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Inheritance

3

Multifactorial and sporadic

Most DORV is sporadic and multifactorial, arising from a combination of rare and common variation, developmental stochasticity and maternal or environmental influences. More than 40 per cent of patients nevertheless carry a chromosomal abnormality, most commonly trisomy 13, trisomy 18 or a 22q11.2 deletion, and recurrence counselling should be based on the identified syndrome or gene when one is found.

Show evidence (1 reference)

PMID:18456715 SUPPORT Human Clinical

"Chromosomal abnormalities were present in 61 of the 149 cases of DORV. Trisomies 13 and 18, and del 22q11 were the most commonly associated cytogenetic lesions; different anatomic subtypes of DORV were noted in trisomies 13 and 18 versus del 22q11."

Documents the heterogeneous chromosomal contribution that underlies the multifactorial, largely sporadic inheritance pattern of DORV.

Autosomal dominant (rare monogenic families) HP:0000006

A minority of DORV is familial and segregates in an autosomal dominant pattern. Reported examples include a TBX20 p.R143W kindred and a MEF2C p.R15C pedigree, both with complete penetrance in the families described.

Autosomal dominant inheritance Penetrance: COMPLETE

Show evidence (1 reference)

PMID:25625280 SUPPORT Human Clinical

"Genetic analyses of the pedigree of the proband revealed that in the family, the mutation co-segregated with DORV transmitted in an autosomal dominant pattern with complete penetrance."

Documents autosomal dominant transmission of DORV with complete penetrance in a TBX20 kindred.

X-linked (ZIC3-associated laterality spectrum) HP:0001417

A small subset of DORV falls within the X-linked laterality spectrum associated with ZIC3, the gene classically causing heterotaxy with complex congenital heart disease in males, with affected and carrier females also reported.

X-linked inheritance

Show evidence (1 reference)

PMID:23427188 SUPPORT Human Clinical

"Disease causing mutations for heterotaxy syndrome were first identified in the X-linked laterality gene, ZIC3."

Establishes ZIC3 as an X-linked laterality gene, the inheritance mode relevant to the ZIC3-associated subset of DORV.

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Subtypes

5

DORV with subaortic ventricular septal defect (VSD type) MONDO:0018498

The most common form. The outlet septum attaches to the cranial (anterosuperior) limb of the septomarginal trabeculation, so the interventricular communication lies beneath the aortic root. Left ventricular blood streams preferentially to the aorta, giving a physiology resembling a large isolated ventricular septal defect: relatively well-saturated systemic flow with pulmonary overcirculation and congestive heart failure when pulmonary stenosis is absent. Repair is typically a straightforward intraventricular baffle tunnelling the left ventricle through the VSD to the aortic valve.

Show evidence (2 references)

PMID:27641710 SUPPORT Other

"The defect is subaortic when the outlet septum is attached to the cranial limb of the trabeculation, subpulmonary when attached to the caudal limb, and doubly committed when attached to the inner heart curvature in the roof of the defect."

Defines the subaortic subtype by the anatomic criterion used here, namely attachment of the outlet septum to the cranial limb of the septomarginal trabeculation.

PMID:17903515 SUPPORT Human Clinical

"Double-outlet right ventricle classification was as follows: subaortic ventricular septal defect with or without pulmonary stenosis in 47%, subpulmonic ventricular septal defect in 23%, noncommitted ventricular septal defect in 26%, and doubly committed ventricular septal defect in 4%."

Quantifies the subaortic VSD subtype as the most frequent form (47%) in a large single-institution DORV cohort.

DORV with subaortic or doubly committed VSD and pulmonary stenosis (Fallot type) MONDO:0020386

A physiologic variant of the committed-VSD forms in which pulmonary stenosis accompanies a subaortic or doubly committed ventricular septal defect. Because the outlet septum is deviated anterosuperiorly into the subpulmonary outflow, the physiology and surgical logic mirror tetralogy of Fallot: cyanosis rather than overcirculation, hypercyanotic spells, and repair combining an intraventricular baffle to the aorta with relief of right ventricular outflow tract obstruction.

Show evidence (2 references)

PMID:37818164 SUPPORT Other

"A subaortic VSD may mean that pulmonary stenosis and small branch pulmonary arteries are likely to develop."

Links the subaortic VSD anatomy to the development of pulmonary stenosis, which is what converts a VSD-type DORV into the Fallot-type physiology.

PMID:37818164 SUPPORT Other

"The surgical outcomes of DORV-Fallot are like those achieved in the TOF, with operative mortality between 0% and 5%."

Confirms DORV-Fallot as a recognised surgical category whose outcomes track those of tetralogy of Fallot.

DORV with subpulmonary VSD (Taussig-Bing anomaly, TGA type) MONDO:0020387

The Taussig-Bing anomaly. The outlet septum attaches to the caudal (posteroinferior) limb of the septomarginal trabeculation, placing the interventricular communication beneath the pulmonary root, with the pulmonary valve overriding the crest of the ventricular septum by more than 50% and bilateral conus. Left ventricular blood streams preferentially into the pulmonary artery while systemic venous return is directed to the aorta, so the physiology is transposition-like with early severe cyanosis. Aortic arch obstruction (coarctation or interrupted arch) and coronary anomalies are frequent. Repair is an arterial switch operation combined with a VSD-to-pulmonary-root baffle, with concomitant arch repair when needed.

Show evidence (2 references)

PMID:27641710 SUPPORT Other

"The defect is subaortic when the outlet septum is attached to the cranial limb of the trabeculation, subpulmonary when attached to the caudal limb, and doubly committed when attached to the inner heart curvature in the roof of the defect."

Defines the subpulmonary subtype anatomically by attachment of the outlet septum to the caudal limb of the septomarginal trabeculation.

PMID:32795522 SUPPORT Human Clinical

"Aortic arch obstruction and coronary anomalies were present in 64% and 41% of patients, respectively."

Documents the high burden of aortic arch obstruction and coronary anomalies that distinguishes the Taussig-Bing subtype and complicates its repair.

DORV with doubly committed (juxta-arterial) ventricular septal defect MONDO:0018498

The rarest positional subtype. The outlet septum is deficient or fibrous and attaches to the inner heart curvature in the roof of the defect, so the interventricular communication lies immediately beneath both semilunar valves, which are in fibrous continuity with one another. An intraventricular tunnel is still feasible but usually requires a right ventriculotomy or transpulmonary approach because the baffle must be anchored to the fibrous tissue between the aortic and pulmonary annuli, with a risk of semilunar valve distortion.

Show evidence (2 references)

PMID:27641710 SUPPORT Other

"The defect is subaortic when the outlet septum is attached to the cranial limb of the trabeculation, subpulmonary when attached to the caudal limb, and doubly committed when attached to the inner heart curvature in the roof of the defect."

Defines the doubly committed subtype by attachment of the outlet septum to the inner heart curvature roofing the defect.

PMID:17903515 SUPPORT Human Clinical

"Double-outlet right ventricle classification was as follows: subaortic ventricular septal defect with or without pulmonary stenosis in 47%, subpulmonic ventricular septal defect in 23%, noncommitted ventricular septal defect in 26%, and doubly committed ventricular septal defect in 4%."

Establishes the doubly committed VSD as the rarest positional subtype (4%) in a large clinical DORV series.

DORV with non-committed (remote) ventricular septal defect MONDO:0020388

The interventricular communication lies outside the limbs of the septomarginal trabeculation, typically in the inlet or apical trabecular septum, and is therefore remote from both arterial roots. This is the most surgically difficult subtype: a baffle must traverse a long, tortuous course at risk of obstructing the tricuspid valve apparatus or the right ventricular outflow tract, so VSD enlargement, multiple patches, root translocation, or staged single-ventricle palliation are often required.

Show evidence (2 references)

PMID:27641710 SUPPORT Other

"Non-committed defects are no longer positioned within the limbs of the septomarginal trabeculation."

Provides the defining anatomic criterion for the non-committed/remote VSD subtype.

PMID:38134423 SUPPORT Human Clinical

"VSD enlargement was significantly more frequent in DORV-ncVSD at 42% (5/12) (P = 0.001)."

Documents the greater surgical complexity of the non-committed VSD subtype, which more often requires enlargement of the interventricular communication to construct an unobstructed baffle.

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Discussions and Knowledge Gaps

1

By what mechanism does a given genetic lesion or teratogenic exposure convert normal outflow tract morphogenesis into the specific DORV subtype it produces, and what determines whether the resulting ventricular septal defect is subaortic, subpulmonary, doubly committed or non-committed?

KNOWLEDGE GAP OPEN dorv_genotype_to_morphology_gap

Attached to

Cardiac Neural Crest and Second Heart Field Disruption Outlet Septum Attachment Determines VSD Commitment

The pathophysiology modelled in this entry describes a coherent developmental chain from neural crest and second-heart-field disruption to the double-outlet connection, and the literature reliably associates particular aetiologies with particular anatomic subtypes (trisomy 13/18 versus 22q11.2 deletion produce different DORV subtypes). What is missing is the mechanistic bridge: no source explains how a specific lesion selects a specific outlet-septum attachment and therefore a specific VSD commitment. Because VSD position, not the DORV label, determines physiology and repair, this gap sits directly between the genetics and the clinically actionable anatomy.

Proposed experiments

Lineage-resolved transcriptomics of the outflow tract across DORV alleles

dorv_allelic_series_oft_transcriptomics

Single-cell and spatial transcriptomics of the murine outflow tract across a panel of DORV-producing alleles (Lrp1, Shroom3, Foxj1, Tbx1), staged through conal rotation, to test whether each lesion perturbs a distinct progenitor compartment rather than converging on one.

Decision criterion

Allele-specific perturbation of distinct neural-crest versus second-heart-field compartments would show that the developmental route, not just the endpoint, differs by aetiology.

Three-dimensional morphometry of outlet septum attachment

dorv_outlet_septum_morphometry

Quantitative three-dimensional morphometry of outlet-septum attachment across the same allelic series, testing whether attachment site predicts the resulting ventricular septal defect commitment.

Decision criterion

A reproducible mapping from allele to attachment site to VSD commitment would supply the missing mechanistic bridge between genotype and the clinically actionable anatomy.

Genotype-to-subtype association in a uniformly classified DORV cohort

dorv_genotype_subtype_cohort

Genotype-to-subtype association analysis in a large clinically phenotyped DORV cohort with uniform ISNPCHD anatomic classification and trio genome sequencing.

Decision criterion

Significant association between specific genomic lesions and specific VSD positions would confirm in humans the genotype-to-morphology relationship suggested by the trisomy 13/18 versus 22q11.2 subtype difference.

Show evidence (2 references)

PMID:37818164 SUPPORT Other

"genetic anomalies or environmental exposures result in the development of DORV from normal structural cardiac anatomy are unknown"

The source states directly that the mechanisms by which specific genetic anomalies or environmental exposures produce DORV from normal structural cardiac anatomy are unknown, which is precisely the gap recorded here.

PMID:18456715 SUPPORT Human Clinical

"different anatomic subtypes of DORV were noted in trisomies 13 and 18 versus del 22q11"

Documents that aetiology and anatomic subtype are correlated, which is what makes the missing mechanistic bridge worth resolving.

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Pathophysiology

10

Cardiac Neural Crest and Second Heart Field Disruption

DORV originates in the two extracardiac progenitor populations that build the cardiac outflow tract. Cardiac neural crest cells delaminate from the dorsal neural tube, migrate through the caudal pharyngeal arches into the distal outflow tract and condense to form the aorticopulmonary septum, while second-heart-field progenitors are added to the arterial pole and provide the myocardium that elongates and rotates the outflow tract. Genetic lesions (chromosomal, transcription-factor, planar-cell-polarity, ciliary) and teratogenic exposures that perturb neural crest migration or second-heart-field addition converge on this step. DORV and tetralogy of Fallot are the two conotruncal phenotypes that most directly report this disturbance.

migratory cardiac neural crest cell CL:2000073 cardiac muscle cell CL:0000746

cardiac neural crest cell migration involved in outflow tract morphogenesis GO:0003253 ⚠ ABNORMAL cardiac neural crest cell development involved in outflow tract morphogenesis GO:0061309 ⚠ ABNORMAL

outflow tract UBERON:0004145

Downstream

Failure of Outflow Tract Rotation and Alignment Deficient or disorganised neural crest and second-heart-field contribution leaves the outflow tract unable to elongate and rotate normally.

Persistence of the Subaortic Conus Perturbed conotruncal maturation prevents the normal resorption of the subaortic conal free wall.

Show evidence (4 references)

PMID:38884738 SUPPORT Other

"Tetralogy of Fallot (TOF) and double-outlet right ventricle (DORV) are conotruncal defects resulting from disturbances of the second heart field and the neural crest, which can occur as isolated malformations or as part of multiorgan syndromes."

Directly identifies disturbance of the second heart field and the neural crest as the developmental origin of DORV.

PMID:18456715 SUPPORT Human Clinical

"The large number of genes associated with DORV in both humans and animal models and the different anatomic subtypes seen in specific aetiologies indicate the likelihood of several distinct pathogenetic mechanisms for DORV, including impairment of neural crest derivative migration and impairment..."

Supports impaired neural crest derivative migration as one of the distinct pathogenetic mechanisms of DORV, alongside disturbed situs and looping.

PMID:32511952 SUPPORT Model Organism

"We demonstrate Shroom3 expression within cardiomyocytes of the ventricles and interventricular septum from E10.5 onward, as well as within cardiac neural crest cells and second heart field cells that populate the cardiac outflow tract."

Localises a DORV-causing planar-cell-polarity effector to precisely the cardiac neural crest and second-heart-field populations that build the outflow tract.

+ 1 more reference

Disturbed Left-Right Patterning and Cardiac Looping

A distinct upstream route to DORV runs through the left-right organiser. Motile monocilia at the embryonic node generate leftward flow that establishes the NODAL laterality cascade; failure of this step randomises cardiac looping and the spatial relationship of the great arteries. This is the mechanism behind Van Praagh type III DORV, the form associated with heterotaxy and atrial isomerism, and explains why laterality genes (ZIC3, CFC1, FOXJ1, NODAL-pathway genes) recur in DORV cohorts. Because a randomised or abnormal loop misplaces the ventricles relative to the arterial poles, it produces the same double-outlet connection by a different developmental route than a primary neural-crest defect.

determination of left/right symmetry GO:0007368 ⚠ ABNORMAL heart looping GO:0001947 ⚠ ABNORMAL cilium movement GO:0003341 ↓ DECREASED

Downstream

Failure of Outflow Tract Rotation and Alignment Randomised or abnormal looping misplaces the ventricles relative to the arterial poles, so the outflow tract cannot align normally.

Heterotaxy The same left-right organiser failure that misaligns the outflow tract also randomises visceral and atrial situs.

Complete atrioventricular canal defect Laterality-associated DORV frequently carries a common atrioventricular valve, the atrioventricular canal defect characteristic of atrial isomerism.

Show evidence (4 references)

PMID:37818164 PARTIAL Other

"Since Van Praagh type III DORV is associated with heterotaxy"

Establishes the heterotaxy-associated (laterality) aetiologic class of DORV; PARTIAL because the source goes on to frame the specific laterality genes as predicted candidates rather than established causes.

PMID:37158461 SUPPORT Model Organism

"Complex CHDs revealed by histological analysis include atrioventricular septal defects, DORV, single ventricle defects as well as abnormal position of the great arteries."

Loss of the master motile-cilia transcription factor Foxj1 in mice produces DORV together with abnormal great-artery position, tying ciliary laterality failure to the double-outlet connection.

PMID:37158461 SUPPORT Model Organism

"Finally, we characterize embryonic-stage CHD in Foxj1 loss-of-function mice, demonstrating randomized heart looping."

Directly links disrupted ciliary left-right patterning to randomised cardiac looping, the morphogenetic step that misaligns the arterial poles.

+ 1 more reference

Failure of Outflow Tract Rotation and Alignment

Normally the arterial pole rotates during looping so the aorta swings rightward and posteriorly over the left ventricle while the pulmonary trunk is displaced anteriorly and leftward. This rotation is driven in part by asymmetric addition of second-heart-field myocardium at the pulmonary side of the outflow tract, which pushes the pulmonary orifice into a higher, more frontal position relative to the aortic orifice (the "pulmonary push"). Deficient or disorganised right ventricular outflow tract expansion leaves the rotation incomplete, so the aortic root is never transferred across the ventricular septum and remains supported by the right ventricle.

cardiac muscle cell CL:0000746

outflow tract morphogenesis GO:0003151 ⚠ ABNORMAL

outflow tract UBERON:0004145

Downstream

Persistence of the Subaortic Conus Incomplete rotation leaves the aortic root above persistent subaortic conal musculature rather than above the left ventricle.

Double Outlet Ventriculo-Arterial Connection Failure to transfer the aortic root across the ventricular septum leaves both arterial trunks supported by the right ventricle.

Show evidence (3 references)

PMID:22826212 SUPPORT Model Organism

"We postulate that normally the pulmonary trunk and orifice are pushed in a higher and more frontal position relative to the aortic orifice by asymmetric addition of SHF-myocardium."

Describes the second-heart-field-driven rotation mechanism whose failure is proposed here as the alignment defect underlying DORV.

PMID:22826212 PARTIAL Model Organism

"Deficient or disorganized right ventricular OFT expansion might explain cardiac malformations with abnormal position of the great arteries, such as double outlet right ventricle."

Proposes deficient outflow tract expansion and rotation as the explanation for DORV; PARTIAL because the source frames it as a postulate.

PMID:38391276 SUPPORT Other

"DORV is not a disease entity in itself, but rather a vast spectrum of disorders associated with maldevelopment of conal muscle and often abnormal expansion of one the great vessels."

Frames DORV as the consequence of conal maldevelopment and abnormal great-vessel expansion rather than a discrete entity.

Persistence of the Subaortic Conus

In the normal heart the subpulmonary conus persists while the subaortic conal free wall resorbs, allowing the aortic valve to descend into fibrous continuity with the mitral valve. In DORV the subaortic conus characteristically persists, producing bilateral (subaortic and subpulmonary) infundibula and abolishing aorto-mitral fibrous continuity, so the aortic root remains elevated on a muscular sleeve above the right ventricle. This is the conal basis of the classical "50% rule": what is really being measured is whether conal muscle still interposes between the arterial root and the left ventricle. The criterion is not absolute, because DORV also occurs with fibrous continuity between the arterial and atrioventricular valves, so bilateral conus is sufficient but not necessary for the diagnosis.

conus arteriosus morphogenesis GO:0003239 ⚠ ABNORMAL outflow tract septum morphogenesis GO:0003148 ⚠ ABNORMAL

conus arteriosus UBERON:0003983 mitral valve UBERON:0002135

Downstream

Double Outlet Ventriculo-Arterial Connection A persistent muscular subaortic conus keeps the aortic root committed to the right ventricle instead of the left. This route is characteristic but not obligatory, since DORV also occurs with arterial-to-atrioventricular valvar fibrous continuity.

Show evidence (5 references)

PMID:37818164 SUPPORT Other

"Normally, the subaortic conus resorbs and brings the aorta in continuity with the mitral valve"

States the normal developmental event, resorption of the subaortic conus producing aorto-mitral continuity, whose failure defines this node.

PMID:37818164 SUPPORT Other

"In DORV, the subaortic conus frequently persists"

Directly documents persistence of the subaortic conus as the characteristic conal abnormality of DORV.

PMID:38391276 SUPPORT Other

"In this review, we aim to underscore the importance of conal muscle, rather than rules surrounding assignment of great arteries to ventricles."

Supports conal muscle, rather than the arbitrary 50% override rule, as the substantive anatomic determinant in DORV.

+ 2 more references

Double Outlet Ventriculo-Arterial Connection

The defining lesion: both arterial trunks arise entirely or predominantly from the morphologic right ventricle. Because the left ventricle has lost its direct arterial outlet, an interventricular communication is obligatory for viable left ventricular egress; a ventricular septal defect (or, in the setting of an atrioventricular septal defect, the common interventricular communication) is therefore present in almost every case. When the interventricular communication is restrictive or absent, the left ventricle receives no adequate outlet and becomes hypoplastic.

heart right ventricle UBERON:0002080 aorta UBERON:0000947 pulmonary artery UBERON:0002012

Downstream

Outlet Septum Attachment Determines VSD Commitment With both roots on the right ventricle the outlet septum is necessarily a right ventricular structure, and its attachment determines which arterial root the interventricular communication faces.

Double outlet right ventricle The double-outlet ventriculo-arterial connection is the defining anatomic phenotype.

Ventricular septal defect Loss of a direct left ventricular arterial outlet makes an interventricular communication obligatory for viable left ventricular egress.

Show evidence (3 references)

PMID:38134423 SUPPORT Human Clinical

"DORV was defined as a congenital cardiovascular malformation in which both great arteries arise entirely or predominantly from the morphologically right ventricle."

Gives the current consensus (ICD-11) definition of the double-outlet ventriculo-arterial connection modelled by this node.

PMID:37818164 SUPPORT Other

"Each great artery should have 50% or greater of the valve diameter coming from the morphologic RV, and there is almost always an interventricular communication: ventricular septal defect (VSD) or atrioventricular septal defect (AVSD)"

Supports both the double-outlet criterion and the near-obligatory presence of an interventricular communication as the sole left ventricular outlet.

PMID:37818164 SUPPORT Other

"In rare cases, where the interventricular communication is restricted or absent"

Documents the rare variant in which no adequate interventricular communication exists, the situation that drives left ventricular hypoplasia.

Outlet Septum Attachment Determines VSD Commitment

Because both arterial trunks are supported by the right ventricle, the outlet septum is itself a right ventricular structure, and the channel between the ventricles is roofed by the inner heart curvature. It is therefore the attachment of the outlet septum, muscular or fibrous, that determines to which subarterial outlet the interventricular communication is committed: the cranial limb of the septomarginal trabeculation gives a subaortic defect, the caudal limb a subpulmonary defect, and the inner heart curvature a doubly committed defect, while defects lying outside the limbs of the trabeculation are non-committed. This single anatomic variable, rather than the DORV label, determines the streaming physiology and the repair strategy.

interventricular septum UBERON:0002094

Downstream

Obligatory Intracardiac Mixing and VSD-Dependent Streaming The position of the interventricular communication relative to the arterial roots dictates how left ventricular blood streams once it crosses the septum.

Outlet Septum Malalignment and Outflow Tract Obstruction Displacement of the outlet septum toward one arterial root both commits the VSD to the other root and narrows the outflow it encroaches upon.

Left Ventricular Hypoplasia and Loss of Biventricular Repair Substrate A restrictive or remote interventricular communication limits fetal left ventricular filling and ejection, so the left ventricle fails to grow.

Show evidence (4 references)

PMID:27641710 SUPPORT Other

"when both arterial trunks arise exclusively or predominantly from the morphologically right ventricle, the outlet septum, of necessity, is itself a right ventricular structure"

Establishes the anatomic premise that makes outlet-septum attachment the determinant of VSD commitment in DORV.

PMID:27641710 SUPPORT Other

"it is the attachment of the outlet septum, which itself can be muscular or fibrous, which determines the commitment of the interventricular communication to the subarterial outlets"

Directly states the causal relationship modelled by this node.

PMID:37818164 SUPPORT Other

"The location of the VSD in DORV as viewed from the morphologic RV may be subpulmonic, subaortic, doubly committed"

Enumerates the positional categories of the interventricular communication that this node generates.

+ 1 more reference

Obligatory Intracardiac Mixing and VSD-Dependent Streaming

All left ventricular output must traverse the ventricular septal defect into the right ventricle, so systemic and pulmonary venous returns mix obligatorily. The clinical expression depends on where the defect sits. With a subaortic defect, oxygenated left ventricular blood streams preferentially into the adjacent aorta and desaturated right ventricular blood into the pulmonary artery, giving a large-VSD physiology with only mild desaturation but marked pulmonary overcirculation. With a subpulmonary (Taussig-Bing) defect the streaming is reversed: oxygenated blood is directed into the pulmonary artery while desaturated systemic venous blood is ejected into the aorta, producing transposition-like physiology with early profound cyanosis. Any superimposed pulmonary stenosis restricts pulmonary blood flow and shifts even a subaortic defect toward cyanosis.

interventricular septum UBERON:0002094 heart right ventricle UBERON:0002080 heart left ventricle UBERON:0002084

Downstream

Cyanosis Streaming of desaturated systemic venous blood into the aorta, or restricted pulmonary blood flow, produces central cyanosis.

Hypoxemia Obligatory intracardiac mixing lowers systemic arterial oxygen saturation.

Pulmonary Overcirculation and Ventricular Volume Overload When pulmonary outflow is unobstructed, the fall in pulmonary vascular resistance after birth drives a large left-to-right shunt.

Show evidence (3 references)

PMID:38391276 SUPPORT Other

"This anatomic variability directly determines physiology and surgical repair options."

Supports the dependence of DORV physiology on the underlying anatomic variant, the core claim of this node.

PMID:37818164 SUPPORT Other

"patients with subaortic VSD or subpulmonary VSD can have pulmonary over-circulation requiring aggressive diuresis"

Documents pulmonary overcirculation as a direct physiologic consequence of unobstructed VSD-mediated shunting in DORV.

PMID:37818164 PARTIAL Other

"These patients may develop increasing cyanosis over time and may even develop hyper-cyanotic spells like patients with TOF."

Supports progressive cyanosis, including hypercyanotic spells, as the alternative physiologic expression when pulmonary blood flow is restricted.

Outlet Septum Malalignment and Outflow Tract Obstruction

The muscular outlet septum partitions the two infundibula, and its displacement into either outflow tract creates subvalvar obstruction. Deviation into the subpulmonary outflow produces subpulmonary and pulmonary stenosis, the lesion that gives a subaortic-VSD heart its Fallot-type physiology. Deviation into the subaortic outflow, or a subpulmonary VSD that diverts fetal left ventricular flow away from the systemic outlet, produces subaortic stenosis and is associated with hypoplasia of the aortic arch, coarctation and interrupted aortic arch, the lesions that dominate the Taussig-Bing anomaly. Chronic obstruction to right ventricular ejection also drives right ventricular hypertrophy.

outflow tract UBERON:0004145 aorta UBERON:0000947

Downstream

Pulmonic stenosis Deviation of the outlet septum into the subpulmonary outflow narrows the right ventricular outflow tract.

Subvalvular aortic stenosis Deviation of the outlet septum into the subaortic outflow narrows the systemic outlet.

Coarctation of aorta Reduced antegrade fetal flow through the systemic outlet is associated with aortic arch hypoplasia and coarctation, especially in the Taussig-Bing form.

Interrupted aortic arch The most severe expression of the same reduced fetal systemic flow is interruption of the aortic arch.

Right ventricular hypertrophy Chronic pressure load from subvalvar or valvar outflow obstruction produces right ventricular hypertrophy.

Show evidence (4 references)

PMID:37818164 SUPPORT Other

"The displacement of this outlet septum into the aortic or pulmonary out"

Identifies displacement of the muscular outlet septum into either outflow tract as the mechanism generating subvalvar obstruction in DORV.

PMID:37818164 SUPPORT Other

"A subaortic VSD may mean that pulmonary stenosis and small branch pulmonary arteries are likely to develop."

Links the subaortic VSD variant specifically to the development of pulmonary stenosis.

PMID:37818164 SUPPORT Other

"A wide variety of cardiac malformations of the heart may accompany DORV including coarctation of the aorta (CoA)"

Documents aortic coarctation among the associated left-sided obstructive lesions of DORV.

+ 1 more reference

Pulmonary Overcirculation and Ventricular Volume Overload

In the absence of pulmonary stenosis, the postnatal fall in pulmonary vascular resistance allows a torrential left-to-right shunt through the ventricular septal defect and into the pulmonary artery. The resulting pulmonary overcirculation produces tachypnoea, feeding difficulty and failure to thrive within the first weeks of life, ventricular volume overload and congestive heart failure, and, if repair is delayed beyond infancy, progressive pulmonary vascular remodelling and irreversible pulmonary arterial hypertension. This is the rationale for completing biventricular repair within the first six months of life or, when repair must be deferred, for interim pulmonary artery banding.

pulmonary artery UBERON:0002012

Downstream

Congestive heart failure Ventricular volume overload from the large shunt produces congestive heart failure.

Tachypnea Increased pulmonary blood flow and pulmonary congestion produce tachypnoea.

Feeding difficulties Tachypnoea and the increased work of breathing imposed by pulmonary overcirculation interrupt sucking and swallowing, so infants tire and feed poorly.

Failure to thrive The metabolic cost of heart failure combined with feeding difficulty causes poor weight gain.

Pulmonary arterial hypertension Sustained high-flow, high-pressure pulmonary circulation drives obstructive pulmonary vascular remodelling.

Show evidence (2 references)

PMID:37818164 SUPPORT Other

"patients with subaortic VSD or subpulmonary VSD can have pulmonary over-circulation requiring aggressive diuresis"

Documents pulmonary overcirculation and the need for decongestive therapy as a direct consequence of unrestricted shunting in DORV.

PMID:37818164 SUPPORT Other

"At times, this may lead to the need for respiratory support and intubation."

Supports the respiratory consequences of pulmonary overcirculation in DORV infants.

Left Ventricular Hypoplasia and Loss of Biventricular Repair Substrate

When the interventricular communication is restrictive, remote from both arterial roots, or absent, fetal left ventricular filling and ejection are reduced and the left ventricle fails to grow. The same anatomic circumstances that limit left ventricular growth, together with straddling or hypoplastic atrioventricular valves and multiple ventricular septal defects, also make an unobstructed intraventricular baffle impossible. This node is therefore the hinge on which the entire management pathway turns: it converts DORV from a biventricular repair problem into a single-ventricle palliation problem.

heart left ventricle UBERON:0002084

Downstream

Hypoplastic left ventricle Reduced fetal left ventricular flow through a restrictive or remote interventricular communication results in an underdeveloped left ventricle.

Show evidence (3 references)

PMID:37818164 SUPPORT Other

"the LV will show an element of hypoplasia, which can vary from mild to severe"

Documents left ventricular hypoplasia as the consequence of a restricted or absent interventricular communication in DORV.

PMID:37818164 SUPPORT Other

"Contraindications to biventricular repair include severe ventricular hypoplasia, abnormal tricuspid chordae, multiple VSDs, and a straddling mitral valve."

Establishes ventricular hypoplasia and associated valve anomalies as the determinants that preclude biventricular repair.

PMID:17903515 SUPPORT Human Clinical

"Factors discriminating among end-states included younger patient age at presentation (P < .001), lower weight (P < .001), and adequacy of left-sided heart structures, especially the size of the left ventricle (P < .001), aortic arch (P < .001), and mitral valve (P = .004)."

Demonstrates empirically that the adequacy of left-sided structures, especially left ventricular size, determines which definitive end-state a DORV patient reaches.

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Pathograph

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Phenotypes

17

Cardiovascular 5

Ventricular septal defect VERY_FREQUENT Ventricular septal defect HP:0001629

Show evidence (1 reference)

PMID:37818164 SUPPORT Other

"Each great artery should have 50% or greater of the valve diameter coming from the morphologic RV, and there is almost always an interventricular communication: ventricular septal defect (VSD) or atrioventricular septal defect (AVSD)"

Documents the near-universal presence of an interventricular communication in DORV and supports the VERY_FREQUENT frequency band.

Pulmonic stenosis FREQUENT Pulmonic stenosis HP:0001642

Show evidence (1 reference)

PMID:17903515 SUPPORT Human Clinical

"Hypoplastic ventricles were present in 39%, pulmonary stenosis was present in 65%, and aortic arch obstruction was present in 24%."

Quantifies pulmonary stenosis in 65% of a 393-patient DORV cohort, supporting a FREQUENT frequency band.

Coarctation of aorta OCCASIONAL Coarctation of aorta HP:0001680

Show evidence (2 references)

PMID:37818164 SUPPORT Other

"A wide variety of cardiac malformations of the heart may accompany DORV including coarctation of the aorta (CoA)"

Directly lists coarctation of the aorta among the malformations accompanying DORV.

PMID:17903515 SUPPORT Human Clinical

"Hypoplastic ventricles were present in 39%, pulmonary stenosis was present in 65%, and aortic arch obstruction was present in 24%."

Quantifies aortic arch obstruction, of which coarctation is the commonest form, in 24% of a large DORV cohort, supporting the OCCASIONAL band.

Congestive heart failure Congestive heart failure HP:0001635

Show evidence (1 reference)

PMID:37818164 PARTIAL Other

"patients with subaortic VSD or subpulmonary VSD can have pulmonary over-circulation requiring aggressive diuresis"

Documents the congestive physiology requiring diuresis; the source describes pulmonary overcirculation and its decongestive treatment rather than naming congestive heart failure, hence PARTIAL.

Pulmonary arterial hypertension Pulmonary arterial hypertension HP:0002092

No quotable source in the current reference set names the pulmonary hypertension endpoint directly, so no evidence item is asserted; the description is retained as uncited clinical context per the project evidence SOP.

Digestive 1

Feeding difficulties Feeding difficulties HP:0011968

No quotable source in the current reference set names the feeding phenotype directly, so no evidence item is asserted; the description is retained as uncited clinical context per the project evidence SOP, in the same way as the adjacent failure-to-thrive entry.

Integument 1

Cyanosis Cyanosis HP:0000961

Show evidence (1 reference)

PMID:37818164 SUPPORT Other

"These patients may develop increasing cyanosis over time and may even develop hyper-cyanotic spells like patients with TOF."

Directly documents progressive cyanosis and hypercyanotic spells as clinical manifestations of DORV.

Respiratory 2

Hypoxemia Hypoxemia HP:0012418

Show evidence (1 reference)

PMID:37818164 PARTIAL Other

"Consideration should be given to the urgent need for atrial septostomy in a patient who is desaturated and has evidence of a poor cardiac output state."

Documents systemic desaturation as a clinical state requiring urgent intervention in DORV; the source describes desaturation rather than using the term hypoxemia, hence PARTIAL.

Tachypnea Tachypnea HP:0002789

Show evidence (1 reference)

PMID:37818164 PARTIAL Other

"At times, this may lead to the need for respiratory support and intubation."

Documents the respiratory decompensation caused by pulmonary overcirculation in DORV, of which tachypnoea is the earliest sign; the source describes escalating respiratory support rather than naming tachypnoea, hence PARTIAL.

Growth 1

Failure to thrive Failure to thrive HP:0001508

No quotable source in the current reference set states the growth phenotype directly, so no evidence item is asserted; the description is retained as uncited clinical context per the project evidence SOP.

Other 7

Double outlet right ventricle OBLIGATE Double outlet right ventricle HP:0001719

Show evidence (1 reference)

PMID:38134423 SUPPORT Human Clinical

"DORV was defined as a congenital cardiovascular malformation in which both great arteries arise entirely or predominantly from the morphologically right ventricle."

States the defining anatomic criterion, which is the phenotype itself.

Subvalvular aortic stenosis Subvalvular aortic stenosis HP:0001682

Show evidence (1 reference)

PMID:37818164 PARTIAL Other

"leading to subaortic/aortic stenosis, CoA and IAA"

Names subaortic stenosis as a consequence of the reduced fetal left ventricular outflow that accompanies a subpulmonary VSD; PARTIAL because the source states the association without specifying the obstructing structure.

Interrupted aortic arch Interrupted aortic arch HP:0011611

Show evidence (1 reference)

PMID:37818164 SUPPORT Other

"interrupted aortic arch (IAA) and aortic arch obstruction"

Lists interrupted aortic arch among the cardiac malformations accompanying DORV.

Right ventricular hypertrophy Right ventricular hypertrophy HP:0001667

Show evidence (1 reference)

PMID:37818164 SUPPORT Other

"the EKG may show right axis deviation with right ventricular hypertrophy"

Documents right ventricular hypertrophy as an electrocardiographic finding in the commonest DORV subtype.

Hypoplastic left ventricle FREQUENT Hypoplastic left ventricle HP:0004383

Show evidence (2 references)

PMID:17903515 SUPPORT Human Clinical

"Hypoplastic ventricles were present in 39%, pulmonary stenosis was present in 65%, and aortic arch obstruction was present in 24%."

Quantifies ventricular hypoplasia in 39% of a 393-patient DORV cohort, supporting a FREQUENT frequency band.

PMID:37818164 SUPPORT Other

"the LV will show an element of hypoplasia, which can vary from mild to severe"

Directly documents left ventricular hypoplasia in DORV with a restricted or absent interventricular communication.

Heterotaxy Heterotaxy HP:0030853

Show evidence (2 references)

PMID:37818164 SUPPORT Other

"Since Van Praagh type III DORV is associated with heterotaxy"

Directly associates a defined anatomic class of DORV with heterotaxy.

PMID:37818164 SUPPORT Other

"laterality defects such as the heterotaxy syndromes of isomerism of the atrial appendages"

Lists heterotaxy with atrial isomerism among the malformations that accompany DORV.

Complete atrioventricular canal defect Complete atrioventricular canal defect HP:0001674

Show evidence (1 reference)

PMID:37818164 SUPPORT Other

"as well as common AV valves can be found with DORV"

Documents a common atrioventricular valve, the hallmark of a complete atrioventricular canal defect, as an associated lesion of DORV.

🧬

Genetic Associations

12

Chromosomal aneuploidy and copy number variation (Chromosomal abnormality)

relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:18456715 SUPPORT Human Clinical

"Chromosomal abnormalities were present in 61 of the 149 cases of DORV. Trisomies 13 and 18, and del 22q11 were the most commonly associated cytogenetic lesions; different anatomic subtypes of DORV were noted in trisomies 13 and 18 versus del 22q11."

Quantifies the chromosomal burden in DORV and names the specific recurrent cytogenetic lesions and their subtype specificity.

PMID:37818164 SUPPORT Other

"More than 40% of patients with DORV have associated chromosomal abnormalities"

Independently quantifies the proportion of DORV patients with a chromosomal abnormality.

TBX1 (22q11.2 deletion syndrome)

Gene: TBX1 hgnc:11592 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:37818164 SUPPORT Other

"22q11.2 deletion syndrome presents in 7% of DORV individuals"

Quantifies the frequency of 22q11.2 deletion among DORV patients.

PMID:38884738 PARTIAL Other

"while mutations of TBX5 and 22q11 deletion, leading to haploinsufficiency of TBX1, cause Holt-Oram and DiGeorge syndrome, respectively."

Attributes the 22q11 deletion phenotype to TBX1 haploinsufficiency; the statement is made in a chapter covering both tetralogy of Fallot and DORV and is not DORV-exclusive, hence PARTIAL.

ZIC3 (X-linked laterality defect with isolated DORV)

Gene: ZIC3 hgnc:12874 relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (2 references)

PMID:23427188 SUPPORT Human Clinical

"Three potentially disease-related missense mutations were detected: c.49G > T (Gly17Cys) in a female with isolated DORV"

Reports a specific ZIC3 missense variant in a patient with isolated DORV.

PMID:23427188 SUPPORT Human Clinical

"ZIC3 mutations were rarely identified in isolated DORV and d-TGA suggesting that a subset of DORV and d-TGA may fall within the spectrum of laterality defects."

Establishes both the rarity of ZIC3 variants in isolated DORV and their mechanistic significance as evidence for a laterality-defect route to DORV.

CFC1 (Laterality-pathway (NODAL co-receptor) variants)

Gene: CFC1 hgnc:18292 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:18456715 SUPPORT Human Clinical

"Mutations and non-synonymous sequence variants in the CFC1 and CSX genes were the most commonly reported monogenic loci associated with DORV in humans; numerous genes are reported in murine models of DORV."

Identifies CFC1 as one of the two most frequently reported monogenic loci in human DORV.

NKX2-5 (Cardiac transcription factor variants)

Gene: NKX2-5 hgnc:2488 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:18456715 SUPPORT Human Clinical

"Mutations and non-synonymous sequence variants in the CFC1 and CSX genes were the most commonly reported monogenic loci associated with DORV in humans; numerous genes are reported in murine models of DORV."

Identifies CSX, the former name of NKX2-5, as one of the two most frequently reported monogenic loci in human DORV.

GATA4 (Endocardial cushion developmental defect (Van Praagh type II DORV))

Gene: GATA4 hgnc:4173 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:37818164 SUPPORT Other

"Van Praagh type II DORV may be related to the consequence of developmental abnormalities of the endocardial cushions such as mutations in GATA4"

Attributes a defined anatomic class of DORV to endocardial cushion defects including GATA4 mutation.

PMID:29468350 SUPPORT In Vitro

"Furthermore, the mutation significantly reduced the synergistic activation between MEF2C and GATA4, another transcription factor linked to CHD."

Demonstrates functionally that GATA4 acts in synergy with MEF2C and that loss of this synergy accompanies a DORV-causing variant.

MEF2C (Autosomal dominant DORV with ventricular septal defect)

Gene: MEF2C hgnc:6996 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:29468350 SUPPORT Human Clinical

"As a result, a novel heterozygous MEF2C mutation, p.R15C, was detected in an index patient with congenital double outlet right ventricle (DORV) as well as ventricular septal defect."

Reports the specific MEF2C variant identified in a DORV proband.

PMID:29468350 SUPPORT In Vitro

"Functional deciphers revealed that the mutant MEF2C protein had a significantly decreased transcriptional activity."

Provides the functional loss-of-function evidence supporting pathogenicity of the MEF2C variant.

TBX20 (Autosomal dominant DORV)

Gene: TBX20 hgnc:11598 relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (2 references)

PMID:25625280 SUPPORT Human Clinical

"Genetic analyses of the pedigree of the proband revealed that in the family, the mutation co-segregated with DORV transmitted in an autosomal dominant pattern with complete penetrance."

Establishes autosomal dominant segregation of the TBX20 variant with DORV in a family.

PMID:25625280 SUPPORT In Vitro

"Functional analysis revealed that mutant TBX20 had a significantly diminished transcriptional activity compared with its wild-type counterpart."

Provides the loss-of-function evidence supporting pathogenicity of the TBX20 variant.

CHD7 (CHARGE syndrome (epigenetic regulator))

Gene: CHD7 hgnc:20626 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:37818164 SUPPORT Other

"mutations in the CHD7 genes result in CHARGE association with the perturbation of the H3K4 methylation"

Identifies CHD7 mutation as the cause of CHARGE association and names the epigenetic mechanism involved.

PMID:37818164 SUPPORT Other

"Congenital heart defects occur in 75% –80% of the patients with CHARGE association including DORV"

Quantifies the congenital heart defect burden of CHARGE association and names DORV explicitly among the defects that occur in it.

LRP1 (Cardiac neural crest lineage perturbation (mouse model of DORV))

Gene: LRP1 hgnc:6692 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:37818164 SUPPORT Model Organism

"our group previously reported the evidence of the perturbance of cardiac neural crest lineage that resulted in DORV in a mouse model of Lrp1 mutation"

Reports an Lrp1 mouse model in which cardiac neural crest perturbation produces DORV.

FOXJ1 (Motile ciliopathy gene causing isolated congenital heart defects)

Gene: FOXJ1 hgnc:3816 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:37158461 SUPPORT Human Clinical

"Here, we report a novel truncating FOXJ1 variant (c.784_799dup; p.Glu267Glyfs*12) identified by clinical exome sequencing from a patient with isolated congenital heart defects (CHD) which included atrial and ventricular septal defects, double outlet right ventricle (DORV) and transposition of..."

Reports the specific FOXJ1 variant identified in a patient whose phenotype included DORV.

PMID:37158461 PARTIAL Human Clinical

"Variant analysis of patients with heterotaxy or heterotaxy-related CHD indicates that pathogenic variants in FOXJ1 are an infrequent cause of heterotaxy."

Bounds the contribution of FOXJ1, supporting its classification as a rare rather than common cause of DORV.

SHROOM3 (Planar cell polarity effector; DORV in mouse loss-of-function models)

Gene: SHROOM3 hgnc:30422 relationship_type: SUSCEPTIBILITY

Show evidence (2 references)

PMID:32511952 SUPPORT Model Organism

"We demonstrate that Shroom3gt/gt mice exhibit variable penetrance of a spectrum of CHDs that include ventricular septal defects, double outlet right ventricle, and thin left ventricular myocardium."

Demonstrates that loss of Shroom3 produces DORV in a mouse model.

PMID:32511952 PARTIAL Human Clinical

"We previously implicated a novel CHD candidate gene, SHROOM3, in a patient with CHD."

Records the human evidence as candidate-level, which is why this entry is typed as a susceptibility rather than a causative locus.

💊

Medical Actions

10

Prostaglandin E1

Action: Pharmacotherapy NCIT:C15986

Agent: prostaglandin E1 CHEBI:15544

Intravenous prostaglandin E1 maintains ductal patency after birth, preserving pulmonary blood flow in DORV with severe pulmonary stenosis or atresia and systemic perfusion when there is aortic arch obstruction. It is a bridge to definitive repair rather than a treatment of the anatomy.

Show evidence (2 references)

PMID:37818164 SUPPORT Other

"prostaglandin E1 infusion and/or atrial septostomy should be considered"

Identifies prostaglandin E1 as the pharmacologic intervention when pulmonary blood flow is inadequate in DORV.

PMID:37818164 SUPPORT Other

"These patients will need their patent ductus arteriosus (PDA) to be kept patent, either with prostaglandin E1 administration or PDA stent placement"

Confirms maintenance of ductal patency with prostaglandin E1 (or a ductal stent) as standard preoperative management.

Diuretic therapy for pulmonary overcirculation

Action: Pharmacotherapy NCIT:C15986

Agent: furosemide CHEBI:47426

Aggressive diuresis is used to control the pulmonary overcirculation and congestive physiology of DORV with an unobstructed pulmonary outflow while awaiting repair; escalation to respiratory support and intubation may be required.

Mechanism Target:

INHIBITS Pulmonary Overcirculation and Ventricular Volume Overload — Diuresis reduces the volume load and pulmonary congestion generated by the large left-to-right shunt without altering the underlying anatomy.

Show evidence (1 reference)

PMID:37818164 SUPPORT Other

"patients with subaortic VSD or subpulmonary VSD can have pulmonary over-circulation requiring aggressive diuresis"

Directly documents diuresis as the medical management of pulmonary overcirculation in DORV.

Palliative control of pulmonary blood flow

Action: Cardiac Therapeutic Procedure NCIT:C80430

Interim procedures used before definitive repair, or as the first stage of a single-ventricle pathway, to balance pulmonary and systemic flow: pulmonary artery banding when there is overcirculation, and a systemic-to-pulmonary (central) shunt or ductal stent when pulmonary blood flow is inadequate. Balloon atrial septostomy is used urgently when a desaturated infant has inadequate atrial-level mixing and a poor cardiac output state.

Mechanism Target:

MODULATES Obligatory Intracardiac Mixing and VSD-Dependent Streaming — Banding, shunting or septostomy rebalances the ratio of pulmonary to systemic flow without correcting the underlying connection.

Show evidence (2 references)

PMID:37818164 SUPPORT Other

"Such palliative procedures include PA band placement for babies with pulmonary over-circulation, PDA stent, or operative central shunt creation for those with inadequate pulmonary blood"

Enumerates the palliative flow-control procedures used in DORV and the physiology each addresses.

PMID:37818164 SUPPORT Other

"Consideration should be given to the urgent need for atrial septostomy in a patient who is desaturated and has evidence of a poor cardiac output state."

Documents the indication for urgent balloon atrial septostomy in DORV.

Kawashima procedure

Action: Cardiac Surgery NCIT:C157806

An intraventricular repair for DORV-TGA in which the ventricular septal defect is baffled to the aortic valve with patch enlargement of the ventriculotomy, after complete resection of the conus. It suits patients with side-by-side great arteries whose coronary anatomy precludes root translocation, and patients whose pulmonary valve is not of adequate size to support the systemic circulation.

Mechanism Target:

INHIBITS Persistence of the Subaortic Conus — Complete resection of the conus removes the muscular sleeve that separates the left ventricle from the aortic valve, allowing the VSD to be rerouted to the aorta.

Show evidence (2 references)

PMID:37818164 SUPPORT Other

"The Kawashima procedure: The VSD is baf"

Names the Kawashima procedure as one of the defined anatomic repairs for DORV-TGA.

PMID:37818164 SUPPORT Other

"In this case, the conus should be resected completely to allow rerouting the VSD to the aortic valve"

Describes the conal resection that is the mechanistic core of the procedure.

Intraventricular baffle repair

Action: Cardiac Surgery NCIT:C157806

The standard biventricular repair for a committed ventricular septal defect: a patch tunnel is constructed from the left ventricle through the VSD to the aortic valve, restoring a series circulation. For a perimembranous or subaortic defect the tunnel is relatively straight and can usually be built through the right atrium; for a doubly committed defect a right ventriculotomy or transpulmonary approach is generally required. A restrictive VSD is enlarged by resecting the ventriculo-infundibular fold and conal septum to prevent late subaortic obstruction. Repair is recommended within the first six months of life to limit the effects of pulmonary overcirculation.

Mechanism Target:

INHIBITS Obligatory Intracardiac Mixing and VSD-Dependent Streaming — The baffle abolishes obligatory intracardiac mixing by giving the left ventricle a dedicated outlet to the aorta.

Show evidence (2 references)

PMID:37818164 SUPPORT Other

"When the VSD is perimembranous or subaortic, a relatively straight intraventricular tunnel can be created between the VSD and the aortic valve"

Describes the intraventricular baffle repair and the anatomy for which it is most straightforward.

PMID:38134423 SUPPORT Human Clinical

"Overall survival at 10 years was 86%. This study shows a trend towards satisfactory early and late outcomes in BVR of simple DORV with committed VSD, compared to complex DORV with ncVSD."

Provides late outcome data for biventricular repair and shows the advantage of a committed VSD over a non-committed one.

Arterial switch operation with VSD-to-pulmonary-root baffle

Action: Cardiac Surgery NCIT:C157806

The preferred anatomic repair for the Taussig-Bing (subpulmonary VSD) form, and also used for selected non-committed VSDs. The ventricular septal defect is baffled to the pulmonary root, which then becomes the neo-aorta after the great arteries are transected and switched with coronary transfer, so the intraventricular tunnel is short and does not impinge on the tricuspid valve. Concomitant aortic arch repair is required in a large minority. In the largest reported single-centre series (225 children) early mortality was 12.9 per cent with 10-year survival of 85 per cent; a smaller 34-patient series reported 11 per cent hospital mortality. Reintervention, most often for pulmonary stenosis, is common.

Mechanism Target:

INHIBITS Obligatory Intracardiac Mixing and VSD-Dependent Streaming — Switching the arterial trunks after baffling the VSD to the pulmonary root restores concordant ventriculo-arterial connections and abolishes the transposition-like streaming of the Taussig-Bing anomaly.

Show evidence (4 references)

PMID:37818164 SUPPORT Other

"this is the most common surgical repair when the pulmonary valve is suitable for systemic circulation"

Identifies the VSD-to-pulmonary-artery baffle plus arterial switch as the most common repair for the transposition-type DORV.

PMID:35691468 SUPPORT Human Clinical

"Early mortality was 12.9% (29/225) with a satisfactory long-term survival rate (10-year survival rate 85.0%)."

Provides early mortality and 10-year survival for primary arterial switch in the Taussig-Bing anomaly.

PMID:35691468 SUPPORT Human Clinical

"87 children (38.7%) received concomitant aortic arch repair."

Quantifies the frequency of concomitant aortic arch repair, reflecting the arch obstruction characteristic of this subtype.

+ 1 more reference

Rastelli-type repair with right ventricle to pulmonary artery conduit

Action: Cardiac Surgery NCIT:C157806

When pulmonary outflow obstruction is valvar and the pulmonary valve cannot support the systemic circulation, the ventricular septal defect is baffled to the aorta and right ventricle to pulmonary artery continuity is restored with a valved conduit (Rastelli) or, in the REV variant, by direct anastomosis of the pulmonary trunk to the infundibulum after a LeCompte manoeuvre. Somatic outgrowth and stenosis of the conduit make reoperation predictable, and Rastelli-type repair carries higher late mortality and reintervention risk than other pathways.

Mechanism Target:

BYPASSES Outlet Septum Malalignment and Outflow Tract Obstruction — A valved right ventricle to pulmonary artery conduit bypasses the obstructed native right ventricular outflow tract.

Show evidence (2 references)

PMID:37818164 SUPPORT Other

"The Rastelli procedure: It is one that includes closing the VSD to the aorta and placing a valved RV to PA conduit for RVOT reconstruction."

Defines the Rastelli procedure as used in DORV.

PMID:17903515 SUPPORT Human Clinical

"For complex double-outlet right ventricle, Rastelli-type repair increased early reintervention risk (P = .04) and late post-repair mortality (P = .02), whereas the arterial switch operation increased early post-repair mortality (P = .02) with a benefit of improved late post-repair survival."

Quantifies the reintervention and late mortality penalty of Rastelli-type repair relative to the arterial switch in complex DORV.

Nikaidoh procedure and root translocation

Action: Cardiac Surgery NCIT:C157806

Posterior translocation of the aortic root, or double root translocation, creates a straight left ventricular outflow tract when routing the VSD to the aorta is not possible or would require a long akinetic tunnel at risk of late subaortic stenosis. It is favoured for remote ventricular septal defects, straddling atrioventricular valves and significant right ventricular hypoplasia. A pulmonary annulus smaller than 5 mm and a coronary artery crossing the right ventricular outflow tract at the transection level are contraindications.

Mechanism Target:

RESTORES Double Outlet Ventriculo-Arterial Connection — Translocating the aortic root posteriorly re-establishes a direct left ventricle to aorta connection rather than tunnelling around the defect.

Show evidence (2 references)

PMID:37818164 SUPPORT Other

"A Nikaidoh procedure may result in a more acceptable anatomic repair with better alignment between the LV and the aorta and preservation of the right ventricular volume"

States the anatomic rationale for the Nikaidoh root translocation in DORV.

PMID:37818164 SUPPORT Other

"we do not offer a Nikaidoh procedure to patients with a pulmonary annulus size of less than 5 mm"

Documents a specific anatomic contraindication to the procedure.

Single-ventricle palliation

Action: Cardiac Surgery NCIT:C157806

When a safe biventricular route cannot be constructed, staged univentricular palliation is used: initial control of pulmonary blood flow with a systemic-to-pulmonary shunt, ductal stent or pulmonary artery band, then a bidirectional cavopulmonary connection, then total cavopulmonary (Fontan) completion at two to three years of age. Any restrictive ventricular septal defect should be enlarged at or before Fontan completion.

Mechanism Target:

BYPASSES Left Ventricular Hypoplasia and Loss of Biventricular Repair Substrate — Staged cavopulmonary palliation works around the inadequate left ventricle rather than attempting to recruit it into a biventricular circulation.

Show evidence (2 references)

PMID:37818164 SUPPORT Other

"Contraindications to biventricular repair include severe ventricular hypoplasia, abnormal tricuspid chordae, multiple VSDs, and a straddling mitral valve."

Defines the anatomic circumstances that select patients into the single-ventricle pathway.

PMID:37818164 SUPPORT Other

"a bidirectional cavopulmonary connection is created"

Documents the staged cavopulmonary sequence of the univentricular pathway in DORV.

Genetic evaluation and counselling

Action: Genetic Counseling NCIT:C15240

Because more than 40 per cent of DORV patients have a chromosomal abnormality and syndromic and laterality disorders are common, clinical genetics assessment with chromosomal microarray, and exome or genome sequencing when microarray is non-diagnostic, is part of standard care. It informs recurrence counselling, prognosis and extracardiac surveillance rather than altering the cardiac repair.

Show evidence (1 reference)

PMID:37818164 SUPPORT Other

"More than 40% of patients with DORV have associated chromosomal abnormalities"

Establishes the high prior probability of a chromosomal diagnosis that justifies routine genetic evaluation in DORV.

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Environmental Factors

2

Maternal diabetes mellitus

Maternal diabetes is a recurrently reported non-genetic risk factor for DORV in both the human case literature and animal studies of DORV teratogenesis.

Show evidence (1 reference)

PMID:18456715 SUPPORT Model Organism

"Animal studies implicate maternal diabetes and prenatal exposure to ethanol, retinoids, theophylline, and valproate in DORV teratogenesis."

Names maternal diabetes among the exposures implicated in DORV teratogenesis; the supporting studies cited are animal studies, hence MODEL_ORGANISM.

Prenatal teratogen exposure

Prenatal exposure to ethanol, retinoids, theophylline and valproate has been implicated in DORV teratogenesis in animal studies. Retinoic acid is particularly plausible mechanistically because tightly bounded retinoic acid signalling is required to maintain and differentiate the second-heart-field progenitors that elongate and septate the outflow tract, so both deficient and excessive signalling perturb the same morphogenetic step that DORV reports.

Show evidence (1 reference)

PMID:18456715 SUPPORT Model Organism

"Animal studies implicate maternal diabetes and prenatal exposure to ethanol, retinoids, theophylline, and valproate in DORV teratogenesis."

Directly names the teratogenic exposures implicated in DORV in animal studies.

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Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Double Outlet Right Ventricle:

Tetralogy of Fallot Not Yet Curated MONDO:0008542

Overlapping Features Tetralogy of Fallot and DORV are not cleanly separable entities: they share a developmental origin in the second heart field and cardiac neural crest, and the boundary between "tetralogy with an overriding aorta" and "DORV with a subaortic or doubly committed VSD and pulmonary stenosis" is set by an arbitrary degree of aortic override rather than by a difference in mechanism. The DORV-Fallot subtype of this entry occupies exactly that overlap, and its physiology and repair (VSD-to-aorta baffle with relief of right ventricular outflow tract obstruction) are those of tetralogy. Overlap can be complete: tetralogy with pulmonary atresia and a single outlet from the right ventricle also satisfies the morphologic definition of DORV.

Distinguishing Features

Degree of aortic override is the operative discriminator; commonly a 50 per cent threshold is applied, but the threshold is conventional rather than mechanistic and different groups apply it differently.
Aortic-to-mitral fibrous continuity is classically retained in tetralogy and classically lost in DORV, but this criterion is unreliable because DORV with preserved arterial-to-atrioventricular valvar continuity is the more common form of DORV.
Bilateral (subaortic and subpulmonary) infundibula favour DORV; a single subpulmonary infundibulum with a resorbed subaortic conus favours tetralogy.
The distinction does not change the operation when the VSD is subaortic and pulmonary stenosis is present, which is why DORV-Fallot outcomes track tetralogy outcomes.

Show evidence (2 references)

PMID:38884738 SUPPORT Human Clinical

"Tetralogy of Fallot (TOF) and double-outlet right ventricle (DORV) are conotruncal defects resulting from disturbances of the second heart field and the neural crest, which can occur as isolated malformations or as part of multiorgan syndromes."

Establishes that the two conditions on either side of this differential share a developmental mechanism, which is why the boundary between them is definitional rather than mechanistic.

PMID:37818164 SUPPORT Human Clinical

"One example would be TOF with DORV and pulmonary atresia."

Documents that a heart can simultaneously satisfy the tetralogy and the DORV definitions, demonstrating that the two categories overlap rather than exclude one another.

Dextro-looped transposition of the great arteries with ventricular septal defect MONDO:0019443

Overlapping Features d-TGA with a VSD is the principal differential for the subpulmonary (Taussig-Bing) subtype, because both produce transposition-like physiology in the newborn: the aorta receives desaturated right ventricular blood and the pulmonary artery receives the oxygenated left ventricular stream. The distinction is one of ventriculo-arterial connection. In d-TGA both connections are discordant, whereas in DORV the aorta is discordant but the pulmonary artery remains concordant with the right ventricle. Where the pulmonary valve overrides the septal crest, the assignment turns on how much of the valve sits over each ventricle, so the same heart may be called Taussig-Bing DORV or d-TGA with an overriding pulmonary artery depending on the override threshold used.

Distinguishing Features

In d-TGA both ventriculo-arterial connections are discordant; in DORV the aorta is discordant while the pulmonary artery is concordant.
When the pulmonary valve overrides, the lesion is called d-TGA if more than half the valve sits above the morphologic left ventricle, and Taussig-Bing DORV if more than half sits above the right ventricle.
Pulmonary-to-mitral fibrous continuity is present in d-TGA with a perimembranous VSD and an overriding pulmonary artery, and absent in the Taussig-Bing malformation.
Both are treated by an arterial switch, but the Taussig-Bing variant additionally requires a baffle routing the VSD to the pulmonary root and carries a high burden of aortic arch obstruction and coronary anomaly.

Show evidence (3 references)

PMID:37818164 SUPPORT Human Clinical

"In contrast, in DORV, the aorta has a discordant connection while the PA has a concordant connection."

States the connection-level criterion that separates DORV from transposition of the great arteries.

PMID:37818164 SUPPORT Human Clinical

"If the majority, more than 50%, of the pulmonary valve sits above the morphologic LV, this would be considered a TGA because the pulmonary trunk has a discordant ventriculo-arterial connection."

Shows that the DORV-versus-TGA assignment for an overriding pulmonary valve is decided by a proportional override threshold.

PMID:37818164 SUPPORT Human Clinical

"In TGA with a perimembranous VSD and overriding PA, the pulmonary –mitral continuity is present, whereas in the Taussig –Bing malformation, the pulmonary–mitral continuity is absent."

Gives the morphologic feature used at the bedside to separate Taussig-Bing DORV from transposition with an overriding pulmonary artery.

🔬

Clinical Trials

1

NCT00972608 NOT_APPLICABLE COMPLETED

Prospective observational study (n = 66, completed) registered for the condition "Double Outlet Right Ventricle", developing and validating an image-based virtual surgical planning protocol: patient MRI, 3D echocardiography and CT are reconstructed into 3D anatomy, candidate repairs are simulated on the model, and the chosen virtual plan is compared against the operation actually performed on postoperative imaging. It is the trial counterpart of the CMR-based baffle-planning workflow captured under diagnosis.

Target Phenotypes: Double outlet right ventricle HP:0001719 Ventricular septal defect HP:0001629

Show evidence (2 references)

clinicaltrials:NCT00972608 SUPPORT Human Clinical

"assess the feasibility of using surgical planning in the treatment of patients with complex cardiac defects"

States the objective of the trial, whose single registered condition on ClinicalTrials.gov is Double Outlet Right Ventricle.

clinicaltrials:NCT00972608 SUPPORT Human Clinical

"Use the developed protocol to prospectively plan and evaluate the possible surgical options for new patients."

Documents the prospective surgical-planning aim that makes this trial relevant to the anatomy-driven repair decision in DORV.

{ }

Source YAML

click to show

name: Double Outlet Right Ventricle
creation_date: "2026-07-31T00:00:00Z"
description: >-
  Double outlet right ventricle (DORV) is a conotruncal ventriculo-arterial
  connection anomaly in which both great arteries arise entirely or
  predominantly from the morphologic right ventricle, so that a ventricular
  septal defect is the only outlet from the left ventricle. DORV is a purely
  morphologic descriptor rather than a single physiologic entity: it corrals a
  broad spectrum of phenotypes whose presentation, repair strategy and prognosis
  are determined not by the DORV label but by the position of the ventricular
  septal defect relative to the arterial roots (subaortic, subpulmonary, doubly
  committed, or non-committed/remote), the spatial relationship of the great
  arteries, and the presence and level of outflow tract obstruction.
  Developmentally DORV arises from disturbed cardiac neural crest migration and
  second-heart-field-driven outflow tract elongation and rotation, with failure
  of subaortic conal absorption so that aorto-mitral fibrous continuity is
  characteristically, though not obligately, absent and both arterial trunks
  remain committed to the right ventricle.
  The resulting obligatory intracardiac mixing expresses itself either as
  cyanosis (subpulmonary VSD, or any VSD with pulmonary stenosis) or as
  pulmonary overcirculation and heart failure (subaortic VSD without pulmonary
  stenosis). Management is anatomy-driven: intraventricular baffle repair for a
  committed VSD, arterial switch with a VSD-to-pulmonary-root baffle for the
  Taussig-Bing (subpulmonary VSD) form, Rastelli/REV or Nikaidoh root
  translocation when the pulmonary valve cannot support the systemic
  circulation, and staged single-ventricle palliation when a safe biventricular
  route cannot be constructed.
category: Complex
parents:
- Congenital heart defect
- Conotruncal defect
synonyms:
- DORV
- double-outlet right ventricle
- double outlet of right ventricle
disease_term:
  preferred_term: double outlet right ventricle
  term:
    id: MONDO:0018089
    label: double outlet right ventricle
has_subtypes:
- name: Subaortic VSD
  subtype_term:
    preferred_term: double outlet right ventricle with subaortic or doubly committed ventricular septal defect
    term:
      id: MONDO:0018498
      label: double outlet right ventricle with subaortic or doubly committed ventricular septal defect
  display_name: DORV with subaortic ventricular septal defect (VSD type)
  review_notes: >-
    MONDO ontology limitation, not a curation error: MONDO:0018498 lumps the
    subaortic and doubly committed defects into a single class, so this subtype
    and the separately curated "Doubly committed VSD" subtype necessarily share
    the same disease_term. They are kept as distinct dismech subtypes because they
    differ in outlet-septum attachment, frequency (47% versus 4%) and surgical
    approach. A split request to MONDO would be needed to bind them separately.
  description: >-
    The most common form. The outlet septum attaches to the cranial (anterosuperior)
    limb of the septomarginal trabeculation, so the interventricular communication
    lies beneath the aortic root. Left ventricular blood streams preferentially to
    the aorta, giving a physiology resembling a large isolated ventricular septal
    defect: relatively well-saturated systemic flow with pulmonary overcirculation
    and congestive heart failure when pulmonary stenosis is absent. Repair is
    typically a straightforward intraventricular baffle tunnelling the left
    ventricle through the VSD to the aortic valve.
  evidence:
  - reference: PMID:27641710
    reference_title: "How should we diagnose and differentiate hearts with double-outlet right ventricle?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The defect is subaortic when the outlet septum is attached to the cranial
      limb of the trabeculation, subpulmonary when attached to the caudal limb,
      and doubly committed when attached to the inner heart curvature in the roof
      of the defect.
    explanation: >-
      Defines the subaortic subtype by the anatomic criterion used here, namely
      attachment of the outlet septum to the cranial limb of the septomarginal
      trabeculation.
  - reference: PMID:17903515
    reference_title: "Determinants of repair type, reintervention, and mortality in 393 children with double-outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Double-outlet right ventricle classification was as follows: subaortic
      ventricular septal defect with or without pulmonary stenosis in 47%,
      subpulmonic ventricular septal defect in 23%, noncommitted ventricular
      septal defect in 26%, and doubly committed ventricular septal defect in 4%.
    explanation: >-
      Quantifies the subaortic VSD subtype as the most frequent form (47%) in a
      large single-institution DORV cohort.
- name: DORV-Fallot
  subtype_term:
    preferred_term: double outlet right ventricle with subaortic or doubly committed ventricular septal defect with pulmonary stenosis
    term:
      id: MONDO:0020386
      label: double outlet right ventricle with subaortic or doubly committed ventricular septal defect with pulmonary stenosis
  display_name: DORV with subaortic or doubly committed VSD and pulmonary stenosis (Fallot type)
  description: >-
    A physiologic variant of the committed-VSD forms in which pulmonary stenosis
    accompanies a subaortic or doubly committed ventricular septal defect. Because
    the outlet septum is deviated anterosuperiorly into the subpulmonary outflow,
    the physiology and surgical logic mirror tetralogy of Fallot: cyanosis rather
    than overcirculation, hypercyanotic spells, and repair combining an
    intraventricular baffle to the aorta with relief of right ventricular outflow
    tract obstruction.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A subaortic VSD may mean that pulmonary stenosis and small branch pulmonary
      arteries are likely to develop.
    explanation: >-
      Links the subaortic VSD anatomy to the development of pulmonary stenosis,
      which is what converts a VSD-type DORV into the Fallot-type physiology.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The surgical outcomes of DORV-Fallot are like those achieved in the TOF,
      with operative mortality between 0% and 5%.
    explanation: >-
      Confirms DORV-Fallot as a recognised surgical category whose outcomes track
      those of tetralogy of Fallot.
- name: Subpulmonary VSD
  subtype_term:
    preferred_term: double outlet right ventricle with subpulmonary ventricular septal defect
    term:
      id: MONDO:0020387
      label: double outlet right ventricle with subpulmonary ventricular septal defect
  display_name: DORV with subpulmonary VSD (Taussig-Bing anomaly, TGA type)
  description: >-
    The Taussig-Bing anomaly. The outlet septum attaches to the caudal
    (posteroinferior) limb of the septomarginal trabeculation, placing the
    interventricular communication beneath the pulmonary root, with the pulmonary
    valve overriding the crest of the ventricular septum by more than 50% and
    bilateral conus. Left ventricular blood streams preferentially into the
    pulmonary artery while systemic venous return is directed to the aorta, so the
    physiology is transposition-like with early severe cyanosis. Aortic arch
    obstruction (coarctation or interrupted arch) and coronary anomalies are
    frequent. Repair is an arterial switch operation combined with a
    VSD-to-pulmonary-root baffle, with concomitant arch repair when needed.
  evidence:
  - reference: PMID:27641710
    reference_title: "How should we diagnose and differentiate hearts with double-outlet right ventricle?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The defect is subaortic when the outlet septum is attached to the cranial
      limb of the trabeculation, subpulmonary when attached to the caudal limb,
      and doubly committed when attached to the inner heart curvature in the roof
      of the defect.
    explanation: >-
      Defines the subpulmonary subtype anatomically by attachment of the outlet
      septum to the caudal limb of the septomarginal trabeculation.
  - reference: PMID:32795522
    reference_title: "Anatomic Risk Factors for Reintervention After Arterial Switch Operation for Taussig-Bing Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aortic arch obstruction and coronary anomalies were present in 64% and 41%
      of patients, respectively.
    explanation: >-
      Documents the high burden of aortic arch obstruction and coronary anomalies
      that distinguishes the Taussig-Bing subtype and complicates its repair.
- name: Doubly committed VSD
  subtype_term:
    preferred_term: double outlet right ventricle with subaortic or doubly committed ventricular septal defect
    term:
      id: MONDO:0018498
      label: double outlet right ventricle with subaortic or doubly committed ventricular septal defect
  display_name: DORV with doubly committed (juxta-arterial) ventricular septal defect
  review_notes: >-
    MONDO ontology limitation, not a curation error: MONDO:0018498 is a lumped
    class covering both subaortic and doubly committed defects, so this subtype
    shares its disease_term with the "Subaortic VSD" subtype above. See the note
    on that subtype.
  description: >-
    The rarest positional subtype. The outlet septum is deficient or fibrous and
    attaches to the inner heart curvature in the roof of the defect, so the
    interventricular communication lies immediately beneath both semilunar valves,
    which are in fibrous continuity with one another. An intraventricular tunnel is
    still feasible but usually requires a right ventriculotomy or transpulmonary
    approach because the baffle must be anchored to the fibrous tissue between the
    aortic and pulmonary annuli, with a risk of semilunar valve distortion.
  evidence:
  - reference: PMID:27641710
    reference_title: "How should we diagnose and differentiate hearts with double-outlet right ventricle?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The defect is subaortic when the outlet septum is attached to the cranial
      limb of the trabeculation, subpulmonary when attached to the caudal limb,
      and doubly committed when attached to the inner heart curvature in the roof
      of the defect.
    explanation: >-
      Defines the doubly committed subtype by attachment of the outlet septum to
      the inner heart curvature roofing the defect.
  - reference: PMID:17903515
    reference_title: "Determinants of repair type, reintervention, and mortality in 393 children with double-outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Double-outlet right ventricle classification was as follows: subaortic
      ventricular septal defect with or without pulmonary stenosis in 47%,
      subpulmonic ventricular septal defect in 23%, noncommitted ventricular
      septal defect in 26%, and doubly committed ventricular septal defect in 4%.
    explanation: >-
      Establishes the doubly committed VSD as the rarest positional subtype (4%)
      in a large clinical DORV series.
- name: Non-committed VSD
  subtype_term:
    preferred_term: double outlet right ventricle with non-committed subpulmonary ventricular septal defect
    term:
      id: MONDO:0020388
      label: double outlet right ventricle with non-committed subpulmonary ventricular septal defect
  display_name: DORV with non-committed (remote) ventricular septal defect
  review_notes: >-
    MONDO ontology limitation, not a curation error: the label of MONDO:0020388 is
    "double outlet right ventricle with non-committed subpulmonary ventricular
    septal defect", which reads oddly because a non-committed (remote) defect is
    by definition not subpulmonary. It is nevertheless the only MONDO class for
    the non-committed form, so it is used here; the dismech description carries
    the correct anatomic definition. Correcting the MONDO label would require an
    upstream ontology request.
  description: >-
    The interventricular communication lies outside the limbs of the septomarginal
    trabeculation, typically in the inlet or apical trabecular septum, and is
    therefore remote from both arterial roots. This is the most surgically
    difficult subtype: a baffle must traverse a long, tortuous course at risk of
    obstructing the tricuspid valve apparatus or the right ventricular outflow
    tract, so VSD enlargement, multiple patches, root translocation, or staged
    single-ventricle palliation are often required.
  evidence:
  - reference: PMID:27641710
    reference_title: "How should we diagnose and differentiate hearts with double-outlet right ventricle?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Non-committed defects are no longer positioned within the limbs of the
      septomarginal trabeculation.
    explanation: >-
      Provides the defining anatomic criterion for the non-committed/remote VSD
      subtype.
  - reference: PMID:38134423
    reference_title: "Multicentre study on late outcomes of biventricular repair of double outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      VSD enlargement was significantly more frequent in DORV-ncVSD at 42% (5/12)
      (P = 0.001).
    explanation: >-
      Documents the greater surgical complexity of the non-committed VSD subtype,
      which more often requires enlargement of the interventricular communication
      to construct an unobstructed baffle.
pathophysiology:
- name: Cardiac Neural Crest and Second Heart Field Disruption
  role: trigger
  biological_scale: CELLULAR
  description: >-
    DORV originates in the two extracardiac progenitor populations that build the
    cardiac outflow tract. Cardiac neural crest cells delaminate from the dorsal
    neural tube, migrate through the caudal pharyngeal arches into the distal
    outflow tract and condense to form the aorticopulmonary septum, while
    second-heart-field progenitors are added to the arterial pole and provide the
    myocardium that elongates and rotates the outflow tract. Genetic lesions
    (chromosomal, transcription-factor, planar-cell-polarity, ciliary) and
    teratogenic exposures that perturb neural crest migration or second-heart-field
    addition converge on this step. DORV and tetralogy of Fallot are the two
    conotruncal phenotypes that most directly report this disturbance.
  cell_types:
  - preferred_term: migratory cardiac neural crest cell
    term:
      id: CL:2000073
      label: migratory cardiac neural crest cell
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac neural crest cell migration involved in outflow tract morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0003253
      label: cardiac neural crest cell migration involved in outflow tract morphogenesis
  - preferred_term: cardiac neural crest cell development involved in outflow tract morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0061309
      label: cardiac neural crest cell development involved in outflow tract morphogenesis
  locations:
  - preferred_term: outflow tract
    term:
      id: UBERON:0004145
      label: outflow tract
  evidence:
  - reference: PMID:38884738
    reference_title: "Human Genetics of Tetralogy of Fallot and Double-Outlet Right Ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Tetralogy of Fallot (TOF) and double-outlet right ventricle (DORV) are
      conotruncal defects resulting from disturbances of the second heart field
      and the neural crest, which can occur as isolated malformations or as part
      of multiorgan syndromes.
    explanation: >-
      Directly identifies disturbance of the second heart field and the neural
      crest as the developmental origin of DORV.
  - reference: PMID:18456715
    reference_title: "Double outlet right ventricle: aetiologies and associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The large number of genes associated with DORV in both humans and animal
      models and the different anatomic subtypes seen in specific aetiologies
      indicate the likelihood of several distinct pathogenetic mechanisms for
      DORV, including impairment of neural crest derivative migration and
      impairment of normal cardiac situs and looping.
    explanation: >-
      Supports impaired neural crest derivative migration as one of the distinct
      pathogenetic mechanisms of DORV, alongside disturbed situs and looping.
  - reference: PMID:32511952
    reference_title: "SHROOM3 is downstream of the planar cell polarity pathway and loss-of-function results in congenital heart defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We demonstrate Shroom3 expression within cardiomyocytes of the ventricles
      and interventricular septum from E10.5 onward, as well as within cardiac
      neural crest cells and second heart field cells that populate the cardiac
      outflow tract.
    explanation: >-
      Localises a DORV-causing planar-cell-polarity effector to precisely the
      cardiac neural crest and second-heart-field populations that build the
      outflow tract.
  - reference: PMID:32511952
    reference_title: "SHROOM3 is downstream of the planar cell polarity pathway and loss-of-function results in congenital heart defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We demonstrate that Shroom3gt/gt mice exhibit variable penetrance of a
      spectrum of CHDs that include ventricular septal defects, double outlet
      right ventricle, and thin left ventricular myocardium.
    explanation: >-
      Shows experimentally that disrupting a planar-cell-polarity effector in
      these progenitor populations produces DORV.
  downstream:
  - target: Failure of Outflow Tract Rotation and Alignment
    description: >-
      Deficient or disorganised neural crest and second-heart-field contribution
      leaves the outflow tract unable to elongate and rotate normally.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38884738
      reference_title: "Human Genetics of Tetralogy of Fallot and Double-Outlet Right Ventricle."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Tetralogy of Fallot (TOF) and double-outlet right ventricle (DORV) are
        conotruncal defects resulting from disturbances of the second heart field
        and the neural crest, which can occur as isolated malformations or as part
        of multiorgan syndromes.
      explanation: >-
        Places the second-heart-field and neural-crest disturbance causally
        upstream of the conotruncal alignment defect that produces DORV.
  - target: Persistence of the Subaortic Conus
    description: >-
      Perturbed conotruncal maturation prevents the normal resorption of the
      subaortic conal free wall.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - conotruncal maturation and conal remodelling
- name: Disturbed Left-Right Patterning and Cardiac Looping
  role: trigger
  biological_scale: TISSUE
  description: >-
    A distinct upstream route to DORV runs through the left-right organiser.
    Motile monocilia at the embryonic node generate leftward flow that establishes
    the NODAL laterality cascade; failure of this step randomises cardiac looping
    and the spatial relationship of the great arteries. This is the mechanism
    behind Van Praagh type III DORV, the form associated with heterotaxy and
    atrial isomerism, and explains why laterality genes (ZIC3, CFC1, FOXJ1,
    NODAL-pathway genes) recur in DORV cohorts. Because a randomised or abnormal
    loop misplaces the ventricles relative to the arterial poles, it produces the
    same double-outlet connection by a different developmental route than a
    primary neural-crest defect.
  biological_processes:
  - preferred_term: determination of left/right symmetry
    modifier: ABNORMAL
    term:
      id: GO:0007368
      label: determination of left/right symmetry
  - preferred_term: heart looping
    modifier: ABNORMAL
    term:
      id: GO:0001947
      label: heart looping
  - preferred_term: cilium movement
    modifier: DECREASED
    term:
      id: GO:0003341
      label: cilium movement
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "Since Van Praagh type III DORV is associated with heterotaxy"
    explanation: >-
      Establishes the heterotaxy-associated (laterality) aetiologic class of DORV;
      PARTIAL because the source goes on to frame the specific laterality genes as
      predicted candidates rather than established causes.
  - reference: PMID:37158461
    reference_title: "Congenital heart defects caused by FOXJ1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Complex CHDs revealed by histological analysis include atrioventricular
      septal defects, DORV, single ventricle defects as well as abnormal position
      of the great arteries.
    explanation: >-
      Loss of the master motile-cilia transcription factor Foxj1 in mice produces
      DORV together with abnormal great-artery position, tying ciliary laterality
      failure to the double-outlet connection.
  - reference: PMID:37158461
    reference_title: "Congenital heart defects caused by FOXJ1."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Finally, we characterize embryonic-stage CHD in Foxj1 loss-of-function mice,
      demonstrating randomized heart looping.
    explanation: >-
      Directly links disrupted ciliary left-right patterning to randomised cardiac
      looping, the morphogenetic step that misaligns the arterial poles.
  - reference: PMID:18456715
    reference_title: "Double outlet right ventricle: aetiologies and associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The large number of genes associated with DORV in both humans and animal
      models and the different anatomic subtypes seen in specific aetiologies
      indicate the likelihood of several distinct pathogenetic mechanisms for
      DORV, including impairment of neural crest derivative migration and
      impairment of normal cardiac situs and looping.
    explanation: >-
      Names impairment of normal cardiac situs and looping as a pathogenetic
      mechanism of DORV distinct from the neural crest route.
  downstream:
  - target: Failure of Outflow Tract Rotation and Alignment
    description: >-
      Randomised or abnormal looping misplaces the ventricles relative to the
      arterial poles, so the outflow tract cannot align normally.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37158461
      reference_title: "Congenital heart defects caused by FOXJ1."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Complex CHDs revealed by histological analysis include atrioventricular
        septal defects, DORV, single ventricle defects as well as abnormal
        position of the great arteries.
      explanation: >-
        Shows that randomised looping from a laterality defect yields both DORV
        and abnormal great-artery position, the alignment failure this edge
        asserts.
  - target: Heterotaxy
    description: >-
      The same left-right organiser failure that misaligns the outflow tract also
      randomises visceral and atrial situs.
    causal_link_type: DIRECT
  - target: Complete atrioventricular canal defect
    description: >-
      Laterality-associated DORV frequently carries a common atrioventricular
      valve, the atrioventricular canal defect characteristic of atrial isomerism.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - atrial isomerism and endocardial cushion malalignment
- name: Failure of Outflow Tract Rotation and Alignment
  role: mediator
  biological_scale: TISSUE
  description: >-
    Normally the arterial pole rotates during looping so the aorta swings
    rightward and posteriorly over the left ventricle while the pulmonary trunk is
    displaced anteriorly and leftward. This rotation is driven in part by
    asymmetric addition of second-heart-field myocardium at the pulmonary side of
    the outflow tract, which pushes the pulmonary orifice into a higher, more
    frontal position relative to the aortic orifice (the "pulmonary push").
    Deficient or disorganised right ventricular outflow tract expansion leaves the
    rotation incomplete, so the aortic root is never transferred across the
    ventricular septum and remains supported by the right ventricle.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: outflow tract morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0003151
      label: outflow tract morphogenesis
  locations:
  - preferred_term: outflow tract
    term:
      id: UBERON:0004145
      label: outflow tract
  evidence:
  - reference: PMID:22826212
    reference_title: "Morphogenesis of outflow tract rotation during cardiac development: the pulmonary push concept."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We postulate that normally the pulmonary trunk and orifice are pushed in a
      higher and more frontal position relative to the aortic orifice by
      asymmetric addition of SHF-myocardium.
    explanation: >-
      Describes the second-heart-field-driven rotation mechanism whose failure is
      proposed here as the alignment defect underlying DORV.
  - reference: PMID:22826212
    reference_title: "Morphogenesis of outflow tract rotation during cardiac development: the pulmonary push concept."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Deficient or disorganized right ventricular OFT expansion might explain
      cardiac malformations with abnormal position of the great arteries, such as
      double outlet right ventricle.
    explanation: >-
      Proposes deficient outflow tract expansion and rotation as the explanation
      for DORV; PARTIAL because the source frames it as a postulate.
  - reference: PMID:38391276
    reference_title: "Double outlet right ventricle - the 50% rule has always been about the conus."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      DORV is not a disease entity in itself, but rather a vast spectrum of
      disorders associated with maldevelopment of conal muscle and often abnormal
      expansion of one the great vessels.
    explanation: >-
      Frames DORV as the consequence of conal maldevelopment and abnormal
      great-vessel expansion rather than a discrete entity.
  downstream:
  - target: Persistence of the Subaortic Conus
    description: >-
      Incomplete rotation leaves the aortic root above persistent subaortic conal
      musculature rather than above the left ventricle.
    causal_link_type: DIRECT
  - target: Double Outlet Ventriculo-Arterial Connection
    description: >-
      Failure to transfer the aortic root across the ventricular septum leaves
      both arterial trunks supported by the right ventricle.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:22826212
      reference_title: "Morphogenesis of outflow tract rotation during cardiac development: the pulmonary push concept."
      supports: PARTIAL
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Deficient or disorganized right ventricular OFT expansion might explain
        cardiac malformations with abnormal position of the great arteries, such
        as double outlet right ventricle.
      explanation: >-
        Proposes, on mouse embryo data, that failed outflow tract expansion and
        rotation explains DORV; PARTIAL because the authors frame this as a
        postulate rather than a demonstrated causal step.
- name: Persistence of the Subaortic Conus
  role: mediator
  biological_scale: TISSUE
  description: >-
    In the normal heart the subpulmonary conus persists while the subaortic conal
    free wall resorbs, allowing the aortic valve to descend into fibrous continuity
    with the mitral valve. In DORV the subaortic conus characteristically persists,
    producing bilateral (subaortic and subpulmonary) infundibula and abolishing
    aorto-mitral fibrous continuity, so the aortic root remains elevated on a
    muscular sleeve above the right ventricle. This is the conal basis of the
    classical "50% rule": what is really being measured is whether conal muscle
    still interposes between the arterial root and the left ventricle. The
    criterion is not absolute, because DORV also occurs with fibrous continuity
    between the arterial and atrioventricular valves, so bilateral conus is
    sufficient but not necessary for the diagnosis.
  biological_processes:
  - preferred_term: conus arteriosus morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0003239
      label: conus arteriosus morphogenesis
  - preferred_term: outflow tract septum morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0003148
      label: outflow tract septum morphogenesis
  locations:
  - preferred_term: conus arteriosus
    term:
      id: UBERON:0003983
      label: conus arteriosus
  - preferred_term: mitral valve
    term:
      id: UBERON:0002135
      label: mitral valve
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Normally, the subaortic conus resorbs and brings the aorta in continuity
      with the mitral valve
    explanation: >-
      States the normal developmental event, resorption of the subaortic conus
      producing aorto-mitral continuity, whose failure defines this node.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "In DORV, the subaortic conus frequently persists"
    explanation: >-
      Directly documents persistence of the subaortic conus as the characteristic
      conal abnormality of DORV.
  - reference: PMID:38391276
    reference_title: "Double outlet right ventricle - the 50% rule has always been about the conus."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In this review, we aim to underscore the importance of conal muscle, rather
      than rules surrounding assignment of great arteries to ventricles.
    explanation: >-
      Supports conal muscle, rather than the arbitrary 50% override rule, as the
      substantive anatomic determinant in DORV.
  - reference: PMID:27641710
    reference_title: "How should we diagnose and differentiate hearts with double-outlet right ventricle?"
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      It was considered, for many years, that presence of bilateral infundibulums,
      or conuses, was a necessity for such a diagnosis.
    explanation: >-
      Records the historical bilateral-conus criterion while flagging that it is no
      longer regarded as necessary, which is why this node is described as
      characteristic rather than obligatory.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      The latter condition is the more common type of DORV
    explanation: >-
      Refutes any obligatory reading of this node: the form of DORV with
      atrioventricular-to-arterial valvar fibrous continuity, i.e. without a
      complete bilateral conus, is stated to be the more common type. Persistence
      of the subaortic conus is therefore a characteristic but not a necessary
      feature.
  downstream:
  - target: Double Outlet Ventriculo-Arterial Connection
    description: >-
      A persistent muscular subaortic conus keeps the aortic root committed to the
      right ventricle instead of the left. This route is characteristic but not
      obligatory, since DORV also occurs with arterial-to-atrioventricular valvar
      fibrous continuity.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - loss of aorto-mitral fibrous continuity
    evidence:
    - reference: PMID:37818164
      reference_title: "Double outlet right ventricle."
      supports: PARTIAL
      evidence_source: OTHER
      snippet: "In DORV, the subaortic conus frequently persists"
      explanation: >-
        Establishes persistence of the subaortic conus as the conal state
        frequently present in DORV, i.e. the anatomic reason the aortic root stays
        on the right ventricle; PARTIAL because the same source records that DORV
        also occurs without a complete bilateral conus.
- name: Double Outlet Ventriculo-Arterial Connection
  role: central_effector
  biological_scale: TISSUE
  description: >-
    The defining lesion: both arterial trunks arise entirely or predominantly from
    the morphologic right ventricle. Because the left ventricle has lost its direct
    arterial outlet, an interventricular communication is obligatory for viable
    left ventricular egress; a ventricular septal defect (or, in the setting of an
    atrioventricular septal defect, the common interventricular communication) is
    therefore present in almost every case. When the interventricular communication
    is restrictive or absent, the left ventricle receives no adequate outlet and
    becomes hypoplastic.
  locations:
  - preferred_term: heart right ventricle
    term:
      id: UBERON:0002080
      label: heart right ventricle
  - preferred_term: aorta
    term:
      id: UBERON:0000947
      label: aorta
  - preferred_term: pulmonary artery
    term:
      id: UBERON:0002012
      label: pulmonary artery
  evidence:
  - reference: PMID:38134423
    reference_title: "Multicentre study on late outcomes of biventricular repair of double outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DORV was defined as a congenital cardiovascular malformation in which both
      great arteries arise entirely or predominantly from the morphologically
      right ventricle.
    explanation: >-
      Gives the current consensus (ICD-11) definition of the double-outlet
      ventriculo-arterial connection modelled by this node.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Each great artery should have 50% or greater of the valve diameter coming
      from the morphologic RV, and there is almost always an interventricular
      communication: ventricular septal defect (VSD) or atrioventricular septal
      defect (AVSD)
    explanation: >-
      Supports both the double-outlet criterion and the near-obligatory presence
      of an interventricular communication as the sole left ventricular outlet.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In rare cases, where the interventricular communication is restricted or
      absent
    explanation: >-
      Documents the rare variant in which no adequate interventricular
      communication exists, the situation that drives left ventricular hypoplasia.
  downstream:
  - target: Outlet Septum Attachment Determines VSD Commitment
    description: >-
      With both roots on the right ventricle the outlet septum is necessarily a
      right ventricular structure, and its attachment determines which arterial
      root the interventricular communication faces.
    causal_link_type: DIRECT
  - target: Double outlet right ventricle
    description: The double-outlet ventriculo-arterial connection is the defining anatomic phenotype.
    causal_link_type: DIRECT
  - target: Ventricular septal defect
    description: >-
      Loss of a direct left ventricular arterial outlet makes an interventricular
      communication obligatory for viable left ventricular egress.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37818164
      reference_title: "Double outlet right ventricle."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        there is almost always an interventricular communication: ventricular
        septal defect (VSD) or atrioventricular septal defect (AVSD)
      explanation: >-
        Documents the near-obligatory interventricular communication that follows
        from the double-outlet connection.
- name: Outlet Septum Attachment Determines VSD Commitment
  role: effector
  biological_scale: TISSUE
  description: >-
    Because both arterial trunks are supported by the right ventricle, the outlet
    septum is itself a right ventricular structure, and the channel between the
    ventricles is roofed by the inner heart curvature. It is therefore the
    attachment of the outlet septum, muscular or fibrous, that determines to which
    subarterial outlet the interventricular communication is committed: the cranial
    limb of the septomarginal trabeculation gives a subaortic defect, the caudal
    limb a subpulmonary defect, and the inner heart curvature a doubly committed
    defect, while defects lying outside the limbs of the trabeculation are
    non-committed. This single anatomic variable, rather than the DORV label,
    determines the streaming physiology and the repair strategy.
  locations:
  - preferred_term: interventricular septum
    term:
      id: UBERON:0002094
      label: interventricular septum
  evidence:
  - reference: PMID:27641710
    reference_title: "How should we diagnose and differentiate hearts with double-outlet right ventricle?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      when both arterial trunks arise exclusively or predominantly from the
      morphologically right ventricle, the outlet septum, of necessity, is itself
      a right ventricular structure
    explanation: >-
      Establishes the anatomic premise that makes outlet-septum attachment the
      determinant of VSD commitment in DORV.
  - reference: PMID:27641710
    reference_title: "How should we diagnose and differentiate hearts with double-outlet right ventricle?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      it is the attachment of the outlet septum, which itself can be muscular or
      fibrous, which determines the commitment of the interventricular
      communication to the subarterial outlets
    explanation: >-
      Directly states the causal relationship modelled by this node.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The location of the VSD in DORV as viewed from the morphologic RV may be
      subpulmonic, subaortic, doubly committed
    explanation: >-
      Enumerates the positional categories of the interventricular communication
      that this node generates.
  - reference: PMID:38391276
    reference_title: "Double outlet right ventricle - the 50% rule has always been about the conus."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This anatomic variability directly determines physiology and surgical repair
      options.
    explanation: >-
      Supports the central claim that the anatomic variant, not the DORV label,
      drives physiology and repair choice.
  downstream:
  - target: Obligatory Intracardiac Mixing and VSD-Dependent Streaming
    description: >-
      The position of the interventricular communication relative to the arterial
      roots dictates how left ventricular blood streams once it crosses the septum.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:38391276
      reference_title: "Double outlet right ventricle - the 50% rule has always been about the conus."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        This anatomic variability directly determines physiology and surgical
        repair options.
      explanation: >-
        States that the anatomic variant determines the physiology, which is the
        causal claim of this edge.
  - target: Outlet Septum Malalignment and Outflow Tract Obstruction
    description: >-
      Displacement of the outlet septum toward one arterial root both commits the
      VSD to the other root and narrows the outflow it encroaches upon.
    causal_link_type: DIRECT
  - target: Left Ventricular Hypoplasia and Loss of Biventricular Repair Substrate
    description: >-
      A restrictive or remote interventricular communication limits fetal left
      ventricular filling and ejection, so the left ventricle fails to grow.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced left ventricular flow during fetal life
    evidence:
    - reference: PMID:37818164
      reference_title: "Double outlet right ventricle."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In rare cases, where the interventricular communication is restricted or
        absent
      explanation: >-
        Identifies the restricted or absent interventricular communication that
        this edge proposes as the antecedent of left ventricular hypoplasia.
- name: Obligatory Intracardiac Mixing and VSD-Dependent Streaming
  role: consequence
  biological_scale: ORGANISM
  description: >-
    All left ventricular output must traverse the ventricular septal defect into
    the right ventricle, so systemic and pulmonary venous returns mix obligatorily.
    The clinical expression depends on where the defect sits. With a subaortic
    defect, oxygenated left ventricular blood streams preferentially into the
    adjacent aorta and desaturated right ventricular blood into the pulmonary
    artery, giving a large-VSD physiology with only mild desaturation but marked
    pulmonary overcirculation. With a subpulmonary (Taussig-Bing) defect the
    streaming is reversed: oxygenated blood is directed into the pulmonary artery
    while desaturated systemic venous blood is ejected into the aorta, producing
    transposition-like physiology with early profound cyanosis. Any superimposed
    pulmonary stenosis restricts pulmonary blood flow and shifts even a subaortic
    defect toward cyanosis.
  locations:
  - preferred_term: interventricular septum
    term:
      id: UBERON:0002094
      label: interventricular septum
  - preferred_term: heart right ventricle
    term:
      id: UBERON:0002080
      label: heart right ventricle
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:38391276
    reference_title: "Double outlet right ventricle - the 50% rule has always been about the conus."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This anatomic variability directly determines physiology and surgical repair
      options.
    explanation: >-
      Supports the dependence of DORV physiology on the underlying anatomic
      variant, the core claim of this node.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      patients with subaortic VSD or subpulmonary VSD can have pulmonary
      over-circulation requiring aggressive diuresis
    explanation: >-
      Documents pulmonary overcirculation as a direct physiologic consequence of
      unobstructed VSD-mediated shunting in DORV.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      These patients may develop increasing cyanosis over time and may even
      develop hyper-cyanotic spells like patients with TOF.
    explanation: >-
      Supports progressive cyanosis, including hypercyanotic spells, as the
      alternative physiologic expression when pulmonary blood flow is restricted.
  downstream:
  - target: Cyanosis
    description: >-
      Streaming of desaturated systemic venous blood into the aorta, or restricted
      pulmonary blood flow, produces central cyanosis.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37818164
      reference_title: "Double outlet right ventricle."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        These patients may develop increasing cyanosis over time and may even
        develop hyper-cyanotic spells like patients with TOF.
      explanation: >-
        Documents cyanosis as the clinical output of inadequate pulmonary blood
        flow and unfavourable streaming in DORV.
  - target: Hypoxemia
    description: Obligatory intracardiac mixing lowers systemic arterial oxygen saturation.
    causal_link_type: DIRECT
  - target: Pulmonary Overcirculation and Ventricular Volume Overload
    description: >-
      When pulmonary outflow is unobstructed, the fall in pulmonary vascular
      resistance after birth drives a large left-to-right shunt.
    causal_link_type: DIRECT
- name: Outlet Septum Malalignment and Outflow Tract Obstruction
  role: consequence
  biological_scale: TISSUE
  description: >-
    The muscular outlet septum partitions the two infundibula, and its displacement
    into either outflow tract creates subvalvar obstruction. Deviation into the
    subpulmonary outflow produces subpulmonary and pulmonary stenosis, the lesion
    that gives a subaortic-VSD heart its Fallot-type physiology. Deviation into the
    subaortic outflow, or a subpulmonary VSD that diverts fetal left ventricular
    flow away from the systemic outlet, produces subaortic stenosis and is
    associated with hypoplasia of the aortic arch, coarctation and interrupted
    aortic arch, the lesions that dominate the Taussig-Bing anomaly. Chronic
    obstruction to right ventricular ejection also drives right ventricular
    hypertrophy.
  locations:
  - preferred_term: outflow tract
    term:
      id: UBERON:0004145
      label: outflow tract
  - preferred_term: aorta
    term:
      id: UBERON:0000947
      label: aorta
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The displacement of this outlet septum into the aortic or pulmonary out
    explanation: >-
      Identifies displacement of the muscular outlet septum into either outflow
      tract as the mechanism generating subvalvar obstruction in DORV.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A subaortic VSD may mean that pulmonary stenosis and small branch pulmonary
      arteries are likely to develop.
    explanation: >-
      Links the subaortic VSD variant specifically to the development of pulmonary
      stenosis.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A wide variety of cardiac malformations of the heart may accompany DORV
      including coarctation of the aorta (CoA)
    explanation: >-
      Documents aortic coarctation among the associated left-sided obstructive
      lesions of DORV.
  - reference: PMID:17903515
    reference_title: "Determinants of repair type, reintervention, and mortality in 393 children with double-outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypoplastic ventricles were present in 39%, pulmonary stenosis was present
      in 65%, and aortic arch obstruction was present in 24%.
    explanation: >-
      Quantifies the frequency of pulmonary stenosis and aortic arch obstruction
      generated by outlet septum malalignment in a large DORV cohort.
  downstream:
  - target: Pulmonic stenosis
    description: >-
      Deviation of the outlet septum into the subpulmonary outflow narrows the
      right ventricular outflow tract.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37818164
      reference_title: "Double outlet right ventricle."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        A subaortic VSD may mean that pulmonary stenosis and small branch
        pulmonary arteries are likely to develop.
      explanation: >-
        Links the outlet-septum configuration that produces a subaortic VSD to the
        development of pulmonary stenosis.
  - target: Subvalvular aortic stenosis
    description: >-
      Deviation of the outlet septum into the subaortic outflow narrows the
      systemic outlet.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37818164
      reference_title: "Double outlet right ventricle."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        leading to subaortic/aortic stenosis, CoA and IAA
      explanation: >-
        Names subaortic stenosis among the left-sided obstructive lesions produced by reduced
        fetal flow through the systemic outflow tract in DORV.
  - target: Coarctation of aorta
    description: >-
      Reduced antegrade fetal flow through the systemic outlet is associated with
      aortic arch hypoplasia and coarctation, especially in the Taussig-Bing form.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced fetal systemic outflow tract flow
    evidence:
    - reference: PMID:37818164
      reference_title: "Double outlet right ventricle."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        leading to subaortic/aortic stenosis, CoA and IAA
      explanation: >-
        Names coarctation of the aorta among the left-sided obstructive lesions produced by reduced
        fetal flow through the systemic outflow tract in DORV.
  - target: Interrupted aortic arch
    description: >-
      The most severe expression of the same reduced fetal systemic flow is
      interruption of the aortic arch.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - reduced fetal systemic outflow tract flow
    evidence:
    - reference: PMID:37818164
      reference_title: "Double outlet right ventricle."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        leading to subaortic/aortic stenosis, CoA and IAA
      explanation: >-
        Names interrupted aortic arch among the left-sided obstructive lesions produced by reduced
        fetal flow through the systemic outflow tract in DORV.
  - target: Right ventricular hypertrophy
    description: >-
      Chronic pressure load from subvalvar or valvar outflow obstruction produces
      right ventricular hypertrophy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37818164
      reference_title: "Double outlet right ventricle."
      supports: PARTIAL
      evidence_source: OTHER
      snippet: >-
        the EKG may show right axis deviation with right ventricular hypertrophy
      explanation: >-
        Documents right ventricular hypertrophy in the subgroup with a subaortic VSD
        and pulmonary stenosis, the group defined by outflow obstruction; PARTIAL because
        the source reports the association rather than the pressure-load mechanism.
- name: Pulmonary Overcirculation and Ventricular Volume Overload
  role: outcome
  biological_scale: ORGANISM
  description: >-
    In the absence of pulmonary stenosis, the postnatal fall in pulmonary vascular
    resistance allows a torrential left-to-right shunt through the ventricular
    septal defect and into the pulmonary artery. The resulting pulmonary
    overcirculation produces tachypnoea, feeding difficulty and failure to thrive
    within the first weeks of life, ventricular volume overload and congestive
    heart failure, and, if repair is delayed beyond infancy, progressive pulmonary
    vascular remodelling and irreversible pulmonary arterial hypertension. This is
    the rationale for completing biventricular repair within the first six months
    of life or, when repair must be deferred, for interim pulmonary artery banding.
  locations:
  - preferred_term: pulmonary artery
    term:
      id: UBERON:0002012
      label: pulmonary artery
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      patients with subaortic VSD or subpulmonary VSD can have pulmonary
      over-circulation requiring aggressive diuresis
    explanation: >-
      Documents pulmonary overcirculation and the need for decongestive therapy as
      a direct consequence of unrestricted shunting in DORV.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At times, this may lead to the need for respiratory support and intubation.
    explanation: >-
      Supports the respiratory consequences of pulmonary overcirculation in DORV
      infants.
  downstream:
  - target: Congestive heart failure
    description: Ventricular volume overload from the large shunt produces congestive heart failure.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37818164
      reference_title: "Double outlet right ventricle."
      supports: PARTIAL
      evidence_source: OTHER
      snippet: >-
        patients with subaortic VSD or subpulmonary VSD can have pulmonary
        over-circulation requiring aggressive diuresis
      explanation: >-
        Documents the congestive consequence of overcirculation and its
        decongestive treatment; heart failure is not named verbatim, hence
        PARTIAL.
  - target: Tachypnea
    description: Increased pulmonary blood flow and pulmonary congestion produce tachypnoea.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37818164
      reference_title: "Double outlet right ventricle."
      supports: PARTIAL
      evidence_source: OTHER
      snippet: >-
        At times, this may lead to the need for respiratory support and intubation.
      explanation: >-
        Documents respiratory decompensation as a consequence of pulmonary
        overcirculation in DORV; PARTIAL because the source describes escalating
        respiratory support rather than tachypnoea specifically.
  - target: Feeding difficulties
    description: >-
      Tachypnoea and the increased work of breathing imposed by pulmonary
      overcirculation interrupt sucking and swallowing, so infants tire and feed
      poorly.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - tachypnoea and increased work of breathing during feeds
  - target: Failure to thrive
    description: >-
      The metabolic cost of heart failure combined with feeding difficulty causes
      poor weight gain.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - increased metabolic demand and reduced caloric intake
  - target: Pulmonary arterial hypertension
    description: >-
      Sustained high-flow, high-pressure pulmonary circulation drives obstructive
      pulmonary vascular remodelling.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - pulmonary vascular remodelling
- name: Left Ventricular Hypoplasia and Loss of Biventricular Repair Substrate
  role: outcome
  biological_scale: TISSUE
  description: >-
    When the interventricular communication is restrictive, remote from both
    arterial roots, or absent, fetal left ventricular filling and ejection are
    reduced and the left ventricle fails to grow. The same anatomic circumstances
    that limit left ventricular growth, together with straddling or hypoplastic
    atrioventricular valves and multiple ventricular septal defects, also make an
    unobstructed intraventricular baffle impossible. This node is therefore the
    hinge on which the entire management pathway turns: it converts DORV from a
    biventricular repair problem into a single-ventricle palliation problem.
  locations:
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the LV will show an element of hypoplasia, which can vary from mild to
      severe
    explanation: >-
      Documents left ventricular hypoplasia as the consequence of a restricted or
      absent interventricular communication in DORV.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Contraindications to biventricular repair include severe ventricular
      hypoplasia, abnormal tricuspid chordae, multiple VSDs, and a straddling
      mitral valve.
    explanation: >-
      Establishes ventricular hypoplasia and associated valve anomalies as the
      determinants that preclude biventricular repair.
  - reference: PMID:17903515
    reference_title: "Determinants of repair type, reintervention, and mortality in 393 children with double-outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Factors discriminating among end-states included younger patient age at
      presentation (P < .001), lower weight (P < .001), and adequacy of left-sided
      heart structures, especially the size of the left ventricle (P < .001),
      aortic arch (P < .001), and mitral valve (P = .004).
    explanation: >-
      Demonstrates empirically that the adequacy of left-sided structures,
      especially left ventricular size, determines which definitive end-state a
      DORV patient reaches.
  downstream:
  - target: Hypoplastic left ventricle
    description: >-
      Reduced fetal left ventricular flow through a restrictive or remote
      interventricular communication results in an underdeveloped left ventricle.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37818164
      reference_title: "Double outlet right ventricle."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        the LV will show an element of hypoplasia, which can vary from mild to
        severe
      explanation: >-
        Documents left ventricular hypoplasia as the direct consequence of a
        restricted or absent interventricular communication.
phenotypes:
- category: Clinical
  name: Double outlet right ventricle
  description: >-
    The defining anatomic lesion: both great arteries arise entirely or
    predominantly from the morphologic right ventricle, with a ventricular septal
    defect as the only left ventricular outlet.
  frequency: OBLIGATE
  diagnostic: true
  phenotype_term:
    preferred_term: Double outlet right ventricle
    term:
      id: HP:0001719
      label: Double outlet right ventricle
  evidence:
  - reference: PMID:38134423
    reference_title: "Multicentre study on late outcomes of biventricular repair of double outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DORV was defined as a congenital cardiovascular malformation in which both
      great arteries arise entirely or predominantly from the morphologically
      right ventricle.
    explanation: >-
      States the defining anatomic criterion, which is the phenotype itself.
- category: Clinical
  name: Ventricular septal defect
  description: >-
    An interventricular communication is present in almost every case of DORV and
    is the sole outlet from the left ventricle. Its position relative to the
    arterial roots defines the anatomic subtypes.
  frequency: VERY_FREQUENT
  diagnostic: true
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Each great artery should have 50% or greater of the valve diameter coming
      from the morphologic RV, and there is almost always an interventricular
      communication: ventricular septal defect (VSD) or atrioventricular septal
      defect (AVSD)
    explanation: >-
      Documents the near-universal presence of an interventricular communication
      in DORV and supports the VERY_FREQUENT frequency band.
- category: Clinical
  name: Cyanosis
  description: >-
    Central cyanosis, typically neonatal or early infantile. It is most severe in
    the Taussig-Bing (subpulmonary VSD) form, where desaturated systemic venous
    blood is streamed into the aorta, and in any DORV with significant pulmonary
    stenosis. Hypercyanotic spells resembling those of tetralogy of Fallot may
    occur.
  phenotype_term:
    preferred_term: Cyanosis
    term:
      id: HP:0000961
      label: Cyanosis
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These patients may develop increasing cyanosis over time and may even
      develop hyper-cyanotic spells like patients with TOF.
    explanation: >-
      Directly documents progressive cyanosis and hypercyanotic spells as clinical
      manifestations of DORV.
- category: Clinical
  name: Hypoxemia
  description: >-
    Reduced systemic arterial oxygen saturation resulting from obligatory
    intracardiac mixing, aggravated when pulmonary blood flow is restricted or when
    streaming directs desaturated blood preferentially to the aorta.
  phenotype_term:
    preferred_term: Hypoxemia
    term:
      id: HP:0012418
      label: Hypoxemia
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      Consideration should be given to the urgent need for atrial septostomy in a
      patient who is desaturated and has evidence of a poor cardiac output state.
    explanation: >-
      Documents systemic desaturation as a clinical state requiring urgent
      intervention in DORV; the source describes desaturation rather than using
      the term hypoxemia, hence PARTIAL.
- category: Clinical
  name: Pulmonic stenosis
  description: >-
    Obstruction of the right ventricular outflow tract, most often from deviation
    of the muscular outlet septum into the subpulmonary infundibulum, but also
    valvar or supravalvar. It is the single most common associated lesion and
    converts an overcirculated DORV into a cyanotic one.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Pulmonic stenosis
    term:
      id: HP:0001642
      label: Pulmonic stenosis
  evidence:
  - reference: PMID:17903515
    reference_title: "Determinants of repair type, reintervention, and mortality in 393 children with double-outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypoplastic ventricles were present in 39%, pulmonary stenosis was present
      in 65%, and aortic arch obstruction was present in 24%.
    explanation: >-
      Quantifies pulmonary stenosis in 65% of a 393-patient DORV cohort,
      supporting a FREQUENT frequency band.
- category: Clinical
  name: Subvalvular aortic stenosis
  description: >-
    Subaortic obstruction produced by posterior deviation of the outlet septum, by
    a restrictive interventricular communication, or by a long non-contractile
    intraventricular baffle after repair. It is characteristic of the
    subpulmonary-VSD (Taussig-Bing) form and is also a recognised late
    postoperative complication.
  phenotype_term:
    preferred_term: Subvalvular aortic stenosis
    term:
      id: HP:0001682
      label: Subvalvular aortic stenosis
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      leading to subaortic/aortic stenosis, CoA and IAA
    explanation: >-
      Names subaortic stenosis as a consequence of the reduced fetal left
      ventricular outflow that accompanies a subpulmonary VSD; PARTIAL because the
      source states the association without specifying the obstructing structure.
- category: Clinical
  name: Coarctation of aorta
  description: >-
    Narrowing of the aortic isthmus, part of the spectrum of aortic arch
    obstruction that accompanies DORV, particularly the Taussig-Bing form in which
    reduced fetal flow through the systemic outlet limits arch growth.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Coarctation of aorta
    term:
      id: HP:0001680
      label: Coarctation of aorta
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A wide variety of cardiac malformations of the heart may accompany DORV
      including coarctation of the aorta (CoA)
    explanation: >-
      Directly lists coarctation of the aorta among the malformations accompanying
      DORV.
  - reference: PMID:17903515
    reference_title: "Determinants of repair type, reintervention, and mortality in 393 children with double-outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypoplastic ventricles were present in 39%, pulmonary stenosis was present
      in 65%, and aortic arch obstruction was present in 24%.
    explanation: >-
      Quantifies aortic arch obstruction, of which coarctation is the commonest
      form, in 24% of a large DORV cohort, supporting the OCCASIONAL band.
- category: Clinical
  name: Interrupted aortic arch
  description: >-
    Complete discontinuity of the aortic arch, the most severe expression of the
    arch obstruction associated with DORV and particularly with the Taussig-Bing
    anomaly.
  phenotype_term:
    preferred_term: Interrupted aortic arch
    term:
      id: HP:0011611
      label: Interrupted aortic arch
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      interrupted aortic arch (IAA) and aortic arch obstruction
    explanation: >-
      Lists interrupted aortic arch among the cardiac malformations accompanying
      DORV.
- category: Clinical
  name: Right ventricular hypertrophy
  description: >-
    Hypertrophy of the morphologic right ventricle, which supports both arterial
    trunks and is additionally pressure-loaded when outflow obstruction is present.
    In the Fallot-type subgroup the electrocardiogram shows right axis deviation
    with right ventricular hypertrophy.
  phenotype_term:
    preferred_term: Right ventricular hypertrophy
    term:
      id: HP:0001667
      label: Right ventricular hypertrophy
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the EKG may show right axis deviation with right ventricular hypertrophy
    explanation: >-
      Documents right ventricular hypertrophy as an electrocardiographic finding
      in the commonest DORV subtype.
- category: Clinical
  name: Congestive heart failure
  description: >-
    Congestive heart failure driven by pulmonary overcirculation and ventricular
    volume overload when pulmonary outflow is unobstructed; also a late
    postoperative problem after Rastelli-type repair with conduit obstruction and
    right ventricular dysfunction.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      patients with subaortic VSD or subpulmonary VSD can have pulmonary
      over-circulation requiring aggressive diuresis
    explanation: >-
      Documents the congestive physiology requiring diuresis; the source describes
      pulmonary overcirculation and its decongestive treatment rather than naming
      congestive heart failure, hence PARTIAL.
- category: Clinical
  name: Tachypnea
  description: >-
    Rapid breathing from pulmonary congestion and increased pulmonary blood flow,
    typically emerging over the first weeks of life as pulmonary vascular
    resistance falls.
  phenotype_term:
    preferred_term: Tachypnea
    term:
      id: HP:0002789
      label: Tachypnea
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      At times, this may lead to the need for respiratory support and intubation.
    explanation: >-
      Documents the respiratory decompensation caused by pulmonary
      overcirculation in DORV, of which tachypnoea is the earliest sign; the
      source describes escalating respiratory support rather than naming
      tachypnoea, hence PARTIAL.
- category: Clinical
  name: Feeding difficulties
  description: >-
    Poor and prolonged feeding in infancy, driven by the tachypnoea and increased
    work of breathing that accompany pulmonary overcirculation. It is the proximate
    cause of the reduced caloric intake that, with the raised metabolic demand of
    heart failure, produces failure to thrive in the unrepaired overcirculated
    forms of DORV.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  notes: >-
    No quotable source in the current reference set names the feeding phenotype
    directly, so no evidence item is asserted; the description is retained as
    uncited clinical context per the project evidence SOP, in the same way as the
    adjacent failure-to-thrive entry.
- category: Clinical
  name: Failure to thrive
  description: >-
    Poor weight gain in infancy resulting from the increased metabolic demand of
    heart failure combined with feeding difficulty, characteristic of the
    overcirculated forms of DORV before repair.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  notes: >-
    No quotable source in the current reference set states the growth phenotype
    directly, so no evidence item is asserted; the description is retained as
    uncited clinical context per the project evidence SOP.
- category: Clinical
  name: Pulmonary arterial hypertension
  description: >-
    Elevated pulmonary arterial pressure from sustained high-flow, high-pressure
    pulmonary circulation. If repair is delayed, obstructive pulmonary vascular
    remodelling becomes irreversible and precludes both biventricular repair and
    Fontan palliation.
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  notes: >-
    No quotable source in the current reference set names the pulmonary
    hypertension endpoint directly, so no evidence item is asserted; the
    description is retained as uncited clinical context per the project evidence
    SOP.
- category: Clinical
  name: Hypoplastic left ventricle
  description: >-
    An underdeveloped left ventricle, arising when the interventricular
    communication is restrictive, remote or absent so that fetal left ventricular
    filling and ejection are reduced. It is the principal determinant of
    ineligibility for biventricular repair.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypoplastic left ventricle
    term:
      id: HP:0004383
      label: Hypoplastic left ventricle
  evidence:
  - reference: PMID:17903515
    reference_title: "Determinants of repair type, reintervention, and mortality in 393 children with double-outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypoplastic ventricles were present in 39%, pulmonary stenosis was present
      in 65%, and aortic arch obstruction was present in 24%.
    explanation: >-
      Quantifies ventricular hypoplasia in 39% of a 393-patient DORV cohort,
      supporting a FREQUENT frequency band.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the LV will show an element of hypoplasia, which can vary from mild to
      severe
    explanation: >-
      Directly documents left ventricular hypoplasia in DORV with a restricted or
      absent interventricular communication.
- category: Clinical
  name: Heterotaxy
  description: >-
    Abnormal left-right arrangement of the thoracic and abdominal viscera with
    atrial isomerism, present in the laterality-associated (Van Praagh type III)
    form of DORV. Its presence carries additional conduction, splenic and venous
    anomalies and worsens surgical risk.
  phenotype_term:
    preferred_term: Heterotaxy
    term:
      id: HP:0030853
      label: Heterotaxy
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Since Van Praagh type III DORV is associated with heterotaxy"
    explanation: >-
      Directly associates a defined anatomic class of DORV with heterotaxy.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      laterality defects such as the heterotaxy syndromes of isomerism of the
      atrial appendages
    explanation: >-
      Lists heterotaxy with atrial isomerism among the malformations that
      accompany DORV.
- category: Clinical
  name: Complete atrioventricular canal defect
  description: >-
    A common atrioventricular valve with a shared atrioventricular junction,
    frequently accompanying DORV in the laterality-associated form. Its presence
    complicates baffle construction and often mandates single-ventricle palliation.
  phenotype_term:
    preferred_term: Complete atrioventricular canal defect
    term:
      id: HP:0001674
      label: Complete atrioventricular canal defect
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      as well as common AV valves can be found with DORV
    explanation: >-
      Documents a common atrioventricular valve, the hallmark of a complete
      atrioventricular canal defect, as an associated lesion of DORV.
prevalence:
- population: Live births
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 6.0
  rate_low: 3.0
  rate_high: 9.0
  notes: >-
    Reported as approximately three to nine per 100,000 live births in a
    contemporary review of DORV.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      DORV is reported to occur in approximately three to nine in 100,000 live
      births
    explanation: >-
      Gives the birth-prevalence range normalised here to cases per 100,000 live
      births.
- population: Individuals with congenital heart defects
  measure_type: UNKNOWN
  notes: >-
    DORV accounts for 1 to 3 per cent of congenital heart defects. This is a
    fraction of the congenital-heart-defect population, not a general-population
    rate, so no rate_per_100000 or prevalence_class is asserted; the
    general-population figure is the birth-prevalence record above.
  evidence:
  - reference: PMID:18456715
    reference_title: "Double outlet right ventricle: aetiologies and associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Double outlet right ventricle (DORV), a clinically significant congenital
      heart defect, occurs in 1-3% of individuals with congenital heart defects.
    explanation: >-
      States the proportion of the congenital heart defect population represented
      by DORV.
genetic:
- name: Chromosomal aneuploidy and copy number variation
  association: Chromosomal abnormality
  relationship_type: SUSCEPTIBILITY
  notes: >-
    More than 40 per cent of patients with DORV carry an associated chromosomal
    abnormality, and most of these also have extracardiac defects. Trisomy 13,
    trisomy 18 and 22q11.2 deletion are the most commonly associated cytogenetic
    lesions, and the anatomic subtype of DORV differs between the trisomies and
    22q11.2 deletion. Chromosome 8 abnormalities, Cri-du-chat (5p15.2 deletion) and
    Jacobsen (11q terminal deletion) syndromes have also been reported. Chromosomal
    microarray is therefore first-line testing in complex or syndromic DORV.
  evidence:
  - reference: PMID:18456715
    reference_title: "Double outlet right ventricle: aetiologies and associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chromosomal abnormalities were present in 61 of the 149 cases of DORV.
      Trisomies 13 and 18, and del 22q11 were the most commonly associated
      cytogenetic lesions; different anatomic subtypes of DORV were noted in
      trisomies 13 and 18 versus del 22q11.
    explanation: >-
      Quantifies the chromosomal burden in DORV and names the specific recurrent
      cytogenetic lesions and their subtype specificity.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      More than 40% of patients with DORV have associated chromosomal
      abnormalities
    explanation: >-
      Independently quantifies the proportion of DORV patients with a chromosomal
      abnormality.
- name: TBX1
  gene_term:
    preferred_term: TBX1
    term:
      id: hgnc:11592
      label: TBX1
  association: 22q11.2 deletion syndrome
  relationship_type: CAUSATIVE
  notes: >-
    The 22q11.2 deletion, whose cardiac phenotype is attributed to
    haploinsufficiency of the T-box transcription factor TBX1 acting in the second
    heart field and pharyngeal mesoderm, is present in approximately 7 per cent of
    individuals with DORV and is one of the most frequently identified genomic
    causes.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      22q11.2 deletion syndrome presents in 7% of DORV individuals
    explanation: >-
      Quantifies the frequency of 22q11.2 deletion among DORV patients.
  - reference: PMID:38884738
    reference_title: "Human Genetics of Tetralogy of Fallot and Double-Outlet Right Ventricle."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      while mutations of TBX5 and 22q11 deletion, leading to haploinsufficiency of
      TBX1, cause Holt-Oram and DiGeorge syndrome, respectively.
    explanation: >-
      Attributes the 22q11 deletion phenotype to TBX1 haploinsufficiency; the
      statement is made in a chapter covering both tetralogy of Fallot and DORV
      and is not DORV-exclusive, hence PARTIAL.
- name: ZIC3
  gene_term:
    preferred_term: ZIC3
    term:
      id: hgnc:12874
      label: ZIC3
  association: X-linked laterality defect with isolated DORV
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >-
    ZIC3, the X-linked laterality gene classically causing heterotaxy with complex
    congenital heart disease, is also mutated in a small subset of patients with
    apparently isolated DORV, placing those cases within the laterality-defect
    spectrum. In a screen of 89 DORV probands a missense variant (c.49G>T,
    p.Gly17Cys) was identified in a female with isolated DORV. The authors describe
    the variants as potentially disease-related and performed functional validation
    only on the separate heterotaxy variant, so this locus is typed as a
    susceptibility rather than an established causative gene for DORV.
  evidence:
  - reference: PMID:23427188
    reference_title: "The phenotypic spectrum of ZIC3 mutations includes isolated d-transposition of the great arteries and double outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three potentially disease-related missense mutations were detected: c.49G >
      T (Gly17Cys) in a female with isolated DORV
    explanation: >-
      Reports a specific ZIC3 missense variant in a patient with isolated DORV.
  - reference: PMID:23427188
    reference_title: "The phenotypic spectrum of ZIC3 mutations includes isolated d-transposition of the great arteries and double outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ZIC3 mutations were rarely identified in isolated DORV and d-TGA suggesting
      that a subset of DORV and d-TGA may fall within the spectrum of laterality
      defects.
    explanation: >-
      Establishes both the rarity of ZIC3 variants in isolated DORV and their
      mechanistic significance as evidence for a laterality-defect route to DORV.
- name: CFC1
  gene_term:
    preferred_term: CFC1
    term:
      id: hgnc:18292
      label: CFC1
  association: Laterality-pathway (NODAL co-receptor) variants
  relationship_type: SUSCEPTIBILITY
  notes: >-
    CFC1 encodes CRYPTIC, an EGF-CFC co-receptor for NODAL signalling in the
    left-right patterning cascade. Together with NKX2-5 (historically CSX), CFC1
    was the most commonly reported monogenic locus associated with DORV in a
    systematic review of the human literature, consistent with the
    laterality-defect route to the double-outlet connection.
  evidence:
  - reference: PMID:18456715
    reference_title: "Double outlet right ventricle: aetiologies and associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations and non-synonymous sequence variants in the CFC1 and CSX genes
      were the most commonly reported monogenic loci associated with DORV in
      humans; numerous genes are reported in murine models of DORV.
    explanation: >-
      Identifies CFC1 as one of the two most frequently reported monogenic loci in
      human DORV.
- name: NKX2-5
  gene_term:
    preferred_term: NKX2-5
    term:
      id: hgnc:2488
      label: NKX2-5
  association: Cardiac transcription factor variants
  relationship_type: SUSCEPTIBILITY
  notes: >-
    NKX2-5 (formerly CSX) is a core cardiac transcription factor required for
    outflow tract and conduction system development. Together with CFC1 it was the
    most commonly reported monogenic locus associated with DORV in the human
    literature, and it is among the genes recurrently implicated in the cell
    lineages that build a mature and separated outflow tract.
  evidence:
  - reference: PMID:18456715
    reference_title: "Double outlet right ventricle: aetiologies and associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations and non-synonymous sequence variants in the CFC1 and CSX genes
      were the most commonly reported monogenic loci associated with DORV in
      humans; numerous genes are reported in murine models of DORV.
    explanation: >-
      Identifies CSX, the former name of NKX2-5, as one of the two most frequently
      reported monogenic loci in human DORV.
- name: GATA4
  gene_term:
    preferred_term: GATA4
    term:
      id: hgnc:4173
      label: GATA4
  association: Endocardial cushion developmental defect (Van Praagh type II DORV)
  relationship_type: SUSCEPTIBILITY
  notes: >-
    GATA4 is a zinc-finger cardiac transcription factor essential for endocardial
    cushion development and septation. Van Praagh type II DORV, the form combining
    the double-outlet connection with atrioventricular valve and ventricular
    malformations, has been attributed to endocardial cushion developmental
    abnormalities including GATA4 mutation. GATA4 also acts synergistically with
    MEF2C, and disruption of that synergy is one route by which MEF2C variants
    cause DORV.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Van Praagh type II DORV may be related to the consequence of developmental
      abnormalities of the endocardial cushions such as mutations in GATA4
    explanation: >-
      Attributes a defined anatomic class of DORV to endocardial cushion defects
      including GATA4 mutation.
  - reference: PMID:29468350
    reference_title: "A Novel MEF2C Loss-of-Function Mutation Associated with Congenital Double Outlet Right Ventricle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, the mutation significantly reduced the synergistic activation
      between MEF2C and GATA4, another transcription factor linked to CHD.
    explanation: >-
      Demonstrates functionally that GATA4 acts in synergy with MEF2C and that
      loss of this synergy accompanies a DORV-causing variant.
- name: MEF2C
  gene_term:
    preferred_term: MEF2C
    term:
      id: hgnc:6996
      label: MEF2C
  association: Autosomal dominant DORV with ventricular septal defect
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    A heterozygous MEF2C missense variant (p.R15C) co-segregating with congenital
    heart disease with complete penetrance was identified in a proband with DORV
    and ventricular septal defect. The mutant protein showed significantly reduced
    transcriptional activity and impaired synergy with GATA4. Reported inheritance
    in the index pedigree was autosomal dominant.
  evidence:
  - reference: PMID:29468350
    reference_title: "A Novel MEF2C Loss-of-Function Mutation Associated with Congenital Double Outlet Right Ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As a result, a novel heterozygous MEF2C mutation, p.R15C, was detected in an
      index patient with congenital double outlet right ventricle (DORV) as well
      as ventricular septal defect.
    explanation: >-
      Reports the specific MEF2C variant identified in a DORV proband.
  - reference: PMID:29468350
    reference_title: "A Novel MEF2C Loss-of-Function Mutation Associated with Congenital Double Outlet Right Ventricle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional deciphers revealed that the mutant MEF2C protein had a
      significantly decreased transcriptional activity.
    explanation: >-
      Provides the functional loss-of-function evidence supporting pathogenicity
      of the MEF2C variant.
- name: TBX20
  gene_term:
    preferred_term: TBX20
    term:
      id: hgnc:11598
      label: TBX20
  association: Autosomal dominant DORV
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >-
    A heterozygous TBX20 missense variant (p.R143W) segregating in an autosomal
    dominant pattern with complete penetrance was identified in a DORV kindred,
    with functional assays showing diminished transcriptional activity. The authors
    frame the finding as increased susceptibility to DORV on the basis of a single
    pedigree, so the locus is typed as a susceptibility here.
  evidence:
  - reference: PMID:25625280
    reference_title: "TBX20 loss-of-function mutation contributes to double outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic analyses of the pedigree of the proband revealed that in the family,
      the mutation co-segregated with DORV transmitted in an autosomal dominant
      pattern with complete penetrance.
    explanation: >-
      Establishes autosomal dominant segregation of the TBX20 variant with DORV in
      a family.
  - reference: PMID:25625280
    reference_title: "TBX20 loss-of-function mutation contributes to double outlet right ventricle."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional analysis revealed that mutant TBX20 had a significantly
      diminished transcriptional activity compared with its wild-type counterpart.
    explanation: >-
      Provides the loss-of-function evidence supporting pathogenicity of the TBX20
      variant.
- name: CHD7
  gene_term:
    preferred_term: CHD7
    term:
      id: hgnc:20626
      label: CHD7
  association: CHARGE syndrome (epigenetic regulator)
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    CHD7 encodes a chromodomain helicase DNA-binding protein whose mutation causes
    CHARGE syndrome through perturbation of H3K4 methylation. Congenital heart
    defects occur in 75 to 80 per cent of individuals with CHARGE and the spectrum
    includes DORV, making CHD7 the principal epigenetic-regulator route to a
    syndromic DORV. De novo enrichment of variants in histone-modifying enzymes has
    also been reported in severe congenital heart disease cohorts that included DORV
    patients.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      mutations in the CHD7 genes result in CHARGE association with the
      perturbation of the H3K4 methylation
    explanation: >-
      Identifies CHD7 mutation as the cause of CHARGE association and names the
      epigenetic mechanism involved.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Congenital heart defects occur in 75% –80% of the patients with CHARGE
      association including DORV
    explanation: >-
      Quantifies the congenital heart defect burden of CHARGE association and
      names DORV explicitly among the defects that occur in it.
- name: LRP1
  gene_term:
    preferred_term: LRP1
    term:
      id: hgnc:6692
      label: LRP1
  association: Cardiac neural crest lineage perturbation (mouse model of DORV)
  relationship_type: SUSCEPTIBILITY
  notes: >-
    LRP1 encodes the low-density lipoprotein receptor-related protein 1. A mouse
    Lrp1 mutant produces DORV through perturbation of the cardiac neural crest
    lineage, providing direct experimental support for the neural-crest route
    modelled in the pathophysiology section. The evidence is model-organism only,
    so the locus is typed as a mechanistic susceptibility.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      our group previously reported the evidence of the perturbance of cardiac
      neural crest lineage that resulted in DORV in a mouse model of Lrp1 mutation
    explanation: >-
      Reports an Lrp1 mouse model in which cardiac neural crest perturbation
      produces DORV.
- name: FOXJ1
  gene_term:
    preferred_term: FOXJ1
    term:
      id: hgnc:3816
      label: FOXJ1
  association: Motile ciliopathy gene causing isolated congenital heart defects
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    FOXJ1 is the master transcriptional regulator of motile ciliogenesis, including
    the cilia of the embryonic left-right organiser. A truncating FOXJ1 variant
    (c.784_799dup; p.Glu267Glyfs*12) was identified by clinical exome sequencing in
    a patient with isolated congenital heart defects comprising atrial and
    ventricular septal defects, DORV and transposition of the great arteries. The
    variant failed to induce ectopic cilia in vivo or to transactivate a downstream
    ciliary target, and Foxj1 loss-of-function mice show randomised heart looping
    with DORV. FOXJ1 variants are nevertheless an infrequent cause of heterotaxy or
    heterotaxy-related congenital heart disease. The relationship is typed
    CAUSATIVE for the reported proband, but rests on a single family with
    functional support rather than on an established gene-disease association for
    DORV as a whole.
  evidence:
  - reference: PMID:37158461
    reference_title: "Congenital heart defects caused by FOXJ1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report a novel truncating FOXJ1 variant (c.784_799dup;
      p.Glu267Glyfs*12) identified by clinical exome sequencing from a patient
      with isolated congenital heart defects (CHD) which included atrial and
      ventricular septal defects, double outlet right ventricle (DORV) and
      transposition of the great arteries.
    explanation: >-
      Reports the specific FOXJ1 variant identified in a patient whose phenotype
      included DORV.
  - reference: PMID:37158461
    reference_title: "Congenital heart defects caused by FOXJ1."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Variant analysis of patients with heterotaxy or heterotaxy-related CHD
      indicates that pathogenic variants in FOXJ1 are an infrequent cause of
      heterotaxy.
    explanation: >-
      Bounds the contribution of FOXJ1, supporting its classification as a rare
      rather than common cause of DORV.
- name: SHROOM3
  gene_term:
    preferred_term: SHROOM3
    term:
      id: hgnc:30422
      label: SHROOM3
  association: Planar cell polarity effector; DORV in mouse loss-of-function models
  relationship_type: SUSCEPTIBILITY
  notes: >-
    SHROOM3 is an actomyosin cytoskeletal effector acting downstream of
    Dishevelled 2 in the noncanonical Wnt planar cell polarity pathway. It is
    expressed in ventricular cardiomyocytes, cardiac neural crest cells and second
    heart field cells populating the outflow tract, and Shroom3 gene-trap mice show
    variably penetrant DORV. The human evidence is candidate-level, so this locus
    is recorded as a mechanistic susceptibility rather than an established DORV
    gene.
  evidence:
  - reference: PMID:32511952
    reference_title: "SHROOM3 is downstream of the planar cell polarity pathway and loss-of-function results in congenital heart defects."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We demonstrate that Shroom3gt/gt mice exhibit variable penetrance of a
      spectrum of CHDs that include ventricular septal defects, double outlet
      right ventricle, and thin left ventricular myocardium.
    explanation: >-
      Demonstrates that loss of Shroom3 produces DORV in a mouse model.
  - reference: PMID:32511952
    reference_title: "SHROOM3 is downstream of the planar cell polarity pathway and loss-of-function results in congenital heart defects."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We previously implicated a novel CHD candidate gene, SHROOM3, in a patient
      with CHD.
    explanation: >-
      Records the human evidence as candidate-level, which is why this entry is
      typed as a susceptibility rather than a causative locus.
environmental:
- name: Maternal diabetes mellitus
  description: >-
    Maternal diabetes is a recurrently reported non-genetic risk factor for DORV in
    both the human case literature and animal studies of DORV teratogenesis.
  effect: RISK
  evidence:
  - reference: PMID:18456715
    reference_title: "Double outlet right ventricle: aetiologies and associations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Animal studies implicate maternal diabetes and prenatal exposure to ethanol,
      retinoids, theophylline, and valproate in DORV teratogenesis.
    explanation: >-
      Names maternal diabetes among the exposures implicated in DORV
      teratogenesis; the supporting studies cited are animal studies, hence
      MODEL_ORGANISM.
- name: Prenatal teratogen exposure
  description: >-
    Prenatal exposure to ethanol, retinoids, theophylline and valproate has been
    implicated in DORV teratogenesis in animal studies. Retinoic acid is
    particularly plausible mechanistically because tightly bounded retinoic acid
    signalling is required to maintain and differentiate the second-heart-field
    progenitors that elongate and septate the outflow tract, so both deficient and
    excessive signalling perturb the same morphogenetic step that DORV reports.
  effect: RISK
  chemicals:
  - ethanol
  - retinoids
  - theophylline
  - valproate
  evidence:
  - reference: PMID:18456715
    reference_title: "Double outlet right ventricle: aetiologies and associations."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Animal studies implicate maternal diabetes and prenatal exposure to ethanol,
      retinoids, theophylline, and valproate in DORV teratogenesis.
    explanation: >-
      Directly names the teratogenic exposures implicated in DORV in animal
      studies.
treatments:
- name: Prostaglandin E1
  description: >-
    Intravenous prostaglandin E1 maintains ductal patency after birth, preserving
    pulmonary blood flow in DORV with severe pulmonary stenosis or atresia and
    systemic perfusion when there is aortic arch obstruction. It is a bridge to
    definitive repair rather than a treatment of the anatomy.
  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
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      prostaglandin E1 infusion and/or atrial septostomy should be considered
    explanation: >-
      Identifies prostaglandin E1 as the pharmacologic intervention when pulmonary
      blood flow is inadequate in DORV.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These patients will need their patent ductus arteriosus (PDA) to be kept
      patent, either with prostaglandin E1 administration or PDA stent placement
    explanation: >-
      Confirms maintenance of ductal patency with prostaglandin E1 (or a ductal
      stent) as standard preoperative management.
- name: Diuretic therapy for pulmonary overcirculation
  description: >-
    Aggressive diuresis is used to control the pulmonary overcirculation and
    congestive physiology of DORV with an unobstructed pulmonary outflow while
    awaiting repair; escalation to respiratory support and intubation may be
    required.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: furosemide
      term:
        id: CHEBI:47426
        label: furosemide
  target_mechanisms:
  - target: Pulmonary Overcirculation and Ventricular Volume Overload
    treatment_effect: INHIBITS
    description: >-
      Diuresis reduces the volume load and pulmonary congestion generated by the
      large left-to-right shunt without altering the underlying anatomy.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      patients with subaortic VSD or subpulmonary VSD can have pulmonary
      over-circulation requiring aggressive diuresis
    explanation: >-
      Directly documents diuresis as the medical management of pulmonary
      overcirculation in DORV.
- name: Palliative control of pulmonary blood flow
  description: >-
    Interim procedures used before definitive repair, or as the first stage of a
    single-ventricle pathway, to balance pulmonary and systemic flow: pulmonary
    artery banding when there is overcirculation, and a systemic-to-pulmonary
    (central) shunt or ductal stent when pulmonary blood flow is inadequate.
    Balloon atrial septostomy is used urgently when a desaturated infant has
    inadequate atrial-level mixing and a poor cardiac output state.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Cardiac Therapeutic Procedure
    term:
      id: NCIT:C80430
      label: Cardiac Therapeutic Procedure
  target_mechanisms:
  - target: Obligatory Intracardiac Mixing and VSD-Dependent Streaming
    treatment_effect: MODULATES
    description: >-
      Banding, shunting or septostomy rebalances the ratio of pulmonary to
      systemic flow without correcting the underlying connection.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Such palliative procedures include PA band placement for babies with
      pulmonary over-circulation, PDA stent, or operative central shunt creation
      for those with inadequate pulmonary blood
    explanation: >-
      Enumerates the palliative flow-control procedures used in DORV and the
      physiology each addresses.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Consideration should be given to the urgent need for atrial septostomy in a
      patient who is desaturated and has evidence of a poor cardiac output state.
    explanation: >-
      Documents the indication for urgent balloon atrial septostomy in DORV.
- name: Kawashima procedure
  description: >-
    An intraventricular repair for DORV-TGA in which the ventricular septal defect
    is baffled to the aortic valve with patch enlargement of the ventriculotomy,
    after complete resection of the conus. It suits patients with side-by-side
    great arteries whose coronary anatomy precludes root translocation, and
    patients whose pulmonary valve is not of adequate size to support the systemic
    circulation.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Cardiac Surgery
    term:
      id: NCIT:C157806
      label: Cardiac Surgery
  target_mechanisms:
  - target: Persistence of the Subaortic Conus
    treatment_effect: INHIBITS
    description: >-
      Complete resection of the conus removes the muscular sleeve that separates
      the left ventricle from the aortic valve, allowing the VSD to be rerouted to
      the aorta.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The Kawashima procedure: The VSD is baf
    explanation: >-
      Names the Kawashima procedure as one of the defined anatomic repairs for
      DORV-TGA.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In this case, the conus should be resected completely to allow rerouting the
      VSD to the aortic valve
    explanation: >-
      Describes the conal resection that is the mechanistic core of the procedure.
- name: Intraventricular baffle repair
  description: >-
    The standard biventricular repair for a committed ventricular septal defect: a
    patch tunnel is constructed from the left ventricle through the VSD to the
    aortic valve, restoring a series circulation. For a perimembranous or subaortic
    defect the tunnel is relatively straight and can usually be built through the
    right atrium; for a doubly committed defect a right ventriculotomy or
    transpulmonary approach is generally required. A restrictive VSD is enlarged by
    resecting the ventriculo-infundibular fold and conal septum to prevent late
    subaortic obstruction. Repair is recommended within the first six months of
    life to limit the effects of pulmonary overcirculation.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Cardiac Surgery
    term:
      id: NCIT:C157806
      label: Cardiac Surgery
  target_mechanisms:
  - target: Obligatory Intracardiac Mixing and VSD-Dependent Streaming
    treatment_effect: INHIBITS
    description: >-
      The baffle abolishes obligatory intracardiac mixing by giving the left
      ventricle a dedicated outlet to the aorta.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      When the VSD is perimembranous or subaortic, a relatively straight
      intraventricular tunnel can be created between the VSD and the aortic valve
    explanation: >-
      Describes the intraventricular baffle repair and the anatomy for which it is
      most straightforward.
  - reference: PMID:38134423
    reference_title: "Multicentre study on late outcomes of biventricular repair of double outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall survival at 10 years was 86%. This study shows a trend towards
      satisfactory early and late outcomes in BVR of simple DORV with committed
      VSD, compared to complex DORV with ncVSD.
    explanation: >-
      Provides late outcome data for biventricular repair and shows the advantage
      of a committed VSD over a non-committed one.
- name: Arterial switch operation with VSD-to-pulmonary-root baffle
  description: >-
    The preferred anatomic repair for the Taussig-Bing (subpulmonary VSD) form,
    and also used for selected non-committed VSDs. The ventricular septal defect is
    baffled to the pulmonary root, which then becomes the neo-aorta after the great
    arteries are transected and switched with coronary transfer, so the
    intraventricular tunnel is short and does not impinge on the tricuspid valve.
    Concomitant aortic arch repair is required in a large minority. In the largest
    reported single-centre series (225 children) early mortality was 12.9 per cent
    with 10-year survival of 85 per cent; a smaller 34-patient series reported 11
    per cent hospital mortality. Reintervention, most often for pulmonary stenosis,
    is common.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Cardiac Surgery
    term:
      id: NCIT:C157806
      label: Cardiac Surgery
  target_mechanisms:
  - target: Obligatory Intracardiac Mixing and VSD-Dependent Streaming
    treatment_effect: INHIBITS
    description: >-
      Switching the arterial trunks after baffling the VSD to the pulmonary root
      restores concordant ventriculo-arterial connections and abolishes the
      transposition-like streaming of the Taussig-Bing anomaly.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      this is the most common surgical repair when the pulmonary valve is suitable
      for systemic circulation
    explanation: >-
      Identifies the VSD-to-pulmonary-artery baffle plus arterial switch as the
      most common repair for the transposition-type DORV.
  - reference: PMID:35691468
    reference_title: "Mid-Term Outcomes of Primary Arterial Switch Operation for Taussig-Bing Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Early mortality was 12.9% (29/225) with a satisfactory long-term survival
      rate (10-year survival rate 85.0%).
    explanation: >-
      Provides early mortality and 10-year survival for primary arterial switch in
      the Taussig-Bing anomaly.
  - reference: PMID:35691468
    reference_title: "Mid-Term Outcomes of Primary Arterial Switch Operation for Taussig-Bing Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      87 children (38.7%) received concomitant aortic arch repair.
    explanation: >-
      Quantifies the frequency of concomitant aortic arch repair, reflecting the
      arch obstruction characteristic of this subtype.
  - reference: PMID:32795522
    reference_title: "Anatomic Risk Factors for Reintervention After Arterial Switch Operation for Taussig-Bing Anomaly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, 41% patients underwent 26 reinterventions for PS.
    explanation: >-
      Documents the high rate of reintervention for pulmonary stenosis after
      arterial switch in the Taussig-Bing anomaly.
- name: Rastelli-type repair with right ventricle to pulmonary artery conduit
  description: >-
    When pulmonary outflow obstruction is valvar and the pulmonary valve cannot
    support the systemic circulation, the ventricular septal defect is baffled to
    the aorta and right ventricle to pulmonary artery continuity is restored with a
    valved conduit (Rastelli) or, in the REV variant, by direct anastomosis of the
    pulmonary trunk to the infundibulum after a LeCompte manoeuvre. Somatic
    outgrowth and stenosis of the conduit make reoperation predictable, and
    Rastelli-type repair carries higher late mortality and reintervention risk than
    other pathways.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Cardiac Surgery
    term:
      id: NCIT:C157806
      label: Cardiac Surgery
  target_mechanisms:
  - target: Outlet Septum Malalignment and Outflow Tract Obstruction
    treatment_effect: BYPASSES
    description: >-
      A valved right ventricle to pulmonary artery conduit bypasses the obstructed
      native right ventricular outflow tract.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The Rastelli procedure: It is one that includes closing the VSD to the aorta
      and placing a valved RV to PA conduit for RVOT reconstruction.
    explanation: >-
      Defines the Rastelli procedure as used in DORV.
  - reference: PMID:17903515
    reference_title: "Determinants of repair type, reintervention, and mortality in 393 children with double-outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      For complex double-outlet right ventricle, Rastelli-type repair increased
      early reintervention risk (P = .04) and late post-repair mortality (P = .02),
      whereas the arterial switch operation increased early post-repair mortality
      (P = .02) with a benefit of improved late post-repair survival.
    explanation: >-
      Quantifies the reintervention and late mortality penalty of Rastelli-type
      repair relative to the arterial switch in complex DORV.
- name: Nikaidoh procedure and root translocation
  description: >-
    Posterior translocation of the aortic root, or double root translocation,
    creates a straight left ventricular outflow tract when routing the VSD to the
    aorta is not possible or would require a long akinetic tunnel at risk of late
    subaortic stenosis. It is favoured for remote ventricular septal defects,
    straddling atrioventricular valves and significant right ventricular
    hypoplasia. A pulmonary annulus smaller than 5 mm and a coronary artery
    crossing the right ventricular outflow tract at the transection level are
    contraindications.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Cardiac Surgery
    term:
      id: NCIT:C157806
      label: Cardiac Surgery
  target_mechanisms:
  - target: Double Outlet Ventriculo-Arterial Connection
    treatment_effect: RESTORES
    description: >-
      Translocating the aortic root posteriorly re-establishes a direct left
      ventricle to aorta connection rather than tunnelling around the defect.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A Nikaidoh procedure may result in a more acceptable anatomic repair with
      better alignment between the LV and the aorta and preservation of the right
      ventricular volume
    explanation: >-
      States the anatomic rationale for the Nikaidoh root translocation in DORV.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      we do not offer a Nikaidoh procedure to patients with a pulmonary annulus
      size of less than 5 mm
    explanation: >-
      Documents a specific anatomic contraindication to the procedure.
- name: Single-ventricle palliation
  description: >-
    When a safe biventricular route cannot be constructed, staged univentricular
    palliation is used: initial control of pulmonary blood flow with a
    systemic-to-pulmonary shunt, ductal stent or pulmonary artery band, then a
    bidirectional cavopulmonary connection, then total cavopulmonary (Fontan)
    completion at two to three years of age. Any restrictive ventricular septal
    defect should be enlarged at or before Fontan completion.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Cardiac Surgery
    term:
      id: NCIT:C157806
      label: Cardiac Surgery
  target_mechanisms:
  - target: Left Ventricular Hypoplasia and Loss of Biventricular Repair Substrate
    treatment_effect: BYPASSES
    description: >-
      Staged cavopulmonary palliation works around the inadequate left ventricle
      rather than attempting to recruit it into a biventricular circulation.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Contraindications to biventricular repair include severe ventricular
      hypoplasia, abnormal tricuspid chordae, multiple VSDs, and a straddling
      mitral valve.
    explanation: >-
      Defines the anatomic circumstances that select patients into the
      single-ventricle pathway.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      a bidirectional cavopulmonary connection is created
    explanation: >-
      Documents the staged cavopulmonary sequence of the univentricular pathway in
      DORV.
- name: Genetic evaluation and counselling
  description: >-
    Because more than 40 per cent of DORV patients have a chromosomal abnormality
    and syndromic and laterality disorders are common, clinical genetics assessment
    with chromosomal microarray, and exome or genome sequencing when microarray is
    non-diagnostic, is part of standard care. It informs recurrence counselling,
    prognosis and extracardiac surveillance rather than altering the cardiac
    repair.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      More than 40% of patients with DORV have associated chromosomal
      abnormalities
    explanation: >-
      Establishes the high prior probability of a chromosomal diagnosis that
      justifies routine genetic evaluation in DORV.
inheritance:
- name: Multifactorial and sporadic
  description: >-
    Most DORV is sporadic and multifactorial, arising from a combination of rare
    and common variation, developmental stochasticity and maternal or environmental
    influences. More than 40 per cent of patients nevertheless carry a chromosomal
    abnormality, most commonly trisomy 13, trisomy 18 or a 22q11.2 deletion, and
    recurrence counselling should be based on the identified syndrome or gene when
    one is found.
  evidence:
  - reference: PMID:18456715
    reference_title: "Double outlet right ventricle: aetiologies and associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Chromosomal abnormalities were present in 61 of the 149 cases of DORV.
      Trisomies 13 and 18, and del 22q11 were the most commonly associated
      cytogenetic lesions; different anatomic subtypes of DORV were noted in
      trisomies 13 and 18 versus del 22q11.
    explanation: >-
      Documents the heterogeneous chromosomal contribution that underlies the
      multifactorial, largely sporadic inheritance pattern of DORV.
- name: Autosomal dominant (rare monogenic families)
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: COMPLETE
  description: >-
    A minority of DORV is familial and segregates in an autosomal dominant pattern.
    Reported examples include a TBX20 p.R143W kindred and a MEF2C p.R15C pedigree,
    both with complete penetrance in the families described.
  evidence:
  - reference: PMID:25625280
    reference_title: "TBX20 loss-of-function mutation contributes to double outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic analyses of the pedigree of the proband revealed that in the family,
      the mutation co-segregated with DORV transmitted in an autosomal dominant
      pattern with complete penetrance.
    explanation: >-
      Documents autosomal dominant transmission of DORV with complete penetrance in
      a TBX20 kindred.
- name: X-linked (ZIC3-associated laterality spectrum)
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  description: >-
    A small subset of DORV falls within the X-linked laterality spectrum associated
    with ZIC3, the gene classically causing heterotaxy with complex congenital heart
    disease in males, with affected and carrier females also reported.
  evidence:
  - reference: PMID:23427188
    reference_title: "The phenotypic spectrum of ZIC3 mutations includes isolated d-transposition of the great arteries and double outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Disease causing mutations for heterotaxy syndrome were first identified in the
      X-linked laterality gene, ZIC3.
    explanation: >-
      Establishes ZIC3 as an X-linked laterality gene, the inheritance mode relevant
      to the ZIC3-associated subset of DORV.
diagnosis:
- name: Fetal echocardiography
  description: >-
    Prenatal echocardiography can establish the DORV diagnosis with high accuracy
    and define the features that predict the surgical pathway, namely VSD position,
    great-artery relationship, ventricular size, outflow tract anatomy and coronary
    anatomy. In a consecutive single-centre series of 46 prenatally diagnosed cases,
    96 per cent were correctly diagnosed and every child received the repair type
    predicted before birth.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There were 46 cases in all and 96% of them were correctly diagnosed.
    explanation: >-
      Quantifies the accuracy of prenatal echocardiographic diagnosis of DORV.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      fetal echocardiography plays a crucial role in prenatal diagnosis
    explanation: >-
      Establishes fetal echocardiography as the primary prenatal diagnostic
      modality for DORV.
- name: Transthoracic echocardiography
  description: >-
    The postnatal diagnostic modality of choice. It delineates the intracardiac
    anatomy and associated haemodynamics, and in particular the position of the
    ventricular septal defect relative to the semilunar valves, the degree of aortic
    override, and whether atrioventricular valve chordal attachments straddle the
    defect, all of which govern surgical planning.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      transthoracic echocardiography remains the diagnostic modality of choice
    explanation: >-
      Identifies transthoracic echocardiography as the first-line postnatal
      diagnostic test in DORV.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The location of the VSD relative to the semilunar valves is key to surgical
      planning and management.
    explanation: >-
      Explains what the echocardiogram must establish, namely the VSD position that
      defines the anatomic subtype and the repair.
- name: Cardiac computed tomography
  description: >-
    High-resolution cardiac CT is used for pre- and postoperative assessment when
    the acoustic window is limited or metallic implants are present. It defines
    coronary artery origins, branch pulmonary arteries and arch anatomy, and its
    three-dimensional reconstructions and printed models support planning of complex
    intraventricular baffle pathways.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CT serves as a safer and high-quality alternative to diagnostic cardiac
      catheterization or MRI
    explanation: >-
      Positions cardiac CT within the DORV diagnostic pathway relative to
      catheterisation and MRI.
- name: Cardiovascular magnetic resonance
  description: >-
    Cardiovascular magnetic resonance is the reference modality for the
    three-dimensional geometry that determines whether DORV can be repaired
    biventricularly. Preoperatively it resolves the spatial relationship between
    the ventricular septal defect and the two arterial roots, which is the
    information required to decide whether an unobstructed intraventricular baffle
    can be constructed and to plan its course; CMR datasets are the input to
    virtual, 3D-printed and virtual-reality baffle-planning models, which are used
    preoperatively to test whether an unobstructed baffle pathway can actually be
    constructed and therefore to predict candidacy for biventricular repair. It
    also supplies biventricular volumes and function and, with 2D and 4D flow,
    quantifies outflow tract dimensions and shunt haemodynamics, all without
    ionising radiation.
    Postoperatively it is used for surveillance of late structural and functional
    complications such as baffle obstruction, conduit and outflow tract disease and
    ventricular dysfunction. Its limitations in this population are long
    acquisition times, the need for breath-holding or anaesthesia in young
    children, and non-conditional implanted devices.
  evidence:
  - reference: PMID:33689734
    reference_title: "Modeling Tool for Rapid Virtual Planning of the Intracardiac Baffle in Double-Outlet Right Ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Preoperative imaging is a critical tool for assessing the feasibility of a
      biventricular repair and for envisioning the potential baffle pathway.
    explanation: >-
      States the preoperative imaging task in DORV that CMR is used to answer,
      namely feasibility of biventricular repair and the baffle pathway.
  - reference: PMID:33689734
    reference_title: "Modeling Tool for Rapid Virtual Planning of the Intracardiac Baffle in Double-Outlet Right Ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Segmentation and 3D printing of CMR based models has been demonstrated to
      inform the surgical planning process for DORV.
    explanation: >-
      Establishes CMR as the imaging substrate for DORV-specific surgical planning
      models.
  - reference: PMID:33689734
    reference_title: "Modeling Tool for Rapid Virtual Planning of the Intracardiac Baffle in Double-Outlet Right Ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Virtual modeling of the baffle pathway by using cardiac magnetic resonance,
      creation of physical templates for the baffle, and visualization in virtual
      reality are feasible and may be beneficial for preoperative planning of
      complex biventricular repairs in DORV.
    explanation: >-
      Documents CMR-based virtual baffle planning as feasible and potentially
      beneficial for preoperative planning of complex DORV repair.
  - reference: PMID:39062326
    reference_title: "Importance of Cardiovascular Magnetic Resonance Applied to Congenital Heart Diseases in Pediatric Age: A Narrative Review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The application of cardiac magnetic resonance imaging (CMRI) in this
      population allows for obtaining detailed information on the defects without
      the necessity of ionizing radiations.
    explanation: >-
      Supports the radiation-free advantage of CMR in the paediatric congenital
      heart disease population to which DORV belongs.
  - reference: PMID:39062326
    reference_title: "Importance of Cardiovascular Magnetic Resonance Applied to Congenital Heart Diseases in Pediatric Age: A Narrative Review."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      giving essential information in the intervention planning and optimal
      awareness of the postoperative anatomy
    explanation: >-
      Supports the pre- and postoperative roles claimed here; PARTIAL because the
      source addresses congenital heart disease generally rather than DORV
      specifically.
  - reference: PMID:38652290
    reference_title: "Recent advances in multimodal imaging in tetralogy of fallot and double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      this review highlights significant advancements in preoperative and
      postoperative imaging for Tetralogy of Fallot (TOF) and double outlet right
      ventricle (DORV)
    explanation: >-
      Establishes that pre- and postoperative multimodality imaging, including
      CMR, is the recognised imaging framework for DORV specifically.
  - reference: PMID:38652290
    reference_title: "Recent advances in multimodal imaging in tetralogy of fallot and double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The utilization of 4D flow techniques for postoperative hemodynamic
      assessment promises new insights into pressure mapping.
    explanation: >-
      Supports the 4D flow component of the postoperative CMR assessment in DORV.
  - reference: PMID:38652290
    reference_title: "Recent advances in multimodal imaging in tetralogy of fallot and double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the inclusion of cardiac magnetic resonance (CMR) parameters as risk score
      predictors for morbidity, and mortality and for timing of pulmonary valve
      replacement (PVR) indicates its significance in clinical management
    explanation: >-
      Documents the prognostic and reintervention-timing role of CMR parameters in
      the postoperative surveillance of DORV and tetralogy of Fallot.
  - reference: PMID:38391276
    reference_title: "Double outlet right ventricle - the 50% rule has always been about the conus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There is a growing appreciation of the utility of cross-sectional imaging in
      complex DORV, and the generation of patient-specific 3D models with virtual
      reality simulations for surgical planning.
    explanation: >-
      Establishes cross-sectional imaging and patient-specific 3D modelling as
      current practice in the assessment of complex DORV.
  - reference: PMID:38391276
    reference_title: "Double outlet right ventricle - the 50% rule has always been about the conus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These models improve the prediction of candidacy for biventricular repair and
      allow the mapping of complex baffle pathways preoperatively.
    explanation: >-
      Links the imaging modality directly to the entry's central decision point,
      namely whether the VSD can be baffled to an arterial root or whether
      single-ventricle palliation is required.
- name: Cardiac catheterisation and angiography
  description: >-
    Diagnostic catheterisation is no longer routine and is reserved for questions
    that non-invasive imaging leaves open: branch pulmonary artery and aortic arch
    anatomy, coronary artery course, the precise location of the interventricular
    communication, and haemodynamic assessment of pulmonary vascular resistance
    before biventricular repair or cavopulmonary palliation. It is also the access
    route for interventional palliation, notably balloon atrial septostomy and
    ductal stenting.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The purpose of additional studies in addition to an echocardiogram would be
      to clarify the details of the anatomy such as branch pulmonary arteries,
      arch anatomies, and coronaries; it may also assist in clarifying the
      location of the VSD.
    explanation: >-
      States the residual anatomic questions that catheterisation and angiography
      are used to resolve after echocardiography in DORV.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CT serves as a safer and high-quality alternative to diagnostic cardiac
      catheterization or MRI
    explanation: >-
      Positions diagnostic catheterisation as the invasive comparator that
      cross-sectional imaging has largely displaced.
- name: Chromosomal microarray and genomic testing
  description: >-
    Because more than 40 per cent of DORV patients carry a chromosomal abnormality,
    genetic evaluation is part of the diagnostic workup: karyotype or FISH when
    aneuploidy or 22q11.2 deletion is strongly suspected, chromosomal microarray as
    the non-targeted first-line test otherwise, and exome or genome sequencing when
    microarray is non-diagnostic.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      More than 40% of patients with DORV have associated chromosomal
      abnormalities
    explanation: >-
      Establishes the diagnostic yield that justifies routine cytogenomic testing
      in DORV.
differential_diagnoses:
- name: Tetralogy of Fallot
  description: >-
    Tetralogy of Fallot and DORV are not cleanly separable entities: they share a
    developmental origin in the second heart field and cardiac neural crest, and
    the boundary between "tetralogy with an overriding aorta" and "DORV with a
    subaortic or doubly committed VSD and pulmonary stenosis" is set by an
    arbitrary degree of aortic override rather than by a difference in mechanism.
    The DORV-Fallot subtype of this entry occupies exactly that overlap, and its
    physiology and repair (VSD-to-aorta baffle with relief of right ventricular
    outflow tract obstruction) are those of tetralogy. Overlap can be complete:
    tetralogy with pulmonary atresia and a single outlet from the right ventricle
    also satisfies the morphologic definition of DORV.
  disease_term:
    preferred_term: tetralogy of Fallot
    term:
      id: MONDO:0008542
      label: tetralogy of fallot
  distinguishing_features:
  - Degree of aortic override is the operative discriminator; commonly a 50 per cent threshold is applied, but the threshold is conventional rather than mechanistic and different groups apply it differently.
  - Aortic-to-mitral fibrous continuity is classically retained in tetralogy and classically lost in DORV, but this criterion is unreliable because DORV with preserved arterial-to-atrioventricular valvar continuity is the more common form of DORV.
  - Bilateral (subaortic and subpulmonary) infundibula favour DORV; a single subpulmonary infundibulum with a resorbed subaortic conus favours tetralogy.
  - The distinction does not change the operation when the VSD is subaortic and pulmonary stenosis is present, which is why DORV-Fallot outcomes track tetralogy outcomes.
  evidence:
  - reference: PMID:38884738
    reference_title: "Human Genetics of Tetralogy of Fallot and Double-Outlet Right Ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Tetralogy of Fallot (TOF) and double-outlet right ventricle (DORV) are
      conotruncal defects resulting from disturbances of the second heart field
      and the neural crest, which can occur as isolated malformations or as part
      of multiorgan syndromes.
    explanation: >-
      Establishes that the two conditions on either side of this differential share
      a developmental mechanism, which is why the boundary between them is
      definitional rather than mechanistic.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One example would be TOF with DORV and pulmonary atresia.
    explanation: >-
      Documents that a heart can simultaneously satisfy the tetralogy and the DORV
      definitions, demonstrating that the two categories overlap rather than
      exclude one another.
  notes: >-
    Because the boundary is conventional, the practical curation position taken in
    this entry is that VSD position and the presence of outflow tract obstruction,
    not the tetralogy-versus-DORV label, determine physiology and the surgical
    route.
- name: Dextro-looped transposition of the great arteries with ventricular septal defect
  description: >-
    d-TGA with a VSD is the principal differential for the subpulmonary
    (Taussig-Bing) subtype, because both produce transposition-like physiology in
    the newborn: the aorta receives desaturated right ventricular blood and the
    pulmonary artery receives the oxygenated left ventricular stream. The
    distinction is one of ventriculo-arterial connection. In d-TGA both
    connections are discordant, whereas in DORV the aorta is discordant but the
    pulmonary artery remains concordant with the right ventricle. Where the
    pulmonary valve overrides the septal crest, the assignment turns on how much
    of the valve sits over each ventricle, so the same heart may be called
    Taussig-Bing DORV or d-TGA with an overriding pulmonary artery depending on
    the override threshold used.
  disease_term:
    preferred_term: dextro-looped transposition of the great arteries
    term:
      id: MONDO:0019443
      label: dextro-looped transposition of the great arteries
  distinguishing_features:
  - In d-TGA both ventriculo-arterial connections are discordant; in DORV the aorta is discordant while the pulmonary artery is concordant.
  - When the pulmonary valve overrides, the lesion is called d-TGA if more than half the valve sits above the morphologic left ventricle, and Taussig-Bing DORV if more than half sits above the right ventricle.
  - Pulmonary-to-mitral fibrous continuity is present in d-TGA with a perimembranous VSD and an overriding pulmonary artery, and absent in the Taussig-Bing malformation.
  - Both are treated by an arterial switch, but the Taussig-Bing variant additionally requires a baffle routing the VSD to the pulmonary root and carries a high burden of aortic arch obstruction and coronary anomaly.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, in DORV, the aorta has a discordant connection while the PA has
      a concordant connection.
    explanation: >-
      States the connection-level criterion that separates DORV from transposition
      of the great arteries.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      If the majority, more than 50%, of the pulmonary valve sits above the
      morphologic LV, this would be considered a TGA because the pulmonary trunk
      has a discordant ventriculo-arterial connection.
    explanation: >-
      Shows that the DORV-versus-TGA assignment for an overriding pulmonary valve
      is decided by a proportional override threshold.
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In TGA with a perimembranous VSD and overriding PA, the pulmonary –mitral
      continuity is present, whereas in the Taussig –Bing malformation, the
      pulmonary–mitral continuity is absent.
    explanation: >-
      Gives the morphologic feature used at the bedside to separate Taussig-Bing
      DORV from transposition with an overriding pulmonary artery.
discussions:
- discussion_id: dorv_genotype_to_morphology_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - Cardiac Neural Crest and Second Heart Field Disruption
  - Outlet Septum Attachment Determines VSD Commitment
  prompt: >-
    By what mechanism does a given genetic lesion or teratogenic exposure convert
    normal outflow tract morphogenesis into the specific DORV subtype it produces,
    and what determines whether the resulting ventricular septal defect is
    subaortic, subpulmonary, doubly committed or non-committed?
  rationale: >-
    The pathophysiology modelled in this entry describes a coherent developmental
    chain from neural crest and second-heart-field disruption to the double-outlet
    connection, and the literature reliably associates particular aetiologies with
    particular anatomic subtypes (trisomy 13/18 versus 22q11.2 deletion produce
    different DORV subtypes). What is missing is the mechanistic bridge: no source
    explains how a specific lesion selects a specific outlet-septum attachment and
    therefore a specific VSD commitment. Because VSD position, not the DORV label,
    determines physiology and repair, this gap sits directly between the genetics
    and the clinically actionable anatomy.
  proposed_experiments:
  - experiment_id: dorv_allelic_series_oft_transcriptomics
    name: Lineage-resolved transcriptomics of the outflow tract across DORV alleles
    description: >-
      Single-cell and spatial transcriptomics of the murine outflow tract across a
      panel of DORV-producing alleles (Lrp1, Shroom3, Foxj1, Tbx1), staged through
      conal rotation, to test whether each lesion perturbs a distinct progenitor
      compartment rather than converging on one.
    decision_criterion: >-
      Allele-specific perturbation of distinct neural-crest versus
      second-heart-field compartments would show that the developmental route, not
      just the endpoint, differs by aetiology.
  - experiment_id: dorv_outlet_septum_morphometry
    name: Three-dimensional morphometry of outlet septum attachment
    description: >-
      Quantitative three-dimensional morphometry of outlet-septum attachment across
      the same allelic series, testing whether attachment site predicts the
      resulting ventricular septal defect commitment.
    decision_criterion: >-
      A reproducible mapping from allele to attachment site to VSD commitment would
      supply the missing mechanistic bridge between genotype and the clinically
      actionable anatomy.
  - experiment_id: dorv_genotype_subtype_cohort
    name: Genotype-to-subtype association in a uniformly classified DORV cohort
    description: >-
      Genotype-to-subtype association analysis in a large clinically phenotyped DORV
      cohort with uniform ISNPCHD anatomic classification and trio genome
      sequencing.
    decision_criterion: >-
      Significant association between specific genomic lesions and specific VSD
      positions would confirm in humans the genotype-to-morphology relationship
      suggested by the trisomy 13/18 versus 22q11.2 subtype difference.
  evidence:
  - reference: PMID:37818164
    reference_title: "Double outlet right ventricle."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      genetic anomalies or environmental exposures result in the development of
      DORV from normal structural cardiac anatomy are unknown
    explanation: >-
      The source states directly that the mechanisms by which specific genetic
      anomalies or environmental exposures produce DORV from normal structural
      cardiac anatomy are unknown, which is precisely the gap recorded here.
  - reference: PMID:18456715
    reference_title: "Double outlet right ventricle: aetiologies and associations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      different anatomic subtypes of DORV were noted in trisomies 13 and 18 versus
      del 22q11
    explanation: >-
      Documents that aetiology and anatomic subtype are correlated, which is what
      makes the missing mechanistic bridge worth resolving.
clinical_trials:
- name: NCT00972608
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Prospective observational study (n = 66, completed) registered for the
    condition "Double Outlet Right Ventricle", developing and validating an
    image-based virtual surgical planning protocol: patient MRI, 3D
    echocardiography and CT are reconstructed into 3D anatomy, candidate repairs
    are simulated on the model, and the chosen virtual plan is compared against
    the operation actually performed on postoperative imaging. It is the trial
    counterpart of the CMR-based baffle-planning workflow captured under
    diagnosis.
  target_phenotypes:
  - preferred_term: Double outlet right ventricle
    term:
      id: HP:0001719
      label: Double outlet right ventricle
  - preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: clinicaltrials:NCT00972608
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      assess the feasibility of using surgical planning in the treatment of
      patients with complex cardiac defects
    explanation: >-
      States the objective of the trial, whose single registered condition on
      ClinicalTrials.gov is Double Outlet Right Ventricle.
  - reference: clinicaltrials:NCT00972608
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Use the developed protocol to prospectively plan and evaluate the possible
      surgical options for new patients.
    explanation: >-
      Documents the prospective surgical-planning aim that makes this trial
      relevant to the anatomy-driven repair decision in DORV.
  notes: >-
    Observational rather than an interventional therapeutic trial; included
    because image-based surgical planning is the active area of clinical
    innovation in DORV and this is the only registered DORV-specific study
    surfaced by the deep-research sweep.
references:
- reference: PMID:17903515
  title: "Determinants of repair type, reintervention, and mortality in 393 children with double-outlet right ventricle."
  findings: []
- reference: PMID:18456715
  title: "Double outlet right ventricle: aetiologies and associations."
  findings: []
- reference: PMID:22826212
  title: "Morphogenesis of outflow tract rotation during cardiac development: the pulmonary push concept."
  findings: []
- reference: PMID:23427188
  title: "The phenotypic spectrum of ZIC3 mutations includes isolated d-transposition of the great arteries and double outlet right ventricle."
  findings: []
- reference: PMID:25625280
  title: "TBX20 loss-of-function mutation contributes to double outlet right ventricle."
  findings: []
- reference: PMID:27641710
  title: "How should we diagnose and differentiate hearts with double-outlet right ventricle?"
  findings: []
- reference: PMID:29468350
  title: "A Novel MEF2C Loss-of-Function Mutation Associated with Congenital Double Outlet Right Ventricle."
  findings: []
- reference: PMID:32511952
  title: "SHROOM3 is downstream of the planar cell polarity pathway and loss-of-function results in congenital heart defects."
  findings: []
- reference: PMID:32795522
  title: "Anatomic Risk Factors for Reintervention After Arterial Switch Operation for Taussig-Bing Anomaly."
  findings: []
- reference: PMID:33689734
  title: "Modeling Tool for Rapid Virtual Planning of the Intracardiac Baffle in Double-Outlet Right Ventricle."
  findings: []
- reference: PMID:35691468
  title: "Mid-Term Outcomes of Primary Arterial Switch Operation for Taussig-Bing Anomaly."
  findings: []
- reference: PMID:37158461
  title: "Congenital heart defects caused by FOXJ1."
  findings: []
- reference: PMID:37818164
  title: "Double outlet right ventricle."
  findings: []
- reference: PMID:38134423
  title: "Multicentre study on late outcomes of biventricular repair of double outlet right ventricle."
  findings: []
- reference: PMID:38391276
  title: "Double outlet right ventricle - the 50% rule has always been about the conus."
  findings: []
- reference: PMID:38652290
  title: "Recent advances in multimodal imaging in tetralogy of fallot and double outlet right ventricle."
  findings: []
- reference: PMID:38884738
  title: "Human Genetics of Tetralogy of Fallot and Double-Outlet Right Ventricle."
  findings: []
- reference: PMID:39062326
  title: "Importance of Cardiovascular Magnetic Resonance Applied to Congenital Heart Diseases in Pediatric Age: A Narrative Review."
  findings: []
datasets: []

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References & Deep Research

References

18

PMID:17903515

Determinants of repair type, reintervention, and mortality in 393 children with double-outlet right ventricle.