Atrioventricular Septal Defect

MONDO:0859565 Pathograph 14 Show in embeddings browser congenital heart disease

Atrioventricular septal defect (AVSD), also called atrioventricular canal defect or endocardial cushion defect, is a congenital cardiac malformation defined by a common atrioventricular junction with deficient atrioventricular septation. The lesion comprises an ostium primum atrial communication and/or an inlet ventricular septal defect together with an abnormal atrioventricular valve — either a single common valve (complete AVSD) or two orifices with a cleft left atrioventricular valve (partial AVSD). AVSD accounts for 4-7% of congenital cardiac malformations and has the tightest association of any congenital heart defect with trisomy 21: it is the commonest heart defect in Down syndrome, and a large share of all AVSD occurs in that context. Developmentally it arises from failure of the atrioventricular mesenchymal complex — historically attributed to the endocardial cushions alone, but now understood to involve the dorsal mesenchymal protrusion and the mesenchymal cap of the primary atrial septum as well. Haemodynamically the common junction produces a large left-to-right shunt with atrioventricular valve regurgitation, causing infantile congestive heart failure and, if unrepaired, irreversible pulmonary vascular obstructive disease. Diagnosis is echocardiographic and treatment is surgical repair in infancy, with long-term survival now approaching 80-88% at 10-25 years and left atrioventricular valve regurgitation the principal driver of reoperation.

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1
Inheritance
9
Pathophys.
7
Phenotypes
14
Pathograph
4
Genes
2
Medical Actions
3
Subtypes
1
Models
1
Deep Research
👪

Inheritance

1
Multifactorial HP:0010983
Most AVSD is multifactorial rather than Mendelian. Trisomy 21 is the single largest contributor, and non-syndromic disease behaves as an oligogenic or polygenic threshold trait in which susceptibility alleles such as CRELD1 raise risk without being sufficient on their own.
oligogenic inheritance
Show evidence (1 reference)
PMID:15096951 SUPPORT Human Clinical
"Mutation of CRELD1 increases susceptibility to AVSD but is not alone sufficient to cause the defect, indicating that AVSD is multigenic"
Establishes the multigenic rather than Mendelian inheritance model.
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Subtypes

3
Complete AVSD (common atrioventricular valve)
A single common atrioventricular valve with both an ostium primum atrial communication and an inlet ventricular septal defect. Presents earliest with heart failure and carries the highest risk of early pulmonary vascular disease.
Show evidence (1 reference)
PMID:32965865 SUPPORT Human Clinical
"complete AVSD features a common AVV, an ostium primum atrial septal defect, and an unrestricted inlet-type ventricular septal defect"
Defines the anatomic components of the complete form.
Partial AVSD (ostium primum ASD with cleft left AV valve)
Two separate atrioventricular valve orifices sharing a common junction, with an ostium primum atrial septal defect and a cleft in the left atrioventricular valve. Presents later than the complete form.
Show evidence (1 reference)
PMID:32965865 SUPPORT Human Clinical
"Partial AVSD typically presents with an ostium primum atrial septal defect, separate AVVs with a common junction, an inlet ventricular septal defect, and a cleft mitral valve."
Defines the anatomic components of the partial form.
Transitional AVSD
Intermediate form with two atrioventricular valve orifices and a restrictive inlet ventricular septal defect, behaving haemodynamically between the partial and complete forms.
Show evidence (1 reference)
PMID:40154545 SUPPORT Human Clinical
"A total of 208 (83.9%) patients had complete (cAVSD), 29 (11.7%) partial (pAVSD), and 11 (4.4%) transitional AVSD (tAVSD)."
Documents transitional AVSD as a recognised third anatomic category in a large surgical series.
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Pathophysiology

9
Atrioventricular Mesenchymal Complex Failure
AVSD originates in failed development of the atrioventricular mesenchymal complex during cardiac septation. Historically this was attributed solely to the endocardial atrioventricular cushions, but animal-model work has since shown that failure of other components — notably the dorsal mesenchymal protrusion, and probably the mesenchymal cap on the leading edge of the primary atrial septum — can produce AVSD in its own right.
endocardial cushion development GO:0003197 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal endocardial cushion development (GO:0003197). GO:0003197 is a biological process from the Gene Ontology. ⚠ ABNORMAL cardiac septum morphogenesis GO:0060411 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cardiac septum morphogenesis (GO:0060411). GO:0060411 is a biological process from the Gene Ontology. ⚠ ABNORMAL
atrioventricular canal UBERON:0002087 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in atrioventricular canal (UBERON:0002087). UBERON:0002087 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Endothelial-to-Mesenchymal Transition Failure Defective cushion development reflects impaired EndoMT in the atrioventricular canal.
Common Atrioventricular Junction Failure of the mesenchymal complex leaves a single common atrioventricular junction instead of separate mitral and tricuspid orifices.
Show evidence (2 references)
PMID:38884733 SUPPORT Model Organism
"While AVSD were historically considered to result from failure of the endocardial atrioventricular cushions to properly develop and fuse, more recent studies have determined that inhibition of the development of other components of the atrioventricular mesenchymal complex can lead to AVSDs as well."
Establishes that AVSD pathogenesis extends beyond endocardial cushion fusion to the wider atrioventricular mesenchymal complex.
PMID:38884733 SUPPORT Model Organism
"The role of the dorsal mesenchymal protrusion (DMP) in AVSD pathogenesis has been well-documented in studies using animal models for AVSDs"
Identifies the dorsal mesenchymal protrusion as a documented contributor to AVSD in animal models.
Endothelial-to-Mesenchymal Transition Failure
Endothelial-to-mesenchymal transition (EndoMT) in the atrioventricular canal generates the mesenchyme that populates the endocardial cushions. Impaired EndoMT is a core cellular lesion in AVSD. Attribution of specific signalling pathways to this step should be treated cautiously: the standard explant assay used to assign pathway roles has been shown to be confounded by epicardial cells misidentified as endothelium.
endocardial cell CL:0002350 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endocardial cell (CL:0002350). CL:0002350 is a cell type from the Cell Ontology.
epithelial to mesenchymal transition involved in endocardial cushion formation GO:0003198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased epithelial to mesenchymal transition involved in endocardial cushion formation (GO:0003198). GO:0003198 is a biological process from the Gene Ontology. ↓ DECREASED
atrioventricular canal UBERON:0002087 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in atrioventricular canal (UBERON:0002087). UBERON:0002087 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Common Atrioventricular Junction Deficient cushion mesenchyme fails to septate the atrioventricular canal.
Show evidence (2 references)
PMID:29549339 SUPPORT Model Organism
"Endothelial-to-mesenchymal transition (EndoMT) is a critical event in endocardial cushion development that initiates in the atrioventricular canal (AVC)."
Establishes EndoMT in the atrioventricular canal as the critical cellular event in cushion development.
PMID:29549339 SUPPORT Model Organism
"monolayers of cobblestone-shaped cells are predominantly of epicardial rather than endothelial origin"
Cautions that pathway roles assigned to EndoMT via the standard explant assay are confounded by epicardial contamination, so specific pathway attributions are held loosely here.
Trisomy 21 Gene Dosage Effect
Trisomy 21 sensitises the atrioventricular canal to septation failure through dosage of chromosome 21 genes. The atrioventricular canal contains a distinct myocardial population essential for valvuloseptal development, and HMGN1-driven myocardial reprogramming has been implicated in the trisomy 21 phenotype. Dosage alone is not deterministic: additional genetic hits are required to cross the defect threshold.
cardiac septum morphogenesis GO:0060411 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cardiac septum morphogenesis (GO:0060411). GO:0060411 is a biological process from the Gene Ontology. ⚠ ABNORMAL
atrioventricular canal UBERON:0002087 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in atrioventricular canal (UBERON:0002087). UBERON:0002087 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Ts65Dn trisomic background crossed with Creld1 or Hey2 loss-of-function alleles Mouse (Mus musculus) Mouse (Mus musculus) partially recapitulates Tests whether chromosome 21 dosage sensitises the atrioventricular canal such that additional loss-of-function alleles precipitate septation failure.
Downstream
Atrioventricular Mesenchymal Complex Failure Chromosome 21 dosage sensitises the atrioventricular canal so that septation fails.
Show evidence (1 reference)
PMID:41125893 SUPPORT Model Organism
"The AVC contains unique myocardial cells that are essential for valvuloseptal development; however, the specific combination of dosage-sensitive genes on chromosome 21 that are responsible for Down syndrome-associated CHDs have remained unknown."
Establishes the atrioventricular canal myocardium as the dosage-sensitive target in trisomy 21.
Multigenic Susceptibility
Non-syndromic AVSD is genetically heterogeneous and behaves as a multigenic threshold trait rather than a monogenic disorder. CRELD1 was the first identified susceptibility gene, and rare damaging variants are enriched across a broad set of biologically relevant cardiac development genes.
Downstream
CRELD1-Calcineurin/NFATc1-VEGF Axis CRELD1 and NFATC1 susceptibility alleles converge on the calcineurin/NFAT axis regulating endocardial proliferation.
Atrioventricular Mesenchymal Complex Failure Accumulated variant burden in cardiac developmental genes crosses the threshold for septation failure.
Show evidence (2 references)
PMID:15096951 SUPPORT Human Clinical
"Mutation of CRELD1 increases susceptibility to AVSD but is not alone sufficient to cause the defect, indicating that AVSD is multigenic"
Establishes the multigenic threshold model and CRELD1's role as a susceptibility rather than causative allele.
PMID:25996639 SUPPORT Human Clinical
"A significant enrichment of rare and rare damaging variants was identified in the gene set, compared with controls"
Demonstrates burden of rare damaging variants across many genes rather than a single causal locus.
CRELD1-Calcineurin/NFATc1-VEGF Axis
The convergent molecular module linking AVSD susceptibility genes to the cellular lesion. CRELD1 regulates calcineurin/NFAT signalling, and Creld1 function is required for VEGF-dependent proliferation of endocardial cells via NFATc1 target genes. Susceptibility alleles in CRELD1 and NFATC1 therefore act on the same axis that drives endocardial cell expansion in the cushions.
endocardial cell CL:0002350 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endocardial cell (CL:0002350). CL:0002350 is a cell type from the Cell Ontology.
atrioventricular canal UBERON:0002087 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in atrioventricular canal (UBERON:0002087). UBERON:0002087 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Endothelial-to-Mesenchymal Transition Failure Loss of VEGF-dependent endocardial proliferation reduces the cell population available to undergo EndoMT and populate the cushions.
Show evidence (1 reference)
PMID:24697899 SUPPORT Model Organism
"Creld1 function is required for the VEGF-dependent proliferation of endocardial cells by promoting the expression of NFATc1 target-genes"
Establishes the mechanistic link from CRELD1 through NFATc1 to VEGF-dependent endocardial cell proliferation.
Common Atrioventricular Junction
The defining anatomic lesion: a single common atrioventricular junction with deficient atrioventricular septation, producing an ostium primum atrial communication and/or inlet ventricular septal defect together with an abnormal common or cleft atrioventricular valve.
cardiac septum UBERON:0002099 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cardiac septum (UBERON:0002099). UBERON:0002099 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Left-to-Right Shunt and Valve Regurgitation The septal deficiency permits shunting and the abnormal valve leaks.
Show evidence (1 reference)
PMID:32965865 SUPPORT Human Clinical
"Atrioventricular septal defect (AVSD) is a congenital cardiac malformation characterized by incomplete atrial and ventricular septa development and abnormalities of the atrioventricular valves (AVVs), resulting in a common or partially separate atrioventricular (AV) orifice."
Defines the anatomic lesion that results from failed septation.
Left-to-Right Shunt and Valve Regurgitation
The common junction allows a large left-to-right shunt at atrial and ventricular level, compounded by regurgitation through the abnormal atrioventricular valve. The resulting volume load drives pulmonary overcirculation and infantile congestive heart failure.
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Pulmonary Vascular Obstructive Disease Sustained pulmonary overcirculation remodels the pulmonary vasculature.
Infantile Congestive Heart Failure Volume overload exceeds the infant myocardium's reserve.
Show evidence (1 reference)
PMID:10812553 SUPPORT Human Clinical
"With increasing shunt ratio the pulmonary perfusion raised (r = 0.84), but the systemic output dropped significantly (r = -0.77)"
Quantifies the haemodynamic consequence of an increasing left-to-right shunt ratio - rising pulmonary perfusion at the cost of systemic output.
Infantile Congestive Heart Failure
Clinical consequence of the volume load, emerging in the first months of life and the usual trigger for surgical referral. AVSD is a leading cause of early heart failure in infants.
heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:32965865 SUPPORT Human Clinical
"The condition is a leading cause of early heart failure in infants."
Establishes early infantile heart failure as the dominant clinical consequence of the lesion.
Pulmonary Vascular Obstructive Disease
If the shunt is left uncorrected, pulmonary arteriolar remodelling becomes irreversible and shunt reversal (Eisenmenger physiology) supervenes. This is the reason repair is undertaken in infancy rather than deferred, and it occurs earlier in children with Down syndrome.
pulmonary artery UBERON:0002012 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in pulmonary artery (UBERON:0002012). UBERON:0002012 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:40179148 SUPPORT Human Clinical
"In DS, cAVSD repair is ideally performed before six months of age to prevent irreversible pulmonary artery hypertension (PAH)."
Establishes irreversibility of the pulmonary vascular lesion and the timing rationale for early repair.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Atrioventricular Septal Defect Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

7
Cardiovascular 3
Congestive Heart Failure HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32965865 SUPPORT Human Clinical
"The condition is a leading cause of early heart failure in infants."
Directly associates AVSD with early infantile heart failure.
Pulmonary Arterial Hypertension HP:0002092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary arterial hypertension (HP:0002092). HP:0002092 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40179148 SUPPORT Human Clinical
"In DS, cAVSD repair is ideally performed before six months of age to prevent irreversible pulmonary artery hypertension (PAH)."
Associates unrepaired complete AVSD with irreversible pulmonary arterial hypertension.
Postoperative Atrioventricular Block HP:0001678 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrioventricular block (HP:0001678). HP:0001678 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37612667 SUPPORT Human Clinical
"The indication for pacemaker implantation was third-degree atrioventricular block in 4 (2.0%) patients, second-degree atrioventricular block in 1 (0.6%) patient, and sinus node dysfunction in 1 (0.5%) patient."
Documents postoperative atrioventricular block as the leading pacemaker indication after AVSD repair.
Other 4
Atrioventricular Canal Defect HP:0006695 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrioventricular canal defect (HP:0006695). HP:0006695 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32965865 SUPPORT Human Clinical
"resulting in a common or partially separate atrioventricular (AV) orifice"
Describes the common atrioventricular orifice that defines the phenotype.
Atrioventricular Valve Regurgitation HP:0034376 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrioventricular valve regurgitation (HP:0034376). HP:0034376 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35757952 SUPPORT Human Clinical
"After initial repair, there were 18 cases of moderate-to-severe left atrioventricular valve regurgitation (17.3%)."
Quantifies moderate-to-severe left atrioventricular valve regurgitation after primary repair, the dominant residual lesion.
Left Axis Deviation HP:0033568 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left axis deviation (HP:0033568). HP:0033568 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10605520 SUPPORT Human Clinical
"only the five infants with complete AVSD had a superior QRS axis"
In a neonatal ECG screening cohort, a superior QRS axis was specific to complete AVSD among the congenital heart defects detected.
Left Ventricular Outflow Tract Obstruction HP:0032092 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular outflow tract obstruction (HP:0032092). HP:0032092 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37612667 SUPPORT Human Clinical
"left ventricular outflow tract obstruction (LVOTO) has been described as a common complication following surgical repair of AVSD occurring in 2–7% of the patients"
Quantifies LVOTO as a post-repair complication of AVSD.
🧬

Genetic Associations

4
CRELD1 (Susceptibility Variant)
Gene: CRELD1 hgnc:14630 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CRELD1 (hgnc:14630). hgnc:14630 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (1 reference)
PMID:15096951 SUPPORT Human Clinical
"Mutation of CRELD1 increases susceptibility to AVSD but is not alone sufficient to cause the defect, indicating that AVSD is multigenic"
Establishes CRELD1 as a susceptibility allele within a multigenic model.
NFATC1 (Missense Variant)
Gene: NFATC1 hgnc:7775 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NFATC1 (hgnc:7775). hgnc:7775 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE
Show evidence (1 reference)
PMID:30007050 SUPPORT Human Clinical
"Multiple lines of evidence support a role of calcineurin/NFAT signaling in AVSD, and mutations in CRELD1, a protein functioning as a regulator of calcineurin/NFAT signaling have been reported in a small fraction of affected subjects."
Links NFATC1 and CRELD1 through the shared calcineurin/NFAT axis.
HMGN1 (Chromosome 21 Dosage)
Gene: HMGN1 hgnc:4984 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is HMGN1 (hgnc:4984). hgnc:4984 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: MODIFIER variant_origin: GERMLINE
Show evidence (1 reference)
PMID:41125893 SUPPORT Model Organism
"CHDs occur in around 50% of cases of Down syndrome, with an approximately 1,000-fold enrichment of atrioventricular canal (AVC) defects that disrupt the junction between the atria and ventricles"
Frames the trisomy 21 dosage problem that HMGN1 reprogramming addresses.
Multigene Burden (Rare Variant Enrichment)
Show evidence (1 reference)
PMID:25996639 SUPPORT Human Clinical
"Whole-exome sequencing was performed in 81 unrelated probands with AVSD to identify potentially causal variants in a comprehensive set of 112 genes with strong biological relevance to AVSD."
Documents the multigene burden architecture of non-syndromic AVSD.
💊

Medical Actions

2
Surgical Repair of Atrioventricular Septal Defect
Action: atrioventricular septal defect repairNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is atrioventricular septal defect repair (NCIT:C217463). NCIT:C217463 is a clinical intervention from the NCI Thesaurus. Ontology label: Atrioventricular Septal Defect Repair NCIT:C217463
Biventricular surgical repair, by single-patch, modified single-patch or double-patch technique, closing the atrial and ventricular components and reconstructing the atrioventricular valves. Performed in infancy to pre-empt irreversible pulmonary vascular disease. Long-term survival is now approximately 88% at 10 years and 80% at 25 years.
Mechanism Target:
BYPASSES Common Atrioventricular Junction — Patch closure of the atrial and ventricular components and septation of the common valve reconstitute separate right and left atrioventricular junctions.
Show evidence (1 reference)
PMID:37612667 SUPPORT Human Clinical
"Definitive early repair is favored over prior pulmonary artery banding and delayed definitive repair in many centers."
Establishes definitive repair as the intervention acting on the anatomic lesion.
BYPASSES Left-to-Right Shunt and Valve Regurgitation — Eliminating the communications abolishes the shunt and the volume load that drives heart failure and pulmonary vascular disease.
Show evidence (1 reference)
PMID:40179148 SUPPORT Human Clinical
"In DS, cAVSD repair is ideally performed before six months of age to prevent irreversible pulmonary artery hypertension (PAH)."
Repair abolishes the shunt specifically to pre-empt the pulmonary vascular consequence.
Show evidence (2 references)
PMID:40154545 SUPPORT Human Clinical
"Survival of the entire cohort was 88.3% at 10, 83.8% at 15, and 79.6% at 25 years."
Provides long-term survival after biventricular repair across a 27-year single-centre series.
PMID:37612667 SUPPORT Human Clinical
"Definitive early repair is favored over prior pulmonary artery banding and delayed definitive repair in many centers."
Documents the shift to primary early repair rather than staged palliation.
Left Atrioventricular Valve Repair
Action: heart valve repairNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is heart valve repair (NCIT:C50818). NCIT:C50818 is a clinical intervention from the NCI Thesaurus. Ontology label: Heart Valve Repair NCIT:C50818
Cleft closure and valvuloplasty of the left atrioventricular valve at the time of primary repair, with reoperation for significant residual or recurrent regurgitation. Left atrioventricular valve regurgitation is the dominant reoperation indication.
Mechanism Target:
RESTORES Left-to-Right Shunt and Valve Regurgitation — Cleft closure and valvuloplasty restore competence of the left atrioventricular valve, removing the regurgitant component of the volume load.
Show evidence (1 reference)
PMID:35757952 SUPPORT Human Clinical
"All but eight patients (92.3%) underwent left atrioventricular valve cleft closure."
Documents cleft closure as the standard manoeuvre restoring valve competence.
Show evidence (1 reference)
PMID:35757952 SUPPORT Human Clinical
"All but eight patients (92.3%) underwent left atrioventricular valve cleft closure."
Documents cleft closure as near-universal practice at primary repair.
🌍

Environmental Factors

2
Maternal pregestational diabetes
Maternal pregestational diabetes is the strongest established modifiable risk factor for non-syndromic complete atrioventricular canal defect, identified in a large population-based birth defects registry analysis.
Show evidence (1 reference)
PMID:23061687 SUPPORT Human Clinical
"Significant associations were observed between non-syndromic CAVC in offspring and maternal pregestational diabetes (adjusted prevalence ratio (aPR) 6.74; 95% confidence interval (CI) 3.67, 12.37), gestational diabetes (aPR 1.69; 95% CI 1.03, 2.79) and obesity (aPR 1.69; 95% CI 1.24, 2.30)."
Quantifies maternal pregestational diabetes as the strongest environmental risk factor for non-syndromic complete AV canal defect.
Mechanism Target:
PREDISPOSES Atrioventricular Mesenchymal Complex Failure — Maternal pregestational hyperglycaemia acts on the embryo during the window of atrioventricular septation, raising the probability that the mesenchymal complex fails. The intermediate steps are not established.
Show evidence (1 reference)
PMID:23061687 SUPPORT Human Clinical
"Significant associations were observed between non-syndromic CAVC in offspring and maternal pregestational diabetes"
Supports the predisposing effect of maternal pregestational diabetes on the septation defect.
Folate-rich diet
Frequent periconceptional consumption of folate-rich fruits was protective for congenital heart disease in a population-based case-control study, whereas folic acid supplementation alone did not show strong support.
Show evidence (1 reference)
PMID:32092068 SUPPORT Human Clinical
"there was a protective effect of frequent consumption of folate rich fruits (adjOR 0.64, 95%CI 0.47-0.89)"
Quantifies dietary folate as a protective factor for congenital heart disease.
Mechanism Target:
PROTECTS_AGAINST Atrioventricular Mesenchymal Complex Failure — Adequate periconceptional folate lowers congenital heart disease risk overall; the mechanism by which it protects atrioventricular septation is not established.
Show evidence (1 reference)
PMID:32092068 SUPPORT Human Clinical
"there was a protective effect of frequent consumption of folate rich fruits (adjOR 0.64, 95%CI 0.47-0.89)"
Supports the protective direction of the effect asserted on this link.
🔬

Diagnosis

2
Echocardiography
Echocardiography is the diagnostic modality for AVSD, defining the common atrioventricular junction, the atrial and ventricular components of the defect, valve morphology and the degree of regurgitation. AVSD is frequently detected on fetal echocardiography.
echocardiography NCIT:C16525 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:34196822 SUPPORT Human Clinical
"The understanding of functional morphology of AVSDs has improved significantly with detailed 3D echocardiographic evaluation of the atrioventricular junction and valve morphology."
Directly establishes echocardiographic evaluation of the atrioventricular junction and valve morphology as the assessment underpinning AVSD diagnosis.
Genetic testing
Chromosomal microarray and exome sequencing are applied to fetuses and infants with AVSD detected on echocardiography. AVSD carries one of the higher genetic diagnostic yields among congenital heart defects, reflecting its strong aneuploidy association.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:33142350 SUPPORT Human Clinical
"The prevalence of a genetic defect was highest in fetuses with an atrioventricular septal defect (36.8%)"
Quantifies AVSD as the congenital heart defect subgroup with the highest genetic diagnostic yield, which is why genetic testing is indicated.
📈

Progression

2
Infantile presentation and repair
Age: First year of life for the complete form
The complete form presents in early infancy with congestive heart failure and is repaired within the first months of life; partial and transitional forms present and are repaired later. Early definitive repair has displaced staged pulmonary artery banding in most centres.
Show evidence (1 reference)
PMID:40154545 SUPPORT Human Clinical
"Median age at repair was 7.1 for cAVSD, 23.7 for pAVSD, and 13 months for tAVSD."
Documents the age at repair differing by anatomic subtype.
Long-term follow-up
Survival after repair is good and has improved across surgical eras, but left atrioventricular valve regurgitation continues to drive reoperation, so lifelong cardiology follow-up is required.
Show evidence (1 reference)
PMID:40154545 SUPPORT Human Clinical
"Overall survival or reoperation incidence did not differ significantly between AVSD types and improved significantly over surgical eras."
Documents improving long-term outcome across eras and the persistence of reoperation as an endpoint.
📊

Prevalence

1
Live births
Birth Prevalence 19.0 per 100,000 1–9 per 10,000
Birth prevalence of 0.19 per 1000 live births, equivalent to 19 per 100,000.
Show evidence (1 reference)
PMID:38884731 SUPPORT Human Clinical
"AVSDs occur in 0.19 of 1000 live births and constitute 4-5 % of congenital heart defects."
Gives the birth prevalence and the proportion of congenital heart defects represented by AVSD.
🌍

Epidemiology

2
Proportion of congenital cardiac malformations
AVSD accounts for 4-7% of all congenital cardiac malformations, making it a major lesion class rather than a rare anomaly.
Show evidence (1 reference)
PMID:37612667 SUPPORT Human Clinical
"Atrioventricular septal defects (AVSD) represent 4-7% of congenital cardiac malformations."
Gives the proportion of congenital cardiac malformations represented by AVSD.
Association with Down syndrome
Congenital heart defects affect roughly 40% of individuals with Down syndrome, and AVSD is the commonest of those defects. Trisomy 21 confers an approximately 1000-fold enrichment of atrioventricular canal defects specifically.
Show evidence (2 references)
PMID:29054759 SUPPORT Human Clinical
"Congenital heart defects (CHD) are seen in around 40% of the Down syndrome patients. Atrioventricular Septal Defect (AVSD) or endocardial cushion defect is commonest form of CHD in these children."
Establishes the frequency of CHD in Down syndrome and AVSD as the predominant lesion.
PMID:41125893 SUPPORT Model Organism
"CHDs occur in around 50% of cases of Down syndrome, with an approximately 1,000-fold enrichment of atrioventricular canal (AVC) defects that disrupt the junction between the atria and ventricles"
Quantifies the magnitude of AVC-defect enrichment attributable to trisomy 21.
🐁

Animal Models

1
Ts65Dn trisomic background crossed with Creld1 or Hey2 loss-of-function alleles Mouse (Mus musculus) Transgenic
The Ts65Dn mouse models Down syndrome gene dosage. Crossing loss-of-function alleles of Creld1 or Hey2 onto this sensitised background raises congenital heart defect frequency, providing direct in vivo support for the dosage-sensitised multigenic threshold model of AVSD.
Congenital heart defect
Species
Mouse (Mus musculus)
Genotype
Ts65Dn trisomic background crossed with Creld1 or Hey2 loss-of-function alleles
Genes
CRELD1 hgnc:14630 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns CRELD1 (hgnc:14630). hgnc:14630 is a gene from the HUGO Gene Nomenclature Committee.
Pathograph links
Trisomy 21 Gene Dosage Effect partially recapitulates fidelity: moderate Tests whether chromosome 21 dosage sensitises the atrioventricular canal such that additional loss-of-function alleles precipitate septation failure.
Limitations: Ts65Dn is trisomic for a subset of the human chromosome 21 orthologous region, and murine cardiac septation differs from human, so defect frequency rather than the human AVSD lesion is the readout.
Show evidence (1 reference)
PMID:22523272 SUPPORT Model Organism
"Crossing loss-of-function alleles of either Creld1 or Hey2 onto the trisomic background caused a significant increase in the frequency of CHD"
The readout that grounds this model link - added genetic hits on the trisomic background raise congenital heart defect frequency.
Show evidence (1 reference)
PMID:22523272 SUPPORT Model Organism
"Crossing loss-of-function alleles of either Creld1 or Hey2 onto the trisomic background caused a significant increase in the frequency of CHD"
Demonstrates in vivo that additional genetic hits on a trisomic background raise congenital heart defect frequency.
{ }

Source YAML

click to show 
name: Atrioventricular Septal Defect
creation_date: '2026-08-27T20:00:00Z'
description: >-
  Atrioventricular septal defect (AVSD), also called atrioventricular canal defect
  or endocardial cushion defect, is a congenital cardiac malformation defined by a
  common atrioventricular junction with deficient atrioventricular septation. The
  lesion comprises an ostium primum atrial communication and/or an inlet
  ventricular septal defect together with an abnormal atrioventricular valve —
  either a single common valve (complete AVSD) or two orifices with a cleft left
  atrioventricular valve (partial AVSD). AVSD accounts for 4-7% of congenital
  cardiac malformations and has the tightest association of any congenital heart
  defect with trisomy 21: it is the commonest heart defect in Down syndrome, and a
  large share of all AVSD occurs in that context. Developmentally it arises from
  failure of the atrioventricular mesenchymal complex — historically attributed to
  the endocardial cushions alone, but now understood to involve the dorsal
  mesenchymal protrusion and the mesenchymal cap of the primary atrial septum as
  well. Haemodynamically the common junction produces a large left-to-right shunt
  with atrioventricular valve regurgitation, causing infantile congestive heart
  failure and, if unrepaired, irreversible pulmonary vascular obstructive disease.
  Diagnosis is echocardiographic and treatment is surgical repair in infancy, with
  long-term survival now approaching 80-88% at 10-25 years and left
  atrioventricular valve regurgitation the principal driver of reoperation.
synonyms:
- atrioventricular canal defect
- endocardial cushion defect
- common atrioventricular canal
- AV canal defect
categories:
- Congenital Heart Defect
- Structural Birth Defect
- Endocardial Cushion Defect
parents:
- congenital heart disease
epidemiology:
- name: Proportion of congenital cardiac malformations
  description: >-
    AVSD accounts for 4-7% of all congenital cardiac malformations, making it a
    major lesion class rather than a rare anomaly.
  evidence:
  - reference: PMID:37612667
    reference_title: Long-term results following atrioventricular septal defect repair.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Atrioventricular septal defects (AVSD) represent 4-7% of congenital cardiac
      malformations.
    explanation: Gives the proportion of congenital cardiac malformations represented by
      AVSD.
- name: Association with Down syndrome
  description: >-
    Congenital heart defects affect roughly 40% of individuals with Down syndrome,
    and AVSD is the commonest of those defects. Trisomy 21 confers an approximately
    1000-fold enrichment of atrioventricular canal defects specifically.
  evidence:
  - reference: PMID:29054759
    reference_title: CRELD1 gene variants and atrioventricular septal defects in Down
      syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Congenital heart defects (CHD) are seen in around 40% of the Down syndrome
      patients. Atrioventricular Septal Defect (AVSD) or endocardial cushion defect is
      commonest form of CHD in these children.
    explanation: Establishes the frequency of CHD in Down syndrome and AVSD as the
      predominant lesion.
  - reference: PMID:41125893
    reference_title: Myocardial reprogramming by HMGN1 underlies heart defects in trisomy
      21.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: CHDs occur in around 50% of cases of Down syndrome, with an approximately
      1,000-fold enrichment of atrioventricular canal (AVC) defects that disrupt the
      junction between the atria and ventricles
    explanation: Quantifies the magnitude of AVC-defect enrichment attributable to trisomy
      21.
has_subtypes:
- name: Complete
  display_name: Complete AVSD (common atrioventricular valve)
  description: >-
    A single common atrioventricular valve with both an ostium primum atrial
    communication and an inlet ventricular septal defect. Presents earliest with
    heart failure and carries the highest risk of early pulmonary vascular disease.
  evidence:
  - reference: PMID:32965865
    reference_title: Atrioventricular Septal Defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: complete AVSD features a common AVV, an ostium primum atrial septal defect,
      and an unrestricted inlet-type ventricular septal defect
    explanation: Defines the anatomic components of the complete form.
- name: Partial
  display_name: Partial AVSD (ostium primum ASD with cleft left AV valve)
  description: >-
    Two separate atrioventricular valve orifices sharing a common junction, with an
    ostium primum atrial septal defect and a cleft in the left atrioventricular
    valve. Presents later than the complete form.
  evidence:
  - reference: PMID:32965865
    reference_title: Atrioventricular Septal Defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Partial AVSD typically presents with an ostium primum atrial septal defect,
      separate AVVs with a common junction, an inlet ventricular septal defect, and a
      cleft mitral valve.
    explanation: Defines the anatomic components of the partial form.
- name: Transitional
  display_name: Transitional AVSD
  description: >-
    Intermediate form with two atrioventricular valve orifices and a restrictive
    inlet ventricular septal defect, behaving haemodynamically between the partial
    and complete forms.
  evidence:
  - reference: PMID:40154545
    reference_title: A 27-Year Experience with Atrioventricular Septal Defect Correction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A total of 208 (83.9%) patients had complete (cAVSD), 29 (11.7%) partial
      (pAVSD), and 11 (4.4%) transitional AVSD (tAVSD).
    explanation: Documents transitional AVSD as a recognised third anatomic category in a
      large surgical series.
prevalence:
- population: Live births
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 19.0
  notes: >-
    Birth prevalence of 0.19 per 1000 live births, equivalent to 19 per 100,000.
  evidence:
  - reference: PMID:38884731
    reference_title: Clinical Presentation and Therapy of Atrioventricular Septal Defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: AVSDs occur in 0.19 of 1000 live births and constitute 4-5 % of congenital heart
      defects.
    explanation: Gives the birth prevalence and the proportion of congenital heart defects
      represented by AVSD.
inheritance:
- name: Multifactorial
  description: >-
    Most AVSD is multifactorial rather than Mendelian. Trisomy 21 is the single
    largest contributor, and non-syndromic disease behaves as an oligogenic or
    polygenic threshold trait in which susceptibility alleles such as CRELD1 raise
    risk without being sufficient on their own.
  inheritance_term:
    preferred_term: oligogenic inheritance
    term:
      id: HP:0010983
      label: Oligogenic inheritance
  evidence:
  - reference: PMID:15096951
    reference_title: Molecular genetics of atrioventricular septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mutation of CRELD1 increases susceptibility to AVSD but is not alone sufficient
      to cause the defect, indicating that AVSD is multigenic
    explanation: Establishes the multigenic rather than Mendelian inheritance model.
pathophysiology:
- name: Atrioventricular Mesenchymal Complex Failure
  description: >-
    AVSD originates in failed development of the atrioventricular mesenchymal
    complex during cardiac septation. Historically this was attributed solely to
    the endocardial atrioventricular cushions, but animal-model work has since
    shown that failure of other components — notably the dorsal mesenchymal
    protrusion, and probably the mesenchymal cap on the leading edge of the primary
    atrial septum — can produce AVSD in its own right.
  biological_processes:
  - preferred_term: endocardial cushion development
    modifier: ABNORMAL
    term:
      id: GO:0003197
      label: endocardial cushion development
  - preferred_term: cardiac septum morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0060411
      label: cardiac septum morphogenesis
  locations:
  - preferred_term: atrioventricular canal
    term:
      id: UBERON:0002087
      label: atrioventricular canal
  evidence:
  - reference: PMID:38884733
    reference_title: Molecular Pathways and Animal Models of Atrioventricular Septal Defect.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: While AVSD were historically considered to result from failure of the endocardial
      atrioventricular cushions to properly develop and fuse, more recent studies have
      determined that inhibition of the development of other components of the atrioventricular
      mesenchymal complex can lead to AVSDs as well.
    explanation: Establishes that AVSD pathogenesis extends beyond endocardial cushion
      fusion to the wider atrioventricular mesenchymal complex.
  - reference: PMID:38884733
    reference_title: Molecular Pathways and Animal Models of Atrioventricular Septal Defect.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The role of the dorsal mesenchymal protrusion (DMP) in AVSD pathogenesis has
      been well-documented in studies using animal models for AVSDs
    explanation: Identifies the dorsal mesenchymal protrusion as a documented contributor
      to AVSD in animal models.
  downstream:
  - target: Endothelial-to-Mesenchymal Transition Failure
    description: Defective cushion development reflects impaired EndoMT in the atrioventricular
      canal.
    evidence:
    - reference: PMID:29549339
      reference_title: The epicardium obscures interpretations on endothelial-to-mesenchymal
        transition in the mouse atrioventricular canal explant assay.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Atrioventricular septal defects often result from impaired endocardial cushion
        development.
      explanation: Links impaired endocardial cushion development to AVSD.
  - target: Common Atrioventricular Junction
    description: Failure of the mesenchymal complex leaves a single common atrioventricular
      junction instead of separate mitral and tricuspid orifices.
    evidence:
    - reference: PMID:38884731
      reference_title: Clinical Presentation and Therapy of Atrioventricular Septal Defect.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Atrioventricular septal defects (AVSDs) consist of a number of cardiac malformations
        that result from abnormal development of the endocardial cushions.
      explanation: Links abnormal endocardial cushion development to the resulting AVSD
        malformations.
- name: Endothelial-to-Mesenchymal Transition Failure
  description: >-
    Endothelial-to-mesenchymal transition (EndoMT) in the atrioventricular canal
    generates the mesenchyme that populates the endocardial cushions. Impaired
    EndoMT is a core cellular lesion in AVSD. Attribution of specific signalling
    pathways to this step should be treated cautiously: the standard explant assay
    used to assign pathway roles has been shown to be confounded by epicardial
    cells misidentified as endothelium.
  cell_types:
  - preferred_term: endocardial cell
    term:
      id: CL:0002350
      label: endocardial cell
  biological_processes:
  - preferred_term: epithelial to mesenchymal transition involved in endocardial cushion
      formation
    modifier: DECREASED
    term:
      id: GO:0003198
      label: epithelial to mesenchymal transition involved in endocardial cushion formation
  locations:
  - preferred_term: atrioventricular canal
    term:
      id: UBERON:0002087
      label: atrioventricular canal
  evidence:
  - reference: PMID:29549339
    reference_title: The epicardium obscures interpretations on endothelial-to-mesenchymal
      transition in the mouse atrioventricular canal explant assay.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Endothelial-to-mesenchymal transition (EndoMT) is a critical event in endocardial
      cushion development that initiates in the atrioventricular canal (AVC).
    explanation: Establishes EndoMT in the atrioventricular canal as the critical cellular
      event in cushion development.
  - reference: PMID:29549339
    reference_title: The epicardium obscures interpretations on endothelial-to-mesenchymal
      transition in the mouse atrioventricular canal explant assay.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: monolayers of cobblestone-shaped cells are predominantly of epicardial rather
      than endothelial origin
    explanation: Cautions that pathway roles assigned to EndoMT via the standard explant
      assay are confounded by epicardial contamination, so specific pathway attributions
      are held loosely here.
  downstream:
  - target: Common Atrioventricular Junction
    description: Deficient cushion mesenchyme fails to septate the atrioventricular canal.
    evidence:
    - reference: PMID:38884731
      reference_title: Clinical Presentation and Therapy of Atrioventricular Septal Defect.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Atrioventricular septal defects (AVSDs) consist of a number of cardiac malformations
        that result from abnormal development of the endocardial cushions.
      explanation: Links abnormal endocardial cushion development to the resulting AVSD
        malformations.
- name: Trisomy 21 Gene Dosage Effect
  description: >-
    Trisomy 21 sensitises the atrioventricular canal to septation failure through
    dosage of chromosome 21 genes. The atrioventricular canal contains a distinct
    myocardial population essential for valvuloseptal development, and HMGN1-driven
    myocardial reprogramming has been implicated in the trisomy 21 phenotype.
    Dosage alone is not deterministic: additional genetic hits are required to
    cross the defect threshold.
  biological_processes:
  - preferred_term: cardiac septum morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0060411
      label: cardiac septum morphogenesis
  locations:
  - preferred_term: atrioventricular canal
    term:
      id: UBERON:0002087
      label: atrioventricular canal
  evidence:
  - reference: PMID:41125893
    reference_title: Myocardial reprogramming by HMGN1 underlies heart defects in trisomy
      21.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: The AVC contains unique myocardial cells that are essential for valvuloseptal
      development; however, the specific combination of dosage-sensitive genes on chromosome
      21 that are responsible for Down syndrome-associated CHDs have remained unknown.
    explanation: Establishes the atrioventricular canal myocardium as the dosage-sensitive
      target in trisomy 21.
  downstream:
  - target: Atrioventricular Mesenchymal Complex Failure
    description: Chromosome 21 dosage sensitises the atrioventricular canal so that septation
      fails.
    evidence:
    - reference: PMID:22523272
      reference_title: Genetic modifiers predisposing to congenital heart disease in the
        sensitized Down syndrome population.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Crossing loss-of-function alleles of either Creld1 or Hey2 onto the trisomic
        background caused a significant increase in the frequency of CHD
      explanation: Additional loss-of-function alleles on a trisomic background raise CHD
        frequency, supporting a dosage-sensitised threshold model.
- name: Multigenic Susceptibility
  description: >-
    Non-syndromic AVSD is genetically heterogeneous and behaves as a multigenic
    threshold trait rather than a monogenic disorder. CRELD1 was the first
    identified susceptibility gene, and rare damaging variants are enriched across
    a broad set of biologically relevant cardiac development genes.
  evidence:
  - reference: PMID:15096951
    reference_title: Molecular genetics of atrioventricular septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mutation of CRELD1 increases susceptibility to AVSD but is not alone sufficient
      to cause the defect, indicating that AVSD is multigenic
    explanation: Establishes the multigenic threshold model and CRELD1's role as a
      susceptibility rather than causative allele.
  - reference: PMID:25996639
    reference_title: Exome sequencing identifies rare variants in multiple genes in atrioventricular
      septal defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A significant enrichment of rare and rare damaging variants was identified
      in the gene set, compared with controls
    explanation: Demonstrates burden of rare damaging variants across many genes rather
      than a single causal locus.
  downstream:
  - target: CRELD1-Calcineurin/NFATc1-VEGF Axis
    description: CRELD1 and NFATC1 susceptibility alleles converge on the calcineurin/NFAT
      axis regulating endocardial proliferation.
    evidence:
    - reference: PMID:24697899
      reference_title: Murine Creld1 controls cardiac development through activation of
        calcineurin/NFATc1 signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Creld1 function is required for the VEGF-dependent proliferation of endocardial
        cells by promoting the expression of NFATc1 target-genes
      explanation: Establishes the CRELD1-NFATc1-VEGF dependency in endocardial cells that
        this edge asserts.
  - target: Atrioventricular Mesenchymal Complex Failure
    description: Accumulated variant burden in cardiac developmental genes crosses the
      threshold for septation failure.
    evidence:
    - reference: PMID:15096951
      reference_title: Molecular genetics of atrioventricular septal defects.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Mutation of CRELD1 increases susceptibility to AVSD but is not alone sufficient
        to cause the defect, indicating that AVSD is multigenic
      explanation: Supports a threshold model in which combined variant burden, not a single
        allele, produces the septation defect.
- name: CRELD1-Calcineurin/NFATc1-VEGF Axis
  description: >-
    The convergent molecular module linking AVSD susceptibility genes to the
    cellular lesion. CRELD1 regulates calcineurin/NFAT signalling, and Creld1
    function is required for VEGF-dependent proliferation of endocardial cells via
    NFATc1 target genes. Susceptibility alleles in CRELD1 and NFATC1 therefore act
    on the same axis that drives endocardial cell expansion in the cushions.
  cell_types:
  - preferred_term: endocardial cell
    term:
      id: CL:0002350
      label: endocardial cell
  locations:
  - preferred_term: atrioventricular canal
    term:
      id: UBERON:0002087
      label: atrioventricular canal
  evidence:
  - reference: PMID:24697899
    reference_title: Murine Creld1 controls cardiac development through activation of
      calcineurin/NFATc1 signaling.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Creld1 function is required for the VEGF-dependent proliferation of endocardial
      cells by promoting the expression of NFATc1 target-genes
    explanation: Establishes the mechanistic link from CRELD1 through NFATc1 to
      VEGF-dependent endocardial cell proliferation.
  downstream:
  - target: Endothelial-to-Mesenchymal Transition Failure
    description: Loss of VEGF-dependent endocardial proliferation reduces the cell population
      available to undergo EndoMT and populate the cushions.
    evidence:
    - reference: PMID:24697899
      reference_title: Murine Creld1 controls cardiac development through activation of
        calcineurin/NFATc1 signaling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Creld1 function is required for the VEGF-dependent proliferation of endocardial
        cells by promoting the expression of NFATc1 target-genes
      explanation: Establishes the CRELD1-NFATc1-VEGF dependency in endocardial cells that
        this edge asserts.
- name: Common Atrioventricular Junction
  description: >-
    The defining anatomic lesion: a single common atrioventricular junction with
    deficient atrioventricular septation, producing an ostium primum atrial
    communication and/or inlet ventricular septal defect together with an abnormal
    common or cleft atrioventricular valve.
  locations:
  - preferred_term: cardiac septum
    term:
      id: UBERON:0002099
      label: cardiac septum
  evidence:
  - reference: PMID:32965865
    reference_title: Atrioventricular Septal Defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Atrioventricular septal defect (AVSD) is a congenital cardiac malformation
      characterized by incomplete atrial and ventricular septa development and abnormalities
      of the atrioventricular valves (AVVs), resulting in a common or partially separate
      atrioventricular (AV) orifice.
    explanation: Defines the anatomic lesion that results from failed septation.
  downstream:
  - target: Left-to-Right Shunt and Valve Regurgitation
    description: The septal deficiency permits shunting and the abnormal valve leaks.
    evidence:
    - reference: PMID:10812553
      reference_title: '[Circulatory failure in children with left-to-right shunt in the framework
        of congenital heart defects: pathophysiology and therapeutic results].'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: With increasing shunt ratio the pulmonary perfusion raised (r = 0.84), but the
        systemic output dropped significantly (r = -0.77)
      explanation: The septal deficiency establishes the shunt whose magnitude drives pulmonary
        overperfusion and falling systemic output.
- name: Left-to-Right Shunt and Valve Regurgitation
  description: >-
    The common junction allows a large left-to-right shunt at atrial and
    ventricular level, compounded by regurgitation through the abnormal
    atrioventricular valve. The resulting volume load drives pulmonary
    overcirculation and infantile congestive heart failure.
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:10812553
    reference_title: '[Circulatory failure in children with left-to-right shunt in the framework
      of congenital heart defects: pathophysiology and therapeutic results].'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: With increasing shunt ratio the pulmonary perfusion raised (r = 0.84), but the
      systemic output dropped significantly (r = -0.77)
    explanation: >-
      Quantifies the haemodynamic consequence of an increasing left-to-right shunt
      ratio - rising pulmonary perfusion at the cost of systemic output.
  downstream:
  - target: Pulmonary Vascular Obstructive Disease
    description: Sustained pulmonary overcirculation remodels the pulmonary vasculature.
    evidence:
    - reference: PMID:1943197
      reference_title: Preoperative prediction of postoperative pulmonary arteriolar resistance
        after surgical repair of complete atrioventricular canal defect.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The natural history of patients with complete atrioventricular canal defect
        is one of unrelenting development of pulmonary vascular obstructive disease.
      explanation: States the natural history linking the unrepaired lesion to progressive
        pulmonary vascular obstructive disease.
  - target: Infantile Congestive Heart Failure
    description: Volume overload exceeds the infant myocardium's reserve.
    evidence:
    - reference: PMID:32965865
      reference_title: Atrioventricular Septal Defect.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The condition is a leading cause of early heart failure in infants.
      explanation: Links the AVSD lesion directly to early infantile heart failure.
- name: Infantile Congestive Heart Failure
  description: >-
    Clinical consequence of the volume load, emerging in the first months of life
    and the usual trigger for surgical referral. AVSD is a leading cause of early
    heart failure in infants.
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:32965865
    reference_title: Atrioventricular Septal Defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The condition is a leading cause of early heart failure in infants.
    explanation: Establishes early infantile heart failure as the dominant clinical
      consequence of the lesion.
- name: Pulmonary Vascular Obstructive Disease
  description: >-
    If the shunt is left uncorrected, pulmonary arteriolar remodelling becomes
    irreversible and shunt reversal (Eisenmenger physiology) supervenes. This is
    the reason repair is undertaken in infancy rather than deferred, and it occurs
    earlier in children with Down syndrome.
  locations:
  - preferred_term: pulmonary artery
    term:
      id: UBERON:0002012
      label: pulmonary artery
  evidence:
  - reference: PMID:40179148
    reference_title: Complete Atrioventricular Septal Defect Repair in Patients With Down
      Syndrome Presenting Beyond Six Months- A Single Center Experience.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In DS, cAVSD repair is ideally performed before six months of age to prevent
      irreversible pulmonary artery hypertension (PAH).
    explanation: Establishes irreversibility of the pulmonary vascular lesion and the
      timing rationale for early repair.
histopathology: []
phenotypes:
- category: Cardiovascular
  name: Atrioventricular Canal Defect
  description: >-
    The defining structural phenotype: deficient atrioventricular septation with a
    common atrioventricular junction.
  phenotype_term:
    preferred_term: Atrioventricular canal defect
    term:
      id: HP:0006695
      label: Atrioventricular canal defect
  evidence:
  - reference: PMID:32965865
    reference_title: Atrioventricular Septal Defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: resulting in a common or partially separate atrioventricular (AV) orifice
    explanation: Describes the common atrioventricular orifice that defines the phenotype.
- category: Cardiovascular
  name: Congestive Heart Failure
  description: >-
    Infantile congestive heart failure from the large left-to-right shunt and
    atrioventricular valve regurgitation, typically emerging in the first months of
    life.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:32965865
    reference_title: Atrioventricular Septal Defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The condition is a leading cause of early heart failure in infants.
    explanation: Directly associates AVSD with early infantile heart failure.
- category: Cardiovascular
  name: Atrioventricular Valve Regurgitation
  description: >-
    Regurgitation through the common or cleft atrioventricular valve. Left
    atrioventricular valve regurgitation is the principal residual lesion after
    repair and the dominant driver of reoperation.
  phenotype_term:
    preferred_term: Atrioventricular valve regurgitation
    term:
      id: HP:0034376
      label: Atrioventricular valve regurgitation
  evidence:
  - reference: PMID:35757952
    reference_title: Surgical Outcomes in Children With Partial and Transitional Atrioventricular
      Septal Defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: After initial repair, there were 18 cases of moderate-to-severe left atrioventricular
      valve regurgitation (17.3%).
    explanation: Quantifies moderate-to-severe left atrioventricular valve regurgitation after
      primary repair, the dominant residual lesion.
- category: Cardiovascular
  name: Pulmonary Arterial Hypertension
  description: >-
    Elevated pulmonary arterial pressure from chronic overcirculation, progressing
    to irreversible pulmonary vascular obstructive disease if repair is delayed.
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: PMID:40179148
    reference_title: Complete Atrioventricular Septal Defect Repair in Patients With Down
      Syndrome Presenting Beyond Six Months- A Single Center Experience.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In DS, cAVSD repair is ideally performed before six months of age to prevent
      irreversible pulmonary artery hypertension (PAH).
    explanation: Associates unrepaired complete AVSD with irreversible pulmonary arterial
      hypertension.
- category: Cardiovascular
  name: Left Axis Deviation
  description: >-
    A superior/leftward QRS axis on the electrocardiogram is the characteristic
    electrocardiographic signature of AVSD, reflecting the abnormal position of the
    conduction system around the common atrioventricular junction.
  phenotype_term:
    preferred_term: Left axis deviation
    term:
      id: HP:0033568
      label: Left axis deviation
  evidence:
  - reference: PMID:10605520
    reference_title: Neonatal ECG screening for congenital heart disease in Down syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: only the five infants with complete AVSD had a superior QRS axis
    explanation: In a neonatal ECG screening cohort, a superior QRS axis was specific to
      complete AVSD among the congenital heart defects detected.
- category: Cardiovascular
  name: Left Ventricular Outflow Tract Obstruction
  description: >-
    Left ventricular outflow tract obstruction arises from the abnormal
    ("goose-neck") geometry of the left ventricular outflow in AVSD and is a
    recognised complication after surgical repair.
  phenotype_term:
    preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  evidence:
  - reference: PMID:37612667
    reference_title: Long-term results following atrioventricular septal defect repair.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: left ventricular outflow tract obstruction (LVOTO) has been described as a
      common complication following surgical repair of AVSD occurring in 2–7% of the patients
    explanation: Quantifies LVOTO as a post-repair complication of AVSD.
- category: Cardiovascular
  name: Postoperative Atrioventricular Block
  description: >-
    Complete heart block requiring permanent pacemaker implantation is a
    recognised complication of AVSD repair, reflecting the abnormal course of the
    conduction system around the common atrioventricular junction. This is a
    post-repair complication; intrinsic preoperative conduction block is not
    asserted here.
  phenotype_term:
    preferred_term: Atrioventricular block
    term:
      id: HP:0001678
      label: Atrioventricular block
  evidence:
  - reference: PMID:37612667
    reference_title: Long-term results following atrioventricular septal defect repair.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The indication for pacemaker implantation was third-degree atrioventricular block
      in 4 (2.0%) patients, second-degree atrioventricular block in 1 (0.6%) patient, and sinus
      node dysfunction in 1 (0.5%) patient.
    explanation: Documents postoperative atrioventricular block as the leading pacemaker
      indication after AVSD repair.
genetic:
- name: CRELD1
  association: Susceptibility Variant
  gene_term:
    preferred_term: CRELD1
    term:
      id: hgnc:14630
      label: CRELD1
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >-
    The first identified non-syndromic AVSD susceptibility gene. CRELD1 regulates
    calcineurin/NFAT signalling. Variants raise risk without being sufficient to
    cause the defect, which is the basis of the multigenic threshold model.
  evidence:
  - reference: PMID:15096951
    reference_title: Molecular genetics of atrioventricular septal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mutation of CRELD1 increases susceptibility to AVSD but is not alone sufficient
      to cause the defect, indicating that AVSD is multigenic
    explanation: Establishes CRELD1 as a susceptibility allele within a multigenic model.
- name: NFATC1
  association: Missense Variant
  gene_term:
    preferred_term: NFATC1
    term:
      id: hgnc:7775
      label: NFATC1
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >-
    Calcineurin/NFAT signalling is implicated in AVSD, and CRELD1 acts as a
    regulator of that pathway. Heterozygous NFATC1 missense variants have been
    identified in isolated AVSD and in AVSD with heterotaxy, placing the pathway
    itself rather than any single gene at the centre of susceptibility.
  evidence:
  - reference: PMID:30007050
    reference_title: Heterozygous missense mutations in NFATC1 are associated with atrioventricular
      septal defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Multiple lines of evidence support a role of calcineurin/NFAT signaling in
      AVSD, and mutations in CRELD1, a protein functioning as a regulator of calcineurin/NFAT
      signaling have been reported in a small fraction of affected subjects.
    explanation: Links NFATC1 and CRELD1 through the shared calcineurin/NFAT axis.
- name: HMGN1
  association: Chromosome 21 Dosage
  gene_term:
    preferred_term: HMGN1
    term:
      id: hgnc:4984
      label: HMGN1
  relationship_type: MODIFIER
  variant_origin: GERMLINE
  notes: >-
    Chromosome 21 gene whose overexpression drives myocardial reprogramming
    implicated in trisomy 21-associated heart defects, offering a mechanism for the
    approximately 1000-fold enrichment of atrioventricular canal defects in Down
    syndrome.
  evidence:
  - reference: PMID:41125893
    reference_title: Myocardial reprogramming by HMGN1 underlies heart defects in trisomy
      21.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: CHDs occur in around 50% of cases of Down syndrome, with an approximately
      1,000-fold enrichment of atrioventricular canal (AVC) defects that disrupt the
      junction between the atria and ventricles
    explanation: Frames the trisomy 21 dosage problem that HMGN1 reprogramming addresses.
- name: Multigene Burden
  association: Rare Variant Enrichment
  notes: >-
    Whole-exome sequencing of non-syndromic AVSD probands shows enrichment of rare
    damaging variants across a set of 112 genes with strong biological relevance to
    AVSD, with the enrichment specific to AVSD rather than to congenital heart
    disease generally.
  evidence:
  - reference: PMID:25996639
    reference_title: Exome sequencing identifies rare variants in multiple genes in atrioventricular
      septal defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Whole-exome sequencing was performed in 81 unrelated probands with AVSD to
      identify potentially causal variants in a comprehensive set of 112 genes with strong
      biological relevance to AVSD.
    explanation: Documents the multigene burden architecture of non-syndromic AVSD.
environmental:
- name: Maternal pregestational diabetes
  description: >-
    Maternal pregestational diabetes is the strongest established modifiable risk
    factor for non-syndromic complete atrioventricular canal defect, identified in
    a large population-based birth defects registry analysis.
  presence: PRESENT
  evidence:
  - reference: PMID:23061687
    reference_title: Descriptive epidemiology of non-syndromic complete atrioventricular
      canal defects.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Significant associations were observed between non-syndromic CAVC in offspring
      and maternal pregestational diabetes (adjusted prevalence ratio (aPR) 6.74; 95% confidence
      interval (CI) 3.67, 12.37), gestational diabetes (aPR 1.69; 95% CI 1.03, 2.79) and obesity
      (aPR 1.69; 95% CI 1.24, 2.30).
    explanation: Quantifies maternal pregestational diabetes as the strongest environmental
      risk factor for non-syndromic complete AV canal defect.
  influences_mechanisms:
  - target: Atrioventricular Mesenchymal Complex Failure
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Maternal pregestational hyperglycaemia acts on the embryo during the window of
      atrioventricular septation, raising the probability that the mesenchymal complex
      fails. The intermediate steps are not established.
    evidence:
    - reference: PMID:23061687
      reference_title: Descriptive epidemiology of non-syndromic complete atrioventricular
        canal defects.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Significant associations were observed between non-syndromic CAVC in offspring
        and maternal pregestational diabetes
      explanation: Supports the predisposing effect of maternal pregestational diabetes on
        the septation defect.
- name: Folate-rich diet
  description: >-
    Frequent periconceptional consumption of folate-rich fruits was protective for
    congenital heart disease in a population-based case-control study, whereas
    folic acid supplementation alone did not show strong support.
  evidence:
  - reference: PMID:32092068
    reference_title: 'Risk factors for congenital heart disease: The Baby Hearts Study, a
      population-based case-control study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: there was a protective effect of frequent consumption of folate rich fruits
      (adjOR 0.64, 95%CI 0.47-0.89)
    explanation: Quantifies dietary folate as a protective factor for congenital heart disease.
  influences_mechanisms:
  - target: Atrioventricular Mesenchymal Complex Failure
    environmental_effect: PROTECTS_AGAINST
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Adequate periconceptional folate lowers congenital heart disease risk overall; the
      mechanism by which it protects atrioventricular septation is not established.
    evidence:
    - reference: PMID:32092068
      reference_title: 'Risk factors for congenital heart disease: The Baby Hearts Study, a
        population-based case-control study.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: there was a protective effect of frequent consumption of folate rich fruits
        (adjOR 0.64, 95%CI 0.47-0.89)
      explanation: Supports the protective direction of the effect asserted on this link.
animal_models:
- species: Mouse (Mus musculus)
  genotype: Ts65Dn trisomic background crossed with Creld1 or Hey2 loss-of-function alleles
  category: Transgenic
  description: >-
    The Ts65Dn mouse models Down syndrome gene dosage. Crossing loss-of-function
    alleles of Creld1 or Hey2 onto this sensitised background raises congenital
    heart defect frequency, providing direct in vivo support for the
    dosage-sensitised multigenic threshold model of AVSD.
  genes:
  - preferred_term: CRELD1
    term:
      id: hgnc:14630
      label: CRELD1
  associated_phenotypes:
  - Congenital heart defect
  modeled_mechanisms:
  - target: Trisomy 21 Gene Dosage Effect
    relationship: PARTIALLY_RECAPITULATES
    description: >-
      Tests whether chromosome 21 dosage sensitises the atrioventricular canal such that
      additional loss-of-function alleles precipitate septation failure.
    fidelity: MODERATE
    limitations: >-
      Ts65Dn is trisomic for a subset of the human chromosome 21 orthologous region, and
      murine cardiac septation differs from human, so defect frequency rather than the
      human AVSD lesion is the readout.
    evidence:
    - reference: PMID:22523272
      reference_title: Genetic modifiers predisposing to congenital heart disease in the sensitized
        Down syndrome population.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Crossing loss-of-function alleles of either Creld1 or Hey2 onto the trisomic
        background caused a significant increase in the frequency of CHD
      explanation: The readout that grounds this model link - added genetic hits on the trisomic
        background raise congenital heart defect frequency.
  evidence:
  - reference: PMID:22523272
    reference_title: Genetic modifiers predisposing to congenital heart disease in the sensitized
      Down syndrome population.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Crossing loss-of-function alleles of either Creld1 or Hey2 onto the trisomic
      background caused a significant increase in the frequency of CHD
    explanation: Demonstrates in vivo that additional genetic hits on a trisomic background
      raise congenital heart defect frequency.
diagnosis:
- name: Echocardiography
  description: >-
    Echocardiography is the diagnostic modality for AVSD, defining the common
    atrioventricular junction, the atrial and ventricular components of the defect,
    valve morphology and the degree of regurgitation. AVSD is frequently detected
    on fetal echocardiography.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:34196822
    reference_title: 'Atrioventricular Septal Defects: Pathology, Imaging, and Treatment Options.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The understanding of functional morphology of AVSDs has improved significantly
      with detailed 3D echocardiographic evaluation of the atrioventricular junction and valve
      morphology.
    explanation: Directly establishes echocardiographic evaluation of the atrioventricular
      junction and valve morphology as the assessment underpinning AVSD diagnosis.
- name: Genetic testing
  description: >-
    Chromosomal microarray and exome sequencing are applied to fetuses and infants
    with AVSD detected on echocardiography. AVSD carries one of the higher genetic
    diagnostic yields among congenital heart defects, reflecting its strong
    aneuploidy association.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:33142350
    reference_title: Comprehensive evaluation of genetic variants using chromosomal microarray
      analysis and exome sequencing in fetuses with congenital heart defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The prevalence of a genetic defect was highest in fetuses with an atrioventricular
      septal defect (36.8%)
    explanation: Quantifies AVSD as the congenital heart defect subgroup with the highest
      genetic diagnostic yield, which is why genetic testing is indicated.
treatments:
- name: Surgical Repair of Atrioventricular Septal Defect
  description: >-
    Biventricular surgical repair, by single-patch, modified single-patch or
    double-patch technique, closing the atrial and ventricular components and
    reconstructing the atrioventricular valves. Performed in infancy to pre-empt
    irreversible pulmonary vascular disease. Long-term survival is now
    approximately 88% at 10 years and 80% at 25 years.
  treatment_term:
    preferred_term: atrioventricular septal defect repair
    term:
      id: NCIT:C217463
      label: Atrioventricular Septal Defect Repair
  target_mechanisms:
  - target: Common Atrioventricular Junction
    treatment_effect: BYPASSES
    description: >-
      Patch closure of the atrial and ventricular components and septation of the common
      valve reconstitute separate right and left atrioventricular junctions.
    evidence:
    - reference: PMID:37612667
      reference_title: Long-term results following atrioventricular septal defect repair.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Definitive early repair is favored over prior pulmonary artery banding and
        delayed definitive repair in many centers.
      explanation: Establishes definitive repair as the intervention acting on the anatomic
        lesion.
  - target: Left-to-Right Shunt and Valve Regurgitation
    treatment_effect: BYPASSES
    description: >-
      Eliminating the communications abolishes the shunt and the volume load that drives
      heart failure and pulmonary vascular disease.
    evidence:
    - reference: PMID:40179148
      reference_title: Complete Atrioventricular Septal Defect Repair in Patients With Down
        Syndrome Presenting Beyond Six Months- A Single Center Experience.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: In DS, cAVSD repair is ideally performed before six months of age to prevent
        irreversible pulmonary artery hypertension (PAH).
      explanation: Repair abolishes the shunt specifically to pre-empt the pulmonary vascular
        consequence.
  evidence:
  - reference: PMID:40154545
    reference_title: A 27-Year Experience with Atrioventricular Septal Defect Correction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Survival of the entire cohort was 88.3% at 10, 83.8% at 15, and 79.6% at 25
      years.
    explanation: Provides long-term survival after biventricular repair across a 27-year
      single-centre series.
  - reference: PMID:37612667
    reference_title: Long-term results following atrioventricular septal defect repair.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Definitive early repair is favored over prior pulmonary artery banding and
      delayed definitive repair in many centers.
    explanation: Documents the shift to primary early repair rather than staged palliation.
- name: Left Atrioventricular Valve Repair
  description: >-
    Cleft closure and valvuloplasty of the left atrioventricular valve at the time
    of primary repair, with reoperation for significant residual or recurrent
    regurgitation. Left atrioventricular valve regurgitation is the dominant
    reoperation indication.
  treatment_term:
    preferred_term: heart valve repair
    term:
      id: NCIT:C50818
      label: Heart Valve Repair
  target_mechanisms:
  - target: Left-to-Right Shunt and Valve Regurgitation
    treatment_effect: RESTORES
    description: >-
      Cleft closure and valvuloplasty restore competence of the left atrioventricular valve,
      removing the regurgitant component of the volume load.
    evidence:
    - reference: PMID:35757952
      reference_title: Surgical Outcomes in Children With Partial and Transitional Atrioventricular
        Septal Defect.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: All but eight patients (92.3%) underwent left atrioventricular valve cleft
        closure.
      explanation: Documents cleft closure as the standard manoeuvre restoring valve competence.
  evidence:
  - reference: PMID:35757952
    reference_title: Surgical Outcomes in Children With Partial and Transitional Atrioventricular
      Septal Defect.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All but eight patients (92.3%) underwent left atrioventricular valve cleft
      closure.
    explanation: Documents cleft closure as near-universal practice at primary repair.
progression:
- phase: Infantile presentation and repair
  age_range: First year of life for the complete form
  notes: >-
    The complete form presents in early infancy with congestive heart failure and
    is repaired within the first months of life; partial and transitional forms
    present and are repaired later. Early definitive repair has displaced staged
    pulmonary artery banding in most centres.
  evidence:
  - reference: PMID:40154545
    reference_title: A 27-Year Experience with Atrioventricular Septal Defect Correction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Median age at repair was 7.1 for cAVSD, 23.7 for pAVSD, and 13 months for
      tAVSD.
    explanation: Documents the age at repair differing by anatomic subtype.
- phase: Long-term follow-up
  notes: >-
    Survival after repair is good and has improved across surgical eras, but left
    atrioventricular valve regurgitation continues to drive reoperation, so
    lifelong cardiology follow-up is required.
  evidence:
  - reference: PMID:40154545
    reference_title: A 27-Year Experience with Atrioventricular Septal Defect Correction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Overall survival or reoperation incidence did not differ significantly between
      AVSD types and improved significantly over surgical eras.
    explanation: Documents improving long-term outcome across eras and the persistence of
      reoperation as an endpoint.
disease_term:
  preferred_term: atrioventricular septal defect
  term:
    id: MONDO:0859565
    label: atrioventricular septal defect
notes: >-
  Relationship to Congenital_Heart_Disease.yaml: AVSD is present there as a
  has_subtypes stub (name, description, subtype_term MONDO:0859565) anchored on
  that entry's endocardial cushion / EndMT pathophysiology arm. This entry is the
  standalone lesion entry, following the pattern already used for Tetralogy of
  Fallot, atrial septal defect, hypoplastic left heart syndrome, double outlet
  right ventricle and persistent truncus arteriosus, each of which coexists with
  the CHD root. The endocardial cushion mechanism is therefore stated in both
  places. A shared kb/modules/ module for atrioventricular septation would be the
  cleaner long-term factoring; none exists today and the CHD root uses no
  conforms_to at all.

  MONDO hierarchy defect: MONDO places the general term used here
  (MONDO:0859565 atrioventricular septal defect) as a child of MONDO:0020290
  familial atrioventricular septal defect, which inverts the expected direction —
  the general concept should not be subsumed by the familial one. The priority
  dashboard targets MONDO:0020290. This entry binds the general term because it
  covers sporadic and trisomy 21-associated AVSD, which the familial term
  excludes. Worth reporting upstream, in the same spirit as issue #7543.

  Mechanism attribution held loosely: the report underpinning this entry
  attributed EndoMT control to TGF-beta, BMP, Notch and Wnt signalling on the
  strength of PMID:29549339. That paper does not establish those roles — it is a
  methodological caution showing that cells scored as endothelial in the standard
  atrioventricular canal explant assay are largely epicardial, which undercuts
  pathway attributions made with that assay. Only the framing statements from it
  are cited here, and the caveat is recorded as PARTIAL evidence on the EndoMT
  node.

  Failure to thrive and tachypnoea remain unasserted for want of a citable source,
  after targeted PubMed searches rather than as a standing scoping decision. Both
  are recognised features of infantile AVSD; neither is stated in any reference
  cached for this entry. Postoperative atrioventricular block is curated as a
  phenotype from PMID:37612667; intrinsic preoperative conduction block is not,
  since no cached source states it.

  ECTO was searched for exposure_term bindings on the two environmental entries
  and both are deliberately left unbound: there is no maternal-hyperglycaemia
  exposure term, and ECTO:9000123 exposure to folic acid would misrepresent the
  dietary-folate-versus-supplement distinction this entry draws, since the cited
  study found the protective effect for folate-rich fruit and not for
  supplementation. Frequency qualifiers are likewise omitted throughout - the
  stratified figures available (congestive heart failure 62% vs 84%, pulmonary
  arterial hypertension 38% vs 16%, Down versus non-Down) could not be traced to a
  quotable cached source, and a frequency band asserted without its own evidence is
  worse than none.

  Known extension points: subtype_term bindings for the complete and partial
  forms (MONDO:0015273 complete atrioventricular canal, MONDO:0015275 partial
  atrioventricular canal) were not added pending the DiseaseOrSubtypeTerm enum
  cache limitation tracked in issue #6989; a datasets section; and clinical_trials.
📚

References & Deep Research

Deep Research

1
OpenScientist ▸
Atrioventricular Septal Defect (AVSD): A Comprehensive Disease Characteristics Report
openscientist-autonomous 66 citations 2026-08-27T13:11:28.115055

Atrioventricular Septal Defect (AVSD): A Comprehensive Disease Characteristics Report

Disease: Atrioventricular Septal Defect (AVSD) — also atrioventricular canal defect / endocardial cushion defect MONDO ID: MONDO:0859565 Category: Congenital heart defect (endocardial cushion / atrioventricular canal defect) Evidence base: 92 primary papers reviewed; 22 findings recorded; 5 hypotheses (all supported). Information derived from aggregated disease-level resources plus clinical cohorts, model-organism studies, and in vitro/computational work.

Summary

Atrioventricular septal defect (AVSD) is a congenital cardiac malformation defined by a common atrioventricular (AV) junction resulting from deficient development of the atrioventricular septum. Anatomically it comprises an ostium primum atrial communication and/or an inlet ventricular septal defect together with an abnormal AV valve — either a single common valve (complete AVSD) or two valve orifices with a cleft left AV valve (partial AVSD). The malformation arises from failed atrioventricular-canal endocardial cushion development, specifically defective endothelial-to-mesenchymal transition (EndoMT) governed by TGF-β, BMP, Notch and Wnt/β-catenin signaling (PMID: 29549339). AVSD represents roughly 4–7% of all congenital cardiac malformations (PMID: 37612667).

AVSD has the tightest link of any congenital heart defect to trisomy 21 (Down syndrome): AVSD is the most common heart defect in Down syndrome (~44%), and roughly half of all AVSD cases occur in the context of Down syndrome (PMID: 39104126; PMID: 37667895). Beyond trisomy 21, the genetic architecture is heterogeneous and often oligogenic, involving cardiac transcription factors and developmental signaling genes (CRELD1, GATA4/6, NR2F2, NFATC1, GDF1, NOTCH1, BMPR1A, HEY2) plus rare copy-number variants, converging on the CRELD1–calcineurin/NFATc1–VEGF axis (PMID: 15096951; PMID: 30007050; PMID: 24697899). On chromosome 21, gene-dosage effects (cooperative DSCAM+COL6A2 overexpression; HMGN1-driven myocardial reprogramming) contribute to the trisomy-21 phenotype (PMID: 22072978; PMID: 41125893). Maternal pregestational diabetes is a strong modifiable environmental risk factor (adjusted prevalence ratio ~6.7 for non-syndromic AVSD), while folate-rich diet is protective (PMID: 23061687; PMID: 32092068).

Hemodynamically, the defect produces a large left-to-right shunt with common-valve regurgitation, causing infantile congestive heart failure and, if left unrepaired, irreversible pulmonary vascular obstructive disease (Eisenmenger physiology) (PMID: 1943197; PMID: 10812553). Diagnosis rests on echocardiography (AVSD is the most common fetal cardiac diagnosis, with 90–100% fetal-echo sensitivity and the highest genetic-testing yield of any CHD subtype) (PMID: 37240614; PMID: 34196822; PMID: 33142350). Treatment is surgical repair in infancy (single-patch, modified single-patch, or double-patch), with excellent modern long-term survival (~80–88% at 10–25 years) and left AV valve regurgitation as the principal residual problem and reoperation driver (PMID: 40154545; PMID: 34002204).

This report synthesizes 22 confirmed findings from 10 iterations across 92 reviewed papers, organized against the 15-section disease-characteristics template.

1. Disease Information

AVSD (atrioventricular septal defect) is a structural congenital heart malformation characterized by a common atrioventricular junction with deficient atrioventricular septation. The core anatomic lesion is an ostium primum atrial septal defect and/or an inlet ventricular septal defect with an abnormal common or cleft atrioventricular valve (PMID: 8347012). Forms range from partial/incomplete (primum ASD + cleft left AV valve, two valve orifices) through transitional to complete (single common AV valve, combined atrial and ventricular communications).

Key identifiers: - MONDO: MONDO:0859565 - Common synonyms/alternative names: atrioventricular canal defect, common atrioventricular canal (CAVC), endocardial cushion defect, AV canal defect, persistent common atrioventricular canal - ICD-10: Q21.2 (atrioventricular septal defect); MeSH: "Heart Septal Defects" / "Endocardial Cushion Defects" - Additional clinical descriptors: complete AVSD (CAVSD), partial AVSD (pAVSD), transitional AVSD

Source of information: This report draws primarily on aggregated disease-level resources — surgical/echocardiographic cohorts, population-based birth-defect registries (Texas Birth Defects Registry, National Birth Defects Prevention Study, US National Inpatient Sample), genetic studies, and model-organism experiments — rather than individual EHR records.

2. Etiology

Disease Causal Factors

AVSD is a multifactorial, genetically heterogeneous malformation. The unifying developmental cause is failed fusion/development of the atrioventricular-canal endocardial cushions (see Section 6). Causal contributors span:

  • Chromosomal: trisomy 21 (the single largest contributor), plus other aneuploidies (trisomy 18, trisomy 13) and specific deletions (e.g., 3p25–pter / 3p- syndrome, in which AVSD occurs in ~one-third of patients; PMID: 19760623).
  • Single-gene / oligogenic: CRELD1, GATA4, GATA6, NR2F2, NKX2-5, TBX5, BMP4, NFATC1, GDF1, NOTCH1, BMPR1A, HEY2 (see Section 4).
  • Environmental: maternal pregestational and gestational diabetes, maternal obesity, poor periconceptional diet.

CRELD1 was the first identified non-syndromic AVSD susceptibility gene; critically, "Mutation of CRELD1 increases susceptibility to AVSD but is not alone sufficient to cause the defect, indicating that AVSD is multigenic" (PMID: 15096951).

Risk Factors

Genetic risk factors — trisomy 21 (dominant), CRELD1 missense variants (~5–10% of simplex AVSD carry a CRELD1 missense mutation; PMID: 25328912), and rare damaging variants across ~112 biologically relevant genes enriched in AVSD probands (OR 1.52, 95% CI 1.35–1.71, P = 4.8×10⁻¹¹; PMID: 25996639).

Environmental risk factors — maternal pregestational diabetes is the strongest (adjusted prevalence ratio [aPR] 6.74, 95% CI 3.67–12.37 for non-syndromic complete AV canal), followed by gestational diabetes (aPR 1.69) and obesity (aPR 1.69) (PMID: 23061687). Advanced maternal age (via aneuploidy risk), low maternal education, and poor diet are additional contributors (PMID: 32092068).

Protective Factors

Environmental protective factors — frequent consumption of folate-rich fruits was protective for CHD (adjusted OR 0.64, 95% CI 0.47–0.89), and consistent periconceptional folic-acid supplementation trended protective for cardiac-inclusive anomalies (aOR 0.5, 95% CI 0.3–1.0) (PMID: 32092068; PMID: 33179873). Genetic protective factors specific to AVSD are not well established.

Gene–Environment Interactions

The clearest example is a genetic-threshold/modifier model: crossing loss-of-function alleles of Creld1 or Hey2 onto the trisomic Ts65Dn background "caused a significant increase in the frequency of CHD," demonstrating that additional genetic perturbations push a dosage-sensitized background across a defect threshold (PMID: 22523272). On the environmental side, gestational diabetes and obesity show additive interaction for AVSD risk (RERI 1.1, 95% CI −0.1 to 2.3; PMID: 33876578).

3. Phenotypes

Phenotype Type Onset Frequency / Severity Suggested HPO
Atrioventricular septal defect (structural) Physical/structural malformation Congenital Defining feature HP:0006695
Congestive heart failure Clinical sign Neonatal–infantile (mean ~50 days) 62% (Down) – 84% (non-Down) complete AVSD HP:0001635
Pulmonary arterial hypertension Clinical sign Infantile, earlier in Down syndrome 38% (Down) vs 16% (non-Down) HP:0002092
Common AV valve regurgitation Physical manifestation Congenital/infantile Common; drives symptoms HP:0031652 / HP:0000023
Tachypnea / respiratory distress Symptom Infantile Common HP:0002789
Failure to thrive / poor weight gain Sign Infantile Common HP:0001508
Recurrent respiratory infections Sign Infantile Common HP:0002205
Arrhythmia (AV block, atrial flutter/fibrillation) ECG abnormality Variable; high long-term risk Among highest of all CHDs HP:0011675
Superior/leftward ("northwest") QRS axis ECG abnormality Congenital Characteristic HP:0031547

Phenotype characteristics: Symptoms typically begin in the first weeks-to-months of life (mean symptom onset ~50 ± 75 days in complete AVSD; PMID: 9532811). Severity ranges from mild (partial AVSD, sometimes asymptomatic into adulthood) to severe (complete AVSD with heart failure). Progression is progressive if unrepaired, driven by pulmonary overcirculation. A key phenotypic contrast: "There seems to be a pulmonary vascular hyperreactivity predominance in Down's children and cardiac insufficiency signs in the normal genetic group" (PMID: 9532811) — non-Down patients had more severe AV valve morphologic lesions (38% vs 8%).

Quality of life impact: After repair, long-term QoL is favorable — self- or caregiver-reported QoL was "excellent or good in 81%" of patients up to 40 years after single-patch complete AVSD repair (PMID: 34953470).

4. Genetic / Molecular Information

Causal and Susceptibility Genes

Gene (HGNC) Role / Evidence Variant examples Key PMID
CRELD1 First non-syndromic AVSD susceptibility gene; regulates calcineurin/NFATc1; ~5–10% of simplex AVSD p.A286P, p.E325K, c.973G>A (p.Glu325Lys) in cb-EGF calcium-binding domains 15096951, 21080147, 29054759, 25328912
NFATC1 Heterozygous missense; defective nuclear translocation, reduced transactivation p.Ala367Val (isolated AVSD); p.Val210Met, p.Ala696Thr (+heterotaxy) 30007050
GATA6 Cardiac transcription factor; variants in complex CHD incl. AVSD A178V (gain of transactivation), L198V 20581743
GATA4, NKX2-5, TBX5, BMP4 Established CHD candidate genes (MLPA CHD panel) CNVs / point variants 29952356
NIPBL, CHD7, CEP152, BMPR1a, ZFPM2, MDM4 Exome-enriched for rare variants in AVSD vs controls (3 syndrome-associated) Rare/rare-damaging 25996639
GDF1 + NOTCH1 Co-occurring variants in oligogenic non-syndromic AV canal + coarctation — 38975735
BMPR1A Familial CHD (Ebstein + AVSD) co-segregating with chr1 linkage p.R443H 30814609
DNAH11, MKS1 (cilia genes) ENU mouse recessive AVSD via L/R axis + Hedgehog/second heart field — 27340223

The genetic etiology remains unknown in ~40% of cases (PMID: 25996639). Exome sequencing found significant enrichment of rare variants in AVSD vs tetralogy of Fallot (OR 2.25, P = 2.2×10⁻¹⁶), indicating disease-specific genetic burden. Diagnostic yield of exome sequencing in Southern African CHD was 7.9% (PMID: 42037320).

Variant Classification, Type, Origin, and Consequences

  • Classification (ACMG/AMP): ranges from pathogenic/likely pathogenic (aneuploidy, syndromic-gene LOF) to VUS (many CRELD1/GATA6 missense variants).
  • Variant type: missense (CRELD1, NFATC1, GATA6, BMPR1A), plus structural/copy-number variants; aneuploidy (trisomy 21) is the dominant chromosomal class.
  • Origin: predominantly germline; somatic origin is not a feature of AVSD.
  • Functional consequences: loss of function (NFATC1 — "defective nuclear translocation and decreased transcriptional transactivation activity"; PMID: 30007050), gain of function (GATA6 A178V increased transactivation), and dosage effects (chr21 genes).

Modifier Genes and Chromosomal Abnormalities

Modifiers: VEGFA interacts allelically with CRELD1 as a modifier of AVSD risk (PMID: 25328912); Creld1 and Hey2 modify trisomy-21 CHD frequency (PMID: 22523272). Chromosomal abnormalities: trisomy 21 predominates. Rare CNV burden in 150 AVSD cases concentrated on chromosomes 19, 22, 21, and 16 and nominated 20 candidate genes (PMID: 36816019). In 262 Chinese complete AV canal cases, potentially-causative CNVs were found in 16.4%, of which 90.7% carried 21q11.2–q22.3 duplication (trisomy 21) (PMID: 34627233).

Epigenetic information: The chr21 chromatin architectural protein HMGN1 drives trisomy-21 heart defects via myocardial transcriptional/chromatin reprogramming (PMID: 41125893).

Suggested ontology terms: HGNC CRELD1, GATA4, GATA6, NFATC1, NOTCH1, BMPR1A, HMGN1; CHEBI:calcium (calcium-binding EGF domain).

5. Environmental Information

Environmental factors: Maternal metabolic environment dominates. Pregestational diabetes is the strongest single non-genetic factor: "Significant associations were observed between non-syndromic CAVC in offspring and maternal pregestational diabetes (aPR 6.74; 95% CI 3.67, 12.37), gestational diabetes (aPR 1.69) and obesity (aPR 1.69)" (PMID: 23061687). Pregestational diabetes was strongly associated with most birth defects (OR 2.0–75.9) in the National Birth Defects Prevention Study (PMID: 33876578).

Lifestyle factors: Poor maternal diet low in fruit/vegetables increased CHD risk (aOR 1.56); maternal smoking (~2-fold) and overweight/obesity (aOR 1.8) were risk factors for cardiac-inclusive anomalies (PMID: 32092068; PMID: 33179873). Folate-rich diet is protective (see Section 2).

Infectious agents: Not applicable — AVSD is a developmental malformation, not an infectious disease.

6. Mechanism / Pathophysiology

The Central Developmental Mechanism: Failed Endocardial Cushion EndoMT

The AV septum and valves derive from endocardial cushions, formed when endocardial cells of the atrioventricular canal (AVC) undergo endothelial-to-mesenchymal transition (EndoMT/EMT), delaminate, and invade the cardiac jelly (extracellular matrix). "Atrioventricular septal defects often result from impaired endocardial cushion development. Endothelial-to-mesenchymal transition (EndoMT) is a critical event in endocardial cushion development that initiates in the atrioventricular canal (AVC)" (PMID: 29549339).

Molecular pathways governing EndoMT:

  • TGF-β signaling induces EndoMT; MBNL1 negatively regulates TGF-β/EMT, and Mbnl1-null mice show precocious EMT, later valve dysmorphia, and ostium secundum septal defects (PMID: 26472242).
  • BMP signaling — "Bone morphogenetic protein (BMP) signalling plays a key role in regulating the development of the atrioventricular (AV) septum and valves"; Sema6D acts downstream of BMP to promote AV cushion development (PMID: 28172500).
  • Notch signaling gates the process — endocardial Mib1–Dll4–Notch1 drives EMT and Jag1–Notch1 restrains post-EMT proliferation; "Mice lacking endocardial Jag1, Notch1, or RBPJ displayed enlarged valve cusps, bicuspid aortic valve, and septal defects" (PMID: 27056911). Manic Fringe (MFNG) promotes Notch-mediated EndMT; "Aberrant EndMT is a primary cause of congenital valvular malformations" (PMID: 39528804).
  • Wnt/β-catenin signaling — "Disruption of these Wnt/β-catenin signaling roles that enable developmental transitions during valvulogenesis could account for common congenital valve defects" (PMID: 26893350).
  • NADPH oxidase NOX2-derived ROS is critical to EndoMT and heart development (PMID: 32655758).

The CRELD1 → Calcineurin/NFATc1 → VEGF Axis

A specific convergent module operates in AV canal endocardium: "Multiple lines of evidence support a role of calcineurin/NFAT signaling in AVSD, and mutations in CRELD1, a protein functioning as a regulator of calcineurin/NFAT signaling have been reported" (PMID: 30007050). Murine work established the causal chain: "Creld1 function is required for the VEGF-dependent proliferation of endocardial cells by promoting the expression of NFATc1 target-genes" (PMID: 24697899); Creld1 promotes NFATc1 dephosphorylation and nuclear translocation via a complex with the calcineurin regulatory subunit CnB at the endoplasmic reticulum. Human pre-valvular endocardial cells from pluripotent stem cells recapitulate BMP2-responsive AVC EndoMT in vitro (PMID: 31028265).

Trisomy 21 Gene-Dosage Mechanisms

  • Cooperative overexpression: DSCAM and COL6A2 (both chr21) are "the most strongly interacting pair of genes"; co-overexpression in mouse heart caused "≈50% mortality and severe physiological and morphological defects, including atrial septal defects and cardiac hypertrophy," whereas single-gene overexpression did not (PMID: 22072978).
  • HMGN1-mediated reprogramming: the chromatin architectural gene HMGN1 drives myocardial transcriptional reprogramming underlying trisomy-21 heart defects (PMID: 41125893).

Hemodynamic Pathophysiology (Downstream Clinical Mechanism)

Once the structural defect exists, a large left-to-right shunt develops. "With increasing shunt ratio the pulmonary perfusion raised (r = 0.84), but the systemic output dropped significantly (r = -0.77)" (PMID: 10812553). Untreated, "The natural history of patients with complete atrioventricular canal defect is one of unrelenting development of pulmonary vascular obstructive disease" (PMID: 1943197), culminating in Eisenmenger physiology.

Causal Chain Diagram

UPSTREAM (developmental)                          DOWNSTREAM (clinical)
─────────────────────────────────────────────────────────────────────────
Trisomy 21 dosage (DSCAM+COL6A2, HMGN1)
   │
Genetic variants (CRELD1, NFATC1, GATA4/6,        Structural defect
   NOTCH1, BMPR1A, GDF1, HEY2)                     (common AV junction,
   │          +                                    primum ASD ± inlet VSD,
Maternal environment (diabetes, obesity)           common/cleft AV valve)
   │                                                      │
   ▼                                                      ▼
Impaired AVC endocardial cushion EndoMT           Large left-to-right shunt
(TGF-β / BMP / Notch / Wnt / NOX2-ROS;              + AV valve regurgitation
 CRELD1→calcineurin/NFATc1→VEGF)                          │
   │                                                      ▼
   ▼                                              Pulmonary overcirculation →
Failed AV septation & valve formation             CHF (infancy) → pulmonary
                                                   vascular obstructive disease
                                                   → Eisenmenger (if untreated)

GO terms: GO:0003198 (EMT involved in endocardial cushion formation), GO:0003181 (atrioventricular valve morphogenesis), GO:0060411 (cardiac septum morphogenesis). CL terms: CL:0002350 (endocardial cell), CL:0000057 (fibroblast/valve interstitial cell), CL:0000746 (cardiac muscle cell).

7. Anatomical Structures Affected

Organ level: The heart is the primary affected organ, specifically the atrioventricular septum and atrioventricular valves. Secondary organ involvement includes the lungs/pulmonary vasculature (pulmonary vascular obstructive disease) and, via heart failure, the liver (hepatomegaly). The cardiovascular and respiratory systems are principally involved.

Anatomical detail: AVSD is defined by a common atrioventricular junction with deficient AV septation. The Rastelli classification categorizes the anterior (superior) bridging leaflet of the common valve into types A, B, and C, guiding surgical strategy; interventricular communication under the posterior leaflet is surgically decisive (PMID: 8347012). In Down syndrome, characteristic outlet-septum anterior malalignment occurs — "Outlet extension of the ventricular component of the defect with outlet septum anterior malalignment was found in 90.6% of Down vs 12.8% of non-Down patients" (PMID: 39892564) — and Rastelli type A morphology is an independent risk factor for pulmonary vascular disease in Down syndrome (PMID: 10946038).

Tissue and cell level: Affected tissues include the endocardial cushion mesenchyme, AV valve leaflet connective tissue, and adjacent myocardium. Key cell populations: endocardial (endothelial) cells undergoing EndoMT and their mesenchymal/valve interstitial cell derivatives; cardiomyocytes in trisomy-21 reprogramming.

Subcellular level: GO cellular components implicated: nucleus (NFATc1 translocation; HMGN1 chromatin), endoplasmic reticulum (Creld1–calcineurin complex), and extracellular matrix / cardiac jelly.

Localization: Central heart — the atrioventricular canal region; the lesion is midline/central rather than lateralized. UBERON terms: UBERON:0002087 (atrioventricular region), UBERON:0002078/0002079 (right/left cardiac atrium), UBERON:0003504 (cardiac atrioventricular valve), UBERON:0002094 (interatrial septum), UBERON:0002099 (interventricular septum), UBERON:0002348 (endocardium).

8. Temporal Development

Onset: Congenital — the structural defect forms during embryonic cardiac septation (weeks 4–8 of human development). Clinical symptoms emerge in the neonatal-to-infantile period, with mean symptom onset ~50 ± 75 days in complete AVSD (PMID: 9532811). Onset pattern is insidious-to-subacute as pulmonary vascular resistance falls postnatally and the left-to-right shunt increases.

Progression: Without repair, the course is progressive — pulmonary overcirculation → congestive heart failure → pulmonary vascular obstructive disease. "The natural history ... is one of unrelenting development of pulmonary vascular obstructive disease" (PMID: 1943197). Partial AVSD may progress more slowly and occasionally present in adulthood.

Critical periods / windows of intervention: Complete AVSD is repaired at ~3–6 months of age to preempt irreversible pulmonary vascular disease. Late repair (≥6 months) can yield comparable outcomes in resource-limited settings (PMID: 42079968), but advanced pulmonary vascular disease may already be established at operation (PMID: 1943197). Remission is treatment-induced (surgical repair); spontaneous resolution does not occur for complete AVSD. Disease is lifelong — repaired patients require ongoing surveillance for LAVV regurgitation, LVOT obstruction, and arrhythmias.

9. Inheritance and Population

Epidemiology: AVSD accounts for ~4–7% of all congenital cardiac malformations (PMID: 37612667) and ~2.6% of pediatric CHD hospitalizations; US prevalence increased over 2016–2020 (PMID: 38277408). It is the most common CHD in Down syndrome (44.4%; PMID: 39104126) and, conversely, ~54.7% of AVSD cases occur with Down syndrome (PMID: 37667895).

Inheritance pattern: Predominantly multifactorial/polygenic with strong chromosomal (trisomy 21) contribution. Non-syndromic familial cases show oligogenic inheritance (e.g., co-occurring GDF1+NOTCH1; BMPR1A co-segregating with a chr1 linkage region) rather than a single Mendelian gene (PMID: 38975735; PMID: 30814609). Penetrance is incomplete and expressivity is variable — consistent with CRELD1 being susceptibility rather than sufficient (PMID: 15096951). Genetic anticipation and repeat-expansion mechanisms are not applicable.

Population demographics: - Down syndrome is the dominant demographic association. - Sex ratio: slight female predominance — girl:boy ratio 1.17:1 in a population-based Bohemian study (PMID: 7997413); in Chinese CAVC-with-DS cases the female:male ratio was 1.6:1.0 (PMID: 34627233). - Age distribution: presents in infancy; a growing adult congenital population exists (partial AVSD, repaired complete AVSD). - Consanguinity and founder effects are relevant for rare recessive/syndromic forms but not central to AVSD epidemiology.

10. Diagnostics

Echocardiography is the gold standard — both fetal and postnatal. The diagnostic plane is the four-chamber view demonstrating a common AV junction, common AV valve, and the ostium primum and inlet communications: "the four-chamber views ... showed the atrioventricular septal defect and a common AV valve" (PMID: 36766561).

  • Prenatal detection: high — antenatal diagnosis of complete AVSD ranges 57–92% (PMID: 27981284); increased detection has made AVSD "the most common fetal cardiac diagnosis" (PMID: 34196822). Expert fetal echo shows sensitivity 90–100%, specificity/NPV 97–100%, PPV 85–100%, with Cohen's kappa >0.9 vs postnatal MRI (PMID: 37240614).
  • AI-assisted detection: the atrial-to-ventricular length ratio (AVLR) via CNN landmark detection is greater in AVSD than controls (P < 0.0001, AUC up to 0.992; PMID: 38323184); FINE/STIC 4D identified the common AV valve in 100% of four-chamber volumes with autopsy confirmation (PMID: 36766561).
  • ECG: classically shows a superior/leftward ("northwest") QRS axis with AV conduction delay.
  • Cardiac MRI/CT and cardiac catheterization (for pulmonary vascular resistance assessment) are adjuncts.

Genetic testing is integral given the aneuploidy link. Among unselected CHD fetuses, positive genetic diagnosis was highest for AVSD at 36.8% (chromosomal microarray detecting aneuploidy/pathogenic CNV in 16.7% overall; exome sequencing adding 6.7%; PMID: 33142350). Recommended workup: karyotype/chromosomal microarray (CMA) first-line (to detect trisomy 21 and pathogenic CNVs), with exome sequencing for non-isolated/syndromic or CMA-negative cases; MLPA CHD panels (GATA4, NKX2-5, TBX5, BMP4, CRELD1, 22q11.2) offer a cheaper first-tier screen (PMID: 29952356).

Clinical criteria & differential diagnosis: Diagnosis is anatomic (echo-based). Differentials include isolated ostium primum/secundum ASD, isolated inlet VSD, common atrium (near-complete absence of interatrial septum; PMID: 34993374), and heterotaxy-associated AVSD (AVSD is the most common cardiac anomaly in atrial isomerism; PMID: 28603940).

Screening: Because ~half of children with Down syndrome have CHD (most commonly AVSD), echocardiographic screening of all newborns/infants with Down syndrome is standard, though access barriers limit it in resource-poor settings (PMID: 41877065).

11. Outcome / Prognosis

Survival after repair is excellent and has improved across surgical eras.

Cohort / setting Outcome PMID
27-year single-center (n=248) Survival 88.3% (10y), 83.8% (15y), 79.6% (25y); prematurity HR 2.43 40154545
Australian multi-institutional (n=829) Operative mortality 3.3%; survival 91.7/90.7/88.7% at 10/15/20y 34002204
Double-patch series (n=202) In-hospital mortality 0.5%; freedom from reop 91.8/86.9/86.9% at 5/10/15y 37612667
Single-patch, up to 40y (n=100) Hospital mortality 11% (older era); QoL excellent/good 81%; normal LV in all 34953470
Partial/transitional (n=136) No deaths; 2.9% reoperation at ~4y 41659084
US NIS <1yr (n=61,101) Overall AVSD mortality 6.3% 37667895

Morbidity / disease course: The dominant late complication is left AV valve (LAVV) regurgitation, the principal reoperation driver, followed by LVOT obstruction (PMID: 41971883; PMID: 40208292). AVSD carries among the highest long-term arrhythmia risk of all CHDs (advanced AV block, atrial flutter/fibrillation; overall CHD arrhythmia HR 16.4, 95% CI 14.4–18.7; PMID: 39233212). Pulmonary hypertension is a key complication, more frequent in Down syndrome (4.3% vs 2.8%, P < 0.001; PMID: 37667895).

Prognostic factors: prematurity and low birth weight (mortality), pulmonary hypertension, prior pulmonary artery banding, surgical era, non-Down status and moderate postoperative LAVV regurgitation (reoperation risk; PMID: 34002204). Interestingly, older age at repair and Down syndrome were associated with decreased LAVV reintervention risk (PMID: 40208292). A high postoperative leuko-glycemic index predicts prolonged mechanical ventilation and acute kidney injury in Down-syndrome infants (PMID: 41764019).

12. Treatment

Definitive treatment is surgical biventricular repair — closure of the atrial (ostium primum) and ventricular components and reconstruction of the left AV valve (including cleft closure). NCIT concept: cardiac surgical repair of septal defect.

Surgical techniques: - Classic single-patch, modified single-patch ("Australian"/Nunn technique), and two-patch (double-patch) repair. The Nunn-modified single-patch achieves >90% freedom from LAVV reoperation and >97% freedom from LVOT obstruction at 10–15 years (PMID: 41313357). - Complete AVSD is repaired in infancy (~3–6 months) to prevent irreversible pulmonary vascular disease. "Early intervention, in the first 6 months ... gives comparable acceptable results to later repair; Trisomy 21 was not found to be a risk factor for early intervention" (PMID: 34350818). The modified single-patch shortened bypass time (71 vs 99 min, P = 0.001), and adding posterior annuloplasty reduced postoperative LAVV regurgitation (2+ regurgitation 43% → 7%, P = 0.03). - Complete cleft closure inhibits significant postoperative LAVV regurgitation (OR 0.36, 95% CI 0.14–0.93; PMID: 39578279). Refractory cases require valve replacement.

Pharmacotherapy (bridging / supportive): Anti-heart-failure therapy — diuretics (furosemide, spironolactone), afterload reduction (ACE inhibitors/enalapril), digoxin — plus nutritional support. Vasodilators lower vascular resistance but can induce hypotension because systemic output does not rise (PMID: 10812553). Pulmonary artery banding is an occasional palliative bridge (but prior banding predicts later mortality; PMID: 34002204). For established pulmonary hypertension, calcium-channel blockers (nifedipine) and modern PH-targeted therapy are used (PMID: 2116616; PMID: 37794522).

Advanced/gene/cell therapies: Not applicable — no gene, RNA, or cell therapies exist for AVSD; treatment is structural/surgical.

Adult AVSD repair is safe with low early mortality but notable late arrhythmia and residual LAVV reoperation (PMID: 40936386).

13. Prevention

Primary prevention targets modifiable maternal risk factors: - Optimize maternal glycemic control before and during pregnancy (pregestational diabetes aPR ~6.7; PMID: 23061687). - Periconceptional folic acid / folate-rich diet — protective for CHD (aOR 0.64; PMID: 32092068); provider awareness of folate's cardiac benefits is low and warrants education (PMID: 41041190). - Weight management and smoking cessation.

Secondary prevention (early detection): - Prenatal screening via the four-chamber view at the mid-trimester anomaly scan; quality of imaging strongly affects detection (PMID: 31131945). - Prenatal detection of AVSD prompts karyotype/aneuploidy workup given the strong trisomy-21 association (PMID: 36766561). - Routine echocardiographic screening of all infants with Down syndrome (PMID: 41877065).

Tertiary prevention (complication prevention): timely surgical repair before irreversible pulmonary vascular disease; lifelong surveillance for LAVV regurgitation, LVOT obstruction, arrhythmias, and pulmonary hypertension.

Genetic counseling: For families with AVSD/CHD, counseling addresses recurrence risk, oligogenic/multifactorial inheritance, and prenatal diagnostic options (CMA, exome sequencing, fetal echocardiography). Immunization/public-health/infectious prevention: not applicable.

14. Other Species / Natural Disease

AVSD (atrioventricular canal defect) occurs naturally across mammals: "The defect has been described in human beings, dogs, cats, pigs, and horses," and a 2021 report added the first documented complete AV canal defect in a pet ferret (Mustela putorius furo) — a 4-year-old male with a loud systolic murmur, dyspnea, cardiomegaly, and pulmonary edema, echocardiographically showing a large ASD, AV valve dysplasia, and VSD, managed palliatively with furosemide, spironolactone, enalapril, and diltiazem (PMID: 33482816).

  • Taxonomy / NCBI Taxon: Homo sapiens (9606), Canis lupus familiaris (9615), Felis catus (9685), Sus scrofa (9823), Equus caballus (9796), Mustela putorius furo (9669).
  • Comparative biology: The same developmental program — endocardial cushion formation via EndoMT under TGF-β/BMP/Notch/Wnt control — operates across vertebrates, indicating strong evolutionary conservation of AV-canal development. Orthologous genes (Creld1, Nfatc1, Notch1, Gata4) are conserved across species.
  • Veterinary relevance: AVSD/AV canal defect is a recognized congenital cardiac malformation in companion animals, typically presenting with murmur and congestive heart failure signs.
  • Zoonotic potential: none (developmental malformation).

15. Model Organisms

Model Type Phenotype recapitulation Key limitation PMID
Creld1 KO mouse (global/conditional) Mammalian knockout Embryonic lethal; essential for septum & valve formation; dissects endocardial calcineurin/NFATc1/VEGF axis Global KO lethal; requires conditional approach 33773996, 24697899
Dnah11, Mks1 ENU mutants Mammalian (cilia genes) Heritable recessive AVSD via L/R axis + Hedgehog/second heart field Specific to cilia-pathway subset 27340223
Ts65Dn (DS model) Trisomy (>100 Hsa21 orthologs) Cardiovascular anomalies (right aortic arch + septal defects) in 8.3% of trisomic newborns; sensitized modifier background Incomplete Hsa21 coverage; low CHD penetrance 17019652, 22523272
Ts16 (trisomy 16) Trisomy Deficient AV septation (primum ASD + VSD) Atypical conotruncal features (DORV, PTA, TOF) resembling DiGeorge; "No heart had the typical morphology seen in ... Down's syndrome" 9231034, 11066038
Tc1 (transchromosomal) Human Chr21 in mouse Models dosage of an intact extra Hsa21 Mosaicism; partial 15068235
DSCR1-restored Ts16 Dosage-rescue DSCR1 restoration did NOT rescue cardiac anomalies → supports oligogenic model Single-gene rescue insufficient 15906378
DSCAM+COL6A2 overexpression mouse Transgenic Co-overexpression → ~50% mortality + ASD + hypertrophy Not a full trisomy model 22072978
Mbnl1-null mouse Knockout Precocious TGF-β/EMT; valve dysmorphia + secundum septal defects Valve phenotype more than classic AVSD 26472242
Notch pathway mice (Jag1/Notch1/RBPJ) Conditional KO Enlarged valve cusps, BAV, septal defects Pathway-specific 27056911
Zebrafish (NFATC1 mutants; AVC transcriptome; MFNG) Vertebrate Cardiac looping/AV canal patterning defects; conserved EMT/TGF-β/Notch/Wnt Two-chamber heart 30007050, 34557935, 39528804
Human iPSC-derived pre-valvular endocardial cells In vitro BMP2-responsive AVC EndoMT; "valve disease in a dish" Lacks in vivo hemodynamics/tissue context 31028265
Syrian hamster; chick cushion explants Vertebrate/ex vivo OFT/AV cushion EndoMT; TGF-β regulation Model-specific 40074779, 26472242

Overall model interpretation: Single-gene KOs (Creld1, Notch pathway) faithfully model the mechanistic EndoMT/calcineurin-NFATc1 axis, while Down-syndrome trisomy models (Ts65Dn, Ts16, Tc1) only partially recapitulate the human balanced AVSD morphology — a key limitation. The DSCR1-rescue negative result and Creld1/Hey2 modifier crosses jointly support an oligogenic, dosage-threshold model (PMID: 15906378; PMID: 22523272). Resources: MGI, IMPC, ZFIN, Cellosaurus.

Mechanistic Model / Interpretation

AVSD is best understood as a convergent endpoint of failed atrioventricular-canal endocardial cushion development, reached by multiple upstream routes (chromosomal, oligogenic, environmental) that all impair endothelial-to-mesenchymal transition and its downstream valve/septum morphogenesis. The pathway logic:

Upstream perturbations              Convergent module                 Structural outcome
──────────────────────  ───────────────────────────────────  ──────────────────────────
Trisomy 21 dosage ──┐
CRELD1 / NFATC1 ─────┤    CRELD1→Calcineurin/NFATc1→VEGF        Deficient AV septation
GATA4/6, NOTCH1 ─────┼──► TGF-β / BMP / Notch / Wnt / NOX2 ──►  + abnormal common/cleft
BMPR1A, GDF1, HEY2 ──┤    driven endocardial EndoMT & valve     AV valve
Maternal diabetes ───┘    remodeling                            (Rastelli A/B/C)

Two features make AVSD distinctive among CHDs: (1) its unusually tight link to trisomy 21, explained by chr21 gene-dosage effects (DSCAM+COL6A2 cooperativity; HMGN1 chromatin reprogramming) acting on a threshold-sensitized cushion program; and (2) the fact that its major residual clinical problem (LAVV regurgitation) is a direct anatomic consequence of the abnormal common-valve leaflet architecture, which surgery can improve but not perfectly normalize.

Evidence Base — Key Literature

PMID Contribution
15096951 CRELD1 as first non-syndromic susceptibility gene; establishes AVSD as multigenic; trisomy-21 link
30007050 NFATC1 LOF mutations cause AVSD; calcineurin/NFAT axis
24697899 Mouse Creld1→NFATc1→VEGF endocardial proliferation mechanism
29549339 AVSD results from impaired cushion EndoMT initiating in the AVC
27056911 / 28172500 / 26893350 Notch / BMP / Wnt control of cushion EMT and septal/valve defects
22072978 / 41125893 Chr21 gene-dosage mechanisms (DSCAM+COL6A2; HMGN1)
25996639 Exome-derived rare-variant enrichment; 6 AVSD genes; 40% unknown etiology
23061687 / 33876578 Maternal diabetes/obesity as environmental risk factors
32092068 Folate protective; maternal risk factors for CHD
37240614 / 34196822 / 33142350 Echocardiographic diagnosis; most common fetal cardiac Dx; highest genetic yield
40154545 / 34002204 / 34953470 Long-term surgical survival & QoL outcomes
41971883 / 40208292 LAVV regurgitation as dominant reoperation driver
39892564 / 10946038 / 8347012 Rastelli anatomy; DS outlet-septum malalignment; type-A PVD risk
39233212 AVSD among highest arrhythmia-risk CHDs
33482816 Cross-species natural occurrence (dog, cat, pig, horse, ferret)
1943197 / 10812553 Left-to-right shunt physiology; unrelenting pulmonary vascular disease

Consistency: Findings were highly consistent across human clinical cohorts, model organisms, and in vitro systems. No hypothesis was refuted; all 5 formal hypotheses (H001–H005) were supported.

Limitations and Knowledge Gaps

  1. ~40% of non-syndromic AVSD lacks a molecular diagnosis (PMID: 25996639) — much of the oligogenic/polygenic architecture and regulatory (non-coding) contribution remains uncharacterized.
  2. DS models imperfectly recapitulate human balanced AVSD morphology (PMID: 9231034); the precise chr21 gene(s) and dosage thresholds driving human AVSD are not fully resolved (HMGN1 and DSCAM+COL6A2 are leading but not sole candidates).
  3. Environmental risk estimates derive largely from broad CHD studies, not AVSD-specific cohorts; folate/diabetes effect sizes for AVSD alone are less precise.
  4. No molecular/epigenetic biomarker exists for prenatal risk stratification or postoperative LAVV-regurgitation prediction; diagnosis remains imaging-based.
  5. Limited data on adult natural history of unrepaired/partial AVSD and on long-term neurodevelopmental and phenotype-stratified QoL outcomes.
  6. Penetrance/expressivity quantification for individual susceptibility variants (e.g., CRELD1) is incomplete.

Proposed Follow-up Experiments / Actions

  1. Large-scale trio whole-genome sequencing of non-syndromic AVSD to capture regulatory/non-coding and structural variants and resolve the "missing 40%," with statistical modeling of oligogenic burden.
  2. Single-cell / spatial transcriptomics of the developing human AV canal (and iPSC-derived pre-valvular endocardial cells) to map cell-type-specific EndoMT programs and how CRELD1/NFATC1/HMGN1 perturbations reprogram them.
  3. Dissect chr21 dosage with combinatorial CRISPR titration of HMGN1, DSCAM, COL6A2 (and modifiers Creld1, Hey2) on trisomic backgrounds to define the defect threshold and rank causal drivers.
  4. Prospective AVSD-specific gene–environment study quantifying interaction between maternal glycemic control/folate status and fetal genotype on AVSD risk and severity.
  5. Develop predictive tools for LAVV regurgitation — integrate 3D-echo valve morphometry (Rastelli type, leaflet geometry) with clinical/genetic data to guide repair technique and surveillance.
  6. Improve prenatal detection through validation and deployment of AI-assisted four-chamber-view screening (AVLR, FINE/STIC) in general obstetric settings, paired with reflex CMA/exome workflows.
  7. Optimize periconceptional prevention by testing structured maternal diabetes-control and folate-supplementation programs, and by educating healthcare providers on folate's cardiac benefits.

Report compiled from 22 confirmed findings, 5 supported hypotheses, and 92 reviewed papers across 10 investigation iterations. Evidence sources: human clinical cohorts, population registries, model organisms (mouse, zebrafish, hamster, chick), and in vitro iPSC systems.

Artifacts

Citations

  1. PMID:29549339
  2. PMID:37612667
  3. PMID:39104126
  4. PMID:37667895
  5. PMID:15096951
  6. PMID:30007050
  7. PMID:24697899
  8. PMID:22072978
  9. PMID:41125893
  10. PMID:23061687
  11. PMID:32092068
  12. PMID:1943197
  13. PMID:10812553
  14. PMID:37240614
  15. PMID:34196822
  16. PMID:33142350
  17. PMID:40154545
  18. PMID:34002204
  19. PMID:8347012
  20. PMID:19760623
  21. PMID:25328912
  22. PMID:25996639
  23. PMID:33179873
  24. PMID:22523272
  25. PMID:33876578
  26. PMID:9532811
  27. PMID:34953470
  28. PMID:42037320
  29. PMID:36816019
  30. PMID:34627233
  31. PMID:26472242
  32. PMID:28172500
  33. PMID:27056911
  34. PMID:39528804
  35. PMID:26893350
  36. PMID:32655758
  37. PMID:31028265
  38. PMID:39892564
  39. PMID:10946038
  40. PMID:42079968
  41. PMID:38277408
  42. PMID:38975735
  43. PMID:30814609
  44. PMID:7997413
  45. PMID:36766561
  46. PMID:27981284
  47. PMID:38323184
  48. PMID:29952356
  49. PMID:34993374
  50. PMID:28603940
  51. PMID:41877065
  52. PMID:41971883
  53. PMID:40208292
  54. PMID:39233212
  55. PMID:41764019
  56. PMID:41313357
  57. PMID:34350818
  58. PMID:39578279
  59. PMID:2116616
  60. PMID:37794522
  61. PMID:40936386
  62. PMID:41041190
  63. PMID:31131945
  64. PMID:33482816
  65. PMID:15906378
  66. PMID:9231034