2 references)

PMID:23269033 SUPPORT Human Clinical

"The latter creates 3 morphologic components inside the right heart, namely the right atrium proper, the atrialized RV, and the functional RV."

Explicit statement of the three-compartment right-heart anatomy created by apical leaflet displacement.

PMID:38884758 SUPPORT Human Clinical

"Although primarily a tricuspid valve defect, the right ventricle itself is often structurally abnormal and weakened (myopathic)."

Confirms that the right ventricular myopathy is intrinsic and not merely a consequence of valve dysfunction.

Tricuspid regurgitation (haemodynamic lesion)

The regurgitant lesion itself: retrograde systolic flow from the right ventricle into the right atrium, usually severe, and the dominant haemodynamic burden of the disease and the target of surgical repair. The tissue-level causes of the leaflet coaptation failure that produces it are modeled upstream, on the apical-displacement and anterosuperior-leaflet nodes, so this node carries a single organism-scale claim rather than bundling the tissue-scale mechanism with its haemodynamic consequence.

Tricuspid valve UBERON:0002134

Downstream

Right heart volume overload and progressive dilation Regurgitant volume is recycled between right atrium and right ventricle each cardiac cycle, loading both chambers.

Show evidence (1 reference)

PMID:26357983 SUPPORT Human Clinical

"highly variable tricuspid valve morphology that usually results in severe regurgitation"

States that the highly variable valve morphology usually culminates in severe regurgitation.

Right heart volume overload and progressive dilation

Chronic regurgitant volume loading dilates the right atrium, the atrialized right ventricle, and the right atrioventricular junction. Annular dilation further separates the leaflet coaptation surfaces, so regurgitation begets regurgitation in a self-reinforcing cycle that drives progressive right heart enlargement and systolic dysfunction over years to decades. Advanced right-sided remodelling is accompanied by left-sided remodelling, and cone reconstruction reverses right ventricular dilation.

Right atrium UBERON:0002078 Right ventricle UBERON:0002080

Downstream

Right-to-left shunting through an interatrial communication Rising right atrial pressure reverses the interatrial pressure gradient across a patent foramen ovale or atrial septal defect.

Atrial remodelling and atrial tachyarrhythmia Progressive right atrial dilation creates the substrate for atrial flutter and fibrillation.

Show evidence (2 references)

PMID:25535206 SUPPORT Human Clinical

"MRI studies showed that the mean functional RV end-diastolic volume decreased after surgery"

Serial MRI showing markedly enlarged preoperative right ventricular volumes that regress once the regurgitant load is abolished, evidencing volume overload as the driver of dilation.

PMID:36368881 SUPPORT Human Clinical

"Patients with AF were older, were more likely men, and had hypertension, renal dysfunction, cardiac devices, and more advanced right-sided and left-sided remodelling."

Mayo Clinic cohort of 682 adults linking advanced right- and left-sided chamber remodelling to arrhythmia burden.

Right-to-left shunting through an interatrial communication

A patent foramen ovale or secundum atrial septal defect is present in most patients. When right atrial pressure exceeds left atrial pressure, deoxygenated blood crosses the septum into the systemic circulation, producing cyanosis, exercise intolerance, and a route for paradoxical embolism. Because the interatrial communication also decompresses the failing right heart, surgical closure is often deliberately partial (subtotal) or a small fenestration is left open.

Interatrial septum UBERON:0002085

Show evidence (2 references)

PMID:1394922 SUPPORT Human Clinical

"Sixteen patients (42%) required tricuspid valve surgery, and 23 (61%) had an atrial septal defect or patent foramen ovale repaired."

Surgical series in which 61% of Ebstein patients had an atrial septal defect or patent foramen ovale requiring repair, quantifying how common the interatrial communication is.

PMID:25535206 SUPPORT Human Clinical

"A 4- to 6-mm interatrial communication was left in all patients."

Surgical practice of deliberately leaving a residual interatrial communication, reflecting its role as a pressure-relief pathway for the failing right heart.

Accessory atrioventricular pathway substrate

Discontinuity of the central fibrous body and the septal atrioventricular ring at the malformed junction leaves direct atrioventricular muscular connections that bypass the atrioventricular node. These accessory pathways are typically right-sided or septal, frequently multiple, and produce ventricular pre-excitation and atrioventricular reentrant tachycardia. Ebstein anomaly is the congenital heart defect most frequently associated with the Wolff-Parkinson-White syndrome.

Cardiac muscle cell CL:0000746

Right atrium UBERON:0002078

Downstream

Ventricular pre-excitation Antegrade conduction over the accessory connection pre-excites ventricular myocardium, shortening the PR interval and inscribing a delta wave.

Show evidence (3 references)

PMID:19937010 SUPPORT Human Clinical

"The 14 surviving patients all show preexcitation, albeit 4 of them intermittently, and all have a right-sided accessory pathway location."

Dutch multicentre paediatric cohort documenting that every pre-excited patient had a right-sided accessory pathway, consistent with the right atrioventricular junction substrate.

PMID:34126268 SUPPORT Human Clinical

"Of the 61 patients with APs, a total of 78 separate APs were identified: 40 right-sided, 37 septal, and 1 left-sided."

Boston Children's series showing accessory pathways in Ebstein anomaly are overwhelmingly right-sided or septal and often multiple, with 78 pathways in 61 patients.

PMID:1394922 SUPPORT Human Clinical

"Ebstein's anomaly is the most commonly occurring congenital abnormality associated with the Wolff-Parkinson-White (WPW) syndrome."

Establishes Ebstein anomaly as the congenital lesion most often underlying WPW syndrome.

Atrial remodelling and atrial tachyarrhythmia

Chronic right atrial dilation and the accompanying electrical and structural remodelling create a reentrant substrate for atrial flutter and atrial fibrillation. Atrial tachyarrhythmias are the commonest late complication of Ebstein anomaly and develop at unusually young ages relative to the general population; in adults, atrial fibrillation is independently associated with hospitalisation for heart failure.

Right atrium UBERON:0002078

Show evidence (2 references)

PMID:26357983 SUPPORT Human Clinical

"Atrial tachyarrhythmias are the most common late complication."

Mayo review identifying atrial tachyarrhythmia as the leading late complication of the disease.

PMID:36368881 SUPPORT Human Clinical

"AF (HR 2.32, 95% CI 1.18 to 4.47; p=0.01) was independently associated with hospitalisation for HF."

Mayo cohort of 682 adults demonstrating that atrial fibrillation independently predicts heart-failure hospitalisation.

Fetal circular shunt physiology

In the most severe fetal presentations, torrential tricuspid regurgitation combined with pulmonary regurgitation across an incompetent or functionally atretic pulmonary valve establishes a circular shunt: blood passes from the aorta through the ductus arteriosus retrogradely into the pulmonary artery, back across the pulmonary valve into the right ventricle, through the incompetent tricuspid valve into the right atrium, and around again, largely bypassing the systemic capillary bed. The resulting massive cardiomegaly, low systemic output, and hydrops carry a high risk of intrauterine demise, and interrupting the circular shunt, by ductal constriction in utero or emergent interruption after birth, is the central management goal.

Ductus arteriosus UBERON:0005440

Downstream

Hydrops fetalis Massive cardiomegaly with low systemic output and venous congestion produces fetal hydrops.

Show evidence (2 references)

PMID:38685467 SUPPORT Human Clinical

"When evaluating fetuses with EA, those with severe cardiomegaly, retrograde or bidirectional shunt at the ductal level, pulmonary valve atresia, circular shunt, left ventricular dysfunction, or fetal hydrops should be considered high risk for intrauterine demise and postnatal morbidity and mortality."

AATS expert consensus identifying circular shunt, ductal-level retrograde flow, and hydrops as the high-risk fetal constellation.

PMID:38217614 SUPPORT Human Clinical

"A circular shunt is a poor prognostic factor associated with Ebstein's anomaly. Targeting the constriction of the ductus arteriosus (DA) in order to limit or resolve the circular shunt, has been shown to improve fetal outcomes."

Literature review establishing the circular shunt as the prognostically decisive fetal lesion and ductal constriction as the therapeutic target.

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Pathograph

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Phenotypes

14

Cardiovascular 5

Interatrial communication FREQUENT Atrial septal defect HP:0001631

Show evidence (1 reference)

PMID:1394922 SUPPORT Human Clinical

"23 (61%) had an atrial septal defect or patent foramen ovale repaired"

61% of a 38-patient surgical Ebstein series had an atrial septal defect or patent foramen ovale, supporting a FREQUENT (30-79%) band.

Right ventricular dilatation HP:0005133

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:32622490 SUPPORT Human Clinical

"Operative intervention is considered for exertional symptoms, progressive right ventricular enlargement, or right ventricular dysfunction."

Establishes progressive right ventricular enlargement as a recognised and clinically actionable feature; the review does not itself quantify frequency, so no frequency band is asserted.

Cardiomegaly HP:0001640

Show evidence (1 reference)

PMID:40317284 SUPPORT Human Clinical

"In patients with EA, the presence of congestive heart failure, cyanosis, significant left ventricular dysfunction, severe cardiomegaly, and persistent arrhythmia increases the risk for morbidity and mortality."

AATS consensus listing severe cardiomegaly among the features that raise morbidity and mortality risk.

Congestive heart failure HP:0001635

Show evidence (1 reference)

PMID:40317284 SUPPORT Human Clinical

"In patients with EA, the presence of congestive heart failure, cyanosis, significant left ventricular dysfunction, severe cardiomegaly, and persistent arrhythmia increases the risk for morbidity and mortality."

Consensus statement identifying congestive heart failure as a recognised manifestation carrying prognostic weight.

Atrial fibrillation OCCASIONAL HP:0005110

Show evidence (2 references)

PMID:36368881 SUPPORT Human Clinical

"At the last encounter, prevalence of AF was 28% (188 patients); of those, 63 (34%) had recurrent AF."

Mayo Clinic cohort of 682 adults with 28% cumulative atrial fibrillation prevalence, placing it in the OCCASIONAL (5-29%) band even after prolonged follow-up.

PMID:36368881 SUPPORT Human Clinical

"Prevalence of AF at baseline was 18% (126 patients); the first episode occurred at a mean age of 43±17 years."

Documents an 18% baseline prevalence and the unusually young mean age of first atrial fibrillation episode.

Integument 1

Cyanosis HP:0000961

Show evidence (1 reference)

PMID:40317284 SUPPORT Human Clinical

"Surgery is recommended for symptoms that include fatigue, decreased objective exercise tolerance, decreased arterial oxygen saturation (cyanosis), and exertional dyspnea."

Consensus document treating cyanosis as a defining symptomatic manifestation and operative indication.

Metabolism 1

Hydrops fetalis HP:0001789

Show evidence (1 reference)

PMID:38685467 SUPPORT Human Clinical

"those with severe cardiomegaly, retrograde or bidirectional shunt at the ductal level, pulmonary valve atresia, circular shunt, left ventricular dysfunction, or fetal hydrops should be considered high risk for intrauterine demise and postnatal morbidity and mortality"

Identifies fetal hydrops as a recognised, prognostically severe manifestation in the fetal subset.

Constitutional 1

Exercise intolerance HP:0003546

Show evidence (1 reference)

PMID:40317284 SUPPORT Human Clinical

"Asymptomatic patients with EA should undergo exercise stress testing with measurement of oxygen consumption to unmask occult exercise intolerance."

Directly documents occult exercise intolerance as a characteristic feature warranting systematic testing.

Other 6

Ebstein anomaly of the tricuspid valve OBLIGATE HP:0010316

Show evidence (1 reference)

PMID:38884759 SUPPORT Human Clinical

"It is characterized by displacement of the tricuspid valve toward the apex of the right ventricle"

Defines the obligate structural lesion of the disease.

Tricuspid regurgitation FREQUENT HP:0005180

Show evidence (2 references)

PMID:26357983 SUPPORT Human Clinical

"highly variable tricuspid valve morphology that usually results in severe regurgitation"

Supports tricuspid regurgitation as the usual, and usually severe, consequence of the valve deformity.

PMID:41819162 SUPPORT Human Clinical

"TR improved from ≥moderate in 78.7% pre-CR to ≤mild in 79.0% at follow-up."

Surgical cohort in which 79% of patients referred for cone repair had at least moderate preoperative tricuspid regurgitation; this is a surgically referred population, so it supports severity rather than an unbiased population frequency.

Ventricular pre-excitation OCCASIONAL HP:0004309

Show evidence (2 references)

PMID:19937010 SUPPORT Human Clinical

"During a follow-up after EA diagnosis of 13 years 3 months (range: 6 days to 28 years 2 months), 16 (17%) of the 93 pediatric EA patients exhibited rhythm disturbances."

Multicentre paediatric cohort in which 17% had rhythm disturbances and all arrhythmic survivors showed pre-excitation, supporting an OCCASIONAL (5-29%) band in childhood.

PMID:19937010 SUPPORT Human Clinical

"The 14 surviving patients all show preexcitation, albeit 4 of them intermittently"

Confirms that pre-excitation accounted for essentially the whole arrhythmic subgroup in that cohort.

Supraventricular tachycardia OCCASIONAL HP:0004755

Show evidence (1 reference)

PMID:19937010 SUPPORT Human Clinical

"The 17% prevalence of rhythm disturbances in pediatric EA patients, most commonly supraventricular arrhythmias, is significantly lower than in adult EA patients."

Quantifies a 17% paediatric rhythm-disturbance prevalence, predominantly supraventricular, supporting the OCCASIONAL band in childhood.

Right bundle branch block HP:0011710

Show evidence (2 references)

PMID:27751284 SUPPORT Human Clinical

"It may show tall and broad P waves as a result of right atrial enlargement, as well as complete or incomplete right bundle-branch block."

Establishes complete or incomplete right bundle branch block as a characteristic electrocardiographic finding; because the source does not distinguish complete from incomplete, the parent term Bundle branch block is used rather than HP:0011712 or HP:6000313.

PMID:28666538 SUPPORT Human Clinical

"In patients with Ebstein's anomaly and supraventricular tachycardia, the absence of right bundle branch block (RBBB) in sinus rhythm is a highly sensitive and specific indicator of the presence of an ipsilateral accessory AP."

Treats right bundle branch block as the expected baseline in Ebstein anomaly, so that its absence is a sensitive and specific marker of an ipsilateral accessory pathway.

Left ventricular noncompaction HP:0030682

Show evidence (2 references)

PMID:23794396 SUPPORT Human Clinical

"The most prevalent CHD in LVNC is Ebstein anomaly, which is a rare form of CHD characterized by apical displacement and partial fusion of the septal and posterior leaflet of the tricuspid valve with the ventricular septum."

Establishes the Ebstein anomaly and left ventricular noncompaction association.

PMID:21127202 SUPPORT Human Clinical

"Among 8 mutation-positive probands, 6 had LVNC, whereas among 133 mutation-negative probands, none had LVNC."

Shows noncompaction is concentrated in the MYH7-mutation-positive subgroup of Ebstein probands and essentially absent from the rest.

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Genetic Associations

4

MYH7

Gene: MYH7 hgnc:7577 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:21127202 SUPPORT Human Clinical

"Ebstein anomaly is a congenital heart malformation that is associated with mutations in MYH7."

Establishes MYH7 as a causal gene for Ebstein anomaly.

PMID:21127202 SUPPORT Human Clinical

"The frequency of MYH7 mutations was significantly different between probands with and without LVNC accompanying Ebstein anomaly (P<0.0001)."

Shows the MYH7 association is specific to the noncompaction-associated subtype.

PMID:23794396 SUPPORT Human Clinical

"which seems to represent a subtype of Ebstein anomaly with autosomal dominant inheritance and variable penetrance"

Characterises the MYH7-associated subtype as autosomal dominant with variable penetrance.

+ 1 more reference

1p36 deletion

relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (1 reference)

PMID:21815254 SUPPORT Human Clinical

"We conclude that Ebstein anomaly is a genetically heterogeneous defect, and that deletion 1p36 and deletion 8p23.1 are the most frequent chromosomal imbalances associated with Ebstein anomaly."

Identifies 1p36 deletion as one of the two commonest chromosomal imbalances in Ebstein anomaly.

8p23.1 deletion (GATA4 region)

Gene: GATA4 hgnc:4173 relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (2 references)

PMID:21815254 SUPPORT Human Clinical

"Array-CGH analysis performed in 10 of the 12 syndromic patients detected an interstitial deletion of about 4 Mb at 8p23.1 in one patient"

Documents the 8p23.1 deletion in a syndromic Ebstein anomaly patient.

PMID:21815254 REFUTE Human Clinical

"In the 28 of 32 nonsyndromic patients who underwent molecular testing, no mutation in GATA4 and NKX2.5 genes were detected."

Argues against intragenic GATA4 point mutation as a common cause of nonsyndromic Ebstein anomaly, restricting the GATA4 link to the deletion context.

NKX2-5

Gene: NKX2-5 hgnc:2488 relationship_type: DISPUTED variant_origin: GERMLINE

Show evidence (2 references)

PMID:28017577 SUPPORT Human Clinical

"Genetic bases of this congenital heart defect may be related to the mutations in myosin heavy chain 7 and NKX2.5, among others."

Review naming NKX2-5 alongside MYH7 as a proposed genetic basis, phrased as a possibility rather than an established cause.

PMID:21815254 REFUTE Human Clinical

"no mutation in GATA4 and NKX2.5 genes were detected"

Negative screen in 28 nonsyndromic patients arguing against NKX2-5 point mutation as a common cause.

💊

Medical Actions

12

Cone reconstruction of the tricuspid valve

Action: cardiac valve procedure Ontology label: Cardiac Valve Procedure NCIT:C99546

The Da Silva cone operation is the contemporary surgical standard. It consists of extensive mobilization of the anterior and inferior leaflets from their abnormal myocardial and chordal attachments, longitudinal plication of the atrialized right ventricle, and reconstruction of a cone of valve tissue reattached at the true annulus, allowing leaflet-to-leaflet coaptation. Right atrial reduction and closure or subtotal closure of the atrial septal communication are usually performed concomitantly. Compared with tricuspid valve replacement, cone repair carries lower rates of valve reoperation and tricuspid stenosis and better preserved right ventricular function at follow-up. Where native septal leaflet tissue is deficient, autologous pericardial patch augmentation gives comparable early results.

Mechanism Target:

INHIBITS Tricuspid regurgitation (haemodynamic lesion) — Rebuilding a coapting cone of leaflet tissue at the true annulus abolishes the regurgitant orifice that drives right heart volume overload.

Show evidence (1 reference)

PMID:25535206 SUPPORT Human Clinical

"Da Silva's cone repair for Ebstein's anomaly creates excellent valve function in all patients. Consecutively, the size of the RV decreases and the antegrade net stroke volume increases 6 months after the operation."

Demonstrates that abolishing regurgitation reverses the right ventricular dilation it caused.

Target Phenotypes: Tricuspid regurgitation HP:0005180 Right ventricular dilatation HP:0005133

Show evidence (6 references)

PMID:25535206 SUPPORT Human Clinical

"The technique consists of extensive leaflet mobilization, longitudinal plication of the atrialized ventricle and cone-shaped reconstruction of the tricuspid valve, allowing for leaflet-to-leaflet coaptation."

Describes the operative components of the cone repair.

PMID:40317284 SUPPORT Human Clinical

"The introduction of the cone procedure has revolutionized surgical management, providing excellent outcomes and durability across a wide range of anatomical variations."

Expert consensus positioning cone repair as the transformative and preferred surgical approach.

PMID:37425446 SUPPORT Human Clinical

"The tricuspid valve replacement group had a higher risk of tricuspid valve reoperation (37% vs 9%; P = .005) and tricuspid stenosis (21% vs 0%; P = .002) compared with the cone repair group."

85-patient comparative series showing cone repair outperforms valve replacement on reoperation and stenosis.

+ 3 more references

Starnes procedure with single-ventricle palliation

Action: cardiovascular surgical procedure Ontology label: Cardiovascular Surgical Procedure NCIT:C49803

For the neonate in refractory cardiogenic shock whose right ventricle is unsalvageable, the tricuspid valve is excluded with a fenestrated patch, an atrial septectomy is performed, and pulmonary blood flow is supplied by a systemic-to-pulmonary artery shunt, committing the patient to a staged single-ventricle pathway. Some children can subsequently be assessed for biventricular conversion.

Target Phenotypes: Congestive heart failure HP:0001635

Show evidence (1 reference)

PMID:38685467 SUPPORT Human Clinical

"Neonates in refractory cardiogenic shock may be palliated with the Starnes procedure. Children may be assessed for later biventricular repair after the Starnes procedure."

Consensus statement defining the indication for the Starnes procedure and the option of later biventricular conversion.

Bidirectional cavopulmonary shunt

Action: cardiovascular surgical procedure Ontology label: Cardiovascular Surgical Procedure NCIT:C49803

A superior cavopulmonary (bidirectional Glenn) anastomosis offloads the failing right ventricle by diverting superior caval return directly to the pulmonary arteries. It is used as an adjunct to valve repair in the setting of severe right ventricular dilation or dysfunction, an elevated right-to-left atrial pressure ratio, or failure to separate from cardiopulmonary bypass, yielding a so-called one-and-a-half ventricle repair.

Show evidence (2 references)

PMID:40317284 SUPPORT Human Clinical

"Bidirectional cavopulmonary shunt is reasonable when there is severe right ventricular dilation, severe right ventricular systolic dysfunction, right atrial pressure: left atrial pressure ratio >1.5, or failure to separate from cardiopulmonary bypass after repair."

Consensus statement specifying the haemodynamic indications for a bidirectional cavopulmonary shunt.

PMID:28017577 SUPPORT Human Clinical

"1.5-ventricular repair (bidirectional Glenn shunt) is indicated for patients with poor right ventricular function"

Independent review confirming the one-and-a-half ventricle strategy for poor right ventricular function.

Catheter ablation of accessory pathways

Action: cardiac ablation Ontology label: Cardiac Ablation NCIT:C100068

Ablation of accessory atrioventricular pathways treats pre-excited tachyarrhythmia. The Ebstein substrate is technically difficult: pathways are often multiple, right-sided or septal, and abnormal atrioventricular junction anatomy degrades mapping. Acute success is high but recurrence is substantially greater than in structurally normal hearts, so repeat procedures are common; ultimate pathway elimination after all procedures is nonetheless achieved in most patients. Ablation is best performed before valve surgery, which can render substrates inaccessible.

Mechanism Target:

INHIBITS Accessory atrioventricular pathway substrate — Ablation lesions interrupt conduction through the anomalous atrioventricular muscular connection.

Show evidence (1 reference)

PMID:34126268 SUPPORT Human Clinical

"At median follow-up of 2.5 (0.2-7) years, ultimate AP elimination after all procedures was 93%."

Demonstrates that ablation ultimately eliminates the accessory pathway substrate in the large majority of patients.

Target Phenotypes: Supraventricular tachycardia HP:0004755 Ventricular preexcitation HP:0004309

Show evidence (2 references)

PMID:34126268 SUPPORT Human Clinical

"However, 19 patients (31%) required repeat procedures (average 1.4 per patient) due to AP recurrence or ablation failure at first attempt. In comparison to early era, recent era ablations had significantly lower recurrence rates at 1 year (62% vs 19%; P = .005)."

Quantifies the high repeat-procedure rate and the era-related improvement in recurrence.

PMID:1394922 SUPPORT Human Clinical

"Patients with Ebstein's anomaly are improved significantly after accessory pathway ablation. The presence of this anomaly should not preclude accessory pathway ablation in these patients."

Long-term comparative outcome study establishing benefit of accessory pathway ablation despite the anomaly.

Concomitant maze procedure

Action: cardiac ablation Ontology label: Cardiac Ablation NCIT:C100068

Surgical atrial ablation performed at the time of tricuspid valve surgery in patients with paroxysmal or continuous atrial fibrillation, addressing the atrial reentrant substrate created by chronic right atrial dilation.

Mechanism Target:

INHIBITS Atrial remodelling and atrial tachyarrhythmia — Maze lesion sets compartmentalise the dilated atrium and interrupt macro-reentrant circuits.

Show evidence (1 reference)

PMID:40317284 SUPPORT Human Clinical

"Concomitant maze procedure at the time of surgery is reasonable when there is paroxysmal or continuous atrial fibrillation."

Consensus recommendation to address the atrial arrhythmia substrate surgically at the time of valve repair.

Target Phenotypes: Atrial fibrillation HP:0005110

Show evidence (1 reference)

PMID:40317284 SUPPORT Human Clinical

"Concomitant maze procedure at the time of surgery is reasonable when there is paroxysmal or continuous atrial fibrillation."

Direct consensus recommendation for the concomitant maze procedure.

Medical closure of the patent ductus arteriosus

Action: Pharmacotherapy NCIT:C15986

Agent: nonsteroidal anti-inflammatory drug NCIT:C257

In the neonate the ductus arteriosus is the pivot of management, because it supplies the retrograde aortopulmonary limb of the circular shunt. A haemodynamically stable neonate with significant pulmonary regurgitation, normal right ventricular systolic pressure, and therefore a risk of circular shunt should have pharmacologic closure of the patent ductus attempted. Neonates without high-risk features may simply be monitored for spontaneous ductal closure.

Mechanism Target:

INHIBITS Fetal circular shunt physiology — Closing or constricting the ductus arteriosus removes the retrograde aortopulmonary limb that sustains the circular shunt.

Show evidence (1 reference)

PMID:38217614 SUPPORT Human Clinical

"Targeting the constriction of the ductus arteriosus (DA) in order to limit or resolve the circular shunt, has been shown to improve fetal outcomes."

Establishes ductal constriction as the mechanism by which the circular shunt is interrupted. Cited here for the mechanism; that study is prenatal transplacental NSAID therapy, whereas this treatment entry is postnatal medical ductal closure.

Show evidence (2 references)

PMID:38685467 SUPPORT Human Clinical

"Hemodynamically stable neonates with significant pulmonary regurgitation at risk for circular shunt with normal right ventricular systolic pressure should have an attempt at medical closure of the PDA."

Consensus statement defining the indication for medical ductal closure.

PMID:38685467 SUPPORT Human Clinical

"Neonates who are hemodynamically stable without pulmonary regurgitation but inadequate antegrade pulmonary blood flow may be considered for a PDA stent or systemic to pulmonary artery shunt."

Consensus statement for the opposite scenario recorded in the notes, in which ductal patency must instead be maintained or augmented by a stent or shunt rather than closed.

Antiarrhythmic pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: antiarrhythmic agent NCIT:C47793

Rate- and rhythm-control drugs for atrioventricular reentrant tachycardia, atrial flutter, and atrial fibrillation. Drug therapy is a secondary line rather than the mainstay: in a multicentre paediatric Ebstein cohort only a minority of patients remained on antiarrhythmic drugs, because symptomatic accessory-pathway arrhythmia is better served by catheter ablation, and surgical candidates with atrial fibrillation are better served by a concomitant maze. Its role is largest in adults with an atrial substrate that ablation and surgery have not eliminated.

Mechanism Target:

INHIBITS Atrial remodelling and atrial tachyarrhythmia — Antiarrhythmic drugs suppress the tachyarrhythmias arising on the dilated-atrium substrate without altering the substrate itself, which is why they control rather than cure and why ablation or a maze is preferred where feasible.

Show evidence (1 reference)

PMID:19937010 SUPPORT Human Clinical

"Only four patients are currently on antiarrhythmic drugs."

Documents ongoing antiarrhythmic drug therapy in the arrhythmic subgroup, while the word "only" and the accompanying ablation result frame drugs as the lesser option.

Target Phenotypes: Supraventricular tachycardia HP:0004755 Atrial fibrillation HP:0005110

Show evidence (2 references)

PMID:19937010 SUPPORT Human Clinical

"Symptomatic patients are well treated with radiofrequency catheter ablation."

The same cohort's conclusion positions ablation, not drug therapy, as the definitive treatment for symptomatic arrhythmia in this disease.

PMID:28457239 SUPPORT Human Clinical

"As the population ages, the need to address atrial fibrillation management and risk stratification for sudden cardiac death becomes ever more pertinent."

Electrophysiology review identifying atrial fibrillation management as a growing clinical need in the ageing Ebstein population, the setting in which drug therapy is most used.

Heart failure pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: diuretic NCIT:C448

Guideline-directed medical therapy for ventricular dysfunction, together with diuretics for the systemic venous congestion produced by chronic tricuspid regurgitation. The AATS consensus frames this specifically around systolic left ventricular dysfunction, where concomitant acquired disease should first be excluded; diuretic use for right-sided congestion is standard supportive practice rather than a disease-specific evidence-based recommendation, and is curated here at that strength.

Target Phenotypes: Congestive heart failure HP:0001635

Show evidence (1 reference)

PMID:40317284 SUPPORT Human Clinical

"In EA patients with evidence of systolic left ventricular dysfunction, concomitant acquired disease should be excluded, and goal-directed medical therapies is recommended."

Consensus recommendation for goal-directed medical therapy, scoped by the source to systolic left ventricular dysfunction.

Prostaglandin E1 to maintain ductal patency

Action: Pharmacotherapy NCIT:C15986

Agent: prostaglandin E1 CHEBI:15544

The mirror image of medical ductal closure. A neonate whose right ventricle cannot generate antegrade flow across the pulmonary valve has ductal-dependent pulmonary blood flow, and prostaglandin E1 is infused to keep the ductus arteriosus open until the circulation is secured. Because the pulmonary atresia in Ebstein anomaly is often functional rather than anatomic, it can reverse as pulmonary vascular resistance falls, so prostaglandin can sometimes be weaned with an expectant strategy rather than committing the infant to a stent or shunt.

Target Phenotypes: Cyanosis HP:0000961

Show evidence (2 references)

PMID:31888914 SUPPORT Human Clinical

"Prostaglandin E1 was started after birth."

Case of Ebstein anomaly with functional pulmonary atresia and reversed ductal flow in which prostaglandin E1 was used to maintain ductal patency after delivery.

PMID:31888914 SUPPORT Human Clinical

"Multidisciplinary team decision was to progressively reduce prostaglandins and have an expectant attitude."

Documents that the functional pulmonary atresia reversed and prostaglandin could be weaned without stent or shunt, supporting the expectant strategy described.

Conservative management and surveillance

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Asymptomatic patients with preserved right heart size and function are managed with observation and serial imaging, which may be successful for many years. Lifelong cardiology follow-up is required because tricuspid regurgitation, right heart dilation, and arrhythmia burden accumulate insidiously.

Show evidence (2 references)

PMID:28017577 SUPPORT Human Clinical

"Asymptomatic patients with Ebstein's anomaly can be conservatively treated and kept under close follow-up, whereas surgical operation is indicated for those patients with evidence of right heart dilation and progressively impaired ventricular systolic function."

Defines the boundary between conservative surveillance and operative intervention.

PMID:32622490 SUPPORT Human Clinical

"Patients with Ebstein anomaly require lifelong follow-up."

Establishes the requirement for indefinite surveillance.

Cardiac transplantation

Action: heart transplantation Ontology label: Heart Transplantation NCIT:C15246

Reserved for end-stage disease with irreparable ventricular dysfunction, particularly where left ventricular function is severely impaired and neither valve repair nor cavopulmonary offloading can be expected to help.

Show evidence (1 reference)

PMID:28017577 SUPPORT Human Clinical

"heart transplantation is used in patients with severe left ventricular dysfunction"

Identifies transplantation as the option for severe left ventricular dysfunction.

Genetic counselling and cascade evaluation

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Genetic testing and family evaluation are warranted in the subset of patients whose Ebstein anomaly is accompanied by left ventricular noncompaction, where an autosomal dominant MYH7-associated subtype with variable penetrance is likely. Chromosomal microarray is appropriate when extracardiac anomalies suggest a syndromic cause. Recurrence-risk counselling for isolated sporadic disease is generally reassuring.

Show evidence (1 reference)

PMID:21127202 SUPPORT Human Clinical

"MYH7 mutations are predominantly found in Ebstein anomaly associated with LVNC and may warrant genetic testing and family evaluation in this subset of patients."

Directly supports targeted genetic testing and family evaluation in the noncompaction subset.

🌍

Environmental Factors

2

First-trimester maternal lithium exposure

Lithium taken in the first trimester is the best-characterised teratogenic exposure associated with Ebstein anomaly. A relative risk of about 400 was estimated in the 1970s from a voluntary case registry; controlled epidemiology has since shown the true excess to be far smaller and dose-related. In a cohort of 1,325,563 pregnancies, first-trimester lithium was associated with an adjusted risk ratio of 1.65 for cardiac malformations overall and 2.66 for right ventricular outflow tract obstruction defects, the category containing Ebstein anomaly, with risk rising above 900 mg/day. The absolute risk to an exposed pregnancy therefore remains low, and management guidance emphasises the lowest effective dose rather than blanket avoidance.

Show evidence (4 references)

PMID:28591541 SUPPORT Human Clinical

"Maternal use of lithium during the first trimester was associated with an increased risk of cardiac malformations, including Ebstein's anomaly; the magnitude of this effect was smaller than had been previously postulated."

Cohort study of over 1.3 million pregnancies confirming a real but modest association.

PMID:28591541 SUPPORT Human Clinical

"The risk ratio was 1.11 (95% CI, 0.46 to 2.64) for a daily dose of 600 mg or less, 1.60 (95% CI, 0.67 to 3.80) for 601 to 900 mg, and 3.22 (95% CI, 1.47 to 7.02) for more than 900 mg."

Establishes the dose-response relationship underlying current prescribing guidance.

PMID:8031346 SUPPORT Human Clinical

"In the 1970s a very strong association was suggested between maternal lithium treatment during pregnancy and Ebstein's anomaly of the heart in the offspring. The relative risk for Ebstein's anomaly among such children was estimated to be 400 on the basis of data collected from a registry of..."

Documents the historical registry-based relative risk of 400 that later controlled studies revised sharply downward.

+ 1 more reference

Mechanism Target:

PREDISPOSES Failure of tricuspid leaflet delamination — First-trimester lithium exposure raises the risk of right ventricular outflow tract obstruction defects, the malformation category containing Ebstein anomaly, implying an effect on the valvulogenic window during which leaflet delamination occurs. The molecular intermediates between lithium exposure and failed delamination are not established.

Show evidence (1 reference)

PMID:28591541 SUPPORT Human Clinical

"The prevalence of right ventricular outflow tract obstruction defects was 0.60% among lithium-exposed infants versus 0.18% among unexposed infants (adjusted risk ratio, 2.66; 95% CI, 1.00 to 7.06)."

Quantifies the excess of the malformation category containing Ebstein anomaly after first-trimester lithium exposure; the epidemiology establishes the association but not the developmental mechanism.

Advanced maternal age

Maternal age over 39 years was associated with an increased prevalence of non-syndromic Ebstein anomaly in a statewide birth-defects registry. This is an epidemiologic association from a descriptive registry analysis, not a demonstrated causal mechanism, and it is deliberately not linked into the pathograph for that reason.

Show evidence (1 reference)

PMID:21465650 SUPPORT Human Clinical

"Variables associated with an increased prevalence of non-syndromic Ebstein anomaly included: maternal age >39 years (compared to those 20-24 years), maternal residence along the Texas-Mexico border (compared to non-border residence), and conception in fall or winter (compared to summer)."

Texas Birth Defects Registry analysis of 188 cases identifying advanced maternal age as an associated variable.

🔬

Diagnosis

6

Transthoracic echocardiography

Echocardiography is diagnostic in most patients, demonstrating apical displacement of the septal leaflet, tethering of leaflet tissue to the right ventricular myocardium, the atrialized right ventricular segment, tricuspid regurgitation severity, and any interatrial communication. It is also the modality that defines repairability for cone reconstruction. Anatomic severity is graded with the Celermajer index, the ratio of the combined right atrial and atrialized right ventricular area to the combined functional right ventricular, left atrial and left ventricular area, banded into four grades. A caveat worth carrying: echocardiographic and cardiac-MRI derived values of that index agree only fairly, so the grade is modality-dependent and should not be compared across imaging methods.

echocardiography NCIT:C16525

Show evidence (4 references)

PMID:32622490 SUPPORT Human Clinical

"Echocardiography is diagnostic in most patients and demonstrates apical displacement of the septal leaflet and variable tethering of leaflet tissue to the right ventricular myocardium."

Establishes echocardiography as the primary diagnostic modality and what it shows.

PMID:23269033 SUPPORT Human Clinical

"Echocardiography is currently the best technique for diagnosing this anomaly, although cardiac magnetic resonance imaging is also gaining traction as an alternative modality."

Independent confirmation of echocardiography as the diagnostic standard, with cardiac MRI as the complementary modality.

PMID:31711824 SUPPORT Human Clinical

"Cel-ind = (right atrium + atrialized right ventricle)/(functional right ventricle + left atrium + left ventricle). On the basis of this assumption, patients were classified as follows: grade 1 = Cel-ind < 0.5, grade 2 = 0.5 to 0.99, grade 3 = 1.0 to 1.49, grade 4 > 1.5."

Gives the Celermajer index formula and its four severity grades, the anatomic severity scale referenced in the description.

+ 1 more reference

Cardiac magnetic resonance imaging

Cardiac MRI provides reliable biventricular volumetry, quantification of the tricuspid regurgitant fraction, and right ventricular stroke volume, and is recommended for comprehensive assessment. It underpins risk stratification and surgical timing decisions that echocardiography alone cannot support.

cardiac magnetic resonance imaging NCIT:C137915

Show evidence (1 reference)

PMID:40317284 SUPPORT Human Clinical

"Cardiac magnetic resonance imaging is recommended for comprehensive imaging of EA for reliable volume assessment of both ventricles, evaluation of tricuspid regurgitation fraction, and right ventricle stroke volume."

Consensus recommendation defining the role of cardiac MRI.

Electrocardiography

The surface electrocardiogram shows tall broad right atrial P waves, PR prolongation, deep Q waves in the right precordial leads, and complete or incomplete right bundle branch block, and may reveal pre-excitation (short PR interval with a delta wave) when an accessory pathway conducts antegradely. Reading the tracing therefore has a diagnostic subtlety worth stating: an Ebstein patient with supraventricular tachycardia and *no* right bundle branch block should raise suspicion of an ipsilateral accessory pathway concealing it.

electrocardiography NCIT:C38053

Show evidence (2 references)

PMID:23269033 SUPPORT Human Clinical

"Its characteristic electrocardiographic findings include tall, broad, right atrial P waves, prolonged PR intervals, and deep Q waves in the right precordial leads."

Enumerates the characteristic electrocardiographic signature of the disease.

PMID:28666538 SUPPORT Human Clinical

"In patients with Ebstein's anomaly and supraventricular tachycardia, the absence of a RBBB pattern in the surface ECG after RFCA should raise suspicion for the presence of multiple accessory pathways."

Supports the interpretive rule that a missing right bundle branch block on the surface ECG points to accessory-pathway conduction rather than to a normal conduction system.

Cardiopulmonary exercise testing

Exercise stress testing with measurement of oxygen consumption is recommended in patients who report themselves as asymptomatic, to unmask occult exercise intolerance that may justify earlier operation.

exercise cardiac stress test NCIT:C168192

Show evidence (1 reference)

PMID:40317284 SUPPORT Human Clinical

"Asymptomatic patients with EA should undergo exercise stress testing with measurement of oxygen consumption to unmask occult exercise intolerance."

Consensus recommendation for objective exercise assessment in apparently asymptomatic patients.

Fetal echocardiography

Fetal echocardiography establishes the prenatal diagnosis and drives prognostication, identifying severe cardiomegaly, ductal-level retrograde or bidirectional flow, pulmonary valve atresia, circular shunt, and left ventricular dysfunction as the high-risk constellation. Several composite prognostic scores exist. Note that a study developing one of them found tricuspid regurgitation velocity, pulmonary artery flow, ductal flow direction, and the left-ventricular Tei index to separate perinatal deaths from survivors, while the older Celermajer index and cardiothoracic area ratio did *not* reach significance in that cohort. The anatomic severity of the valve lesion is therefore not by itself a reliable fetal prognostic marker; the ductal and left ventricular findings carry the signal.

fetal ultrasound imaging NCIT:C222238

Show evidence (3 references)

PMID:38685467 SUPPORT Human Clinical

"When evaluating fetuses with EA, those with severe cardiomegaly, retrograde or bidirectional shunt at the ductal level, pulmonary valve atresia, circular shunt, left ventricular dysfunction, or fetal hydrops should be considered high risk"

Defines the prenatal risk-stratification findings obtained by fetal echocardiography.

PMID:31008542 SUPPORT Human Clinical

"we established a novel combinatorial scoring system, the TRIPP score, including the four significant factors: TR maximum velocity, pulmonary artery flow, direction of ductal flow and LV-Tei index."

Identifies the four fetal echocardiographic parameters that predicted perinatal mortality in 31 fetuses with tricuspid valve dysplasia or Ebstein anomaly.

PMID:31008542 REFUTE Human Clinical

"In contrast, there was no significant difference in Celermajer index, CTAR or right-to-left ventricular diameter ratio."

Argues against the Celermajer index and cardiothoracic area ratio as fetal prognostic markers in this cohort, which is why the description does not present anatomic severity as predictive in utero.

Electrophysiology study

Invasive electrophysiological mapping localises accessory pathways before ablation. Because surgical repair can render arrhythmia substrates inaccessible, comprehensive presurgical electrophysiological assessment with potential ablation is recommended.

cardiac catheterization NCIT:C38044

Show evidence (1 reference)

PMID:28457239 SUPPORT Human Clinical

"Surgical techniques that render arrhythmia substrates unreachable mandate comprehensive presurgical electrophysiological assessment and potential ablation."

Electrophysiology review establishing the rationale for presurgical invasive electrophysiological study.

📈

Progression

3

Fetal presentation

Severe forms are detectable by mid-gestation fetal echocardiography. Severe cardiomegaly, retrograde or bidirectional ductal flow, pulmonary valve atresia, circular shunt, left ventricular dysfunction, and hydrops mark fetuses at high risk of intrauterine demise and postnatal death. Transplacental non-steroidal anti-inflammatory therapy aimed at constricting the ductus arteriosus is an emerging approach to interrupting the circular shunt in utero.

Show evidence (2 references)

PMID:38685467 SUPPORT Human Clinical

"When evaluating fetuses with EA, those with severe cardiomegaly, retrograde or bidirectional shunt at the ductal level, pulmonary valve atresia, circular shunt, left ventricular dysfunction, or fetal hydrops should be considered high risk for intrauterine demise and postnatal morbidity and mortality."

Defines the high-risk fetal phenotype.

PMID:38217614 SUPPORT Human Clinical

"82% of fetuses were able to achieve ductal constriction with prenatal NSAID therapy. For fetuses who achieved ductal constriction, fetal demise was less likely (6%) when compared to those who were unable to achieve the same (50%)."

Literature review quantifying fetal outcomes with and without successful ductal constriction, illustrating the prognostic weight of the circular shunt.

Neonatal presentation

Symptomatic neonates present with cyanosis and cardiogenic shock, often compounded by functional pulmonary atresia as pulmonary vascular resistance falls. Management is stratified by haemodynamic stability: unstable neonates with a circular shunt require emergent interruption of that shunt and are most often palliated with the Starnes procedure, whereas stable neonates undergo ductal closure or, if pulmonary blood flow is inadequate, ductal stenting or a systemic-to-pulmonary artery shunt. Operation in the neonatal period carries high mortality.

Show evidence (2 references)

PMID:38685467 SUPPORT Human Clinical

"Neonates who are unstable with a circular shunt should have emergent interruption of the circular shunt. Neonates who are unstable are most commonly palliated with the Starnes procedure. Neonates who are stable should undergo ductal closure."

Consensus algorithm for the neonatal phase, defining the stability-stratified management pathway.

PMID:26357983 SUPPORT Human Clinical

"Neonatal operation has high operative mortality, whereas operation performed beyond infancy and into adulthood has low operative mortality."

Contrasts the prognosis of neonatal versus later operation.

Childhood and adult course

Beyond infancy the disease is often indolent for years. Tricuspid regurgitation, right heart dilation, and arrhythmia burden accumulate over decades, with atrial tachyarrhythmias emerging as the commonest late complication and atrial fibrillation developing at a mean age in the early forties. Mild anatomic variants may be diagnosed incidentally in an asymptomatic adult. Late survival and quality of life after operation are excellent for most hospital survivors, but reduced right ventricular function and reoperation for recurrent regurgitation remain challenges.

Show evidence (2 references)

PMID:26357983 SUPPORT Human Clinical

"Late survival and quality of life for hospital survivors are excellent for the majority of patients in all age brackets. Atrial tachyarrhythmias are the most common late complication."

Characterises the long-term course after operation and the dominant late complication.

PMID:38884759 SUPPORT Human Clinical

"presentation varies from severe heart failure symptoms and arrhythmia in neonatal life to asymptomatic adults"

Documents the full breadth of the clinical spectrum from neonate to asymptomatic adult.

📊

Prevalence

3

Worldwide

Birth Prevalence 5.0 per 100,000 (5.0–10.0) 1–9 per 100,000

Birth prevalence reported as between 0.5 and 1 in 20,000, i.e. 5-10 per 100,000 live births. Other sources place it much lower (approximately 1 in 210,000 in one review), and ascertainment differences between registries, fetal series, and clinical cohorts account for much of the spread.

Show evidence (3 references)

PMID:38884759 SUPPORT Human Clinical

"a rare, congenital cardiac defect of the tricuspid valve with a birth prevalence between 0.5 and 1 in 20,000"

Gives the birth prevalence range used for the normalized rate.

PMID:31384377 SUPPORT Human Clinical

"The lesion is rare, with an incidence of approximately 1 in 20,000."

Independent estimate at the lower end of the same range.

PMID:38884758 SUPPORT Human Clinical

"Ebstein anomaly is a rare congenital heart defect, accounting for less than 1% of cardiac malformations and occurring in approximately 1 out of 210,000 live births."

A markedly lower estimate from a contemporaneous review, recorded to show the true spread of published figures rather than presenting a single value as settled.

Texas live births, 1999-2005 (Texas Birth Defects Registry)

Birth Prevalence 7.2 per 100,000 1–9 per 100,000

Registry-based birth prevalence of 0.72 per 10,000 live births from 188 definite cases, equivalent to 7.2 per 100,000. This active-surveillance registry estimate is at the upper end of the range reported in clinical reviews.

Show evidence (1 reference)

PMID:21465650 SUPPORT Human Clinical

"There were 188 definite cases of Ebstein anomaly identified in the TBDR. The overall prevalence was 0.72 per 10,000 live births."

Population-based registry estimate of birth prevalence.

Proportion of all congenital heart disease

Unknown Rare

Ebstein anomaly accounts for well under 1% of congenital heart disease; individual reviews give figures from about 0.5% to under 1.5%. It is nonetheless the most common congenital anomaly of the tricuspid valve.

Show evidence (2 references)

PMID:38884759 SUPPORT Human Clinical

"EA accounts for about 0.5% of all congenital heart diseases (CHD)"

Gives the proportion of all congenital heart disease.

PMID:36151322 SUPPORT Human Clinical

"Ebstein anomaly is the most common form of tricuspid valve congenital anomalies."

Establishes its rank among congenital tricuspid valve anomalies despite its overall rarity.

⚖️

Clinical Burden

Variable

Burden spans the full range: fetal circular shunt with hydrops is frequently lethal in utero, symptomatic neonates face high operative mortality, and a mild anatomic variant may be an incidental finding in an asymptomatic adult. Even presumed-mild disease nonetheless carries a six-fold excess 35-year mortality over matched controls, so the low end of the range is not benign.

Mortality is elevated across the whole severity spectrum. In a two-country nationwide registry study of 530 patients matched to 5,300 controls, even patients with presumed mild anatomy had a 35-year cumulative mortality of 11% versus 4% in controls, while presumed severe disease carried a hazard ratio of 36.2. Mortality has improved for patients diagnosed in the modern era. Morbidity is driven by progressive tricuspid regurgitation with right heart failure and by arrhythmia; atrial fibrillation independently predicts heart-failure hospitalisation in adults. Pregnancy is generally well tolerated in women with NYHA class II symptoms and no cyanosis.

Show evidence (4 references)

PMID:37344044 SUPPORT Human Clinical

"Patients with a presumed mild EA anatomy displayed a 35-year cumulative mortality of 11% (vs 4% for the matched control subjects; P < 0.001), yielding an HR for mortality of 6.0 (95% CI: 2.7-13.6), whereas patients with presumed severe EA demonstrated an HR of 36.2 (95% CI: 15.5-84.4) compared..."

Nationwide Danish-Swedish registry data quantifying excess mortality across the severity spectrum.

PMID:37344044 SUPPORT Human Clinical

"Mortality in patients with EA is high irrespective of presence of concomitant congenital cardiac malformations and time of diagnosis compared with the general population, but overall mortality has improved in the contemporary era."

Registry conclusion on both the persistent excess mortality and its improvement over time.

PMID:34404328 SUPPORT Human Clinical

"Patients with NYHA class II symptoms and no cyanosis generally tolerate pregnancy well."

Small tertiary-centre case series of eight pregnancies supporting generally favourable pregnancy tolerance in mildly symptomatic, acyanotic women.

+ 1 more reference

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Ebstein Anomaly:

Tricuspid valve dysplasia

Overlapping Features Congenital dysplasia of the tricuspid valve produces severe tricuspid regurgitation and right heart enlargement that can closely mimic Ebstein anomaly, particularly in the fetus and neonate. It is distinguished by the absence of leaflet-to-myocardium adherence and of apical displacement of the functional annulus, so there is no atrialized right ventricular segment.

Distinguishing Features

Leaflets are thickened and dysplastic but delaminated, hinging at the true annulus
No apical displacement of the functional tricuspid orifice
No atrialized right ventricular segment
Accessory atrioventricular pathways are not characteristic

Show evidence (1 reference)

PMID:38884760 SUPPORT Human Clinical

"The anatomic hallmarks of this entity are the downward displacement of the attachment of the septal and posterior leaflets of the tricuspid valve."

Names downward leaflet attachment displacement as the anatomic hallmark that separates Ebstein anomaly from other tricuspid valve malformations such as dysplasia.

Isolated left ventricular noncompaction MONDO:0018901

Overlapping Features Left ventricular noncompaction can occur in isolation, and shares MYH7 as a genetic cause with the Ebstein-plus-noncompaction subtype. It is distinguished by the absence of any tricuspid valve malformation. Because the two can co-segregate within one family carrying a single MYH7 variant, relatives of an Ebstein proband may manifest either phenotype.

Distinguishing Features

Prominent left ventricular trabeculation without tricuspid valve malformation
No apical displacement of tricuspid leaflets or atrialized right ventricle
May be the manifesting phenotype in a relative sharing the same MYH7 variant

Show evidence (1 reference)

PMID:23794396 SUPPORT Human Clinical

"Although LVNC often occurs in an isolated entity, it may also be present in various types of congenital heart disease (CHD)."

Establishes isolated left ventricular noncompaction as a distinct entity that overlaps genetically with the Ebstein-associated form.

Wolff-Parkinson-White syndrome without structural heart disease Not Yet Curated MONDO:0008685

Overlapping Features Pre-excitation and atrioventricular reentrant tachycardia in a structurally normal heart is far more common than Ebstein-associated pre-excitation and is distinguished by normal echocardiography. The distinction matters procedurally: ablation in Ebstein anomaly involves a more difficult substrate with multiple right-sided and septal pathways and a higher recurrence rate.

Distinguishing Features

Structurally normal heart on echocardiography
Usually a single accessory pathway, in any location
Substantially lower ablation recurrence rate

Show evidence (1 reference)

PMID:34126268 SUPPORT Human Clinical

"Catheter ablation of accessory pathways (APs) in Ebstein anomaly (EA) has been associated with a high recurrence risk."

Establishes the procedural distinction between Ebstein-associated and structurally normal accessory pathway substrates.

📊

Related Datasets

1

Array CGH in congenital heart disease geo:GSE7527

Sub-megabase-resolution BAC array comparative genomic hybridization screen of 104 patients with congenital heart disease as the sole abnormality at diagnosis, plus some of their parents, searching for DNA copy number changes in non-syndromic CHD.

human MICROARRAY n=119 BAC array CGH (sub-megabase resolution)

Conditions: non-syndromic congenital heart disease

PMID:18713793

Relevance triage: the cohort is non-syndromic congenital heart disease generally, not Ebstein anomaly specifically, but exactly one sample in the GEO series metadata is annotated with an Ebstein anomaly diagnosis. It is included because copy number variation is the one genetic mechanism with reproducible support in Ebstein anomaly (1p36 and 8p23.1 deletions), and this is the closest available primary copy-number dataset; the single Ebstein sample means it cannot support any Ebstein-specific quantitative claim. No Ebstein-anomaly-specific transcriptomic, proteomic, or copy-number dataset exists in GEO. The other candidates surfaced by dataset discovery were gene-only matches on MYH7, GATA4, and NKX2-5 that are about hypertrophic cardiomyopathy, ovarian cancer, and transcription-factor binding respectively, and were rejected as Named Entity Confusion.

🧫

Experimental Models

1

Mouse and canine models of tricuspid valve malformation

No animal model is established as fully recapitulating the specific combination of septal and inferior leaflet adherence to myocardium, apical displacement of the functional orifice, and an atrialized right ventricular segment that characterises human Ebstein anomaly. Mouse models displaying features of the malformation and a naturally occurring canine tricuspid valve malformation have been described and compared with the human condition.

Show evidence (1 reference)

PMID:38884760 SUPPORT Model Organism

"Furthermore, mouse models that show features of Ebstein's anomaly and the naturally occurring model of canine tricuspid valve malformation are described and compared to the human model."

Review chapter cataloguing the available mouse and naturally occurring canine models and their relationship to the human disease.

{ }

Source YAML

click to show

name: Ebstein Anomaly
creation_date: '2026-08-09T00:00:00Z'
category: Complex
description: >
  Ebstein anomaly is a rare congenital malformation of the tricuspid valve and right
  ventricle in which the septal and posteroinferior leaflets fail to delaminate from
  the underlying ventricular myocardium during valvulogenesis. The functional leaflet
  hinge points are displaced apically into the right ventricular cavity, dividing the
  ventricle into a thin-walled "atrialized" proximal portion contiguous with the right
  atrium and a smaller distal functional chamber. The anterosuperior leaflet is
  typically large, redundant and fenestrated, with abnormal chordal and muscular
  attachments that further impair coaptation. The resulting tricuspid regurgitation,
  right atrial dilation, and right ventricular myopathy produce a clinical spectrum
  spanning fetal circular shunt and hydrops, neonatal cyanotic heart failure, and
  incidental diagnosis in an asymptomatic adult. An interatrial communication is
  present in most patients and permits right-to-left shunting with cyanosis and
  paradoxical embolism. Discontinuity of the central fibrous body at the abnormal
  atrioventricular junction leaves accessory atrioventricular pathways, making Ebstein
  anomaly the congenital heart defect most strongly associated with ventricular
  pre-excitation; atrial fibrillation and flutter dominate the arrhythmia burden in
  adults. Cone reconstruction of the tricuspid valve is the contemporary surgical
  standard, with the Starnes procedure reserved for the unrepairable neonate.
disease_term:
  preferred_term: Ebstein anomaly
  term:
    id: MONDO:0009144
    label: Ebstein anomaly
parents:
- Congenital heart defect
- Tricuspid valve disease
synonyms:
- Ebstein's anomaly
- Ebstein malformation of the tricuspid valve
- Ebstein anomaly of the tricuspid valve
- Downward displacement of the tricuspid valve
references:
- reference: PMID:38685467
  title: "The American Association for Thoracic Surgery (AATS) 2024 expert consensus document: Management of neonates and infants with Ebstein anomaly."
- reference: PMID:40317284
  title: "The American Association for Thoracic Surgery (AATS) 2025 Expert Consensus Document: Management of Ebstein anomaly in children and adults."
has_subtypes:
- name: MYH7-LVNC
  display_name: MYH7-associated Ebstein anomaly with left ventricular noncompaction
  description: >
    The Mendelian minority of Ebstein anomaly: a heterozygous MYH7 sarcomeric variant
    co-segregating with left ventricular noncompaction, transmitted autosomal dominantly
    with variable penetrance and variable expressivity, so a relative carrying the same
    variant may manifest isolated noncompaction, isolated Ebstein anomaly, or both. It
    accounted for 8 of 141 unselected probands, and noncompaction was confined almost
    entirely to this group. This subtype is the reason genetic testing and cascade family
    evaluation are recommended when Ebstein anomaly presents alongside noncompaction.
    Note this is a *genetic* subtype; the Carpentier A-D anatomic grading and the
    Celermajer severity index are severity scales rather than subtypes and are curated
    under `diagnosis` instead.
  genes:
  - preferred_term: MYH7
    term:
      id: hgnc:7577
      label: MYH7
  evidence:
  - reference: PMID:21127202
    reference_title: "Mutations in the sarcomere gene MYH7 in Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among 8 mutation-positive probands, 6 had LVNC, whereas among 133 mutation-negative probands, none had LVNC."
    explanation: Establishes the subtype boundary, since noncompaction is essentially confined to the MYH7-mutation-positive group.
  - reference: PMID:23794396
    reference_title: "Ebstein anomaly associated with left ventricular noncompaction: an autosomal dominant condition that can be caused by mutations in MYH7."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which seems to represent a subtype of Ebstein anomaly with autosomal dominant inheritance and variable penetrance"
    explanation: The source itself frames this constellation as a subtype of Ebstein anomaly, which is the basis for modeling it as one here.
pathophysiology:
- name: Failure of tricuspid leaflet delamination
  description: >
    During normal atrioventricular valvulogenesis the tricuspid leaflets are excavated
    from the inner layer of the right ventricular myocardium by an undermining and
    delamination process involving localized apoptosis and extracellular matrix
    remodelling of the developing valve primordium. In Ebstein anomaly this
    delamination is incomplete, so the septal and posteroinferior leaflets remain
    adherent to the underlying ventricular myocardium and interventricular septum
    rather than forming discrete, freely mobile, chordally tethered structures. This is
    the primary developmental lesion from which every downstream feature of the disease
    follows.
  biological_scale: TISSUE
  locations:
  - preferred_term: Tricuspid valve
    term:
      id: UBERON:0002134
      label: tricuspid valve
  - preferred_term: Tricuspid valve leaflet
    term:
      id: UBERON:0005484
      label: tricuspid valve leaflet
  biological_processes:
  - preferred_term: Tricuspid valve morphogenesis
    term:
      id: GO:0003186
      label: tricuspid valve morphogenesis
    modifier: ABNORMAL
  - preferred_term: Atrioventricular valve morphogenesis
    term:
      id: GO:0003181
      label: atrioventricular valve morphogenesis
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Cardiac valve cell
    term:
      id: CL:1000147
      label: cardiac valve cell
  - preferred_term: Endocardial cell
    term:
      id: CL:0002350
      label: endocardial cell
  downstream:
  - target: Apical displacement of the functional tricuspid orifice
    causal_link_type: DIRECT
    description: >
      Because the leaflets remain attached to myocardium instead of hinging at the true
      atrioventricular junction, the effective valve orifice comes to lie apically
      within the right ventricle.
    evidence:
    - reference: PMID:23794396
      reference_title: "Ebstein anomaly associated with left ventricular noncompaction: an autosomal dominant condition that can be caused by mutations in MYH7."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "characterized by apical displacement and partial fusion of the septal and posterior leaflet of the tricuspid valve with the ventricular septum"
      explanation: States the two features together, so that the failure of leaflets to separate from the septum and their apical displacement are described as one lesion.
  - target: Accessory atrioventricular pathway substrate
    causal_link_type: DIRECT
    description: >
      Downward displacement of the septal leaflet is associated with discontinuity of
      the central fibrous body and septal atrioventricular ring, leaving direct
      atrioventricular muscular connections.
    evidence:
    - reference: PMID:19937010
      reference_title: "A multicenter, long-term study on arrhythmias in children with Ebstein anomaly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The downward displacement of the septal tricuspid valve leaflet is associated with discontinuity of the central fibrous body and septal atrioventricular ring and, hence, with direct muscular connections."
      explanation: Directly links the delamination and displacement lesion to the anatomic substrate for accessory pathways.
  evidence:
  - reference: PMID:26357983
    reference_title: "Ebstein anomaly review: what's now, what's next?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is a right ventricular myopathy with failure of tricuspid valve delamination and highly variable tricuspid valve morphology that usually results in severe regurgitation."
    explanation: Mayo Clinic review establishing failure of delamination plus right ventricular myopathy as the defining lesion.
  - reference: PMID:23269033
    reference_title: "When lithium hurts: a look at Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The current opinion among authors is that it is a genetically heterogeneous condition caused by failure of delamination of the TV leaflets from the underlying myocardium and the interventricular septum."
    explanation: Review stating the delamination-failure mechanism and adherence to both myocardium and interventricular septum.
  - reference: PMID:21127202
    reference_title: "Mutations in the sarcomere gene MYH7 in Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ebstein anomaly is a rare congenital heart malformation characterized by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium."
    explanation: Independent characterization of leaflet adherence to underlying myocardium as the anatomic hallmark.
- name: Apical displacement of the functional tricuspid orifice
  description: >
    The functional tricuspid annulus is displaced downward (apically) into the right
    ventricle, well below the true anatomic atrioventricular junction. Echocardiography
    demonstrates apical displacement of the septal leaflet with variable tethering of
    leaflet tissue to the right ventricular myocardium, and in many hearts the valve is
    additionally rotated towards the right ventricular outflow tract.
  biological_scale: TISSUE
  locations:
  - preferred_term: Tricuspid valve anulus
    term:
      id: UBERON:0005997
      label: tricuspid valve anulus
  downstream:
  - target: Atrialization of the right ventricle
    causal_link_type: DIRECT
    description: >
      The myocardium interposed between the true annulus and the displaced functional
      orifice is incorporated into the right atrial chamber.
    evidence:
    - reference: PMID:23269033
      reference_title: "When lithium hurts: a look at Ebstein anomaly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The latter creates 3 morphologic components inside the right heart, namely the right atrium proper, the atrialized RV, and the functional RV."
      explanation: Attributes the atrialized right ventricular compartment directly to the apical displacement described in the preceding sentence of the same abstract.
  - target: Tricuspid regurgitation (haemodynamic lesion)
    causal_link_type: DIRECT
    description: >
      Displaced, tethered and rotated leaflets cannot appose during systole.
    evidence:
    - reference: PMID:36151322
      reference_title: "Multimodality Imaging in Ebstein Anomaly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In severe forms, it results in significant tricuspid regurgitation and requires surgical repair."
      explanation: Links the graded septal-leaflet displacement and valve rotation described immediately before it to significant tricuspid regurgitation.
  evidence:
  - reference: PMID:32622490
    reference_title: "Ebstein Anomaly in the Adult Patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Echocardiography is diagnostic in most patients and demonstrates apical displacement of the septal leaflet and variable tethering of leaflet tissue to the right ventricular myocardium."
    explanation: Mayo Clinic review describing apical displacement and leaflet tethering as the diagnostic anatomic finding.
  - reference: PMID:36151322
    reference_title: "Multimodality Imaging in Ebstein Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The tricuspid valve is abnormal with different degrees of displacement of the septal leaflet and abnormal rotation of the valve towards the right ventricular outflow tract."
    explanation: Imaging review documenting both the graded septal-leaflet displacement and the rotational component of the deformity.
- name: Anterosuperior leaflet redundancy and abnormal tethering
  description: >
    The anterosuperior leaflet is usually not displaced but is enlarged, redundant, and
    frequently fenestrated, with abnormal chordal and direct muscular attachments to the
    right ventricular free wall. This sail-like leaflet is the tissue that cone
    reconstruction mobilizes and rotates to build a competent neo-valve, so its
    morphology determines repairability. Multiple valve orifices, and the absence of the
    severe inferior leaflet displacement or extreme valve rotation that liberate spare
    tissue, are the intraoperative features that predict a need for pericardial patch
    augmentation of a deficient septal leaflet.
  biological_scale: TISSUE
  locations:
  - preferred_term: Tricuspid valve leaflet
    term:
      id: UBERON:0005484
      label: tricuspid valve leaflet
  downstream:
  - target: Tricuspid regurgitation (haemodynamic lesion)
    causal_link_type: DIRECT
    description: >
      Tethering and fenestration of the redundant anterosuperior leaflet compound the
      coaptation defect produced by apical displacement of the other leaflets.
    evidence:
    - reference: PMID:41819162
      reference_title: "Septal leaflet augmentation during Da Silva cone repair: Valvar function and anatomic features compared to nonpatch repair."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "TR improved from ≥moderate in 78.7% pre-CR to ≤mild in 79.0% at follow-up."
      explanation: Surgical reconstruction that mobilizes and reattaches this leaflet tissue converts moderate-or-worse regurgitation to mild-or-less in most patients, indicating the leaflet morphology was responsible for the coaptation failure.
  evidence:
  - reference: PMID:41819162
    reference_title: "Septal leaflet augmentation during Da Silva cone repair: Valvar function and anatomic features compared to nonpatch repair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intraoperative factors associated with patch use were multiple TV orifices"
    explanation: Single-centre surgical series identifying multiple tricuspid valve orifices as an intraoperative feature that leaves insufficient native tissue for a patch-free cone repair.
  - reference: PMID:41819162
    reference_title: "Septal leaflet augmentation during Da Silva cone repair: Valvar function and anatomic features compared to nonpatch repair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "absence of severe inferior leaflet displacement (OR, 3.24; 95% CI, 1.11-9.47; P = .03), and absence of extreme TV rotation (OR, 3.19; 95% CI, 1.21-8.41; P = .02)"
    explanation: The same series showing that hearts without severe inferior leaflet displacement or extreme valve rotation more often needed patch augmentation, quantifying how leaflet morphology governs repairability.
- name: Atrialization of the right ventricle
  description: >
    The segment of right ventricular myocardium lying between the true anatomic
    tricuspid annulus and the displaced functional orifice becomes thin-walled and
    dyskinetic, and contracts in phase with the right atrium rather than the ventricle.
    Three morphologic components are therefore recognisable within the right heart: the
    right atrium proper, the atrialized right ventricle, and a reduced functional right
    ventricle. The loss of effective ventricular volume, compounded by an intrinsic
    right ventricular myopathy, limits antegrade pulmonary blood flow.
  biological_scale: TISSUE
  locations:
  - preferred_term: Right ventricle
    term:
      id: UBERON:0002080
      label: heart right ventricle
  - preferred_term: Right atrium
    term:
      id: UBERON:0002078
      label: right cardiac atrium
  cell_types:
  - preferred_term: Cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  downstream:
  - target: Right heart volume overload and progressive dilation
    causal_link_type: DIRECT
    description: >
      A dyskinetic atrialized segment and a small functional ventricle reduce forward
      stroke volume and amplify chamber dilation.
    evidence:
    - reference: PMID:25535206
      reference_title: "Da Silva's cone repair for Ebstein's anomaly: effect on right ventricular size and function."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the mean antegrade net stroke volume of the RV increased (pre 65 ± 28 ml; post 75 ± 30 ml, P = 0.057)"
      explanation: Plication of the atrialized segment together with valve reconstruction raises antegrade stroke volume, indicating the atrialized compartment was contributing to impaired forward flow; the effect did not reach significance in this 20-patient series.
  evidence:
  - reference: PMID:23269033
    reference_title: "When lithium hurts: a look at Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The latter creates 3 morphologic components inside the right heart, namely the right atrium proper, the atrialized RV, and the functional RV."
    explanation: Explicit statement of the three-compartment right-heart anatomy created by apical leaflet displacement.
  - reference: PMID:38884758
    reference_title: "Clinical Presentation and Therapy of Ebstein Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although primarily a tricuspid valve defect, the right ventricle itself is often structurally abnormal and weakened (myopathic)."
    explanation: Confirms that the right ventricular myopathy is intrinsic and not merely a consequence of valve dysfunction.
- name: Tricuspid regurgitation (haemodynamic lesion)
  description: >
    The regurgitant lesion itself: retrograde systolic flow from the right ventricle
    into the right atrium, usually severe, and the dominant haemodynamic burden of the
    disease and the target of surgical repair. The tissue-level causes of the leaflet
    coaptation failure that produces it are modeled upstream, on the apical-displacement
    and anterosuperior-leaflet nodes, so this node carries a single organism-scale claim
    rather than bundling the tissue-scale mechanism with its haemodynamic consequence.
  biological_scale: ORGANISM
  locations:
  - preferred_term: Tricuspid valve
    term:
      id: UBERON:0002134
      label: tricuspid valve
  downstream:
  - target: Right heart volume overload and progressive dilation
    causal_link_type: DIRECT
    description: >
      Regurgitant volume is recycled between right atrium and right ventricle each
      cardiac cycle, loading both chambers.
    evidence:
    - reference: PMID:25535206
      reference_title: "Da Silva's cone repair for Ebstein's anomaly: effect on right ventricular size and function."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Echocardiography at follow-up revealed mild or absent tricuspid regurgitation in 16 patients."
      explanation: In the same cohort in which regurgitation was abolished, right ventricular end-diastolic volume fell by roughly half, showing that the regurgitant load was what sustained the dilation.
  evidence:
  - reference: PMID:26357983
    reference_title: "Ebstein anomaly review: what's now, what's next?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "highly variable tricuspid valve morphology that usually results in severe regurgitation"
    explanation: States that the highly variable valve morphology usually culminates in severe regurgitation.
- name: Right heart volume overload and progressive dilation
  description: >
    Chronic regurgitant volume loading dilates the right atrium, the atrialized right
    ventricle, and the right atrioventricular junction. Annular dilation further
    separates the leaflet coaptation surfaces, so regurgitation begets regurgitation in
    a self-reinforcing cycle that drives progressive right heart enlargement and
    systolic dysfunction over years to decades. Advanced right-sided remodelling is
    accompanied by left-sided remodelling, and cone reconstruction reverses right
    ventricular dilation.
  biological_scale: ORGANISM
  locations:
  - preferred_term: Right atrium
    term:
      id: UBERON:0002078
      label: right cardiac atrium
  - preferred_term: Right ventricle
    term:
      id: UBERON:0002080
      label: heart right ventricle
  downstream:
  - target: Right-to-left shunting through an interatrial communication
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Rising right atrial pressure reverses the interatrial pressure gradient across a
      patent foramen ovale or atrial septal defect.
    evidence:
    - reference: PMID:40317284
      reference_title: "The American Association for Thoracic Surgery (AATS) 2025 Expert Consensus Document: Management of Ebstein anomaly in children and adults."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "right atrial pressure: left atrial pressure ratio >1.5"
      explanation: The consensus uses an elevated right-to-left atrial pressure ratio as a decision threshold, evidencing that right atrial pressure exceeds left atrial pressure in advanced disease, which is the gradient reversal that drives right-to-left shunting.
  - target: Atrial remodelling and atrial tachyarrhythmia
    causal_link_type: DIRECT
    description: >
      Progressive right atrial dilation creates the substrate for atrial flutter and
      fibrillation.
    evidence:
    - reference: PMID:36368881
      reference_title: "Prognostic implications of atrial fibrillation in adults with Ebstein anomaly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients with AF were older, were more likely men, and had hypertension, renal dysfunction, cardiac devices, and more advanced right-sided and left-sided remodelling."
      explanation: Cross-sectional association between chamber remodelling and atrial fibrillation in 682 adults; the design cannot establish the direction of causation, hence PARTIAL.
  evidence:
  - reference: PMID:25535206
    reference_title: "Da Silva's cone repair for Ebstein's anomaly: effect on right ventricular size and function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI studies showed that the mean functional RV end-diastolic volume decreased after surgery"
    explanation: Serial MRI showing markedly enlarged preoperative right ventricular volumes that regress once the regurgitant load is abolished, evidencing volume overload as the driver of dilation.
  - reference: PMID:36368881
    reference_title: "Prognostic implications of atrial fibrillation in adults with Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with AF were older, were more likely men, and had hypertension, renal dysfunction, cardiac devices, and more advanced right-sided and left-sided remodelling."
    explanation: Mayo Clinic cohort of 682 adults linking advanced right- and left-sided chamber remodelling to arrhythmia burden.
- name: Right-to-left shunting through an interatrial communication
  description: >
    A patent foramen ovale or secundum atrial septal defect is present in most patients.
    When right atrial pressure exceeds left atrial pressure, deoxygenated blood crosses
    the septum into the systemic circulation, producing cyanosis, exercise intolerance,
    and a route for paradoxical embolism. Because the interatrial communication also
    decompresses the failing right heart, surgical closure is often deliberately partial
    (subtotal) or a small fenestration is left open.
  biological_scale: ORGANISM
  locations:
  - preferred_term: Interatrial septum
    term:
      id: UBERON:0002085
      label: interatrial septum
  evidence:
  - reference: PMID:1394922
    reference_title: "Effect of Ebstein's anomaly on short- and long-term outcome of surgically treated patients with Wolff-Parkinson-White syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sixteen patients (42%) required tricuspid valve surgery, and 23 (61%) had an atrial septal defect or patent foramen ovale repaired."
    explanation: Surgical series in which 61% of Ebstein patients had an atrial septal defect or patent foramen ovale requiring repair, quantifying how common the interatrial communication is.
  - reference: PMID:25535206
    reference_title: "Da Silva's cone repair for Ebstein's anomaly: effect on right ventricular size and function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 4- to 6-mm interatrial communication was left in all patients."
    explanation: Surgical practice of deliberately leaving a residual interatrial communication, reflecting its role as a pressure-relief pathway for the failing right heart.
- name: Accessory atrioventricular pathway substrate
  description: >
    Discontinuity of the central fibrous body and the septal atrioventricular ring at
    the malformed junction leaves direct atrioventricular muscular connections that
    bypass the atrioventricular node. These accessory pathways are typically right-sided
    or septal, frequently multiple, and produce ventricular pre-excitation and
    atrioventricular reentrant tachycardia. Ebstein anomaly is the congenital heart
    defect most frequently associated with the Wolff-Parkinson-White syndrome.
  biological_scale: TISSUE
  locations:
  - preferred_term: Right atrium
    term:
      id: UBERON:0002078
      label: right cardiac atrium
  cell_types:
  - preferred_term: Cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  downstream:
  - target: Ventricular pre-excitation
    causal_link_type: DIRECT
    description: >
      Antegrade conduction over the accessory connection pre-excites ventricular
      myocardium, shortening the PR interval and inscribing a delta wave.
    evidence:
    - reference: PMID:19937010
      reference_title: "A multicenter, long-term study on arrhythmias in children with Ebstein anomaly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Thus, a potential substrate for accessory atrioventricular connections and ventricular preexcitation is created"
      explanation: States the causal step from the anomalous atrioventricular muscular connections to ventricular pre-excitation.
  evidence:
  - reference: PMID:19937010
    reference_title: "A multicenter, long-term study on arrhythmias in children with Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 14 surviving patients all show preexcitation, albeit 4 of them intermittently, and all have a right-sided accessory pathway location."
    explanation: Dutch multicentre paediatric cohort documenting that every pre-excited patient had a right-sided accessory pathway, consistent with the right atrioventricular junction substrate.
  - reference: PMID:34126268
    reference_title: "Accessory pathway ablation in Ebstein anomaly: A challenging substrate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the 61 patients with APs, a total of 78 separate APs were identified: 40 right-sided, 37 septal, and 1 left-sided."
    explanation: Boston Children's series showing accessory pathways in Ebstein anomaly are overwhelmingly right-sided or septal and often multiple, with 78 pathways in 61 patients.
  - reference: PMID:1394922
    reference_title: "Effect of Ebstein's anomaly on short- and long-term outcome of surgically treated patients with Wolff-Parkinson-White syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ebstein's anomaly is the most commonly occurring congenital abnormality associated with the Wolff-Parkinson-White (WPW) syndrome."
    explanation: Establishes Ebstein anomaly as the congenital lesion most often underlying WPW syndrome.
- name: Atrial remodelling and atrial tachyarrhythmia
  description: >
    Chronic right atrial dilation and the accompanying electrical and structural
    remodelling create a reentrant substrate for atrial flutter and atrial fibrillation.
    Atrial tachyarrhythmias are the commonest late complication of Ebstein anomaly and
    develop at unusually young ages relative to the general population; in adults,
    atrial fibrillation is independently associated with hospitalisation for heart
    failure.
  biological_scale: ORGANISM
  locations:
  - preferred_term: Right atrium
    term:
      id: UBERON:0002078
      label: right cardiac atrium
  evidence:
  - reference: PMID:26357983
    reference_title: "Ebstein anomaly review: what's now, what's next?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Atrial tachyarrhythmias are the most common late complication."
    explanation: Mayo review identifying atrial tachyarrhythmia as the leading late complication of the disease.
  - reference: PMID:36368881
    reference_title: "Prognostic implications of atrial fibrillation in adults with Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AF (HR 2.32, 95% CI 1.18 to 4.47; p=0.01) was independently associated with hospitalisation for HF."
    explanation: Mayo cohort of 682 adults demonstrating that atrial fibrillation independently predicts heart-failure hospitalisation.
- name: Fetal circular shunt physiology
  description: >
    In the most severe fetal presentations, torrential tricuspid regurgitation combined
    with pulmonary regurgitation across an incompetent or functionally atretic pulmonary
    valve establishes a circular shunt: blood passes from the aorta through the ductus
    arteriosus retrogradely into the pulmonary artery, back across the pulmonary valve
    into the right ventricle, through the incompetent tricuspid valve into the right
    atrium, and around again, largely bypassing the systemic capillary bed. The
    resulting massive cardiomegaly, low systemic output, and hydrops carry a high risk
    of intrauterine demise, and interrupting the circular shunt, by ductal constriction
    in utero or emergent interruption after birth, is the central management goal.
  biological_scale: ORGANISM
  locations:
  - preferred_term: Ductus arteriosus
    term:
      id: UBERON:0005440
      label: ductus arteriosus
  downstream:
  - target: Hydrops fetalis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Massive cardiomegaly with low systemic output and venous congestion produces
      fetal hydrops.
    evidence:
    - reference: PMID:38217614
      reference_title: "Fetal circular shunt in Ebstein's anomaly and non-steroidal anti-inflammatory treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Of all the fetuses with hydrops, 50% had resoluation of hydrops with prenatal NSAID treatment."
      explanation: Hydrops resolved in half of treated fetuses once the ductus was constricted and the circular shunt interrupted, indicating the shunt was driving the hydrops.
  evidence:
  - reference: PMID:38685467
    reference_title: "The American Association for Thoracic Surgery (AATS) 2024 expert consensus document: Management of neonates and infants with Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When evaluating fetuses with EA, those with severe cardiomegaly, retrograde or bidirectional shunt at the ductal level, pulmonary valve atresia, circular shunt, left ventricular dysfunction, or fetal hydrops should be considered high risk for intrauterine demise and postnatal morbidity and mortality."
    explanation: AATS expert consensus identifying circular shunt, ductal-level retrograde flow, and hydrops as the high-risk fetal constellation.
  - reference: PMID:38217614
    reference_title: "Fetal circular shunt in Ebstein's anomaly and non-steroidal anti-inflammatory treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A circular shunt is a poor prognostic factor associated with Ebstein's anomaly. Targeting the constriction of the ductus arteriosus (DA) in order to limit or resolve the circular shunt, has been shown to improve fetal outcomes."
    explanation: Literature review establishing the circular shunt as the prognostically decisive fetal lesion and ductal constriction as the therapeutic target.
phenotypes:
- category: Structural
  name: Ebstein anomaly of the tricuspid valve
  description: >
    Apical displacement of the septal and posteroinferior tricuspid leaflets with
    adherence to the underlying myocardium and atrialization of the inlet right
    ventricle. This is the defining structural lesion and is present by definition.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Ebstein anomaly of the tricuspid valve
    term:
      id: HP:0010316
      label: Ebstein anomaly of the tricuspid valve
  evidence:
  - reference: PMID:38884759
    reference_title: "Human Genetics of Ebstein Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is characterized by displacement of the tricuspid valve toward the apex of the right ventricle"
    explanation: Defines the obligate structural lesion of the disease.
- category: Structural
  name: Tricuspid regurgitation
  description: >
    Retrograde systolic flow from the right ventricle into the right atrium through the
    non-coapting malformed valve, and the principal haemodynamic burden of the disease.
    Regurgitation of some degree follows directly from the leaflet deformity and is
    near-universal in clinically recognised cases, but the band recorded here is the
    floor that the cited quantitative sources actually support: 79% of a surgically
    referred cohort had at least moderate regurgitation before repair, and the review
    literature says the valve morphology "usually" results in severe regurgitation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Tricuspid regurgitation
    term:
      id: HP:0005180
      label: Tricuspid regurgitation
  evidence:
  - reference: PMID:26357983
    reference_title: "Ebstein anomaly review: what's now, what's next?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "highly variable tricuspid valve morphology that usually results in severe regurgitation"
    explanation: Supports tricuspid regurgitation as the usual, and usually severe, consequence of the valve deformity.
  - reference: PMID:41819162
    reference_title: "Septal leaflet augmentation during Da Silva cone repair: Valvar function and anatomic features compared to nonpatch repair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TR improved from ≥moderate in 78.7% pre-CR to ≤mild in 79.0% at follow-up."
    explanation: Surgical cohort in which 79% of patients referred for cone repair had at least moderate preoperative tricuspid regurgitation; this is a surgically referred population, so it supports severity rather than an unbiased population frequency.
- category: Structural
  name: Interatrial communication
  description: >
    Patent foramen ovale or secundum atrial septal defect, permitting right-to-left
    shunting when right atrial pressure is elevated.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:1394922
    reference_title: "Effect of Ebstein's anomaly on short- and long-term outcome of surgically treated patients with Wolff-Parkinson-White syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "23 (61%) had an atrial septal defect or patent foramen ovale repaired"
    explanation: 61% of a 38-patient surgical Ebstein series had an atrial septal defect or patent foramen ovale, supporting a FREQUENT (30-79%) band.
- category: Structural
  name: Right ventricular dilatation
  description: >
    Enlargement of the functional and atrialized right ventricle from chronic
    regurgitant volume loading. Progressive right ventricular enlargement is one of the
    accepted indications for operation.
  phenotype_term:
    preferred_term: Right ventricular dilatation
    term:
      id: HP:0005133
      label: Right ventricular dilatation
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:32622490
    reference_title: "Ebstein Anomaly in the Adult Patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Operative intervention is considered for exertional symptoms, progressive right ventricular enlargement, or right ventricular dysfunction."
    explanation: Establishes progressive right ventricular enlargement as a recognised and clinically actionable feature; the review does not itself quantify frequency, so no frequency band is asserted.
- category: Structural
  name: Cardiomegaly
  description: >
    Marked enlargement of the cardiac silhouette from right atrial and atrialized right
    ventricular dilation, classically described as a wall-to-wall heart. Severe
    cardiomegaly is a recognised high-risk feature in fetuses, neonates, and older
    patients.
  phenotype_term:
    preferred_term: Cardiomegaly
    term:
      id: HP:0001640
      label: Cardiomegaly
  evidence:
  - reference: PMID:40317284
    reference_title: "The American Association for Thoracic Surgery (AATS) 2025 Expert Consensus Document: Management of Ebstein anomaly in children and adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with EA, the presence of congestive heart failure, cyanosis, significant left ventricular dysfunction, severe cardiomegaly, and persistent arrhythmia increases the risk for morbidity and mortality."
    explanation: AATS consensus listing severe cardiomegaly among the features that raise morbidity and mortality risk.
- category: Functional
  name: Cyanosis
  description: >
    Arterial desaturation from right-to-left interatrial shunting, most pronounced in
    the neonatal period and on exertion. Falling arterial oxygen saturation is an
    accepted indication for operation.
  phenotype_term:
    preferred_term: Cyanosis
    term:
      id: HP:0000961
      label: Cyanosis
  evidence:
  - reference: PMID:40317284
    reference_title: "The American Association for Thoracic Surgery (AATS) 2025 Expert Consensus Document: Management of Ebstein anomaly in children and adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surgery is recommended for symptoms that include fatigue, decreased objective exercise tolerance, decreased arterial oxygen saturation (cyanosis), and exertional dyspnea."
    explanation: Consensus document treating cyanosis as a defining symptomatic manifestation and operative indication.
- category: Functional
  name: Congestive heart failure
  description: >
    Right-predominant heart failure from volume overload and right ventricular myopathy.
    Presents in the neonate as cardiogenic shock and in the adult as fatigue, oedema,
    and hepatic congestion.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:40317284
    reference_title: "The American Association for Thoracic Surgery (AATS) 2025 Expert Consensus Document: Management of Ebstein anomaly in children and adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with EA, the presence of congestive heart failure, cyanosis, significant left ventricular dysfunction, severe cardiomegaly, and persistent arrhythmia increases the risk for morbidity and mortality."
    explanation: Consensus statement identifying congestive heart failure as a recognised manifestation carrying prognostic weight.
- category: Functional
  name: Exercise intolerance
  description: >
    Reduced objective exercise capacity, often occult in patients who report themselves
    as asymptomatic, which is why exercise testing with oxygen-consumption measurement
    is recommended in apparently asymptomatic patients.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:40317284
    reference_title: "The American Association for Thoracic Surgery (AATS) 2025 Expert Consensus Document: Management of Ebstein anomaly in children and adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Asymptomatic patients with EA should undergo exercise stress testing with measurement of oxygen consumption to unmask occult exercise intolerance."
    explanation: Directly documents occult exercise intolerance as a characteristic feature warranting systematic testing.
- category: Electrophysiological
  name: Ventricular pre-excitation
  description: >
    Antegrade conduction over an accessory atrioventricular pathway, producing a short
    PR interval and a delta wave. Pathways are typically right-sided or septal and are
    frequently multiple.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Ventricular preexcitation
    term:
      id: HP:0004309
      label: Ventricular preexcitation
  evidence:
  - reference: PMID:19937010
    reference_title: "A multicenter, long-term study on arrhythmias in children with Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During a follow-up after EA diagnosis of 13 years 3 months (range: 6 days to 28 years 2 months), 16 (17%) of the 93 pediatric EA patients exhibited rhythm disturbances."
    explanation: Multicentre paediatric cohort in which 17% had rhythm disturbances and all arrhythmic survivors showed pre-excitation, supporting an OCCASIONAL (5-29%) band in childhood.
  - reference: PMID:19937010
    reference_title: "A multicenter, long-term study on arrhythmias in children with Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 14 surviving patients all show preexcitation, albeit 4 of them intermittently"
    explanation: Confirms that pre-excitation accounted for essentially the whole arrhythmic subgroup in that cohort.
- category: Electrophysiological
  name: Supraventricular tachycardia
  description: >
    Atrioventricular reentrant tachycardia mediated by an accessory pathway, together
    with atrial flutter and atrioventricular nodal reentry. The predominant arrhythmia
    of childhood and adolescence in this disease.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Supraventricular tachycardia
    term:
      id: HP:0004755
      label: Supraventricular tachycardia
  evidence:
  - reference: PMID:19937010
    reference_title: "A multicenter, long-term study on arrhythmias in children with Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 17% prevalence of rhythm disturbances in pediatric EA patients, most commonly supraventricular arrhythmias, is significantly lower than in adult EA patients."
    explanation: Quantifies a 17% paediatric rhythm-disturbance prevalence, predominantly supraventricular, supporting the OCCASIONAL band in childhood.
- category: Electrophysiological
  name: Right bundle branch block
  description: >
    Delayed right ventricular activation from the abnormal right-sided conduction
    system, inscribing a complete or incomplete right bundle branch block pattern on the
    surface electrocardiogram. Because the block is the expected baseline finding, its
    *absence* in a patient with supraventricular tachycardia is itself informative: an
    ipsilateral accessory pathway pre-exciting the right ventricle conceals the block,
    which reappears once the pathway is ablated. No frequency band is recorded because
    neither cited source quantifies how many patients are affected.
  phenotype_term:
    preferred_term: Bundle branch block
    term:
      id: HP:0011710
      label: Bundle branch block
  evidence:
  - reference: PMID:27751284
    reference_title: "Absent right bundle branch block: Is it a clue of pre-excitation in Ebstein's anomaly?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It may show tall and broad P waves as a result of right atrial enlargement, as well as complete or incomplete right bundle-branch block."
    explanation: Establishes complete or incomplete right bundle branch block as a characteristic electrocardiographic finding; because the source does not distinguish complete from incomplete, the parent term Bundle branch block is used rather than HP:0011712 or HP:6000313.
  - reference: PMID:28666538
    reference_title: "The relevance of looking for right bundle branch block in catheter ablation of Ebstein's anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with Ebstein's anomaly and supraventricular tachycardia, the absence of right bundle branch block (RBBB) in sinus rhythm is a highly sensitive and specific indicator of the presence of an ipsilateral accessory AP."
    explanation: Treats right bundle branch block as the expected baseline in Ebstein anomaly, so that its absence is a sensitive and specific marker of an ipsilateral accessory pathway.
- category: Electrophysiological
  name: Atrial fibrillation
  description: >
    Sustained atrial fibrillation arising on a substrate of chronic right atrial
    dilation, developing at an unusually young mean age and following a recurrent
    pattern in a third of affected adults.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:36368881
    reference_title: "Prognostic implications of atrial fibrillation in adults with Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the last encounter, prevalence of AF was 28% (188 patients); of those, 63 (34%) had recurrent AF."
    explanation: Mayo Clinic cohort of 682 adults with 28% cumulative atrial fibrillation prevalence, placing it in the OCCASIONAL (5-29%) band even after prolonged follow-up.
  - reference: PMID:36368881
    reference_title: "Prognostic implications of atrial fibrillation in adults with Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prevalence of AF at baseline was 18% (126 patients); the first episode occurred at a mean age of 43±17 years."
    explanation: Documents an 18% baseline prevalence and the unusually young mean age of first atrial fibrillation episode.
- category: Fetal
  name: Hydrops fetalis
  description: >
    Fetal anasarca with effusions arising from severe cardiomegaly, low combined
    ventricular output, and circular-shunt physiology. Marks a very high risk of
    intrauterine demise.
  phenotype_term:
    preferred_term: Hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
  evidence:
  - reference: PMID:38685467
    reference_title: "The American Association for Thoracic Surgery (AATS) 2024 expert consensus document: Management of neonates and infants with Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "those with severe cardiomegaly, retrograde or bidirectional shunt at the ductal level, pulmonary valve atresia, circular shunt, left ventricular dysfunction, or fetal hydrops should be considered high risk for intrauterine demise and postnatal morbidity and mortality"
    explanation: Identifies fetal hydrops as a recognised, prognostically severe manifestation in the fetal subset.
- category: Structural
  name: Left ventricular noncompaction
  subtype: MYH7-LVNC
  description: >
    Prominent left ventricular trabeculations with deep intertrabecular recesses,
    co-occurring with Ebstein anomaly particularly in the MYH7-associated subtype.
    Ebstein anomaly is the commonest congenital heart defect found alongside left
    ventricular noncompaction.
  phenotype_term:
    preferred_term: Left ventricular noncompaction
    term:
      id: HP:0030682
      label: Left ventricular noncompaction
  evidence:
  - reference: PMID:23794396
    reference_title: "Ebstein anomaly associated with left ventricular noncompaction: an autosomal dominant condition that can be caused by mutations in MYH7."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most prevalent CHD in LVNC is Ebstein anomaly, which is a rare form of CHD characterized by apical displacement and partial fusion of the septal and posterior leaflet of the tricuspid valve with the ventricular septum."
    explanation: Establishes the Ebstein anomaly and left ventricular noncompaction association.
  - reference: PMID:21127202
    reference_title: "Mutations in the sarcomere gene MYH7 in Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among 8 mutation-positive probands, 6 had LVNC, whereas among 133 mutation-negative probands, none had LVNC."
    explanation: Shows noncompaction is concentrated in the MYH7-mutation-positive subgroup of Ebstein probands and essentially absent from the rest.
progression:
- phase: Fetal presentation
  notes: >
    Severe forms are detectable by mid-gestation fetal echocardiography. Severe
    cardiomegaly, retrograde or bidirectional ductal flow, pulmonary valve atresia,
    circular shunt, left ventricular dysfunction, and hydrops mark fetuses at high risk
    of intrauterine demise and postnatal death. Transplacental non-steroidal
    anti-inflammatory therapy aimed at constricting the ductus arteriosus is an emerging
    approach to interrupting the circular shunt in utero.
  evidence:
  - reference: PMID:38685467
    reference_title: "The American Association for Thoracic Surgery (AATS) 2024 expert consensus document: Management of neonates and infants with Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When evaluating fetuses with EA, those with severe cardiomegaly, retrograde or bidirectional shunt at the ductal level, pulmonary valve atresia, circular shunt, left ventricular dysfunction, or fetal hydrops should be considered high risk for intrauterine demise and postnatal morbidity and mortality."
    explanation: Defines the high-risk fetal phenotype.
  - reference: PMID:38217614
    reference_title: "Fetal circular shunt in Ebstein's anomaly and non-steroidal anti-inflammatory treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "82% of fetuses were able to achieve ductal constriction with prenatal NSAID therapy. For fetuses who achieved ductal constriction, fetal demise was less likely (6%) when compared to those who were unable to achieve the same (50%)."
    explanation: Literature review quantifying fetal outcomes with and without successful ductal constriction, illustrating the prognostic weight of the circular shunt.
- phase: Neonatal presentation
  notes: >
    Symptomatic neonates present with cyanosis and cardiogenic shock, often compounded by
    functional pulmonary atresia as pulmonary vascular resistance falls. Management is
    stratified by haemodynamic stability: unstable neonates with a circular shunt require
    emergent interruption of that shunt and are most often palliated with the Starnes
    procedure, whereas stable neonates undergo ductal closure or, if pulmonary blood flow
    is inadequate, ductal stenting or a systemic-to-pulmonary artery shunt. Operation in
    the neonatal period carries high mortality.
  evidence:
  - reference: PMID:38685467
    reference_title: "The American Association for Thoracic Surgery (AATS) 2024 expert consensus document: Management of neonates and infants with Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonates who are unstable with a circular shunt should have emergent interruption of the circular shunt. Neonates who are unstable are most commonly palliated with the Starnes procedure. Neonates who are stable should undergo ductal closure."
    explanation: Consensus algorithm for the neonatal phase, defining the stability-stratified management pathway.
  - reference: PMID:26357983
    reference_title: "Ebstein anomaly review: what's now, what's next?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonatal operation has high operative mortality, whereas operation performed beyond infancy and into adulthood has low operative mortality."
    explanation: Contrasts the prognosis of neonatal versus later operation.
- phase: Childhood and adult course
  notes: >
    Beyond infancy the disease is often indolent for years. Tricuspid regurgitation,
    right heart dilation, and arrhythmia burden accumulate over decades, with atrial
    tachyarrhythmias emerging as the commonest late complication and atrial fibrillation
    developing at a mean age in the early forties. Mild anatomic variants may be
    diagnosed incidentally in an asymptomatic adult. Late survival and quality of life
    after operation are excellent for most hospital survivors, but reduced right
    ventricular function and reoperation for recurrent regurgitation remain challenges.
  evidence:
  - reference: PMID:26357983
    reference_title: "Ebstein anomaly review: what's now, what's next?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Late survival and quality of life for hospital survivors are excellent for the majority of patients in all age brackets. Atrial tachyarrhythmias are the most common late complication."
    explanation: Characterises the long-term course after operation and the dominant late complication.
  - reference: PMID:38884759
    reference_title: "Human Genetics of Ebstein Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presentation varies from severe heart failure symptoms and arrhythmia in neonatal life to asymptomatic adults"
    explanation: Documents the full breadth of the clinical spectrum from neonate to asymptomatic adult.
diagnosis:
- name: Transthoracic echocardiography
  description: >
    Echocardiography is diagnostic in most patients, demonstrating apical displacement of
    the septal leaflet, tethering of leaflet tissue to the right ventricular myocardium,
    the atrialized right ventricular segment, tricuspid regurgitation severity, and any
    interatrial communication. It is also the modality that defines repairability for
    cone reconstruction. Anatomic severity is graded with the Celermajer index, the ratio
    of the combined right atrial and atrialized right ventricular area to the combined
    functional right ventricular, left atrial and left ventricular area, banded into four
    grades. A caveat worth carrying: echocardiographic and cardiac-MRI derived values of
    that index agree only fairly, so the grade is modality-dependent and should not be
    compared across imaging methods.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:32622490
    reference_title: "Ebstein Anomaly in the Adult Patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Echocardiography is diagnostic in most patients and demonstrates apical displacement of the septal leaflet and variable tethering of leaflet tissue to the right ventricular myocardium."
    explanation: Establishes echocardiography as the primary diagnostic modality and what it shows.
  - reference: PMID:23269033
    reference_title: "When lithium hurts: a look at Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Echocardiography is currently the best technique for diagnosing this anomaly, although cardiac magnetic resonance imaging is also gaining traction as an alternative modality."
    explanation: Independent confirmation of echocardiography as the diagnostic standard, with cardiac MRI as the complementary modality.
  - reference: PMID:31711824
    reference_title: "Severity Scores for Ebstein Anomaly: Credibility and Usefulness of Echocardiographic vs Magnetic Resonance Assessments of the Celermajer Index."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cel-ind = (right atrium + atrialized right ventricle)/(functional right ventricle + left atrium + left ventricle). On the basis of this assumption, patients were classified as follows: grade 1 = Cel-ind < 0.5, grade 2 = 0.5 to 0.99, grade 3 = 1.0 to 1.49, grade 4 > 1.5."
    explanation: Gives the Celermajer index formula and its four severity grades, the anatomic severity scale referenced in the description.
  - reference: PMID:31711824
    reference_title: "Severity Scores for Ebstein Anomaly: Credibility and Usefulness of Echocardiographic vs Magnetic Resonance Assessments of the Celermajer Index."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The agreement between imaging methods was only fair (kappa = 0.39, P = 0.002) for the 4-grade classification"
    explanation: Supports the caveat that the Celermajer grade is modality-dependent, with only fair agreement between echocardiographic and cardiac-MRI assessment in 37 unoperated adults.
- name: Cardiac magnetic resonance imaging
  description: >
    Cardiac MRI provides reliable biventricular volumetry, quantification of the
    tricuspid regurgitant fraction, and right ventricular stroke volume, and is
    recommended for comprehensive assessment. It underpins risk stratification and
    surgical timing decisions that echocardiography alone cannot support.
  diagnosis_term:
    preferred_term: cardiac magnetic resonance imaging
    term:
      id: NCIT:C137915
      label: Magnetic Resonance Imaging of the Heart
  evidence:
  - reference: PMID:40317284
    reference_title: "The American Association for Thoracic Surgery (AATS) 2025 Expert Consensus Document: Management of Ebstein anomaly in children and adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac magnetic resonance imaging is recommended for comprehensive imaging of EA for reliable volume assessment of both ventricles, evaluation of tricuspid regurgitation fraction, and right ventricle stroke volume."
    explanation: Consensus recommendation defining the role of cardiac MRI.
- name: Electrocardiography
  description: >
    The surface electrocardiogram shows tall broad right atrial P waves, PR prolongation,
    deep Q waves in the right precordial leads, and complete or incomplete right bundle
    branch block, and may reveal pre-excitation (short PR interval with a delta wave)
    when an accessory pathway conducts antegradely. Reading the tracing therefore has a
    diagnostic subtlety worth stating: an Ebstein patient with supraventricular
    tachycardia and *no* right bundle branch block should raise suspicion of an
    ipsilateral accessory pathway concealing it.
  diagnosis_term:
    preferred_term: electrocardiography
    term:
      id: NCIT:C38053
      label: Electrocardiography
  evidence:
  - reference: PMID:23269033
    reference_title: "When lithium hurts: a look at Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Its characteristic electrocardiographic findings include tall, broad, right atrial P waves, prolonged PR intervals, and deep Q waves in the right precordial leads."
    explanation: Enumerates the characteristic electrocardiographic signature of the disease.
  - reference: PMID:28666538
    reference_title: "The relevance of looking for right bundle branch block in catheter ablation of Ebstein's anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with Ebstein's anomaly and supraventricular tachycardia, the absence of a RBBB pattern in the surface ECG after RFCA should raise suspicion for the presence of multiple accessory pathways."
    explanation: Supports the interpretive rule that a missing right bundle branch block on the surface ECG points to accessory-pathway conduction rather than to a normal conduction system.
- name: Cardiopulmonary exercise testing
  description: >
    Exercise stress testing with measurement of oxygen consumption is recommended in
    patients who report themselves as asymptomatic, to unmask occult exercise
    intolerance that may justify earlier operation.
  diagnosis_term:
    preferred_term: exercise cardiac stress test
    term:
      id: NCIT:C168192
      label: Exercise Cardiac Stress Test
  evidence:
  - reference: PMID:40317284
    reference_title: "The American Association for Thoracic Surgery (AATS) 2025 Expert Consensus Document: Management of Ebstein anomaly in children and adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Asymptomatic patients with EA should undergo exercise stress testing with measurement of oxygen consumption to unmask occult exercise intolerance."
    explanation: Consensus recommendation for objective exercise assessment in apparently asymptomatic patients.
- name: Fetal echocardiography
  description: >
    Fetal echocardiography establishes the prenatal diagnosis and drives prognostication,
    identifying severe cardiomegaly, ductal-level retrograde or bidirectional flow,
    pulmonary valve atresia, circular shunt, and left ventricular dysfunction as the
    high-risk constellation. Several composite prognostic scores exist. Note that a study
    developing one of them found tricuspid regurgitation velocity, pulmonary artery flow,
    ductal flow direction, and the left-ventricular Tei index to separate perinatal deaths
    from survivors, while the older Celermajer index and cardiothoracic area ratio did
    *not* reach significance in that cohort. The anatomic severity of the valve lesion is
    therefore not by itself a reliable fetal prognostic marker; the ductal and left
    ventricular findings carry the signal.
  diagnosis_term:
    preferred_term: fetal ultrasound imaging
    term:
      id: NCIT:C222238
      label: Fetal Ultrasound Imaging
  evidence:
  - reference: PMID:38685467
    reference_title: "The American Association for Thoracic Surgery (AATS) 2024 expert consensus document: Management of neonates and infants with Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "When evaluating fetuses with EA, those with severe cardiomegaly, retrograde or bidirectional shunt at the ductal level, pulmonary valve atresia, circular shunt, left ventricular dysfunction, or fetal hydrops should be considered high risk"
    explanation: Defines the prenatal risk-stratification findings obtained by fetal echocardiography.
  - reference: PMID:31008542
    reference_title: "Fetal echocardiographic prediction score for perinatal mortality in tricuspid valve dysplasia and Ebstein's anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we established a novel combinatorial scoring system, the TRIPP score, including the four significant factors: TR maximum velocity, pulmonary artery flow, direction of ductal flow and LV-Tei index."
    explanation: Identifies the four fetal echocardiographic parameters that predicted perinatal mortality in 31 fetuses with tricuspid valve dysplasia or Ebstein anomaly.
  - reference: PMID:31008542
    reference_title: "Fetal echocardiographic prediction score for perinatal mortality in tricuspid valve dysplasia and Ebstein's anomaly."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, there was no significant difference in Celermajer index, CTAR or right-to-left ventricular diameter ratio."
    explanation: Argues against the Celermajer index and cardiothoracic area ratio as fetal prognostic markers in this cohort, which is why the description does not present anatomic severity as predictive in utero.
- name: Electrophysiology study
  description: >
    Invasive electrophysiological mapping localises accessory pathways before ablation.
    Because surgical repair can render arrhythmia substrates inaccessible, comprehensive
    presurgical electrophysiological assessment with potential ablation is recommended.
  diagnosis_term:
    preferred_term: cardiac catheterization
    term:
      id: NCIT:C38044
      label: Cardiac Catheterization
  evidence:
  - reference: PMID:28457239
    reference_title: "Ebstein Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surgical techniques that render arrhythmia substrates unreachable mandate comprehensive presurgical electrophysiological assessment and potential ablation."
    explanation: Electrophysiology review establishing the rationale for presurgical invasive electrophysiological study.
treatments:
- name: Cone reconstruction of the tricuspid valve
  description: >
    The Da Silva cone operation is the contemporary surgical standard. It consists of
    extensive mobilization of the anterior and inferior leaflets from their abnormal
    myocardial and chordal attachments, longitudinal plication of the atrialized right
    ventricle, and reconstruction of a cone of valve tissue reattached at the true
    annulus, allowing leaflet-to-leaflet coaptation. Right atrial reduction and closure
    or subtotal closure of the atrial septal communication are usually performed
    concomitantly. Compared with tricuspid valve replacement, cone repair carries lower
    rates of valve reoperation and tricuspid stenosis and better preserved right
    ventricular function at follow-up. Where native septal leaflet tissue is deficient,
    autologous pericardial patch augmentation gives comparable early results.
  context: Symptomatic disease, or asymptomatic severe tricuspid regurgitation with right ventricular enlargement and favourable valve anatomy
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cardiac valve procedure
    term:
      id: NCIT:C99546
      label: Cardiac Valve Procedure
  target_phenotypes:
  - preferred_term: Tricuspid regurgitation
    term:
      id: HP:0005180
      label: Tricuspid regurgitation
  - preferred_term: Right ventricular dilatation
    term:
      id: HP:0005133
      label: Right ventricular dilatation
  target_mechanisms:
  - target: Tricuspid regurgitation (haemodynamic lesion)
    treatment_effect: INHIBITS
    description: >
      Rebuilding a coapting cone of leaflet tissue at the true annulus abolishes the
      regurgitant orifice that drives right heart volume overload.
    evidence:
    - reference: PMID:25535206
      reference_title: "Da Silva's cone repair for Ebstein's anomaly: effect on right ventricular size and function."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Da Silva's cone repair for Ebstein's anomaly creates excellent valve function in all patients. Consecutively, the size of the RV decreases and the antegrade net stroke volume increases 6 months after the operation."
      explanation: Demonstrates that abolishing regurgitation reverses the right ventricular dilation it caused.
  notes: >
    Residual or recurrent greater than mild-to-moderate tricuspid regurgitation at
    discharge was more common after cone repair than after valve replacement in one
    comparative series (36% vs 5%), but this did not translate into a higher risk of
    reoperation or death at last follow-up.
  evidence:
  - reference: PMID:25535206
    reference_title: "Da Silva's cone repair for Ebstein's anomaly: effect on right ventricular size and function."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The technique consists of extensive leaflet mobilization, longitudinal plication of the atrialized ventricle and cone-shaped reconstruction of the tricuspid valve, allowing for leaflet-to-leaflet coaptation."
    explanation: Describes the operative components of the cone repair.
  - reference: PMID:40317284
    reference_title: "The American Association for Thoracic Surgery (AATS) 2025 Expert Consensus Document: Management of Ebstein anomaly in children and adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The introduction of the cone procedure has revolutionized surgical management, providing excellent outcomes and durability across a wide range of anatomical variations."
    explanation: Expert consensus positioning cone repair as the transformative and preferred surgical approach.
  - reference: PMID:37425446
    reference_title: "Comparative outcomes and risk analysis after cone repair or tricuspid valve replacement for Ebstein's anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The tricuspid valve replacement group had a higher risk of tricuspid valve reoperation (37% vs 9%; P = .005) and tricuspid stenosis (21% vs 0%; P = .002) compared with the cone repair group."
    explanation: 85-patient comparative series showing cone repair outperforms valve replacement on reoperation and stenosis.
  - reference: PMID:37425446
    reference_title: "Comparative outcomes and risk analysis after cone repair or tricuspid valve replacement for Ebstein's anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Residual/recurrent greater than mild-to-moderate tricuspid regurgitation at discharge was higher after cone repair compared with tricuspid valve replacement (36% vs 5%; P = .010)."
    explanation: Records the one outcome on which cone repair fared worse, so the comparison is not presented one-sidedly.
  - reference: PMID:41819162
    reference_title: "Septal leaflet augmentation during Da Silva cone repair: Valvar function and anatomic features compared to nonpatch repair."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autologous pericardial patch augmentation of the septal leaflet provides comparable early TV function and freedom from reoperation, making it an effective complement during CR."
    explanation: Supports pericardial patch augmentation as an equivalent-outcome technical variant when septal leaflet tissue is deficient.
  - reference: PMID:33020344
    reference_title: "Cone Repair in Adult Patients with Ebstein Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cone repair for Ebstein anomaly can achieve nearly anatomical reconstruction of the tricuspid valve with promising outcomes."
    explanation: Independent surgical review confirming that cone repair achieves near-anatomic tricuspid reconstruction, and extending the technique explicitly to adult patients.
- name: Starnes procedure with single-ventricle palliation
  description: >
    For the neonate in refractory cardiogenic shock whose right ventricle is unsalvageable,
    the tricuspid valve is excluded with a fenestrated patch, an atrial septectomy is
    performed, and pulmonary blood flow is supplied by a systemic-to-pulmonary artery
    shunt, committing the patient to a staged single-ventricle pathway. Some children can
    subsequently be assessed for biventricular conversion.
  context: Neonate in refractory cardiogenic shock with an unrepairable right ventricle
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cardiovascular surgical procedure
    term:
      id: NCIT:C49803
      label: Cardiovascular Surgical Procedure
  target_phenotypes:
  - preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:38685467
    reference_title: "The American Association for Thoracic Surgery (AATS) 2024 expert consensus document: Management of neonates and infants with Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonates in refractory cardiogenic shock may be palliated with the Starnes procedure. Children may be assessed for later biventricular repair after the Starnes procedure."
    explanation: Consensus statement defining the indication for the Starnes procedure and the option of later biventricular conversion.
- name: Bidirectional cavopulmonary shunt
  description: >
    A superior cavopulmonary (bidirectional Glenn) anastomosis offloads the failing right
    ventricle by diverting superior caval return directly to the pulmonary arteries. It is
    used as an adjunct to valve repair in the setting of severe right ventricular dilation
    or dysfunction, an elevated right-to-left atrial pressure ratio, or failure to
    separate from cardiopulmonary bypass, yielding a so-called one-and-a-half ventricle
    repair.
  context: Severe right ventricular dilation or systolic dysfunction, or failure to wean from bypass after repair
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cardiovascular surgical procedure
    term:
      id: NCIT:C49803
      label: Cardiovascular Surgical Procedure
  evidence:
  - reference: PMID:40317284
    reference_title: "The American Association for Thoracic Surgery (AATS) 2025 Expert Consensus Document: Management of Ebstein anomaly in children and adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bidirectional cavopulmonary shunt is reasonable when there is severe right ventricular dilation, severe right ventricular systolic dysfunction, right atrial pressure: left atrial pressure ratio >1.5, or failure to separate from cardiopulmonary bypass after repair."
    explanation: Consensus statement specifying the haemodynamic indications for a bidirectional cavopulmonary shunt.
  - reference: PMID:28017577
    reference_title: "Ebstein's Anomaly: Genetics, Clinical Manifestations, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "1.5-ventricular repair (bidirectional Glenn shunt) is indicated for patients with poor right ventricular function"
    explanation: Independent review confirming the one-and-a-half ventricle strategy for poor right ventricular function.
- name: Catheter ablation of accessory pathways
  description: >
    Ablation of accessory atrioventricular pathways treats pre-excited tachyarrhythmia.
    The Ebstein substrate is technically difficult: pathways are often multiple,
    right-sided or septal, and abnormal atrioventricular junction anatomy degrades
    mapping. Acute success is high but recurrence is substantially greater than in
    structurally normal hearts, so repeat procedures are common; ultimate pathway
    elimination after all procedures is nonetheless achieved in most patients. Ablation
    is best performed before valve surgery, which can render substrates inaccessible.
  context: Symptomatic accessory-pathway-mediated tachyarrhythmia, ideally addressed before surgical repair
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cardiac ablation
    term:
      id: NCIT:C100068
      label: Cardiac Ablation
  target_phenotypes:
  - preferred_term: Supraventricular tachycardia
    term:
      id: HP:0004755
      label: Supraventricular tachycardia
  - preferred_term: Ventricular preexcitation
    term:
      id: HP:0004309
      label: Ventricular preexcitation
  target_mechanisms:
  - target: Accessory atrioventricular pathway substrate
    treatment_effect: INHIBITS
    description: >
      Ablation lesions interrupt conduction through the anomalous atrioventricular
      muscular connection.
    evidence:
    - reference: PMID:34126268
      reference_title: "Accessory pathway ablation in Ebstein anomaly: A challenging substrate."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "At median follow-up of 2.5 (0.2-7) years, ultimate AP elimination after all procedures was 93%."
      explanation: Demonstrates that ablation ultimately eliminates the accessory pathway substrate in the large majority of patients.
  notes: >
    Recurrence is the principal limitation: 31% of patients required repeat procedures in
    a large paediatric series, though outcomes have improved substantially in the modern
    era.
  evidence:
  - reference: PMID:34126268
    reference_title: "Accessory pathway ablation in Ebstein anomaly: A challenging substrate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, 19 patients (31%) required repeat procedures (average 1.4 per patient) due to AP recurrence or ablation failure at first attempt. In comparison to early era, recent era ablations had significantly lower recurrence rates at 1 year (62% vs 19%; P = .005)."
    explanation: Quantifies the high repeat-procedure rate and the era-related improvement in recurrence.
  - reference: PMID:1394922
    reference_title: "Effect of Ebstein's anomaly on short- and long-term outcome of surgically treated patients with Wolff-Parkinson-White syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with Ebstein's anomaly are improved significantly after accessory pathway ablation. The presence of this anomaly should not preclude accessory pathway ablation in these patients."
    explanation: Long-term comparative outcome study establishing benefit of accessory pathway ablation despite the anomaly.
- name: Concomitant maze procedure
  description: >
    Surgical atrial ablation performed at the time of tricuspid valve surgery in patients
    with paroxysmal or continuous atrial fibrillation, addressing the atrial reentrant
    substrate created by chronic right atrial dilation.
  context: Paroxysmal or continuous atrial fibrillation at the time of cardiac surgery
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cardiac ablation
    term:
      id: NCIT:C100068
      label: Cardiac Ablation
  target_phenotypes:
  - preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  target_mechanisms:
  - target: Atrial remodelling and atrial tachyarrhythmia
    treatment_effect: INHIBITS
    description: >
      Maze lesion sets compartmentalise the dilated atrium and interrupt macro-reentrant
      circuits.
    evidence:
    - reference: PMID:40317284
      reference_title: "The American Association for Thoracic Surgery (AATS) 2025 Expert Consensus Document: Management of Ebstein anomaly in children and adults."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Concomitant maze procedure at the time of surgery is reasonable when there is paroxysmal or continuous atrial fibrillation."
      explanation: Consensus recommendation to address the atrial arrhythmia substrate surgically at the time of valve repair.
  evidence:
  - reference: PMID:40317284
    reference_title: "The American Association for Thoracic Surgery (AATS) 2025 Expert Consensus Document: Management of Ebstein anomaly in children and adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Concomitant maze procedure at the time of surgery is reasonable when there is paroxysmal or continuous atrial fibrillation."
    explanation: Direct consensus recommendation for the concomitant maze procedure.
- name: Medical closure of the patent ductus arteriosus
  description: >
    In the neonate the ductus arteriosus is the pivot of management, because it supplies
    the retrograde aortopulmonary limb of the circular shunt. A haemodynamically stable
    neonate with significant pulmonary regurgitation, normal right ventricular systolic
    pressure, and therefore a risk of circular shunt should have pharmacologic closure of
    the patent ductus attempted. Neonates without high-risk features may simply be
    monitored for spontaneous ductal closure.
  context: Haemodynamically stable neonate with significant pulmonary regurgitation, normal right ventricular systolic pressure, and risk of a circular shunt
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nonsteroidal anti-inflammatory drug
      term:
        id: NCIT:C257
        label: Nonsteroidal Antiinflammatory Drug
  target_mechanisms:
  - target: Fetal circular shunt physiology
    treatment_effect: INHIBITS
    description: >
      Closing or constricting the ductus arteriosus removes the retrograde aortopulmonary
      limb that sustains the circular shunt.
    evidence:
    - reference: PMID:38217614
      reference_title: "Fetal circular shunt in Ebstein's anomaly and non-steroidal anti-inflammatory treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Targeting the constriction of the ductus arteriosus (DA) in order to limit or resolve the circular shunt, has been shown to improve fetal outcomes."
      explanation: Establishes ductal constriction as the mechanism by which the circular shunt is interrupted. Cited here for the mechanism; that study is prenatal transplacental NSAID therapy, whereas this treatment entry is postnatal medical ductal closure.
  notes: >
    The mirror-image scenario is deliberately not folded into this entry, because it is
    the opposite intervention: a stable neonate without pulmonary regurgitation but with
    inadequate antegrade pulmonary blood flow needs ductal patency maintained or
    augmented, by a ductal stent or a systemic-to-pulmonary artery shunt, rather than
    closed.
  evidence:
  - reference: PMID:38685467
    reference_title: "The American Association for Thoracic Surgery (AATS) 2024 expert consensus document: Management of neonates and infants with Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hemodynamically stable neonates with significant pulmonary regurgitation at risk for circular shunt with normal right ventricular systolic pressure should have an attempt at medical closure of the PDA."
    explanation: Consensus statement defining the indication for medical ductal closure.
  - reference: PMID:38685467
    reference_title: "The American Association for Thoracic Surgery (AATS) 2024 expert consensus document: Management of neonates and infants with Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neonates who are hemodynamically stable without pulmonary regurgitation but inadequate antegrade pulmonary blood flow may be considered for a PDA stent or systemic to pulmonary artery shunt."
    explanation: Consensus statement for the opposite scenario recorded in the notes, in which ductal patency must instead be maintained or augmented by a stent or shunt rather than closed.
- name: Antiarrhythmic pharmacotherapy
  description: >
    Rate- and rhythm-control drugs for atrioventricular reentrant tachycardia, atrial
    flutter, and atrial fibrillation. Drug therapy is a secondary line rather than the
    mainstay: in a multicentre paediatric Ebstein cohort only a minority of patients
    remained on antiarrhythmic drugs, because symptomatic accessory-pathway arrhythmia is
    better served by catheter ablation, and surgical candidates with atrial fibrillation
    are better served by a concomitant maze. Its role is largest in adults with an atrial
    substrate that ablation and surgery have not eliminated.
  context: Symptomatic atrial or accessory-pathway-mediated tachyarrhythmia not eliminated by ablation or surgery
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: antiarrhythmic agent
      term:
        id: NCIT:C47793
        label: Antiarrhythmic Agent
  target_phenotypes:
  - preferred_term: Supraventricular tachycardia
    term:
      id: HP:0004755
      label: Supraventricular tachycardia
  - preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  target_mechanisms:
  - target: Atrial remodelling and atrial tachyarrhythmia
    treatment_effect: INHIBITS
    description: >
      Antiarrhythmic drugs suppress the tachyarrhythmias arising on the dilated-atrium
      substrate without altering the substrate itself, which is why they control rather
      than cure and why ablation or a maze is preferred where feasible.
    evidence:
    - reference: PMID:19937010
      reference_title: "A multicenter, long-term study on arrhythmias in children with Ebstein anomaly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Only four patients are currently on antiarrhythmic drugs."
      explanation: Documents ongoing antiarrhythmic drug therapy in the arrhythmic subgroup, while the word "only" and the accompanying ablation result frame drugs as the lesser option.
  evidence:
  - reference: PMID:19937010
    reference_title: "A multicenter, long-term study on arrhythmias in children with Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Symptomatic patients are well treated with radiofrequency catheter ablation."
    explanation: The same cohort's conclusion positions ablation, not drug therapy, as the definitive treatment for symptomatic arrhythmia in this disease.
  - reference: PMID:28457239
    reference_title: "Ebstein Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As the population ages, the need to address atrial fibrillation management and risk stratification for sudden cardiac death becomes ever more pertinent."
    explanation: Electrophysiology review identifying atrial fibrillation management as a growing clinical need in the ageing Ebstein population, the setting in which drug therapy is most used.
- name: Heart failure pharmacotherapy
  description: >
    Guideline-directed medical therapy for ventricular dysfunction, together with
    diuretics for the systemic venous congestion produced by chronic tricuspid
    regurgitation. The AATS consensus frames this specifically around systolic left
    ventricular dysfunction, where concomitant acquired disease should first be excluded;
    diuretic use for right-sided congestion is standard supportive practice rather than a
    disease-specific evidence-based recommendation, and is curated here at that strength.
  context: Ventricular systolic dysfunction, or systemic venous congestion from chronic tricuspid regurgitation
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: diuretic
      term:
        id: NCIT:C448
        label: Diuretic
  target_phenotypes:
  - preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:40317284
    reference_title: "The American Association for Thoracic Surgery (AATS) 2025 Expert Consensus Document: Management of Ebstein anomaly in children and adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In EA patients with evidence of systolic left ventricular dysfunction, concomitant acquired disease should be excluded, and goal-directed medical therapies is recommended."
    explanation: Consensus recommendation for goal-directed medical therapy, scoped by the source to systolic left ventricular dysfunction.
- name: Prostaglandin E1 to maintain ductal patency
  description: >
    The mirror image of medical ductal closure. A neonate whose right ventricle cannot
    generate antegrade flow across the pulmonary valve has ductal-dependent pulmonary
    blood flow, and prostaglandin E1 is infused to keep the ductus arteriosus open until
    the circulation is secured. Because the pulmonary atresia in Ebstein anomaly is often
    functional rather than anatomic, it can reverse as pulmonary vascular resistance
    falls, so prostaglandin can sometimes be weaned with an expectant strategy rather than
    committing the infant to a stent or shunt.
  context: Neonate with ductal-dependent pulmonary blood flow from anatomic or functional pulmonary atresia
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prostaglandin E1
      term:
        id: CHEBI:15544
        label: prostaglandin E1
  target_phenotypes:
  - preferred_term: Cyanosis
    term:
      id: HP:0000961
      label: Cyanosis
  notes: >
    Curated from a single well-documented case rather than a cohort, so the evidence is
    marked PARTIAL. Note the direction of effect is opposite to that of the medical
    ductal-closure entry: the two are selected between on whether the neonate is at risk
    of a circular shunt or of inadequate pulmonary blood flow.
  evidence:
  - reference: PMID:31888914
    reference_title: "Ebstein's anomaly with 'reversible' functional pulmonary atresia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prostaglandin E1 was started after birth."
    explanation: Case of Ebstein anomaly with functional pulmonary atresia and reversed ductal flow in which prostaglandin E1 was used to maintain ductal patency after delivery.
  - reference: PMID:31888914
    reference_title: "Ebstein's anomaly with 'reversible' functional pulmonary atresia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Multidisciplinary team decision was to progressively reduce prostaglandins and have an expectant attitude."
    explanation: Documents that the functional pulmonary atresia reversed and prostaglandin could be weaned without stent or shunt, supporting the expectant strategy described.
- name: Conservative management and surveillance
  description: >
    Asymptomatic patients with preserved right heart size and function are managed with
    observation and serial imaging, which may be successful for many years. Lifelong
    cardiology follow-up is required because tricuspid regurgitation, right heart
    dilation, and arrhythmia burden accumulate insidiously.
  context: Asymptomatic patients without significant right heart dilation or dysfunction
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:28017577
    reference_title: "Ebstein's Anomaly: Genetics, Clinical Manifestations, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Asymptomatic patients with Ebstein's anomaly can be conservatively treated and kept under close follow-up, whereas surgical operation is indicated for those patients with evidence of right heart dilation and progressively impaired ventricular systolic function."
    explanation: Defines the boundary between conservative surveillance and operative intervention.
  - reference: PMID:32622490
    reference_title: "Ebstein Anomaly in the Adult Patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with Ebstein anomaly require lifelong follow-up."
    explanation: Establishes the requirement for indefinite surveillance.
- name: Cardiac transplantation
  description: >
    Reserved for end-stage disease with irreparable ventricular dysfunction, particularly
    where left ventricular function is severely impaired and neither valve repair nor
    cavopulmonary offloading can be expected to help.
  context: End-stage ventricular dysfunction not amenable to repair
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  evidence:
  - reference: PMID:28017577
    reference_title: "Ebstein's Anomaly: Genetics, Clinical Manifestations, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "heart transplantation is used in patients with severe left ventricular dysfunction"
    explanation: Identifies transplantation as the option for severe left ventricular dysfunction.
- name: Genetic counselling and cascade evaluation
  description: >
    Genetic testing and family evaluation are warranted in the subset of patients whose
    Ebstein anomaly is accompanied by left ventricular noncompaction, where an autosomal
    dominant MYH7-associated subtype with variable penetrance is likely. Chromosomal
    microarray is appropriate when extracardiac anomalies suggest a syndromic cause.
    Recurrence-risk counselling for isolated sporadic disease is generally reassuring.
  context: Ebstein anomaly with left ventricular noncompaction, a suggestive family history, or extracardiac anomalies
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:21127202
    reference_title: "Mutations in the sarcomere gene MYH7 in Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MYH7 mutations are predominantly found in Ebstein anomaly associated with LVNC and may warrant genetic testing and family evaluation in this subset of patients."
    explanation: Directly supports targeted genetic testing and family evaluation in the noncompaction subset.
genetic:
- name: MYH7
  subtype: MYH7-LVNC
  gene_term:
    preferred_term: MYH7
    term:
      id: hgnc:7577
      label: MYH7
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  frequency: about 6% of unselected Ebstein anomaly probands, concentrated in those with left ventricular noncompaction
  notes: >
    Heterozygous MYH7 variants, encoding beta-myosin heavy chain, define an autosomal
    dominant subtype of Ebstein anomaly that co-segregates with left ventricular
    noncompaction and shows variable penetrance. Most reported variants are missense, and
    some are alleles previously described in hypertrophic cardiomyopathy. How a sarcomeric
    defect produces a valve-delamination phenotype is not mechanistically resolved.
  case_fractions:
  - population: Population-based cohort of 141 unrelated Ebstein anomaly probands
    case_fraction_percent: 6.0
    cohort_size: 141
    notes: Heterozygous MYH7 mutations identified in 8 of 141 probands by next-generation and direct DNA sequencing.
    evidence:
    - reference: PMID:21127202
      reference_title: "Mutations in the sarcomere gene MYH7 in Ebstein anomaly."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Heterozygous mutations were identified in 8 of 141 samples (6%)."
      explanation: Quantifies the MYH7 share of unselected Ebstein anomaly probands.
  evidence:
  - reference: PMID:21127202
    reference_title: "Mutations in the sarcomere gene MYH7 in Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ebstein anomaly is a congenital heart malformation that is associated with mutations in MYH7."
    explanation: Establishes MYH7 as a causal gene for Ebstein anomaly.
  - reference: PMID:21127202
    reference_title: "Mutations in the sarcomere gene MYH7 in Ebstein anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The frequency of MYH7 mutations was significantly different between probands with and without LVNC accompanying Ebstein anomaly (P<0.0001)."
    explanation: Shows the MYH7 association is specific to the noncompaction-associated subtype.
  - reference: PMID:23794396
    reference_title: "Ebstein anomaly associated with left ventricular noncompaction: an autosomal dominant condition that can be caused by mutations in MYH7."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which seems to represent a subtype of Ebstein anomaly with autosomal dominant inheritance and variable penetrance"
    explanation: Characterises the MYH7-associated subtype as autosomal dominant with variable penetrance.
  - reference: PMID:21604106
    reference_title: "Ebstein's anomaly may be caused by mutations in the sarcomere protein gene MYH7."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This might represent a specific subtype of Ebstein's anomaly with a Mendelian inheritance pattern."
    explanation: Independent review framing the MYH7 subtype as the Mendelian fraction of an otherwise sporadic disease.
- name: 1p36 deletion
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >
    Terminal 1p36 deletion is one of the two chromosomal imbalances most often found in
    syndromic Ebstein anomaly. The responsible gene within the interval has not been
    identified.
  evidence:
  - reference: PMID:21815254
    reference_title: "Ebstein anomaly: Genetic heterogeneity and association with microdeletions 1p36 and 8p23.1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that Ebstein anomaly is a genetically heterogeneous defect, and that deletion 1p36 and deletion 8p23.1 are the most frequent chromosomal imbalances associated with Ebstein anomaly."
    explanation: Identifies 1p36 deletion as one of the two commonest chromosomal imbalances in Ebstein anomaly.
- name: 8p23.1 deletion (GATA4 region)
  gene_term:
    preferred_term: GATA4
    term:
      id: hgnc:4173
      label: GATA4
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >
    Interstitial 8p23.1 deletion encompassing GATA4 has been detected in syndromic
    Ebstein anomaly. Direct sequencing of GATA4 and NKX2-5 in nonsyndromic patients from
    the same cohort found no point mutations, so the evidence supports dosage imbalance
    across the region rather than intragenic GATA4 mutation as the mechanism in these
    patients.
  evidence:
  - reference: PMID:21815254
    reference_title: "Ebstein anomaly: Genetic heterogeneity and association with microdeletions 1p36 and 8p23.1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Array-CGH analysis performed in 10 of the 12 syndromic patients detected an interstitial deletion of about 4 Mb at 8p23.1 in one patient"
    explanation: Documents the 8p23.1 deletion in a syndromic Ebstein anomaly patient.
  - reference: PMID:21815254
    reference_title: "Ebstein anomaly: Genetic heterogeneity and association with microdeletions 1p36 and 8p23.1."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In the 28 of 32 nonsyndromic patients who underwent molecular testing, no mutation in GATA4 and NKX2.5 genes were detected."
    explanation: Argues against intragenic GATA4 point mutation as a common cause of nonsyndromic Ebstein anomaly, restricting the GATA4 link to the deletion context.
- name: NKX2-5
  gene_term:
    preferred_term: NKX2-5
    term:
      id: hgnc:2488
      label: NKX2-5
  relationship_type: DISPUTED
  variant_origin: GERMLINE
  notes: >
    NKX2-5 is a long-standing candidate gene for Ebstein anomaly on the basis of its role
    in cardiac septation and atrioventricular junction development and of isolated case
    reports, but a systematic screen of 28 nonsyndromic patients detected no NKX2-5
    mutations. The candidate status therefore remains unconfirmed.
  evidence:
  - reference: PMID:28017577
    reference_title: "Ebstein's Anomaly: Genetics, Clinical Manifestations, and Management."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic bases of this congenital heart defect may be related to the mutations in myosin heavy chain 7 and NKX2.5, among others."
    explanation: Review naming NKX2-5 alongside MYH7 as a proposed genetic basis, phrased as a possibility rather than an established cause.
  - reference: PMID:21815254
    reference_title: "Ebstein anomaly: Genetic heterogeneity and association with microdeletions 1p36 and 8p23.1."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "no mutation in GATA4 and NKX2.5 genes were detected"
    explanation: Negative screen in 28 nonsyndromic patients arguing against NKX2-5 point mutation as a common cause.
inheritance:
- name: Autosomal dominant MYH7-associated subtype
  description: >
    Most Ebstein anomaly is sporadic and genetically unexplained. A minority is Mendelian:
    the MYH7-associated subtype that co-segregates with left ventricular noncompaction is
    autosomal dominant with variable penetrance and variable expressivity, so a relative
    carrying the same variant may manifest isolated noncompaction, isolated Ebstein
    anomaly, or both. Chromosomal microdeletions at 1p36 and 8p23.1 account for a further
    syndromic fraction.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  evidence:
  - reference: PMID:23794396
    reference_title: "Ebstein anomaly associated with left ventricular noncompaction: an autosomal dominant condition that can be caused by mutations in MYH7."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which seems to represent a subtype of Ebstein anomaly with autosomal dominant inheritance and variable penetrance"
    explanation: Establishes autosomal dominant inheritance with variable penetrance for the MYH7-associated subtype.
  - reference: PMID:38884760
    reference_title: "Molecular Pathways and Animal Models of Ebstein's Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the studies summarized here provide, in aggregate, evidence for monogenic and oligogenic factors driving pathogenesis"
    explanation: Review concluding that both monogenic and oligogenic contributions operate, consistent with a predominantly non-Mendelian disease containing a Mendelian minority.
environmental:
- name: First-trimester maternal lithium exposure
  description: >
    Lithium taken in the first trimester is the best-characterised teratogenic exposure
    associated with Ebstein anomaly. A relative risk of about 400 was estimated in the
    1970s from a voluntary case registry; controlled epidemiology has since shown the true
    excess to be far smaller and dose-related. In a cohort of 1,325,563 pregnancies,
    first-trimester lithium was associated with an adjusted risk ratio of 1.65 for cardiac
    malformations overall and 2.66 for right ventricular outflow tract obstruction
    defects, the category containing Ebstein anomaly, with risk rising above 900 mg/day.
    The absolute risk to an exposed pregnancy therefore remains low, and management
    guidance emphasises the lowest effective dose rather than blanket avoidance.
  effect: Increases risk of Ebstein anomaly and other cardiac malformations when taken in the first trimester, in a dose-dependent manner
  exposure_term:
    preferred_term: exposure to lithium carbonate
    term:
      id: ECTO:9001149
      label: exposure to lithium carbonate
  chemicals:
  - lithium carbonate
  influences_mechanisms:
  - target: Failure of tricuspid leaflet delamination
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      First-trimester lithium exposure raises the risk of right ventricular outflow tract
      obstruction defects, the malformation category containing Ebstein anomaly, implying
      an effect on the valvulogenic window during which leaflet delamination occurs. The
      molecular intermediates between lithium exposure and failed delamination are not
      established.
    evidence:
    - reference: PMID:28591541
      reference_title: "Lithium Use in Pregnancy and the Risk of Cardiac Malformations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The prevalence of right ventricular outflow tract obstruction defects was 0.60% among lithium-exposed infants versus 0.18% among unexposed infants (adjusted risk ratio, 2.66; 95% CI, 1.00 to 7.06)."
      explanation: Quantifies the excess of the malformation category containing Ebstein anomaly after first-trimester lithium exposure; the epidemiology establishes the association but not the developmental mechanism.
  evidence:
  - reference: PMID:28591541
    reference_title: "Lithium Use in Pregnancy and the Risk of Cardiac Malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Maternal use of lithium during the first trimester was associated with an increased risk of cardiac malformations, including Ebstein's anomaly; the magnitude of this effect was smaller than had been previously postulated."
    explanation: Cohort study of over 1.3 million pregnancies confirming a real but modest association.
  - reference: PMID:28591541
    reference_title: "Lithium Use in Pregnancy and the Risk of Cardiac Malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The risk ratio was 1.11 (95% CI, 0.46 to 2.64) for a daily dose of 600 mg or less, 1.60 (95% CI, 0.67 to 3.80) for 601 to 900 mg, and 3.22 (95% CI, 1.47 to 7.02) for more than 900 mg."
    explanation: Establishes the dose-response relationship underlying current prescribing guidance.
  - reference: PMID:8031346
    reference_title: "A reevaluation of risk of in utero exposure to lithium."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the 1970s a very strong association was suggested between maternal lithium treatment during pregnancy and Ebstein's anomaly of the heart in the offspring. The relative risk for Ebstein's anomaly among such children was estimated to be 400 on the basis of data collected from a registry of voluntarily submitted cases."
    explanation: Documents the historical registry-based relative risk of 400 that later controlled studies revised sharply downward.
  - reference: PMID:8031346
    reference_title: "A reevaluation of risk of in utero exposure to lithium."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "No women who took lithium during pregnancy were found among four case-control studies of Ebstein's anomaly involving 25, 34, 59, and 89 affected children, respectively."
    explanation: Case-control data arguing against the very large effect size originally claimed, and the basis for the modern revised estimate.
- name: Advanced maternal age
  description: >
    Maternal age over 39 years was associated with an increased prevalence of
    non-syndromic Ebstein anomaly in a statewide birth-defects registry. This is an
    epidemiologic association from a descriptive registry analysis, not a demonstrated
    causal mechanism, and it is deliberately not linked into the pathograph for that
    reason.
  effect: Associated with increased birth prevalence of non-syndromic Ebstein anomaly
  evidence:
  - reference: PMID:21465650
    reference_title: "Epidemiology of Ebstein anomaly: prevalence and patterns in Texas, 1999-2005."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variables associated with an increased prevalence of non-syndromic Ebstein anomaly included: maternal age >39 years (compared to those 20-24 years), maternal residence along the Texas-Mexico border (compared to non-border residence), and conception in fall or winter (compared to summer)."
    explanation: Texas Birth Defects Registry analysis of 188 cases identifying advanced maternal age as an associated variable.
prevalence:
- population: Worldwide
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 5.0
  rate_low: 5.0
  rate_high: 10.0
  notes: >
    Birth prevalence reported as between 0.5 and 1 in 20,000, i.e. 5-10 per 100,000 live
    births. Other sources place it much lower (approximately 1 in 210,000 in one review),
    and ascertainment differences between registries, fetal series, and clinical cohorts
    account for much of the spread.
  evidence:
  - reference: PMID:38884759
    reference_title: "Human Genetics of Ebstein Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a rare, congenital cardiac defect of the tricuspid valve with a birth prevalence between 0.5 and 1 in 20,000"
    explanation: Gives the birth prevalence range used for the normalized rate.
  - reference: PMID:31384377
    reference_title: "Ebstein's Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The lesion is rare, with an incidence of approximately 1 in 20,000."
    explanation: Independent estimate at the lower end of the same range.
  - reference: PMID:38884758
    reference_title: "Clinical Presentation and Therapy of Ebstein Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ebstein anomaly is a rare congenital heart defect, accounting for less than 1% of cardiac malformations and occurring in approximately 1 out of 210,000 live births."
    explanation: A markedly lower estimate from a contemporaneous review, recorded to show the true spread of published figures rather than presenting a single value as settled.
- population: Texas live births, 1999-2005 (Texas Birth Defects Registry)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 7.2
  notes: >
    Registry-based birth prevalence of 0.72 per 10,000 live births from 188 definite cases,
    equivalent to 7.2 per 100,000. This active-surveillance registry estimate is at the
    upper end of the range reported in clinical reviews.
  evidence:
  - reference: PMID:21465650
    reference_title: "Epidemiology of Ebstein anomaly: prevalence and patterns in Texas, 1999-2005."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were 188 definite cases of Ebstein anomaly identified in the TBDR. The overall prevalence was 0.72 per 10,000 live births."
    explanation: Population-based registry estimate of birth prevalence.
- population: Proportion of all congenital heart disease
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >
    Ebstein anomaly accounts for well under 1% of congenital heart disease; individual
    reviews give figures from about 0.5% to under 1.5%. It is nonetheless the most common
    congenital anomaly of the tricuspid valve.
  evidence:
  - reference: PMID:38884759
    reference_title: "Human Genetics of Ebstein Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EA accounts for about 0.5% of all congenital heart diseases (CHD)"
    explanation: Gives the proportion of all congenital heart disease.
  - reference: PMID:36151322
    reference_title: "Multimodality Imaging in Ebstein Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ebstein anomaly is the most common form of tricuspid valve congenital anomalies."
    explanation: Establishes its rank among congenital tricuspid valve anomalies despite its overall rarity.
differential_diagnoses:
- name: Tricuspid valve dysplasia
  description: >
    Congenital dysplasia of the tricuspid valve produces severe tricuspid regurgitation and
    right heart enlargement that can closely mimic Ebstein anomaly, particularly in the
    fetus and neonate. It is distinguished by the absence of leaflet-to-myocardium
    adherence and of apical displacement of the functional annulus, so there is no
    atrialized right ventricular segment.
  distinguishing_features:
  - Leaflets are thickened and dysplastic but delaminated, hinging at the true annulus
  - No apical displacement of the functional tricuspid orifice
  - No atrialized right ventricular segment
  - Accessory atrioventricular pathways are not characteristic
  evidence:
  - reference: PMID:38884760
    reference_title: "Molecular Pathways and Animal Models of Ebstein's Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The anatomic hallmarks of this entity are the downward displacement of the attachment of the septal and posterior leaflets of the tricuspid valve."
    explanation: Names downward leaflet attachment displacement as the anatomic hallmark that separates Ebstein anomaly from other tricuspid valve malformations such as dysplasia.
- name: Isolated left ventricular noncompaction
  description: >
    Left ventricular noncompaction can occur in isolation, and shares MYH7 as a genetic
    cause with the Ebstein-plus-noncompaction subtype. It is distinguished by the absence
    of any tricuspid valve malformation. Because the two can co-segregate within one
    family carrying a single MYH7 variant, relatives of an Ebstein proband may manifest
    either phenotype.
  disease_term:
    preferred_term: left ventricular noncompaction
    term:
      id: MONDO:0018901
      label: left ventricular noncompaction
  distinguishing_features:
  - Prominent left ventricular trabeculation without tricuspid valve malformation
  - No apical displacement of tricuspid leaflets or atrialized right ventricle
  - May be the manifesting phenotype in a relative sharing the same MYH7 variant
  evidence:
  - reference: PMID:23794396
    reference_title: "Ebstein anomaly associated with left ventricular noncompaction: an autosomal dominant condition that can be caused by mutations in MYH7."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although LVNC often occurs in an isolated entity, it may also be present in various types of congenital heart disease (CHD)."
    explanation: Establishes isolated left ventricular noncompaction as a distinct entity that overlaps genetically with the Ebstein-associated form.
- name: Wolff-Parkinson-White syndrome without structural heart disease
  description: >
    Pre-excitation and atrioventricular reentrant tachycardia in a structurally normal
    heart is far more common than Ebstein-associated pre-excitation and is distinguished
    by normal echocardiography. The distinction matters procedurally: ablation in Ebstein
    anomaly involves a more difficult substrate with multiple right-sided and septal
    pathways and a higher recurrence rate.
  disease_term:
    preferred_term: Wolff-Parkinson-White syndrome
    term:
      id: MONDO:0008685
      label: Wolff-Parkinson-White syndrome
  distinguishing_features:
  - Structurally normal heart on echocardiography
  - Usually a single accessory pathway, in any location
  - Substantially lower ablation recurrence rate
  evidence:
  - reference: PMID:34126268
    reference_title: "Accessory pathway ablation in Ebstein anomaly: A challenging substrate."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Catheter ablation of accessory pathways (APs) in Ebstein anomaly (EA) has been associated with a high recurrence risk."
    explanation: Establishes the procedural distinction between Ebstein-associated and structurally normal accessory pathway substrates.
clinical_burden:
  burden_level: VARIABLE
  rationale: >
    Burden spans the full range: fetal circular shunt with hydrops is frequently lethal in
    utero, symptomatic neonates face high operative mortality, and a mild anatomic variant
    may be an incidental finding in an asymptomatic adult. Even presumed-mild disease
    nonetheless carries a six-fold excess 35-year mortality over matched controls, so the
    low end of the range is not benign.
  notes: >
    Mortality is elevated across the whole severity spectrum. In a two-country nationwide
    registry study of 530 patients matched to 5,300 controls, even patients with presumed
    mild anatomy had a 35-year cumulative mortality of 11% versus 4% in controls, while
    presumed severe disease carried a hazard ratio of 36.2. Mortality has improved for
    patients diagnosed in the modern era. Morbidity is driven by progressive tricuspid
    regurgitation with right heart failure and by arrhythmia; atrial fibrillation
    independently predicts heart-failure hospitalisation in adults. Pregnancy is generally
    well tolerated in women with NYHA class II symptoms and no cyanosis.
  evidence:
  - reference: PMID:37344044
    reference_title: "Mortality in Patients With Ebstein Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with a presumed mild EA anatomy displayed a 35-year cumulative mortality of 11% (vs 4% for the matched control subjects; P < 0.001), yielding an HR for mortality of 6.0 (95% CI: 2.7-13.6), whereas patients with presumed severe EA demonstrated an HR of 36.2 (95% CI: 15.5-84.4) compared with control subjects and a cumulative mortality of 18% 35 years following diagnosis."
    explanation: Nationwide Danish-Swedish registry data quantifying excess mortality across the severity spectrum.
  - reference: PMID:37344044
    reference_title: "Mortality in Patients With Ebstein Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mortality in patients with EA is high irrespective of presence of concomitant congenital cardiac malformations and time of diagnosis compared with the general population, but overall mortality has improved in the contemporary era."
    explanation: Registry conclusion on both the persistent excess mortality and its improvement over time.
  - reference: PMID:34404328
    reference_title: "Ebstein's anomaly during pregnancy: experience from a tertiary care centre - a case series and review of literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with NYHA class II symptoms and no cyanosis generally tolerate pregnancy well."
    explanation: Small tertiary-centre case series of eight pregnancies supporting generally favourable pregnancy tolerance in mildly symptomatic, acyanotic women.
  - reference: PMID:32622490
    reference_title: "Ebstein Anomaly in the Adult Patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pregnancy generally is well tolerated."
    explanation: Independent review confirming that pregnancy is usually tolerated in adults with Ebstein anomaly.
experimental_models:
- name: Mouse and canine models of tricuspid valve malformation
  description: >
    No animal model is established as fully recapitulating the specific combination of
    septal and inferior leaflet adherence to myocardium, apical displacement of the
    functional orifice, and an atrialized right ventricular segment that characterises
    human Ebstein anomaly. Mouse models displaying features of the malformation and a
    naturally occurring canine tricuspid valve malformation have been described and
    compared with the human condition.
  evidence:
  - reference: PMID:38884760
    reference_title: "Molecular Pathways and Animal Models of Ebstein's Anomaly."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Furthermore, mouse models that show features of Ebstein's anomaly and the naturally occurring model of canine tricuspid valve malformation are described and compared to the human model."
    explanation: Review chapter cataloguing the available mouse and naturally occurring canine models and their relationship to the human disease.
discussions:
- discussion_id: myh7_sarcomere_to_valve_mechanism
  prompt: >
    How does a sarcomeric beta-myosin heavy chain defect produce a tricuspid valve
    delamination phenotype?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Failure of tricuspid leaflet delamination
  rationale: >
    MYH7 encodes a contractile protein of the cardiomyocyte sarcomere, yet MYH7 variants
    cause a valve morphogenesis defect. The intervening steps, whether altered myocardial
    mechanics during the valvulogenic window perturb the apoptotic and matrix-remodelling
    programme that delaminates the leaflets or some other route operates, are not
    established. The absence of an animal model reproducing the full Ebstein phenotype is
    the main barrier to resolving this.
  proposed_experiments:
  - experiment_id: exp_ebstein_myh7_delamination_model
    name: Conditional Ebstein-associated MYH7 variant in developing right ventricular myocardium
    description: >-
      Express an Ebstein-associated MYH7 missense variant conditionally in the developing
      right ventricular myocardium and quantify, across the valvulogenic window, leaflet
      delamination extent, the position of the functional tricuspid hinge relative to the
      true annulus, and apoptosis in the myocardium underlying the septal and inferior
      leaflet primordia.
    decision_criterion: >-
      Reproduction of apical hinge displacement with retained leaflet-myocardial adherence
      would establish that a sarcomeric defect is sufficient to cause the delamination
      phenotype.
  - experiment_id: exp_ebstein_av_junction_single_cell
    name: Single-cell transcriptomic profiling of the developing atrioventricular junction
    description: >-
      Profile the developing atrioventricular junction in an MYH7-variant model versus
      wild type at successive timepoints spanning the delamination window, to identify
      which cell populations and programmes diverge before the anatomic lesion is
      established.
  evidence:
  - reference: PMID:38884760
    reference_title: "Molecular Pathways and Animal Models of Ebstein's Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although Ebstein's anomaly remains one of the least understood cardiac malformations to date"
    explanation: Authoritative review stating that the disease mechanism remains among the least understood in structural cardiac malformation.
notes: >
  No GeneReviews chapter exists for Ebstein anomaly; a PubMed search for
  "Ebstein anomaly GeneReviews[All Fields]" returned no results, consistent with the
  disease being predominantly sporadic rather than Mendelian. Genetic content here is
  therefore built from primary cohort and cytogenetic studies rather than from a
  GeneReviews clinical-characteristics baseline.
datasets:
- accession: geo:GSE7527
  title: Array CGH in congenital heart disease
  description: >-
    Sub-megabase-resolution BAC array comparative genomic hybridization screen of 104
    patients with congenital heart disease as the sole abnormality at diagnosis, plus
    some of their parents, searching for DNA copy number changes in non-syndromic CHD.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MICROARRAY
  sample_count: 119
  conditions:
  - non-syndromic congenital heart disease
  platform: BAC array CGH (sub-megabase resolution)
  publication: PMID:18713793
  genes:
  - preferred_term: GATA4
    term:
      id: hgnc:4173
      label: GATA4
  notes: >-
    Relevance triage: the cohort is non-syndromic congenital heart disease generally, not
    Ebstein anomaly specifically, but exactly one sample in the GEO series metadata is
    annotated with an Ebstein anomaly diagnosis. It is included because copy number
    variation is the one genetic mechanism with reproducible support in Ebstein anomaly
    (1p36 and 8p23.1 deletions), and this is the closest available primary copy-number
    dataset; the single Ebstein sample means it cannot support any Ebstein-specific
    quantitative claim. No Ebstein-anomaly-specific transcriptomic, proteomic, or
    copy-number dataset exists in GEO. The other candidates surfaced by dataset discovery
    were gene-only matches on MYH7, GATA4, and NKX2-5 that are about hypertrophic
    cardiomyopathy, ovarian cancer, and transcription-factor binding respectively, and
    were rejected as Named Entity Confusion.

📚

References & Deep Research

References

2

PMID:38685467

The American Association for Thoracic Surgery (AATS) 2024 expert consensus document: Management of neonates and infants with Ebstein anomaly.

No top-level findings curated for this source.

PMID:40317284

The American Association for Thoracic Surgery (AATS) 2025 Expert Consensus Document: Management of Ebstein anomaly in children and adults.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

Ebstein Anomaly — Comprehensive Disease Characteristics Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 37 citations 2026-08-09T03:38:14.762322

Ebstein Anomaly — Comprehensive Disease Characteristics Research Report

1. Disease Information

Overview. Ebstein anomaly (EA) is a rare, congenital malformation of the tricuspid valve and right ventricle. The defining lesion is apical (downward) displacement of the functional tricuspid annulus into the right ventricle, caused by failure of delamination of the septal and posterior (inferior) leaflets from the underlying myocardium during valvulogenesis. This produces "atrialization" of the inlet portion of the right ventricle (the RV segment proximal to the displaced valve becomes thin-walled and functions as an extension of the right atrium), a redundant and often abnormally attached anterior/anterosuperior leaflet, a functionally smaller (distal) true right ventricle, tricuspid regurgitation, and right atrial enlargement. Severity ranges from mild (incidental, adult-diagnosed) to severe forms presenting with massive cardiomegaly and circulatory failure in the fetus/neonate ("Ebstein's anomaly-like" fetal hydrops).

Key identifiers: - OMIM: 224700 (EBSTEIN ANOMALY) — https://omim.org/entry/224700 - Orphanet: ORPHA:1880 (Ebstein malformation of the tricuspid valve) - MONDO: MONDO:0009144 - ICD-10: Q22.5 (Ebstein's anomaly) - ICD-11: LA61.0 (or equivalent congenital tricuspid malformation code) - MeSH: D004437 (Ebstein Anomaly) - HPO (as a phenotype/malformation term): HP:0010316 (Ebstein anomaly)

Synonyms/alternative names: Ebstein's anomaly; Ebstein malformation of the tricuspid valve; Ebstein's disease; tricuspid valve atrialization; downward displacement of the tricuspid valve.

Evidence base character: Much of the mechanistic and epidemiologic literature is aggregated disease-level data — population birth-defect registries (e.g., National Birth Defects Prevention Study, Danish/Swedish national registries), multicenter surgical/echocardiographic case series, and candidate-gene/exome cohorts — rather than individual-patient EHR mining, though single-center EHR-derived case series (e.g., fetal echocardiographic cohorts, CICU admission cohorts) also contribute.

2. Etiology

Disease Causal Factors

EA is etiologically heterogeneous: the majority of cases are sporadic, with a minority attributable to identifiable monogenic causes (sarcomeric gene mutations), chromosomal microdeletions, or teratogenic exposure (notably lithium). The unifying developmental mechanism is failure of normal delamination/apoptotic remodeling of the septal and inferior tricuspid leaflets from the ventricular myocardium during valvulogenesis (roughly weeks 9–16 of human gestation), leaving the leaflets tethered directly to endocardium/myocardium rather than forming discrete mobile leaflets tethered by chordae to papillary muscles.

Genetic Risk Factors

MYH7 (β-myosin heavy chain, sarcomere gene; 14q11.2): Heterozygous MYH7 mutations were identified in 8/141 (6%) unrelated EA probands in a next-generation/Sanger sequencing cohort, with 7 distinct mutations (5 novel, 2 previously known HCM-causing variants). This defines an autosomal-dominant subtype of EA associated with left ventricular noncompaction (LVNC). (PMID:21604106 — "Ebstein's anomaly may be caused by mutations in the sarcomere protein gene MYH7"; PMID:23794396 — familial EA + LVNC autosomal dominant, MYH7; PMID:25444217 — familial EA, LVNC, and VSD with MYH7 mutation.)
NKX2-5 and GATA4: Candidate transcription-factor genes implicated in isolated and familial EA and broader congenital heart disease (CHD); GATA4 also implicated via 8p23.1 microdeletion (PMID:21815254 — "Ebstein anomaly: Genetic heterogeneity and association with microdeletions 1p36 and 8p23.1"). NKX2-5/GATA4/TBX5 act combinatorially in cardiac septation/valvulogenesis gene regulatory networks.
Chromosomal microdeletions: 1p36 deletion syndrome and 8p23.1 deletion syndrome are recurrently associated with EA or EA-like tricuspid valve malformation.
Exome/targeted-panel studies: A 47-case EA cohort sequenced for 50 candidate genes (including NKX2-5, GATA4, MYH7) implicated myocardial-development pathway genes (PLOS ONE, PMID not directly captured — "Genetic Variants in Isolated Ebstein Anomaly Implicated in Myocardial Development Pathways").
Most sporadic EA is not explained by a single identified gene; recurrence risk in siblings of an isolated case is low (empirically ~1%), consistent with predominantly sporadic/multifactorial causation, with monogenic causes concentrated in familial or syndromic clusters (especially the MYH7/LVNC subtype).

Environmental Risk Factors

Lithium (maternal first-trimester exposure): Historically implicated with a very high relative risk (~400) based on voluntary case-registry data from the 1970s, now understood to be a substantial overestimate. Contemporary controlled studies (case-control and cohort, including the large NEJM cohort, PMID:28591541 — Lithium Use in Pregnancy and the Risk of Cardiac Malformations) show a modest increase in cardiac-malformation risk with first-trimester lithium exposure, disproportionately affecting right-ventricular-outflow/tricuspid lesions (most likely EA); absolute risk of EA specifically is estimated at roughly 1–2 per 1000 (0.1–0.2%) with exposure, versus ~1 in 20,000 baseline. Risk appears dose-dependent, increasing above ~900 mg/day lithium.
Other implicated teratogens/exposures (less strongly supported, from the National Birth Defects Prevention Study, PMID: PMC6711372 — "Potential risk factors for Ebstein anomaly"): benzodiazepine use, certain maternal illnesses/exposures during the periconceptional period; findings are exploratory given the rarity of the defect and generally require replication.
Maternal diabetes and other general CHD risk factors have been examined but are not specifically or strongly linked to EA the way lithium is.

Protective Factors

No well-established genetic or environmental protective factors are documented in the literature; folic acid periconceptional supplementation is a general CHD-risk-reduction measure but is not specifically validated for EA.

Gene–Environment Interactions

No specific validated gene–environment interaction has been characterized for EA (e.g., no data indicating lithium risk is modified by a specific genotype). This remains an evidence gap.

Suggested ontology terms: HGNC:MYH7 (HGNC:7577), HGNC:NKX2-5 (HGNC:2488), HGNC:GATA4 (HGNC:4237); CHEBI term for lithium (CHEBI:30145, lithium(1+)); GENO terms for LOSS_OF_FUNCTION/dominant-negative variant classes.

3. Phenotypes

Cardiac structural phenotypes

Apical displacement of the septal/inferior tricuspid leaflet — HP:0031653 (if available) or best-fit HP:0001702/HP:0025269-class terms; more precisely the defining structural anomaly maps to HP:0010316 Ebstein anomaly itself, and component features:
Tricuspid valve regurgitation — HP:0005180 (Tricuspid regurgitation)
Tricuspid stenosis (less common) — HP:0031653 / related term
Right atrial enlargement / cardiomegaly — HP:0004268 (Atrial septal defect, if concurrent), HP:0001680 cardiomegaly-related term, HP:0025168 (Right atrial enlargement, if present in HPO)
Atrialized right ventricle / functionally diminished RV
Right ventricular outflow tract obstruction (in severe fetal forms) — HP:0031090-class term
Patent foramen ovale / atrial septal defect (common concurrent lesion, right-to-left shunting causing cyanosis) — HP:0001631 (Atrial septal defect)
Pulmonary atresia/stenosis (severe neonatal presentations) — HP:0002637/HP:0001640-class terms

Functional/clinical phenotypes

Cyanosis (from right-to-left interatrial shunting) — HP:0000961
Heart failure/right ventricular failure — HP:0001635 (Congestive heart failure)
Arrhythmia, particularly supraventricular tachyarrhythmias and Wolff-Parkinson-White (WPW) pre-excitation:
5–25% of EA patients have WPW syndrome, making EA the CHD most strongly associated with accessory AV pathways; ~10–25% have one or more accessory pathways, up to 50% of whom have multiple pathways.
Atrial fibrillation occurs in roughly one-third of adult EA patients.
Pediatric rhythm-disturbance prevalence ~17% (lower than adults), predominantly supraventricular.
HP terms: HP:0001680 (Arrhythmia — non-specific term), HP:0004757 (Ventricular preexcitation), HP:0001671 (Atrial fibrillation), HP:0004308 (Ventricular arrhythmia)
Right bundle branch block — HP:0011711
Sudden cardiac death risk — increased due to arrhythmia substrate

Fetal/neonatal-specific phenotypes

Fetal hydrops in severe forms
Massive cardiomegaly (cardiothoracic ratio) in utero
Pulmonary hypoplasia secondary to cardiomegaly compressing developing lungs — HP:0002089

Phenotype characteristics

Age of onset: Spans a continuum from severe prenatal presentation (detectable by mid-gestation fetal echocardiography, often associated with poor outcome) to incidental adult diagnosis of mild anatomic variants. Neonatal presentation with cyanosis and heart failure occurs in more severe anatomic forms; milder cases may be asymptomatic until childhood or adulthood, when arrhythmia or exertional symptoms prompt evaluation.
Severity: Highly variable — graded clinically/echocardiographically (e.g., Carpentier classification types A–D of leaflet tethering, and the echocardiographic Great Ormond Street Echo, "GOSE," score in the fetal/neonatal setting).
Progression: Can be progressive over decades due to worsening tricuspid regurgitation, right heart dilation, and arrhythmia burden; some patients remain stable for long periods with mild disease.
Frequency of specific features: Tricuspid regurgitation is nearly universal; WPW/accessory pathways occur in a substantial minority (5–25%); atrial septal communication (ASD/PFO) is very common; cyanosis frequency depends on shunt direction and pulmonary flow.

Quality of life impact

Impact on functional capacity correlates with disease severity: patients with severe RV dysfunction and heart failure have significant exercise limitation (reduced NYHA functional class); arrhythmia burden (recurrent SVT/AF) independently reduces quality of life and increases healthcare utilization; patients undergoing successful cone reconstruction generally show improved functional status and exercise tolerance postoperatively. Detailed disease-specific EQ-5D/SF-36 data for EA specifically is sparse in the literature relative to more common CHD lesions — this is a data gap.

4. Genetic/Molecular Information

Causal genes (monogenic subsets)

Gene	HGNC	OMIM gene	Role in EA
MYH7	HGNC:7577	160760	Autosomal-dominant EA + LVNC subtype; ~6% of EA probands in one cohort (PMID:21604106)
NKX2-5	HGNC:2488	600584	Candidate gene; broader CHD transcription factor, implicated in isolated/familial EA
GATA4	HGNC:4237	600576	Candidate gene; implicated via 8p23.1 microdeletion (PMID:21815254) and direct sequence variants

Pathogenic variant characteristics

Variant type: Predominantly missense variants in MYH7 (consistent with sarcomeric dominant-negative/gain-of-function mechanisms as in hypertrophic/dilated cardiomyopathy); some MYH7 variants identified in EA cohorts were previously known HCM-causing alleles, suggesting pleiotropy of specific MYH7 residues across cardiomyopathy and valvulopathy phenotypes.
Classification: Variant pathogenicity in these small EA cohorts is largely based on segregation with LVNC/EA phenotype in families, absence from population databases, and known cardiomyopathy association (per ACMG/AMP-style reasoning); formal ClinVar-level classification varies by variant.
Allele frequency: EA-associated MYH7 variants are rare/private, consistent with rarity in gnomAD population databases (specific frequencies not systematically reported in the identified literature — check ClinVar/gnomAD directly for individual variants).
Origin: Predominantly germline; familial cases show autosomal dominant transmission with variable expressivity (EA, isolated LVNC, or both, and VSD in some kindreds — PMID:25444217).
Functional consequence: Sarcomeric dysfunction (myosin motor domain or lever-arm alterations) is hypothesized to disrupt normal myocardial mechanics during the valvulogenic remodeling window, secondarily impairing tricuspid leaflet delamination — a proposed but not fully mechanistically resolved link between a sarcomere-protein defect and a valve-morphogenesis phenotype.

Modifier genes

Not well characterized for EA specifically; TBX5 is a co-regulator with NKX2-5/GATA4 in cardiac septation networks and is a plausible modifier/candidate but lacks EA-specific validation in the retrieved literature.

Chromosomal abnormalities

1p36 deletion syndrome — associated with EA/EA-like tricuspid malformation (PMID:21815254)
8p23.1 microdeletion (encompassing GATA4) — associated with EA (PMID:21815254)

Epigenetic information

No EA-specific epigenetic (DNA methylation/chromatin) studies were identified in this search; this is an evidence gap relative to more common CHD lesions.

Suggested ontology terms: GO:0060420 (regulation of heart growth), GO:0003158 (endothelium development), GO:0003170 (heart valve development), GO:0055008 (cardiac muscle tissue morphogenesis); CL terms for cardiac valve interstitial cells and endocardial cells involved in valvulogenesis.

5. Environmental Information

Environmental factors

Lithium (see Etiology above) — the single best-characterized environmental/pharmacologic risk factor, historically over-estimated but confirmed at a modest, dose-related elevated risk in modern cohort studies (PMID:28591541, NEJM 2017; PMID:8031346 — "A reevaluation of risk of in utero exposure to lithium").
Possible associations with other maternal medication exposures examined in the National Birth Defects Prevention Study (benzodiazepines and others) are preliminary/hypothesis-generating (PMC6711372).

Lifestyle factors

No robust, EA-specific lifestyle risk factor (smoking, alcohol, diet) has been established in the literature reviewed; general CHD teratogen avoidance guidance applies but is not EA-specific.

Infectious agents

No infectious etiology is established for EA; it is a structural/developmental cardiac malformation, not known to be triggered by a specific pathogen.

6. Mechanism / Pathophysiology

Developmental mechanism (causal chain)

Trigger: Genetic lesion (e.g., MYH7 sarcomeric variant, NKX2-5/GATA4 dysregulation) or teratogenic exposure (lithium) perturbs normal atrioventricular valvulogenesis during fetal cardiac development.
Failure of leaflet delamination: Normally, the septal and inferior (posterior) tricuspid leaflets separate ("delaminate") from the underlying ventricular myocardium via a program of localized apoptosis/extracellular matrix remodeling, becoming free, mobile, chordally-tethered structures. In EA, this delamination process is incomplete, leaving the septal and inferior leaflets adherent to (or "plastered" against) the myocardium.
Apical (downward) displacement of the functional tricuspid annulus: Because the leaflets remain attached to myocardium rather than forming a discrete annular hinge point, the effective/functional tricuspid orifice is displaced apically into the right ventricle, well below the true anatomic tricuspid annulus.
Atrialization of the right ventricle: The portion of right ventricular myocardium between the true (anatomic) tricuspid annulus and the displaced functional valve becomes thin-walled, dyskinetic, and functionally continuous with the right atrium — the "atrialized RV."
Anterosuperior leaflet abnormality: The anterosuperior leaflet, while typically not displaced, is frequently enlarged, redundant, fenestrated, and tethered by abnormal chordal/muscular attachments to the RV free wall, further impairing coaptation.
Tricuspid regurgitation / functional right ventricular dysfunction: Failure of leaflet coaptation causes tricuspid regurgitation; a functionally small, distal "true" right ventricle plus a large, thin atrialized segment reduces effective RV pump function.
Downstream hemodynamic consequences: Right atrial dilation, elevated right atrial pressure, right-to-left shunting across an associated ASD/PFO (causing cyanosis when present), reduced pulmonary blood flow in severe cases, and — in the most severe fetal presentations — massive cardiomegaly, pulmonary hypoplasia (via mechanical lung compression), and hydrops.
Arrhythmogenic substrate: The abnormal atrioventricular junction anatomy predisposes to accessory atrioventricular conduction pathways (WPW), and atrial dilation predisposes to atrial fibrillation/flutter and other supraventricular arrhythmias, creating risk for sudden cardiac death.

Molecular pathways

Cardiac transcription factor network: NKX2-5–GATA4–TBX5 complex regulating genes required for cardiac septation and AV valve/junction formation (PMC3370385, PMC6503026).
Sarcomere gene pathway: MYH7-encoded β-myosin heavy chain — primarily characterized in the context of hypertrophic/dilated cardiomyopathy and LVNC signaling, with EA representing a less common but reported phenotypic manifestation, presumably via altered myocardial mechanical signaling during the valvulogenic remodeling window (mechanism incompletely resolved — see Springer Nature chapter "Molecular Pathways and Animal Models of Ebstein's Anomaly," 2023).
Second heart field (SHF)–derived AV canal signaling: In zebrafish, the transcription factor foxn4 acts with tbx5 to direct AV boundary formation by regulating tbx2b expression, establishing the developmental logic of AV valve delamination that is disrupted in EA-like phenotypes (relevant developmental biology parallel, not EA-specific human data).

Cellular processes

Endocardial cushion formation and epithelial-to-mesenchymal transition (EMT) at the AV canal.
Localized programmed cell death (apoptosis) in myocardium underlying the developing septal/inferior leaflets, a step required for normal delamination — presumed disrupted in EA.
Extracellular matrix remodeling of the developing valve leaflets.

Tissue damage / remodeling mechanisms

Chronic tricuspid regurgitation and RV volume overload drive progressive right atrial and (atrialized) right ventricular dilation, myocardial wall thinning, and fibrosis over time; longstanding RV dysfunction can secondarily affect left ventricular function via ventricular interdependence (documented in the Da Silva cone-repair outcome literature, where LV function improves after cone repair — PMC12295748).

Biochemical/functional abnormalities

Primary defect is structural/mechanical (valve-myocardial adhesion and displacement) rather than a discrete enzymatic or receptor-level biochemical lesion, distinguishing EA mechanistically from metabolic or channelopathic cardiac disease.

Molecular profiling

Systematic transcriptomic, proteomic, or metabolomic profiling specific to EA valve/myocardial tissue was not identified in this search — this is a notable data/methods gap; most molecular data derive from candidate-gene sequencing rather than unbiased -omics of affected tissue.

Suggested GO terms: GO:0003171 (atrioventricular valve development), GO:0003190 (atrioventricular valve formation), GO:0055010 (ventricular cardiac muscle tissue morphogenesis), GO:0060412 (ventricular septum morphogenesis), GO:0097084 (vascular associated smooth muscle cell development — if relevant to valve interstitial lineage), GO:0006915 (apoptotic process, for leaflet delamination).

Suggested CL terms: CL:0002138 (endocardial cell), CL:0000670 (primary heart field cardiomyocyte / cardiac muscle cell — as best fit), valve interstitial cell (if a CL term exists), cardiac neural crest-derived cell (where relevant to AV cushion mesenchyme).

7. Anatomical Structures Affected

Organ level

Primary: Heart — specifically the tricuspid valve (UBERON:0002102) and right ventricle (UBERON:0002080)/right atrium (UBERON:0002078).
Secondary/complication-related: Lungs (pulmonary hypoplasia in severe fetal cases, UBERON:0002048), liver/systemic venous system (secondary to right heart failure and systemic venous congestion).
Body systems: Cardiovascular system primarily; secondary respiratory involvement in severe fetal/neonatal disease.

Tissue/cell level

Valve leaflet fibrous/connective tissue (septal, inferior/posterior, and anterosuperior tricuspid leaflets) — UBERON:0002145 (heart valve) as parent term.
Ventricular myocardium of the atrialized right ventricle.
Endocardium/endocardial cushion-derived tissue.
Conduction system tissue (relevant to accessory pathway formation) — UBERON structures for the AV node/His bundle region.

Subcellular level

Not specifically characterized beyond generic cardiomyocyte sarcomeric structures (relevant to the MYH7 subtype) — GO Cellular Component: GO:0030017 (sarcomere), GO:0030016 (myofibril).

Localization

Right-heart-restricted anatomic defect (left heart structures are typically anatomically normal except in LVNC-overlap MYH7-associated cases, where left ventricular noncompaction co-occurs).
Not laterality-relevant in the classic sense (it is inherently a right-sided cardiac malformation, not a bilateral/asymmetric process).

8. Temporal Development

Onset

Congenital: EA originates in utero during atrioventricular valve morphogenesis (roughly the first trimester through mid-gestation).
Clinical presentation spans: prenatal detection via fetal echocardiography (severe forms, sometimes with poor prognosis), neonatal presentation with cyanosis/heart failure (moderate-severe forms), or delayed diagnosis in childhood through adulthood — sometimes incidentally — in mild anatomic variants.

Progression

Disease course pattern: Can be stable for extended periods (especially milder anatomic forms) or progressive, with worsening tricuspid regurgitation, right heart enlargement, and increasing arrhythmia burden over years to decades.
Progression drivers: Chronic volume overload from tricuspid regurgitation, progressive RV/RA dilation, development or worsening of arrhythmia substrate.
Fetal cases with severe cardiomegaly and hydrops carry high risk of in utero or neonatal demise; a cited case series found in-utero mortality of 37.5% and neonatal mortality of 50% in a high-risk fetal cohort, with ~30% one-year mortality overall in prenatally/neonatally diagnosed severe disease.
Long-term registry data (Danish/Swedish nationwide cohorts, PMID/JACC 2023 — "Mortality in Patients With Ebstein Anomaly") found 35-year cumulative mortality of 11% even among patients with anticipated mild EA, with higher mortality in those with associated cardiac lesions; mortality has decreased in patients diagnosed in the modern era compared with earlier eras.

Patterns

Critical period: The valvulogenic window (delamination of AV valve leaflets) is the developmental critical period during which the causal insult (genetic or teratogenic) acts.
Remission: Not applicable in the classic sense (structural malformation), but successful surgical (cone) reconstruction can produce durable, near-normalization of valve competence and functional status for many years.

9. Inheritance and Population

Epidemiology

Prevalence at birth: Estimates vary by source/methodology — approximately 1 in 20,000 to 1 in 100,000 live births (Orphanet); other studies report 3–5, 4.4, or up to 7 per 100,000 live births (Texas birth-defects registry, PMID:21465650 — "Epidemiology of Ebstein anomaly: prevalence and patterns in Texas, 1999–2005"); broader estimates place incidence at 1.2–5 per 100,000 live births, or as high as 50–100 per million live births in some critical-CHD classifications.
EA comprises <1% of all congenital heart defects.
No strong sex predilection is generally reported (roughly equal male:female distribution), though some individual series show slight variation.

Inheritance pattern (for genetically resolved subsets)

Autosomal dominant inheritance is documented for the MYH7-associated EA/LVNC subtype, with variable expressivity across kindred members (isolated LVNC, isolated EA, or both, plus VSD in some families) (PMID:23794396, PMID:25444217).
The majority of EA cases are sporadic, without a clearly Mendelian inheritance pattern, consistent with multifactorial or de novo genetic causation, or non-genetic (e.g., lithium) etiology.
Chromosomal microdeletion cases (1p36, 8p23.1) typically arise de novo but can rarely be inherited from a similarly affected/carrier parent.

Penetrance / expressivity

Variable expressivity is documented within MYH7-mutation-positive families (different family members manifesting EA, LVNC, or both) (PMID:23794396).
Penetrance estimates for specific MYH7 variants in the EA context are not precisely quantified in the retrieved literature.

Population demographics

No strong evidence for a specific ethnic/geographic founder effect in EA (unlike many monogenic disorders); it is broadly distributed geographically.
Sibling recurrence risk for isolated/sporadic EA is empirically low (~1%), consistent with predominantly sporadic causation.

10. Diagnostics

Clinical/imaging tests

Transthoracic and fetal echocardiography are the primary diagnostic modalities — demonstrating apical displacement of septal/inferior tricuspid leaflets (displacement index typically defined as >8 mm/m² BSA in adults, or specific fetal apical displacement thresholds), atrialized RV, and tricuspid regurgitation severity.
Cardiac MRI: Used for RV volumetric assessment, atrialized RV quantification, and risk stratification (e.g., RV end-diastolic volume index, RVEF) — cardiovascular magnetic resonance-based risk prediction models for major adverse events and atrial tachyarrhythmia have been published (PMC5749347).
Electrocardiography (ECG): Right bundle branch block pattern, evidence of pre-excitation (WPW pattern — short PR interval, delta wave) when accessory pathways are present.
Electrophysiology study: For mapping and characterizing accessory pathways prior to ablation, given the high (~25%) prevalence of accessory pathways and frequent multiplicity of pathways in EA.
Chest radiography: Classic "wall-to-wall heart" cardiomegaly appearance in severe cases.

Fetal-specific diagnostics and scoring

Fetal echocardiography allows in-utero diagnosis and prognostication; key prognostic sonographic features include cardiothoracic index >0.55, relative foramen ovale/atrial septal ratio <0.3, right ventricular outflow tract obstruction, tricuspid valve displacement index >2.5, absence of reverse flow in the ductus arteriosus, and RV:LV ratio >2 (PMID:23819422 and related fetal Ebstein prognosis literature).
Great Ormond Street Echo (GOSE) score: A validated ratio-based echocardiographic prognostic index; e.g., a GOSE score ratio of 1.1–1.49 corresponds to ~10% early mortality in acyanotic patients but up to 100% mortality in cyanotic patients, illustrating the strong prognostic interaction between anatomic severity and physiologic (cyanosis) status.

Genetic testing

Not part of routine diagnostic workup for isolated/sporadic EA given its predominantly non-Mendelian nature, but recommended when EA is accompanied by left ventricular noncompaction, a family history suggestive of autosomal dominant transmission, or additional syndromic features — targeted sequencing/panel testing for MYH7 (and consideration of NKX2-5, GATA4) is reasonable in these contexts.
Chromosomal microarray (CMA): Indicated when EA occurs with additional dysmorphic features or extracardiac anomalies, to detect 1p36 or 8p23.1 microdeletions.
Whole exome/genome sequencing: Used in research cohorts (e.g., 47-case, 50-gene candidate panel study) to identify novel variants in myocardial-development pathway genes; not yet standard clinical practice for isolated EA.

Clinical criteria / differential diagnosis

Diagnosis is primarily echocardiographic/anatomic rather than criteria-based (no DSM/consensus clinical scoring system analogous to other diseases).
Differential diagnosis includes other causes of severe tricuspid regurgitation and right heart enlargement: tricuspid valve dysplasia (a distinct entity without the same degree of leaflet delamination failure/annular displacement), pulmonary atresia with intact ventricular septum, uhl anomaly (parchment right ventricle), and other causes of fetal cardiomegaly/hydrops.

Screening

No population-based newborn or prenatal screening program specifically targets EA (given its rarity); detection occurs opportunistically via routine obstetric anomaly ultrasound or, postnatally, via clinical evaluation of murmur/cyanosis/arrhythmia.

11. Outcome/Prognosis

Survival and mortality

Population-level cohort data (Danish/Swedish national registries, patients born 1970–2017, 530 EA patients vs. 5,300 matched controls, median follow-up 11 years; JACC 2023, PMID for "Mortality in Patients With Ebstein Anomaly"): 35-year cumulative mortality of 11%, even in patients with anticipated mild disease; patients with associated cardiac lesions had higher mortality than isolated EA; mortality has declined in the modern diagnostic/treatment era relative to earlier decades; most common cause of late death was cardiac-related.
Fetal/neonatal cohorts: Substantially worse — one high-risk case series reported in-utero mortality of 37.5% and neonatal mortality of 50%; broader estimates place 1-year mortality at ~30% for prenatally/neonatally diagnosed cases, heavily dependent on anatomic severity and cyanosis status (per GOSE score stratification above).
Postoperative mortality risk factors (surgical cohorts): RV end-diastolic volume index >200 mL/m², RV ejection fraction <40%, and age >50 years at time of operation.

Morbidity and functional outcomes

Progressive tricuspid regurgitation and right heart failure are the principal drivers of morbidity in unrepaired or inadequately repaired disease.
Arrhythmia-related morbidity (recurrent SVT, atrial fibrillation, WPW-mediated tachyarrhythmia) is common and can itself precipitate heart failure or, rarely, sudden cardiac death.
Post cone-repair, RV size decreases and antegrade stroke volume increases as early as 6 months postoperatively (PMID:25535206 — Da Silva cone repair effect on RV size/function); mid-term studies (2025) additionally document recovery of RV function and improvement of LV function after cone repair (PMC12295748), supporting a ventricular-interdependence mechanism for the pre-repair LV dysfunction sometimes observed.

Prognostic factors

Anatomic severity (degree of leaflet displacement/tethering, Carpentier type), presence/degree of cyanosis, RV size and function (echocardiographic and MRI-derived indices), presence of associated lesions (pulmonary stenosis/atresia, ASD), and arrhythmia burden are the principal prognostic determinants identified across the fetal, pediatric, and adult literature.
A 2025 review specifically synthesizes "poor prognostic factors" in EA (PMC12859563 — "Complex Considerations for a Complex Disease: Identifying Poor Prognostic Factors in Ebstein's Anomaly").

12. Treatment

Pharmacotherapy

Antiarrhythmic medications (e.g., beta-blockers, class III agents) for rate/rhythm control of atrial fibrillation/flutter and supraventricular tachyarrhythmias.
Heart failure pharmacotherapy (diuretics, and standard heart-failure agents as adapted for right-heart-predominant failure) in patients with RV dysfunction.
Prostaglandin E1 in neonates with ductal-dependent pulmonary blood flow (severe forms with functional pulmonary atresia) to maintain ductal patency pending intervention.
NCIT term: NCIT:C15986 (Pharmacotherapy) as the generic action term, with specific agents captured via therapeutic_agent (e.g., CHEBI terms for individual antiarrhythmics).

Interventional electrophysiology

Catheter ablation of accessory pathways (for WPW) and arrhythmia substrates — though EA-associated ablation carries a notably higher recurrence rate (30–40%) compared with the general population (5–10%), reflecting the complex, often multiple accessory-pathway anatomy in EA.
NCIT term: consider NCIT:C15329 (Surgical Procedure) parent or a more specific interventional cardiology procedure term if available; therapeutic_modality: DEVICE may apply for catheter-based ablation technology.

Surgical treatment

Cone reconstruction (Da Silva cone repair): The current preferred definitive surgical technique — extensive mobilization of the (dysplastic but present) leaflet tissue, longitudinal plication of the atrialized right ventricle, and reconstruction of a cone-shaped, leaflet-to-leaflet coapting neo-tricuspid valve using the patient's own (mobilized ± patch-augmented) leaflet tissue. Reported to produce excellent valve competence in the large majority of patients, with RV size normalization and improved antegrade stroke volume by 6 months, and documented mid-term (multi-year) recovery of both RV and LV function (PMID:25535206; PMC12295748). Variants include septal leaflet augmentation with autologous pericardial patch when native septal leaflet tissue is severely deficient (2025 comparative outcomes literature).
Staged single-ventricle palliation (Starnes procedure): Reserved for the most severe, unrepairable neonatal forms (severe RV hypoplasia/dysfunction) — tricuspid valve exclusion with fenestrated patch, atrial septectomy, and a modified BT shunt or similar systemic-to-pulmonary shunt, as a bridge toward staged single-ventricle (Fontan-pathway) palliation. A cone operation can subsequently be performed after a prior Starnes procedure in select cases (biventricular "conversion") with reported favorable initial outcomes.
Cardiac transplantation: Considered in end-stage cases with severe, irreparable ventricular dysfunction.
NCIT terms: NCIT:C15329 (Surgical Procedure), and more specific valve-repair/reconstruction terms if available in NCIT; therapeutic_modality: SURGERY.

Supportive/rehabilitative care

Standard heart-failure supportive management, activity guidance, and longitudinal cardiology follow-up (arrhythmia surveillance, RV function monitoring).
NCIT:C15747 (Supportive Care).

Experimental / emerging approaches

No gene therapy, RNA-based therapy, or targeted molecular therapy is currently established or in active clinical trials specific to EA (the disease is structural/surgical rather than a target for molecular correction), consistent with its developmental/anatomic (rather than progressive metabolic or degenerative) pathophysiology. Ongoing research is concentrated in surgical technique refinement (e.g., septal leaflet augmentation approaches, 2025) and risk-stratification/outcomes modeling (fetal echocardiographic prognostic markers, CMR-based risk prediction) rather than pharmacologic/molecular intervention.

Treatment outcomes

Cone repair: high rates of excellent postoperative valve competence, with RV remodeling (size reduction, functional improvement) documented from 6 months through multi-year follow-up.
Ablation for WPW/accessory pathways in EA: elevated recurrence (30–40%) relative to structurally normal hearts, reflecting anatomic complexity.
Population-level surgical outcome studies (PMC6852467 — "Early and Long-Term Outcomes of Surgical Treatment of Ebstein's Anomaly") document continued improvement in both early and late surgical outcomes over time as technique (particularly cone reconstruction) has matured.

Treatment strategy

Management is stratified by anatomic severity, degree of cyanosis, RV function, and presence of arrhythmia: mild, asymptomatic cases may be managed with surveillance alone; moderate-severe symptomatic disease with significant TR/RV dilation is generally directed toward cone reconstruction; the most severe neonatal forms with minimal functional RV may require staged single-ventricle palliation (Starnes-first strategy) rather than primary biventricular repair.

13. Prevention

Primary prevention: Avoidance/minimization of first-trimester lithium exposure in women who are or may become pregnant is the principal identified, modifiable primary-prevention strategy; when lithium is clinically necessary for maternal bipolar disorder management, guidance emphasizes using the lowest effective dose, therapeutic drug monitoring, and consideration of dose-related risk (>900 mg/day associated with higher malformation risk) (see PMC10596010 — "Lithium management in pregnant patients with bipolar disorder").
Secondary prevention: Fetal anomaly ultrasound/echocardiography enables early detection, allowing for informed counseling, planned delivery at a center with cardiac surgical/ECMO capability, and early postnatal intervention planning — this does not prevent the malformation but mitigates downstream morbidity/mortality via optimized perinatal management.
Genetic counseling: Recommended for families with a known MYH7 variant or other identified monogenic cause, given autosomal dominant inheritance and variable expressivity in that subset; recurrence-risk counseling for sporadic/isolated EA is generally reassuring (low empiric recurrence risk) absent an identified familial genetic cause.
Prenatal genetic testing/counseling: Consideration of targeted variant testing in subsequent pregnancies when a causal familial variant has been identified.
No vaccine, public health, or population-level environmental intervention is applicable given the rarity and largely sporadic/idiosyncratic (lithium-exposure-driven or de novo genetic) nature of EA.

14. Other Species / Natural Disease

Naturally occurring EA-like disease in companion/domestic animals: Not well documented as a recognized naturally occurring veterinary clinical entity analogous to human EA; tricuspid valve dysplasia is described in dogs (e.g., Labrador Retrievers) as a distinct congenital tricuspid malformation, but it is generally classified separately from "Ebstein-like" apical displacement with leaflet-myocardial adhesion, and formal cross-species nosological equivalence to human EA is not firmly established in the retrieved literature — recommend checking OMIA directly for any curated veterinary entries.
Comparative/orthologous developmental biology: Zebrafish (Danio rerio) atrioventricular canal development studies (foxn4/tbx5/tbx2b pathway) provide the closest comparative developmental-biology parallel for the delamination/AV-boundary-formation process disrupted in human EA, though these are developmental models of the normal AV valve program rather than models reproducing an EA disease phenotype per se.

15. Model Organisms

Mouse models: Both mouse and zebrafish genes have been catalogued as associated with EA via cross-species phenotype-matching approaches (linking model-organism cardiac phenotype ontology annotations to candidate human EA genes); specific validated mouse knockout models fully recapitulating the EA leaflet-delamination-failure phenotype were not identified with a specific citation in this search — this appears to be an area with limited dedicated animal-model literature relative to more common structural CHD lesions (see the 2023 review chapter "Molecular Pathways and Animal Models of Ebstein's Anomaly," Springer, for the most current synthesis).
Zebrafish models: Zebrafish AV canal/valve development work (foxn4–tbx5–tbx2b transcriptional pathway) establishes the relevant normal developmental program; loss-of-function perturbation of these genes disrupts AV boundary formation in a manner mechanistically analogous to (but not an established formal model of) human EA.
Model characteristics/limitations: No single animal model is described in the retrieved literature as fully recapitulating the specific combination of septal/inferior leaflet myocardial adhesion, functional annular displacement, and atrialized RV segment characteristic of human EA; existing models primarily inform the normal AV valvulogenesis program whose disruption is inferred (rather than directly demonstrated) to underlie EA.
Applications: Zebrafish AV-canal models are useful for dissecting the transcriptional regulatory logic of valve leaflet delamination and could in principle be used to test candidate EA genes (e.g., MYH7 orthologs, NKX2-5/GATA4 pathway members) for AV valve phenotypes, but this specific application to EA candidate genes was not documented with a citation in the retrieved search results.
Resources: MGI (Mouse Genome Informatics) and ZFIN (Zebrafish Information Network) are the appropriate primary databases to query directly for any curated EA-relevant knockout/mutant phenotype records (not exhaustively queried in this search pass).

Summary of Key Data Gaps (for curation flagging)

Molecular profiling (transcriptomic/proteomic) of EA-affected valve/myocardial tissue is essentially absent from the literature reviewed.
Dedicated animal models that recapitulate the specific EA leaflet-delamination-failure phenotype (as opposed to general AV valve developmental biology) are not well established.
Quantitative penetrance estimates for specific MYH7 (or other) pathogenic variants in the EA context are not precisely defined.
Disease-specific quality-of-life instrument data (EQ-5D/SF-36) specific to EA populations is sparse.
Gene–environment interaction data (e.g., whether lithium risk is modified by genotype) is absent.
Veterinary/natural-disease cross-species correlates are not well substantiated in this pass and should be checked directly against OMIA before curation.

Suggested Ontology Term Summary Table

Category	Suggested term(s)
Disease	MONDO:0009144; OMIM:224700; ORPHA:1880; ICD-10 Q22.5
Phenotype (HPO)	HP:0010316 (Ebstein anomaly), HP:0005180 (Tricuspid regurgitation), HP:0004757 (Ventricular preexcitation), HP:0001671 (Atrial fibrillation), HP:0011711 (RBBB), HP:0000961 (Cyanosis), HP:0001635 (Congestive heart failure), HP:0001631 (Atrial septal defect), HP:0002089 (Pulmonary hypoplasia)
Genes	HGNC:7577 (MYH7), HGNC:2488 (NKX2-5), HGNC:4237 (GATA4)
GO — biological process	GO:0003171/GO:0003190 (AV valve development/formation), GO:0055010 (ventricular cardiac muscle tissue morphogenesis), GO:0006915 (apoptotic process)
CL	CL:0002138 (endocardial cell)
UBERON	UBERON:0002102 (tricuspid valve), UBERON:0002080 (right cardiac ventricle), UBERON:0002078 (right cardiac atrium)
CHEBI	CHEBI:30145 (lithium(1+))
NCIT (treatment)	NCIT:C15329 (Surgical Procedure — cone reconstruction), NCIT:C15986 (Pharmacotherapy), NCIT:C15747 (Supportive Care)

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References

Deep Research

Ebstein Anomaly — Comprehensive Disease Characteristics Research Report

1. Disease Information

2. Etiology

Disease Causal Factors

Genetic Risk Factors

Environmental Risk Factors

Protective Factors

Gene–Environment Interactions

3. Phenotypes

Cardiac structural phenotypes

Functional/clinical phenotypes

Fetal/neonatal-specific phenotypes

Phenotype characteristics

Quality of life impact

4. Genetic/Molecular Information

Causal genes (monogenic subsets)

Pathogenic variant characteristics

Modifier genes

Chromosomal abnormalities

Epigenetic information

5. Environmental Information

Environmental factors

Lifestyle factors

Infectious agents

6. Mechanism / Pathophysiology

Developmental mechanism (causal chain)

Molecular pathways

Cellular processes

Tissue damage / remodeling mechanisms

Biochemical/functional abnormalities

Molecular profiling

7. Anatomical Structures Affected

Organ level

Tissue/cell level

Subcellular level

Localization

8. Temporal Development

Onset

Progression

Patterns

9. Inheritance and Population

Epidemiology

Inheritance pattern (for genetically resolved subsets)

Penetrance / expressivity

Population demographics

10. Diagnostics

Clinical/imaging tests

Fetal-specific diagnostics and scoring

Genetic testing

Clinical criteria / differential diagnosis

Screening

11. Outcome/Prognosis

Survival and mortality

Morbidity and functional outcomes

Prognostic factors

12. Treatment

Pharmacotherapy

Interventional electrophysiology