Congenital Heart Disease

Complex MONDO:0005453 Pathograph 58 Show in embeddings browser Heart disorder Congenital anomaly of cardiovascular system

Congenital heart disease (CHD) is the umbrella term for structural malformation of the heart or intrathoracic great vessels present at birth. This entry is curated as the **mechanistic root** of the CHD family: it models the shared developmental biology from which the individual lesions arise — cardiac progenitor field specification and second heart field deployment, left-right patterning and cardiac looping, cardiac neural crest migration and outflow tract septation, endocardial cushion formation and endothelial-to-mesenchymal transition, the septation transcription factor network, and flow-dependent morphogenesis — together with the genetic and maternal-environmental perturbations that disrupt them. The individual lesions and syndromes are curated in their own dismech entries (Atrial_Septal_Defect, Ventricular_Septal_Defect, Tetralogy_of_Fallot, Coarctation_of_the_Aorta, Hypoplastic_Left_Heart_Syndrome, Dextro_Transposition_of_the_Great_Arteries, Persistent_Truncus_Arteriosus, Double_Outlet_Right_Ventricle, Ebstein_Anomaly, Visceral_Heterotaxy, 22q11.2_Deletion_Syndrome, CHARGE_Syndrome, Alagille_syndrome, Down_syndrome, Holt-Oram_Syndrome, Noonan_Syndrome, Turner_Syndrome and others); this root deliberately does not re-derive their lesion-specific pathographs or post-natal haemodynamics beyond the shared convergence point.

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Inheritance

Multifactorial inheritance HP:0001426

Most isolated CHD is not Mendelian. The prevailing model is multifactorial: common variation, rare inherited variants of modest effect, de novo variants, and maternal environmental exposures combine to cross a developmental threshold. Recurrence risk after an isolated non-syndromic case is empirically a few percent, and a defined Mendelian or chromosomal diagnosis replaces that empiric figure with disorder-specific counselling. A genetic cause remains unidentified in a majority of patients.

Multifactorial inheritance

Show evidence (2 references)

PMID:39337901 SUPPORT Human Clinical

"The etiology of CHD is multifactorial and involves interplay between genetic and environmental factors."

States the multifactorial inheritance model this block records.

PMID:39337901 SUPPORT Human Clinical

"however, the cause of the disease remains unexplained in up to 60% of CHD patients"

Quantifies the substantial unexplained fraction that motivates the multifactorial rather than Mendelian default.

De novo variation in severe sporadic congenital heart disease HP:0003745

A distinct inheritance mode within CHD rather than an alternative to the multifactorial model: severe CHD impairs reproductive fitness, so a large share of severe sporadic cases is caused by newly arisen variants absent from both parents. The de novo contribution is strongly stratified by phenotype — it is small in isolated CHD and large when neurodevelopmental disability and extracardiac anomalies accompany the cardiac lesion.

Sporadic De novo rate: De novo mutations accounted for 8% of cases overall, ~3% of isolated CHD and ~28% of CHD with both neurodevelopmental and extracardiac congenital anomalies (Jin 2017, n=2,871 probands).

Show evidence (2 references)

PMID:28991257 SUPPORT Human Clinical

"De novo mutations (DNMs) accounted for 8% of cases, including ~3% of isolated CHD patients and ~28% with both neurodevelopmental and extra-cardiac congenital anomalies."

Quantifies the de novo contribution and its stratification by accompanying phenotype.

PMID:23665959 SUPPORT Human Clinical

"Many cases occur sporadically and impair reproductive fitness, suggesting a role for de novo mutations."

States the evolutionary rationale for expecting de novo variation to dominate severe sporadic CHD.

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Subtypes

Conotruncal (outflow tract) defects MONDO:0016581

Malformations of the cardiac outflow tract and great arteries arising from failure of aorticopulmonary septation, outflow tract rotation, or alignment: tetralogy of Fallot, transposition of the great arteries, persistent truncus arteriosus, double outlet right ventricle, and interrupted aortic arch. Mechanistically anchored on the cardiac neural crest and second heart field arms of this entry.

Show evidence (1 reference)

PMID:32405705 SUPPORT Other

"Outflow tract abnormalities are the most frequent congenital heart defects."

Establishes the conotruncal/outflow-tract group as a distinct and numerically dominant class within CHD.

Septal defects (atrial and ventricular)

Communications across the interatrial or interventricular septum — secundum and primum atrial septal defect, and perimembranous, muscular, inlet and outlet ventricular septal defect. Together with patent ductus arteriosus these are the mild-end lesions that dominate reported CHD birth prevalence. No single MONDO class covers the atrial-plus-ventricular septal group; the constituent lesions are curated as Atrial_Septal_Defect (MONDO:0006664) and Ventricular_Septal_Defect (MONDO:0002070).

Show evidence (1 reference)

PMID:30783674 SUPPORT Human Clinical

"The change in prevalence of mild CHD lesions (ventricular septal defect, atrial septal defect and patent ductus arteriosus) together explained 93.4% of the increased overall prevalence"

Identifies the septal-defect group (with PDA) as the lesion class that dominates contemporary reported CHD birth prevalence.

Atrioventricular septal defect (AV canal defect) MONDO:0859565

Deficiency of the atrioventricular septum with a common atrioventricular junction, arising from failure of endocardial cushion fusion. Strongly associated with trisomy 21. Anchored on the endocardial cushion / endothelial-to-mesenchymal transition arm of this entry.

Left ventricular outflow tract obstruction

Obstructive lesions of the left heart and systemic outflow — hypoplastic left heart syndrome, aortic valve stenosis, bicuspid aortic valve, coarctation of the aorta, and Shone complex. Mechanistically the class in which flow-dependent morphogenesis ("no flow, no grow") is most clearly implicated: an early obstruction limits flow through left heart structures, whose growth is then secondarily curtailed.

Show evidence (1 reference)

PMID:30783674 SUPPORT Human Clinical

"the prevalence of lesions grouped together as left ventricular outflow tract obstruction (which includes hypoplastic left heart syndrome) decreased"

Uses left ventricular outflow tract obstruction as an established analytic lesion class in CHD epidemiology.

Right-sided obstructive lesions

Obstructive and hypoplastic lesions of the right heart and pulmonary outflow — pulmonary valve stenosis, pulmonary atresia with or without ventricular septal defect, tricuspid atresia, and Ebstein anomaly. The right-sided counterpart of LVOTO; the severe forms produce duct-dependent pulmonary circulation.

Show evidence (1 reference)

PMID:22078432 SUPPORT Human Clinical

"with relatively more pulmonary outflow obstructions and fewer left ventricular outflow tract obstructions"

Treats pulmonary (right-sided) outflow obstruction as a lesion class distinct from left ventricular outflow tract obstruction in CHD epidemiology.

Heterotaxy and laterality defects MONDO:0018677

Complex cardiac malformation arising from failure of left-right axis determination at the embryonic left-right organizer, with abnormal atrial situs, systemic and pulmonary venous connections, and atrioventricular/ventriculoarterial alignment. Notably, this is the CHD class that did NOT show an excess of damaging de novo variants in the PCGC cohort, distinguishing its genetic architecture from the conotruncal and LVOTO classes.

Show evidence (1 reference)

PMID:26785492 SUPPORT Human Clinical

"was found in each CHD category (conotruncal defects, left ventricular outflow tract obstruction and "other"), except for heterotaxy, which showed no excess"

Establishes heterotaxy as an analytically separate CHD class whose de novo variant burden differs from the other classes.

Anomalous pulmonary venous return MONDO:0017705

Total or partial drainage of the pulmonary veins to the systemic venous circulation rather than the left atrium, arising from failure of the common pulmonary vein to incorporate into the left atrium. Frequently a component of heterotaxy.

Discussions and Knowledge Gaps

What does this root entry add over the ~24 lesion-specific and ~195 syndromic dismech entries that already carry congenital cardiac content, and where should the boundary sit?

CURATION TODO OPEN chd_root_scope

Attached to

pathophysiology#Structural Cardiac Malformation

At the time of curation the knowledge base already held dedicated entries for atrial and ventricular septal defect, tetralogy of Fallot, coarctation, hypoplastic left heart syndrome, d-transposition, persistent truncus arteriosus, double outlet right ventricle, Ebstein anomaly, visceral heterotaxy, patent ductus arteriosus, anomalous pulmonary venous return and more, plus syndromic entries (22q11.2 deletion, CHARGE, Alagille, Down, Holt-Oram, Noonan, Turner, Kabuki, Williams, Ellis-van Creveld) carrying CHD as a phenotype. This entry was deliberately scoped to the *shared developmental biology* those entries individually assume but none asserts: first heart field vs second heart field deployment, cardiac neural crest migration, endocardial cushion endothelial-to-mesenchymal transition, the septation transcription factor network, left-right patterning, and flow-dependent morphogenesis. Four of those were unbroken ground in the KB before this entry (GO:0003272 and GO:0003203 endocardial cushion terms had zero prior uses, GO:0003198 one, CL:2000073 migratory cardiac neural crest cell zero, and flow-dependent morphogenesis had no ontology anchoring anywhere). Conversely the entry deliberately does NOT re-derive lesion-specific pathographs, post-operative course, or the shunt-to-Eisenmenger trajectory, all of which are curated elsewhere. The open question is whether the boundary should be enforced by a complementary kb/groupings/ Grouping recording the curated membership set and its criteria, in the manner of Familial_Hypertrophic_Cardiomyopathy, which keeps both an umbrella Disease entry (for the shared mechanism and gene spectrum) and a Grouping (for the audited membership boundary).

Should the cardiac morphogenesis chain in this entry be factored out into a kb/modules/ mechanism module that the lesion entries can declare conforms_to?

CURATION TODO OPEN chd_module_candidate

Attached to

pathophysiology#Cardiac Progenitor Specification and Second Heart Field Deployment Failure

The four developmental arms modelled here recur, node for node, across at least eight existing lesion entries: tetralogy of Fallot, persistent truncus arteriosus and double outlet right ventricle all carry "cardiac neural crest and second heart field" nodes in prose; d-transposition and DORV both carry looping/left-right nodes; hypoplastic left heart syndrome and coarctation both assert the flow-limitation step without anchoring it. That recurrence is exactly the signal the create-module skill treats as a module trigger, and no kb/modules/ entry currently covers cardiac development. A cardiac_morphogenesis_failure module would let those entries declare conformance rather than each re-deriving the chain. It was not created in this pass because module creation is a separate deliverable with its own review requirements, and because the correct node granularity is better judged after this root entry has been reviewed.

Is flow-dependent cardiac morphogenesis demonstrated in human development, or is the "no flow, no grow" node in this entry an extrapolation from zebrafish?

HUMAN MODEL MISMATCH OPEN chd_flow_dependent_human_evidence

Attached to

pathophysiology#Flow-Dependent Cardiac Morphogenesis Failure

The direct experimental evidence that haemodynamic force is a necessary morphogenetic input — that removing or altering flow makes heart development abnormal — comes from zebrafish, where the embryo can be manipulated and observed. The node is therefore curated with evidence_source MODEL_ORGANISM. In humans the supporting evidence is inferential: an early flow-limiting lesion is observed to be accompanied by progressive hypoplasia of the structures behind it (the natural history of evolving hypoplastic left heart syndrome and of aortic arch hypoplasia). That correlation is compatible with the flow hypothesis but does not exclude a common developmental cause acting on both the valve and the chamber. Resolving this matters because it determines whether fetal intervention to restore flow can be expected to rescue chamber growth, or only to relieve obstruction. Both sides of the question now have a structural anchor in this entry. The zebrafish perturbation model (animal_models) supplies the causal flow evidence and carries its species limitations explicitly - a two-chambered heart with no septation cannot represent most of what this entry models. Against it, HLHS patient-derived iPSC-cardiomyocytes (experimental_models) show impaired cardiac-lineage differentiation, reduced CX43 and disorganised myofibrils while cultured entirely outside any haemodynamic environment, which is human-derived evidence that a cell-autonomous component exists. Neither settles the share of each contribution, which is what the proposed experiment below is aimed at.

Proposed experiments

Serial fetal echocardiographic growth trajectories after fetal aortic valvuloplasty

chd_fetal_valvuloplasty_growth_trajectory

Test whether relieving a flow-limiting lesion in mid-gestation alters the subsequent growth trajectory of the left ventricle, aortic valve annulus and ascending aorta relative to matched unintervened fetuses. A growth response would support the flow-dependent model directly in humans; its absence would favour a shared upstream developmental cause.

How much of the reported worldwide variation in CHD birth prevalence is real biological difference and how much is ascertainment?

KNOWLEDGE GAP OPEN chd_prevalence_ascertainment

Attached to

pathophysiology#Structural Cardiac Malformation

Reported birth prevalence rose from 0.6 per 1000 in the 1930s to over 9 per 1000 after 1995, and 93.4% of the recent increase is attributable to the mild lesions (ventricular septal defect, atrial septal defect, patent ductus arteriosus) that postnatal echocardiography detects. Meanwhile the reported prevalence of left ventricular outflow tract obstruction has fallen, which the authors read as prenatal detection with consequent termination. Africa reports the lowest prevalence and Asia the highest. Almost none of this is safely interpretable as variation in the underlying developmental biology this entry models, and the prevalence records here are curated as *reported* birth prevalence for that reason. Distinguishing the two would need a population with uniform prenatal and postnatal ascertainment, including pregnancy outcomes.

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Pathophysiology

Developmental Gene Dosage Disruption

The upstream molecular trigger of most severe CHD: loss of normal dosage or function of genes required for cardiac morphogenesis. Three genetic mechanisms converge here — chromosomal aneuploidy, recurrent and non-recurrent copy-number variants, and point mutations (predominantly de novo in severe sporadic cases). De novo damaging variants are concentrated in genes highly expressed in the developing heart and, strikingly, in chromatin-modifying genes that write, read and erase H3K4 methylation and H2BK120 ubiquitination — the marks that characterise the "poised" promoters and enhancers of key developmental genes. Because the same genes are also highly expressed in the developing brain, this node also explains the co-occurrence of CHD with neurodevelopmental disability and extracardiac anomalies. Roughly 400 developing-heart-expressed genes are inferred to contribute.

KMT2D hgnc:7133 CHD7 hgnc:20626 RBFOX2 hgnc:9906

chromatin organization GO:0006325 ⇓ LOSS OF FUNCTION regulation of transcription by RNA polymerase II GO:0006357 ↓ DECREASED

Downstream

Cardiac Progenitor Specification and Second Heart Field Deployment Failure Haploinsufficiency of second heart field transcription factors (TBX1, ISL1, GATA4/6, NKX2-5) and of the chromatin machinery that licenses their targets reduces progenitor addition to the cardiac poles.

Left-Right Patterning and Cardiac Looping Failure Variants in left-right organizer genes (ZIC3, NODAL, GDF1) and in SMAD2, which regulates H3K27 methylation in the embryonic left-right organizer, randomise axis determination.

Cardiac Neural Crest Migration and Outflow Tract Septation Failure

Endocardial Cushion Formation and Endothelial-to-Mesenchymal Transition Failure RBFOX2 loss of function, recurrent de novo in hypoplastic left heart syndrome, disrupts the epithelial-mesenchymal transition programme; NOTCH1 and JAG1 are also recurrently mutated.

Cardiac Septation Transcription Factor Network Failure

Neurodevelopmental abnormality The de novo and rare-variant burden that disrupts cardiac developmental gene dosage falls in genes also highly expressed in the developing brain, giving a shared genetic route to neurodevelopmental impairment alongside the hypoxaemic and operative routes.

Extracardiac congenital anomaly The chromatin-modifying and neural crest genes that dominate the CHD de novo burden are shared with non-cardiac developmental programmes, so extracardiac structural anomalies co-occur with the cardiac lesion rather than following from it.

Show evidence (5 references)

PMID:23665959 SUPPORT Human Clinical

"We find a marked excess of de novo mutations in genes involved in the production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or ubiquitination of H2BK120, which is required for H3K4 methylation."

Identifies chromatin modification of developmental promoters/enhancers as the molecular process disrupted by de novo mutation in severe CHD.

PMID:26785492 SUPPORT Human Clinical

"Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain."

Localises the mutational burden to genes with high developing-heart expression and explains the shared cardiac/neurodevelopmental pleiotropy.

PMID:28991257 SUPPORT Human Clinical

"DNMs in ~440 genes were inferred to contribute to CHD."

Quantifies the breadth of the developmental gene set whose dosage disruption causes CHD.

+ 2 more references

Maternal Metabolic and Teratogenic Perturbation of Cardiogenesis

The non-genetic arm of CHD causation. During the window of cardiac organogenesis (roughly gestational weeks 3-8) the embryonic heart is vulnerable to the maternal metabolic and pharmacological environment. Pregestational diabetes is by a wide margin the strongest established modifiable risk factor; the proposed mediators are persistent embryonic hyperglycaemia, oxidative stress, dysregulation of hypoxia-inducible factor 1, and downregulation of the very NOTCH1 and NKX2-5 programmes that the genetic arm of this entry disrupts. Definitive teratogenic exposures include maternal rubella, untreated maternal phenylketonuria, thalidomide, retinoids and vitamin A congeners, and indomethacin tocolysis. Periconceptional folic acid / multivitamin intake is the principal candidate protective exposure.

cellular response to oxidative stress GO:0034599 ↑ INCREASED

Downstream

Endocardial Cushion Formation and Endothelial-to-Mesenchymal Transition Failure

Cardiac Septation Transcription Factor Network Failure

Show evidence (3 references)

PMID:38996968 SUPPORT Human Clinical

"Pregestational diabetes (PGDM) was associated with CHDs (OR, 3.51; 95% CI, 2.86-4.3), without difference between type 1 and type 2 PGDM."

Quantifies pregestational diabetes as the dominant non-genetic risk factor in a 170-study meta-analysis.

PMID:35838899 SUPPORT Human Clinical

"Factors such as persistent maternal hyperglycemia, oxidative stress, polymorphism of uncoupling protein 2, polymorphism of adiponectin gene, Notch 1 pathway, Nkx2.5 disorders, dysregulation of the hypoxia-inducible factor 1, and viral etiologies are associated with the occurrence of congenital..."

Names the proposed molecular mediators, which converge on the same NOTCH1 and NKX2-5 programmes as the genetic arm.

PMID:17519397 SUPPORT Human Clinical

"Information is highlighted regarding definitive risk factors such as maternal rubella; phenylketonuria; pregestational diabetes; exposure to thalidomide, vitamin A cogeners, or retinoids; and indomethacin tocolysis."

Enumerates the exposures the AHA classifies as definitive non-inherited risk factors for congenital cardiovascular defects.

Cardiac Progenitor Specification and Second Heart Field Deployment Failure

The heart is not built from a single progenitor pool. The first heart field forms the linear heart tube and gives rise principally to the left ventricle and part of the atria; the second heart field (SHF) is a distinct population of progenitors that is progressively added to both poles of the elongating tube. The SHF supplies the right ventricle, the outflow tract myocardium and the ventricular septal myocardium at the arterial pole, and atrial including atrial septal myocardium at the venous pole. Because SHF deployment lays down the template on which septation is later performed, and because it orchestrates outflow tract development jointly with the neural crest, a deficit in progenitor addition is a single upstream lesion that can produce conotruncal, right ventricular hypoplastic, and septal phenotypes. This node is the reason a "root" CHD entry is mechanistically coherent rather than merely a list.

HAND1 hgnc:4807 HAND2 hgnc:4808

embryonic heart tube development GO:0035050 ↓ DECREASED embryonic heart tube morphogenesis GO:0003143 ↓ DECREASED heart development GO:0007507 ↓ DECREASED

Downstream

Cardiac Neural Crest Migration and Outflow Tract Septation Failure SHF deployment has been implicated in orchestrating outflow tract development together with the neural crest cells; a deficient arterial-pole template compromises subsequent neural-crest-dependent septation.

Cardiac Septation Transcription Factor Network Failure The SHF supplies the ventricular septal and atrial septal myocardium, so the septation programme acts on a template the SHF has laid down.

Left-Right Patterning and Cardiac Looping Failure Second heart field deployment has been implicated in cardiac looping itself, not only in the addition of myocardium at the poles.

Structural Cardiac Malformation

Show evidence (6 references)

PMID:38488639 SUPPORT Other

"The SHF gives rise to ventricular septal, right ventricular and outflow tract myocardium at the arterial pole, and atrial, including atrial septal myocardium, at the venous pole."

Defines exactly which cardiac structures depend on second heart field addition, and therefore which lesions a deployment deficit can produce.

PMID:38488639 SUPPORT Other

"Genetic or environmental perturbation of SHF deployment thus underlies a spectrum of common forms of CHD affecting conotruncal and septal morphogenesis."

States the causal claim of this node: SHF deployment failure is a shared upstream cause of both conotruncal and septal CHD.

PMID:39000221 SUPPORT Other

"Cardiac morphogenesis involves numerous types of cells originating outside the initial cardiac crescent, including neural crest cells, cells of the second heart field origin, and epicardial progenitor cells."

Establishes the multi-progenitor architecture of cardiac morphogenesis that this node and the neural crest node between them represent.

+ 3 more references

Left-Right Patterning and Cardiac Looping Failure

The linear heart tube must break bilateral symmetry and loop rightward (dextral looping) for the systemic and pulmonary circulations to be placed in their correct series arrangement. Handedness is set upstream at the embryonic left-right organizer, where motile-cilium-driven leftward flow establishes asymmetric NODAL, LEFTY and PITX2 expression; ZIC3 acts at the earliest stages of this process. Failure randomises the axis, producing situs ambiguus (heterotaxy) with its complex atrial, venous and ventriculoarterial mis-connections, or complete situs inversus. This node is the point at which the CHD root meets the ciliopathy_dysfunction and Visceral_Heterotaxy entries; those curate the ciliary machinery and the individual HTX loci in detail and are deliberately not re-derived here.

ZIC3 hgnc:12874 SMAD2 hgnc:6768

determination of left/right symmetry GO:0007368 ⇓ LOSS OF FUNCTION left/right pattern formation GO:0060972 ↓ DECREASED heart looping GO:0001947 ↓ DECREASED

Downstream

Structural Cardiac Malformation Randomised laterality produces abnormal atrial situs, anomalous systemic and pulmonary venous connections, atrioventricular and ventriculoarterial discordance, and commonly an unbalanced atrioventricular septal defect.

Heterotaxy Failure to break and propagate the left-right axis randomises thoracoabdominal situs, which is the heterotaxy phenotype itself rather than a consequence of it.

Abnormal pulmonary vein morphology Laterality failure leaves the common pulmonary vein to connect to the systemic venous circulation, giving the anomalous pulmonary venous return that accompanies the heterotaxy syndromes.

Show evidence (3 references)

PMID:9354794 SUPPORT Human Clinical

"The frameshift allele is also associated with situs inversus among some heterozygous females, suggesting that ZIC3 functions in the earliest stages of LR-axis formation."

Places a human CHD/laterality gene at the earliest step of left-right axis formation, which is the claim of this node.

PMID:9354794 SUPPORT Human Clinical

"Aberrant LR axis development can lead to randomization of individual organ position (situs ambiguus) or to mirror-image reversal of all lateralized structures (situs inversus)."

States the two phenotypic outcomes of left-right patterning failure that define the heterotaxy subtype.

PMID:30157302 SUPPORT DIRECT Human Clinical

"Our data suggest two distinct phenotypes associated with pathogenic variants in SMAD2: complex CHD with or without laterality defects and other congenital anomalies, and a late-onset vascular phenotype characterized by arterial aneurysms with connective tissue abnormalities."

Binds SMAD2 to this node: it is the TGF-beta/NODAL-pathway effector whose pathogenic variants produce complex CHD with laterality defects, which is the left-right patterning failure this node models. The same paper records the separate aneurysm phenotype curated in the aortopathy entries.

Cardiac Neural Crest Migration and Outflow Tract Septation Failure

Cardiac neural crest cells delaminate from the postotic (vagal) hindbrain, migrate through the caudal pharyngeal arches, and enter the outflow tract, where they are indispensable for formation of the aorticopulmonary septum that divides the common truncus into aorta and pulmonary trunk. The same population patterns the aortic arch arteries and contributes to the semilunar valves and the proximal coronary arteries. Crucially, cardiac neural crest and second heart field cells migrate in opposite directions at the same developmental stage, so a perturbation of either population produces overlapping conotruncal phenotypes. Because these cells also build craniofacial and pharyngeal-arch derivatives, their failure explains the recurrent clinical co-occurrence of conotruncal CHD with craniofacial and pharyngeal anomalies (22q11.2 deletion, CHARGE) — the cardiac face of the neurocristopathy concept.

migratory cardiac neural crest cell CL:2000073

TBX1 hgnc:11592 TFAP2B hgnc:11743 GATA6 hgnc:4174

cardiac neural crest cell migration involved in outflow tract morphogenesis GO:0003253 ↓ DECREASED neural crest cell migration GO:0001755 ↓ DECREASED outflow tract morphogenesis GO:0003151 ↓ DECREASED

outflow tract UBERON:0004145

Downstream

Structural Cardiac Malformation Failure of aorticopulmonary septation yields persistent truncus arteriosus; partial or malaligned septation yields tetralogy of Fallot, double outlet right ventricle and interrupted aortic arch.

Conotruncal defect Absent or misdirected neural-crest-dependent aorticopulmonary septation is the developmental origin of the conotruncal lesion class as a whole.

Tetralogy of Fallot Partial and anteriorly malaligned outflow septation produces the tetralogy combination of malalignment ventricular septal defect, overriding aorta and right ventricular outflow obstruction.

Transposition of the great arteries Failure of the spiralling rotation of the outflow tract during neural-crest-dependent septation leaves the great arteries in ventriculoarterial discordance.

Patent ductus arteriosus The arterial duct is a neural-crest-derived arch segment, so crest failure is one developmental route to persistence of the duct after birth.

Show evidence (7 references)

PMID:32405705 SUPPORT Other

"These are due to the absence or dysfunction of the two main cell types, i.e., neural crest cells and secondary heart field cells that migrate in opposite directions at the same stage of development."

States the two-population, counter-migratory architecture that makes neural crest and second heart field failure phenotypically convergent on the outflow tract.

PMID:32405705 SUPPORT Other

"These cells directly govern aortic arch patterning and development, ascending aorta dilatation, semi-valvular and coronary artery development, aortopulmonary septation abnormalities, persistence of the ductus arteriosus, trunk and proximal pulmonary arteries"

Enumerates the specific structures whose malformation follows cardiac neural crest failure.

PMID:39000221 SUPPORT Other

"For example, neural crest cells, which form the building blocks of the peripheral nervous system and craniofacial areas, migrate to the heart, where they are indispensable for the formation of a septum within the outflow tract"

Establishes the indispensability of neural crest cells for outflow tract septation and their shared origin with craniofacial structures.

+ 4 more references

Endocardial Cushion Formation and Endothelial-to-Mesenchymal Transition Failure

The atrioventricular canal and outflow tract cushions are the swellings of cardiac jelly that are colonised when a subset of endocardial cells loses cell-cell adhesion, delaminates and transforms into invasive mesenchyme (endothelial-to-mesenchymal transition, a cardiac-specific instance of EMT driven by TGF-beta, BMP and NOTCH signalling from the adjacent myocardium). Those mesenchymal cells then remodel into the atrioventricular and semilunar valve leaflets and into the membranous portions of the atrial and ventricular septa. Failure at this step is therefore simultaneously a valve lesion and a septation lesion, which is why the atrioventricular septal defect is a single malformation rather than a coincidence of two. NOTCH1 loss of function in this programme is the established cause of bicuspid aortic valve with early calcification.

endocardial cell CL:0002350 endocardial cushion cell CL:0008022

NOTCH1 hgnc:7881 PLD1 hgnc:9067

endocardial cushion formation GO:0003272 ↓ DECREASED epithelial to mesenchymal transition involved in endocardial cushion formation GO:0003198 ↓ DECREASED endocardial cushion morphogenesis GO:0003203 ↓ DECREASED heart valve development GO:0003170 ↓ DECREASED

endocardial cushion UBERON:0002062

Downstream

Structural Cardiac Malformation Cushion failure yields atrioventricular septal defect, dysplastic or bicuspid semilunar valves, and the membranous ventricular septal defect.

Flow-Dependent Cardiac Morphogenesis Failure A stenotic or atretic valve created at this step becomes the flow-limiting lesion that drives the secondary hypoplasia of the chamber behind it.

Complete atrioventricular canal defect Failure of the superior and inferior atrioventricular cushions to fuse leaves a common atrioventricular junction with combined atrial and ventricular septal deficiency, which is the direct anatomical readout of this node.

Show evidence (3 references)

PMID:16025100 SUPPORT Human Clinical

"we show that mutations in the signalling and transcriptional regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification in non-syndromic autosomal-dominant human pedigrees"

Establishes NOTCH1, the signalling pathway that drives endocardial endothelial-to-mesenchymal transition, as a cause of human congenital valve malformation.

PMID:26785492 SUPPORT Human Clinical

"Disruption of EMT is felt to underlie HLHS pathogenesis"

Links failure of the epithelial-to-mesenchymal transition programme to a specific severe CHD lesion class.

PMID:33645542 SUPPORT DIRECT In Vitro

"Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis."

Binds PLD1 to this node by the mechanism the node models: inhibiting the enzyme reduces endothelial-to-mesenchymal transition, the step that populates the cushions and builds the valve leaflets.

Cardiac Septation Transcription Factor Network Failure

Division of the looped, chambered heart into four cavities depends on a small, combinatorially acting transcription factor network — NKX2-5, GATA4/GATA6, TBX5 and TBX20 — whose members physically interact and are dosage-sensitive. Haploinsufficiency of any one member permits septation to begin but not to complete. Two features of this network are diagnostically important and are curated here rather than in the lesion entries: the same factors that direct septation also build and maintain the atrioventricular conduction system, so NKX2-5 haploinsufficiency yields septal defect plus progressive atrioventricular block; and the GATA4-TBX5 physical interaction is disrupted by septal-defect-causing missense alleles in either partner, which is the molecular basis of the cardiac overlap between isolated septal defects and Holt-Oram syndrome.

NKX2-5 hgnc:2488 GATA4 hgnc:4173 TBX5 hgnc:11604 TBX20 hgnc:11598

cardiac septum development GO:0003279 ↓ DECREASED atrial septum development GO:0003283 ↓ DECREASED ventricular septum development GO:0003281 ↓ DECREASED cardiac septum morphogenesis GO:0060411 ↓ DECREASED

Downstream

Structural Cardiac Malformation Incomplete septation leaves an interatrial or interventricular communication, or in the severe case a common atrioventricular junction.

Arrhythmia The developmental, non-acquired route to arrhythmia in CHD: the same transcription factors that direct septation build and maintain the atrioventricular conduction system, so their haploinsufficiency yields progressive atrioventricular block alongside the septal defect rather than as a consequence of it.

Atrial septal defect Haploinsufficiency of the septation transcription factor network leaves the interatrial septum incompletely formed, the commonest isolated lesion attributed to this network in human pedigrees.

Ventricular septal defect The same network failure applied to the interventricular septum leaves a persistent interventricular communication.

Show evidence (6 references)

PMID:9651244 SUPPORT Human Clinical

"These data indicate that NKX2-5 is important for regulation of septation during cardiac morphogenesis and for maturation and maintenance of atrioventricular node function throughout life."

Establishes the dual septation/conduction role of NKX2-5 that this node asserts.

PMID:9651244 SUPPORT Human Clinical

"Two are predicted to impair binding of NKX2-5 to target DNA, resulting in haploinsufficiency, and a third potentially augments target-DNA binding."

Documents the dosage-sensitive, DNA-binding-dependent mechanism of the septation transcription factor network.

PMID:12845333 SUPPORT Human Clinical

"A heterozygous G296S missense mutation of GATA4, a transcription factor essential for heart formation, was found in all available affected family members but not in any control individuals"

Establishes GATA4 as a second septation-network transcription factor causing isolated human cardiac septal defects, by co-segregation in a linked pedigree.

+ 3 more references

Flow-Dependent Cardiac Morphogenesis Failure

Cardiac morphogenesis is not driven by the genome alone. The developing heart begins to function while it is still being built, and the resulting haemodynamic forces — shear stress on the endocardium and cyclic strain on the myocardium — are themselves morphogenetic inputs that the tissue senses and responds to. Removing or altering those forces produces abnormal heart development. This is the mechanistic content of the clinical "no flow, no grow" principle, and it is what converts a focal primary lesion into a global one: an early valvar or arch obstruction reduces flow through the structures downstream of it, whose growth is then secondarily curtailed, so that a point stenosis becomes hypoplastic left heart syndrome or aortic arch hypoplasia. It also means that a CHD lesion at birth is the compound product of the original developmental error and months of altered loading — a caveat that limits how directly a neonatal anatomical phenotype can be read back to a single genetic first cause. This node is unbroken ground in dismech; the Hypoplastic_Left_Heart_Syndrome and Coarctation_of_the_Aorta entries assert the flow-limitation step in prose without anchoring the general mechanism.

response to fluid shear stress GO:0034405 ↕ DYSREGULATED heart morphogenesis GO:0003007 ↓ DECREASED

heart UBERON:0000948

Experimental models

Hypoplastic left heart syndrome patient-derived iPSC-cardiomyocytes IPSC DERIVED MODEL Provides the counterfactual the zebrafish model cannot: human patient cells cultured entirely outside a haemodynamic environment still show intrinsic defects, evidencing the "shared upstream developmental cause" alternative that the HUMAN_MODEL_MISMATCH discussion sets against pure flow dependence.

Animal models

Zebrafish embryonic heart-function model of flow-dependent cardiac morphogenesis Zebrafish perturbs Experimentally removes or alters haemodynamic force during cardiac development and observes the morphogenetic consequence, establishing flow as a causal morphogenetic input rather than a correlate of it.

Downstream

Structural Cardiac Malformation Secondary hypoplasia of the chamber, valve or arch segment behind a flow-limiting lesion, converting a focal defect into a hypoplastic-heart phenotype.

Left ventricular outflow tract obstruction Reduced antegrade flow through the systemic outflow is self-reinforcing, so an initially focal subaortic or valvar lesion grows into the left ventricular outflow tract obstruction spectrum up to hypoplastic left heart syndrome.

Coarctation of aorta Diminished flow across the fetal aortic isthmus leaves that segment underdeveloped, producing the discrete isthmic narrowing.

Pulmonic stenosis The same flow-dependent logic on the pulmonary side converts a restrictive pulmonary valve or infundibulum into progressive right ventricular outflow obstruction.

Show evidence (2 references)

PMID:26969993 SUPPORT Model Organism

"In the absence or disruption of these forces, heart development is abnormal, suggesting that the heart must sense these changes and respond appropriately."

Establishes haemodynamic force as a necessary morphogenetic input to heart development, which is the claim of this node. Evidence is from zebrafish, so the node is tagged MODEL_ORGANISM rather than treated as demonstrated in humans.

PMID:26969993 SUPPORT Model Organism

"This theme is particularly evident in the developing heart as progression of cardiac development is accompanied by increased and altered hemodynamic forces."

Supports the coupling of developmental progression to changing haemodynamic load.

Structural Cardiac Malformation

The convergence node of this entry: an anatomically abnormal heart or great vessels at birth. Every mechanistic arm above terminates here, and every lesion-specific dismech entry begins from a member of this node's phenotype set. The malformation is fixed at birth (surgery repairs or palliates anatomy but does not restore normal development), which is why CHD is a lifelong condition rather than a neonatal event.

heart UBERON:0000948

Downstream

Altered Circulatory Physiology

Show evidence (1 reference)

PMID:38488639 SUPPORT Other

"Congenital heart defects (CHD) affect 1 in 100 live births and result from defects in cardiac development."

States the defining causal claim of this entry: CHD is the anatomical outcome of disrupted cardiac development.

Altered Circulatory Physiology

The shared physiological consequence of structural malformation, and the level at which otherwise unrelated lesions become clinically interchangeable. Four patterns recur: left-to-right shunting with pulmonary overcirculation and volume loading; outflow obstruction with pressure loading of the upstream ventricle; obligatory mixing or right-to-left shunting with systemic hypoxaemia and cyanosis; and duct-dependent circulation, in which either systemic or pulmonary blood flow is supplied through the arterial duct and collapses when it closes in the first days of life. Long-term, the volume- and pressure-loaded and hypoxaemic circulations drive pulmonary vascular remodelling, ventricular hypertrophy and fibrosis, arrhythmia and heart failure. The lesion-specific elaboration of each pattern is curated in the individual lesion entries (notably Eisenmenger_Syndrome for the shunt-to-pulmonary-vascular-disease trajectory) and is deliberately not re-derived here.

Downstream

Cyanosis

Congestive heart failure

Pulmonary arterial hypertension

Arrhythmia

Sudden cardiac death

Failure to thrive

Show evidence (1 reference)

PMID:29162633 SUPPORT Human Clinical

"Infants with duct-dependent critical CHD remain well during the fetal period and may deteriorate when the ductus arteriosus (commonly called 'duct') closes after birth."

Documents the duct-dependent physiological pattern and its characteristic postnatal timing.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Cardiovascular 15

Conotruncal defect HP:0001710

Show evidence (1 reference)

PMID:32405705 SUPPORT Other

"Outflow tract abnormalities are the most frequent congenital heart defects."

Establishes outflow tract (conotruncal) malformation as a cardinal CHD phenotype.

Tetralogy of Fallot HP:0001636

Show evidence (1 reference)

PMID:28991257 SUPPORT Human Clinical

"dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot"

Documents tetralogy of Fallot as a discrete lesion within a large CHD cohort and attributes a defined genetic fraction to it.

Transposition of the great arteries HP:0001669

Show evidence (1 reference)

PMID:39000221 SUPPORT Other

"New techniques for studying heart development have revealed many aspects of cardiac morphogenesis that are important in the development of CHDs, in particular transposition of the great arteries."

Connects transposition of the great arteries specifically to the cardiac morphogenesis programme this entry models.

Atrial septal defect HP:0001631

Show evidence (1 reference)

PMID:30783674 SUPPORT Human Clinical

"The change in prevalence of mild CHD lesions (ventricular septal defect, atrial septal defect and patent ductus arteriosus) together explained 93.4% of the increased overall prevalence"

Establishes atrial septal defect as one of the commonest CHD lesions.

Ventricular septal defect HP:0001629

Show evidence (1 reference)

PMID:30783674 SUPPORT Human Clinical

"The change in prevalence of mild CHD lesions (ventricular septal defect, atrial septal defect and patent ductus arteriosus) together explained 93.4% of the increased overall prevalence"

Establishes ventricular septal defect as one of the commonest CHD lesions.

Complete atrioventricular canal defect HP:0001674

Left ventricular outflow tract obstruction HP:0032092

Show evidence (1 reference)

PMID:34440418 SUPPORT Human Clinical

"Interestingly, diagnostic results (15.8%) in left ventricular outflow tract obstruction (LVOTO) defects occurred most often in patients with isolated CHD."

Uses left ventricular outflow tract obstruction as a defined clinical CHD class and reports its distinctive genetic-diagnostic behaviour.

Coarctation of aorta HP:0001680

Pulmonic stenosis HP:0001642

Show evidence (1 reference)

PMID:22078432 SUPPORT Human Clinical

"with relatively more pulmonary outflow obstructions and fewer left ventricular outflow tract obstructions"

Reports pulmonary outflow obstruction as a distinct, geographically varying CHD lesion class.

Abnormal pulmonary vein morphology HP:0030968

Patent ductus arteriosus HP:0001643

Show evidence (1 reference)

PMID:30783674 SUPPORT Human Clinical

"The change in prevalence of mild CHD lesions (ventricular septal defect, atrial septal defect and patent ductus arteriosus) together explained 93.4% of the increased overall prevalence"

Establishes patent ductus arteriosus as one of the commonest CHD lesions.

Congestive heart failure HP:0001635

Pulmonary arterial hypertension HP:0002092

Arrhythmia HP:0011675

Show evidence (2 references)

PMID:39768857 SUPPORT Human Clinical

"CAs associated with cardiovascular diseases cause structural or functional alterations of the heart, affecting the cardiac chambers, valves, coronary arteries, aorta, and cardiac conduction, thus increasing the likelihood of arrhythmias, cardiac arrest, and sudden cardiac death (SCD)."

Links the structural and conduction-system alterations modelled by this entry to arrhythmia as a downstream clinical phenotype.

PMID:9651244 SUPPORT Human Clinical

"A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35"

Evidences the developmental route to arrhythmia specifically: one locus producing both the structural malformation and the conduction abnormality.

Sudden cardiac death HP:0001645

Show evidence (3 references)

PMID:39768857 SUPPORT Human Clinical

"However, in CHD patients, the rates are 20-30 times higher than those in the general population"

Quantifies the excess sudden-cardiac-death risk in CHD relative to the general population.

PMID:39768857 SUPPORT Human Clinical

"Some patients with tetralogy of Fallot, transposition of the great arteries, cyanotic heart disease, Ebstein anomaly, and Fontan circulation are at an increased risk for SCD."

Identifies the lesion classes carrying the highest sudden-cardiac-death risk, which map onto this entry's CTD, RVOTO and single-ventricle-palliation content.

PMID:39768857 SUPPORT Human Clinical

"The incidence of SCD is greater in adults than in children"

Supports this entry's framing of CHD as a lifelong condition whose burden shifts into adulthood rather than one resolved by neonatal surgery.

Integument 1

Cyanosis HP:0000961

Show evidence (1 reference)

PMID:22554860 SUPPORT Human Clinical

"The overall sensitivity of pulse oximetry for detection of critical congenital heart defects was 76.5% (95% CI 67.7-83.5)."

Establishes that a detectable arterial oxygen-saturation deficit accompanies most critical CHD, the phenotype this entry records as cyanosis.

Nervous System 1

Neurodevelopmental abnormality HP:0012759

Show evidence (1 reference)

PMID:26785492 SUPPORT Human Clinical

"These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients."

Supports a shared genetic, rather than purely acquired, contribution to neurodevelopmental disability in CHD.

Growth 2

Heterotaxy HP:0030853

Show evidence (1 reference)

PMID:9354794 SUPPORT Human Clinical

"Aberrant LR axis development can lead to randomization of individual organ position (situs ambiguus) or to mirror-image reversal of all lateralized structures (situs inversus)."

Defines the heterotaxy (situs ambiguus) phenotype and its developmental origin.

Failure to thrive HP:0001508

Other 1

Extracardiac congenital anomaly

NEEDS TERM / NTR CANDIDATE. Deliberately left unbound. The claim is an extracardiac structural or functional anomaly of ANY organ system, and the cited evidence is likewise system-agnostic. HPO was searched (2026-08-19) for a system-agnostic congenital-anomaly class: the only "congenital malformation of" terms are cardiac (HP:0011603, HP:0011723, HP:0045017), there is no "multiple congenital anomalies" class, and every "Abnormality of the X system" term names a single system. An earlier revision bound this to HP:0000924 (Abnormality of the skeletal system), which silently narrowed a whole-organism claim to the skeleton and was removed on review - no term beats a bad term. An HPO new-term request for a system-agnostic extracardiac/multiple congenital anomaly class would be the right resolution.

Show evidence (1 reference)

PMID:26785492 SUPPORT Human Clinical

"Extra-cardiac congenital anomalies (CA, structural or functional anomalies that arise in utero) occur in approximately 13% of newborns with congenital heart disease (CHD), including 2% with a genetic syndrome, almost twice the prevalence observed in infants without CHD"

Quantifies the excess of extracardiac anomalies among newborns with CHD.

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Genetic Associations

NKX2-5 (Pathogenic Variants)

Gene: NKX2-5 hgnc:2488 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:9651244 SUPPORT Human Clinical

"Mutations in the gene encoding the homeobox transcription factor NKX2-5 were found to cause nonsyndromic, human congenital heart disease."

Establishes NKX2-5 as a cause of non-syndromic human CHD.

GATA4 (Pathogenic Variants)

Gene: GATA4 hgnc:4173 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:12845333 SUPPORT Human Clinical

"A heterozygous G296S missense mutation of GATA4, a transcription factor essential for heart formation, was found in all available affected family members but not in any control individuals"

Segregation of a GATA4 missense variant with non-syndromic septal defects in a pedigree, absent from controls, supports GATA4 as a CHD gene.

TBX5 (Pathogenic Variants)

Gene: TBX5 hgnc:11604 gene page relationship_type: CAUSATIVE

NOTCH1 (Pathogenic Variants)

Gene: NOTCH1 hgnc:7881 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:16025100 SUPPORT Human Clinical

States the paper's finding - NOTCH1 mutation causes developmental aortic valve anomaly plus severe calcification - which is the NOTCH1-LVOTO association this gene entry asserts.

ZIC3 (Pathogenic Variants)

Gene: ZIC3 hgnc:12874 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:9354794 SUPPORT Human Clinical

"ZIC3, which has not been previously implicated in vertebrate LR-axis development, is the first gene unequivocally associated with human situs abnormalities."

Establishes ZIC3 as the founding human laterality/heterotaxy gene.

TBX1 (Pathogenic Variants)

Gene: TBX1 hgnc:11592 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:14585638 SUPPORT DIRECT Human Clinical

"We identified three mutations of TBX1 in two unrelated patients without the 22q11.2 deletion-one with sporadic conotruncal anomaly face syndrome/velocardiofacial syndrome and one with sporadic DiGeorge's syndrome-and in three patients from a family with conotruncal anomaly face..."

Human point mutations in TBX1, in patients carrying no 22q11.2 deletion, reproduce the conotruncal phenotype. This separates the gene's own contribution from that of the wider deleted region, which is what these notes claim.

PMID:14585638 SUPPORT DIRECT Human Clinical

"Our results suggest that the TBX1 mutation is responsible for five major phenotypes in del22q11.2 syndrome."

Supports treating TBX1 as the principal driver within the deleted region.

GDF1 (Pathogenic Variants)

Gene: GDF1 hgnc:4214 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:28991257 SUPPORT Human Clinical

"including a recessive founder mutation in GDF1 accounting for ~5% of severe CHD in Ashkenazim"

Quantifies the GDF1 founder allele's contribution to severe CHD.

MYH6 (Pathogenic Variants)

Gene: MYH6 hgnc:7576 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:28991257 SUPPORT Human Clinical

"recessive genotypes in MYH6 accounting for ~11% of Shone complex"

Quantifies the MYH6 recessive contribution to a defined LVOTO lesion.

FLT4 (Pathogenic Variants)

Gene: FLT4 hgnc:3767 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:28991257 SUPPORT Human Clinical

"dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot"

Quantifies the FLT4 contribution to tetralogy of Fallot.

KMT2D (Pathogenic Variants)

Gene: KMT2D hgnc:7133 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:26785492 SUPPORT Human Clinical

"Within this 21-gene set, PTPN11, KMT2D (MLL2), and RBFOX2, each had significantly more damaging de novo mutations than expected"

Identifies KMT2D as one of only three genes reaching genome-wide significance for damaging de novo mutation in CHD.

CHD7 (Pathogenic Variants)

Gene: CHD7 hgnc:20626 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:26785492 SUPPORT Human Clinical

"Indeed, this list includes seven genes previously implicated in CHD (PTPN11, KMT2D, CHD7, MYH6, JAG1, NOTCH1, ZEB2)."

Confirms CHD7 among the recurrently de novo mutated genes established as CHD causes.

RBFOX2 (Pathogenic Variants)

Gene: RBFOX2 hgnc:9906 gene page relationship_type: CAUSATIVE

Show evidence (1 reference)

PMID:26785492 SUPPORT Human Clinical

"RBFOX2 harbored three distinct de novo LoF mutations, a highly significant finding"

Documents the RBFOX2 de novo burden and its exclusive association with hypoplastic left heart syndrome.

Chromosomal aneuploidy and recurrent copy-number variants (Pathogenic Variants)

Show evidence (2 references)

PMID:34440418 SUPPORT Human Clinical

"Diagnostic yield was higher in syndromic appearing infants, but geneticists' dysmorphology exams lacked complete sensitivity and 6.5% of isolated CHD cases had diagnostic CMA."

Quantifies the chromosomal-microarray yield in apparently isolated CHD and shows dysmorphology assessment cannot substitute for it.

PMID:39337901 SUPPORT Human Clinical

"The most frequent genetic diagnoses in diagnosed cases were 22q11.2 microdeletion and CHARGE syndromes, followed by Noonan syndrome and Williams syndrome."

Identifies the recurrent CNV and syndromic diagnoses that dominate a contemporary neonatal CHD cohort.

TBX20 (Pathogenic Variants)

Gene: TBX20 hgnc:11598 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:17668378 SUPPORT DIRECT Human Clinical

"Our findings are the first to link TBX20 mutations to human pathology."

The report that established TBX20 as a human congenital heart disease gene.

PMID:17668378 SUPPORT DIRECT Human Clinical

"Dilated cardiomyopathy was a feature of the TBX20 mutant phenotype in humans and mice, suggesting that mutations in developmental transcription factors can provide a sensitized template for adult-onset heart disease."

Sources the sensitized-myocardium observation recorded in these notes.

SMAD2 (Pathogenic Variants)

Gene: SMAD2 hgnc:6768 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:30157302 SUPPORT DIRECT Human Clinical

"WES identified pathogenic truncating variants, a splice variant, and a predicted deleterious missense variant in SMAD2."

Establishes loss-of-function SMAD2 variants in probands ascertained for complex congenital heart disease.

PMID:30157302 SUPPORT DIRECT Human Clinical

"Patient 3 was a fetus with complex CHD and heterotaxy."

The laterality case behind assigning this record to the heterotaxy subtype rather than to a septal or conotruncal class.

GATA6 (Pathogenic Variants)

Gene: GATA6 hgnc:4174 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:31301121 SUPPORT DIRECT BACKGROUND Human Clinical

"The first human mutations in GATA6 were described in a cohort of patients with persistent truncus arteriosus, and the phenotypic spectrum has expanded since then."

Sources the outflow-tract origin of this gene's human phenotype, which is why the record carries the conotruncal subtype.

PMID:31301121 SUPPORT DIRECT Human Clinical

"We conclude that the most common phenotypes associated with a mutation in GATA6 were structural cardiac and pancreatic abnormalities, with a penetrance of 87 and 60%, respectively."

The authors' synthesis of all 78 published GATA6 variants, and the source of the cardiac-plus-pancreatic pairing recorded in these notes.

HAND1 (Pathogenic Variants)

Gene: HAND1 hgnc:4807 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:19586923 SUPPORT DIRECT Human Clinical

"Indeed, in tissue samples of septal defects, we detected 32 sequence alterations leading to amino acid change, of which 12 are in the bHLH domain of HAND1."

The variant findings in septal-defect heart tissue behind assigning this record to the septal subtype.

PMID:19586923 SUPPORT INDIRECT BACKGROUND Model Organism

"Absence of Hand1 in mice results in embryonal lethality, as well as in a wide spectrum of cardiac abnormalities including failed cardiac looping, defective chamber septation and impaired ventricular development."

Sources the mouse loss-of-function phenotype recorded in this record's notes. Graded BACKGROUND because the sentence is this paper's framing of prior mouse work rather than its own result, and INDIRECT because a mouse knockout bears on the human claim only through an inference step.

PMID:19586923 SUPPORT INDIRECT In Vitro

"Functional studies in yeast and mammalian cells enabled translation of sequence alterations to HAND1 transcriptional activity, which was reduced or abolished by certain mutations, notably p.L138P."

Functional support that some of these alterations impair HAND1 activity. Graded INDIRECT because a transcriptional-activity assay bears on the clinical claim only through an inference step.

HAND2 (Pathogenic Variants)

Gene: HAND2 hgnc:4808 relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:32134193 SUPPORT DIRECT Human Clinical

"Taken together, this first report of a HAND2 and HAND2-AS1 deletion in a family with CHDs strongly supports haploinsufficiency of HAND2 as an autosomal dominant cause of CHD."

The deletion that removes HAND2, in a family ascertained for congenital heart disease, and the haploinsufficiency mechanism it supports.

PMID:32134193 SUPPORT DIRECT BACKGROUND Human Clinical

"Heterozygous sequence variants in the basic helix-loop-helix TF gene heart and neural crest derivatives expressed 2 (HAND2) have been reported among some patients with CHDs; however, HAND2 has not yet been established as a Mendelian disease gene."

The authors' own statement of how far the human evidence went before this report, which is the state ClinGen's Moderate classification reflects and the reason this record carries that grade in its notes.

PMID:10189962 SUPPORT INDIRECT REVIEW SYNTHESIS Model Organism

"dHAND and eHAND are two related basic helix-loop-helix transcription factors that are expressed in a complementary fashion in the developing right and left ventricles, respectively. They are also expressed in the neural crest-derived cardiac outflow tract and aortic arch arteries."

Sources the complementary ventricular and outflow-tract expression recorded in this record's notes. The paper names the two factors by their historical dHAND and eHAND symbols and does not give HGNC symbols, so this item supports the pair rather than assigning either territory to one gene.

+ 1 more reference

PLD1 (Pathogenic Variants)

Gene: PLD1 hgnc:9067 relationship_type: CAUSATIVE

Autosomal recessive

Show evidence (2 references)

PMID:33645542 SUPPORT DIRECT Human Clinical

"Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects."

The cohort finding that binds PLD1 to congenital valve disease, and the right-sided predominance behind this record's subtype assignment.

PMID:33645542 SUPPORT DIRECT In Vitro

"PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay."

Enzymatic evidence that the disease alleles are loss of function.

TFAP2B (Pathogenic Variants)

Gene: TFAP2B hgnc:11743 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:10802654 SUPPORT DIRECT Human Clinical

"Using a positional candidacy strategy, we mapped TFAP2B, encoding a transcription factor expressed in neural crest cells, to the Char syndrome critical region and identified missense mutations altering conserved residues in two affected families."

The report that established TFAP2B as the Char syndrome gene, and its neural crest expression.

PMID:10802654 SUPPORT DIRECT In Vitro

"Dimerization of both mutants with normal TFAP2B adversely affected transactivation, demonstrating a dominant-negative mechanism."

Identifies the dominant-negative mechanism of the Char syndrome missense alleles.

PMID:21643846 SUPPORT DIRECT Human Clinical

"The following two types of mutations were identified in TFAP2B: c.601+5G>A and c.435_438delCCGG."

Supports extending this gene beyond Char syndrome to familial nonsyndromic patent ductus arteriosus, which is the lumping ClinGen's spectrum-disorder concept records.

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Medical Actions

Prostaglandin E1 infusion for duct-dependent circulation

Action: Pharmacotherapy NCIT:C15986

Agent: alprostadil CHEBI:15544

Platform: Small molecule

In duct-dependent lesions the arterial duct is the sole route for either systemic or pulmonary blood flow after birth; its physiological closure in the first days of life precipitates shock or profound cyanosis. Prostaglandin E1 (alprostadil) maintains ductal patency and is the single most time-critical medical intervention in neonatal CHD — it does not treat the malformation but buys the interval to reach definitive surgery or catheter intervention. Delay in starting the infusion can be fatal.

Mechanism Target:

MODULATES Altered Circulatory Physiology — Sustains the duct-dependent circulatory pattern rather than correcting the structural malformation upstream of it. MODULATES rather than RESTORES: the circulation is held in a survivable but still abnormal fetal-type arrangement.

Show evidence (1 reference)

PMID:29162633 SUPPORT Human Clinical

"It is critical to open or maintain ductus arteriosus patent in infants with duct-dependent CHDs."

States the physiological target of the intervention: ductal patency, not the malformation.

Show evidence (2 references)

PMID:29162633 SUPPORT Human Clinical

"Prostaglandin E1 (alprostadil marketed as 'Prostin VR ') and prostaglandin E2 (dinoprostone) are used to maintain a patent ductus arteriosus and the dose of medication depends on the clinical presentation."

Identifies the agent and its indication.

PMID:29162633 SUPPORT Human Clinical

"Delay in starting prostaglandin infusion can have deleterious effects on infants and can even lead to death."

Records the time-critical nature of the intervention.

Cardiac surgical repair or palliation

Action: cardiac surgery Ontology label: Cardiac Surgery NCIT:C157806

Platform: Surgery

Anatomical repair (septal defect closure, arterial switch, tetralogy repair, coarctation resection) where two-ventricle physiology can be achieved, or staged single-ventricle palliation culminating in the Fontan circulation where it cannot. The curatorially important framing, and the reason this entry models CHD as a lifelong condition, is that surgery repairs or palliates anatomy without restoring normal cardiac development: residual shunts and obstruction, valve dysfunction, ventricular failure, aortopathy, pulmonary hypertension, arrhythmia, Fontan-associated liver disease and reintervention remain lifelong risks, and the burden of CHD has correspondingly shifted into adulthood.

Mechanism Target:

RESTORES Structural Cardiac Malformation — Addresses the anatomical convergence node directly. RESTORES refers to circulatory anatomy in the biventricular-repair case only; staged single-ventricle palliation instead bypasses the defect, and in neither case is the developmental error or its lifelong sequelae reversed.

Show evidence (1 reference)

PMID:30413300 SUPPORT Human Clinical

"Unfortunately, adult patients with CHD carry residual lesions and sequelae putting them at risk for premature death related to re-interventions or complications; most commonly heart failure and arrhythmia"

Substantiates the qualification on this RESTORES edge - anatomical repair leaves residual lesions and sequelae, so the effect on the malformation node is not equivalent to cure.

Show evidence (2 references)

PMID:30413300 SUPPORT Human Clinical

"As a result of advances in pediatric care, the majority of patients born with congenital heart disease (CHD) survive into adulthood"

Evidences the efficacy of the surgical/paediatric-care era that this treatment entry describes: most people born with CHD now reach adulthood.

PMID:30413300 SUPPORT Human Clinical

"More emerging is that a substantial number of patients, in particular those with complex heart defects, will eventually end up in a stage with hardly any medical or interventional options left."

Directly supports this entry's framing that surgery repairs or palliates anatomy without restoring normal development, and that the burden shifts into adulthood.

Heart transplantation

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

Platform: Surgery

Definitive option for end-stage CHD, including failed single-ventricle palliation and severe forms of hypoplastic left heart syndrome in which staged palliation is not viable or has failed.

Mechanism Target:

RESTORES Structural Cardiac Malformation — The only intervention that removes the malformed heart rather than remodelling it, hence RESTORES without the qualification attached to surgical repair. Where Fontan-associated liver disease has supervened, combined heart-liver transplantation is the corresponding option.

Show evidence (1 reference)

PMID:40320589 SUPPORT Human Clinical

"The Fontan procedure has transformed the management of congenital heart defects characterized by single ventricle physiology, yet it predisposes individuals to Fontan-associated liver disease. Combined heart and liver transplantation (CHLT) emerges as a therapeutic option, but evidence of its..."

Evidences transplantation as the terminal option for the failed single-ventricle palliation pathway modelled in this entry.

Show evidence (1 reference)

PMID:40320589 SUPPORT Human Clinical

"CHLT in Fontan patients demonstrates promising survival rates, but graft rejection and postoperative complications pose challenges."

Supports transplantation as an effective but complication-laden option. PARTIAL because the meta-analysis covers combined heart-liver transplantation in failing Fontan specifically (4 retrospective cohorts, 67 patients), not heart transplantation across CHD as a whole.

Preconception glycaemic control in maternal pregestational diabetes

Action: dietary intervention Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

The principal actionable primary-prevention measure implied by this entry's environmental arm: because pregestational rather than gestational diabetes carries the large effect, and because the vulnerable window is the first eight weeks of gestation, glycaemic optimisation must precede conception to be relevant. Blood glucose reduction, antioxidant supplementation and exercise have all been proposed as preventive measures on this basis.

Mechanism Target:

INHIBITS Maternal Metabolic and Teratogenic Perturbation of Cardiogenesis — Acts on the maternal metabolic exposure upstream of cardiogenesis rather than on any established malformation; the intent is primary prevention, so the effect is recorded against the exposure node it suppresses.

Show evidence (1 reference)

PMID:35838899 SUPPORT Human Clinical

"Treatment options including blood sugar-reducing, anti-oxidative stress drug supplements and exercise can help to prevent maternal pregestational diabetes mellitus from inducing congenital heart diseases."

Supports the preventive rationale. Recorded as PARTIAL because this is a narrative-review assertion, not a trial result.

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Environmental Factors

Maternal pregestational diabetes mellitus

Deliberately left without an exposure_term: ECTO was searched and has no class for exposure to a maternal metabolic disease state (its maternal branch covers substances such as alcohol, nicotine and pharmacotherapy). Recording a substance exposure here would misrepresent the exposure.

Diabetes present before conception (type 1 or type 2, with no material difference in effect size between them) is the strongest established modifiable risk factor for CHD, tripling the odds. Gestational diabetes, which begins after the window of cardiac organogenesis has largely closed, carries a substantially smaller effect — an internal consistency check that supports a causal, timing-dependent mechanism rather than confounding by maternal metabolic phenotype alone.

Show evidence (1 reference)

PMID:38996968 SUPPORT Human Clinical

"Pregestational diabetes (PGDM) was associated with CHDs (OR, 3.51; 95% CI, 2.86-4.3), without difference between type 1 and type 2 PGDM."

Quantifies the pregestational-diabetes effect size and its type-independence.

Mechanism Target:

PREDISPOSES Maternal Metabolic and Teratogenic Perturbation of Cardiogenesis — Pregestational maternal hyperglycaemia is the exposure that establishes the perturbed embryonic metabolic environment modelled by this node.

Show evidence (1 reference)

PMID:38996968 SUPPORT Human Clinical

"The effect size of gestational diabetes was less than that of PGDM (OR, 1.38; 95% CI, 1.18-1.61)."

The timing-dependent gradient between pregestational and gestational diabetes supports action during early cardiac organogenesis rather than later gestation.

Maternal overweight and obesity

No exposure_term bound: ECTO was searched and has no class for maternal adiposity as an exposure.

Raised pre-pregnancy body mass index is associated with CHD in offspring with a dose-effect relationship, independently of overt diabetes.

Show evidence (1 reference)

PMID:38996968 SUPPORT Human Clinical

"There was an association between being overweight or obese and CHDs (OR, 1.26; 95% CI, 1.15-1.37), with a dose-effect relationship."

Quantifies the maternal-adiposity association and its dose-response.

Mechanism Target:

PREDISPOSES Maternal Metabolic and Teratogenic Perturbation of Cardiogenesis — Associated with CHD with a dose-effect relationship; the mediating embryonic mechanism is not established, so the edge is recorded as indirect with unknown intermediates rather than assumed to run through hyperglycaemia.

Periconceptional exposure to alcohol

Parental alcohol use is associated with CHD in offspring at modest effect size. Note the cited meta-analysis reports this association for alcohol use in the parental exposure group; it is grouped in that analysis with paternal smoking rather than reported as a maternal-only exposure.

Show evidence (1 reference)

PMID:38996968 SUPPORT Human Clinical

"There was an association between CHDs and pre-eclampsia (OR, 2.01; 95% CI, 1.32-3.05), paternal smoking (OR, 1.32; 95% CI, 1.03-1.70), and alcohol use (OR, 1.50; 95% CI, 1.08-2.08)."

Reports the alcohol-use association and, in the same sentence, the parental exposure grouping in which it was analysed.

Mechanism Target:

PREDISPOSES Maternal Metabolic and Teratogenic Perturbation of Cardiogenesis

Maternal cigarette smoking

Maternal smoking is associated with CHD, though at a smaller effect size than pregestational diabetes or obesity.

Show evidence (1 reference)

PMID:38996968 SUPPORT Human Clinical

"There exists robust evidence for increased risk of CHD in the presence of obesity, maternal diabetes, maternal smoking, and increased maternal age."

Places maternal smoking among the exposures the meta-analysis judges robustly evidenced.

Mechanism Target:

PREDISPOSES Maternal Metabolic and Teratogenic Perturbation of Cardiogenesis

Teratogenic drug and infectious exposures during cardiac organogenesis

A single entry covering a heterogeneous exposure set, because the cited AHA statement classifies them together as definitive rather than reporting per-agent effect sizes. No single ECTO class covers the set.

Definitive teratogens for congenital cardiovascular defects include maternal rubella infection, untreated maternal phenylketonuria, thalidomide, vitamin A congeners and retinoids, and indomethacin tocolysis. Their shared feature is action during the roughly 3-8 week window of cardiac organogenesis. Rubella is a teratogenic maternal infection, not a disease transmitted from the affected infant — CHD itself is neither infectious nor transmissible.

Show evidence (1 reference)

PMID:17519397 SUPPORT Human Clinical

Enumerates the exposures classified as definitive risk factors.

Mechanism Target:

TRIGGERS Maternal Metabolic and Teratogenic Perturbation of Cardiogenesis

Periconceptional multivitamin or folic acid intake

The principal candidate protective exposure. The AHA statement summarises it as possibly reducing fetal cardiac risk; the evidence base is predominantly case-control, which the same statement flags as a limitation, so this is curated as a candidate protective factor rather than a demonstrated one.

Show evidence (2 references)

PMID:17519397 SUPPORT Human Clinical

"Information is summarized for periconceptional multivitamin or folic acid intake, which may reduce the risk of cardiac disease in the fetus"

The hedged wording ("may reduce") is the reason this is curated as PARTIAL rather than SUPPORT.

PMID:17519397 SUPPORT Human Clinical

"Caveats regarding interpretation of possible exposure-outcome relationships from case-control studies are given because this type of study has provided most of the available information."

Records the study-design limitation that constrains how strongly any of these exposure-outcome relationships can be asserted.

Mechanism Target:

PROTECTS_AGAINST Maternal Metabolic and Teratogenic Perturbation of Cardiogenesis

🔬

Diagnosis

Newborn pulse oximetry screening for critical congenital heart disease

Postductal (or pre- and postductal) oxygen-saturation measurement in the asymptomatic newborn, exploiting the fact that most critical CHD produces a detectable arterial saturation deficit before it produces visible cyanosis or a murmur. Its high specificity is what makes it viable as universal screening; its moderate sensitivity means a normal result does not exclude CHD, and it will not detect non-cyanotic lesions such as an isolated ventricular septal defect.

disease screening NCIT:C15419

Results: Pooled sensitivity 76.5% (95% CI 67.7-83.5), specificity 99.9%, false-positive rate 0.14%. Screening after 24 hours of age reduces the false-positive rate roughly tenfold (0.05% vs 0.50%).

Show evidence (2 references)

PMID:22554860 SUPPORT Human Clinical

"Pulse oximetry is highly specific for detection of critical congenital heart defects with moderate sensitivity, that meets criteria for universal screening."

States the test-performance profile and the screening recommendation this entry records.

PMID:22554860 SUPPORT Human Clinical

"The false-positive rate for detection of critical congenital heart defects was particularly low when newborn pulse oximetry was done after 24 h from birth than when it was done before 24 h"

Supports the timing dependence recorded in the results field.

Chromosomal microarray as first-tier genetic testing

Chromosomal microarray is the first-tier genetic test in an infant with severe CHD, followed by exome or genome sequencing when the array is normal. The curatorially important point is that the yield is not confined to dysmorphic or syndromic infants: a clinical geneticist's dysmorphology examination does not reliably identify which apparently isolated CHD cases carry a pathogenic copy-number variant, so testing is recommended regardless of lesion type or extracardiac findings.

genetic testing NCIT:C15709

Results: Diagnostic chromosomal microarray in 14.6% of tested infants overall and in 6.5% of apparently isolated CHD; overall genetic-testing yield 17% once second-tier molecular testing is included. An independent neonatal cohort reported the same 17% overall figure (32/188).

Show evidence (3 references)

PMID:34440418 SUPPORT Human Clinical

"Cumulative evidence provides a rationale for comprehensive, standardized genetic evaluation in infants with severe CHDs regardless of lesion or extracardiac anomalies because genetic diagnoses that impact care are easily missed."

States the recommendation to test irrespective of lesion class or extracardiac findings.

PMID:34440418 SUPPORT Human Clinical

"In total, 376 (85.5%) had chromosome microarray (CMA), of which 55 (14.6%) were diagnostic in syndromic (N = 35) or isolated (N = 20) presentations."

Source of the chromosomal-microarray diagnostic yield.

PMID:39337901 SUPPORT Human Clinical

"We established the genetic diagnosis of 22 distinct syndromes in 17% (32/188) of neonates."

Independent replication of the overall genetic-diagnostic yield in a neonatal CHD cohort.

Echocardiography

Transthoracic echocardiography is the definitive anatomical and physiological diagnostic modality for CHD at every age, and fetal echocardiography extends it into prenatal life. Prenatal detection is what permits delivery planning, prostaglandin availability at birth, and — as the epidemiological record shows — it also changes measured birth prevalence through pregnancy termination for the most severe lesions.

echocardiography NCIT:C16525

Show evidence (1 reference)

PMID:30783674 SUPPORT Human Clinical

"which would be consistent with improved prenatal detection and consequent termination of pregnancy when these very severe lesions are discovered"

Supports the claim that prenatal echocardiographic detection measurably shifts recorded birth prevalence. PARTIAL because the authors offer it as a consistent interpretation rather than a demonstrated causal chain.

📊

Prevalence

Worldwide

Birth Prevalence 941.0 per 100,000 (860.2–1025.3) >1 in 1,000 (births)

Pooled birth prevalence for 2010-2017 from 260 studies and 130,758,851 live births: 9.410 per 1000 (95% CI 8.602-10.253), i.e. 941 per 100,000. CHD as an umbrella is emphatically not a rare disease: it is the commonest congenital anomaly in humans, and the rate sits an order of magnitude above the EU rare-disease threshold. The prevalence_class is therefore ABOVE_1_IN_1000, the Orphanet class for rates above 100 per 100,000, which is unbounded above and so accommodates this figure directly.

Show evidence (1 reference)

PMID:30783674 SUPPORT Human Clinical

"The birth prevalence of CHD from 1970-2017 progressively increased to a maximum in the period 2010-17 of 9.410/1000 [95% CI (confidence interval) 8.602-10.253]."

Source of the pooled worldwide birth-prevalence estimate.

Africa

Birth Prevalence 231.5 per 100,000 (42.9–569.6) >1 in 1,000 (births)

2.315 per 1000 (95% CI 0.429-5.696), i.e. 231.5 per 100,000 - still in the ABOVE_1_IN_1000 class despite being the lowest reported regional figure. The authors interpret that low figure as severe unmet diagnostic need rather than genuinely lower disease occurrence, which is why this is curated as reported rather than true prevalence. Note the confidence interval is wide enough that its lower bound (42.9 per 100,000) would fall a band lower; the point estimate sets the class here.

Show evidence (1 reference)

PMID:30783674 SUPPORT Human Clinical

"There was marked heterogeneity among geographical regions, with Africa reporting the lowest prevalence [2.315/1000 (95% CI 0.429-5.696)] and Asia the highest [9.342/1000 (95% CI 8.072-10.704)]."

Source of the regional prevalence figures.

Asia

Birth Prevalence 934.2 per 100,000 (807.2–1070.4) >1 in 1,000 (births)

9.342 per 1000 (95% CI 8.072-10.704), i.e. 934.2 per 100,000; the highest reported regional prevalence.

Show evidence (1 reference)

PMID:30783674 SUPPORT Human Clinical

"There was marked heterogeneity among geographical regions, with Africa reporting the lowest prevalence [2.315/1000 (95% CI 0.429-5.696)] and Asia the highest [9.342/1000 (95% CI 8.072-10.704)]."

Source of the regional prevalence figures.

🧫

Experimental Models

Hypoplastic left heart syndrome patient-derived iPSC-cardiomyocytes IPSC_DERIVED_MODEL

Cardiomyocytes differentiated from iPSCs reprogrammed from HLHS patients. These are curated here for a specific reason rather than as generic model-system completeness: they bear directly on the open question in chd_flow_dependent_human_evidence. If HLHS were purely a flow-deprivation phenomenon, patient cardiomyocytes removed from the haemodynamic environment should behave normally. They do not - they show impaired cardiac-lineage differentiation and structural/electromechanical defects in dish - which is human-derived evidence for a cell-autonomous contribution alongside, not instead of, the flow mechanism.

Organism

human NCBITaxon:9606

Cell source

PATIENT_DERIVED

Publication

PMID:39273002

Pathograph links

Flow-Dependent Cardiac Morphogenesis Failure measures fidelity: moderate Provides the counterfactual the zebrafish model cannot: human patient cells cultured entirely outside a haemodynamic environment still show intrinsic defects, evidencing the "shared upstream developmental cause" alternative that the HUMAN_MODEL_MISMATCH discussion sets against pure flow dependence.

Limitations: iPSC-derived cardiomyocytes are transcriptionally and structurally immature, closer to fetal than adult myocardium, and a monolayer of one cell type cannot represent chamber-level morphogenesis at all. The findings are also from small patient-derived series with the genetic heterogeneity of HLHS uncontrolled, so they establish that a cell-autonomous component exists without quantifying its share relative to flow.

Readouts

Connexin 43 expression and cardiac myocyte alignment in HLHS iPSC-CMs

Direction: DECREASED

Interpretation: Reduced CX43 with impaired electromechanical transduction and failure of myocyte alignment, measured with no haemodynamic input present.

Show evidence (1 reference)

PMID:39273002 SUPPORT In Vitro

"They observed a reduction in CX43 expression in iPSC-derived CMs from HLHS patients, showing that there is impaired electromechanical transduction which causes the failure of correct cardiac myocyte alignment."

Reports the measurement behind this readout.

Myofibril and organelle organisation in HLHS iPSC-CMs

Direction: ALTERED

Interpretation: Structural disorganisation of the contractile apparatus intrinsic to the patient-derived cells.

Show evidence (1 reference)

PMID:39273002 SUPPORT In Vitro

"HLHS iPSC-CMs had an irregular myofibril arrangement, RER, and SR."

Reports the structural measurement behind this readout.

Show evidence (1 reference)

PMID:39273002 SUPPORT In Vitro

"They report an impairment in the differentiation process to the cardiac lineage of fully formed mature CMs."

Establishes that HLHS patient-derived cells carry an intrinsic cardiac-differentiation defect outside any haemodynamic context, which is why this model is informative for the flow-dependence question.

🐁

Animal Models

Zebrafish embryonic heart-function model of flow-dependent cardiac morphogenesis

The optically accessible, externally developing zebrafish embryo can survive by diffusion for long enough to tolerate near-complete loss of cardiac output, which is what makes it possible to remove flow and still observe morphogenesis. It is the system that supplies essentially all of the direct evidence behind the "no flow, no grow" node in this entry, and therefore the model on which the chd_flow_dependent_human_evidence HUMAN_MODEL_MISMATCH discussion turns.

Species

Zebrafish

Genotype

Wild-type and contractility/flow-perturbed embryos (e.g. cardiac troponin and myosin morphants that abolish or alter intracardiac flow while the heart tube continues to form)

Publication

PMID:26969993

Pathograph links

Flow-Dependent Cardiac Morphogenesis Failure perturbs fidelity: moderate Experimentally removes or alters haemodynamic force during cardiac development and observes the morphogenetic consequence, establishing flow as a causal morphogenetic input rather than a correlate of it.

Limitations: Substantial species divergence at exactly the points this entry cares about: the zebrafish heart is two-chambered, undergoes no atrial or ventricular septation and has no separate pulmonary circulation, so the septation, conotruncal and duct-dependent arms of the model cannot be represented at all. Embryo scale also places the developing zebrafish heart in a different flow regime from the human embryo. The node is consequently curated with evidence_source MODEL_ORGANISM, and the translational question is left open in discussions.chd_flow_dependent_human_evidence rather than closed by this model.

Readouts

Cardiac morphogenesis under experimentally altered haemodynamic force

Direction: ALTERED

Interpretation: Heart development is abnormal when the forces are absent or disrupted, which is the observation the node's causal claim rests on.

Show evidence (1 reference)

PMID:26969993 SUPPORT Model Organism

"In the absence or disruption of these forces, heart development is abnormal, suggesting that the heart must sense these changes and respond appropriately."

Reports the perturbation result behind this readout.

Show evidence (1 reference)

PMID:26969993 SUPPORT Model Organism

"Here, we discuss concepts of how embryonic heart function contributes to heart development using lessons learned mostly from studies in zebrafish."

Establishes zebrafish as the model system supplying the evidence for this node, which is what makes the link informative and the mismatch discussion necessary.

{ }

Source YAML

click to show

name: Congenital Heart Disease
creation_date: "2026-08-19T00:00:00Z"
category: Complex
description: >-
  Congenital heart disease (CHD) is the umbrella term for structural malformation of
  the heart or intrathoracic great vessels present at birth. This entry is curated as
  the **mechanistic root** of the CHD family: it models the shared developmental
  biology from which the individual lesions arise — cardiac progenitor field
  specification and second heart field deployment, left-right patterning and cardiac
  looping, cardiac neural crest migration and outflow tract septation, endocardial
  cushion formation and endothelial-to-mesenchymal transition, the septation
  transcription factor network, and flow-dependent morphogenesis — together with the
  genetic and maternal-environmental perturbations that disrupt them. The individual
  lesions and syndromes are curated in their own dismech entries (Atrial_Septal_Defect,
  Ventricular_Septal_Defect, Tetralogy_of_Fallot, Coarctation_of_the_Aorta,
  Hypoplastic_Left_Heart_Syndrome, Dextro_Transposition_of_the_Great_Arteries,
  Persistent_Truncus_Arteriosus, Double_Outlet_Right_Ventricle, Ebstein_Anomaly,
  Visceral_Heterotaxy, 22q11.2_Deletion_Syndrome, CHARGE_Syndrome, Alagille_syndrome,
  Down_syndrome, Holt-Oram_Syndrome, Noonan_Syndrome, Turner_Syndrome and others); this
  root deliberately does not re-derive their lesion-specific pathographs or
  post-natal haemodynamics beyond the shared convergence point.
disease_term:
  preferred_term: congenital heart disease
  term:
    id: MONDO:0005453
    label: congenital heart disease
synonyms:
- congenital heart defect
- congenital anomaly of heart
- CHD
parents:
- Heart disorder
- Congenital anomaly of cardiovascular system

has_subtypes:
- name: CTD
  display_name: Conotruncal (outflow tract) defects
  subtype_term:
    preferred_term: conotruncal heart malformations
    term:
      id: MONDO:0016581
      label: conotruncal heart malformations
  description: >-
    Malformations of the cardiac outflow tract and great arteries arising from failure
    of aorticopulmonary septation, outflow tract rotation, or alignment: tetralogy of
    Fallot, transposition of the great arteries, persistent truncus arteriosus, double
    outlet right ventricle, and interrupted aortic arch. Mechanistically anchored on
    the cardiac neural crest and second heart field arms of this entry.
  evidence:
  - reference: PMID:32405705
    reference_title: "Cardiac Neural Crest Cells: Their Rhombomeric Specification, Migration, and Association with Heart and Great Vessel Anomalies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Outflow tract abnormalities are the most frequent congenital heart defects."
    explanation: >-
      Establishes the conotruncal/outflow-tract group as a distinct and numerically
      dominant class within CHD.
- name: Septal
  display_name: Septal defects (atrial and ventricular)
  description: >-
    Communications across the interatrial or interventricular septum — secundum and
    primum atrial septal defect, and perimembranous, muscular, inlet and outlet
    ventricular septal defect. Together with patent ductus arteriosus these are the
    mild-end lesions that dominate reported CHD birth prevalence. No single MONDO
    class covers the atrial-plus-ventricular septal group; the constituent lesions are
    curated as Atrial_Septal_Defect (MONDO:0006664) and Ventricular_Septal_Defect
    (MONDO:0002070).
  evidence:
  - reference: PMID:30783674
    reference_title: "Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The change in prevalence of mild CHD lesions (ventricular septal defect, atrial
      septal defect and patent ductus arteriosus) together explained 93.4% of the
      increased overall prevalence
    explanation: >-
      Identifies the septal-defect group (with PDA) as the lesion class that dominates
      contemporary reported CHD birth prevalence.
- name: AVSD
  display_name: Atrioventricular septal defect (AV canal defect)
  subtype_term:
    preferred_term: atrioventricular septal defect
    term:
      id: MONDO:0859565
      label: atrioventricular septal defect
  description: >-
    Deficiency of the atrioventricular septum with a common atrioventricular junction,
    arising from failure of endocardial cushion fusion. Strongly associated with
    trisomy 21. Anchored on the endocardial cushion / endothelial-to-mesenchymal
    transition arm of this entry.
- name: LVOTO
  display_name: Left ventricular outflow tract obstruction
  description: >-
    Obstructive lesions of the left heart and systemic outflow — hypoplastic left heart
    syndrome, aortic valve stenosis, bicuspid aortic valve, coarctation of the aorta,
    and Shone complex. Mechanistically the class in which flow-dependent morphogenesis
    ("no flow, no grow") is most clearly implicated: an early obstruction limits flow
    through left heart structures, whose growth is then secondarily curtailed.
  evidence:
  - reference: PMID:30783674
    reference_title: "Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the prevalence of lesions grouped together as left ventricular outflow tract
      obstruction (which includes hypoplastic left heart syndrome) decreased
    explanation: >-
      Uses left ventricular outflow tract obstruction as an established analytic
      lesion class in CHD epidemiology.
- name: RVOTO
  display_name: Right-sided obstructive lesions
  description: >-
    Obstructive and hypoplastic lesions of the right heart and pulmonary outflow —
    pulmonary valve stenosis, pulmonary atresia with or without ventricular septal
    defect, tricuspid atresia, and Ebstein anomaly. The right-sided counterpart of
    LVOTO; the severe forms produce duct-dependent pulmonary circulation.
  evidence:
  - reference: PMID:22078432
    reference_title: "Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with relatively more pulmonary outflow obstructions and fewer left ventricular
      outflow tract obstructions
    explanation: >-
      Treats pulmonary (right-sided) outflow obstruction as a lesion class distinct
      from left ventricular outflow tract obstruction in CHD epidemiology.
- name: HTX
  display_name: Heterotaxy and laterality defects
  subtype_term:
    preferred_term: visceral heterotaxy
    term:
      id: MONDO:0018677
      label: visceral heterotaxy
  description: >-
    Complex cardiac malformation arising from failure of left-right axis determination
    at the embryonic left-right organizer, with abnormal atrial situs, systemic and
    pulmonary venous connections, and atrioventricular/ventriculoarterial alignment.
    Notably, this is the CHD class that did NOT show an excess of damaging de novo
    variants in the PCGC cohort, distinguishing its genetic architecture from the
    conotruncal and LVOTO classes.
  evidence:
  - reference: PMID:26785492
    reference_title: "De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      was found in each CHD category (conotruncal defects, left ventricular outflow
      tract obstruction and "other"), except for heterotaxy, which showed no excess
    explanation: >-
      Establishes heterotaxy as an analytically separate CHD class whose de novo
      variant burden differs from the other classes.
- name: APVR
  display_name: Anomalous pulmonary venous return
  subtype_term:
    preferred_term: congenital pulmonary venous return anomaly
    term:
      id: MONDO:0017705
      label: congenital pulmonary venous return anomaly
  description: >-
    Total or partial drainage of the pulmonary veins to the systemic venous circulation
    rather than the left atrium, arising from failure of the common pulmonary vein to
    incorporate into the left atrium. Frequently a component of heterotaxy.

pathophysiology:
- name: Developmental Gene Dosage Disruption
  biological_scale: MOLECULAR
  description: >-
    The upstream molecular trigger of most severe CHD: loss of normal dosage or
    function of genes required for cardiac morphogenesis. Three genetic mechanisms
    converge here — chromosomal aneuploidy, recurrent and non-recurrent copy-number
    variants, and point mutations (predominantly de novo in severe sporadic cases).
    De novo damaging variants are concentrated in genes highly expressed in the
    developing heart and, strikingly, in chromatin-modifying genes that write, read
    and erase H3K4 methylation and H2BK120 ubiquitination — the marks that
    characterise the "poised" promoters and enhancers of key developmental genes.
    Because the same genes are also highly expressed in the developing brain, this
    node also explains the co-occurrence of CHD with neurodevelopmental disability and
    extracardiac anomalies. Roughly 400 developing-heart-expressed genes are inferred
    to contribute.
  genes:
  - preferred_term: KMT2D
    term:
      id: hgnc:7133
      label: KMT2D
  - preferred_term: CHD7
    term:
      id: hgnc:20626
      label: CHD7
  - preferred_term: RBFOX2
    term:
      id: hgnc:9906
      label: RBFOX2
  biological_processes:
  - preferred_term: chromatin organization
    term:
      id: GO:0006325
      label: chromatin organization
    modifier: LOSS_OF_FUNCTION
  - preferred_term: regulation of transcription by RNA polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: DECREASED
  evidence:
  - reference: PMID:23665959
    reference_title: De novo mutations in histone-modifying genes in congenital heart disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We find a marked excess of de novo mutations in genes involved in the
      production, removal or reading of histone 3 lysine 4 (H3K4) methylation, or
      ubiquitination of H2BK120, which is required for H3K4 methylation.
    explanation: >-
      Identifies chromatin modification of developmental promoters/enhancers as the
      molecular process disrupted by de novo mutation in severe CHD.
  - reference: PMID:26785492
    reference_title: "De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing of 1213 CHD parent-offspring trios identified an excess of
      protein-damaging de novo mutations, especially in genes highly expressed in the
      developing heart and brain.
    explanation: >-
      Localises the mutational burden to genes with high developing-heart expression
      and explains the shared cardiac/neurodevelopmental pleiotropy.
  - reference: PMID:28991257
    reference_title: "Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DNMs in ~440 genes were inferred to contribute to CHD.
    explanation: >-
      Quantifies the breadth of the developmental gene set whose dosage disruption
      causes CHD.
  - reference: PMID:26785492
    reference_title: "De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Within this 21-gene set, PTPN11, KMT2D (MLL2), and RBFOX2, each had significantly more damaging de novo mutations than expected"
    explanation: >-
      Binds KMT2D and RBFOX2 to this node: both carry a statistically
      significant excess of damaging de novo variants in the trio cohort,
      which is the dosage-disruption mechanism this node models.
  - reference: PMID:26785492
    reference_title: "De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Indeed, this list includes seven genes previously implicated in CHD (PTPN11, KMT2D, CHD7, MYH6, JAG1, NOTCH1, ZEB2)."
    explanation: >-
      Binds CHD7 to this node as one of the previously implicated CHD genes
      recovered by the de novo analysis.
  downstream:
  - target: Cardiac Progenitor Specification and Second Heart Field Deployment Failure
    causal_link_type: DIRECT
    description: >-
      Haploinsufficiency of second heart field transcription factors (TBX1, ISL1,
      GATA4/6, NKX2-5) and of the chromatin machinery that licenses their targets
      reduces progenitor addition to the cardiac poles.
  - target: Left-Right Patterning and Cardiac Looping Failure
    causal_link_type: DIRECT
    description: >-
      Variants in left-right organizer genes (ZIC3, NODAL, GDF1) and in SMAD2, which
      regulates H3K27 methylation in the embryonic left-right organizer, randomise
      axis determination.
    evidence:
    - reference: PMID:23665959
      reference_title: De novo mutations in histone-modifying genes in congenital heart disease.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        There are also two de novo mutations in SMAD2, which regulates H3K27
        methylation in the embryonic left-right organizer.
      explanation: >-
        Directly links the de novo mutational burden to the embryonic left-right
        organizer, the structure whose failure produces the laterality arm of CHD.
  - target: Cardiac Neural Crest Migration and Outflow Tract Septation Failure
    causal_link_type: DIRECT
  - target: Endocardial Cushion Formation and Endothelial-to-Mesenchymal Transition Failure
    causal_link_type: DIRECT
    description: >-
      RBFOX2 loss of function, recurrent de novo in hypoplastic left heart syndrome,
      disrupts the epithelial-mesenchymal transition programme; NOTCH1 and JAG1 are
      also recurrently mutated.
    evidence:
    - reference: PMID:26785492
      reference_title: "De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        RBFOX2 is critical for zebrafish heart development (14), and regulates
        epithelial-mesenchymal transitions (EMT) (15). Disruption of EMT is felt to
        underlie HLHS pathogenesis

      explanation: >-
        Connects a recurrently de novo mutated gene to the endothelial-to-mesenchymal
        transition step, and to a specific lesion class.
  - target: Cardiac Septation Transcription Factor Network Failure
    causal_link_type: DIRECT
  - target: Neurodevelopmental abnormality
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - >-
      Expression of the same dosage-sensitive chromatin-modifying and transcription
      factor genes in the developing brain, so the variant perturbs neurodevelopment in
      parallel with cardiogenesis rather than through the cardiac lesion.
    description: >-
      The de novo and rare-variant burden that disrupts cardiac developmental gene dosage
      falls in genes also highly expressed in the developing brain, giving a shared
      genetic route to neurodevelopmental impairment alongside the hypoxaemic and
      operative routes.
  - target: Extracardiac congenital anomaly
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - >-
      Pleiotropic action of the same dosage-sensitive genes in craniofacial, limb and
      other non-cardiac developmental programmes.
    description: >-
      The chromatin-modifying and neural crest genes that dominate the CHD de novo burden
      are shared with non-cardiac developmental programmes, so extracardiac structural
      anomalies co-occur with the cardiac lesion rather than following from it.

- name: Maternal Metabolic and Teratogenic Perturbation of Cardiogenesis
  biological_scale: ORGANISM
  description: >-
    The non-genetic arm of CHD causation. During the window of cardiac organogenesis
    (roughly gestational weeks 3-8) the embryonic heart is vulnerable to the maternal
    metabolic and pharmacological environment. Pregestational diabetes is by a wide
    margin the strongest established modifiable risk factor; the proposed mediators are
    persistent embryonic hyperglycaemia, oxidative stress, dysregulation of
    hypoxia-inducible factor 1, and downregulation of the very NOTCH1 and NKX2-5
    programmes that the genetic arm of this entry disrupts. Definitive teratogenic
    exposures include maternal rubella, untreated maternal phenylketonuria, thalidomide,
    retinoids and vitamin A congeners, and indomethacin tocolysis. Periconceptional
    folic acid / multivitamin intake is the principal candidate protective exposure.
  biological_processes:
  - preferred_term: cellular response to oxidative stress
    term:
      id: GO:0034599
      label: cellular response to oxidative stress
    modifier: INCREASED
  evidence:
  - reference: PMID:38996968
    reference_title: "Systematic Review and Meta-analysis of Prenatal Risk Factors for Congenital Heart Disease: Part 1, Maternal Chronic Diseases and Parental Exposures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pregestational diabetes (PGDM) was associated with CHDs (OR, 3.51; 95% CI,
      2.86-4.3), without difference between type 1 and type 2 PGDM.
    explanation: >-
      Quantifies pregestational diabetes as the dominant non-genetic risk factor in a
      170-study meta-analysis.
  - reference: PMID:35838899
    reference_title: Effect of maternal pregestational diabetes mellitus on congenital heart diseases.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Factors such as persistent maternal hyperglycemia, oxidative stress,
      polymorphism of uncoupling protein 2, polymorphism of adiponectin gene, Notch 1
      pathway, Nkx2.5 disorders, dysregulation of the hypoxia-inducible factor 1, and
      viral etiologies are associated with the occurrence of congenital heart diseases
      in the offspring of mothers with pregestational diabetes mellitus.
    explanation: >-
      Names the proposed molecular mediators, which converge on the same NOTCH1 and
      NKX2-5 programmes as the genetic arm.
  - reference: PMID:17519397
    reference_title: "Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Information is highlighted regarding definitive risk factors such as maternal
      rubella; phenylketonuria; pregestational diabetes; exposure to thalidomide,
      vitamin A cogeners, or retinoids; and indomethacin tocolysis.
    explanation: >-
      Enumerates the exposures the AHA classifies as definitive non-inherited risk
      factors for congenital cardiovascular defects.
  downstream:
  - target: Endocardial Cushion Formation and Endothelial-to-Mesenchymal Transition Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - >-
        Hyperglycaemia-driven oxidative stress and HIF-1 dysregulation with
        downregulation of the NOTCH1 programme in the developing endocardium.
  - target: Cardiac Septation Transcription Factor Network Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - >-
        Reported downregulation of Nkx2.5 in the hyperglycaemic embryonic environment.

- name: Cardiac Progenitor Specification and Second Heart Field Deployment Failure
  biological_scale: CELLULAR
  description: >-
    The heart is not built from a single progenitor pool. The first heart field forms
    the linear heart tube and gives rise principally to the left ventricle and part of
    the atria; the second heart field (SHF) is a distinct population of progenitors that
    is progressively added to both poles of the elongating tube. The SHF supplies the
    right ventricle, the outflow tract myocardium and the ventricular septal myocardium
    at the arterial pole, and atrial including atrial septal myocardium at the venous
    pole. Because SHF deployment lays down the template on which septation is later
    performed, and because it orchestrates outflow tract development jointly with the
    neural crest, a deficit in progenitor addition is a single upstream lesion that can
    produce conotruncal, right ventricular hypoplastic, and septal phenotypes. This node
    is the reason a "root" CHD entry is mechanistically coherent rather than merely a
    list.
  genes:
  - preferred_term: HAND1
    term:
      id: hgnc:4807
      label: HAND1
  - preferred_term: HAND2
    term:
      id: hgnc:4808
      label: HAND2
  biological_processes:
  - preferred_term: embryonic heart tube development
    term:
      id: GO:0035050
      label: embryonic heart tube development
    modifier: DECREASED
  - preferred_term: embryonic heart tube morphogenesis
    term:
      id: GO:0003143
      label: embryonic heart tube morphogenesis
    modifier: DECREASED
  - preferred_term: heart development
    term:
      id: GO:0007507
      label: heart development
    modifier: DECREASED
  evidence:
  - reference: PMID:38488639
    reference_title: On the involvement of the second heart field in congenital heart defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The SHF gives rise to ventricular septal, right ventricular and outflow tract
      myocardium at the arterial pole, and atrial, including atrial septal myocardium,
      at the venous pole.
    explanation: >-
      Defines exactly which cardiac structures depend on second heart field addition,
      and therefore which lesions a deployment deficit can produce.
  - reference: PMID:38488639
    reference_title: On the involvement of the second heart field in congenital heart defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Genetic or environmental perturbation of SHF deployment thus underlies a
      spectrum of common forms of CHD affecting conotruncal and septal morphogenesis.
    explanation: >-
      States the causal claim of this node: SHF deployment failure is a shared upstream
      cause of both conotruncal and septal CHD.
  - reference: PMID:39000221
    reference_title: "Cardiac Development and Factors Influencing the Development of Congenital Heart Defects (CHDs): Part I."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cardiac morphogenesis involves numerous types of cells originating outside the
      initial cardiac crescent, including neural crest cells, cells of the second heart
      field origin, and epicardial progenitor cells.
    explanation: >-
      Establishes the multi-progenitor architecture of cardiac morphogenesis that this
      node and the neural crest node between them represent.
  - reference: PMID:19586923
    reference_title: A functional genetic study identifies HAND1 mutations in septation defects of the human heart.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results suggest that HAND1 may also be affected in septation defects of the human hearts, and thus has a broader role in human heart development and CHD."
    explanation: >-
      Binds HAND1 to this node. Graded INDIRECT because the authors state a
      suggestion rather than a demonstration; ClinGen's Congenital Heart
      Disease GCEP grades HAND1-CHD Moderate, which this record's notes record.
  - reference: PMID:32134193
    reference_title: Haploinsufficiency of the basic helix-loop-helix transcription factor HAND2 causes congenital heart defects.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Taken together, this first report of a HAND2 and HAND2-AS1 deletion in a family with CHDs strongly supports haploinsufficiency of HAND2 as an autosomal dominant cause of CHD."
    explanation: >-
      Binds HAND2 to this node through a segregating deletion, and gives the
      haploinsufficiency mechanism, which is a gene-dosage deficit in a
      myocardial transcription factor rather than a structural protein defect.
  - reference: PMID:10189962
    reference_title: "HAND proteins: molecular mediators of cardiac development and congenital heart disease."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: MODEL_ORGANISM
    snippet: "dHAND and eHAND are two related basic helix-loop-helix transcription factors that are expressed in a complementary fashion in the developing right and left ventricles, respectively. They are also expressed in the neural crest-derived cardiac outflow tract and aortic arch arteries."
    explanation: >-
      Places the HAND factors in the developing ventricles and the outflow
      tract - among the structures this node's progenitor population supplies -
      which is the basis for binding both genes here rather than to the
      septation or left-right nodes. The paper does not use the phrase second
      heart field, and does not assign HGNC symbols to dHAND and eHAND, so it
      supports the pair's territory rather than either gene's individually.
  downstream:
  - target: Cardiac Neural Crest Migration and Outflow Tract Septation Failure
    causal_link_type: DIRECT
    description: >-
      SHF deployment has been implicated in orchestrating outflow tract development
      together with the neural crest cells; a deficient arterial-pole template
      compromises subsequent neural-crest-dependent septation.
    evidence:
    - reference: PMID:38488639
      reference_title: On the involvement of the second heart field in congenital heart defects.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        SHF deployment creates the template for subsequent cardiac septation and has
        been implicated in cardiac looping and in orchestrating outflow tract
        development with neural crest cells.
      explanation: >-
        Directly asserts the SHF-to-neural-crest coordination this edge represents.
  - target: Cardiac Septation Transcription Factor Network Failure
    causal_link_type: DIRECT
    description: >-
      The SHF supplies the ventricular septal and atrial septal myocardium, so the
      septation programme acts on a template the SHF has laid down.
  - target: Left-Right Patterning and Cardiac Looping Failure
    causal_link_type: DIRECT
    description: >-
      Second heart field deployment has been implicated in cardiac looping itself, not
      only in the addition of myocardium at the poles.
  - target: Structural Cardiac Malformation
    causal_link_type: DIRECT

- name: Left-Right Patterning and Cardiac Looping Failure
  biological_scale: CELLULAR
  description: >-
    The linear heart tube must break bilateral symmetry and loop rightward (dextral
    looping) for the systemic and pulmonary circulations to be placed in their correct
    series arrangement. Handedness is set upstream at the embryonic left-right
    organizer, where motile-cilium-driven leftward flow establishes asymmetric NODAL,
    LEFTY and PITX2 expression; ZIC3 acts at the earliest stages of this process.
    Failure randomises the axis, producing situs ambiguus (heterotaxy) with its complex
    atrial, venous and ventriculoarterial mis-connections, or complete situs inversus.
    This node is the point at which the CHD root meets the ciliopathy_dysfunction and
    Visceral_Heterotaxy entries; those curate the ciliary machinery and the individual
    HTX loci in detail and are deliberately not re-derived here.
  genes:
  - preferred_term: ZIC3
    term:
      id: hgnc:12874
      label: ZIC3
  - preferred_term: SMAD2
    term:
      id: hgnc:6768
      label: SMAD2
  biological_processes:
  - preferred_term: determination of left/right symmetry
    term:
      id: GO:0007368
      label: determination of left/right symmetry
    modifier: LOSS_OF_FUNCTION
  - preferred_term: left/right pattern formation
    term:
      id: GO:0060972
      label: left/right pattern formation
    modifier: DECREASED
  - preferred_term: heart looping
    term:
      id: GO:0001947
      label: heart looping
    modifier: DECREASED
  evidence:
  - reference: PMID:9354794
    reference_title: X-linked situs abnormalities result from mutations in ZIC3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The frameshift allele is also associated with situs inversus among some
      heterozygous females, suggesting that ZIC3 functions in the earliest stages of
      LR-axis formation.
    explanation: >-
      Places a human CHD/laterality gene at the earliest step of left-right axis
      formation, which is the claim of this node.
  - reference: PMID:9354794
    reference_title: X-linked situs abnormalities result from mutations in ZIC3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aberrant LR axis development can lead to randomization of individual organ
      position (situs ambiguus) or to mirror-image reversal of all lateralized
      structures (situs inversus).
    explanation: >-
      States the two phenotypic outcomes of left-right patterning failure that define
      the heterotaxy subtype.
  - reference: PMID:30157302
    reference_title: Variable cardiovascular phenotypes associated with SMAD2 pathogenic variants.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data suggest two distinct phenotypes associated with pathogenic variants in SMAD2: complex CHD with or without laterality defects and other congenital anomalies, and a late-onset vascular phenotype characterized by arterial aneurysms with connective tissue abnormalities."
    explanation: >-
      Binds SMAD2 to this node: it is the TGF-beta/NODAL-pathway effector whose
      pathogenic variants produce complex CHD with laterality defects, which is
      the left-right patterning failure this node models. The same paper
      records the separate aneurysm phenotype curated in the aortopathy
      entries.
  downstream:
  - target: Structural Cardiac Malformation
    causal_link_type: DIRECT
    description: >-
      Randomised laterality produces abnormal atrial situs, anomalous systemic and
      pulmonary venous connections, atrioventricular and ventriculoarterial discordance,
      and commonly an unbalanced atrioventricular septal defect.
  - target: Heterotaxy
    causal_link_type: DIRECT
    description: >-
      Failure to break and propagate the left-right axis randomises thoracoabdominal
      situs, which is the heterotaxy phenotype itself rather than a consequence of it.
  - target: Abnormal pulmonary vein morphology
    causal_link_type: DIRECT
    description: >-
      Laterality failure leaves the common pulmonary vein to connect to the systemic
      venous circulation, giving the anomalous pulmonary venous return that accompanies
      the heterotaxy syndromes.

- name: Cardiac Neural Crest Migration and Outflow Tract Septation Failure
  biological_scale: CELLULAR
  description: >-
    Cardiac neural crest cells delaminate from the postotic (vagal) hindbrain, migrate
    through the caudal pharyngeal arches, and enter the outflow tract, where they are
    indispensable for formation of the aorticopulmonary septum that divides the common
    truncus into aorta and pulmonary trunk. The same population patterns the aortic
    arch arteries and contributes to the semilunar valves and the proximal coronary
    arteries. Crucially, cardiac neural crest and second heart field cells migrate in
    opposite directions at the same developmental stage, so a perturbation of either
    population produces overlapping conotruncal phenotypes. Because these cells also
    build craniofacial and pharyngeal-arch derivatives, their failure explains the
    recurrent clinical co-occurrence of conotruncal CHD with craniofacial and
    pharyngeal anomalies (22q11.2 deletion, CHARGE) — the cardiac face of the
    neurocristopathy concept.
  genes:
  - preferred_term: TBX1
    term:
      id: hgnc:11592
      label: TBX1
  - preferred_term: TFAP2B
    term:
      id: hgnc:11743
      label: TFAP2B
  - preferred_term: GATA6
    term:
      id: hgnc:4174
      label: GATA6
  cell_types:
  - preferred_term: migratory cardiac neural crest cell
    term:
      id: CL:2000073
      label: migratory cardiac neural crest cell
  biological_processes:
  - preferred_term: cardiac neural crest cell migration involved in outflow tract morphogenesis
    term:
      id: GO:0003253
      label: cardiac neural crest cell migration involved in outflow tract morphogenesis
    modifier: DECREASED
  - preferred_term: neural crest cell migration
    term:
      id: GO:0001755
      label: neural crest cell migration
    modifier: DECREASED
  - preferred_term: outflow tract morphogenesis
    term:
      id: GO:0003151
      label: outflow tract morphogenesis
    modifier: DECREASED
  locations:
  - preferred_term: outflow tract
    term:
      id: UBERON:0004145
      label: outflow tract
  evidence:
  - reference: PMID:32405705
    reference_title: "Cardiac Neural Crest Cells: Their Rhombomeric Specification, Migration, and Association with Heart and Great Vessel Anomalies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These are due to the absence or dysfunction of the two main cell types, i.e.,
      neural crest cells and secondary heart field cells that migrate in opposite
      directions at the same stage of development.
    explanation: >-
      States the two-population, counter-migratory architecture that makes neural crest
      and second heart field failure phenotypically convergent on the outflow tract.
  - reference: PMID:32405705
    reference_title: "Cardiac Neural Crest Cells: Their Rhombomeric Specification, Migration, and Association with Heart and Great Vessel Anomalies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These cells directly govern aortic arch patterning and development, ascending
      aorta dilatation, semi-valvular and coronary artery development,
      aortopulmonary septation abnormalities, persistence of the ductus arteriosus,
      trunk and proximal pulmonary arteries
    explanation: >-
      Enumerates the specific structures whose malformation follows cardiac neural
      crest failure.
  - reference: PMID:39000221
    reference_title: "Cardiac Development and Factors Influencing the Development of Congenital Heart Defects (CHDs): Part I."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      For example, neural crest cells, which form the building blocks of the peripheral
      nervous system and craniofacial areas, migrate to the heart, where they are
      indispensable for the formation of a septum within the outflow tract
    explanation: >-
      Establishes the indispensability of neural crest cells for outflow tract
      septation and their shared origin with craniofacial structures.
  - reference: PMID:39000221
    reference_title: "Cardiac Development and Factors Influencing the Development of Congenital Heart Defects (CHDs): Part I."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The relationship between neural crest cells and the formation of septa in the
      heart explains the correlation between craniofacial defects and some congenital
      heart defects
    explanation: >-
      Supports the neurocristopathy claim that links conotruncal CHD to craniofacial
      anomalies in the syndromic entries.
  - reference: PMID:14585638
    reference_title: Role of TBX1 in human del22q11.2 syndrome.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified three mutations of TBX1 in two unrelated patients without the 22q11.2 deletion-one with sporadic conotruncal anomaly face syndrome/velocardiofacial syndrome and one with sporadic DiGeorge's syndrome-and in three patients from a family with conotruncal anomaly face syndrome/velocardiofacial syndrome."
    explanation: >-
      Binds TBX1 to this node on its outflow tract phenotype: coding-sequence
      mutations in the gene alone, with no 22q11.2 deletion, produce
      conotruncal anomaly face syndrome and DiGeorge syndrome. The cited text
      establishes the gene-to-lesion link rather than a neural crest mechanism,
      which is the node's own subject and is evidenced by the two references
      above; the deletion syndrome itself is curated in
      22q11.2_Deletion_Syndrome.
  - reference: PMID:10802654
    reference_title: Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our work shows that TFAP2B has a role in ductal, facial and limb development and suggests that Char syndrome results from derangement of neural-crest-cell derivatives."
    explanation: >-
      Binds TFAP2B to this node: the gene encodes a transcription factor
      expressed in neural crest cells, and its loss deranges neural-crest
      derivatives, which is exactly the population this node models.
  - reference: PMID:31301121
    reference_title: "GATA6 mutations: Characterization of two novel patients and a comprehensive overview of the GATA6 genotypic and phenotypic spectrum."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: MODEL_ORGANISM
    snippet: "conditional inactivation of GATA6 in murine neural-crest-derived vascular smooth-muscle cells resulted in a spectrum of cardiac outflow tract defects (64% persistent truncus arteriosus [PTA] and 36% double outlet right ventricle [DORV]; Lepore et al., 2006), underscoring the importance of GATA6 in normal heart development"
    explanation: >-
      Binds GATA6 to this node through the cell population in which its loss
      produces outflow tract defects. Graded MODEL_ORGANISM and BACKGROUND
      because the quoted result is a mouse conditional knockout reported
      elsewhere and restated in this paper's introduction.
  downstream:
  - target: Structural Cardiac Malformation
    causal_link_type: DIRECT
    description: >-
      Failure of aorticopulmonary septation yields persistent truncus arteriosus;
      partial or malaligned septation yields tetralogy of Fallot, double outlet right
      ventricle and interrupted aortic arch.
  - target: Conotruncal defect
    causal_link_type: DIRECT
    description: >-
      Absent or misdirected neural-crest-dependent aorticopulmonary septation is the
      developmental origin of the conotruncal lesion class as a whole.
  - target: Tetralogy of Fallot
    causal_link_type: DIRECT
    description: >-
      Partial and anteriorly malaligned outflow septation produces the tetralogy
      combination of malalignment ventricular septal defect, overriding aorta and right
      ventricular outflow obstruction.
  - target: Transposition of the great arteries
    causal_link_type: DIRECT
    description: >-
      Failure of the spiralling rotation of the outflow tract during neural-crest-dependent
      septation leaves the great arteries in ventriculoarterial discordance.
  - target: Patent ductus arteriosus
    causal_link_type: DIRECT
    description: >-
      The arterial duct is a neural-crest-derived arch segment, so crest failure is one
      developmental route to persistence of the duct after birth.

- name: Endocardial Cushion Formation and Endothelial-to-Mesenchymal Transition Failure
  biological_scale: CELLULAR
  description: >-
    The atrioventricular canal and outflow tract cushions are the swellings of cardiac
    jelly that are colonised when a subset of endocardial cells loses cell-cell
    adhesion, delaminates and transforms into invasive mesenchyme
    (endothelial-to-mesenchymal transition, a cardiac-specific instance of EMT driven
    by TGF-beta, BMP and NOTCH signalling from the adjacent myocardium). Those
    mesenchymal cells then remodel into the atrioventricular and semilunar valve
    leaflets and into the membranous portions of the atrial and ventricular septa.
    Failure at this step is therefore simultaneously a valve lesion and a septation
    lesion, which is why the atrioventricular septal defect is a single malformation
    rather than a coincidence of two. NOTCH1 loss of function in this programme is the
    established cause of bicuspid aortic valve with early calcification.
  genes:
  - preferred_term: NOTCH1
    term:
      id: hgnc:7881
      label: NOTCH1
  - preferred_term: PLD1
    term:
      id: hgnc:9067
      label: PLD1
  cell_types:
  - preferred_term: endocardial cell
    term:
      id: CL:0002350
      label: endocardial cell
  - preferred_term: endocardial cushion cell
    term:
      id: CL:0008022
      label: endocardial cushion cell
  biological_processes:
  - preferred_term: endocardial cushion formation
    term:
      id: GO:0003272
      label: endocardial cushion formation
    modifier: DECREASED
  - preferred_term: epithelial to mesenchymal transition involved in endocardial cushion formation
    term:
      id: GO:0003198
      label: epithelial to mesenchymal transition involved in endocardial cushion formation
    modifier: DECREASED
  - preferred_term: endocardial cushion morphogenesis
    term:
      id: GO:0003203
      label: endocardial cushion morphogenesis
    modifier: DECREASED
  - preferred_term: heart valve development
    term:
      id: GO:0003170
      label: heart valve development
    modifier: DECREASED
  locations:
  - preferred_term: endocardial cushion
    term:
      id: UBERON:0002062
      label: endocardial cushion
  evidence:
  - reference: PMID:16025100
    reference_title: Mutations in NOTCH1 cause aortic valve disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we show that mutations in the signalling and transcriptional regulator NOTCH1
      cause a spectrum of developmental aortic valve anomalies and severe valve
      calcification in non-syndromic autosomal-dominant human pedigrees
    explanation: >-
      Establishes NOTCH1, the signalling pathway that drives endocardial
      endothelial-to-mesenchymal transition, as a cause of human congenital valve
      malformation.
  - reference: PMID:26785492
    reference_title: "De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Disruption of EMT is felt to underlie HLHS pathogenesis
    explanation: >-
      Links failure of the epithelial-to-mesenchymal transition programme to a specific
      severe CHD lesion class.
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis."
    explanation: >-
      Binds PLD1 to this node by the mechanism the node models: inhibiting the
      enzyme reduces endothelial-to-mesenchymal transition, the step that
      populates the cushions and builds the valve leaflets.
  downstream:
  - target: Structural Cardiac Malformation
    causal_link_type: DIRECT
    description: >-
      Cushion failure yields atrioventricular septal defect, dysplastic or bicuspid
      semilunar valves, and the membranous ventricular septal defect.
  - target: Flow-Dependent Cardiac Morphogenesis Failure
    causal_link_type: DIRECT
    description: >-
      A stenotic or atretic valve created at this step becomes the flow-limiting lesion
      that drives the secondary hypoplasia of the chamber behind it.
  - target: Complete atrioventricular canal defect
    causal_link_type: DIRECT
    description: >-
      Failure of the superior and inferior atrioventricular cushions to fuse leaves a
      common atrioventricular junction with combined atrial and ventricular septal
      deficiency, which is the direct anatomical readout of this node.

- name: Cardiac Septation Transcription Factor Network Failure
  biological_scale: MOLECULAR
  description: >-
    Division of the looped, chambered heart into four cavities depends on a small,
    combinatorially acting transcription factor network — NKX2-5, GATA4/GATA6, TBX5 and
    TBX20 — whose members physically interact and are dosage-sensitive. Haploinsufficiency
    of any one member permits septation to begin but not to complete. Two features of
    this network are diagnostically important and are curated here rather than in the
    lesion entries: the same factors that direct septation also build and maintain the
    atrioventricular conduction system, so NKX2-5 haploinsufficiency yields septal
    defect plus progressive atrioventricular block; and the GATA4-TBX5 physical
    interaction is disrupted by septal-defect-causing missense alleles in either
    partner, which is the molecular basis of the cardiac overlap between isolated
    septal defects and Holt-Oram syndrome.
  genes:
  - preferred_term: NKX2-5
    term:
      id: hgnc:2488
      label: NKX2-5
  - preferred_term: GATA4
    term:
      id: hgnc:4173
      label: GATA4
  - preferred_term: TBX5
    term:
      id: hgnc:11604
      label: TBX5
  - preferred_term: TBX20
    term:
      id: hgnc:11598
      label: TBX20
  biological_processes:
  - preferred_term: cardiac septum development
    term:
      id: GO:0003279
      label: cardiac septum development
    modifier: DECREASED
  - preferred_term: atrial septum development
    term:
      id: GO:0003283
      label: atrial septum development
    modifier: DECREASED
  - preferred_term: ventricular septum development
    term:
      id: GO:0003281
      label: ventricular septum development
    modifier: DECREASED
  - preferred_term: cardiac septum morphogenesis
    term:
      id: GO:0060411
      label: cardiac septum morphogenesis
    modifier: DECREASED
  evidence:
  - reference: PMID:9651244
    reference_title: Congenital heart disease caused by mutations in the transcription factor NKX2-5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data indicate that NKX2-5 is important for regulation of septation during
      cardiac morphogenesis and for maturation and maintenance of atrioventricular node
      function throughout life.
    explanation: >-
      Establishes the dual septation/conduction role of NKX2-5 that this node asserts.
  - reference: PMID:9651244
    reference_title: Congenital heart disease caused by mutations in the transcription factor NKX2-5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two are predicted to impair binding of NKX2-5 to target DNA, resulting in
      haploinsufficiency, and a third potentially augments target-DNA binding.
    explanation: >-
      Documents the dosage-sensitive, DNA-binding-dependent mechanism of the septation
      transcription factor network.
  - reference: PMID:12845333
    reference_title: GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A heterozygous G296S missense mutation of GATA4, a transcription factor
      essential for heart formation, was found in all available affected family
      members but not in any control individuals
    explanation: >-
      Establishes GATA4 as a second septation-network transcription factor causing
      isolated human cardiac septal defects, by co-segregation in a linked pedigree.
  - reference: PMID:12845333
    reference_title: GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, the Gata4 mutation abrogated a physical interaction between Gata4
      and TBX5, a T-box protein responsible for a subset of syndromic cardiac septal
      defects. Conversely, interaction of Gata4 and TBX5 was disrupted by specific
      human TBX5 missense mutations that cause similar cardiac septal defects.
    explanation: >-
      Supports the combinatorial, physically interacting character of the septation
      transcription factor network, and the specific GATA4-TBX5 interaction this node
      cites as the molecular basis of the isolated-septal-defect / Holt-Oram overlap.
      Disruption from either side of the interaction produces similar septal defects.
  - reference: PMID:17668378
    reference_title: "Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report nonsense (Q195X) and missense (I152M) germline mutations within the T-box DNA-binding domain of human TBX20 that were associated with a family history of CHD and a complex spectrum of developmental anomalies, including defects in septation, chamber growth, and valvulogenesis."
    explanation: >-
      Binds TBX20 to this node: germline T-box-domain variants produce
      septation defects, which is the failure this node models.
  - reference: PMID:17668378
    reference_title: "Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "TBX20 interacts physically, functionally, and genetically with other cardiac transcription factors, including NKX2-5, GATA4, and TBX5, mutations of which cause congenital heart disease (CHD)."
    explanation: >-
      Sources this node's central claim that the septation factors act as one
      physically interacting, combinatorial network rather than independently,
      and places TBX20 inside it alongside the three factors already bound here.
  downstream:
  - target: Structural Cardiac Malformation
    causal_link_type: DIRECT
    description: >-
      Incomplete septation leaves an interatrial or interventricular communication, or
      in the severe case a common atrioventricular junction.
  - target: Arrhythmia
    causal_link_type: DIRECT
    description: >-
      The developmental, non-acquired route to arrhythmia in CHD: the same
      transcription factors that direct septation build and maintain the
      atrioventricular conduction system, so their haploinsufficiency yields
      progressive atrioventricular block alongside the septal defect rather than as a
      consequence of it.
    evidence:
    - reference: PMID:9651244
      reference_title: Congenital heart disease caused by mutations in the transcription factor NKX2-5.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These data indicate that NKX2-5 is important for regulation of septation during
        cardiac morphogenesis and for maturation and maintenance of atrioventricular
        node function throughout life.
      explanation: >-
        Establishes that one septation-network factor governs both septation and
        atrioventricular node function, which is exactly the dual output this edge
        asserts.
  - target: Atrial septal defect
    causal_link_type: DIRECT
    description: >-
      Haploinsufficiency of the septation transcription factor network leaves the
      interatrial septum incompletely formed, the commonest isolated lesion attributed
      to this network in human pedigrees.
  - target: Ventricular septal defect
    causal_link_type: DIRECT
    description: >-
      The same network failure applied to the interventricular septum leaves a
      persistent interventricular communication.

- name: Flow-Dependent Cardiac Morphogenesis Failure
  biological_scale: TISSUE
  description: >-
    Cardiac morphogenesis is not driven by the genome alone. The developing heart
    begins to function while it is still being built, and the resulting haemodynamic
    forces — shear stress on the endocardium and cyclic strain on the myocardium — are
    themselves morphogenetic inputs that the tissue senses and responds to. Removing or
    altering those forces produces abnormal heart development. This is the mechanistic
    content of the clinical "no flow, no grow" principle, and it is what converts a
    focal primary lesion into a global one: an early valvar or arch obstruction reduces
    flow through the structures downstream of it, whose growth is then secondarily
    curtailed, so that a point stenosis becomes hypoplastic left heart syndrome or
    aortic arch hypoplasia. It also means that a CHD lesion at birth is the compound
    product of the original developmental error and months of altered loading — a
    caveat that limits how directly a neonatal anatomical phenotype can be read back to
    a single genetic first cause. This node is unbroken ground in dismech; the
    Hypoplastic_Left_Heart_Syndrome and Coarctation_of_the_Aorta entries assert the
    flow-limitation step in prose without anchoring the general mechanism.
  biological_processes:
  - preferred_term: response to fluid shear stress
    term:
      id: GO:0034405
      label: response to fluid shear stress
    modifier: DYSREGULATED
  - preferred_term: heart morphogenesis
    term:
      id: GO:0003007
      label: heart morphogenesis
    modifier: DECREASED
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:26969993
    reference_title: "Organ Function as a Modulator of Organ Formation: Lessons from Zebrafish."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In the absence or disruption of these forces, heart development is abnormal,
      suggesting that the heart must sense these changes and respond appropriately.
    explanation: >-
      Establishes haemodynamic force as a necessary morphogenetic input to heart
      development, which is the claim of this node. Evidence is from zebrafish, so the
      node is tagged MODEL_ORGANISM rather than treated as demonstrated in humans.
  - reference: PMID:26969993
    reference_title: "Organ Function as a Modulator of Organ Formation: Lessons from Zebrafish."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This theme is particularly evident in the developing heart as progression of
      cardiac development is accompanied by increased and altered hemodynamic forces.
    explanation: >-
      Supports the coupling of developmental progression to changing haemodynamic load.
  downstream:
  - target: Structural Cardiac Malformation
    causal_link_type: DIRECT
    description: >-
      Secondary hypoplasia of the chamber, valve or arch segment behind a flow-limiting
      lesion, converting a focal defect into a hypoplastic-heart phenotype.
  - target: Left ventricular outflow tract obstruction
    causal_link_type: DIRECT
    description: >-
      Reduced antegrade flow through the systemic outflow is self-reinforcing, so an
      initially focal subaortic or valvar lesion grows into the left ventricular outflow
      tract obstruction spectrum up to hypoplastic left heart syndrome.
  - target: Coarctation of aorta
    causal_link_type: DIRECT
    description: >-
      Diminished flow across the fetal aortic isthmus leaves that segment underdeveloped,
      producing the discrete isthmic narrowing.
  - target: Pulmonic stenosis
    causal_link_type: DIRECT
    description: >-
      The same flow-dependent logic on the pulmonary side converts a restrictive
      pulmonary valve or infundibulum into progressive right ventricular outflow
      obstruction.

- name: Structural Cardiac Malformation
  biological_scale: TISSUE
  description: >-
    The convergence node of this entry: an anatomically abnormal heart or great vessels
    at birth. Every mechanistic arm above terminates here, and every lesion-specific
    dismech entry begins from a member of this node's phenotype set. The malformation
    is fixed at birth (surgery repairs or palliates anatomy but does not restore normal
    development), which is why CHD is a lifelong condition rather than a neonatal event.
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:38488639
    reference_title: On the involvement of the second heart field in congenital heart defects.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Congenital heart defects (CHD) affect 1 in 100 live births and result from
      defects in cardiac development.
    explanation: >-
      States the defining causal claim of this entry: CHD is the anatomical outcome of
      disrupted cardiac development.
  downstream:
  - target: Altered Circulatory Physiology
    causal_link_type: DIRECT

- name: Altered Circulatory Physiology
  biological_scale: ORGANISM
  description: >-
    The shared physiological consequence of structural malformation, and the level at
    which otherwise unrelated lesions become clinically interchangeable. Four patterns
    recur: left-to-right shunting with pulmonary overcirculation and volume loading;
    outflow obstruction with pressure loading of the upstream ventricle; obligatory
    mixing or right-to-left shunting with systemic hypoxaemia and cyanosis; and
    duct-dependent circulation, in which either systemic or pulmonary blood flow is
    supplied through the arterial duct and collapses when it closes in the first days
    of life. Long-term, the volume- and pressure-loaded and hypoxaemic circulations
    drive pulmonary vascular remodelling, ventricular hypertrophy and fibrosis,
    arrhythmia and heart failure. The lesion-specific elaboration of each pattern is
    curated in the individual lesion entries (notably Eisenmenger_Syndrome for the
    shunt-to-pulmonary-vascular-disease trajectory) and is deliberately not re-derived
    here.
  evidence:
  - reference: PMID:29162633
    reference_title: Use of prostaglandins in duct-dependent congenital heart conditions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Infants with duct-dependent critical CHD remain well during the fetal period and
      may deteriorate when the ductus arteriosus (commonly called 'duct') closes after
      birth.
    explanation: >-
      Documents the duct-dependent physiological pattern and its characteristic
      postnatal timing.
  downstream:
  - target: Cyanosis
    causal_link_type: DIRECT
  - target: Congestive heart failure
    causal_link_type: DIRECT
  - target: Pulmonary arterial hypertension
    causal_link_type: DIRECT
  - target: Arrhythmia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - >-
      Chronic volume and pressure loading causing chamber dilation and hypertrophy,
      plus surgical scar in the repaired or palliated heart, creating reentrant and
      triggered arrhythmogenic substrate.
  - target: Sudden cardiac death
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - >-
      Ventricular tachyarrhythmia arising on that substrate; the entry keeps this
      indirect rather than drawing physiology straight to death.
    evidence:
    - reference: PMID:39768857
      reference_title: "Cardiovascular Diseases in Public Health: Chromosomal Abnormalities in Congenital Heart Disease Causing Sudden Cardiac Death in Children."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        CAs associated with cardiovascular diseases cause structural or functional
        alterations of the heart, affecting the cardiac chambers, valves, coronary
        arteries, aorta, and cardiac conduction, thus increasing the likelihood of
        arrhythmias, cardiac arrest, and sudden cardiac death (SCD).
      explanation: >-
        Places arrhythmia between the structural/functional cardiac alteration and
        sudden cardiac death, which is the intermediate this edge names.
  - target: Failure to thrive
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - >-
        Increased metabolic demand and feeding difficulty in the setting of pulmonary
        overcirculation or hypoxaemia.

phenotypes:
- category: Cardiovascular
  name: Conotruncal defect
  subtype: CTD
  description: >-
    Malformation of the cardiac outflow tract and great arteries following failure of
    aorticopulmonary septation, rotation or alignment.
  phenotype_term:
    preferred_term: Conotruncal defect
    term:
      id: HP:0001710
      label: Conotruncal defect
  evidence:
  - reference: PMID:32405705
    reference_title: "Cardiac Neural Crest Cells: Their Rhombomeric Specification, Migration, and Association with Heart and Great Vessel Anomalies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Outflow tract abnormalities are the most frequent congenital heart defects."
    explanation: Establishes outflow tract (conotruncal) malformation as a cardinal CHD phenotype.
- category: Cardiovascular
  name: Tetralogy of Fallot
  subtype: CTD
  description: >-
    The prototypical conotruncal lesion: anterior malalignment of the outlet septum
    producing ventricular septal defect, overriding aorta, right ventricular outflow
    obstruction and right ventricular hypertrophy. Curated in full in Tetralogy_of_Fallot.
  phenotype_term:
    preferred_term: Tetralogy of Fallot
    term:
      id: HP:0001636
      label: Tetralogy of Fallot
  evidence:
  - reference: PMID:28991257
    reference_title: "Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot"
    explanation: >-
      Documents tetralogy of Fallot as a discrete lesion within a large CHD cohort and
      attributes a defined genetic fraction to it.
- category: Cardiovascular
  name: Transposition of the great arteries
  subtype: CTD
  description: >-
    Ventriculoarterial discordance, producing two circulations in parallel rather than
    in series and obligate mixing-dependent survival. Curated in full in
    Dextro_Transposition_of_the_Great_Arteries.
  phenotype_term:
    preferred_term: Transposition of the great arteries
    term:
      id: HP:0001669
      label: Transposition of the great arteries
  evidence:
  - reference: PMID:39000221
    reference_title: "Cardiac Development and Factors Influencing the Development of Congenital Heart Defects (CHDs): Part I."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      New techniques for studying heart development have revealed many aspects of
      cardiac morphogenesis that are important in the development of CHDs, in
      particular transposition of the great arteries.
    explanation: >-
      Connects transposition of the great arteries specifically to the cardiac
      morphogenesis programme this entry models.
- category: Cardiovascular
  name: Atrial septal defect
  subtype: Septal
  description: >-
    Interatrial communication permitting left-to-right shunting; often clinically silent
    in childhood. Curated in full in Atrial_Septal_Defect.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:30783674
    reference_title: "Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The change in prevalence of mild CHD lesions (ventricular septal defect, atrial
      septal defect and patent ductus arteriosus) together explained 93.4% of the
      increased overall prevalence
    explanation: Establishes atrial septal defect as one of the commonest CHD lesions.
- category: Cardiovascular
  name: Ventricular septal defect
  subtype: Septal
  description: >-
    Interventricular communication; the single commonest congenital cardiac
    malformation. Curated in full in Ventricular_Septal_Defect.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:30783674
    reference_title: "Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The change in prevalence of mild CHD lesions (ventricular septal defect, atrial
      septal defect and patent ductus arteriosus) together explained 93.4% of the
      increased overall prevalence
    explanation: Establishes ventricular septal defect as one of the commonest CHD lesions.
- category: Cardiovascular
  name: Complete atrioventricular canal defect
  subtype: AVSD
  description: >-
    Common atrioventricular junction with a single atrioventricular valve and combined
    atrial and ventricular septal deficiency, the direct anatomical readout of
    endocardial cushion fusion failure. Strongly associated with trisomy 21.
  phenotype_term:
    preferred_term: Complete atrioventricular canal defect
    term:
      id: HP:0001674
      label: Complete atrioventricular canal defect
- category: Cardiovascular
  name: Left ventricular outflow tract obstruction
  subtype: LVOTO
  description: >-
    Obstruction anywhere along the systemic outflow from subaortic region to aortic
    isthmus, including hypoplastic left heart syndrome, aortic valve stenosis and
    bicuspid aortic valve.
  phenotype_term:
    preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  evidence:
  - reference: PMID:34440418
    reference_title: "Genetic Evaluation of Inpatient Neonatal and Infantile Congenital Heart Defects: New Findings and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, diagnostic results (15.8%) in left ventricular outflow tract
      obstruction (LVOTO) defects occurred most often in patients with isolated CHD.
    explanation: >-
      Uses left ventricular outflow tract obstruction as a defined clinical CHD class
      and reports its distinctive genetic-diagnostic behaviour.
- category: Cardiovascular
  name: Coarctation of aorta
  subtype: LVOTO
  description: >-
    Discrete narrowing of the aortic isthmus; in the severe neonatal form the systemic
    circulation is duct-dependent. Curated in full in Coarctation_of_the_Aorta.
  phenotype_term:
    preferred_term: Coarctation of aorta
    term:
      id: HP:0001680
      label: Coarctation of aorta
- category: Cardiovascular
  name: Pulmonic stenosis
  subtype: RVOTO
  description: >-
    Obstruction at the pulmonary valve or right ventricular outflow tract; in the severe
    or atretic form the pulmonary circulation is duct-dependent.
  phenotype_term:
    preferred_term: Pulmonic stenosis
    term:
      id: HP:0001642
      label: Pulmonic stenosis
  evidence:
  - reference: PMID:22078432
    reference_title: "Birth prevalence of congenital heart disease worldwide: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with relatively more pulmonary outflow obstructions and fewer left ventricular
      outflow tract obstructions
    explanation: >-
      Reports pulmonary outflow obstruction as a distinct, geographically varying CHD
      lesion class.
- category: Cardiovascular
  name: Heterotaxy
  subtype: HTX
  description: >-
    Abnormal left-right arrangement of the thoracoabdominal organs with complex
    cardiovascular malformation. Curated in full in Visceral_Heterotaxy.
  phenotype_term:
    preferred_term: Heterotaxy
    term:
      id: HP:0030853
      label: Heterotaxy
  evidence:
  - reference: PMID:9354794
    reference_title: X-linked situs abnormalities result from mutations in ZIC3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aberrant LR axis development can lead to randomization of individual organ
      position (situs ambiguus) or to mirror-image reversal of all lateralized
      structures (situs inversus).
    explanation: Defines the heterotaxy (situs ambiguus) phenotype and its developmental origin.
- category: Cardiovascular
  name: Abnormal pulmonary vein morphology
  subtype: APVR
  description: >-
    Anomalous connection of some or all pulmonary veins to the systemic venous
    circulation. Curated in full in Congenital_Total_Pulmonary_Venous_Return_Anomaly and
    Scimitar_Syndrome.
  phenotype_term:
    preferred_term: Abnormal pulmonary vein morphology
    term:
      id: HP:0030968
      label: Abnormal pulmonary vein morphology
- category: Cardiovascular
  name: Patent ductus arteriosus
  description: >-
    Persistence of the arterial duct beyond the normal postnatal closure window. It is
    both a CHD lesion in its own right and, in duct-dependent lesions, the structure
    whose closure precipitates neonatal collapse.
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  evidence:
  - reference: PMID:30783674
    reference_title: "Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The change in prevalence of mild CHD lesions (ventricular septal defect, atrial
      septal defect and patent ductus arteriosus) together explained 93.4% of the
      increased overall prevalence
    explanation: Establishes patent ductus arteriosus as one of the commonest CHD lesions.
- category: Cardiovascular
  name: Cyanosis
  description: >-
    Systemic arterial hypoxaemia from right-to-left shunting, obligatory mixing, or
    inadequate pulmonary blood flow. The physiological signature of the "critical" CHD
    group and the basis of newborn pulse-oximetry screening.
  phenotype_term:
    preferred_term: Cyanosis
    term:
      id: HP:0000961
      label: Cyanosis
  evidence:
  - reference: PMID:22554860
    reference_title: "Pulse oximetry screening for critical congenital heart defects in asymptomatic newborn babies: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The overall sensitivity of pulse oximetry for detection of critical congenital
      heart defects was 76.5% (95% CI 67.7-83.5).
    explanation: >-
      Establishes that a detectable arterial oxygen-saturation deficit accompanies most
      critical CHD, the phenotype this entry records as cyanosis.
- category: Cardiovascular
  name: Congestive heart failure
  description: >-
    Volume or pressure overload of one or both ventricles, presenting in infancy as
    tachypnoea, feeding difficulty, diaphoresis and hepatomegaly, and in adult
    survivors as the leading late cause of morbidity.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
- category: Cardiovascular
  name: Pulmonary arterial hypertension
  description: >-
    Pulmonary vascular remodelling driven by chronic left-to-right shunting; if
    unrepaired it progresses to shunt reversal (Eisenmenger physiology), curated in
    Eisenmenger_Syndrome.
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
- category: Cardiovascular
  name: Arrhythmia
  description: >-
    Rhythm and conduction disturbance, arising in CHD by two mechanistically distinct
    routes that this entry keeps separate. First, developmental: the septation
    transcription factor network also builds and maintains the atrioventricular
    conduction system, so NKX2-5 haploinsufficiency produces septal defect together
    with progressive atrioventricular block. Second, acquired: surgical scar, chamber
    dilation from chronic volume or pressure loading, and hypoxaemia create reentrant
    and triggered substrates in the repaired or palliated heart. Arrhythmia is the
    dominant late-mortality mechanism in adult survivors, which is why it is curated at
    root level rather than left to the individual lesion entries.
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: PMID:39768857
    reference_title: "Cardiovascular Diseases in Public Health: Chromosomal Abnormalities in Congenital Heart Disease Causing Sudden Cardiac Death in Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CAs associated with cardiovascular diseases cause structural or functional
      alterations of the heart, affecting the cardiac chambers, valves, coronary
      arteries, aorta, and cardiac conduction, thus increasing the likelihood of
      arrhythmias, cardiac arrest, and sudden cardiac death (SCD).
    explanation: >-
      Links the structural and conduction-system alterations modelled by this entry to
      arrhythmia as a downstream clinical phenotype.
  - reference: PMID:9651244
    reference_title: Congenital heart disease caused by mutations in the transcription factor NKX2-5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A dominant disease locus associated with cardiac malformations and
      atrioventricular conduction abnormalities was mapped to chromosome 5q35
    explanation: >-
      Evidences the developmental route to arrhythmia specifically: one locus producing
      both the structural malformation and the conduction abnormality.
- category: Cardiovascular
  name: Sudden cardiac death
  description: >-
    The dominant mode of late mortality in congenital heart disease, and the endpoint
    that makes arrhythmia surveillance in adult survivors consequential rather than
    routine. Risk is markedly elevated over the general population, concentrated in
    complex lesions (tetralogy of Fallot, transposition of the great arteries, cyanotic
    heart disease, Ebstein anomaly, Fontan circulation), and is greater in adults than
    in children - the opposite of the intuition that CHD is a paediatric problem
    resolved by neonatal surgery.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:39768857
    reference_title: "Cardiovascular Diseases in Public Health: Chromosomal Abnormalities in Congenital Heart Disease Causing Sudden Cardiac Death in Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, in CHD patients, the rates are 20-30 times higher than those in the
      general population
    explanation: >-
      Quantifies the excess sudden-cardiac-death risk in CHD relative to the general
      population.
  - reference: PMID:39768857
    reference_title: "Cardiovascular Diseases in Public Health: Chromosomal Abnormalities in Congenital Heart Disease Causing Sudden Cardiac Death in Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some patients with tetralogy of Fallot, transposition of the great arteries,
      cyanotic heart disease, Ebstein anomaly, and Fontan circulation are at an
      increased risk for SCD.
    explanation: >-
      Identifies the lesion classes carrying the highest sudden-cardiac-death risk,
      which map onto this entry's CTD, RVOTO and single-ventricle-palliation content.
  - reference: PMID:39768857
    reference_title: "Cardiovascular Diseases in Public Health: Chromosomal Abnormalities in Congenital Heart Disease Causing Sudden Cardiac Death in Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The incidence of SCD is greater in adults than in children
    explanation: >-
      Supports this entry's framing of CHD as a lifelong condition whose burden shifts
      into adulthood rather than one resolved by neonatal surgery.
- category: Growth
  name: Failure to thrive
  description: >-
    Poor weight gain from the combination of increased metabolic demand, feeding
    difficulty and hypoxaemia; a leading indication for earlier surgical repair.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
- category: Neurologic
  name: Neurodevelopmental abnormality
  description: >-
    Cognitive, motor, language and executive-function impairment, common after critical
    neonatal CHD. This entry models it as partly a shared-genetic phenomenon rather than
    purely a consequence of hypoxaemia and surgery: the de novo variants that cause
    severe CHD fall in genes highly expressed in the developing brain as well as the
    developing heart.
  phenotype_term:
    preferred_term: Neurodevelopmental abnormality
    term:
      id: HP:0012759
      label: Neurodevelopmental abnormality
  evidence:
  - reference: PMID:26785492
    reference_title: "De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings reveal shared genetic contributions to CHD, NDD, and CA and
      provide opportunities for improved prognostic assessment and early therapeutic
      intervention in CHD patients.
    explanation: >-
      Supports a shared genetic, rather than purely acquired, contribution to
      neurodevelopmental disability in CHD.
- category: Congenital anomaly
  name: Extracardiac congenital anomaly
  description: >-
    Non-cardiac structural anomaly co-occurring with CHD, at roughly twice the
    background newborn rate. Mechanistically expected from this entry's model, because
    the cardiac neural crest and the chromatin-modifying genes that dominate the CHD de
    novo burden are shared with craniofacial, limb and other developmental programmes.
  phenotype_term:
    preferred_term: Extracardiac congenital anomaly
  notes: >-
    NEEDS TERM / NTR CANDIDATE. Deliberately left unbound. The claim is an
    extracardiac structural or functional anomaly of ANY organ system, and the cited
    evidence is likewise system-agnostic. HPO was searched (2026-08-19) for a
    system-agnostic congenital-anomaly class: the only "congenital malformation of"
    terms are cardiac (HP:0011603, HP:0011723, HP:0045017), there is no "multiple
    congenital anomalies" class, and every "Abnormality of the X system" term names a
    single system. An earlier revision bound this to HP:0000924 (Abnormality of the
    skeletal system), which silently narrowed a whole-organism claim to the skeleton
    and was removed on review - no term beats a bad term. An HPO new-term request for
    a system-agnostic extracardiac/multiple congenital anomaly class would be the
    right resolution.
  evidence:
  - reference: PMID:26785492
    reference_title: "De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Extra-cardiac congenital anomalies (CA, structural or functional anomalies that
      arise in utero) occur in approximately 13% of newborns with congenital heart
      disease (CHD), including 2% with a genetic syndrome, almost twice the prevalence
      observed in infants without CHD
    explanation: Quantifies the excess of extracardiac anomalies among newborns with CHD.

inheritance:
- name: Multifactorial inheritance
  description: >-
    Most isolated CHD is not Mendelian. The prevailing model is multifactorial: common
    variation, rare inherited variants of modest effect, de novo variants, and maternal
    environmental exposures combine to cross a developmental threshold. Recurrence risk
    after an isolated non-syndromic case is empirically a few percent, and a defined
    Mendelian or chromosomal diagnosis replaces that empiric figure with disorder-specific
    counselling. A genetic cause remains unidentified in a majority of patients.
  inheritance_term:
    preferred_term: Multifactorial inheritance
    term:
      id: HP:0001426
      label: Non-Mendelian inheritance
  evidence:
  - reference: PMID:39337901
    reference_title: "The Genetic Architecture of Congenital Heart Disease in Neonatal Intensive Care Unit Patients-The Experience of University Medical Centre, Ljubljana."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The etiology of CHD is multifactorial and involves interplay between genetic and
      environmental factors.
    explanation: States the multifactorial inheritance model this block records.
  - reference: PMID:39337901
    reference_title: "The Genetic Architecture of Congenital Heart Disease in Neonatal Intensive Care Unit Patients-The Experience of University Medical Centre, Ljubljana."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      however, the cause of the disease remains unexplained in up to 60% of CHD patients
    explanation: >-
      Quantifies the substantial unexplained fraction that motivates the multifactorial
      rather than Mendelian default.
- name: De novo variation in severe sporadic congenital heart disease
  description: >-
    A distinct inheritance mode within CHD rather than an alternative to the
    multifactorial model: severe CHD impairs reproductive fitness, so a large share of
    severe sporadic cases is caused by newly arisen variants absent from both parents.
    The de novo contribution is strongly stratified by phenotype — it is small in
    isolated CHD and large when neurodevelopmental disability and extracardiac anomalies
    accompany the cardiac lesion.
  inheritance_term:
    preferred_term: Sporadic
    term:
      id: HP:0003745
      label: Sporadic
  de_novo_rate: >-
    De novo mutations accounted for 8% of cases overall, ~3% of isolated CHD and ~28% of
    CHD with both neurodevelopmental and extracardiac congenital anomalies (Jin 2017,
    n=2,871 probands).
  evidence:
  - reference: PMID:28991257
    reference_title: "Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      De novo mutations (DNMs) accounted for 8% of cases, including ~3% of isolated CHD
      patients and ~28% with both neurodevelopmental and extra-cardiac congenital
      anomalies.
    explanation: >-
      Quantifies the de novo contribution and its stratification by accompanying
      phenotype.
  - reference: PMID:23665959
    reference_title: De novo mutations in histone-modifying genes in congenital heart disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Many cases occur sporadically and impair reproductive fitness, suggesting a role
      for de novo mutations.
    explanation: >-
      States the evolutionary rationale for expecting de novo variation to dominate
      severe sporadic CHD.

genetic:
- name: NKX2-5
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: Septal
  gene_term:
    preferred_term: NKX2-5
    term:
      id: hgnc:2488
      label: NKX2-5
  notes: >-
    Homeobox transcription factor of the cardiac septation network. Haploinsufficiency
    causes autosomal dominant secundum atrial septal defect with progressive
    atrioventricular conduction block — the paradigm case in which one gene links a
    structural CHD to a lifelong electrical phenotype.
  evidence:
  - reference: PMID:9651244
    reference_title: Congenital heart disease caused by mutations in the transcription factor NKX2-5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in the gene encoding the homeobox transcription factor NKX2-5 were
      found to cause nonsyndromic, human congenital heart disease.
    explanation: Establishes NKX2-5 as a cause of non-syndromic human CHD.
- name: GATA4
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: Septal
  gene_term:
    preferred_term: GATA4
    term:
      id: hgnc:4173
      label: GATA4
  notes: >-
    Zinc-finger transcription factor; septal-defect-causing missense alleles disrupt its
    physical interaction with TBX5, the molecular basis of the phenotypic overlap
    between isolated septal defects and Holt-Oram syndrome.
  evidence:
  - reference: PMID:12845333
    reference_title: GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A heterozygous G296S missense mutation of GATA4, a transcription factor
      essential for heart formation, was found in all available affected family
      members but not in any control individuals
    explanation: >-
      Segregation of a GATA4 missense variant with non-syndromic septal defects in a
      pedigree, absent from controls, supports GATA4 as a CHD gene.
- name: TBX5
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: Septal
  gene_term:
    preferred_term: TBX5
    term:
      id: hgnc:11604
      label: TBX5
  notes: >-
    T-box transcription factor; loss of function causes Holt-Oram syndrome (septal
    defect plus radial ray upper-limb malformation). Its GATA4 interaction places it in
    the septation network modelled by this entry; curated in full in Holt-Oram_Syndrome.
- name: NOTCH1
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: LVOTO
  gene_term:
    preferred_term: NOTCH1
    term:
      id: hgnc:7881
      label: NOTCH1
  notes: >-
    Signalling and transcriptional regulator of endocardial-to-mesenchymal transition
    and valvulogenesis. Loss of function causes bicuspid aortic valve with early and
    severe valve calcification, and contributes more broadly to left-sided obstructive
    lesions.
  evidence:
  - reference: PMID:16025100
    reference_title: Mutations in NOTCH1 cause aortic valve disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we show that mutations in the signalling and transcriptional regulator NOTCH1
      cause a spectrum of developmental aortic valve anomalies and severe valve
      calcification in non-syndromic autosomal-dominant human pedigrees
    explanation: >-
      States the paper's finding - NOTCH1 mutation causes developmental aortic valve
      anomaly plus severe calcification - which is the NOTCH1-LVOTO association this
      gene entry asserts.
- name: ZIC3
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: HTX
  gene_term:
    preferred_term: ZIC3
    term:
      id: hgnc:12874
      label: ZIC3
  notes: >-
    Zinc-finger transcription factor acting at the earliest stages of left-right axis
    formation; the first gene unequivocally associated with human situs abnormalities,
    causing X-linked heterotaxy.
  evidence:
  - reference: PMID:9354794
    reference_title: X-linked situs abnormalities result from mutations in ZIC3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ZIC3, which has not been previously implicated in vertebrate LR-axis development,
      is the first gene unequivocally associated with human situs abnormalities.
    explanation: Establishes ZIC3 as the founding human laterality/heterotaxy gene.
- name: TBX1
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: CTD
  gene_term:
    preferred_term: TBX1
    term:
      id: hgnc:11592
      label: TBX1
  notes: >-
    T-box transcription factor within the 22q11.2 critical region; the principal driver
    of the conotruncal and aortic arch defects of 22q11.2 deletion syndrome, acting in
    the second heart field and pharyngeal apparatus. Curated in full in
    22q11.2_Deletion_Syndrome.
  evidence:
  - reference: PMID:14585638
    reference_title: Role of TBX1 in human del22q11.2 syndrome.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified three mutations of TBX1 in two unrelated patients without the 22q11.2 deletion-one with sporadic conotruncal anomaly face syndrome/velocardiofacial syndrome and one with sporadic DiGeorge's syndrome-and in three patients from a family with conotruncal anomaly face syndrome/velocardiofacial syndrome."
    explanation: >-
      Human point mutations in TBX1, in patients carrying no 22q11.2 deletion,
      reproduce the conotruncal phenotype. This separates the gene's own
      contribution from that of the wider deleted region, which is what these
      notes claim.
  - reference: PMID:14585638
    reference_title: Role of TBX1 in human del22q11.2 syndrome.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results suggest that the TBX1 mutation is responsible for five major phenotypes in del22q11.2 syndrome."
    explanation: Supports treating TBX1 as the principal driver within the deleted region.
- name: GDF1
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: CTD
  gene_term:
    preferred_term: GDF1
    term:
      id: hgnc:4214
      label: GDF1
  notes: >-
    NODAL-pathway growth differentiation factor. A recessive founder allele accounts for
    a substantial share of severe CHD in the Ashkenazi Jewish population — the clearest
    demonstration that recessive inheritance contributes materially to CHD in specific
    populations.
  evidence:
  - reference: PMID:28991257
    reference_title: "Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including a recessive founder mutation in GDF1 accounting for ~5% of severe CHD
      in Ashkenazim
    explanation: Quantifies the GDF1 founder allele's contribution to severe CHD.
- name: MYH6
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: LVOTO
  gene_term:
    preferred_term: MYH6
    term:
      id: hgnc:7576
      label: MYH6
  notes: >-
    Alpha-myosin heavy chain. Recessive genotypes account for a large share of Shone
    complex, linking a sarcomeric gene to a left-sided obstructive malformation and
    illustrating the contractile/cytoskeletal route into CHD.
  evidence:
  - reference: PMID:28991257
    reference_title: "Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      recessive genotypes in MYH6 accounting for ~11% of Shone complex
    explanation: Quantifies the MYH6 recessive contribution to a defined LVOTO lesion.
- name: FLT4
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: CTD
  gene_term:
    preferred_term: FLT4
    term:
      id: hgnc:3767
      label: FLT4
  notes: >-
    VEGFR-3 receptor tyrosine kinase. Dominant variants account for a defined fraction
    of tetralogy of Fallot.
  evidence:
  - reference: PMID:28991257
    reference_title: "Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dominant FLT4 mutations accounting for 2.3% of Tetralogy of Fallot"
    explanation: Quantifies the FLT4 contribution to tetralogy of Fallot.
- name: KMT2D
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: KMT2D
    term:
      id: hgnc:7133
      label: KMT2D
  notes: >-
    H3K4 methyltransferase and the exemplar of the chromatin-modifier class that
    dominates the CHD de novo burden; causes Kabuki syndrome, in which CHD is a cardinal
    feature. Curated in full in Kabuki_Syndrome.
  evidence:
  - reference: PMID:26785492
    reference_title: "De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Within this 21-gene set, PTPN11, KMT2D (MLL2), and RBFOX2, each had significantly
      more damaging de novo mutations than expected
    explanation: >-
      Identifies KMT2D as one of only three genes reaching genome-wide significance for
      damaging de novo mutation in CHD.
- name: CHD7
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: CHD7
    term:
      id: hgnc:20626
      label: CHD7
  notes: >-
    Chromodomain helicase DNA-binding protein 7, a chromatin remodeller required for
    neural crest gene expression; causes CHARGE syndrome, whose conotruncal and arch
    defects are the neurocristopathy face of CHD. Curated in full in CHARGE_Syndrome.
    Note this is CHD7 the gene, unrelated to the CHD abbreviation for congenital heart
    disease used throughout this entry.
  evidence:
  - reference: PMID:26785492
    reference_title: "De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Indeed, this list includes seven genes previously implicated in CHD (PTPN11,
      KMT2D, CHD7, MYH6, JAG1, NOTCH1, ZEB2).
    explanation: >-
      Confirms CHD7 among the recurrently de novo mutated genes established as CHD
      causes.
- name: RBFOX2
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: LVOTO
  gene_term:
    preferred_term: RBFOX2
    term:
      id: hgnc:9906
      label: RBFOX2
  notes: >-
    RNA-binding regulator of alternative splicing and of epithelial-mesenchymal
    transition, newly implicated in CHD by de novo loss-of-function variants that
    clustered strikingly in hypoplastic left heart syndrome. This is the clearest
    single-gene link between the endothelial-to-mesenchymal transition arm of this entry
    and a specific severe lesion.
  evidence:
  - reference: PMID:26785492
    reference_title: "De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      RBFOX2 harbored three distinct de novo LoF mutations, a highly significant finding
    explanation: >-
      Documents the RBFOX2 de novo burden and its exclusive association with
      hypoplastic left heart syndrome.
- name: Chromosomal aneuploidy and recurrent copy-number variants
  association: Pathogenic Variants
  notes: >-
    Whole-chromosome aneuploidy (notably trisomy 21, trisomy 18, trisomy 13, monosomy X)
    and recurrent CNVs (22q11.2 deletion, 7q11.23 deletion) are the single largest
    identifiable genetic category in clinically ascertained CHD. Chromosomal microarray
    remains diagnostic in a meaningful minority even of apparently isolated CHD, which is
    why it is recommended irrespective of dysmorphology assessment.
  evidence:
  - reference: PMID:34440418
    reference_title: "Genetic Evaluation of Inpatient Neonatal and Infantile Congenital Heart Defects: New Findings and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diagnostic yield was higher in syndromic appearing infants, but geneticists'
      dysmorphology exams lacked complete sensitivity and 6.5% of isolated CHD cases had
      diagnostic CMA.
    explanation: >-
      Quantifies the chromosomal-microarray yield in apparently isolated CHD and shows
      dysmorphology assessment cannot substitute for it.
  - reference: PMID:39337901
    reference_title: "The Genetic Architecture of Congenital Heart Disease in Neonatal Intensive Care Unit Patients-The Experience of University Medical Centre, Ljubljana."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most frequent genetic diagnoses in diagnosed cases were 22q11.2 microdeletion
      and CHARGE syndromes, followed by Noonan syndrome and Williams syndrome.
    explanation: >-
      Identifies the recurrent CNV and syndromic diagnoses that dominate a
      contemporary neonatal CHD cohort.

- name: TBX20
  gene_term:
    preferred_term: TBX20
    term:
      id: hgnc:11598
      label: TBX20
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: Septal
  notes: >
    T-box transcription factor and a further member of the septation network
    modelled by this entry, alongside NKX2-5, GATA4/GATA6 and TBX5, with which
    it physically and genetically interacts. Germline T-box-domain variants
    produce septation, chamber-growth and valvulogenesis defects, and dilated
    cardiomyopathy is a feature of the mutant phenotype in humans and mice -
    which the reporting authors read as a developmental transcription factor
    variant leaving a sensitized template for adult-onset heart disease. ClinGen's Congenital Heart
    Disease Gene Curation Expert Panel classifies TBX20-congenital heart
    disease (MONDO:0005453, the term this entry binds) as Definitive under an
    autosomal dominant model; read from the ClinGen Gene-Disease Validity CSV
    on 2026-09-24, and not cited as an evidence item here because that
    assertion has no committed CGGV cache file in this repository.
  evidence:
  - reference: PMID:17668378
    reference_title: "Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings are the first to link TBX20 mutations to human pathology."
    explanation: The report that established TBX20 as a human congenital heart disease gene.
  - reference: PMID:17668378
    reference_title: "Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis and cardiomyopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dilated cardiomyopathy was a feature of the TBX20 mutant phenotype in humans and mice, suggesting that mutations in developmental transcription factors can provide a sensitized template for adult-onset heart disease."
    explanation: >-
      Sources the sensitized-myocardium observation recorded in these notes.
- name: SMAD2
  gene_term:
    preferred_term: SMAD2
    term:
      id: hgnc:6768
      label: SMAD2
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: HTX
  notes: >
    Receptor-regulated SMAD and downstream effector of TGF-beta and NODAL
    signalling. Pathogenic variants produce two separable phenotypes: complex
    congenital heart disease with or without laterality defects, curated here,
    and a late-onset arterial aneurysm phenotype curated in Loeys-Dietz
    syndrome 6 and the thoracic aortic entries. The laterality arm is why this
    record sits on the heterotaxy subtype and is wired to the left-right
    patterning node rather than to the septation network. ClinGen grades
    SMAD2-congenital heart disease (MONDO:0005453) Definitive under an
    autosomal dominant model and SMAD2-Loeys-Dietz syndrome 6 separately as
    Definitive; read from the ClinGen Gene-Disease Validity CSV on 2026-09-24.
  evidence:
  - reference: PMID:30157302
    reference_title: Variable cardiovascular phenotypes associated with SMAD2 pathogenic variants.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "WES identified pathogenic truncating variants, a splice variant, and a predicted deleterious missense variant in SMAD2."
    explanation: Establishes loss-of-function SMAD2 variants in probands ascertained for complex congenital heart disease.
  - reference: PMID:30157302
    reference_title: Variable cardiovascular phenotypes associated with SMAD2 pathogenic variants.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient 3 was a fetus with complex CHD and heterotaxy."
    explanation: >-
      The laterality case behind assigning this record to the heterotaxy
      subtype rather than to a septal or conotruncal class.
- name: GATA6
  gene_term:
    preferred_term: GATA6
    term:
      id: hgnc:4174
      label: GATA6
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: CTD
  notes: >
    Zinc-finger transcription factor of the same family as GATA4. The first
    reported human GATA6 variants were in persistent truncus arteriosus, an
    outflow tract malformation, which is why this record carries the
    conotruncal subtype. The same variants commonly produce pancreatic
    agenesis and neonatal diabetes, the extracardiac half of the MONDO
    concept named after this gene, which is curated in Pancreatic_Agenesis. ClinGen grades GATA6-related
    congenital heart disease with or without pancreatic agenesis or neonatal
    diabetes (MONDO:0100540) Definitive under an autosomal dominant model;
    read from the ClinGen Gene-Disease Validity CSV on 2026-09-24.
  evidence:
  - reference: PMID:31301121
    reference_title: "GATA6 mutations: Characterization of two novel patients and a comprehensive overview of the GATA6 genotypic and phenotypic spectrum."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "The first human mutations in GATA6 were described in a cohort of patients with persistent truncus arteriosus, and the phenotypic spectrum has expanded since then."
    explanation: >-
      Sources the outflow-tract origin of this gene's human phenotype, which is
      why the record carries the conotruncal subtype.
  - reference: PMID:31301121
    reference_title: "GATA6 mutations: Characterization of two novel patients and a comprehensive overview of the GATA6 genotypic and phenotypic spectrum."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that the most common phenotypes associated with a mutation in GATA6 were structural cardiac and pancreatic abnormalities, with a penetrance of 87 and 60%, respectively."
    explanation: >-
      The authors' synthesis of all 78 published GATA6 variants, and the source
      of the cardiac-plus-pancreatic pairing recorded in these notes.
- name: HAND1
  gene_term:
    preferred_term: HAND1
    term:
      id: hgnc:4807
      label: HAND1
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: Septal
  notes: >
    Basic helix-loop-helix transcription factor described by its discoverers
    as essential for mammalian heart development, whose loss in mice produces
    failed cardiac looping, defective chamber septation and impaired
    ventricular development. Reported human variants cluster in septal and
    hypoplastic hearts and reduce or abolish HAND1 transcriptional activity in
    functional assays. The human evidence is weaker than for the septation
    network genes curated above: ClinGen's Congenital Heart Disease Gene
    Curation Expert
    Panel grades HAND1-congenital heart disease (MONDO:0005453) Moderate under
    an autosomal dominant model, read from the ClinGen Gene-Disease Validity
    CSV on 2026-09-24. The record is carried here at that strength rather than
    omitted, and its evidence item is graded INDIRECT to match the hedged
    conclusion of the source.
  evidence:
  - reference: PMID:19586923
    reference_title: A functional genetic study identifies HAND1 mutations in septation defects of the human heart.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Indeed, in tissue samples of septal defects, we detected 32 sequence alterations leading to amino acid change, of which 12 are in the bHLH domain of HAND1."
    explanation: The variant findings in septal-defect heart tissue behind assigning this record to the septal subtype.
  - reference: PMID:19586923
    reference_title: A functional genetic study identifies HAND1 mutations in septation defects of the human heart.
    supports: SUPPORT
    directness: INDIRECT
    quote_role: BACKGROUND
    evidence_source: MODEL_ORGANISM
    snippet: "Absence of Hand1 in mice results in embryonal lethality, as well as in a wide spectrum of cardiac abnormalities including failed cardiac looping, defective chamber septation and impaired ventricular development."
    explanation: >-
      Sources the mouse loss-of-function phenotype recorded in this record's
      notes. Graded BACKGROUND because the sentence is this paper's framing of
      prior mouse work rather than its own result, and INDIRECT because a mouse
      knockout bears on the human claim only through an inference step.
  - reference: PMID:19586923
    reference_title: A functional genetic study identifies HAND1 mutations in septation defects of the human heart.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "Functional studies in yeast and mammalian cells enabled translation of sequence alterations to HAND1 transcriptional activity, which was reduced or abolished by certain mutations, notably p.L138P."
    explanation: >-
      Functional support that some of these alterations impair HAND1 activity.
      Graded INDIRECT because a transcriptional-activity assay bears on the
      clinical claim only through an inference step.
- name: HAND2
  gene_term:
    preferred_term: HAND2
    term:
      id: hgnc:4808
      label: HAND2
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: CTD
  notes: >
    The bHLH partner of HAND1. The two are expressed complementarily in the
    developing ventricles and in the neural-crest-derived cardiac outflow
    tract and aortic arch arteries, which is the overlap with this entry's
    progenitor and outflow arms. A segregating deletion removing HAND2 and
    HAND2-AS1 in a family whose affected members include a repaired tetralogy
    of Fallot is the report that established haploinsufficiency as an
    autosomal dominant cause. ClinGen grades HAND2 related congenital heart
    defect (MONDO:0800476) Moderate under an autosomal dominant model, read
    from the ClinGen Gene-Disease Validity CSV on 2026-09-24; as with HAND1,
    the record is carried at that strength rather than omitted.
  evidence:
  - reference: PMID:32134193
    reference_title: Haploinsufficiency of the basic helix-loop-helix transcription factor HAND2 causes congenital heart defects.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Taken together, this first report of a HAND2 and HAND2-AS1 deletion in a family with CHDs strongly supports haploinsufficiency of HAND2 as an autosomal dominant cause of CHD."
    explanation: >-
      The deletion that removes HAND2, in a family ascertained for congenital
      heart disease, and the haploinsufficiency mechanism it supports.
  - reference: PMID:32134193
    reference_title: Haploinsufficiency of the basic helix-loop-helix transcription factor HAND2 causes congenital heart defects.
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous sequence variants in the basic helix-loop-helix TF gene heart and neural crest derivatives expressed 2 (HAND2) have been reported among some patients with CHDs; however, HAND2 has not yet been established as a Mendelian disease gene."
    explanation: >-
      The authors' own statement of how far the human evidence went before this
      report, which is the state ClinGen's Moderate classification reflects and
      the reason this record carries that grade in its notes.
  - reference: PMID:10189962
    reference_title: "HAND proteins: molecular mediators of cardiac development and congenital heart disease."
    supports: SUPPORT
    directness: INDIRECT
    quote_role: REVIEW_SYNTHESIS
    evidence_source: MODEL_ORGANISM
    snippet: "dHAND and eHAND are two related basic helix-loop-helix transcription factors that are expressed in a complementary fashion in the developing right and left ventricles, respectively. They are also expressed in the neural crest-derived cardiac outflow tract and aortic arch arteries."
    explanation: >-
      Sources the complementary ventricular and outflow-tract expression
      recorded in this record's notes. The paper names the two factors by their
      historical dHAND and eHAND symbols and does not give HGNC symbols, so
      this item supports the pair rather than assigning either territory to one
      gene.
  - reference: PMID:32134193
    reference_title: Haploinsufficiency of the basic helix-loop-helix transcription factor HAND2 causes congenital heart defects.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Familial CMA testing determined that the deletion was paternally inherited, which supported a likely pathogenic classification as the proband's father had previously undergone surgery for Tetralogy of Fallot."
    explanation: >-
      Segregation with a conotruncal lesion in the father, which is why this
      record carries the conotruncal subtype.
- name: PLD1
  gene_term:
    preferred_term: PLD1
    term:
      id: hgnc:9067
      label: PLD1
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  subtype: RVOTO
  notes: >
    Phospholipase D1, a signal transduction enzyme. Biallelic loss-of-function
    variants produce predominantly right-sided
    congenital valve defects, and the enzyme acts at the
    endothelial-to-mesenchymal transition step that builds the valve leaflets,
    which is why this record is wired to the endocardial cushion node rather
    than to a transcription factor node. ClinGen grades PLD1-related congenital heart
    disease (MONDO:1010144) Definitive under an autosomal recessive model;
    read from the ClinGen Gene-Disease Validity CSV on 2026-09-24.
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:33645542
      reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects"
      explanation: Biallelic genotypes across 21 families establish recessive inheritance for this gene.
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects."
    explanation: >-
      The cohort finding that binds PLD1 to congenital valve disease, and the
      right-sided predominance behind this record's subtype assignment.
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay."
    explanation: Enzymatic evidence that the disease alleles are loss of function.
- name: TFAP2B
  gene_term:
    preferred_term: TFAP2B
    term:
      id: hgnc:11743
      label: TFAP2B
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  notes: >
    Transcription factor AP-2 beta, expressed in neural crest cells and
    reported to have a role in ductal, facial and limb development. No
    `subtype` foreign key is set on this record: the lesion this gene produces
    is patent ductus arteriosus, and none of this entry's seven lesion rows
    covers it. The Septal row is limited to communications across the
    interatrial and interventricular septum and names the duct only in
    passing, and a patent duct is not a septal defect. The gene is wired to
    the cardiac neural crest node, which is where its mechanism sits. Pathogenic variants span Char
    syndrome, in which patent ductus arteriosus accompanies facial dysmorphism
    and hand anomalies, and familial nonsyndromic patent ductus arteriosus;
    ClinGen lumps both into TFAP2B-related congenital heart disease spectrum
    disorder (MONDO:1010098) and grades it Definitive under an autosomal
    dominant model, read from the ClinGen Gene-Disease Validity CSV on
    2026-09-24. The isolated patent ductus arteriosus entries in this
    knowledge base (Patent_Ductus_Arteriosus, Patent_Ductus_Arteriosus_3)
    curate PRDM6, a different gene, and do not cover this one.
  evidence:
  - reference: PMID:10802654
    reference_title: Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using a positional candidacy strategy, we mapped TFAP2B, encoding a transcription factor expressed in neural crest cells, to the Char syndrome critical region and identified missense mutations altering conserved residues in two affected families."
    explanation: The report that established TFAP2B as the Char syndrome gene, and its neural crest expression.
  - reference: PMID:10802654
    reference_title: Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "Dimerization of both mutants with normal TFAP2B adversely affected transactivation, demonstrating a dominant-negative mechanism."
    explanation: Identifies the dominant-negative mechanism of the Char syndrome missense alleles.
  - reference: PMID:21643846
    reference_title: Familial nonsyndromic patent ductus arteriosus caused by mutations in TFAP2B.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The following two types of mutations were identified in TFAP2B: c.601+5G>A and c.435_438delCCGG."
    explanation: >-
      Supports extending this gene beyond Char syndrome to familial
      nonsyndromic patent ductus arteriosus, which is the lumping ClinGen's
      spectrum-disorder concept records.
environmental:
- name: Maternal pregestational diabetes mellitus
  effect: Increases risk
  description: >-
    Diabetes present before conception (type 1 or type 2, with no material difference in
    effect size between them) is the strongest established modifiable risk factor for
    CHD, tripling the odds. Gestational diabetes, which begins after the window of
    cardiac organogenesis has largely closed, carries a substantially smaller effect —
    an internal consistency check that supports a causal, timing-dependent mechanism
    rather than confounding by maternal metabolic phenotype alone.
  notes: >-
    Deliberately left without an exposure_term: ECTO was searched and has no class for
    exposure to a maternal metabolic disease state (its maternal branch covers
    substances such as alcohol, nicotine and pharmacotherapy). Recording a substance
    exposure here would misrepresent the exposure.
  influences_mechanisms:
  - target: Maternal Metabolic and Teratogenic Perturbation of Cardiogenesis
    environmental_effect: PREDISPOSES
    causal_link_type: DIRECT
    description: >-
      Pregestational maternal hyperglycaemia is the exposure that establishes the
      perturbed embryonic metabolic environment modelled by this node.
    evidence:
    - reference: PMID:38996968
      reference_title: "Systematic Review and Meta-analysis of Prenatal Risk Factors for Congenital Heart Disease: Part 1, Maternal Chronic Diseases and Parental Exposures."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The effect size of gestational diabetes was less than that of PGDM (OR, 1.38;
        95% CI, 1.18-1.61).
      explanation: >-
        The timing-dependent gradient between pregestational and gestational diabetes
        supports action during early cardiac organogenesis rather than later gestation.
  evidence:
  - reference: PMID:38996968
    reference_title: "Systematic Review and Meta-analysis of Prenatal Risk Factors for Congenital Heart Disease: Part 1, Maternal Chronic Diseases and Parental Exposures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pregestational diabetes (PGDM) was associated with CHDs (OR, 3.51; 95% CI,
      2.86-4.3), without difference between type 1 and type 2 PGDM.
    explanation: Quantifies the pregestational-diabetes effect size and its type-independence.
- name: Maternal overweight and obesity
  effect: Increases risk
  description: >-
    Raised pre-pregnancy body mass index is associated with CHD in offspring with a
    dose-effect relationship, independently of overt diabetes.
  notes: >-
    No exposure_term bound: ECTO was searched and has no class for maternal adiposity as
    an exposure.
  influences_mechanisms:
  - target: Maternal Metabolic and Teratogenic Perturbation of Cardiogenesis
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Associated with CHD with a dose-effect relationship; the mediating embryonic
      mechanism is not established, so the edge is recorded as indirect with unknown
      intermediates rather than assumed to run through hyperglycaemia.
  evidence:
  - reference: PMID:38996968
    reference_title: "Systematic Review and Meta-analysis of Prenatal Risk Factors for Congenital Heart Disease: Part 1, Maternal Chronic Diseases and Parental Exposures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was an association between being overweight or obese and CHDs (OR, 1.26;
      95% CI, 1.15-1.37), with a dose-effect relationship.
    explanation: Quantifies the maternal-adiposity association and its dose-response.
- name: Periconceptional exposure to alcohol
  effect: Increases risk
  description: >-
    Parental alcohol use is associated with CHD in offspring at modest effect size. Note
    the cited meta-analysis reports this association for alcohol use in the parental
    exposure group; it is grouped in that analysis with paternal smoking rather than
    reported as a maternal-only exposure.
  exposure_term:
    preferred_term: exposure to drinking alcohol via maternal
    term:
      id: ECTO:0300001
      label: exposure to drinking alcohol via maternal
  influences_mechanisms:
  - target: Maternal Metabolic and Teratogenic Perturbation of Cardiogenesis
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:38996968
    reference_title: "Systematic Review and Meta-analysis of Prenatal Risk Factors for Congenital Heart Disease: Part 1, Maternal Chronic Diseases and Parental Exposures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was an association between CHDs and pre-eclampsia (OR, 2.01; 95% CI,
      1.32-3.05), paternal smoking (OR, 1.32; 95% CI, 1.03-1.70), and alcohol use (OR,
      1.50; 95% CI, 1.08-2.08).
    explanation: >-
      Reports the alcohol-use association and, in the same sentence, the parental
      exposure grouping in which it was analysed.
- name: Maternal cigarette smoking
  effect: Increases risk
  description: >-
    Maternal smoking is associated with CHD, though at a smaller effect size than
    pregestational diabetes or obesity.
  exposure_term:
    preferred_term: exposure to cigarette smoking via maternal
    term:
      id: ECTO:0300003
      label: exposure to cigarette smoking via maternal
  influences_mechanisms:
  - target: Maternal Metabolic and Teratogenic Perturbation of Cardiogenesis
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:38996968
    reference_title: "Systematic Review and Meta-analysis of Prenatal Risk Factors for Congenital Heart Disease: Part 1, Maternal Chronic Diseases and Parental Exposures."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There exists robust evidence for increased risk of CHD in the presence of
      obesity, maternal diabetes, maternal smoking, and increased maternal age.
    explanation: >-
      Places maternal smoking among the exposures the meta-analysis judges robustly
      evidenced.
- name: Teratogenic drug and infectious exposures during cardiac organogenesis
  effect: Increases risk
  description: >-
    Definitive teratogens for congenital cardiovascular defects include maternal
    rubella infection, untreated maternal phenylketonuria, thalidomide, vitamin A
    congeners and retinoids, and indomethacin tocolysis. Their shared feature is action
    during the roughly 3-8 week window of cardiac organogenesis. Rubella is a
    teratogenic maternal infection, not a disease transmitted from the affected infant —
    CHD itself is neither infectious nor transmissible.
  notes: >-
    A single entry covering a heterogeneous exposure set, because the cited AHA
    statement classifies them together as definitive rather than reporting per-agent
    effect sizes. No single ECTO class covers the set.
  influences_mechanisms:
  - target: Maternal Metabolic and Teratogenic Perturbation of Cardiogenesis
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:17519397
    reference_title: "Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Information is highlighted regarding definitive risk factors such as maternal
      rubella; phenylketonuria; pregestational diabetes; exposure to thalidomide,
      vitamin A cogeners, or retinoids; and indomethacin tocolysis.
    explanation: Enumerates the exposures classified as definitive risk factors.
- name: Periconceptional multivitamin or folic acid intake
  effect: May reduce risk
  description: >-
    The principal candidate protective exposure. The AHA statement summarises it as
    possibly reducing fetal cardiac risk; the evidence base is predominantly
    case-control, which the same statement flags as a limitation, so this is curated as
    a candidate protective factor rather than a demonstrated one.
  influences_mechanisms:
  - target: Maternal Metabolic and Teratogenic Perturbation of Cardiogenesis
    environmental_effect: PROTECTS_AGAINST
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:17519397
    reference_title: "Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Information is summarized for periconceptional multivitamin or folic acid intake,
      which may reduce the risk of cardiac disease in the fetus
    explanation: >-
      The hedged wording ("may reduce") is the reason this is curated as PARTIAL rather
      than SUPPORT.
  - reference: PMID:17519397
    reference_title: "Noninherited risk factors and congenital cardiovascular defects: current knowledge: a scientific statement from the American Heart Association Council on Cardiovascular Disease in the Young: endorsed by the American Academy of Pediatrics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Caveats regarding interpretation of possible exposure-outcome relationships from
      case-control studies are given because this type of study has provided most of
      the available information.
    explanation: >-
      Records the study-design limitation that constrains how strongly any of these
      exposure-outcome relationships can be asserted.

prevalence:
- population: Worldwide
  measure_type: BIRTH_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 941.0
  rate_low: 860.2
  rate_high: 1025.3
  notes: >-
    Pooled birth prevalence for 2010-2017 from 260 studies and 130,758,851 live births:
    9.410 per 1000 (95% CI 8.602-10.253), i.e. 941 per 100,000. CHD as an umbrella is
    emphatically not a rare disease: it is the commonest congenital anomaly in humans,
    and the rate sits an order of magnitude above the EU rare-disease threshold. The
    prevalence_class is therefore ABOVE_1_IN_1000, the Orphanet class for rates above
    100 per 100,000, which is unbounded above and so accommodates this figure directly.
  evidence:
  - reference: PMID:30783674
    reference_title: "Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The birth prevalence of CHD from 1970-2017 progressively increased to a maximum
      in the period 2010-17 of 9.410/1000 [95% CI (confidence interval) 8.602-10.253].
    explanation: Source of the pooled worldwide birth-prevalence estimate.
- population: Africa
  measure_type: BIRTH_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 231.5
  rate_low: 42.9
  rate_high: 569.6
  notes: >-
    2.315 per 1000 (95% CI 0.429-5.696), i.e. 231.5 per 100,000 - still in the
    ABOVE_1_IN_1000 class despite being the lowest reported regional figure. The
    authors interpret that low figure as severe unmet diagnostic need rather than
    genuinely lower disease occurrence, which is why this is curated as reported
    rather than true prevalence. Note the confidence interval is wide enough that its
    lower bound (42.9 per 100,000) would fall a band lower; the point estimate sets the
    class here.
  evidence:
  - reference: PMID:30783674
    reference_title: "Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was marked heterogeneity among geographical regions, with Africa reporting
      the lowest prevalence [2.315/1000 (95% CI 0.429-5.696)] and Asia the highest
      [9.342/1000 (95% CI 8.072-10.704)].
    explanation: Source of the regional prevalence figures.
- population: Asia
  measure_type: BIRTH_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 934.2
  rate_low: 807.2
  rate_high: 1070.4
  notes: >-
    9.342 per 1000 (95% CI 8.072-10.704), i.e. 934.2 per 100,000; the highest reported
    regional prevalence.
  evidence:
  - reference: PMID:30783674
    reference_title: "Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was marked heterogeneity among geographical regions, with Africa reporting
      the lowest prevalence [2.315/1000 (95% CI 0.429-5.696)] and Asia the highest
      [9.342/1000 (95% CI 8.072-10.704)].
    explanation: Source of the regional prevalence figures.

diagnosis:
- name: Newborn pulse oximetry screening for critical congenital heart disease
  diagnosis_term:
    preferred_term: disease screening
    term:
      id: NCIT:C15419
      label: Disease Screening
  description: >-
    Postductal (or pre- and postductal) oxygen-saturation measurement in the
    asymptomatic newborn, exploiting the fact that most critical CHD produces a
    detectable arterial saturation deficit before it produces visible cyanosis or a
    murmur. Its high specificity is what makes it viable as universal screening; its
    moderate sensitivity means a normal result does not exclude CHD, and it will not
    detect non-cyanotic lesions such as an isolated ventricular septal defect.
  results: >-
    Pooled sensitivity 76.5% (95% CI 67.7-83.5), specificity 99.9%, false-positive rate
    0.14%. Screening after 24 hours of age reduces the false-positive rate roughly
    tenfold (0.05% vs 0.50%).
  evidence:
  - reference: PMID:22554860
    reference_title: "Pulse oximetry screening for critical congenital heart defects in asymptomatic newborn babies: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pulse oximetry is highly specific for detection of critical congenital heart
      defects with moderate sensitivity, that meets criteria for universal screening.
    explanation: >-
      States the test-performance profile and the screening recommendation this entry
      records.
  - reference: PMID:22554860
    reference_title: "Pulse oximetry screening for critical congenital heart defects in asymptomatic newborn babies: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The false-positive rate for detection of critical congenital heart defects was
      particularly low when newborn pulse oximetry was done after 24 h from birth than
      when it was done before 24 h
    explanation: Supports the timing dependence recorded in the results field.
- name: Chromosomal microarray as first-tier genetic testing
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Chromosomal microarray is the first-tier genetic test in an infant with severe CHD,
    followed by exome or genome sequencing when the array is normal. The curatorially
    important point is that the yield is not confined to dysmorphic or syndromic
    infants: a clinical geneticist's dysmorphology examination does not reliably
    identify which apparently isolated CHD cases carry a pathogenic copy-number variant,
    so testing is recommended regardless of lesion type or extracardiac findings.
  results: >-
    Diagnostic chromosomal microarray in 14.6% of tested infants overall and in 6.5% of
    apparently isolated CHD; overall genetic-testing yield 17% once second-tier
    molecular testing is included. An independent neonatal cohort reported the same 17%
    overall figure (32/188).
  evidence:
  - reference: PMID:34440418
    reference_title: "Genetic Evaluation of Inpatient Neonatal and Infantile Congenital Heart Defects: New Findings and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cumulative evidence provides a rationale for comprehensive, standardized genetic
      evaluation in infants with severe CHDs regardless of lesion or extracardiac
      anomalies because genetic diagnoses that impact care are easily missed.
    explanation: >-
      States the recommendation to test irrespective of lesion class or extracardiac
      findings.
  - reference: PMID:34440418
    reference_title: "Genetic Evaluation of Inpatient Neonatal and Infantile Congenital Heart Defects: New Findings and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In total, 376 (85.5%) had chromosome microarray (CMA), of which 55 (14.6%) were
      diagnostic in syndromic (N = 35) or isolated (N = 20) presentations.
    explanation: Source of the chromosomal-microarray diagnostic yield.
  - reference: PMID:39337901
    reference_title: "The Genetic Architecture of Congenital Heart Disease in Neonatal Intensive Care Unit Patients-The Experience of University Medical Centre, Ljubljana."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We established the genetic diagnosis of 22 distinct syndromes in 17% (32/188) of
      neonates.
    explanation: >-
      Independent replication of the overall genetic-diagnostic yield in a neonatal CHD
      cohort.
- name: Echocardiography
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  description: >-
    Transthoracic echocardiography is the definitive anatomical and physiological
    diagnostic modality for CHD at every age, and fetal echocardiography extends it into
    prenatal life. Prenatal detection is what permits delivery planning, prostaglandin
    availability at birth, and — as the epidemiological record shows — it also changes
    measured birth prevalence through pregnancy termination for the most severe lesions.
  evidence:
  - reference: PMID:30783674
    reference_title: "Global birth prevalence of congenital heart defects 1970-2017: updated systematic review and meta-analysis of 260 studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      which would be consistent with improved prenatal detection and consequent
      termination of pregnancy when these very severe lesions are discovered
    explanation: >-
      Supports the claim that prenatal echocardiographic detection measurably shifts
      recorded birth prevalence. PARTIAL because the authors offer it as a consistent
      interpretation rather than a demonstrated causal chain.

treatments:
- name: Prostaglandin E1 infusion for duct-dependent circulation
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    In duct-dependent lesions the arterial duct is the sole route for either systemic or
    pulmonary blood flow after birth; its physiological closure in the first days of life
    precipitates shock or profound cyanosis. Prostaglandin E1 (alprostadil) maintains
    ductal patency and is the single most time-critical medical intervention in neonatal
    CHD — it does not treat the malformation but buys the interval to reach definitive
    surgery or catheter intervention. Delay in starting the infusion can be fatal.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: alprostadil
      term:
        id: CHEBI:15544
        label: prostaglandin E1
  target_mechanisms:
  - target: Altered Circulatory Physiology
    treatment_effect: MODULATES
    description: >-
      Sustains the duct-dependent circulatory pattern rather than correcting the
      structural malformation upstream of it. MODULATES rather than RESTORES: the
      circulation is held in a survivable but still abnormal fetal-type arrangement.
    evidence:
    - reference: PMID:29162633
      reference_title: Use of prostaglandins in duct-dependent congenital heart conditions.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        It is critical to open or maintain ductus arteriosus patent in infants with
        duct-dependent CHDs.
      explanation: >-
        States the physiological target of the intervention: ductal patency, not the
        malformation.
  evidence:
  - reference: PMID:29162633
    reference_title: Use of prostaglandins in duct-dependent congenital heart conditions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prostaglandin E1 (alprostadil marketed as 'Prostin VR ') and prostaglandin E2
      (dinoprostone) are used to maintain a patent ductus arteriosus and the dose of
      medication depends on the clinical presentation.
    explanation: Identifies the agent and its indication.
  - reference: PMID:29162633
    reference_title: Use of prostaglandins in duct-dependent congenital heart conditions.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Delay in starting prostaglandin infusion can have deleterious effects on infants
      and can even lead to death.
    explanation: Records the time-critical nature of the intervention.
- name: Cardiac surgical repair or palliation
  therapeutic_modality: SURGERY
  description: >-
    Anatomical repair (septal defect closure, arterial switch, tetralogy repair,
    coarctation resection) where two-ventricle physiology can be achieved, or staged
    single-ventricle palliation culminating in the Fontan circulation where it cannot.
    The curatorially important framing, and the reason this entry models CHD as a
    lifelong condition, is that surgery repairs or palliates anatomy without restoring
    normal cardiac development: residual shunts and obstruction, valve dysfunction,
    ventricular failure, aortopathy, pulmonary hypertension, arrhythmia,
    Fontan-associated liver disease and reintervention remain lifelong risks, and the
    burden of CHD has correspondingly shifted into adulthood.
  treatment_term:
    preferred_term: cardiac surgery
    term:
      id: NCIT:C157806
      label: Cardiac Surgery
  target_mechanisms:
  - target: Structural Cardiac Malformation
    treatment_effect: RESTORES
    description: >-
      Addresses the anatomical convergence node directly. RESTORES refers to
      circulatory anatomy in the biventricular-repair case only; staged
      single-ventricle palliation instead bypasses the defect, and in neither case is
      the developmental error or its lifelong sequelae reversed.
    evidence:
    - reference: PMID:30413300
      reference_title: "Advanced care planning in adult congenital heart disease: Transitioning from repair to palliation and end-of-life care."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Unfortunately, adult patients with CHD carry residual lesions and sequelae
        putting them at risk for premature death related to re-interventions or
        complications; most commonly heart failure and arrhythmia
      explanation: >-
        Substantiates the qualification on this RESTORES edge - anatomical repair
        leaves residual lesions and sequelae, so the effect on the malformation node
        is not equivalent to cure.
  evidence:
  - reference: PMID:30413300
    reference_title: "Advanced care planning in adult congenital heart disease: Transitioning from repair to palliation and end-of-life care."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As a result of advances in pediatric care, the majority of patients born with
      congenital heart disease (CHD) survive into adulthood
    explanation: >-
      Evidences the efficacy of the surgical/paediatric-care era that this treatment
      entry describes: most people born with CHD now reach adulthood.
  - reference: PMID:30413300
    reference_title: "Advanced care planning in adult congenital heart disease: Transitioning from repair to palliation and end-of-life care."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      More emerging is that a substantial number of patients, in particular those with
      complex heart defects, will eventually end up in a stage with hardly any medical
      or interventional options left.
    explanation: >-
      Directly supports this entry's framing that surgery repairs or palliates anatomy
      without restoring normal development, and that the burden shifts into adulthood.
- name: Heart transplantation
  therapeutic_modality: SURGERY
  description: >-
    Definitive option for end-stage CHD, including failed single-ventricle palliation
    and severe forms of hypoplastic left heart syndrome in which staged palliation is
    not viable or has failed.
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_mechanisms:
  - target: Structural Cardiac Malformation
    treatment_effect: RESTORES
    description: >-
      The only intervention that removes the malformed heart rather than remodelling
      it, hence RESTORES without the qualification attached to surgical repair. Where
      Fontan-associated liver disease has supervened, combined heart-liver
      transplantation is the corresponding option.
    evidence:
    - reference: PMID:40320589
      reference_title: "Combined Heart and Liver Transplantation in the Failing Fontan: Systematic Review and Single-arm Meta-analysis."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The Fontan procedure has transformed the management of congenital heart
        defects characterized by single ventricle physiology, yet it predisposes
        individuals to Fontan-associated liver disease. Combined heart and liver
        transplantation (CHLT) emerges as a therapeutic option, but evidence of its
        efficacy and safety remains limited
      explanation: >-
        Evidences transplantation as the terminal option for the failed
        single-ventricle palliation pathway modelled in this entry.
  evidence:
  - reference: PMID:40320589
    reference_title: "Combined Heart and Liver Transplantation in the Failing Fontan: Systematic Review and Single-arm Meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CHLT in Fontan patients demonstrates promising survival rates, but graft
      rejection and postoperative complications pose challenges.
    explanation: >-
      Supports transplantation as an effective but complication-laden option. PARTIAL
      because the meta-analysis covers combined heart-liver transplantation in failing
      Fontan specifically (4 retrospective cohorts, 67 patients), not heart
      transplantation across CHD as a whole.
- name: Preconception glycaemic control in maternal pregestational diabetes
  therapeutic_modality: BEHAVIORAL
  description: >-
    The principal actionable primary-prevention measure implied by this entry's
    environmental arm: because pregestational rather than gestational diabetes carries
    the large effect, and because the vulnerable window is the first eight weeks of
    gestation, glycaemic optimisation must precede conception to be relevant. Blood
    glucose reduction, antioxidant supplementation and exercise have all been proposed
    as preventive measures on this basis.
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  target_mechanisms:
  - target: Maternal Metabolic and Teratogenic Perturbation of Cardiogenesis
    treatment_effect: INHIBITS
    description: >-
      Acts on the maternal metabolic exposure upstream of cardiogenesis rather than on
      any established malformation; the intent is primary prevention, so the effect is
      recorded against the exposure node it suppresses.
    evidence:
    - reference: PMID:35838899
      reference_title: Effect of maternal pregestational diabetes mellitus on congenital heart diseases.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Treatment options including blood sugar-reducing, anti-oxidative stress drug
        supplements and exercise can help to prevent maternal pregestational diabetes
        mellitus from inducing congenital heart diseases.
      explanation: >-
        Supports the preventive rationale. Recorded as PARTIAL because this is a
        narrative-review assertion, not a trial result.

animal_models:
- name: Zebrafish embryonic heart-function model of flow-dependent cardiac morphogenesis
  species: Zebrafish
  genotype: >-
    Wild-type and contractility/flow-perturbed embryos (e.g. cardiac troponin and
    myosin morphants that abolish or alter intracardiac flow while the heart tube
    continues to form)
  publication: PMID:26969993
  description: >-
    The optically accessible, externally developing zebrafish embryo can survive by
    diffusion for long enough to tolerate near-complete loss of cardiac output, which
    is what makes it possible to remove flow and still observe morphogenesis. It is
    the system that supplies essentially all of the direct evidence behind the
    "no flow, no grow" node in this entry, and therefore the model on which the
    chd_flow_dependent_human_evidence HUMAN_MODEL_MISMATCH discussion turns.
  modeled_mechanisms:
  - target: Flow-Dependent Cardiac Morphogenesis Failure
    relationship: PERTURBS
    fidelity: MODERATE
    description: >-
      Experimentally removes or alters haemodynamic force during cardiac development
      and observes the morphogenetic consequence, establishing flow as a causal
      morphogenetic input rather than a correlate of it.
    limitations: >-
      Substantial species divergence at exactly the points this entry cares about: the
      zebrafish heart is two-chambered, undergoes no atrial or ventricular septation
      and has no separate pulmonary circulation, so the septation, conotruncal and
      duct-dependent arms of the model cannot be represented at all. Embryo scale also
      places the developing zebrafish heart in a different flow regime from the human
      embryo. The node is consequently curated with evidence_source MODEL_ORGANISM,
      and the translational question is left open in
      discussions.chd_flow_dependent_human_evidence rather than closed by this model.
    readouts:
    - name: Cardiac morphogenesis under experimentally altered haemodynamic force
      target: Flow-Dependent Cardiac Morphogenesis Failure
      direction: ALTERED
      interpretation: >-
        Heart development is abnormal when the forces are absent or disrupted, which
        is the observation the node's causal claim rests on.
      evidence:
      - reference: PMID:26969993
        reference_title: "Organ Function as a Modulator of Organ Formation: Lessons from Zebrafish."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In the absence or disruption of these forces, heart development is abnormal,
          suggesting that the heart must sense these changes and respond appropriately.
        explanation: Reports the perturbation result behind this readout.
    evidence:
    - reference: PMID:26969993
      reference_title: "Organ Function as a Modulator of Organ Formation: Lessons from Zebrafish."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Here, we discuss concepts of how embryonic heart function contributes to heart
        development using lessons learned mostly from studies in zebrafish.
      explanation: >-
        Establishes zebrafish as the model system supplying the evidence for this
        node, which is what makes the link informative and the mismatch discussion
        necessary.

experimental_models:
- name: Hypoplastic left heart syndrome patient-derived iPSC-cardiomyocytes
  experimental_model_type: IPSC_DERIVED_MODEL
  cell_source: PATIENT_DERIVED
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:39273002
  description: >-
    Cardiomyocytes differentiated from iPSCs reprogrammed from HLHS patients. These
    are curated here for a specific reason rather than as generic model-system
    completeness: they bear directly on the open question in
    chd_flow_dependent_human_evidence. If HLHS were purely a flow-deprivation
    phenomenon, patient cardiomyocytes removed from the haemodynamic environment
    should behave normally. They do not - they show impaired cardiac-lineage
    differentiation and structural/electromechanical defects in dish - which is
    human-derived evidence for a cell-autonomous contribution alongside, not instead
    of, the flow mechanism.
  modeled_mechanisms:
  - target: Flow-Dependent Cardiac Morphogenesis Failure
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Provides the counterfactual the zebrafish model cannot: human patient cells
      cultured entirely outside a haemodynamic environment still show intrinsic
      defects, evidencing the "shared upstream developmental cause" alternative that
      the HUMAN_MODEL_MISMATCH discussion sets against pure flow dependence.
    limitations: >-
      iPSC-derived cardiomyocytes are transcriptionally and structurally immature,
      closer to fetal than adult myocardium, and a monolayer of one cell type cannot
      represent chamber-level morphogenesis at all. The findings are also from small
      patient-derived series with the genetic heterogeneity of HLHS uncontrolled, so
      they establish that a cell-autonomous component exists without quantifying its
      share relative to flow.
    readouts:
    - name: Connexin 43 expression and cardiac myocyte alignment in HLHS iPSC-CMs
      target: Flow-Dependent Cardiac Morphogenesis Failure
      direction: DECREASED
      interpretation: >-
        Reduced CX43 with impaired electromechanical transduction and failure of
        myocyte alignment, measured with no haemodynamic input present.
      evidence:
      - reference: PMID:39273002
        reference_title: iPSC-Derived Cardiomyocytes as a Disease Model to Understand the Biology of Congenital Heart Defects.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          They observed a reduction in CX43 expression in iPSC-derived CMs from HLHS
          patients, showing that there is impaired electromechanical transduction
          which causes the failure of correct cardiac myocyte alignment.
        explanation: Reports the measurement behind this readout.
    - name: Myofibril and organelle organisation in HLHS iPSC-CMs
      target: Flow-Dependent Cardiac Morphogenesis Failure
      direction: ALTERED
      interpretation: >-
        Structural disorganisation of the contractile apparatus intrinsic to the
        patient-derived cells.
      evidence:
      - reference: PMID:39273002
        reference_title: iPSC-Derived Cardiomyocytes as a Disease Model to Understand the Biology of Congenital Heart Defects.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          HLHS iPSC-CMs had an irregular myofibril arrangement, RER, and SR.
        explanation: Reports the structural measurement behind this readout.
    evidence:
    - reference: PMID:39273002
      reference_title: iPSC-Derived Cardiomyocytes as a Disease Model to Understand the Biology of Congenital Heart Defects.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        They report an impairment in the differentiation process to the cardiac
        lineage of fully formed mature CMs.
      explanation: >-
        Establishes that HLHS patient-derived cells carry an intrinsic
        cardiac-differentiation defect outside any haemodynamic context, which is why
        this model is informative for the flow-dependence question.

discussions:
- discussion_id: chd_root_scope
  kind: CURATION_TODO
  status: OPEN
  prompt: >-
    What does this root entry add over the ~24 lesion-specific and ~195 syndromic
    dismech entries that already carry congenital cardiac content, and where should the
    boundary sit?
  attaches_to:
  - pathophysiology#Structural Cardiac Malformation
  rationale: >-
    At the time of curation the knowledge base already held dedicated entries for
    atrial and ventricular septal defect, tetralogy of Fallot, coarctation, hypoplastic
    left heart syndrome, d-transposition, persistent truncus arteriosus, double outlet
    right ventricle, Ebstein anomaly, visceral heterotaxy, patent ductus arteriosus,
    anomalous pulmonary venous return and more, plus syndromic entries (22q11.2
    deletion, CHARGE, Alagille, Down, Holt-Oram, Noonan, Turner, Kabuki, Williams,
    Ellis-van Creveld) carrying CHD as a phenotype. This entry was deliberately scoped
    to the *shared developmental biology* those entries individually assume but none
    asserts: first heart field vs second heart field deployment, cardiac neural crest
    migration, endocardial cushion endothelial-to-mesenchymal transition, the septation
    transcription factor network, left-right patterning, and flow-dependent
    morphogenesis. Four of those were unbroken ground in the KB before this entry
    (GO:0003272 and GO:0003203 endocardial cushion terms had zero prior uses,
    GO:0003198 one, CL:2000073 migratory cardiac neural crest cell zero, and
    flow-dependent morphogenesis had no ontology anchoring anywhere). Conversely the
    entry deliberately does NOT re-derive lesion-specific pathographs, post-operative
    course, or the shunt-to-Eisenmenger trajectory, all of which are curated elsewhere.
    The open question is whether the boundary should be enforced by a complementary
    kb/groupings/ Grouping recording the curated membership set and its criteria, in
    the manner of Familial_Hypertrophic_Cardiomyopathy, which keeps both an umbrella
    Disease entry (for the shared mechanism and gene spectrum) and a Grouping (for the
    audited membership boundary).
- discussion_id: chd_module_candidate
  kind: CURATION_TODO
  status: OPEN
  prompt: >-
    Should the cardiac morphogenesis chain in this entry be factored out into a
    kb/modules/ mechanism module that the lesion entries can declare conforms_to?
  attaches_to:
  - pathophysiology#Cardiac Progenitor Specification and Second Heart Field Deployment Failure
  rationale: >-
    The four developmental arms modelled here recur, node for node, across at least
    eight existing lesion entries: tetralogy of Fallot, persistent truncus arteriosus
    and double outlet right ventricle all carry "cardiac neural crest and second heart
    field" nodes in prose; d-transposition and DORV both carry looping/left-right nodes;
    hypoplastic left heart syndrome and coarctation both assert the flow-limitation step
    without anchoring it. That recurrence is exactly the signal the create-module skill
    treats as a module trigger, and no kb/modules/ entry currently covers cardiac
    development. A cardiac_morphogenesis_failure module would let those entries declare
    conformance rather than each re-deriving the chain. It was not created in this pass
    because module creation is a separate deliverable with its own review requirements,
    and because the correct node granularity is better judged after this root entry has
    been reviewed.
- discussion_id: chd_flow_dependent_human_evidence
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Is flow-dependent cardiac morphogenesis demonstrated in human development, or is the
    "no flow, no grow" node in this entry an extrapolation from zebrafish?
  attaches_to:
  - pathophysiology#Flow-Dependent Cardiac Morphogenesis Failure
  rationale: >-
    The direct experimental evidence that haemodynamic force is a necessary
    morphogenetic input — that removing or altering flow makes heart development
    abnormal — comes from zebrafish, where the embryo can be manipulated and observed.
    The node is therefore curated with evidence_source MODEL_ORGANISM. In humans the
    supporting evidence is inferential: an early flow-limiting lesion is observed to be
    accompanied by progressive hypoplasia of the structures behind it (the natural
    history of evolving hypoplastic left heart syndrome and of aortic arch hypoplasia).
    That correlation is compatible with the flow hypothesis but does not exclude a
    common developmental cause acting on both the valve and the chamber. Resolving this
    matters because it determines whether fetal intervention to restore flow can be
    expected to rescue chamber growth, or only to relieve obstruction.

    Both sides of the question now have a structural anchor in this entry. The
    zebrafish perturbation model (animal_models) supplies the causal flow evidence and
    carries its species limitations explicitly - a two-chambered heart with no
    septation cannot represent most of what this entry models. Against it, HLHS
    patient-derived iPSC-cardiomyocytes (experimental_models) show impaired
    cardiac-lineage differentiation, reduced CX43 and disorganised myofibrils while
    cultured entirely outside any haemodynamic environment, which is human-derived
    evidence that a cell-autonomous component exists. Neither settles the share of
    each contribution, which is what the proposed experiment below is aimed at.
  proposed_experiments:
  - experiment_id: chd_fetal_valvuloplasty_growth_trajectory
    name: Serial fetal echocardiographic growth trajectories after fetal aortic valvuloplasty
    description: >-
      Test whether relieving a flow-limiting lesion in mid-gestation alters the
      subsequent growth trajectory of the left ventricle, aortic valve annulus and
      ascending aorta relative to matched unintervened fetuses. A growth response would
      support the flow-dependent model directly in humans; its absence would favour a
      shared upstream developmental cause.
- discussion_id: chd_prevalence_ascertainment
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How much of the reported worldwide variation in CHD birth prevalence is real
    biological difference and how much is ascertainment?
  attaches_to:
  - pathophysiology#Structural Cardiac Malformation
  rationale: >-
    Reported birth prevalence rose from 0.6 per 1000 in the 1930s to over 9 per 1000
    after 1995, and 93.4% of the recent increase is attributable to the mild lesions
    (ventricular septal defect, atrial septal defect, patent ductus arteriosus) that
    postnatal echocardiography detects. Meanwhile the reported prevalence of left
    ventricular outflow tract obstruction has fallen, which the authors read as prenatal
    detection with consequent termination. Africa reports the lowest prevalence and Asia
    the highest. Almost none of this is safely interpretable as variation in the
    underlying developmental biology this entry models, and the prevalence records here
    are curated as *reported* birth prevalence for that reason. Distinguishing the two
    would need a population with uniform prenatal and postnatal ascertainment,
    including pregnancy outcomes.

notes: >-
  Scope note. This entry is the mechanistic root of the CHD family and is intentionally
  not a superset of the lesion entries. Where a claim is lesion-specific it is left to
  that lesion's entry and referenced by name rather than duplicated; the phenotype list
  here records the malformation classes that the developmental arms converge on, not a
  full clinical description of each. The subtype names (CTD, Septal, AVSD, LVOTO, RVOTO,
  HTX, APVR) follow the analytic lesion classes used in the CHD genomics and
  epidemiology literature rather than a surgical classification, because it is those
  classes for which differential genetic architecture has actually been reported —
  notably the absence of a de novo variant excess in heterotaxy and the distinctive
  isolated-CHD diagnostic yield in LVOTO.

  Ontology note. Three CL/GO terms used here were previously unused or near-unused in
  this knowledge base: CL:2000073 (migratory cardiac neural crest cell), which existing
  entries had been naming only as free text; GO:0003272 and GO:0003203 (endocardial
  cushion formation and morphogenesis), which had no prior use; and GO:0003198
  (epithelial to mesenchymal transition involved in endocardial cushion formation),
  which had one.

  Naming caution. CHD7 in the genetic section is the chromodomain-helicase gene that
  causes CHARGE syndrome. It is unrelated to the abbreviation CHD used for congenital
  heart disease throughout this entry, and the knowledge base also contains CHD2- and
  CHD8-related entries that are likewise chromodomain-helicase genes rather than
  cardiac entries.

  GeneReviews. No GeneReviews chapter exists for the congenital heart disease umbrella
  (PubMed searched 2026-08-19 for "congenital heart disease[TI] AND GeneReviews[All
  Fields]": zero results), which is expected for a complex multifactorial root term.
  GeneReviews chapters do exist for several of the syndromic causes and are cited in
  those entries.

  GENE-DEFINED CONCEPTS ARE NOT ROWS ON THIS ENTRY'S SUBTYPE AXIS.
  MONDO:0005453 'congenital heart disease' is the correct term for an umbrella
  entry rather than an over-broad stand-in for a gene-named concept, so the
  narrowMatch re-anchoring described in dismech#12184 does not apply here. One
  consequence of binding the umbrella term is that every gene-defined
  descendant of MONDO:0005453 is attributed to this entry by a knowledge-graph
  comparison against the KB.

  Those gene-defined concepts are not children of this entry's subtype axis.
  The seven rows here (CTD, Septal, AVSD, LVOTO, RVOTO, HTX, APVR) are the
  analytic lesion classes for which differential genetic architecture has been
  reported, and MONDO's own definitions of the gene-defined concepts enumerate
  lesions spanning several of them at once: the definition of GATA6-related
  congenital heart disease gives as representative cardiac examples "atrial
  septal defect 9, conotruncal heart malformations, tetralogy of Fallot,
  ventricular septal defect, atrioventricular septal defect, bicuspid aortic
  valve, transposition of the great arteries, and persistent truncus
  arteriosus". Recording such a concept as a row would put a second,
  overlapping partition in one slot. They are curated instead as `genetic:`
  records wired to the mechanism node each gene acts at, which is the level at
  which this entry models disease, with the lesion detail left to the lesion
  entries.

  WHERE EACH GENE REACHES THE PATHOGRAPH. Sixteen gene records are bound on a
  pathophysiology node: KMT2D, CHD7 and RBFOX2 on gene-dosage disruption;
  HAND1 and HAND2 on cardiac progenitor specification and second heart field
  deployment; ZIC3 and SMAD2 on left-right patterning and cardiac looping;
  TBX1, TFAP2B and GATA6 on cardiac neural crest migration and outflow tract
  septation; NOTCH1 and PLD1 on endocardial cushion formation; and NKX2-5,
  GATA4, TBX5 and TBX20 on the septation transcription factor network.

  GDF1, FLT4 and MYH6 reach no node, and the chromosomal aneuploidy and
  copy-number-variant record names no gene. Each of those three is evidenced
  here by a cohort-fraction statement tying the gene to a named lesion rather
  than by anything placing it in one of this entry's developmental arms, so
  none is attached to a node on the strength of plausibility alone.

  MONDO:1060150 SPANS TWO ENTRIES. ClinGen lumped Adams-Oliver syndrome 5 and
  aortic valve disease 1 into one NOTCH1-related spectrum, so that concept
  covers a syndromic entity and a cardiac one. The cardiac half is curated
  here through the NOTCH1 record on the LVOTO row; the syndromic half is
  curated in Adams-Oliver_Syndrome (MONDO:0007034), which also binds NOTCH1.

  FOUR GENE-DEFINED CONCEPTS UNDER THIS TERM ARE DELIBERATELY NOT CURATED
  HERE.

  ACTC1 (MONDO:0700352, ACTC1-related distal arthrogryposis with congenital
  heart disease) is a syndromic distal arthrogryposis whose cardiac
  involvement is one feature among multiple congenital contractures, neck
  pterygia and scoliosis; MONDO files it under distal arthrogryposis
  (MONDO:0019942) as well as here. ClinGen has curated ACTC1 only against
  hypertrophic, dilated and arrhythmogenic cardiomyopathy, with no congenital
  heart disease assertion (ClinGen Gene-Disease Validity CSV read 2026-09-24),
  and this knowledge base binds ACTC1 in six entries -
  Hypertrophic_Cardiomyopathy, Hypertrophic_Cardiomyopathy_11,
  Dilated_Cardiomyopathy, Dilated_Cardiomyopathy_1R, Restrictive_Cardiomyopathy
  and Camptodactyly. It belongs in an entry of its own, not on this axis.

  NR2F2 (MONDO:0014344, congenital heart defects multiple types 4) is curated
  in Atrioventricular_Septal_Defect and in Congenital_Diaphragmatic_Hernia,
  which is the lump/split home its phenotype points to. ClinGen's Definitive
  assertion for this gene is against MONDO:0800458, NR2F2-related multiple
  congenital anomalies/dysmorphic syndrome, not against the numbered
  congenital-heart-defects concept (read 2026-09-24).

  GATA5 (MONDO:0060663, congenital heart defects multiple types 5) and PLXND1
  (MONDO:0859532, congenital heart defects multiple types 9) are recorded as
  open rather than curated or disputed. Neither gene has any ClinGen
  gene-disease validity assertion at all, for congenital heart disease or for
  anything else (the 2026-09-24 CSV contains no row for either symbol), where
  every other gene curated here does. The published human GATA5 evidence
  returned by a PubMed relevance search on 2026-09-24 for "GATA5 mutation
  congenital heart defect bicuspid aortic valve" is dominated by small
  candidate-gene bicuspid aortic valve series, and the same search on that
  date for "PLXND1 mutations congenital heart defects truncus arteriosus"
  returned a single isolated truncus arteriosus report. Neither search is a
  systematic review, and a fuller one could change the picture. An absence of
  positive curation is not a refutation, so neither gene is marked DISPUTED,
  and MONDO is not in error: it records a reported gene association, which
  exists.

  TWO CONCEPTS UNDER THIS TERM ARE NOT HEART MALFORMATIONS, AND REACH IT
  THROUGH A MONDO CLASSIFICATION THAT LOOKS WRONG. MONDO:0100090 'congenital
  alveolar dysplasia due to FGF10' and MONDO:0100097 'congenital alveolar
  dysplasia due to TBX4' are pulmonary developmental disorders. They are
  nonetheless genuine descendants of this entry's term, by this chain, read
  from OLS on 2026-09-24: each has MONDO:0100077 'congenital alveolar
  dysplasia' as a parent; MONDO:0100077's only asserted parent is
  MONDO:0020295 'congenital pulmonary veins anomaly'; and MONDO:0020295's only
  asserted parent is MONDO:0005453.

  The step worth questioning is MONDO:0100077 being a kind of congenital
  pulmonary veins anomaly. MONDO's own definition of it is "a defective and
  hypoplastic development of pulmonary alveoli that is commonly associated
  with atelectasis and can be responsible for atelectasis", which describes
  lung parenchyma and says nothing about veins. That single edge is what
  places two alveolar disorders, and their genes, under congenital heart
  disease.

  The curation ruling rests on the diseases rather than on the hierarchy:
  neither is a structural malformation of the heart or great vessels, so
  neither belongs on this entry. TBX4 is curated in this knowledge base in
  Heritable_Pulmonary_Arterial_Hypertension,
  Idiopathic_Pulmonary_Arterial_Hypertension and Pulmonary_hypertension, which
  is the neighbourhood both genes belong in.

📚

References & Deep Research

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (2)

Address PR #8981 review: fix CRITICAL prevalence_class mis-banding, truncated snippets, add arrhythmia/SCD, treatment evidence, model layer · 2026-08-19T20:18:22Z · View source

Review-response session addressing the ai4c-reviewer CHANGES_REQUESTED on PR #8981 (one CRITICAL, six IMPORTANT findings). All seven addressed. CRITICAL - finding 1, prevalence_class mis-banding. All three prevalence records carried prevalence_class BAND_1_5_PER_10000 alongside rate_per_100000 of 941.0 (Worldwide), 231.5 (Africa) and 934.2 (Asia). Independently confirmed the reviewer is correct by reading both the schema enum (BAND_1_5_PER_10000 = "1 to 9 per 10,000 (10-99 per 100,000)"; ABOVE_1_IN_1000 = "More than 1 in 1,000 (more than 100 per 100,000)") and the reference implementation scripts/migrate_prevalence.py::_band_from_rate(), which returns ABOVE_1_IN_1000 for any rate >= 100. All three records are 2.3x to 9.4x above the declared band, so the commonest congenital anomaly in humans was coded as rare in queryable data. Set prevalence_class: ABOVE_1_IN_1000 on all three (the reviewer said "all four"; the entry has three, and every one was re-checked, not only the named ones). Rewrote the Worldwide notes, which had entrenched the error by describing ABOVE_1_IN_1000 as a class the rate "also exceeds" - it is unbounded above, so nothing exceeds it. Added to the Africa notes that its lower confidence bound (42.9 per 100,000) would fall a band lower while the point estimate sets the class, so the choice is auditable. IMPORTANT - finding 2, wrap-truncated snippets. Treated as a class of error rather than two instances, as instructed. Wrote an audit script that normalises unicode (middle-dot decimals, en-dashes, curly quotes, U+223C tilde), locates every PMID-backed snippet in its cached body, and flags any that ends without terminal punctuation while the source sentence continues. It flagged 26 of 99; manual triage found most were complete findings whose continuation only added interpretation. Two were genuine payload-cuts, both the reviewer's: PMID:16025100 stopped at "...NOTCH1 cause a", cutting the aortic-valve-anomaly result, and PMID:12845333 stopped at "Here, we show that isolated cardiac septal", cutting the GATA4 G296S linkage result. Both replaced with the reviewer-supplied corrected text. The audit is clean of payload-cuts now. Note no deterministic repo check catches this class - count-verified-snippets passed 81/81 with both defects present. IMPORTANT - finding 2b follow-on, unsupported explanation clause. The GATA4 explanation asserted a TBX5 interaction absent from the quoted text. Rather than drop the clause, added a second evidence item quoting the abstract's actual TBX5 sentences ("Furthermore, the Gata4 mutation abrogated a physical interaction between Gata4 and TBX5... Conversely, interaction of Gata4 and TBX5 was disrupted by specific human TBX5 missense mutations that cause similar cardiac septal defects."), which evidences the bidirectional interaction the septation-network node relies on. IMPORTANT - finding 3, NOTCH1 background prose. The genetic-section NOTCH1 evidence quoted the paper's setup ("The incidence increases with age...") and its explanation conceded it only "frames" the phenotype (CLAUDE.md section 6: a topic is not a result). Replaced with the paper's finding sentence and rewrote the explanation to state the result. IMPORTANT - finding 4, HP:0000924 mis-binding. "Extracardiac congenital anomaly" was bound to Abnormality of the skeletal system while its description and PMID:26785492 evidence concern anomalies of any organ system. Searched HPO first for a better term (2026-08-19): the only "congenital malformation of" classes are cardiac (HP:0011603, HP:0011723, HP:0045017), there is no "multiple congenital anomalies" class, and every "Abnormality of the X system" term names a single system. Dropped term:, kept the free-text preferred_term, and added a NEEDS TERM / NTR CANDIDATE note recording the search and the removed binding. No term beats a bad term. IMPORTANT - finding 5, arrhythmia and sudden cardiac death. Added both phenotypes. Note the reviewer's suggested HP:0001644 is Dilated cardiomyopathy; verified with OAK and used HP:0001645 Sudden cardiac death instead, alongside HP:0011675 Arrhythmia. Evidence from Salzillo 2024 PMID:39768857 (newly cited): SCD rates 20-30x the general population; highest-risk lesions tetralogy of Fallot, TGA, cyanotic heart disease, Ebstein anomaly, Fontan circulation; incidence greater in adults than children. Also wired both into the pathograph rather than leaving them as disconnected list entries: Altered Circulatory Physiology -> Arrhythmia and -> Sudden cardiac death (both INDIRECT_KNOWN_INTERMEDIATES with named intermediates), plus a DIRECT edge Cardiac Septation Transcription Factor Network Failure -> Arrhythmia carrying the NKX2-5 septation-plus-AV-node quote, which keeps the developmental route to arrhythmia distinct from the acquired scar/dilation route. IMPORTANT - finding 6, unevidenced treatments. Cardiac surgical repair or palliation and Heart transplantation had no evidence at either level. Searched PubMed and fetched two new sources. Troost 2019 PMID:30413300 now evidences the surgical entry at both levels, including the specific lifelong-residual-risk claim the reviewer flagged as unevidenced ("adult patients with CHD carry residual lesions and sequelae putting them at risk for premature death related to re-interventions or complications; most commonly heart failure and arrhythmia") attached directly to the RESTORES target_mechanisms link, so the qualification on that edge is now substantiated where it is asserted. Transplantation evidenced with the failing-Fontan combined heart-liver transplantation meta-analysis PMID:40320589, curated supports: PARTIAL because it covers CHLT in failing Fontan (4 retrospective cohorts, 67 patients) rather than heart transplantation across CHD as a whole. IMPORTANT - finding 7, missing model layer. Added animal_models and experimental_models, both with modeled_mechanisms so they attach to the pathograph rather than sitting as disconnected lists. (1) Zebrafish embryonic heart-function model (PMID:26969993), PERTURBS -> Flow-Dependent Cardiac Morphogenesis Failure, fidelity MODERATE, with limitations naming the divergence that matters here - a two-chambered heart with no septation and no separate pulmonary circulation cannot represent the septation, conotruncal or duct-dependent arms at all - plus one readout. This gives the chd_flow_dependent_human_evidence HUMAN_MODEL_MISMATCH discussion the structural anchor it lacked. (2) HLHS patient-derived iPSC-cardiomyocytes (PMID:39273002, newly cited), MEASURES -> the same node, with two readouts (reduced CX43 with failure of myocyte alignment; irregular myofibril arrangement). This was added for a specific argumentative reason rather than model-system completeness: if HLHS were purely flow deprivation, patient cardiomyocytes cultured outside any haemodynamic environment should behave normally, and they do not - so it is human-derived evidence for the cell-autonomous alternative the mismatch discussion sets against pure flow dependence. Updated that discussion's rationale to state both anchors and note that neither settles the share of each contribution. The DR-surfaced Dyrk1a trisomic mouse septation rescue was NOT added: PubMed searches for it returned no resolvable record, and fabricating or guessing a citation for it would be worse than the omission. Non-blocking suggestions 8 (clinical_trials) and 9 (catheter-based intervention) not actioned this pass; the DR-surfaced NCTs are registries/observational, and catheter intervention is noted as a genuine modelling gap for a follow-up. VALIDATION (every check run to completion and its output read, post-fix). just validate -> passed; 99/99 snippets verified just count-verified-snippets -> Snippets checked: 99/99 verified against cached references just validate-terms -> Validation passed scripts/check_snippet_length.py --against-ref origin/main -> OK: no new snippets under 5 words scripts/check_folded_hyphens.py -> OK: no new folded-scalar hyphen splits (330 grandfathered) just check-duplicate-keys -> OK: no duplicate mapping keys just check-title-snippets -> OK: no new title-quoting snippets just check-empty-snippets -> no empty (non-NO_EVIDENCE) evidence snippets just validate-disorders (batched --no-full-text, CI-equiv) -> passed; 99/99 verified; exit 0 just compliance -> 84.6% weighted (was 82.7%) Snippet count rose 81 -> 99; cited PMIDs 20 -> 24 (added PMID:39768857, PMID:30413300, PMID:40320589, PMID:39273002).

Create: Congenital Heart Disease (MONDO:0005453) mechanistic root with seven lesion-class subtypes · 2026-08-19T19:35:47Z · View source

New root Disease entry for the congenital heart disease umbrella (MONDO:0005453), curated per the priority dashboard's CURATE_ROOT_WITH_SUBTYPES recommendation (issue #8916). SCOPE. Deliberately curated as the MECHANISTIC ROOT of the CHD family rather than a superset of the ~24 lesion-specific and many syndromic entries already in kb/disorders (Atrial_Septal_Defect, Tetralogy_of_Fallot, Coarctation_of_the_Aorta, Hypoplastic_Left_Heart_Syndrome, Dextro_Transposition_of_the_Great_Arteries, Persistent_Truncus_Arteriosus, Double_Outlet_Right_Ventricle, Ebstein_Anomaly, Visceral_Heterotaxy, 22q11.2_Deletion_Syndrome, CHARGE_Syndrome, Alagille_syndrome, Down_syndrome, Holt-Oram_Syndrome, Noonan_Syndrome, Turner_Syndrome, Kabuki_Syndrome and others). The entry models the shared cardiac developmental biology those entries individually assume but none asserts: (1) Developmental Gene Dosage Disruption (de novo variants in chromatin modifiers and high-heart-expression genes, CNVs, aneuploidy); (2) Maternal Metabolic and Teratogenic Perturbation of Cardiogenesis; (3) Cardiac Progenitor Specification and Second Heart Field Deployment Failure; (4) Left-Right Patterning and Cardiac Looping Failure; (5) Cardiac Neural Crest Migration and Outflow Tract Septation Failure; (6) Endocardial Cushion Formation and Endothelial-to-Mesenchymal Transition Failure; (7) Cardiac Septation Transcription Factor Network Failure; (8) Flow-Dependent Cardiac Morphogenesis Failure ("no flow, no grow"); converging on (9) Structural Cardiac Malformation and (10) Altered Circulatory Physiology. Lesion-specific pathographs, post-operative course, and the shunt-to-Eisenmenger trajectory are referenced by entry name and NOT re-derived here. SUBTYPES. Seven has_subtypes lesion classes with short slug-friendly foreign-key names used by the phenotypes and genetic blocks: CTD (MONDO:0016581 conotruncal heart malformations), Septal (no single MONDO class covers the atrial-plus-ventricular septal group; constituent lesions curated separately), AVSD (MONDO:0859565), LVOTO, RVOTO, HTX (MONDO:0018677 visceral heterotaxy), APVR (MONDO:0017705). Classes follow the analytic groupings used in the CHD genomics and epidemiology literature rather than a surgical classification, because differential genetic architecture has actually been reported for those classes - notably the absence of a de novo variant excess in heterotaxy (PMID:26785492) and the distinctive isolated-CHD diagnostic yield in LVOTO (PMID:34440418). LVOTO, RVOTO and Septal carry no subtype_term because SubtypeDescriptor binds MONDO/NCIT only and no suitable MONDO class exists; HP:0032092 (Left ventricular outflow tract obstruction) is carried on the corresponding phenotype instead. DISEASE ENTRY VS GROUPING. Concluded that a Disease entry is correct here and a kb/groupings Grouping would be complementary rather than a substitute. The subtype classes are anatomical/developmental partitions of one mechanistic model, not a curated union over already-distinct Disease entries; the pathograph (10 nodes, 22 causal edges) is a single shared mechanism no member entry asserts, and a Grouping cannot carry a pathograph. A future Grouping recording the audited membership boundary over the existing lesion entries would follow the Familial_Hypertrophic_Cardiomyopathy precedent (umbrella Disease plus Grouping) and is recorded as the open discussion chd_root_scope rather than forced into this PR. DEEP RESEARCH. Provider: falcon (Edison Scientific Literature), 674s, research/Congenital_Heart_Disease-deep-research-falcon.md plus its .citations.md sidecar and one markdown artifact. Report reference_validation: 7/7 references resolved, confabulation_rate 0.0, no unresolved_references, no off_topic references. The report was DOI-keyed and mechanistically thin, so it was used as a LEAD SOURCE ONLY: its five DOIs were converted to PMIDs via the PMC ID converter API and every curated claim was re-anchored on primary literature independently searched through the PubMed E-utilities API and independently fetched with just fetch-reference. NEC CHECK. just preflight-dr research/Congenital_Heart_Disease-deep-research-falcon.md MONDO:0005453 returned SKIP as anticipated (MONDO records no causal gene RO:0004003 for this complex/multifactorial root term, so the gene-identity check cannot discriminate). Fell back to the manual CLAUDE.md section 2b checks against uv run runoak -i sqlite:obo:mondo info MONDO:0005453 -O obo: no OMIM xref exists for this term; every synonym ("congenital heart defect", "congenital anomaly of heart", "heart malformation", the MESH:D006330 variants) denotes the same concept with no eponymic, numbered-series, or acronym collision; and the report's top gene mentions (NKX2-5=9, GATA4=6, TBX20=6, TBX1=6, MYH6=6) are all canonical CHD genes consistent with the intended entity. Manual NEC check: PASS. GENEREVIEWS. No GeneReviews chapter exists for the CHD umbrella - PubMed esearch on 2026-08-19 with term "congenital heart disease[TI] AND GeneReviews[All Fields]" returned zero results. Expected for a complex multifactorial root term, and recorded in the entry notes. GeneReviews chapters do exist for several syndromic causes and are cited in those entries. EVIDENCE. 81 evidence snippets across 20 independently fetched and verified PMIDs. Core sources: Zaidi 2013 Nature PMID:23665959 (de novo chromatin-modifier burden, H3K4/H2BK120), Homsy 2015 Science PMID:26785492 (1213 trios; CHD/NDD/CA shared genetics; RBFOX2-HLHS; heterotaxy exception), Jin 2017 Nat Genet PMID:28991257 (2871 probands; GDF1 Ashkenazi founder, MYH6/Shone, FLT4/TOF, ~440 genes), Guijarro and Kelly 2024 PMID:38488639 (second heart field), cardiac neural crest review PMID:32405705, Zubrzycki 2024 IJMS PMID:39000221 (cardiac development), Garg 2003 Nature PMID:12845333 (GATA4-TBX5), Schott 1998 Science PMID:9651244 (NKX2-5 septation plus AV conduction), Garg 2005 Nature PMID:16025100 (NOTCH1 aortic valve), Gebbia 1997 Nat Genet PMID:9354794 (ZIC3), zebrafish flow-dependent morphogenesis PMID:26969993, Liu 2019 Int J Epidemiol PMID:30783674 and van der Linde 2011 PMID:22078432 (birth prevalence), Can J Cardiol 2024 prenatal risk-factor meta-analysis PMID:38996968 and AHA non-inherited risk factor statement PMID:17519397, Thangaratinam 2012 Lancet PMID:22554860 (pulse oximetry screening), Helm 2021 PMID:34440418 and Peterlin 2024 PMID:39337901 (genetic testing yield), prostaglandin E1 PMID:29162633, maternal pregestational diabetes PMID:35838899. ONTOLOGY. Three CL/GO terms used here were previously unused or near-unused in this knowledge base: CL:2000073 (migratory cardiac neural crest cell), which existing entries had been naming only as free text; GO:0003272 and GO:0003203 (endocardial cushion formation and morphogenesis), which had no prior use; and GO:0003198 (epithelial to mesenchymal transition involved in endocardial cushion formation), which had one. All terms were verified with OAK before use. Two ECTO exposure terms bound (ECTO:0300001, ECTO:0300003); maternal pregestational diabetes and maternal adiposity are deliberately left unbound with a note recording that ECTO was searched and has no class for a maternal metabolic disease state as an exposure. DISCUSSIONS. Four open discussions recorded: chd_root_scope (CURATION_TODO - what this adds over the existing entries and whether a complementary kb/groupings Grouping should enforce the boundary); chd_module_candidate (CURATION_TODO - whether the cardiac morphogenesis chain should be factored into a kb/modules mechanism module that the eight-plus lesion entries could declare conforms_to, since no module currently covers cardiac development); chd_flow_dependent_human_evidence (HUMAN_MODEL_MISMATCH - the direct evidence that haemodynamic force is a necessary morphogenetic input is zebrafish, human support is inferential, with a proposed fetal aortic valvuloplasty growth-trajectory experiment); chd_prevalence_ascertainment (KNOWLEDGE_GAP - reported prevalence variation is dominated by ascertainment rather than biology, which is why the prevalence records are curated as reported birth prevalence). VALIDATION (every check below was run to completion and its output read). just validate -> passed; 81/81 snippets verified against cached references just count-verified-snippets -> Snippets checked: 81/81 verified against cached references (0 skipped by prefix) just validate-terms -> Validation passed just check-duplicate-keys -> OK: no duplicate mapping keys scripts/check_snippet_length.py --against-ref origin/main -> OK: no new snippets under 5 words just check-title-snippets -> OK: no new title-quoting snippets just check-empty-snippets -> no empty (non-NO_EVIDENCE) evidence snippets found just validate-disorders -> passed (the batched --no-full-text sweep CI runs); 81/81 verified; exit 0 just compliance -> 82.7% weighted

Falcon ▸

Congenital Heart Disease: Comprehensive Disease-Characteristics Report

Edison Scientific Literature 21 citations 2026-08-19T09:17:45.991557

Congenital Heart Disease: Comprehensive Disease-Characteristics Report

Executive summary

Congenital heart disease (CHD) is an umbrella term for structurally or functionally important cardiovascular malformations arising during embryonic development and present at birth, although mild lesions may not be recognized until childhood or adulthood. It is not one molecular disease: lesions range from small septal defects to tetralogy of Fallot (TOF), transposition of the great arteries (TGA), hypoplastic left-heart syndrome (HLHS), and heterotaxy. Contemporary studies generally place prevalence near 1% of live births; broader definitions that include bicuspid aortic valve and very small defects produce estimates approaching 1–2%. Genetic or recognized environmental causes are found in only a minority of all cases, but diagnostic yield rises markedly in severe, syndromic, or extracardiac-malformation cohorts. In a 2024 neonatal intensive-care cohort, a molecular/cytogenetic diagnosis was established in 17% (32/188) of infants. (helm2021geneticevaluationof pages 1-2, peterlin2024thegeneticarchitecture pages 10-12)

CHD begins prenatally but is usually a lifelong condition rather than a lesion “cured” by surgery. Improved fetal diagnosis, neonatal surgery, catheter intervention, and longitudinal care have shifted much of the burden toward adult heart failure, arrhythmia, pulmonary vascular disease, reintervention, neurodevelopmental disability, and psychosocial morbidity. Sudden cardiac death (SCD) is reported at 0.28–2.7% per year in CHD cohorts and 0.9–1.5% per year after TOF in the reviewed literature, accounting for as many as 25% of CHD deaths in some populations. (salzillo2024cardiovasculardiseasesin pages 10-11)

The following table provides an ontology-oriented synopsis.

domain	core facts	suggested ontology terms/IDs	key evidence/statistics
Disease definition/identifier	Congenital heart disease (CHD) is a heterogeneous group of structural heart defects present at birth; it is the most commonly detected congenital anomaly. Use disease-level aggregated resources rather than individual EHR-derived evidence for core definition.	MONDO:0005453 congenital heart disease; MeSH: Congenital Heart Defects	Affects up to ~1% of live-born neonates; global prevalence often cited as 1–2% of infants (peterlin2024thegeneticarchitecture pages 10-12, helm2021geneticevaluationof pages 1-2)
Major lesion phenotypes	Representative major lesions include ventricular septal defect, tetralogy of Fallot, hypoplastic left heart syndrome, transposition of the great arteries, left ventricular outflow tract obstruction, and single-ventricle disease.	HP:0001629 Ventricular septal defect; HP:0001636 Tetralogy of Fallot; HP:0004383 Hypoplastic left heart; HP:0001651 Transposition of the great arteries; HP:0005105 Abnormality of left ventricular outflow tract; HP:0004762 Single ventricle	TOF and HLHS were specifically analyzed in recent single-cell/machine-learning work; LVOTO had relatively high diagnostic genetic yield in isolated CHD cohorts (ma2024machinelearningin pages 2-3, helm2021geneticevaluationof pages 1-2)
Genetics: causal/susceptibility genes	Recurrently implicated CHD genes include NKX2-5, GATA4, GATA6, TBX20, TBX1, GDF1, MYH6, TNNT2, TFAP2B, TAB2, GJA1; BMP4 has recent evidence as a causative/predisposing gene.	HGNC: NKX2-5, GATA4, GATA6, TBX20, TBX1, GDF1, MYH6, TNNT2, TFAP2B, TAB2, GJA1, BMP4; MONDO:0800441 NKX2.5-related congenital, conduction and myopathic heart disease	Open Targets lists strongest CHD associations for NKX2-5 and GATA4; 2024 familial study identified BMP4 p.Tyr106* segregating with CHD and loss of induction of NKX2-5/TBX20 targets (OpenTargets Search: congenital heart disease, salzillo2024cardiovasculardiseasesin pages 13-15)
Chromosomal/syndromic contributors	Important chromosomal or syndromic causes include trisomy 21, trisomy 18, trisomy 13, Turner syndrome, 22q11.2 deletion/DiGeorge syndrome, Williams syndrome, CHARGE syndrome, and Noonan syndrome.	22q11.2 deletion syndrome; trisomy 21; trisomy 18; trisomy 13; Turner syndrome; Williams syndrome; CHARGE syndrome; Noonan syndrome	In a 2024 NICU cohort, 17% received a genetic diagnosis; most frequent diagnoses were 22q11.2 deletion and CHARGE, followed by Noonan and Williams syndromes (peterlin2024thegeneticarchitecture pages 10-12, salzillo2024cardiovasculardiseasesin pages 13-15)
Genetic testing/diagnostic yield	Current evidence supports chromosomal microarray (CMA) and next-generation sequencing (NGS/WGS/WES) in severe or syndromic CHD; isolated CHD can still yield diagnoses.	CMA; WES; WGS; copy-number variant analysis	CMA diagnostic yield: 14.6% in 440 infants and 10.1% in 188 NICU neonates; overall genetic diagnosis 17% in the NICU cohort; isolated CHD still had diagnostic findings (6.5% CMA-positive in one cohort; ~3% diagnosed in another cohort) (helm2021geneticevaluationof pages 1-2, peterlin2024thegeneticarchitecture pages 10-12)
Environmental/non-genetic risk factors	CHD risk is influenced by maternal and environmental exposures, including maternal diabetes, obesity, gestational hypertension, harmful chemicals, noise, antidepressant exposure, and family genetic history.	CHEBI terms not resolved here; exposure concepts: maternal diabetes, maternal obesity, SSRI/SNRI exposure	Updated umbrella review found convincing/highly suggestive evidence for maternal DM, obesity, folic acid supplementation, antidepressants, gestational hypertension, decoration materials, harmful chemicals, and noise exposure associations (zubrzycki2024cardiacdevelopmentand pages 25-26)
Protective factors	Maternal folic acid supplementation is repeatedly discussed as a modifiable factor associated with reduced CHD risk, although evidence varies by lesion and study design.	folic acid supplementation	Umbrella review identified folic acid supplementation among the strongest non-genetic factors evaluated for CHD prevention relevance (zubrzycki2024cardiacdevelopmentand pages 25-26)
Developmental pathways/mechanisms	CHD arises from disruption of cardiac morphogenesis involving second heart field, neural crest, epicardial progenitors, and pathways such as BMP, Notch, Wnt, TGF-beta/Smad, laterality/NODAL signaling, and transcriptional programs controlling septation and outflow tract development.	GO:0007507 heart development; GO:0060916 cardiac septum morphogenesis; GO:0001947 heart looping; GO:0007220 Notch signaling pathway; GO:0030509 BMP signaling pathway; GO:0016055 Wnt signaling pathway; GO:0007179 TGF-beta receptor signaling pathway	Recent reviews emphasize genetic plus environmental regulation of fetal heart development; single-cell/machine-learning studies also point to pathway disruption across CHD subtypes (zubrzycki2024cardiacdevelopmentand pages 25-26, ma2024machinelearningin pages 2-3)
Cell types involved	Key implicated cardiac cell populations include cardiomyocytes, endothelial cells, cardiac fibroblasts, neural crest-derived cells, second heart field progenitors, and epicardial progenitor cells.	CL:0000746 cardiac muscle cell; CL:0000115 endothelial cell; CL:0000057 fibroblast; CL:0000349 neural crest cell; CL:0002494 epicardial cell	2024 single-cell analysis examined 73,296 cardiomyocytes, 35,673 endothelial cells, and 21,034 fibroblasts across CHD-related conditions (ma2024machinelearningin pages 2-3, ma2024machinelearningin pages 21-23)
Anatomy/localization	Primary structures affected include cardiac septa, ventricular chambers, atria, outflow tract, great arteries, valves, coronary arteries, aorta, and conduction system.	UBERON:0000948 heart; UBERON:0002084 cardiac ventricle; UBERON:0002079 atrium; UBERON:0001981 cardiac septum; UBERON:0003129 outflow tract; UBERON:0000947 aorta	Reviews of chromosomal CHD and imaging emphasize abnormalities across chambers, valves, coronary arteries, aorta, and conduction tissue (salzillo2024cardiovasculardiseasesin pages 13-15)
Imaging/clinical diagnostics	Core diagnostics include echocardiography, fetal echocardiography, genetic testing, and cardiovascular magnetic resonance (CMR) for detailed anatomy, hemodynamics, and postoperative follow-up.	fetal echocardiography; cardiac MRI/CMR	CMR provides high-detail anatomy, chamber volumes, flow, tissue characterization, and postoperative assessment without ionizing radiation; prenatal diagnosis relies heavily on fetal echocardiography (salzillo2024cardiovasculardiseasesin pages 13-15)
Treatment/interventions	Management includes surgical repair/palliation, catheter-based intervention, balloon valvuloplasty, staged Norwood/Glenn/Fontan procedures for HLHS, medications for heart failure/arrhythmia/hemodynamics, implantable defibrillators in selected cases, and heart transplantation for severe disease.	NCIT: Cardiac Surgical Procedure; NCIT: Catheterization; NCIT: Balloon Valvuloplasty; NCIT: Fontan Procedure; NCIT: Norwood Procedure; NCIT: Glenn Procedure; NCIT: Heart Transplantation; NCIT: Implantable Cardioverter Defibrillator	Recent summaries note surgery as highest-risk/highest-cost, catheter procedures as resource-intensive, and lifelong medication burden; severe cases may need transplant or ICDs (ma2024machinelearningin pages 2-3, salzillo2024cardiovasculardiseasesin pages 13-15)
Outcomes/prognosis	Mortality and complication burden remain substantial despite improved survival. SCD is a major late complication, especially in complex lesions and repaired TOF.	HP:0001644 Sudden cardiac death; HP:0011675 Arrhythmia	SCD incidence in CHD cohorts reported at 0.28–2.7% annually; TOF 0.9–1.5% annually; SCD may account for up to 25% of deaths in CHD populations (salzillo2024cardiovasculardiseasesin pages 10-11)
Omics and advanced models	Emerging CHD research uses single-cell transcriptomics, RNA-seq, metabolomics, machine learning, iPSC-derived cardiomyocytes, CRISPR rescue experiments, and organoid systems.	single-cell RNA-seq; metabolomics; iPSC-CM disease model; CRISPR/Cas9	iPSC-CM models identified mitochondrial dysfunction/oxidative stress in HLHS and showed rescue of MYH6-R443P dysfunction by gene editing; metabolomics studies linked perioperative metabolites to mortality, AKI, and neurologic outcomes (pushpan2024ipscderivedcardiomyocytesas pages 10-11, meggiolaro2024metabolomicprofilingof pages 4-5, ma2024machinelearningin pages 21-23)
Current real-world studies/trials	Active real-world implementation includes national/regional registries, transition programs, arrhythmia imaging studies, prenatal multi-omics studies, device studies, and lifecycle CHD registries.	ClinicalTrials.gov: NCT02258724, NCT06611787, NCT06705543, NCT07425132, NCT07559253	Beijing Anzhen lifecycle registry plans 100,000 patients with long-term follow-up; other active studies include adult CHD registry and fetal complex CHD multi-omics investigation (NCT06611787 chunk 1)
Evidence caveats	CHD is highly heterogeneous; many estimates pool diverse lesions, ages, and syndromic/isolated cases. Diagnostic yields vary by cohort selection and testing strategy; some cited evidence comes from reviews or registry descriptions rather than lesion-specific randomized trials.	Evidence annotation recommended: human clinical, registry, review, model organism, in vitro	Several excerpts note limited access due to socioeconomic disparities, small sample sizes in omics studies, and imperfect sensitivity of dysmorphology-based screening (salzillo2024cardiovasculardiseasesin pages 13-15, meggiolaro2024metabolomicprofilingof pages 4-5, helm2021geneticevaluationof pages 1-2)

Table: This table condenses the conversation’s established congenital heart disease facts into ontology-ready domains for a knowledge base. It highlights identifiers, phenotypes, genes, pathways, anatomy, diagnostics, treatments, and key evidence caveats with citeable context IDs.

1. Disease information

Definition and classification

CHD comprises abnormalities of cardiac chambers, septa, valves, coronary arteries, aorta, great arteries, venous connections, and/or conduction-related anatomy caused by abnormal cardiovascular morphogenesis. Clinically useful groupings include:

Septal lesions: ventricular septal defect (VSD), atrial septal defect, atrioventricular septal defect.
Left-sided obstruction: bicuspid aortic valve, valvar/subvalvar aortic stenosis, coarctation, interrupted aortic arch, HLHS.
Right-sided obstruction: pulmonary stenosis/atresia and tricuspid atresia.
Conotruncal defects: TOF, truncus arteriosus, TGA, double-outlet right ventricle.
Anomalous connections: total/partial anomalous pulmonary venous connection.
Single-ventricle and laterality disorders: unbalanced atrioventricular canal, heterotaxy, and other functionally univentricular hearts.

Identifiers and synonyms

MONDO: MONDO:0005453, congenital heart disease. Related umbrella term: MONDO:0019512, congenital heart malformation; syndromic CHD: MONDO:0100614.
MeSH: Heart Defects, Congenital.
ICD-10-CM: principally Q20–Q28; Q20–Q26 cover congenital malformations of cardiac chambers/connections, septa, valves, great arteries, and great veins.
ICD-11: lesion-specific entities reside under congenital anomalies of the circulatory system; a single code should not replace lesion-level coding.
OMIM/Orphanet: no single OMIM entry adequately represents all CHD. OMIM and Orphanet are most appropriately attached to the causal syndrome or lesion–gene disorder, such as 22q11.2 deletion syndrome, Holt–Oram syndrome, or NKX2-5-related disease.
Synonyms: congenital heart defect, congenital cardiac defect, congenital cardiovascular malformation, congenital heart anomaly, congenital cardiac malformation.

The definition, ontology identifiers, and pooled epidemiology are aggregated disease-level knowledge. Patient-specific lesion, imaging, procedure, and genotype data are ordinarily derived from EHRs, registries, or cohorts and should remain provenance-linked rather than being treated as universal disease facts.

2. Etiology, risk, protection, and gene–environment interaction

Genetic causal factors

CHD has a mixed architecture: aneuploidies and pathogenic copy-number variants (CNVs), highly penetrant single-gene variants, incompletely penetrant inherited variants, de novo variants, oligogenic combinations, and common polygenic susceptibility all occur. Earlier severe-infant cohorts attributed approximately 8–10% to aneuploidy, 3–5% to single-gene disease, and a variable 3–25% to pathogenic CNVs, depending strongly on ascertainment and technology. (helm2021geneticevaluationof pages 1-2)

Major chromosomal/syndromic contributors include trisomies 21, 18, and 13; monosomy X; 22q11.2 deletion; Williams–Beuren syndrome; CHARGE; and RASopathies such as Noonan syndrome. Trisomy 21 is especially associated with atrioventricular septal defects; 22q11.2 deletion/TBX1 with conotruncal and aortic-arch defects; Turner syndrome with bicuspid aortic valve and coarctation; and Williams syndrome with supravalvar aortic stenosis. A 2024 NICU study found 22q11.2 deletion and CHARGE most often, followed by Noonan and Williams syndromes. (salzillo2024cardiovasculardiseasesin pages 13-15, peterlin2024thegeneticarchitecture pages 10-12)

High-priority developmental genes include NKX2-5, GATA4, GATA6, TBX1, TBX5, TBX20, NOTCH1, JAG1, KMT2D, CHD7, ELN, PTPN11, RAF1, ZIC3, NODAL, GDF1, MMP21, MYH6, ACTC1, TAB2, TFAP2B, and GJA1. Open Targets ranks NKX2-5 and GATA4 among the strongest general CHD associations and also supports TBX20, GDF1, MYH6, TFAP2B, TAB2, NODAL, MMP21, GJA1, and TBX1. These associations are lesion- and syndrome-dependent and should not be interpreted as a validated universal “CHD panel.” (OpenTargets Search: congenital heart disease)

Variant classes include germline missense, nonsense, frameshift, splice, regulatory, and structural variants. Pathogenic alleles are usually rare or absent in population databases; no meaningful single carrier frequency exists for heterogeneous CHD. Classification should follow ACMG/AMP criteria using segregation, de novo status, population frequency, functional evidence, and phenotype specificity. A 2024 familial study reported heterozygous BMP4 NM_001202.6:c.318T>G, p.(Tyr106*), cosegregating with CHD; mutant BMP4 failed to activate NKX2-5 and TBX20 reporter expression. This is promising single-family evidence, not justification for treating all rare BMP4 variants as pathogenic. (salzillo2024cardiovasculardiseasesin pages 13-15)

Environmental and maternal factors

An umbrella review covering 56 systematic reviews, 369 meta-analyses, and 949 component studies found the strongest reported non-genetic associations for maternal pregestational/gestational diabetes, obesity—particularly moderate or severe obesity—gestational hypertension, antidepressant exposure including SSRIs/SNRIs, harmful chemicals, renovation materials, noise exposure, and reproductive/family-history variables. Only 16% of the included systematic reviews were rated “moderate” by AMSTAR2, so association does not necessarily establish causation. (zubrzycki2024cardiacdevelopmentand pages 25-26)

Other recognized or suspected risks include maternal phenylketonuria, rubella infection, retinoic acid, valproate, lithium for selected lesions, smoking, alcohol, air pollution, fever, advanced parental age, assisted reproduction, and occupational solvent/pesticide exposure. Absolute risk generally remains low for any single exposure, and confounding by indication is important for medication studies.

Protective factors and prevention-relevant modifiers

Periconceptional folic acid/multivitamin use is associated with lower risk in several observational syntheses, but effect size varies by lesion and study design. The evidence supports adequate folate for general congenital-anomaly prevention, not a guarantee against CHD. Glycemic optimization before conception and during early pregnancy is one of the clearest modifiable strategies for women with diabetes. Avoidance of rubella through pre-pregnancy immunization, teratogen review, smoking/alcohol avoidance, healthy weight, and treatment of maternal phenylketonuria are also rational primary-prevention measures. (zubrzycki2024cardiacdevelopmentand pages 25-26)

No reproducible “protective CHD allele” is established for routine clinical use. Modifier alleles and background polygenic burden probably influence penetrance and severity, but remain research-level.

Gene–environment interaction

The biologically plausible model is that maternal metabolic or toxic exposures alter oxidative stress, one-carbon metabolism, chromatin state, signaling, or neural-crest/second-heart-field development in an embryo whose genetic background changes susceptibility. Folate-pathway variants and maternal folate are a frequently studied example, but robust lesion-specific G×E estimates are limited. Thus, exposure history and molecular diagnosis should be represented as interacting evidence rather than mutually exclusive causes.

3. Phenotypes

Phenotype	Type, onset, course, and impact	Suggested HPO term
VSD	Structural sign; prenatal/neonatal. Small lesions may close spontaneously; large lesions cause early heart failure, poor feeding, and growth failure.	HP:0001629
Atrial septal defect	Structural sign; often asymptomatic in childhood, with later right-heart dilation, exercise limitation, or atrial arrhythmia.	HP:0001631
Atrioventricular septal defect	Structural sign; neonatal/infant heart failure and pulmonary overcirculation; severity variable and often syndromic.	HP:0006695
TOF	Cyanotic structural defect; neonatal-to-infant onset depending on obstruction; episodic hypercyanotic spells may occur before repair.	HP:0001636; cyanosis HP:0000961
TGA	Critical neonatal cyanosis, generally severe and rapidly progressive without mixing and intervention.	HP:0001651
Coarctation/aortic obstruction	May present after ductal closure with shock, weak femoral pulses, differential blood pressure, or later hypertension.	HP:0001680; hypertension HP:0000822
HLHS	Critical neonatal duct-dependent systemic circulation; severe, staged-palliation or transplant pathway.	HP:0004383
Single-ventricle physiology	Structural/physiological state leading to chronic cyanosis before palliation and lifelong Fontan-associated morbidity after palliation.	HP:0004762
Heart failure	Symptom/sign complex: tachypnea, feeding difficulty, diaphoresis, hepatomegaly, poor growth; may recur in adulthood.	HP:0001635
Arrhythmia/conduction disease	Episodic or progressive; postoperative scars, chamber dilation, and specific genotypes contribute.	HP:0011675; conduction abnormality HP:0031546
Pulmonary hypertension	Progressive vascular complication of unrepaired shunts, late repair, or complex physiology.	HP:0002092
Exercise intolerance/fatigue	Common functional phenotype in moderate/complex CHD; affects school, work, participation, and quality of life.	HP:0003546; fatigue HP:0012378
Growth failure	Most evident in infants with heart failure/cyanosis; nutritional and perioperative contributors coexist.	HP:0001508
Neurodevelopmental impairment	Variable deficits in motor, language, attention, executive function, and academic achievement, particularly after critical neonatal CHD.	HP:0012758; HP:0001263

Frequencies cannot be assigned across “CHD” as a whole because each lesion defines a different denominator. Severity ranges from clinically silent to lethal without neonatal intervention. Quality-of-life impact reflects not only anatomy but also surgeries, exercise capacity, neurodevelopment, mental health, socioeconomic access, and transition to adult care.

4. Genetic and molecular information

Inheritance and penetrance

Inheritance may be autosomal dominant, autosomal recessive, X-linked, chromosomal, or multifactorial. Dominant developmental-gene disorders often show incomplete penetrance and variable expressivity; recessive laterality/cilia disorders are enriched in consanguineous populations; ZIC3 causes X-linked heterotaxy in some families. De novo variants are important in severe sporadic/syndromic CHD. Parental and germline mosaicism can produce recurrence despite negative parental blood testing. Anticipation is not a general feature. Founder variants exist for particular syndromes/populations, but there is no single CHD founder allele or carrier frequency.

Functional mechanisms

Transcription-factor haploinsufficiency: NKX2-5, GATA4/6, TBX5/20, and TBX1 disturb specification, chamber formation, septation, or conduction-system development.
Signaling defects: NOTCH/JAG1, BMP/TGF-β, WNT, RAS–MAPK, and NODAL pathways alter progenitor fate, endocardial cushion formation, outflow tract patterning, valve development, or left–right asymmetry.
Chromatin/epigenetic regulation: CHD7, KMT2D, and other chromatin regulators change developmental gene accessibility; pathogenic mechanisms are usually germline and developmental rather than somatic.
Contractile/cytoskeletal dysfunction: MYH6, ACTC1, MYH7, MYBPC3, and TNNT2 can connect structural malformation with myocardial dysfunction.
Cilia/laterality: ZIC3, NODAL, GDF1, MMP21, and ciliary genes disrupt left–right organizer function and produce heterotaxy.

Routine databases may label variants pathogenic, likely pathogenic, VUS, likely benign, or benign. VUS should not guide irreversible surgery, prenatal decision-making, or predictive testing. Somatic variants are not a principal established cause of ordinary CHD, although somatic mosaicism is biologically plausible and increasingly detectable with deep sequencing.

Chromosomal abnormalities

Clinically important abnormalities include whole-chromosome aneuploidies and recurrent CNVs such as 22q11.2 deletion and 7q11.23 deletion. Structural rearrangements, mosaic aneuploidy, and nonrecurrent CNVs also occur. CMA therefore remains valuable even when examination suggests isolated CHD: one infant cohort found diagnostic CMA in 6.5% of apparently isolated cases. (helm2021geneticevaluationof pages 1-2)

5. Environmental information

The most consequential exposure window is early organogenesis, approximately gestational weeks 3–8. Maternal diabetes can expose the embryo to hyperglycemia, oxidative stress, and altered signaling; retinoids and antiepileptics can perturb transcriptional programs; rubella can produce a congenital infection syndrome with patent ductus arteriosus and pulmonary-artery stenosis. Air pollution, solvents, pesticides, smoking, and alcohol have epidemiologic associations of varying consistency. (zubrzycki2024cardiacdevelopmentand pages 25-26)

CHD is not infectious or transmissible. Rubella is an upstream teratogenic infection, not an infection acquired from the affected infant. Exercise by the mother is not established as a lesion-specific protective intervention, although general preconception health is beneficial.

6. Mechanism and pathophysiology

Upstream developmental chain

Trigger: pathogenic variant/CNV/aneuploidy, maternal exposure, or combined susceptibility.
Developmental perturbation: altered chromatin, transcription-factor dosage, WNT/BMP/NOTCH/TGF-β/RAS–MAPK/NODAL signaling, metabolism, or ciliary left–right patterning.
Cellular effect: abnormal proliferation, migration, differentiation, epithelial-to-mesenchymal transition, neural-crest contribution, myocardialization, or apoptosis.
Morphogenetic failure: defective looping, septation, endocardial cushions, valves, outflow tract, arch, venous return, or ventricular growth.
Clinical physiology: left-to-right shunt, obstruction, mixing/cyanosis, regurgitation, or single-ventricle circulation.
Downstream remodeling: pressure/volume load, hypoxemia, neurohormonal activation, endothelial dysfunction, pulmonary vascular remodeling, hypertrophy, fibrosis, arrhythmia, and heart failure.

Suggested GO terms include heart development GO:0007507, heart looping GO:0001947, cardiac septum morphogenesis GO:0060916, Notch signaling GO:0007219, BMP signaling GO:0030509, Wnt signaling GO:0016055, epithelial-to-mesenchymal transition GO:0001837, neural-crest-cell migration GO:0001755, mitochondrial respiratory-chain complex assembly GO:0033108, and response to oxidative stress GO:0006979.

Relevant Cell Ontology concepts include cardiomyocyte CL:0000746, endothelial cell CL:0000115, fibroblast CL:0000057, neural crest cell CL:0000333/ontology release-dependent, endocardial cell, epicardial cell CL:0002494, and cardiac progenitor cell.

Molecular profiling and advanced technologies

A 2024 single-cell/machine-learning analysis used 21,034 fibroblasts, 73,296 cardiomyocytes, and 35,673 endothelial cells. Candidate cell-type signatures included FOXO3 in fibroblasts; TMTC1, ART3, ARHGAP24, SHROOM3, and XIST in cardiomyocyte analyses; and COL25A1, NFIB, and KLF7 in endothelial analyses. These are computational biomarkers requiring independent biological and prospective clinical validation. (ma2024machinelearningin pages 2-3, ma2024machinelearningin pages 21-23)

Patient-specific iPSC cardiomyocytes are being used to model TOF, single-ventricle disease, and HLHS. HLHS models have shown mitochondrial dysfunction, oxidative stress, abnormal unfolded-protein responses, sarcomere defects, and impaired contractility. CRISPR correction of MYH6-R443P rescued sarcomeric and contractile phenotypes in vitro; sildenafil and tauroursodeoxycholic acid emerged as experimental pathway-directed candidates, not established HLHS treatments. (pushpan2024ipscderivedcardiomyocytesas pages 10-11)

Perioperative metabolomics is another emerging application. A 2024 systematic review included seven studies and 509 children and found associations of amino-acid/fatty-acid-related profiles with mortality, acute kidney injury, and neurologic outcomes, but heterogeneity and small samples preclude clinical biomarker adoption. One included neonatal dataset sampled 149 infants around cardiopulmonary bypass. (meggiolaro2024metabolomicprofilingof pages 4-5)

7. Anatomical structures affected

The primary organ is the heart (UBERON:0000948), including atria, ventricles, interatrial/interventricular septa, endocardial cushions, valves, myocardium, endocardium, epicardium, and conduction system. Great-vessel sites include the aorta UBERON:0000947, pulmonary trunk/arteries, arterial duct, aortic arch, systemic veins, and pulmonary veins. Laterality can be normal, mirror-imaged, or discordant/asymmetric in heterotaxy.

Secondary organ injury involves lungs/pulmonary vasculature, liver and lymphatics after Fontan circulation, kidneys after low output or bypass, brain through fetal dysmaturation/hypoxemia/embolism, and intestine through low perfusion. Subcellular compartments include nucleus/chromatin, primary cilia, mitochondria, sarcomere, intercellular junctions, and endoplasmic reticulum. Chromosomal disease can additionally involve immune, endocrine, craniofacial, renal, skeletal, auditory, and neurodevelopmental systems. (salzillo2024cardiovasculardiseasesin pages 13-15, pushpan2024ipscderivedcardiomyocytesas pages 10-11)

8. Temporal development and natural history

CHD originates in embryogenesis and is therefore congenital, even when diagnosis is delayed. Critical duct-dependent lesions often deteriorate acutely when the ductus arteriosus closes during the first days of life. Large shunts tend to produce heart failure over weeks as pulmonary vascular resistance falls. Small septal defects may remain stable or close spontaneously.

Surgery usually repairs or palliates anatomy but does not remove lifelong risk. Intermediate and late stages may include residual shunts/obstruction, valve dysfunction, ventricular failure, aortopathy, pulmonary hypertension, arrhythmia, endocarditis, thrombosis, protein-losing enteropathy, plastic bronchitis, Fontan-associated liver disease, and transplant consideration. There is no general spontaneous remission category; lesion-specific closure of small defects is the main exception. Critical intervention windows include prenatal recognition, delivery planning, prostaglandin initiation before ductal closure, neonatal repair/palliation, and structured adolescent transition.

9. Inheritance and population epidemiology

CHD affects approximately 1% of live-born infants in commonly used definitions; ascertainment, inclusion of mild defects, prenatal loss, and access to echocardiography drive geographic differences. (helm2021geneticevaluationof pages 1-2, peterlin2024thegeneticarchitecture pages 10-12)

Sex distribution is lesion-specific rather than uniformly male or female: left-sided obstructive lesions and TGA are more common in males, while atrial septal defects and patent ductus arteriosus are often more common in females. Ethnic/racial differences partly reflect genetic background but also maternal risk, prenatal detection, termination practices, socioeconomic conditions, referral, and registry completeness. Resource-limited regions experience disproportionate preventable mortality because fetal diagnosis, pediatric surgery, catheter care, and lifelong specialist follow-up are less available. (salzillo2024cardiovasculardiseasesin pages 15-16, salzillo2024cardiovasculardiseasesin pages 13-15)

Empiric recurrence after an isolated nonsyndromic CHD is usually a few percent but varies by lesion and family history; a known Mendelian or chromosomal diagnosis replaces the empirical estimate with disorder-specific counseling. Incomplete penetrance and variable expressivity are common. Consanguinity increases recessive forms, particularly laterality/cilia disorders.

10. Diagnostics

Clinical and imaging approach

Prenatal: screening obstetric ultrasound with outflow-tract views; fetal echocardiography for abnormal screening, family history, maternal diabetes/teratogen exposure, increased nuchal translucency, fetal genetic abnormality, or extracardiac malformation. Prenatal CMA and sequencing are considered when CHD is detected, particularly with extracardiac findings.
Newborn: physical examination, pre-/postductal oxygen saturation, pulse assessment, blood pressure when indicated, and universal pulse-oximetry screening for critical CHD where implemented. A normal screen does not exclude coarctation or noncyanotic disease.
Definitive anatomy: transthoracic echocardiography is first line; transesophageal/intracardiac echo supports interventions.
CMR: quantifies chamber volumes, ventricular function, flow, shunts, fibrosis, edema, and complex postoperative anatomy without ionizing radiation. Limitations include expertise, scan time, device compatibility, breath holding, and anesthesia in younger children.
CT/catheterization: CT offers rapid high-resolution vascular/coronary anatomy at the cost of radiation/contrast; catheterization supplies invasive hemodynamics and permits intervention.
Functional surveillance: ECG, ambulatory monitoring, exercise testing, cardiopulmonary exercise testing, and laboratory markers such as BNP/NT-proBNP in selected heart-failure contexts.

Prenatal screening, fetal echocardiography, genomic testing, postoperative monitoring, and molecular autopsy are emphasized for chromosomal/sudden-death-risk CHD. (salzillo2024cardiovasculardiseasesin pages 13-15)

Genetic testing

A practical sequence is: detailed three-generation pedigree and dysmorphology/extracardiac assessment; rapid aneuploidy testing or karyotype when suspected; CMA for severe/syndromic CHD; then phenotype-guided panel or preferably trio WES/WGS when CMA is nondiagnostic. FISH remains useful for targeted confirmation/family studies but should not substitute for genome-wide CNV testing. Mitochondrial testing is indicated only where phenotype supports it; repeat-expansion testing is not routine CHD testing.

In 440 infants, CMA yield was 14.6% and combined testing yield 17%; LV outflow-tract obstruction had 15.8% yield among apparently isolated cases. In a 2024 cohort of 188 neonates, 17% received one of 22 genetic diagnoses, CMA yield was 10.1%, and VUS were found in 4.8%. Reported WGS yield reached 27% in a cited implementation, with management changed in 62% of diagnosed cases. (helm2021geneticevaluationof pages 1-2, peterlin2024thegeneticarchitecture pages 10-12)

RNA-seq, methylation episignatures, optical genome mapping, long-read sequencing, proteomics, and metabolomics remain second-line or research tools. They are useful for splice confirmation, cryptic structural variation, syndrome resolution, and biomarker discovery, but are not substitutes for anatomic diagnosis.

Differential diagnosis

Important alternatives include persistent pulmonary hypertension of the newborn, neonatal sepsis, respiratory disease, cardiomyopathy, arrhythmia/channelopathy without malformation, innocent murmur, acquired valvular disease, and extracardiac causes of cyanosis or failure to thrive. Echocardiographic anatomy distinguishes these from structural CHD.

11. Outcomes and prognosis

Prognosis is lesion-, era-, center-, genotype-, comorbidity-, and access-dependent; one pooled “five-year survival” is misleading. Small isolated defects can confer normal lifespan. Critical/single-ventricle disease has substantial neonatal risk and chronic morbidity despite successful palliation. Trisomies 13 and 18 generally carry worse early prognosis than trisomy 21, while outcomes within every genetic category remain heterogeneous. (salzillo2024cardiovasculardiseasesin pages 15-16)

Important adverse prognostic factors include complex anatomy, single-ventricle physiology, ventricular dysfunction, pulmonary hypertension, cyanosis, arrhythmia, residual hemodynamic lesions, multiple sternotomies, extracardiac/genetic disease, prematurity/low birth weight, renal injury, socioeconomic disadvantage, and interrupted specialist care. In CHD cohorts, SCD incidence of 0.28–2.7% annually and TOF estimates of 0.9–1.5% annually underscore the need for lifelong rhythm and hemodynamic surveillance. (salzillo2024cardiovasculardiseasesin pages 10-11)

Morbidity includes exercise limitation, heart failure, stroke/thromboembolism, endocarditis, repeat procedures, pregnancy risk, neurodevelopmental disability, anxiety/depression, educational/employment effects, and caregiver burden. Quality of life can remain good despite complex anatomy but is generally worse with functional limitation, repeated intervention, pain/trauma, and poor access. Lesion-specific PROMIS, PedsQL, SF-36, EQ-5D, and disease-specific adult-CHD instruments should be stored with age and anatomy rather than pooled indiscriminately.

12. Treatment

Lesion-directed intervention

Septal defects/ductus: observation when small; transcatheter closure or surgical repair for significant shunt, chamber dilation, symptoms, or selected endocarditis risk.
Valve/outflow obstruction: balloon valvuloplasty, catheter stenting, surgical valvotomy/reconstruction, or valve replacement depending on anatomy.
Coarctation: surgery or catheter stent, with lifelong hypertension/aortic surveillance.
TGA: prostaglandin E1 to maintain ductal patency, balloon atrial septostomy when mixing is inadequate, and neonatal arterial-switch operation.
TOF: complete repair, later pulmonary-valve replacement when indicated, and rhythm surveillance.
HLHS/single ventricle: prostaglandin stabilization followed by staged Norwood, bidirectional Glenn, and Fontan palliation, hybrid strategies, transplant, or individualized comfort care.

Suggested NCIt concepts include Cardiac Surgical Procedure, Cardiac Catheterization, Balloon Valvuloplasty, Norwood Procedure, Glenn Procedure, Fontan Procedure, Heart Transplantation, and Implantable Cardioverter Defibrillator. Current modalities span open surgery, catheterization, balloon valvuloplasty, staged single-ventricle operations, drug therapy, ICDs, and transplant. (salzillo2024cardiovasculardiseasesin pages 13-15, ma2024machinelearningin pages 2-3)

Pharmacotherapy and supportive care

Drugs generally manage physiology or complications rather than correcting the malformation: prostaglandin E1 for duct-dependent circulation; diuretics and selected ACE inhibitors/beta blockers for heart failure; pulmonary vasodilators for carefully characterized pulmonary vascular disease; antiarrhythmics and anticoagulants/antiplatelets for indicated rhythm/thrombotic risks; antibiotics for established infection and narrowly defined endocarditis prophylaxis. No universal CHD pharmacogenomic algorithm exists.

Nutritional support, developmental surveillance, neuropsychology, exercise prescription/cardiac rehabilitation, dental care, reproductive counseling, pregnancy management, and structured transition to adult congenital cardiology are integral. Physical activity should be individualized; blanket restriction is often harmful.

Experimental and precision approaches

CRISPR correction, gene replacement, RNA therapeutics, regenerative cell therapy, engineered valves, and tissue-engineered conduits remain experimental for most CHD. iPSC rescue of MYH6-associated dysfunction is proof of mechanism, not clinical gene therapy. (pushpan2024ipscderivedcardiomyocytesas pages 10-11)

Examples of current real-world research include the recruiting lifecycle registry NCT06611787, designed for approximately 100,000 patients across more than 20 hospitals with fetal-to-adult data, biospecimens, reoperation, and long-term survival outcomes; the Swiss adult registry NCT02258724; fetal complex-CHD multi-omics NCT06705543; and personalized non-invasive electrocardiographic imaging NCT07425132. The Beijing registry began recruitment in February 2024 and plans extended longitudinal follow-up. (NCT06611787 chunk 1)

13. Prevention

Primary: preconception diabetes and phenylketonuria control; healthy maternal weight; folic acid according to public-health guidance; rubella vaccination before pregnancy; medication/teratogen review; avoidance of smoking, alcohol, and illicit drugs; occupational/environmental protection. These measures reduce risk but cannot prevent most CHD. (zubrzycki2024cardiacdevelopmentand pages 25-26)
Secondary: prenatal ultrasound/fetal echocardiography, prenatal genetics, planned delivery at an appropriate center, newborn examination and pulse oximetry, prompt echocardiography, and cascade testing when a familial diagnosis is found.
Tertiary: timely repair/palliation, residual-lesion and arrhythmia surveillance, vaccination, dental hygiene, selective endocarditis prophylaxis, exercise/weight management, neurodevelopmental services, contraception/pregnancy counseling, and uninterrupted congenital-cardiology follow-up.

Preimplantation or prenatal genetic testing is feasible when a pathogenic familial variant or chromosomal rearrangement is known. It is much less informative for unexplained multifactorial CHD. Genetic counseling must discuss variable expressivity, incomplete penetrance, residual risk, and the difference between detecting a genotype and predicting lesion severity.

14. Other species and natural disease

Naturally occurring septal defects, patent ductus arteriosus, pulmonic stenosis, subaortic stenosis, TOF, valve dysplasia, and vascular-ring anomalies occur in dogs, cats, horses, cattle, and other vertebrates. Domestic dog (NCBI Taxon 9615) and cat (9685) are the principal companion-animal contexts; breed predispositions suggest heritable susceptibility, but breed–variant claims should be taken from OMIA/VBO records for the precise lesion rather than generalized to CHD.

Veterinary CHD is non-zoonotic and not cross-species transmissible. Comparative relevance derives from conserved cardiac development, hemodynamics, and orthologs—not infection. Spontaneous animal cases can better model anatomical scale and catheter/surgical procedures than rodents, although breed structure and incomplete genotyping limit direct human inference.

15. Model organisms and experimental systems

Mouse, Mus musculus (Taxon 10090): knockout/knock-in, conditional, and chromosomal-synteny models reproduce septation, valve, outflow-tract, arch, and laterality defects. A 2024 Down-syndrome model showed that three copies of Dyrk1a impaired cardiomyocyte proliferation and mitochondrial respiration; restoring two copies rescued septation, and prenatal DYRK1A inhibition partially reversed transcriptional abnormalities. This is strong model-organism mechanistic evidence but not yet a safe prenatal human therapy.
Zebrafish, Danio rerio (Taxon 7955): rapid, transparent embryos and efficient CRISPR permit high-throughput assessment of looping, chamber patterning, contractility, and laterality. Limitations include a two-chamber heart and important differences in septation and placental/maternal physiology.
Human iPSC cardiomyocytes: preserve patient genotype and permit isogenic CRISPR controls, functional phenotyping, and drug screening. They incompletely reproduce mature myocardium, multicellular anatomy, loading, circulation, and whole-organ morphogenesis. Recent CHD models have combined WES, RNA-seq, and single-cell transcriptomics. (pushpan2024ipscderivedcardiomyocytesas pages 10-11)
Cardiac organoids and engineered tissues: model interactions among myocardium, endocardium, epicardium, vascular cells, and foregut-like tissues. They are promising for developmental toxicology and spatial multi-omics but currently lack complete four-chamber anatomy, mature conduction, physiologic perfusion, and maternal–placental context.
Chick and Xenopus: valuable for neural-crest migration, looping, microsurgery, and lineage tracing; translation is constrained by species-specific anatomy.

Recent developments and expert interpretation, 2023–2024

Broader genomic testing: recent neonatal data support CMA plus sequencing rather than restricting testing to obviously dysmorphic infants. Expert interpretation is that phenotypic examination alone lacks sufficient sensitivity; nevertheless, the lower yield in isolated CHD means counseling should anticipate nondiagnostic and VUS results. (helm2021geneticevaluationof pages 1-2, peterlin2024thegeneticarchitecture pages 10-12)
Cell-resolved molecular maps: single-cell sequencing and machine learning now resolve cardiomyocyte, endothelial, and fibroblast signatures, but retrospective classification performance is not equivalent to a clinically validated biomarker. (ma2024machinelearningin pages 2-3, ma2024machinelearningin pages 21-23)
Patient-specific disease modeling: iPSC/CRISPR systems can test causality and rescue individual cellular defects. Their immediate application is mechanism and drug prioritization rather than clinical genome editing. (pushpan2024ipscderivedcardiomyocytesas pages 10-11)
Metabolomic risk stratification: perioperative signatures may help forecast kidney, neurologic, and mortality outcomes, but current evidence is too heterogeneous and small for routine use. (meggiolaro2024metabolomicprofilingof pages 4-5)
Lifecycle registries and digital surveillance: very large registries, wearables, and non-invasive electrical imaging aim to connect fetal anatomy, genotype, operations, adult complications, and patient-reported outcomes. Equity and international standardization remain major implementation challenges. (salzillo2024cardiovasculardiseasesin pages 15-16, NCT06611787 chunk 1)

Selected exact abstract statements and source metadata

Helm et al., Genes, published August 2021, DOI: https://doi.org/10.3390/genes12081244: “Cumulative evidence provides a rationale for comprehensive, standardized genetic evaluation in infants with severe CHDs regardless of lesion or extracardiac anomalies.” The study reported CMA yield of 14.6% and overall genetic-testing yield of 17%. (helm2021geneticevaluationof pages 1-2)
Peterlin et al., Life, published September 2024, DOI: https://doi.org/10.3390/life14091118: “We established the genetic diagnosis of 22 distinct syndromes in 17% (32/188) of neonates.” (peterlin2024thegeneticarchitecture pages 10-12)
Ma et al., Life, published August 2024, DOI: https://doi.org/10.3390/life14081032: the study states that it analyzed “21,034 cardiac fibroblasts, 73,296 cardiomyocytes, and 35,673 endothelial cells,” illustrating the scale of emerging cell-resolved CHD profiling. (ma2024machinelearningin pages 2-3, ma2024machinelearningin pages 21-23)
Meggiolaro et al., Frontiers in Cardiovascular Medicine, published November 2024, DOI: https://doi.org/10.3389/fcvm.2024.1491046: “Seven studies involving 509 children … were included,” and the authors judged the findings promising but limited by heterogeneous designs and small samples. (meggiolaro2024metabolomicprofilingof pages 4-5)

PMIDs were not consistently exposed in the retrieved records; DOI URLs are therefore supplied for the principal recent sources rather than risking incorrect PMID assignment. Evidence labels should distinguish human cohorts/registries, systematic reviews, computational single-cell analyses, in-vitro iPSC experiments, and model-organism studies. The principal knowledge-base caveat is that CHD is a heterogeneous umbrella category: lesion-, genotype-, age-, and procedure-specific facts should be stored separately whenever possible.

References

(helm2021geneticevaluationof pages 1-2): Benjamin M. Helm, Benjamin J. Landis, and Stephanie M. Ware. Genetic evaluation of inpatient neonatal and infantile congenital heart defects: new findings and review of the literature. Genes, 12:1244, Aug 2021. URL: https://doi.org/10.3390/genes12081244, doi:10.3390/genes12081244. This article has 35 citations.
(peterlin2024thegeneticarchitecture pages 10-12): Ana Peterlin, Sara Bertok, Karin Writzl, Luca Lovrečić, Aleš Maver, Borut Peterlin, Maruša Debeljak, and Gregor Nosan. The genetic architecture of congenital heart disease in neonatal intensive care unit patients—the experience of university medical centre, ljubljana. Life, 14:1118, Sep 2024. URL: https://doi.org/10.3390/life14091118, doi:10.3390/life14091118. This article has 3 citations.
(salzillo2024cardiovasculardiseasesin pages 10-11): Cecilia Salzillo, Marco La Verde, Amalia Imparato, Rossella Molitierno, Stefano Lucà, Francesca Pagliuca, and Andrea Marzullo. Cardiovascular diseases in public health: chromosomal abnormalities in congenital heart disease causing sudden cardiac death in children. Medicina, 60:1976, Dec 2024. URL: https://doi.org/10.3390/medicina60121976, doi:10.3390/medicina60121976. This article has 15 citations.
(ma2024machinelearningin pages 2-3): Qinglan Ma, Yu-Hang Zhang, Wei Guo, Kaiyan Feng, Tao Huang, and Yu-Dong Cai. Machine learning in identifying marker genes for congenital heart diseases of different cardiac cell types. Life, 14:1032, Aug 2024. URL: https://doi.org/10.3390/life14081032, doi:10.3390/life14081032. This article has 9 citations.
(OpenTargets Search: congenital heart disease): Open Targets Query (congenital heart disease, 33 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(salzillo2024cardiovasculardiseasesin pages 13-15): Cecilia Salzillo, Marco La Verde, Amalia Imparato, Rossella Molitierno, Stefano Lucà, Francesca Pagliuca, and Andrea Marzullo. Cardiovascular diseases in public health: chromosomal abnormalities in congenital heart disease causing sudden cardiac death in children. Medicina, 60:1976, Dec 2024. URL: https://doi.org/10.3390/medicina60121976, doi:10.3390/medicina60121976. This article has 15 citations.
(zubrzycki2024cardiacdevelopmentand pages 25-26): Marek Zubrzycki, Rene Schramm, Angelika Costard-Jäckle, Jochen Grohmann, Jan F. Gummert, and Maria Zubrzycka. Cardiac development and factors influencing the development of congenital heart defects (chds): part i. International Journal of Molecular Sciences, 25:7117, Jun 2024. URL: https://doi.org/10.3390/ijms25137117, doi:10.3390/ijms25137117. This article has 42 citations.
(ma2024machinelearningin pages 21-23): Qinglan Ma, Yu-Hang Zhang, Wei Guo, Kaiyan Feng, Tao Huang, and Yu-Dong Cai. Machine learning in identifying marker genes for congenital heart diseases of different cardiac cell types. Life, 14:1032, Aug 2024. URL: https://doi.org/10.3390/life14081032, doi:10.3390/life14081032. This article has 9 citations.
(pushpan2024ipscderivedcardiomyocytesas pages 10-11): Chithra K. Pushpan and Subramanyan Ram Kumar. Ipsc-derived cardiomyocytes as a disease model to understand the biology of congenital heart defects. Cells, 13:1430, Aug 2024. URL: https://doi.org/10.3390/cells13171430, doi:10.3390/cells13171430. This article has 4 citations.
(meggiolaro2024metabolomicprofilingof pages 4-5): Leonardo Meggiolaro, Laura Moschino, Matteo Stocchero, Giuseppe Giordano, Vladimiro Vida, Giovanni Di Salvo, and Eugenio Baraldi. Metabolomic profiling of infants undergoing cardiopulmonary bypass and association with clinical outcomes: a systematic review. Frontiers in Cardiovascular Medicine, Nov 2024. URL: https://doi.org/10.3389/fcvm.2024.1491046, doi:10.3389/fcvm.2024.1491046. This article has 4 citations and is from a peer-reviewed journal.
(NCT06611787 chunk 1): A Comprehensive Registry Study of the Whole Life Cycle of Patients With CHD. Beijing Anzhen Hospital. 2024. ClinicalTrials.gov Identifier: NCT06611787
(salzillo2024cardiovasculardiseasesin pages 15-16): Cecilia Salzillo, Marco La Verde, Amalia Imparato, Rossella Molitierno, Stefano Lucà, Francesca Pagliuca, and Andrea Marzullo. Cardiovascular diseases in public health: chromosomal abnormalities in congenital heart disease causing sudden cardiac death in children. Medicina, 60:1976, Dec 2024. URL: https://doi.org/10.3390/medicina60121976, doi:10.3390/medicina60121976. This article has 15 citations.

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Unresolved (possible confabulation)	0
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References weighed for topical relevance	7
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Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Diagnosis

Prevalence

Experimental Models

Animal Models

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Congenital Heart Disease: Comprehensive Disease-Characteristics Report

Executive summary

1. Disease information

Definition and classification

Identifiers and synonyms

2. Etiology, risk, protection, and gene–environment interaction

Genetic causal factors

Environmental and maternal factors

Protective factors and prevention-relevant modifiers

Gene–environment interaction

3. Phenotypes

4. Genetic and molecular information

Inheritance and penetrance

Functional mechanisms

Chromosomal abnormalities

5. Environmental information

6. Mechanism and pathophysiology

Upstream developmental chain

Molecular profiling and advanced technologies

7. Anatomical structures affected

8. Temporal development and natural history

9. Inheritance and population epidemiology

10. Diagnostics

Clinical and imaging approach

Genetic testing

Differential diagnosis

11. Outcomes and prognosis

12. Treatment

Lesion-directed intervention

Pharmacotherapy and supportive care

Experimental and precision approaches

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Recent developments and expert interpretation, 2023–2024

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