Patent Ductus Arteriosus 3

Mendelian MONDO:0024266 Pathograph 25 Show in embeddings browser Patent Ductus Arteriosus Congenital Heart Defect

Patent ductus arteriosus 3 (PDA3) is the isolated, nonsyndromic Mendelian form of patent ductus arteriosus caused by heterozygous variants in PRDM6, which encodes a vascular-smooth-muscle-restricted PR/SET-domain protein with histone methyltransferase activity that regulates the ductal smooth muscle gene program. Whether it represses or promotes the contractile arm of that program is disputed. Loss of PRDM6 function disturbs the program required for postnatal constriction and remodeling of the ductus arteriosus, so the duct fails to close in infants who are neither preterm nor syndromic. Affected individuals present with the hemodynamic consequences of a persistent left-to-right aortopulmonary shunt, and a subset also carry coarctation of the aorta.

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1
Mappings
1
Inheritance
9
Pathophys.
5
Phenotypes
3
Hypotheses
3
Gaps
25
Pathograph
1
Genes
3
Variants
5
Medical Actions
3
Differentials
2
Datasets
3
Models
8
References
1
Deep Research
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Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
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Mappings

ICD-10-CM
ICD10CM:Q25.0 Patent ductus arteriosus
skos:broadMatch
semapv:ManualMappingCuration
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Inheritance

1
Autosomal dominant HP:0000006
PDA3 segregates as an autosomal dominant trait: heterozygous PRDM6 variants were identified by combined linkage analysis and whole-exome sequencing in families with isolated nonsyndromic patent ductus arteriosus, and heterozygous variants have since been reported in further probands with PDA with or without coarctation of the aorta. Penetrance is incomplete: obligate carriers in the index kindred are reported unaffected. Expressivity is variable, ranging from isolated patent ductus arteriosus to patent ductus arteriosus with coarctation of the aorta among carriers.
Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE
Show evidence (1 reference)
PMID:27181681 SUPPORT Human Clinical
"Using combined genome-wide linkage analysis and whole-exome sequencing (WES), we identified independent mutations in PRDM6"
Linkage plus exome sequencing in PDA families is the study design that established the dominant, familial transmission of PRDM6 variants in nonsyndromic PDA.
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Mechanistic Hypotheses

3
PRDM6 loss releases ductal smooth muscle from a proliferative, undifferentiated state
prdm6_premature_differentiation ALTERNATIVE
Evidence balance 1 support
In the model proposed with the original human genetic finding, PRDM6 keeps ductal vascular smooth muscle cells undifferentiated so that they proliferate and populate the ductal media; PRDM6 falls postnatally as contraction-competent cells accumulate. On this view loss of PRDM6 activity causes premature differentiation and a shortage of the smooth muscle needed for the remodeling that permanently occludes the duct.
The developmental expression time course underpinning this model is reported in the paper's abstract without naming the species. It is graded MODEL_ORGANISM because a time course sampling the ductus arteriosus before and after birth is only practicable in an animal, and the deep-research report for this entry records it as mouse immunofluorescence at E14.5, E17.5 and P0.5.
Pathograph links
Deregulated Ductal Smooth Muscle Transcriptional Program -> Premature Ductal Smooth Muscle Differentiation DIRECT On the premature-differentiation model, the same loss of repression instead releases ductal smooth muscle cells from an undifferentiated proliferative state too early.
Premature Ductal Smooth Muscle Differentiation -> Impaired Ductal Wall Remodeling DIRECT
Impaired Ductal Wall Remodeling -> Failure of Postnatal Ductal Closure DIRECT Permanent closure requires the intimal and medial remodeling step, so a duct that cannot remodel stays open even if it constricts.
Show evidence (1 reference)
PMID:27181681 SUPPORT Model Organism
"This dynamic change suggests that PRDM6 plays a key role in maintaining VSMCs in an undifferentiated stage in order to promote their proliferation and that its loss of activity results in premature differentiation and impaired remodeling of the DA."
This is the authors' explicit statement of the premature-differentiation model that this hypothesis group records.
PRDM6 is required to build ductal smooth muscle contractile identity
prdm6_smc_identity ALTERNATIVE
Evidence balance 1 support
Conditional deletion of Prdm6 in the neural-crest lineage gives a fully penetrant patent ductus arteriosus in which the duct is normally invested with smooth muscle but is hypocontractile, and a ductus-enriched contractile gene program is downregulated. On this view PRDM6 is needed to establish, rather than to restrain, the contractile program, and PDA follows from failure of active constriction.
This runs in the opposite direction to the premature-differentiation model with respect to whether PRDM6 represses or promotes contractile gene expression; the discrepancy is recorded as an open discussion in this entry.
Pathograph links
Deregulated Ductal Smooth Muscle Transcriptional Program -> Loss of Ductal Smooth Muscle Contractile Identity DIRECT On the smooth-muscle-identity model, the altered program is specifically a loss of ductus-enriched contractile gene expression.
Loss of Ductal Smooth Muscle Contractile Identity -> Impaired Ductal Contractile Tone DIRECT Loss of the contractile gene program is read out as loss of the tone that program exists to generate.
Impaired Ductal Contractile Tone -> Failure of Postnatal Ductal Closure DIRECT Functional closure is achieved by constriction, so a duct that cannot generate tone cannot take the first step of closing.
Show evidence (1 reference)
PMID:36749647 SUPPORT Model Organism
"RNA-Seq analyses on DA and ascending aorta samples at E18.5 identified a DA-enriched gene program that included many SMC-selective contractile associated proteins that was downregulated by Prdm6 depletion."
Downregulation of the ductal contractile program on Prdm6 loss is the central observation behind this hypothesis.
PRDM6 acts earlier, on cardiac neural crest specification and migration
prdm6_cncc_specification EMERGING
Evidence balance 1 support
A separate mouse study places Prdm6 upstream of the smooth muscle program altogether, as a regulator of cardiac neural crest cell specification, delamination, and migration acting through Wnt1, Tfap2b, and Sox9 and through H4K20 monomethylation. Patent ductus arteriosus in that model is one outcome of a broader neural crest defect that also produces ventricular noncompaction.
Pathograph links
Deregulated Ductal Smooth Muscle Transcriptional Program -> Impaired Cardiac Neural Crest Cell Specification and Migration DIRECT In the neural crest model the affected program is a network of crest specification genes rather than the mature smooth muscle contractile program.
Impaired Cardiac Neural Crest Cell Specification and Migration -> Failure of Postnatal Ductal Closure INDIRECT KNOWN INTERMEDIATES
Show evidence (1 reference)
PMID:35108221 SUPPORT Model Organism
"we showed that disruption of Prdm6 was associated with impaired CNCC differentiation, delamination, and migration and led to patent ductus arteriosus (DA) and ventricular noncompaction"
This states the neural-crest route from Prdm6 disruption to patent ductus arteriosus that this hypothesis group records.
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Discussions and Knowledge Gaps

3
Does PRDM6 loss cause patent ductus arteriosus by releasing ductal smooth muscle cells into premature differentiation, or by failing to build their contractile identity in the first place?
CONTROVERSY OPEN prdm6_direction_of_effect
Attached to
pathophysiology#Deregulated Ductal Smooth Muscle Transcriptional Program pathophysiology#Loss of Ductal Smooth Muscle Contractile Identity pathophysiology#Premature Ductal Smooth Muscle Differentiation mechanistic_hypotheses#prdm6_premature_differentiation mechanistic_hypotheses#prdm6_smc_identity
The two published models assign opposite signs to the same molecule. The human genetic study describes PRDM6 as a transcriptional suppressor of contractile proteins that holds ductal smooth muscle cells undifferentiated, so that loss of function produces premature differentiation. The conditional knockout study finds that loss of Prdm6 downregulates a ductus-enriched contractile gene program and reduces ductal tone, which is what a positive, identity-building role predicts. Both are supported by direct data, though not symmetrically: two independent conditional-knockout datasets report reduced contractile gene expression on Prdm6 loss, while the premature-differentiation model rests on an expression time course plus in vitro assays, and its reduced-proliferation corollary was subsequently refuted by Ki67 measurement. The entry carries both rather than silently retiring one. Resolving the direction of effect matters because it determines whether a therapeutic aimed at the ductal smooth muscle program would need to promote or restrain contractile differentiation.
Proposed experiments
Contractile gene program in dose-matched PRDM6 loss
prdm6_dose_matched_contractile_program
Profile the contractile gene program and the proliferative index of ductal smooth muscle across a PRDM6 dosage series (heterozygous patient-variant knock-in, heterozygous null, homozygous null) in the same ductal tissue and at matched developmental stages, so that the direction of effect is read from one comparable experiment rather than across two study designs.
Readouts
Ductal contractile gene expression
pathophysiology#Loss of Ductal Smooth Muscle Contractile Identity
Interpretation: Downregulation across the dosage series favors the identity-building model.
Ductal smooth muscle proliferative index
pathophysiology#Premature Ductal Smooth Muscle Differentiation
Interpretation: An early fall in proliferation with early contractile marker gain favors the premature-differentiation model.
Would support
pathophysiology#Loss of Ductal Smooth Muscle Contractile Identity
Would refute
pathophysiology#Premature Ductal Smooth Muscle Differentiation
Supporting outcome
  • Ductal contractile gene expression falls with reducing PRDM6 dose while the proliferative index is unchanged or increased.
Refuting outcome
  • Contractile markers appear earlier than in wild-type ducts and the proliferative index falls, with medial cellularity reduced at term.
Show evidence (2 references)
PMID:27181681 SUPPORT Model Organism
"This dynamic change suggests that PRDM6 plays a key role in maintaining VSMCs in an undifferentiated stage in order to promote their proliferation and that its loss of activity results in premature differentiation and impaired remodeling of the DA."
One side of the disagreement: PRDM6 restrains differentiation, so its loss causes premature differentiation.
PMID:36749647 SUPPORT Model Organism
"RNA-Seq analyses on DA and ascending aorta samples at E18.5 identified a DA-enriched gene program that included many SMC-selective contractile associated proteins that was downregulated by Prdm6 depletion."
The other side: Prdm6 loss reduces rather than releases contractile gene expression in the ductus.
Does the Prdm6-null duct stay open because neural crest cells never populate its media, or because the smooth muscle that does populate it cannot contract?
CONTROVERSY OPEN prdm6_crest_versus_contractility
Attached to
pathophysiology#Impaired Cardiac Neural Crest Cell Specification and Migration pathophysiology#Loss of Ductal Smooth Muscle Contractile Identity mechanistic_hypotheses#prdm6_cncc_specification mechanistic_hypotheses#prdm6_smc_identity
Two labs ran the same Wnt1-Cre2 Prdm6fl/fl cross and disagree on the finding the crest model rests on. One reports the ductal media dramatically depleted of neural-crest-derived cells by E17.5; the other reports investment and medial morphology indistinguishable from controls, finds no migration defect in outflow-tract smooth muscle culture, and points out that the same study's SM22-Cre model, in which Prdm6 goes only after crest migration is complete, also gives a patent duct. The two groups used different reporters and detection methods, which is the explanation offered for the discrepancy but has not been tested. This is a sharper disagreement than the direction-of-effect one, because the two positions predict different treatable steps: a cell-supply failure fixed before birth, or a contractile failure present in a normally built wall.
Proposed experiments
Reporter-matched replication of ductal neural crest investment
prdm6_crest_investment_replication
Quantify neural-crest-derived cells in the ductal media of Wnt1-Cre2 Prdm6fl/fl embryos at a fixed stage, with both reporters and both detection methods run side by side on the same litters, so the discrepancy is tested rather than attributed to methodology.
Readouts
Neural-crest-derived cell fraction in the ductal tunica media
pathophysiology#Impaired Cardiac Neural Crest Cell Specification and Migration
Interpretation: A deficit reproduced under both detection methods would settle the question for the crest model; a deficit visible under only one would locate the disagreement in the assay.
Would support
pathophysiology#Impaired Cardiac Neural Crest Cell Specification and Migration
Would refute
pathophysiology#Loss of Ductal Smooth Muscle Contractile Identity
Supporting outcome
  • Neural-crest-derived cells are reduced in the mutant ductal media under both reporters and both detection methods.
Refuting outcome
  • Investment is normal under both methods, leaving the contractile defect as the operative lesion.
Show evidence (2 references)
PMID:35108221 SUPPORT Model Organism
"The examination of the DA of Prdm6fl/fl Wnt1-Cre2 ZsGreen1 mice at E17.5 showed dramatically reduced ZsGreen1-positive (NCC-derived) cells in the tunica media compared with those of the WT littermates"
The crest-depletion side of the disagreement.
PMID:36749647 SUPPORT Model Organism
"As shown in Figure 4, we did not detect differences in neural crest cell investment of the ductus or the morphology of the ductus medial SMC layer."
The normal-investment side, from the same genotype.
Do the mouse ductal and neural crest phenotypes reflect what heterozygous PRDM6 variants do in the human ductus arteriosus?
HUMAN MODEL MISMATCH OPEN prdm6_human_tissue_gap
Attached to
pathophysiology#Impaired Cardiac Neural Crest Cell Specification and Migration pathophysiology#Impaired Ductal Contractile Tone
Every mechanistic step below the variant itself rests on mouse models that delete Prdm6 homozygously in a lineage-restricted way and are perinatally lethal, while human PDA3 is a viable heterozygous condition. One of those models also produces ventricular noncompaction, which is not reported in PRDM6 variant carriers, so the models are not simply milder or stronger versions of the human disease. No human ductal tissue from a PRDM6 variant carrier has been profiled. The dosage mismatch is not merely quantitative: in the mouse, losing one copy of Prdm6 leaves ductal closure intact, whereas in humans a single altered copy is sufficient to cause disease.
Proposed experiments
Molecular profiling of ductal tissue from PRDM6 variant carriers
prdm6_human_ductal_tissue
Collect ductal tissue at the time of surgical ligation from patients with a confirmed heterozygous PRDM6 variant and profile smooth muscle contractile gene expression, medial cellularity, and intimal cushion formation against duct tissue from term infants closing without a PRDM6 variant.
Readouts
Ductal medial smooth muscle contractile marker expression
pathophysiology#Impaired Ductal Contractile Tone
Interpretation: Reduced contractile marker expression in human carrier tissue would carry the mouse finding across to the human duct.
Would support
pathophysiology#Impaired Ductal Contractile Tone
Supporting outcome
  • Carrier ductal tissue shows reduced contractile marker expression and absent intimal cushion formation relative to non-carrier term ductal tissue.
Refuting outcome
  • Carrier ductal tissue is indistinguishable from non-carrier term ductal tissue in contractile marker expression and medial structure.
Show evidence (1 reference)
PMID:36749647 SUPPORT Model Organism
"Taken together these data indicated that PRDM6 expression was absolutely required for DA closure, that Cre expression alone or deletion of 1 copy of PRDM6 had no effect on ductus closure, and that the floxed PRDM6 allele behaved in a manner similar to the WT allele."
A heterozygous mouse deletion leaves ductal closure normal while human heterozygous variants cause disease, which is the dosage mismatch this discussion records.
⚙

Pathophysiology

9
PRDM6 Loss-of-Function Variants
Mechanism confidence: Established
Heterozygous germline PRDM6 variants are the initiating lesion in PDA3. In vitro characterization of the variants found in PDA families showed loss of function, either because the mutant protein is redistributed within the cell or because its methyltransferase activity is altered.
Genetic context PRDM6 hgnc:9350 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns PRDM6 (hgnc:9350). hgnc:9350 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
PRDM6 histone methyltransferase activity GO:0042054 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal PRDM6 histone methyltransferase activity, annotated with histone methyltransferase activity (GO:0042054). GO:0042054 is a molecular function from the Gene Ontology. ⚠ ABNORMAL
ductus arteriosus UBERON:0005440 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in ductus arteriosus (UBERON:0005440). UBERON:0005440 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Deregulated Ductal Smooth Muscle Transcriptional Program Because PRDM6 acts on chromatin as a smooth-muscle-restricted transcriptional repressor, loss of its activity is read out directly as a change in the ductal transcriptional program.
Show evidence (2 references)
PMID:27181681 SUPPORT Human Clinical
"Our findings identify PRDM6 mutations as underlying genetic causes of nonsyndromic isolated PDA in humans and implicates the wild-type protein in epigenetic regulation of ductus remodeling."
This states directly that PRDM6 mutations are a genetic cause of isolated nonsyndromic PDA in humans, which is the lesion this node represents.
PMID:27181681 SUPPORT In Vitro
"In vitro assays showed that the mutations cause loss of function either by intracellular redistribution of the protein and/or by alteration of its methyltransferase activities."
Cell-based assays establish the loss-of-function consequence recorded in this node's genetic context.
Deregulated Ductal Smooth Muscle Transcriptional Program
Mechanism confidence: Established
PRDM6 binds and regulates a large fraction of the genes whose expression it controls in outflow tract smooth muscle, and its loss shifts the ductus-specific gene program. This node is the shared molecular consequence from which the competing cellular models of PDA3 diverge.
PRDM6 acts earlier, on cardiac neural crest specification and migration PRDM6 is required to build ductal smooth muscle contractile identity PRDM6 loss releases ductal smooth muscle from a proliferative, undifferentiated state
ductal vascular smooth muscle cell CL:0000359 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ductal vascular smooth muscle cell, annotated with vascular associated smooth muscle cell (CL:0000359). CL:0000359 is a cell type from the Cell Ontology.
PRDM6-dependent transcriptional control of the ductal smooth muscle program GO:0006357 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated PRDM6-dependent transcriptional control of the ductal smooth muscle program, annotated with regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology. ↕ DYSREGULATED
ductus arteriosus UBERON:0005440 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in ductus arteriosus (UBERON:0005440). UBERON:0005440 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Loss of Ductal Smooth Muscle Contractile Identity On the smooth-muscle-identity model, the altered program is specifically a loss of ductus-enriched contractile gene expression. PRDM6 is required to build ductal smooth muscle contractile identity
Premature Ductal Smooth Muscle Differentiation On the premature-differentiation model, the same loss of repression instead releases ductal smooth muscle cells from an undifferentiated proliferative state too early. PRDM6 loss releases ductal smooth muscle from a proliferative, undifferentiated state
Impaired Cardiac Neural Crest Cell Specification and Migration In the neural crest model the affected program is a network of crest specification genes rather than the mature smooth muscle contractile program. PRDM6 acts earlier, on cardiac neural crest specification and migration
Show evidence (3 references)
PMID:36749647 SUPPORT Model Organism
"Chromatin immunoprecipitation-sequencing experiments in outflow tract SMCs demonstrated that 50% of the genes Prdm6 depletion altered contained Prdm6 binding sites."
Occupancy at half the responsive genes puts a substantial part of the program change under direct Prdm6 binding. The authors stop short of a wholly direct mechanism: they report that with few exceptions Prdm6 was not bound at the smooth-muscle-specific promoters themselves, and raise the possibility that the identity effect is secondary to other transcriptional machinery.
PMID:36749647 SUPPORT Model Organism
"Of the 519 genes that were more highly expressed in the DA by at least 1.5-fold, 319 of those were significantly (P < 0.01) downregulated by Prdm6 depletion."
Quantifies how much of the ductus-versus-aorta expression signature depends on Prdm6, which is the scale of the program change this node asserts.
PMID:36749647 SUPPORT Model Organism
"Prdm6 depletion altered the expression level of many genes previously implicated in DA closure (see ref. 34 for a review), including the PGE2 receptor, EP4; the transcription factors Tfap2b, myocardin, Foxc1, and Hand2; the Notch signaling components, Jag1 and Notch3; SM MHC; integrin linked..."
Names the ductal-closure genes affected, including EP4 and Tfap2b, tying this program to the closure machinery and to the other genetic forms of PDA.
Loss of Ductal Smooth Muscle Contractile Identity
Mechanism confidence: Provisional
Ductal smooth muscle cells lose the contraction-associated gene expression that distinguishes the ductus arteriosus from the adjacent aorta, while still populating the vessel wall normally.
PRDM6 is required to build ductal smooth muscle contractile identity
ductal vascular smooth muscle cell CL:0000359 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ductal vascular smooth muscle cell, annotated with vascular associated smooth muscle cell (CL:0000359). CL:0000359 is a cell type from the Cell Ontology.
smooth muscle cell differentiation GO:0051145 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal smooth muscle cell differentiation (GO:0051145). GO:0051145 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Prdm6fl/fl SM22-Cre mouse Mouse recapitulates Contractile transcripts are the genes most reduced in this duct, which is the claim the identity node makes, obtained without touching the crest lineage.
Downstream
Impaired Ductal Contractile Tone Loss of the contractile gene program is read out as loss of the tone that program exists to generate. PRDM6 is required to build ductal smooth muscle contractile identity
Show evidence (2 references)
PMID:36749647 SUPPORT Model Organism
"Lineage tracing experiments in Wnt1Cre2 Prdm6fl/fl ROSA26LacZ mice revealed normal neural crest-derived SMC investment of the outflow tract."
Normal smooth muscle investment with a defective duct localizes the lesion to cell identity and function rather than to cell number in this model. Note that a second group reports the opposite in the same genotype; see the refuting item below and the crest-versus-contractility discussion.
PMID:35108221 REFUTE Model Organism
"The examination of the DA of Prdm6fl/fl Wnt1-Cre2 ZsGreen1 mice at E17.5 showed dramatically reduced ZsGreen1-positive (NCC-derived) cells in the tunica media compared with those of the WT littermates"
A second lab, using the same Wnt1-Cre2 Prdm6fl/fl genotype with a different reporter, finds the ductal media depleted of neural-crest-derived cells. That contradicts the normal-investment premise this node rests on.
Premature Ductal Smooth Muscle Differentiation
Mechanism confidence: Hypothetical
Ductal smooth muscle cells exit the proliferative, undifferentiated state too early, so the ductal wall is differentiated on the wrong schedule when the postnatal remodeling window opens. The originally proposed corollary, that the medial cell population is thereby depleted, is refuted by the Ki67 evidence recorded on this node.
PRDM6 loss releases ductal smooth muscle from a proliferative, undifferentiated state
ductal vascular smooth muscle cell CL:0000359 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ductal vascular smooth muscle cell, annotated with vascular associated smooth muscle cell (CL:0000359). CL:0000359 is a cell type from the Cell Ontology.
smooth muscle cell proliferation GO:0048659 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal smooth muscle cell proliferation (GO:0048659). GO:0048659 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Impaired Ductal Wall Remodeling PRDM6 loss releases ductal smooth muscle from a proliferative, undifferentiated state
Show evidence (1 reference)
PMID:35108221 REFUTE Model Organism
"Taken together, these findings indicated that the patency of the DA in Prdm6fl/fl Wnt1-Cre2 ZsGreen1 mice was not caused by impaired proliferation of NCC-derived SMCs."
Ki67 staining found no proliferation deficit in the Prdm6-depleted duct, which refutes the reduced-proliferation half of the premature-differentiation model. The proliferation descriptor is therefore left as ABNORMAL rather than DECREASED, and the node is retained only as the differentiation-timing claim.
Impaired Cardiac Neural Crest Cell Specification and Migration
Mechanism confidence: Hypothetical
In the neural crest model, cardiac neural crest cells fail to complete epithelial-mesenchymal transition and migration, being retained in the dorsal neural tube, with diminished H4K20 monomethylation and increased Wnt1 transcript levels driving the migration defect.
PRDM6 acts earlier, on cardiac neural crest specification and migration
migratory cardiac neural crest cell CL:2000073 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves migratory cardiac neural crest cell (CL:2000073). CL:2000073 is a cell type from the Cell Ontology.
neural crest cell differentiation GO:0014033 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal neural crest cell differentiation (GO:0014033). GO:0014033 is a biological process from the Gene Ontology. ⚠ ABNORMAL neural crest cell migration GO:0001755 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neural crest cell migration (GO:0001755). GO:0001755 is a biological process from the Gene Ontology. ↓ DECREASED epithelial to mesenchymal transition GO:0001837 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased epithelial to mesenchymal transition (GO:0001837). GO:0001837 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Prdm6fl/fl Wnt1-Cre2 ZsGreen1 mouse Mouse recapitulates The model is the sole source of the neural-crest route in this entry, with lineage tracing and single-cell transcriptomics supporting the migration defect.
Downstream
Failure of Postnatal Ductal Closure PRDM6 acts earlier, on cardiac neural crest specification and migration
Show evidence (3 references)
PMID:35108221 SUPPORT Model Organism
"This defect was associated with diminished H4K20 monomethylation and G1-S progression and augmented Wnt1 transcript levels in pre-EMT and neural tube clusters, which we showed was the major driver of the impaired CNCC migration."
This gives the chromatin and Wnt1 mechanism behind the migration defect this node represents.
PMID:36749647 REFUTE Model Organism
"As shown in Figure 4, we did not detect differences in neural crest cell investment of the ductus or the morphology of the ductus medial SMC layer."
A direct failure to replicate the investment defect on which this node's mechanism depends.
PMID:36749647 REFUTE Model Organism
"Since Prdm6 depletion in this model occurs only after the migration and SMC differentiation of neural crest cells, it seems unlikely that the patent DA phenotype observed in Wnt1Cre2 Prdm6fl/fl mice was due primarily to a failure of neural crest migration."
The genetic timing argument: a patent duct in a model where Prdm6 is deleted after crest migration has finished cannot be explained by failed migration.
Impaired Ductal Contractile Tone
Mechanism confidence: Provisional
The ductus arteriosus generates insufficient smooth muscle tone to constrict after birth. Myography of ductal segments from Prdm6-depleted embryos shows reduced tone and contractility despite normal smooth muscle investment.
PRDM6 is required to build ductal smooth muscle contractile identity
vascular associated smooth muscle contraction GO:0014829 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased vascular associated smooth muscle contraction (GO:0014829). GO:0014829 is a biological process from the Gene Ontology. ↓ DECREASED
ductus arteriosus UBERON:0005440 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in ductus arteriosus (UBERON:0005440). UBERON:0005440 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Wnt1Cre2 Prdm6fl/fl mouse Mouse recapitulates Myography on ductal segments provides the physiological measurement of reduced contractility that the tone node asserts.
Downstream
Failure of Postnatal Ductal Closure Functional closure is achieved by constriction, so a duct that cannot generate tone cannot take the first step of closing. PRDM6 is required to build ductal smooth muscle contractile identity
Show evidence (1 reference)
PMID:36749647 SUPPORT Model Organism
"myography measurements on DA segments isolated from E18.5 embryos indicated that Prdm6 depletion significantly reduced DA tone and contractility"
Direct physiological measurement of reduced ductal tone is the observation this node records.
Impaired Ductal Wall Remodeling
Mechanism confidence: Provisional
The intimal thickening and medial reorganization that normally convert the functionally constricted duct into a permanently occluded ligamentum arteriosum do not proceed. Failure of this smooth-muscle-driven remodeling step is the common endpoint shared by the syndromic and nonsyndromic genetic forms of PDA.
PRDM6 loss releases ductal smooth muscle from a proliferative, undifferentiated state
ductal vascular smooth muscle cell CL:0000359 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ductal vascular smooth muscle cell, annotated with vascular associated smooth muscle cell (CL:0000359). CL:0000359 is a cell type from the Cell Ontology.
intimal thickening and fibrotic remodeling of the ductal wall GO:0048771 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased intimal thickening and fibrotic remodeling of the ductal wall, annotated with tissue remodeling (GO:0048771). GO:0048771 is a biological process from the Gene Ontology. ↓ DECREASED
ductus arteriosus UBERON:0005440 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in ductus arteriosus (UBERON:0005440). UBERON:0005440 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Failure of Postnatal Ductal Closure Permanent closure requires the intimal and medial remodeling step, so a duct that cannot remodel stays open even if it constricts. PRDM6 loss releases ductal smooth muscle from a proliferative, undifferentiated state
Show evidence (2 references)
PMID:19955832 SUPPORT Other
"Genes that interfere with the remodeling of vascular smooth muscle cells (VSMCs) of the ductal media are affected in virtually all of these anomalies."
This review of the genetic forms of PDA places failed smooth-muscle-driven remodeling of the ductal media at the convergence point, which is what this node represents.
PMID:36749647 SUPPORT Other
"Full anatomic closure takes place over a longer period and involves intimal thickening and eventual fibrotic remodeling of the DA into a remnant structure known as the ligamentum arteriosum"
Defines the remodeling process, distinct from functional constriction, whose failure this node records. Graded OTHER because the sentence is background physiology the authors cite to a review, not a result of their experiments.
Failure of Postnatal Ductal Closure
Mechanism confidence: Established
The ductus arteriosus does not undergo the functional constriction and subsequent anatomic obliteration that normally follow birth, and remains patent in a term infant with no prematurity-related or syndromic explanation.
ductus arteriosus closure GO:0097070 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves absent ductus arteriosus closure (GO:0097070). GO:0097070 is a biological process from the Gene Ontology. ∅ ABSENT
ductus arteriosus UBERON:0005440 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in ductus arteriosus (UBERON:0005440). UBERON:0005440 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Wnt1Cre2 Prdm6fl/fl mouse Mouse recapitulates The model reproduces the defining lesion of PDA3 with complete penetrance.
Prdm6fl/fl Wnt1-Cre2 ZsGreen1 mouse Mouse partially recapitulates The model produces patent ductus arteriosus, but as one element of a broader neural crest phenotype that includes ventricular noncompaction.
Prdm6fl/fl SM22-Cre mouse Mouse recapitulates Completely penetrant ductal patency in both sexes.
Downstream
Patent ductus arteriosus The unclosed duct is the clinical lesion itself, so this edge is the mechanism-to-phenotype step rather than a further consequence.
Coarctation of aorta Drawn because the aortic isthmus carries ductal smooth muscle at its junction with the duct, so the same smooth-muscle lesion is a plausible route to arch narrowing. The intermediate steps are not established, and the co-occurrence rests on a three-patient series.
Persistent Left-to-Right Aortopulmonary Shunt An open duct shunts once pulmonary vascular resistance falls after birth.
Show evidence (3 references)
PMID:23055849 SUPPORT Human Clinical
"PDA in term infants is usually associated with a functional defect, whereas in preterm infants it is associated with immaturity."
This distinguishes the intrinsic ductal defect operating in term infants, which is the setting of PDA3, from prematurity-associated failure to close.
PMID:36749647 SUPPORT Model Organism
"Prdm6 depletion in Wnt1-expressing cells during development resulted in perinatal lethality and a completely penetrant patent ductus arteriosus (DA) phenotype."
Complete penetrance of patent ductus arteriosus on Prdm6 loss supports this node as the consequence of the upstream ductal defect.
PMID:36749647 SUPPORT Model Organism
"While this procedure resulted in premature DA closure in all littermate controls, it had no effect on DA closure in Wnt1Cre2 Prdm6fl/fl fetuses"
Prostaglandin inhibition closes the duct in controls but not in the mutant, so the closure trigger is intact while the duct cannot execute it, which is the distinction this node turns on.
Persistent Left-to-Right Aortopulmonary Shunt
Mechanism confidence: Established
With the duct open and pulmonary vascular resistance falling after birth, blood shunts from the aorta into the pulmonary artery. The resulting pulmonary overcirculation and left heart volume load produce the clinical findings of the lesion.
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.
Downstream
Heart murmur Continuous flow across the duct is audible.
Congestive heart failure Left heart volume loading from a large shunt produces heart failure.
Pulmonary arterial hypertension Sustained overcirculation remodels the pulmonary vasculature over years, so the step runs through pulmonary vascular disease rather than directly.
Show evidence (1 reference)
PMID:24560920 SUPPORT Human Clinical
"PDA closure is indicated in any patient with signs of left ventricular volume overload due to a ductus"
Left ventricular volume overload is the recognized hemodynamic consequence of the persistent shunt that this node represents.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Patent Ductus Arteriosus 3 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

5
Patent ductus arteriosus OBLIGATE Cardiovascular HP:0001643 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Patent ductus arteriosus (HP:0001643). HP:0001643 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:27181681 SUPPORT Human Clinical
"Our findings identify PRDM6 mutations as underlying genetic causes of nonsyndromic isolated PDA in humans and implicates the wild-type protein in epigenetic regulation of ductus remodeling."
This establishes isolated nonsyndromic patent ductus arteriosus as the phenotype caused by PRDM6 mutations.
PMID:38071433 SUPPORT Human Clinical
"Pathogenic variants in PRDM6, which encodes a smooth-muscle-cell-specific transcription factor, have now been etiologically associated with non-syndromic PDA."
An independent group confirms the PRDM6-PDA association in their patients.
Coarctation of aorta Cardiovascular HP:0001680 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coarctation of aorta (HP:0001680). HP:0001680 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38071433 SUPPORT Human Clinical
"We present three patients with PDA and CoA found to harbor PRDM6 variants, including a novel, likely-pathogenic variant."
This is the direct report of coarctation of the aorta co-occurring with PDA in PRDM6 variant carriers.
Heart murmur Cardiovascular HP:0030148 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Heart murmur (HP:0030148). HP:0030148 is a phenotype from the Human Phenotype Ontology.
Cited from the general patent ductus arteriosus literature rather than from a PRDM6 cohort: this is a consequence of the shunt lesion, not a PDA3-specific finding. Bound to the general HP:0030148 rather than to HP:0031670 Continuous heart murmur: no reference cached for this entry uses the word continuous, so the narrower term would outrun its evidence.
Show evidence (1 reference)
PMID:23055849 SUPPORT Human Clinical
"Clinical signs of ductal patency include murmur, tachycardia, bounding peripheral pulses, and congestive heart failure and associated symptoms."
Murmur is listed first among the clinical signs of ductal patency, the lesion PDA3 causes.
Congestive heart failure Cardiovascular 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.
Cited from the general patent ductus arteriosus literature rather than from a PRDM6 cohort: this is a consequence of the shunt lesion, not a PDA3-specific finding.
Show evidence (1 reference)
PMID:23055849 SUPPORT Human Clinical
"Clinical signs of ductal patency include murmur, tachycardia, bounding peripheral pulses, and congestive heart failure and associated symptoms."
Names congestive heart failure outright as a clinical sign of ductal patency.
Pulmonary arterial hypertension Cardiovascular 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.
Cited from the general patent ductus arteriosus literature rather than from a PRDM6 cohort: this is a consequence of the shunt lesion, not a PDA3-specific finding.
Show evidence (1 reference)
PMID:24560920 SUPPORT Human Clinical
"In cases of left-to-right PDA with severe pulmonary arterial hypertension, closure may be performed under specific conditions."
Severe pulmonary arterial hypertension is recognized as a state a left-to-right duct can reach, and it changes closure decisions.
🧬

Genetic Associations

1
PRDM6 (Causal)
Gene: PRDM6 hgnc:9350 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PRDM6 (hgnc:9350). hgnc:9350 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:27181681 SUPPORT Human Clinical
"Our findings identify PRDM6 mutations as underlying genetic causes of nonsyndromic isolated PDA in humans and implicates the wild-type protein in epigenetic regulation of ductus remodeling."
Direct statement of PRDM6 as the causal gene for this entity.
PMID:27181681 SUPPORT In Vitro
"In vitro assays showed that the mutations cause loss of function either by intracellular redistribution of the protein and/or by alteration of its methyltransferase activities."
Establishes loss of function as the mechanism of the disease-associated variants.
Variants (3)
c.1646G>A (p.Arg549Gln) Pathogenic
missense variant LOF
Missense variant in the fourth zinc-finger region. Reported in the index kindred and characterized in vitro as loss of function through cytoplasmic mislocalization of the protein.
Identifiers: ClinVar:VCV000243049
c.788G>C (p.Cys263Ser) Pathogenic
missense variant LOF
Missense variant in the SET (PR) domain, the catalytic region, reported in a proband with affected mother and maternal grandfather.
Identifiers: ClinVar:VCV000243050
c.1385A>G (p.Gln462Arg) Pathogenic
missense variant LOF
Missense variant reported in an affected mother and daughter.
Identifiers: ClinVar:VCV000243051
💊

Medical Actions

5
Transcatheter device closure
Action: transcatheter ductal occlusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is transcatheter ductal occlusion, annotated with Interventional Cardiac Catheterization (NCIT:C168283). NCIT:C168283 is a clinical intervention from the NCI Thesaurus. Ontology label: Interventional Cardiac Catheterization NCIT:C168283
Platform: Device
Catheter-delivered coils or duct occluders close the duct and are the standard of care for most patients. Because PDA3 is a structural failure of ductal smooth muscle rather than a prostaglandin-mediated failure to constrict, mechanical closure, not pharmacological closure, is the definitive treatment.
Mechanism Target:
Persistent Left-to-Right Aortopulmonary Shunt — Occluding the duct abolishes the shunt; it does not correct the underlying smooth muscle defect.
Show evidence (2 references)
PMID:24560920 SUPPORT Human Clinical
"Transcatheter PDA closure is the standard of care in most cases and PDA closure is indicated in any patient with signs of left ventricular volume overload due to a ductus."
Establishes transcatheter closure as standard of care and states the indication.
PMID:24560920 SUPPORT Human Clinical
"Coils and the Amplatzer Duct Occluder are used most frequently for PDA closure worldwide, with a high occlusion rate and few complications."
Names the devices used and supports the efficacy and safety of the approach.
Surgical ductal ligation
Action: surgical ductal ligationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is surgical ductal ligation, annotated with Ligation (NCIT:C15270). NCIT:C15270 is a clinical intervention from the NCI Thesaurus. Ontology label: Ligation NCIT:C15270
Platform: Surgery
Surgical ligation or division of the duct remains an option where transcatheter closure is not feasible, notably in very small infants in whom device delivery is technically difficult.
Mechanism Target:
Persistent Left-to-Right Aortopulmonary Shunt — Ligation interrupts the shunt at the duct.
Show evidence (2 references)
PMID:23055849 SUPPORT Human Clinical
"Three management strategies are currently available for PDA: fluid restriction and diuretics (as clinically appropriate), medical intervention, and surgical ligation."
Lists surgical ligation among the established management strategies for a persistent duct.
PMID:24560920 SUPPORT Human Clinical
"Transcatheter PDA closure in preterm or low-bodyweight infants remains a highly challenging procedure and further device and catheter design development is indicated before transcatheter closure is the treatment of choice in this delicate patient population."
Supports retaining a surgical option where the transcatheter route is technically challenging.
Cyclooxygenase-inhibitor pharmacologic closure
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: indomethacin CHEBI:49662 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses indomethacin, annotated with indometacin (CHEBI:49662). CHEBI:49662 is a therapeutic agent from Chemical Entities of Biological Interest. ibuprofen CHEBI:5855 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ibuprofen (CHEBI:5855). CHEBI:5855 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Indomethacin and ibuprofen close the duct in preterm infants by suppressing the prostaglandin E2 tone that maintains patency. They are recorded here for contrast rather than as a treatment for this disease: PDA3 is a defect of the ductal smooth muscle program rather than of the prostaglandin signal, and in the Prdm6-deficient mouse duct the same prostaglandin-inhibition manoeuvre that closes control ducts does nothing. No trial of pharmacologic closure in a PRDM6 variant carrier has been reported.
Mechanism Target:
Failure of Postnatal Ductal Closure — The intended target is the prostaglandin tone holding the duct open. In PDA3 the block sits downstream of that signal, which is why this link is recorded with refuting evidence rather than as a working treatment.
Show evidence (3 references)
PMID:23055849 SUPPORT Human Clinical
"Pharmacologic closure can be achieved via administration of intravenous indomethacin or ibuprofen lysine."
Establishes the pharmacologic closure option that exists for a persistent duct, the paradigm this entry is contrasting against.
PMID:36749647 REFUTE Model Organism
"While this procedure resulted in premature DA closure in all littermate controls, it had no effect on DA closure in Wnt1Cre2 Prdm6fl/fl fetuses"
Refutes pharmacologic closure as a treatment route when the PRDM6-dependent ductal program is lost: prostaglandin inhibition closed control ducts and not Prdm6-deficient ones.
PMID:36749647 REFUTE Model Organism
"As with indomethacin treatment, oxygen exposure for 1 hour did not stimulate DA closure in Wnt1Cre2 Prdm6fl/fl animals (data not shown)."
The second physiological closure trigger also fails, reinforcing that the block is downstream of the closure signals rather than in them.
Supportive care for a symptomatic shunt
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Fluid restriction and diuretics manage the volume-loaded circulation of a large shunt while closure is arranged. This treats the hemodynamic consequence, not the duct.
Mechanism Target:
Persistent Left-to-Right Aortopulmonary Shunt — Reducing circulating volume lessens the load the shunt imposes without altering the shunt itself.
Show evidence (1 reference)
PMID:23055849 SUPPORT Human Clinical
"Three management strategies are currently available for PDA: fluid restriction and diuretics (as clinically appropriate), medical intervention, and surgical ligation."
Lists fluid restriction and diuretics as one of the established management strategies for a persistent duct.
Genetic counseling and cascade family evaluation
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Autosomal dominant transmission puts a 50 percent chance of inheriting the variant on each pregnancy of a carrier parent. That is the transmission risk and not the risk of disease: penetrance is incomplete, so a carrier child may never develop a patent duct, and counseling has to separate the two numbers. Expressivity among carriers ranges from isolated patent ductus arteriosus to patent ductus arteriosus with coarctation of the aorta. First-degree relatives of an affected individual warrant evaluation.
Show evidence (1 reference)
PMID:27181681 SUPPORT INDIRECT Human Clinical
"Using combined genome-wide linkage analysis and whole-exome sequencing (WES), we identified independent mutations in PRDM6"
Familial linkage transmission is what makes recurrence-risk counseling and relative evaluation applicable; the counseling recommendation follows from the inheritance pattern rather than being stated in the paper.
🔬

Diagnosis

2
Echocardiographic identification of ductal patency
Transthoracic echocardiography establishes the presence of the duct and the magnitude of the shunt, including the left heart volume loading that drives the decision to close.
echocardiography NCIT:C16525 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:23055849 SUPPORT Human Clinical
"Symptoms are not always present; therefore, diagnostic imaging is critical if a PDA is suspected on clinical grounds."
States the necessity of imaging for diagnosis, which echocardiography provides for this lesion.
PRDM6 sequencing
Molecular confirmation of PDA3 requires demonstrating a heterozygous PRDM6 variant. The causal gene was found by exome sequencing, and sequencing remains the route to the diagnosis in a term infant with isolated PDA and a suggestive family history.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:27181681 SUPPORT Human Clinical
"Using combined genome-wide linkage analysis and whole-exome sequencing (WES), we identified independent mutations in PRDM6"
Sequencing is the method by which PRDM6 variants are identified in affected individuals.
📈

Progression

3
Neonatal presentation
The duct is patent at birth in a term infant. A continuous murmur, tachycardia, or bounding pulses may be found on routine examination, but a small duct can be clinically silent, so detection often depends on imaging rather than symptoms.
Show evidence (1 reference)
PMID:23055849 SUPPORT Human Clinical
"Symptoms are not always present; therefore, diagnostic imaging is critical if a PDA is suspected on clinical grounds."
Supports the possibility of a clinically silent duct at this phase.
Hemodynamically significant shunt
With a large duct, left ventricular volume overload develops and drives the decision to close. This is the phase at which intervention is indicated.
Show evidence (1 reference)
PMID:24560920 SUPPORT Human Clinical
"PDA closure is indicated in any patient with signs of left ventricular volume overload due to a ductus"
Names left ventricular volume overload as the state that defines this phase and triggers closure.
Pulmonary vascular disease
Sustained overcirculation in an unclosed duct raises pulmonary artery pressure. Once severe pulmonary arterial hypertension is established, closure is no longer straightforward and becomes conditional.
Show evidence (1 reference)
PMID:24560920 SUPPORT Human Clinical
"In cases of left-to-right PDA with severe pulmonary arterial hypertension, closure may be performed under specific conditions."
That closure becomes conditional at this stage is what distinguishes this phase from the preceding one.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
PDA3 is known from a small number of families and probands rather than from any population-based estimate. The original report described independent mutations in families with nonsyndromic PDA; a later series added three patients with PDA and coarctation of the aorta. No prevalence figure for the PRDM6-related form has been published, so no rate is recorded here.
Show evidence (1 reference)
PMID:38071433 SUPPORT Human Clinical
"We present three patients with PDA and CoA found to harbor PRDM6 variants, including a novel, likely-pathogenic variant."
A three-patient series is the scale at which the PRDM6-related form is reported, supporting a case-count rather than a population rate.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Patent Ductus Arteriosus 3:

Char syndrome
Overlapping Features The syndromic Mendelian form of PDA, caused by TFAP2B variants, in which ductal patency comes with facial dysmorphism and hand anomalies. PDA3 is by definition isolated and nonsyndromic, so the extracardiac features separate them.
Distinguishing Features
  • Facial dysmorphism and fifth-finger anomalies absent in PDA3
  • TFAP2B rather than PRDM6 as the causal gene
Show evidence (1 reference)
PMID:19955832 SUPPORT Other
"Genetic research has identified the cause of syndromic forms of PDA, such as the TFAP2B mutations in Char syndrome."
Identifies Char syndrome and its causal gene as the syndromic genetic alternative to a nonsyndromic PRDM6-related duct.
Prematurity-associated patent ductus arteriosus
Overlapping Features Far the commonest cause of a persistent duct, in which failure to close follows immaturity of the oxygen- and prostaglandin-dependent closure mechanisms rather than an intrinsic genetic defect of the ductal wall. This form is often responsive to cyclooxygenase inhibition, which is not the treatment paradigm for PDA3.
Distinguishing Features
  • Preterm gestation
  • Failure of the prostaglandin-dependent closure mechanism rather than a ductal smooth muscle gene defect
Show evidence (1 reference)
PMID:23055849 SUPPORT Human Clinical
"PDA in term infants is usually associated with a functional defect, whereas in preterm infants it is associated with immaturity."
Draws exactly the distinction that separates a genetic term-infant duct from the prematurity-associated form.
📊

Related Datasets

2
Effect of smooth muscle specific PRDM6 depletion on Aorta and Ductus Arterious (DA) development geo:GSE221004
mouse BULK RNA SEQ n=24
PMID:36749647
The RNA-seq comparison of ductus arteriosus against ascending aorta with and without Prdm6 depletion that identifies the downregulated ductus-enriched contractile gene program curated in this entry. Relevance triaged manually: the series is about the ductus arteriosus and the causal gene of this entry, not merely a PRDM6 gene-name match.
Determining the PRDM6 genomic binding sites in primary outflow tract smooth muscle cells geo:GSE221094
mouse CHIP SEQ n=4
PMID:36749647
The ChIP-seq series behind the finding that half the genes altered by Prdm6 depletion carry Prdm6 binding sites, which is what supports a primary transcriptional mechanism in this entry rather than a secondary effect.
🐁

Animal Models

3
Wnt1Cre2 Prdm6fl/fl mouse
Conditional deletion of Prdm6 in Wnt1-expressing cells gives perinatal lethality with a fully penetrant patent ductus arteriosus, normal neural-crest-derived smooth muscle investment of the outflow tract, and reduced ductal tone on myography.
Species
Mouse
Genotype
Wnt1Cre2 Prdm6fl/fl (neural-crest-lineage conditional Prdm6 deletion)
Publication
PMID:36749647
Pathograph links
Failure of Postnatal Ductal Closure recapitulates fidelity: moderate The model reproduces the defining lesion of PDA3 with complete penetrance.
Limitations: Human PDA3 arises from heterozygous variants with partial loss of function, whereas this model is a homozygous conditional null restricted to the neural-crest lineage, and it is perinatally lethal in a way human PDA3 is not.
Readouts
Patent ductus arteriosus at birth
Direction: ABOLISHED
Interpretation: Ductal closure is abolished in every mutant, the structural correlate of this node.
Show evidence (1 reference)
PMID:36749647 SUPPORT Model Organism
"Prdm6 depletion in Wnt1-expressing cells during development resulted in perinatal lethality and a completely penetrant patent ductus arteriosus (DA) phenotype."
Reports the ductal patency measurement behind this readout.
Show evidence (1 reference)
PMID:36749647 SUPPORT Model Organism
"As depicted in Figure 3, we observed a patent DA in all Wnt1Cre2 Prdm6fl/fl mice, but not in littermate control animals"
The patency finding in this exact genotype against littermate controls is what makes the model informative for the ductal closure node.
Impaired Ductal Contractile Tone recapitulates fidelity: moderate Myography on ductal segments provides the physiological measurement of reduced contractility that the tone node asserts.
Limitations: Tone was measured in embryonic (E18.5) ductal segments ex vivo, so it does not capture the postnatal oxygen- and prostaglandin-dependent constriction that fails in the human disease.
Readouts
Ductal tone and contractility by myography
Direction: DECREASED
Interpretation: Reduced tone is the direct functional correlate of the contractility node.
Show evidence (1 reference)
PMID:36749647 SUPPORT Model Organism
"myography measurements on DA segments isolated from E18.5 embryos indicated that Prdm6 depletion significantly reduced DA tone and contractility"
Reports the myography measurement behind this readout.
Depolarization-induced ductal constriction
Direction: ABOLISHED
Interpretation: The duct cannot contract even to a depolarizing stimulus that bypasses receptor signaling, placing the defect in the contractile apparatus itself.
Show evidence (1 reference)
PMID:36749647 SUPPORT Model Organism
"While 50 mM KCl resulted in an 80% decrease in the diameter of DA segments isolated from littermate controls, it had virtually no effect on DA segments isolated from Wnt1Cre2 Prdm6fl/fl mouse embryos"
Reports the KCl challenge behind this readout.
Oxygen-induced ductal constriction
Direction: ABOLISHED
Interpretation: The rise in oxygen tension that normally constricts the duct after birth produces no response, which is the physiological form of the closure failure.
Show evidence (1 reference)
PMID:36749647 SUPPORT Model Organism
"Time-limited exposures to increasing oxygen concentrations in the circulating buffer resulted in significant constriction of control DA segments as expected (Figure 5C), but this response was completely absent in Prdm6-depleted DA segments."
Reports the oxygen challenge behind this readout.
Show evidence (1 reference)
PMID:36749647 SUPPORT Model Organism
"we examined Prdm6's role in SMCs in vivo using cell type-specific knockout mouse models"
States the model system, a cell-type-specific conditional knockout, that this animal model record describes.
Prdm6fl/fl Wnt1-Cre2 ZsGreen1 mouse
Disruption of Prdm6 in cardiac neural crest cells impairs their differentiation, delamination, and migration and produces patent ductus arteriosus together with ventricular noncompaction.
Species
Mouse
Genotype
Prdm6fl/fl Wnt1-Cre2 ZsGreen1 (neural-crest-lineage conditional Prdm6 deletion with a ZsGreen1 lineage reporter)
Publication
PMID:35108221
Pathograph links
Impaired Cardiac Neural Crest Cell Specification and Migration recapitulates fidelity: moderate The model is the sole source of the neural-crest route in this entry, with lineage tracing and single-cell transcriptomics supporting the migration defect.
Limitations: The crest defect has not been demonstrated in human PDA3 tissue, and this model also produces ventricular noncompaction, which is not a reported feature of the human PRDM6-related phenotype.
Readouts
Retention of neural crest cells in the dorsal neural tube
Direction: INCREASED
Interpretation: Failure to leave the neural tube is the cellular correlate of the migration defect this node asserts.
Show evidence (1 reference)
PMID:35108221 SUPPORT Model Organism
"Loss of Prdm6 in CNCCs diminished its expression in the pre-epithelial-mesenchymal transition (pre-EMT) cluster, resulting in the retention of NCCs in the dorsal neural tube."
Reports the retention measurement behind this readout.
Show evidence (1 reference)
PMID:35108221 SUPPORT Model Organism
"we showed that disruption of Prdm6 was associated with impaired CNCC differentiation, delamination, and migration and led to patent ductus arteriosus (DA) and ventricular noncompaction"
Establishes that this model is informative for a crest mechanism that ends in patent ductus arteriosus.
Failure of Postnatal Ductal Closure partially recapitulates fidelity: low The model produces patent ductus arteriosus, but as one element of a broader neural crest phenotype that includes ventricular noncompaction.
Limitations: Human PDA3 is by definition isolated and nonsyndromic, so a model whose ductal lesion comes packaged with ventricular noncompaction departs from the human entity in exactly the feature that defines it.
Notes
This is the same conditional cross as the Wnt1Cre2 Prdm6fl/fl record above, differing in the lineage reporter (ZsGreen1 here, ROSA26LacZ there). It is kept as a separate record because the two labs report opposite results for ductal neural-crest investment in that shared genotype, which is the substance of the crest-versus-contractility discussion. The same study also reports a patent duct in a Prdm6fl/fl SM22-Cre smooth-muscle-restricted cross, which is not curated as its own record here.
Show evidence (1 reference)
PMID:35108221 SUPPORT Model Organism
"Here, we identified Prdm6 as an epigenetic modifier that temporally and spatially regulates the expression of NCC specifiers and determines the fate of a subset of migrating cardiac NCCs (CNCCs)."
Establishes the neural-crest role of Prdm6 that makes this model informative for the crest mechanism curated here.
Prdm6fl/fl SM22-Cre mouse
Deleting Prdm6 in smooth muscle rather than in the neural crest lineage still gives a completely penetrant patent duct, with contractile genes as the most downregulated transcripts and proliferation unchanged. This is the model that carries the most weight in the crest-versus-contractility disagreement: Prdm6 is lost here only after crest migration and differentiation are complete, so a patent duct in this cross cannot be explained by failed crest migration.
Species
Mouse
Genotype
Prdm6fl/fl SM22-Cre (smooth-muscle-restricted conditional Prdm6 deletion)
Publication
PMID:35108221
Pathograph links
Loss of Ductal Smooth Muscle Contractile Identity recapitulates fidelity: moderate Contractile transcripts are the genes most reduced in this duct, which is the claim the identity node makes, obtained without touching the crest lineage.
Limitations: A homozygous conditional null, whereas human PDA3 is heterozygous; and the duct is smaller than in the crest-restricted cross, so the two lineages are not fully interchangeable.
Readouts
Ductal contractile gene expression
Direction: DECREASED
Interpretation: Tagln and Myh11 as the top downregulated genes is the transcriptional signature of lost contractile identity.
Show evidence (1 reference)
PMID:35108221 SUPPORT Model Organism
"bulk RNA-Seq analysis of E17.5 DA from Prdm6fl/fl SM22-Cre mice and WT littermates identified contractile proteins, such as Tagln and Myh11, as the most downregulated genes in the DA of Prdm6fl/fl SM22-Cre mice versus WT littermates"
Reports the RNA-seq measurement behind this readout.
Ductal smooth muscle proliferation by Ki67
Direction: UNCHANGED
Interpretation: A negative result that matters: the duct fails with a normal proliferative index, so the lesion is differentiation, not cell supply.
Show evidence (1 reference)
PMID:35108221 SUPPORT Model Organism
"Once again, we detected no significant difference in Ki67 staining between Prdm6fl/fl SM22-Cre and WT littermates"
Reports the Ki67 measurement behind this readout.
Failure of Postnatal Ductal Closure recapitulates fidelity: moderate Completely penetrant ductal patency in both sexes.
Limitations: Homozygous conditional null and perinatally lethal, unlike the human heterozygous condition.
Show evidence (1 reference)
PMID:35108221 SUPPORT Model Organism
"The cross-section examination of the DA showed complete patency of DA (Figure 5B), a completely penetrant trait in both male and female mice"
Establishes complete penetrance of the closure failure in this model.
Show evidence (1 reference)
PMID:35108221 SUPPORT Model Organism
"Gross anatomical examination of the cardiovascular system showed a PDA, albeit with a smaller diameter compared with Prdm6fl/fl Wnt1-Cre2 ZsGreen1 mice"
Establishes the ductal phenotype in the smooth-muscle-restricted cross.
{ }

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name: Patent Ductus Arteriosus 3
creation_date: "2026-09-03T09:20:00Z"
description: >-
  Patent ductus arteriosus 3 (PDA3) is the isolated, nonsyndromic Mendelian form
  of patent ductus arteriosus caused by heterozygous variants in PRDM6, which
  encodes a vascular-smooth-muscle-restricted PR/SET-domain protein with histone
  methyltransferase activity that regulates the ductal smooth muscle gene
  program. Whether it represses or promotes the contractile arm of that program
  is disputed. Loss of PRDM6 function disturbs the program required for postnatal
  constriction and remodeling of the ductus arteriosus, so the duct fails to close
  in infants who are neither preterm nor syndromic. Affected individuals present
  with the hemodynamic consequences of a persistent left-to-right aortopulmonary
  shunt, and a subset also carry coarctation of the aorta.
category: Mendelian
disease_term:
  preferred_term: patent ductus arteriosus 3
  term:
    id: MONDO:0024266
    label: patent ductus arteriosus 3
parents:
- Patent Ductus Arteriosus
- Congenital Heart Defect
synonyms:
- PDA3
- PRDM6 patent ductus arteriosus
- patent ductus arteriosus caused by mutation in PRDM6
- PRDM6-related nonsyndromic patent ductus arteriosus
notes: >-
  The entry carries both readings of PRDM6's direction of effect rather than
  choosing one; see the mechanistic_hypotheses groups and the
  prdm6_direction_of_effect discussion.
  No GeneReviews chapter exists for PDA3 or for PRDM6 (PubMed searches for
  "PRDM6 GeneReviews" and "patent ductus arteriosus GeneReviews" return no
  matching chapter), so no GeneReviews phenotype baseline was available. The
  only GeneReviews chapter covering a Mendelian PDA is Char Syndrome, caused by
  TFAP2B, which is the gene assigned to PDA2 (OMIM 617035); PDA1 (OMIM 607411) is
  a separate locus. Char syndrome is a different, syndromic entity and is curated
  here only as a differential diagnosis.
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
inheritance:
- name: Autosomal dominant
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >-
    PDA3 segregates as an autosomal dominant trait: heterozygous PRDM6 variants
    were identified by combined linkage analysis and whole-exome sequencing in
    families with isolated nonsyndromic patent ductus arteriosus, and
    heterozygous variants have since been reported in further probands with PDA
    with or without coarctation of the aorta. Penetrance is incomplete: obligate
    carriers in the index kindred are reported unaffected. Expressivity is variable,
    ranging from isolated patent ductus arteriosus to patent ductus arteriosus with
    coarctation of the aorta among carriers.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:27181681
    reference_title: "Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using combined genome-wide linkage analysis and whole-exome sequencing (WES), we identified independent mutations in PRDM6
    explanation: >-
      Linkage plus exome sequencing in PDA families is the study design that
      established the dominant, familial transmission of PRDM6 variants in
      nonsyndromic PDA.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    PDA3 is known from a small number of families and probands rather than from
    any population-based estimate. The original report described independent
    mutations in families with nonsyndromic PDA; a later series added three
    patients with PDA and coarctation of the aorta. No prevalence figure for the
    PRDM6-related form has been published, so no rate is recorded here.
  evidence:
  - reference: PMID:38071433
    reference_title: "Patent ductus arteriosus and coarctation of the aorta in association with PRDM6 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present three patients with PDA and CoA found to harbor PRDM6 variants, including a novel, likely-pathogenic variant.
    explanation: >-
      A three-patient series is the scale at which the PRDM6-related form is
      reported, supporting a case-count rather than a population rate.
mechanistic_hypotheses:
- hypothesis_group_id: prdm6_premature_differentiation
  hypothesis_label: PRDM6 loss releases ductal smooth muscle from a proliferative, undifferentiated state
  status: ALTERNATIVE
  description: >-
    In the model proposed with the original human genetic finding, PRDM6 keeps
    ductal vascular smooth muscle cells undifferentiated so that they proliferate
    and populate the ductal media; PRDM6 falls postnatally as contraction-competent
    cells accumulate. On this view loss of PRDM6 activity causes premature
    differentiation and a shortage of the smooth muscle needed for the remodeling
    that permanently occludes the duct.
  notes: >-
    The developmental expression time course underpinning this model is reported in
    the paper's abstract without naming the species. It is graded MODEL_ORGANISM
    because a time course sampling the ductus arteriosus before and after birth is
    only practicable in an animal, and the deep-research report for this entry
    records it as mouse immunofluorescence at E14.5, E17.5 and P0.5.
  evidence:
  - reference: PMID:27181681
    reference_title: "Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This dynamic change suggests that PRDM6 plays a key role in maintaining VSMCs in an undifferentiated stage in order to promote their proliferation and that its loss of activity results in premature differentiation and impaired remodeling of the DA.
    explanation: >-
      This is the authors' explicit statement of the premature-differentiation
      model that this hypothesis group records.
- hypothesis_group_id: prdm6_smc_identity
  hypothesis_label: PRDM6 is required to build ductal smooth muscle contractile identity
  status: ALTERNATIVE
  description: >-
    Conditional deletion of Prdm6 in the neural-crest lineage gives a fully
    penetrant patent ductus arteriosus in which the duct is normally invested with
    smooth muscle but is hypocontractile, and a ductus-enriched contractile gene
    program is downregulated. On this view PRDM6 is needed to establish, rather
    than to restrain, the contractile program, and PDA follows from failure of
    active constriction.
  notes: >-
    This runs in the opposite direction to the premature-differentiation model
    with respect to whether PRDM6 represses or promotes contractile gene
    expression; the discrepancy is recorded as an open discussion in this entry.
  evidence:
  - reference: PMID:36749647
    reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      RNA-Seq analyses on DA and ascending aorta samples at E18.5 identified a DA-enriched gene program that included many SMC-selective contractile associated proteins that was downregulated by Prdm6 depletion.
    explanation: >-
      Downregulation of the ductal contractile program on Prdm6 loss is the
      central observation behind this hypothesis.
- hypothesis_group_id: prdm6_cncc_specification
  hypothesis_label: PRDM6 acts earlier, on cardiac neural crest specification and migration
  status: EMERGING
  description: >-
    A separate mouse study places Prdm6 upstream of the smooth muscle program
    altogether, as a regulator of cardiac neural crest cell specification,
    delamination, and migration acting through Wnt1, Tfap2b, and Sox9 and through
    H4K20 monomethylation. Patent ductus arteriosus in that model is one outcome of
    a broader neural crest defect that also produces ventricular noncompaction.
  evidence:
  - reference: PMID:35108221
    reference_title: "Prdm6 controls heart development by regulating neural crest cell differentiation and migration."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we showed that disruption of Prdm6 was associated with impaired CNCC differentiation, delamination, and migration and led to patent ductus arteriosus (DA) and ventricular noncompaction
    explanation: >-
      This states the neural-crest route from Prdm6 disruption to patent ductus
      arteriosus that this hypothesis group records.
progression:
- phase: Neonatal presentation
  notes: >-
    The duct is patent at birth in a term infant. A continuous murmur, tachycardia,
    or bounding pulses may be found on routine examination, but a small duct can be
    clinically silent, so detection often depends on imaging rather than symptoms.
  evidence:
  - reference: PMID:23055849
    reference_title: "Patent ductus arteriosus: an overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Symptoms are not always present; therefore, diagnostic imaging is critical if a PDA is suspected on clinical grounds.
    explanation: >-
      Supports the possibility of a clinically silent duct at this phase.
- phase: Hemodynamically significant shunt
  notes: >-
    With a large duct, left ventricular volume overload develops and drives the
    decision to close. This is the phase at which intervention is indicated.
  evidence:
  - reference: PMID:24560920
    reference_title: "Transcatheter closure of patent ductus arteriosus: past, present and future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PDA closure is indicated in any patient with signs of left ventricular volume overload due to a ductus
    explanation: >-
      Names left ventricular volume overload as the state that defines this phase
      and triggers closure.
- phase: Pulmonary vascular disease
  notes: >-
    Sustained overcirculation in an unclosed duct raises pulmonary artery pressure.
    Once severe pulmonary arterial hypertension is established, closure is no longer
    straightforward and becomes conditional.
  evidence:
  - reference: PMID:24560920
    reference_title: "Transcatheter closure of patent ductus arteriosus: past, present and future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In cases of left-to-right PDA with severe pulmonary arterial hypertension, closure may be performed under specific conditions.
    explanation: >-
      That closure becomes conditional at this stage is what distinguishes this
      phase from the preceding one.
pathophysiology:
- name: PRDM6 Loss-of-Function Variants
  description: >-
    Heterozygous germline PRDM6 variants are the initiating lesion in PDA3.
    In vitro characterization of the variants found in PDA families showed loss of
    function, either because the mutant protein is redistributed within the cell or
    because its methyltransferase activity is altered.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  genetic_context:
    gene:
      preferred_term: PRDM6
      term:
        id: hgnc:9350
        label: PRDM6
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: PRDM6 histone methyltransferase activity
    modifier: ABNORMAL
    term:
      id: GO:0042054
      label: histone methyltransferase activity
  locations:
  - preferred_term: ductus arteriosus
    term:
      id: UBERON:0005440
      label: ductus arteriosus
  evidence:
  - reference: PMID:27181681
    reference_title: "Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings identify PRDM6 mutations as underlying genetic causes of nonsyndromic isolated PDA in humans and implicates the wild-type protein in epigenetic regulation of ductus remodeling.
    explanation: >-
      This states directly that PRDM6 mutations are a genetic cause of isolated
      nonsyndromic PDA in humans, which is the lesion this node represents.
  - reference: PMID:27181681
    reference_title: "Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro assays showed that the mutations cause loss of function either by intracellular redistribution of the protein and/or by alteration of its methyltransferase activities.
    explanation: >-
      Cell-based assays establish the loss-of-function consequence recorded in
      this node's genetic context.
  downstream:
  - target: Deregulated Ductal Smooth Muscle Transcriptional Program
    causal_link_type: DIRECT
    description: >-
      Because PRDM6 acts on chromatin as a smooth-muscle-restricted transcriptional
      repressor, loss of its activity is read out directly as a change in the ductal
      transcriptional program.
    evidence:
    - reference: PMID:27181681
      reference_title: "Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        we identified independent mutations in PRDM6, which encodes a nuclear protein that is specific to vascular smooth muscle cells (VSMC), has histone methyl transferase activities, and acts as a transcriptional suppressor of contractile proteins
      explanation: >-
        The gene product's identity as a VSMC-specific chromatin-modifying
        transcriptional repressor is what makes the step from variant to altered
        transcriptional program direct.
- name: Deregulated Ductal Smooth Muscle Transcriptional Program
  description: >-
    PRDM6 binds and regulates a large fraction of the genes whose expression it
    controls in outflow tract smooth muscle, and its loss shifts the ductus-specific
    gene program. This node is the shared molecular consequence from which the
    competing cellular models of PDA3 diverge.
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  cell_types:
  - preferred_term: ductal vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: PRDM6-dependent transcriptional control of the ductal smooth muscle program
    modifier: DYSREGULATED
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
  locations:
  - preferred_term: ductus arteriosus
    term:
      id: UBERON:0005440
      label: ductus arteriosus
  evidence:
  - reference: PMID:36749647
    reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Chromatin immunoprecipitation-sequencing experiments in outflow tract SMCs demonstrated that 50% of the genes Prdm6 depletion altered contained Prdm6 binding sites.
    explanation: >-
      Occupancy at half the responsive genes puts a substantial part of the program
      change under direct Prdm6 binding. The authors stop short of a wholly direct
      mechanism: they report that with few exceptions Prdm6 was not bound at the
      smooth-muscle-specific promoters themselves, and raise the possibility that
      the identity effect is secondary to other transcriptional machinery.
  - reference: PMID:36749647
    reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Of the 519 genes that were more highly expressed in the DA by at least 1.5-fold, 319 of those were significantly (P < 0.01) downregulated by Prdm6 depletion.
    explanation: >-
      Quantifies how much of the ductus-versus-aorta expression signature depends on
      Prdm6, which is the scale of the program change this node asserts.
  - reference: PMID:36749647
    reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Prdm6 depletion altered the expression level of many genes previously implicated in DA closure (see ref. 34 for a review), including the PGE2 receptor, EP4; the transcription factors Tfap2b, myocardin, Foxc1, and Hand2; the Notch signaling components, Jag1 and Notch3; SM MHC; integrin linked kinase; and fibulin1.
    explanation: >-
      Names the ductal-closure genes affected, including EP4 and Tfap2b, tying this
      program to the closure machinery and to the other genetic forms of PDA.
  downstream:
  - target: Loss of Ductal Smooth Muscle Contractile Identity
    causal_link_type: DIRECT
    hypothesis_groups:
    - prdm6_smc_identity
    description: >-
      On the smooth-muscle-identity model, the altered program is specifically a
      loss of ductus-enriched contractile gene expression.
    evidence:
    - reference: PMID:36749647
      reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        RNA-Seq analyses on DA and ascending aorta samples at E18.5 identified a DA-enriched gene program that included many SMC-selective contractile associated proteins that was downregulated by Prdm6 depletion.
      explanation: >-
        This is the transcriptional measurement linking loss of Prdm6 to loss of
        the ductal contractile identity program.
  - target: Premature Ductal Smooth Muscle Differentiation
    causal_link_type: DIRECT
    hypothesis_groups:
    - prdm6_premature_differentiation
    description: >-
      On the premature-differentiation model, the same loss of repression instead
      releases ductal smooth muscle cells from an undifferentiated proliferative
      state too early.
  - target: Impaired Cardiac Neural Crest Cell Specification and Migration
    causal_link_type: DIRECT
    hypothesis_groups:
    - prdm6_cncc_specification
    description: >-
      In the neural crest model the affected program is a network of crest
      specification genes rather than the mature smooth muscle contractile program.
    evidence:
    - reference: PMID:35108221
      reference_title: "Prdm6 controls heart development by regulating neural crest cell differentiation and migration."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Bulk and single-cell RNA-Seq analyses of the DA and CNCCs identified Prdm6 as a regulator of a network of CNCC specification genes, including Wnt1, Tfap2b, and Sox9.
      explanation: >-
        This identifies the crest specification network as the transcriptional
        target set in this alternative route.
- name: Loss of Ductal Smooth Muscle Contractile Identity
  description: >-
    Ductal smooth muscle cells lose the contraction-associated gene expression that
    distinguishes the ductus arteriosus from the adjacent aorta, while still
    populating the vessel wall normally.
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: ductal vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: smooth muscle cell differentiation
    modifier: ABNORMAL
    term:
      id: GO:0051145
      label: smooth muscle cell differentiation
  evidence:
  - reference: PMID:36749647
    reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Lineage tracing experiments in Wnt1Cre2 Prdm6fl/fl ROSA26LacZ mice revealed normal neural crest-derived SMC investment of the outflow tract.
    explanation: >-
      Normal smooth muscle investment with a defective duct localizes the lesion to
      cell identity and function rather than to cell number in this model. Note that
      a second group reports the opposite in the same genotype; see the refuting item
      below and the crest-versus-contractility discussion.
  - reference: PMID:35108221
    reference_title: "Prdm6 controls heart development by regulating neural crest cell differentiation and migration."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The examination of the DA of Prdm6fl/fl Wnt1-Cre2 ZsGreen1 mice at E17.5 showed dramatically reduced ZsGreen1-positive (NCC-derived) cells in the tunica media compared with those of the WT littermates
    explanation: >-
      A second lab, using the same Wnt1-Cre2 Prdm6fl/fl genotype with a different
      reporter, finds the ductal media depleted of neural-crest-derived cells. That
      contradicts the normal-investment premise this node rests on.
  downstream:
  - target: Impaired Ductal Contractile Tone
    causal_link_type: DIRECT
    hypothesis_groups:
    - prdm6_smc_identity
    description: >-
      Loss of the contractile gene program is read out as loss of the tone that
      program exists to generate.
- name: Premature Ductal Smooth Muscle Differentiation
  description: >-
    Ductal smooth muscle cells exit the proliferative, undifferentiated state too
    early, so the ductal wall is differentiated on the wrong schedule when the
    postnatal remodeling window opens. The originally proposed corollary, that the
    medial cell population is thereby depleted, is refuted by the Ki67 evidence
    recorded on this node.
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  cell_types:
  - preferred_term: ductal vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: smooth muscle cell proliferation
    modifier: ABNORMAL
    term:
      id: GO:0048659
      label: smooth muscle cell proliferation
  evidence:
  - reference: PMID:35108221
    reference_title: "Prdm6 controls heart development by regulating neural crest cell differentiation and migration."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Taken together, these findings indicated that the patency of the DA in Prdm6fl/fl Wnt1-Cre2 ZsGreen1 mice was not caused by impaired proliferation of NCC-derived SMCs.
    explanation: >-
      Ki67 staining found no proliferation deficit in the Prdm6-depleted duct, which
      refutes the reduced-proliferation half of the premature-differentiation model.
      The proliferation descriptor is therefore left as ABNORMAL rather than
      DECREASED, and the node is retained only as the differentiation-timing claim.
  notes: >-
    The proliferation arm of this model is contradicted by direct measurement: the
    original human paper inferred reduced proliferation from a developmental
    expression time course, while the conditional knockout that tested it with Ki67
    found none. What survives is the claim about differentiation timing, not about
    medial cell number.
  downstream:
  - target: Impaired Ductal Wall Remodeling
    causal_link_type: DIRECT
    hypothesis_groups:
    - prdm6_premature_differentiation
    evidence:
    - reference: PMID:27181681
      reference_title: "Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        its loss of activity results in premature differentiation and impaired remodeling of the DA
      explanation: >-
        This states the premature-differentiation step and the impaired remodeling
        it is proposed to cause as one causal claim.
- name: Impaired Cardiac Neural Crest Cell Specification and Migration
  description: >-
    In the neural crest model, cardiac neural crest cells fail to complete
    epithelial-mesenchymal transition and migration, being retained in the dorsal
    neural tube, with diminished H4K20 monomethylation and increased Wnt1
    transcript levels driving the migration defect.
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  cell_types:
  - preferred_term: migratory cardiac neural crest cell
    term:
      id: CL:2000073
      label: migratory cardiac neural crest cell
  biological_processes:
  - preferred_term: neural crest cell differentiation
    modifier: ABNORMAL
    term:
      id: GO:0014033
      label: neural crest cell differentiation
  - preferred_term: neural crest cell migration
    modifier: DECREASED
    term:
      id: GO:0001755
      label: neural crest cell migration
  - preferred_term: epithelial to mesenchymal transition
    modifier: DECREASED
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
  notes: >-
    Contested. The group that proposed this route reports depleted neural-crest
    investment of the ductal media; the group that curated the contractility route
    reports normal investment in the same genotype, found no migration defect in
    outflow-tract smooth muscle culture, and argues that a patent duct in an
    SM22-Cre model, where deletion happens only after crest migration is complete,
    makes a migration defect an unlikely primary cause. Both positions are cited
    here and the disagreement is carried as an open discussion.
  evidence:
  - reference: PMID:35108221
    reference_title: "Prdm6 controls heart development by regulating neural crest cell differentiation and migration."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This defect was associated with diminished H4K20 monomethylation and G1-S progression and augmented Wnt1 transcript levels in pre-EMT and neural tube clusters, which we showed was the major driver of the impaired CNCC migration.
    explanation: >-
      This gives the chromatin and Wnt1 mechanism behind the migration defect this
      node represents.
  - reference: PMID:36749647
    reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      As shown in Figure 4, we did not detect differences in neural crest cell investment of the ductus or the morphology of the ductus medial SMC layer.
    explanation: >-
      A direct failure to replicate the investment defect on which this node's
      mechanism depends.
  - reference: PMID:36749647
    reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Since Prdm6 depletion in this model occurs only after the migration and SMC differentiation of neural crest cells, it seems unlikely that the patent DA phenotype observed in Wnt1Cre2 Prdm6fl/fl mice was due primarily to a failure of neural crest migration.
    explanation: >-
      The genetic timing argument: a patent duct in a model where Prdm6 is deleted
      after crest migration has finished cannot be explained by failed migration.
  downstream:
  - target: Failure of Postnatal Ductal Closure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - prdm6_cncc_specification
    evidence:
    - reference: PMID:35108221
      reference_title: "Prdm6 controls heart development by regulating neural crest cell differentiation and migration."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we showed that disruption of Prdm6 was associated with impaired CNCC differentiation, delamination, and migration and led to patent ductus arteriosus (DA) and ventricular noncompaction
      explanation: >-
        This links the crest defect to patent ductus arteriosus as its outcome.
- name: Impaired Ductal Contractile Tone
  description: >-
    The ductus arteriosus generates insufficient smooth muscle tone to constrict
    after birth. Myography of ductal segments from Prdm6-depleted embryos shows
    reduced tone and contractility despite normal smooth muscle investment.
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: vascular associated smooth muscle contraction
    modifier: DECREASED
    term:
      id: GO:0014829
      label: vascular associated smooth muscle contraction
  locations:
  - preferred_term: ductus arteriosus
    term:
      id: UBERON:0005440
      label: ductus arteriosus
  evidence:
  - reference: PMID:36749647
    reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      myography measurements on DA segments isolated from E18.5 embryos indicated that Prdm6 depletion significantly reduced DA tone and contractility
    explanation: >-
      Direct physiological measurement of reduced ductal tone is the observation
      this node records.
  downstream:
  - target: Failure of Postnatal Ductal Closure
    causal_link_type: DIRECT
    hypothesis_groups:
    - prdm6_smc_identity
    description: >-
      Functional closure is achieved by constriction, so a duct that cannot generate
      tone cannot take the first step of closing.
- name: Impaired Ductal Wall Remodeling
  description: >-
    The intimal thickening and medial reorganization that normally convert the
    functionally constricted duct into a permanently occluded ligamentum arteriosum
    do not proceed. Failure of this smooth-muscle-driven remodeling step is the
    common endpoint shared by the syndromic and nonsyndromic genetic forms of PDA.
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  cell_types:
  - preferred_term: ductal vascular smooth muscle cell
    term:
      id: CL:0000359
      label: vascular associated smooth muscle cell
  biological_processes:
  - preferred_term: intimal thickening and fibrotic remodeling of the ductal wall
    modifier: DECREASED
    term:
      id: GO:0048771
      label: tissue remodeling
  locations:
  - preferred_term: ductus arteriosus
    term:
      id: UBERON:0005440
      label: ductus arteriosus
  evidence:
  - reference: PMID:19955832
    reference_title: "Insights into the pathogenesis and genetic background of patency of the ductus arteriosus."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Genes that interfere with the remodeling of vascular smooth muscle cells (VSMCs) of the ductal media are affected in virtually all of these anomalies.
    explanation: >-
      This review of the genetic forms of PDA places failed smooth-muscle-driven
      remodeling of the ductal media at the convergence point, which is what this
      node represents.
  - reference: PMID:36749647
    reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Full anatomic closure takes place over a longer period and involves intimal thickening and eventual fibrotic remodeling of the DA into a remnant structure known as the ligamentum arteriosum
    explanation: >-
      Defines the remodeling process, distinct from functional constriction, whose
      failure this node records. Graded OTHER because the sentence is background
      physiology the authors cite to a review, not a result of their experiments.
  downstream:
  - target: Failure of Postnatal Ductal Closure
    causal_link_type: DIRECT
    hypothesis_groups:
    - prdm6_premature_differentiation
    description: >-
      Permanent closure requires the intimal and medial remodeling step, so a duct
      that cannot remodel stays open even if it constricts.
- name: Failure of Postnatal Ductal Closure
  description: >-
    The ductus arteriosus does not undergo the functional constriction and
    subsequent anatomic obliteration that normally follow birth, and remains patent
    in a term infant with no prematurity-related or syndromic explanation.
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  biological_processes:
  - preferred_term: ductus arteriosus closure
    modifier: ABSENT
    term:
      id: GO:0097070
      label: ductus arteriosus closure
  locations:
  - preferred_term: ductus arteriosus
    term:
      id: UBERON:0005440
      label: ductus arteriosus
  evidence:
  - reference: PMID:23055849
    reference_title: "Patent ductus arteriosus: an overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PDA in term infants is usually associated with a functional defect, whereas in preterm infants it is associated with immaturity.
    explanation: >-
      This distinguishes the intrinsic ductal defect operating in term infants,
      which is the setting of PDA3, from prematurity-associated failure to close.
  - reference: PMID:36749647
    reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Prdm6 depletion in Wnt1-expressing cells during development resulted in perinatal lethality and a completely penetrant patent ductus arteriosus (DA) phenotype.
    explanation: >-
      Complete penetrance of patent ductus arteriosus on Prdm6 loss supports this
      node as the consequence of the upstream ductal defect.
  - reference: PMID:36749647
    reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      While this procedure resulted in premature DA closure in all littermate controls, it had no effect on DA closure in Wnt1Cre2 Prdm6fl/fl fetuses
    explanation: >-
      Prostaglandin inhibition closes the duct in controls but not in the mutant, so
      the closure trigger is intact while the duct cannot execute it, which is the
      distinction this node turns on.
  downstream:
  - target: Patent ductus arteriosus
    causal_link_type: DIRECT
    description: >-
      The unclosed duct is the clinical lesion itself, so this edge is the
      mechanism-to-phenotype step rather than a further consequence.
  - target: Coarctation of aorta
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Drawn because the aortic isthmus carries ductal smooth muscle at its junction
      with the duct, so the same smooth-muscle lesion is a plausible route to arch
      narrowing. The intermediate steps are not established, and the co-occurrence
      rests on a three-patient series.
    evidence:
    - reference: PMID:38071433
      reference_title: "Patent ductus arteriosus and coarctation of the aorta in association with PRDM6 variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We present three patients with PDA and CoA found to harbor PRDM6 variants, including a novel, likely-pathogenic variant.
      explanation: >-
        The co-occurrence this edge records, at the strength the series supports.
  - target: Persistent Left-to-Right Aortopulmonary Shunt
    causal_link_type: DIRECT
    description: >-
      An open duct shunts once pulmonary vascular resistance falls after birth.
    evidence:
    - reference: PMID:23055849
      reference_title: "Patent ductus arteriosus: an overview."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In the neonate, however, persistent patency of the ductus arteriosus (DA) is associated with significant morbidity and mortality.
      explanation: >-
        Establishes that persistent patency, not merely a structural finding, carries
        hemodynamic consequence.
- name: Persistent Left-to-Right Aortopulmonary Shunt
  description: >-
    With the duct open and pulmonary vascular resistance falling after birth, blood
    shunts from the aorta into the pulmonary artery. The resulting pulmonary
    overcirculation and left heart volume load produce the clinical findings of the
    lesion.
  biological_scale: ORGANISM
  mechanism_confidence: ESTABLISHED
  locations:
  - preferred_term: pulmonary artery
    term:
      id: UBERON:0002012
      label: pulmonary artery
  evidence:
  - reference: PMID:24560920
    reference_title: "Transcatheter closure of patent ductus arteriosus: past, present and future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PDA closure is indicated in any patient with signs of left ventricular volume overload due to a ductus
    explanation: >-
      Left ventricular volume overload is the recognized hemodynamic consequence of
      the persistent shunt that this node represents.
  downstream:
  - target: Heart murmur
    causal_link_type: DIRECT
    description: >-
      Continuous flow across the duct is audible.
    evidence:
    - reference: PMID:23055849
      reference_title: "Patent ductus arteriosus: an overview."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinical signs of ductal patency include murmur, tachycardia, bounding peripheral pulses, and congestive heart failure and associated symptoms.
      explanation: >-
        Names murmur as a sign produced by ductal patency, which is this edge.
  - target: Congestive heart failure
    causal_link_type: DIRECT
    description: >-
      Left heart volume loading from a large shunt produces heart failure.
    evidence:
    - reference: PMID:23055849
      reference_title: "Patent ductus arteriosus: an overview."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Clinical signs of ductal patency include murmur, tachycardia, bounding peripheral pulses, and congestive heart failure and associated symptoms.
      explanation: >-
        The same list names congestive heart failure as a consequence of ductal
        patency.
  - target: Pulmonary arterial hypertension
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Sustained overcirculation remodels the pulmonary vasculature over years, so
      the step runs through pulmonary vascular disease rather than directly.
    evidence:
    - reference: PMID:24560920
      reference_title: "Transcatheter closure of patent ductus arteriosus: past, present and future."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In cases of left-to-right PDA with severe pulmonary arterial hypertension, closure may be performed under specific conditions.
      explanation: >-
        A left-to-right duct reaching severe pulmonary arterial hypertension is the
        end state this edge records.
phenotypes:
- category: Cardiovascular
  name: Patent ductus arteriosus
  description: >-
    Persistent postnatal patency of the ductus arteriosus in the absence of a
    syndromic diagnosis or prematurity. This is the defining lesion of PDA3.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  evidence:
  - reference: PMID:27181681
    reference_title: "Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings identify PRDM6 mutations as underlying genetic causes of nonsyndromic isolated PDA in humans and implicates the wild-type protein in epigenetic regulation of ductus remodeling.
    explanation: >-
      This establishes isolated nonsyndromic patent ductus arteriosus as the
      phenotype caused by PRDM6 mutations.
  - reference: PMID:38071433
    reference_title: "Patent ductus arteriosus and coarctation of the aorta in association with PRDM6 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic variants in PRDM6, which encodes a smooth-muscle-cell-specific transcription factor, have now been etiologically associated with non-syndromic PDA.
    explanation: >-
      An independent group confirms the PRDM6-PDA association in their patients.
- category: Cardiovascular
  name: Coarctation of aorta
  description: >-
    Narrowing of the thoracic aorta at the isthmus, reported alongside patent
    ductus arteriosus in PRDM6 variant carriers. Because the aortic isthmus and the
    ductus share ductal smooth muscle at their junction, a smooth-muscle-identity
    lesion is a plausible route to both, but the reported series is three patients
    and does not by itself establish coarctation as a component of PDA3. No
    frequency band is assigned: the only series was ascertained for the
    PDA-plus-coarctation combination, so it cannot estimate how often carriers have
    it.
  phenotype_term:
    preferred_term: Coarctation of aorta
    term:
      id: HP:0001680
      label: Coarctation of aorta
  evidence:
  - reference: PMID:38071433
    reference_title: "Patent ductus arteriosus and coarctation of the aorta in association with PRDM6 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present three patients with PDA and CoA found to harbor PRDM6 variants, including a novel, likely-pathogenic variant.
    explanation: >-
      This is the direct report of coarctation of the aorta co-occurring with PDA
      in PRDM6 variant carriers.
- category: Cardiovascular
  name: Heart murmur
  description: >-
    A murmur is the usual presenting sign of an unrepaired duct. The classic
    finding is the continuous machinery murmur of flow across the duct through both
    systole and diastole.
  phenotype_term:
    preferred_term: Heart murmur
    term:
      id: HP:0030148
      label: Heart murmur
  evidence:
  - reference: PMID:23055849
    reference_title: "Patent ductus arteriosus: an overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical signs of ductal patency include murmur, tachycardia, bounding peripheral pulses, and congestive heart failure and associated symptoms.
    explanation: >-
      Murmur is listed first among the clinical signs of ductal patency, the lesion
      PDA3 causes.
  notes: >-
    Cited from the general patent ductus arteriosus literature rather than from a
    PRDM6 cohort: this is a consequence of the shunt lesion, not a
    PDA3-specific finding. Bound to the general HP:0030148 rather than to
    HP:0031670 Continuous heart murmur: no reference cached for this entry uses the
    word continuous, so the narrower term would outrun its evidence.
- category: Cardiovascular
  name: Congestive heart failure
  description: >-
    Volume loading of the left heart from a large shunt produces heart failure
    with the associated feeding difficulty and failure to thrive of infancy.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:23055849
    reference_title: "Patent ductus arteriosus: an overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical signs of ductal patency include murmur, tachycardia, bounding peripheral pulses, and congestive heart failure and associated symptoms.
    explanation: >-
      Names congestive heart failure outright as a clinical sign of ductal patency.
  notes: >-
    Cited from the general patent ductus arteriosus literature rather than from a
    PRDM6 cohort: this is a consequence of the shunt lesion, not a
    PDA3-specific finding.
- category: Cardiovascular
  name: Pulmonary arterial hypertension
  description: >-
    Sustained pulmonary overcirculation from an unrepaired duct can raise pulmonary
    artery pressure and, if untreated, progress to irreversible pulmonary vascular
    disease with shunt reversal.
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
  evidence:
  - reference: PMID:24560920
    reference_title: "Transcatheter closure of patent ductus arteriosus: past, present and future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In cases of left-to-right PDA with severe pulmonary arterial hypertension, closure may be performed under specific conditions.
    explanation: >-
      Severe pulmonary arterial hypertension is recognized as a state a
      left-to-right duct can reach, and it changes closure decisions.
  notes: >-
    Cited from the general patent ductus arteriosus literature rather than from a
    PRDM6 cohort: this is a consequence of the shunt lesion, not a
    PDA3-specific finding.
genetic:
- name: PRDM6
  association: Causal
  presence: Positive
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: PRDM6
    term:
      id: hgnc:9350
      label: PRDM6
  notes: >-
    PRDM6 encodes a nuclear PR/SET-domain protein restricted to vascular smooth
    muscle cells, with histone methyltransferase activity. The discovery paper
    describes it as a transcriptional suppressor of contractile proteins; the
    conditional knockout work reads the same gene as required to build that
    contractile program, and the entry carries the disagreement rather than
    settling it. Heterozygous variants cause
    isolated nonsyndromic patent ductus arteriosus.
    The parent entry Patent_Ductus_Arteriosus curates PRDM6 as a developmental
    susceptibility locus for PDA generally and explicitly does not curate it there
    as a deterministic Mendelian cause; this entry is where the Mendelian
    PRDM6-caused form is curated. The three variants listed carry ClinVar accessions,
    each classified Pathogenic for patent ductus arteriosus 3; their domain
    assignments come from the primary article's body, which is not in the reference
    cache, so they are described rather than cited to a snippet.
  variants:
  - name: c.1646G>A (p.Arg549Gln)
    description: >-
      Missense variant in the fourth zinc-finger region. Reported in the index
      kindred and characterized in vitro as loss of function through cytoplasmic
      mislocalization of the protein.
    clinical_significance: PATHOGENIC
    regulatory_category: LOF
    type: missense_variant
    identifiers:
    - ClinVar:VCV000243049
  - name: c.788G>C (p.Cys263Ser)
    description: >-
      Missense variant in the SET (PR) domain, the catalytic region, reported in a
      proband with affected mother and maternal grandfather.
    clinical_significance: PATHOGENIC
    regulatory_category: LOF
    type: missense_variant
    identifiers:
    - ClinVar:VCV000243050
  - name: c.1385A>G (p.Gln462Arg)
    description: >-
      Missense variant reported in an affected mother and daughter.
    clinical_significance: PATHOGENIC
    regulatory_category: LOF
    type: missense_variant
    identifiers:
    - ClinVar:VCV000243051
  evidence:
  - reference: PMID:27181681
    reference_title: "Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings identify PRDM6 mutations as underlying genetic causes of nonsyndromic isolated PDA in humans and implicates the wild-type protein in epigenetic regulation of ductus remodeling.
    explanation: >-
      Direct statement of PRDM6 as the causal gene for this entity.
  - reference: PMID:27181681
    reference_title: "Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro assays showed that the mutations cause loss of function either by intracellular redistribution of the protein and/or by alteration of its methyltransferase activities.
    explanation: >-
      Establishes loss of function as the mechanism of the disease-associated
      variants.
animal_models:
- name: Wnt1Cre2 Prdm6fl/fl mouse
  species: Mouse
  genotype: Wnt1Cre2 Prdm6fl/fl (neural-crest-lineage conditional Prdm6 deletion)
  publication: PMID:36749647
  description: >-
    Conditional deletion of Prdm6 in Wnt1-expressing cells gives perinatal
    lethality with a fully penetrant patent ductus arteriosus, normal
    neural-crest-derived smooth muscle investment of the outflow tract, and reduced
    ductal tone on myography.
  evidence:
  - reference: PMID:36749647
    reference_title: Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we examined Prdm6's role in SMCs in vivo using cell type-specific knockout mouse models
    explanation: >-
      States the model system, a cell-type-specific conditional knockout, that this
      animal model record describes.
  modeled_mechanisms:
  - target: Failure of Postnatal Ductal Closure
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The model reproduces the defining lesion of PDA3 with complete penetrance.
    limitations: >-
      Human PDA3 arises from heterozygous variants with partial loss of function,
      whereas this model is a homozygous conditional null restricted to the
      neural-crest lineage, and it is perinatally lethal in a way human PDA3 is not.
    readouts:
    - name: Patent ductus arteriosus at birth
      target: Failure of Postnatal Ductal Closure
      direction: ABOLISHED
      interpretation: >-
        Ductal closure is abolished in every mutant, the structural correlate of
        this node.
      evidence:
      - reference: PMID:36749647
        reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Prdm6 depletion in Wnt1-expressing cells during development resulted in perinatal lethality and a completely penetrant patent ductus arteriosus (DA) phenotype.
        explanation: >-
          Reports the ductal patency measurement behind this readout.
    evidence:
    - reference: PMID:36749647
      reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        As depicted in Figure 3, we observed a patent DA in all Wnt1Cre2 Prdm6fl/fl mice, but not in littermate control animals
      explanation: >-
        The patency finding in this exact genotype against littermate controls is
        what makes the model informative for the ductal closure node.
  - target: Impaired Ductal Contractile Tone
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Myography on ductal segments provides the physiological measurement of reduced
      contractility that the tone node asserts.
    limitations: >-
      Tone was measured in embryonic (E18.5) ductal segments ex vivo, so it does not
      capture the postnatal oxygen- and prostaglandin-dependent constriction that
      fails in the human disease.
    readouts:
    - name: Ductal tone and contractility by myography
      target: Impaired Ductal Contractile Tone
      direction: DECREASED
      interpretation: >-
        Reduced tone is the direct functional correlate of the contractility node.
      evidence:
      - reference: PMID:36749647
        reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          myography measurements on DA segments isolated from E18.5 embryos indicated that Prdm6 depletion significantly reduced DA tone and contractility
        explanation: >-
          Reports the myography measurement behind this readout.
    - name: Depolarization-induced ductal constriction
      target: Impaired Ductal Contractile Tone
      direction: ABOLISHED
      interpretation: >-
        The duct cannot contract even to a depolarizing stimulus that bypasses
        receptor signaling, placing the defect in the contractile apparatus itself.
      evidence:
      - reference: PMID:36749647
        reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          While 50 mM KCl resulted in an 80% decrease in the diameter of DA segments isolated from littermate controls, it had virtually no effect on DA segments isolated from Wnt1Cre2 Prdm6fl/fl mouse embryos
        explanation: >-
          Reports the KCl challenge behind this readout.
    - name: Oxygen-induced ductal constriction
      target: Impaired Ductal Contractile Tone
      direction: ABOLISHED
      interpretation: >-
        The rise in oxygen tension that normally constricts the duct after birth
        produces no response, which is the physiological form of the closure
        failure.
      evidence:
      - reference: PMID:36749647
        reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Time-limited exposures to increasing oxygen concentrations in the circulating buffer resulted in significant constriction of control DA segments as expected (Figure 5C), but this response was completely absent in Prdm6-depleted DA segments.
        explanation: >-
          Reports the oxygen challenge behind this readout.
- name: Prdm6fl/fl Wnt1-Cre2 ZsGreen1 mouse
  species: Mouse
  genotype: Prdm6fl/fl Wnt1-Cre2 ZsGreen1 (neural-crest-lineage conditional Prdm6 deletion with a ZsGreen1 lineage reporter)
  publication: PMID:35108221
  description: >-
    Disruption of Prdm6 in cardiac neural crest cells impairs their differentiation,
    delamination, and migration and produces patent ductus arteriosus together with
    ventricular noncompaction.
  notes: >-
    This is the same conditional cross as the Wnt1Cre2 Prdm6fl/fl record above,
    differing in the lineage reporter (ZsGreen1 here, ROSA26LacZ there). It is kept
    as a separate record because the two labs report opposite results for ductal
    neural-crest investment in that shared genotype, which is the substance of the
    crest-versus-contractility discussion. The same study also reports a patent duct
    in a Prdm6fl/fl SM22-Cre smooth-muscle-restricted cross, which is not curated as
    its own record here.
  evidence:
  - reference: PMID:35108221
    reference_title: Prdm6 controls heart development by regulating neural crest cell differentiation and migration.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Here, we identified Prdm6 as an epigenetic modifier that temporally and spatially regulates the expression of NCC specifiers and determines the fate of a subset of migrating cardiac NCCs (CNCCs).
    explanation: >-
      Establishes the neural-crest role of Prdm6 that makes this model informative
      for the crest mechanism curated here.
  modeled_mechanisms:
  - target: Impaired Cardiac Neural Crest Cell Specification and Migration
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The model is the sole source of the neural-crest route in this entry, with
      lineage tracing and single-cell transcriptomics supporting the migration
      defect.
    limitations: >-
      The crest defect has not been demonstrated in human PDA3 tissue, and this
      model also produces ventricular noncompaction, which is not a reported feature
      of the human PRDM6-related phenotype.
    readouts:
    - name: Retention of neural crest cells in the dorsal neural tube
      target: Impaired Cardiac Neural Crest Cell Specification and Migration
      direction: INCREASED
      interpretation: >-
        Failure to leave the neural tube is the cellular correlate of the migration
        defect this node asserts.
      evidence:
      - reference: PMID:35108221
        reference_title: "Prdm6 controls heart development by regulating neural crest cell differentiation and migration."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Loss of Prdm6 in CNCCs diminished its expression in the pre-epithelial-mesenchymal transition (pre-EMT) cluster, resulting in the retention of NCCs in the dorsal neural tube.
        explanation: >-
          Reports the retention measurement behind this readout.
    evidence:
    - reference: PMID:35108221
      reference_title: "Prdm6 controls heart development by regulating neural crest cell differentiation and migration."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we showed that disruption of Prdm6 was associated with impaired CNCC differentiation, delamination, and migration and led to patent ductus arteriosus (DA) and ventricular noncompaction
      explanation: >-
        Establishes that this model is informative for a crest mechanism that ends
        in patent ductus arteriosus.
  - target: Failure of Postnatal Ductal Closure
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      The model produces patent ductus arteriosus, but as one element of a broader
      neural crest phenotype that includes ventricular noncompaction.
    limitations: >-
      Human PDA3 is by definition isolated and nonsyndromic, so a model whose ductal
      lesion comes packaged with ventricular noncompaction departs from the human
      entity in exactly the feature that defines it.
- name: Prdm6fl/fl SM22-Cre mouse
  species: Mouse
  genotype: Prdm6fl/fl SM22-Cre (smooth-muscle-restricted conditional Prdm6 deletion)
  publication: PMID:35108221
  description: >-
    Deleting Prdm6 in smooth muscle rather than in the neural crest lineage still
    gives a completely penetrant patent duct, with contractile genes as the most
    downregulated transcripts and proliferation unchanged. This is the model that
    carries the most weight in the crest-versus-contractility disagreement: Prdm6 is
    lost here only after crest migration and differentiation are complete, so a
    patent duct in this cross cannot be explained by failed crest migration.
  evidence:
  - reference: PMID:35108221
    reference_title: "Prdm6 controls heart development by regulating neural crest cell differentiation and migration."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Gross anatomical examination of the cardiovascular system showed a PDA, albeit with a smaller diameter compared with Prdm6fl/fl Wnt1-Cre2 ZsGreen1 mice
    explanation: >-
      Establishes the ductal phenotype in the smooth-muscle-restricted cross.
  modeled_mechanisms:
  - target: Loss of Ductal Smooth Muscle Contractile Identity
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Contractile transcripts are the genes most reduced in this duct, which is the
      claim the identity node makes, obtained without touching the crest lineage.
    limitations: >-
      A homozygous conditional null, whereas human PDA3 is heterozygous; and the
      duct is smaller than in the crest-restricted cross, so the two lineages are
      not fully interchangeable.
    readouts:
    - name: Ductal contractile gene expression
      target: Loss of Ductal Smooth Muscle Contractile Identity
      direction: DECREASED
      interpretation: >-
        Tagln and Myh11 as the top downregulated genes is the transcriptional
        signature of lost contractile identity.
      evidence:
      - reference: PMID:35108221
        reference_title: "Prdm6 controls heart development by regulating neural crest cell differentiation and migration."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          bulk RNA-Seq analysis of E17.5 DA from Prdm6fl/fl SM22-Cre mice and WT littermates identified contractile proteins, such as Tagln and Myh11, as the most downregulated genes in the DA of Prdm6fl/fl SM22-Cre mice versus WT littermates
        explanation: >-
          Reports the RNA-seq measurement behind this readout.
    - name: Ductal smooth muscle proliferation by Ki67
      target: Loss of Ductal Smooth Muscle Contractile Identity
      direction: UNCHANGED
      interpretation: >-
        A negative result that matters: the duct fails with a normal proliferative
        index, so the lesion is differentiation, not cell supply.
      evidence:
      - reference: PMID:35108221
        reference_title: "Prdm6 controls heart development by regulating neural crest cell differentiation and migration."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Once again, we detected no significant difference in Ki67 staining between Prdm6fl/fl SM22-Cre and WT littermates
        explanation: >-
          Reports the Ki67 measurement behind this readout.
  - target: Failure of Postnatal Ductal Closure
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Completely penetrant ductal patency in both sexes.
    limitations: >-
      Homozygous conditional null and perinatally lethal, unlike the human
      heterozygous condition.
    evidence:
    - reference: PMID:35108221
      reference_title: "Prdm6 controls heart development by regulating neural crest cell differentiation and migration."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The cross-section examination of the DA showed complete patency of DA (Figure 5B), a completely penetrant trait in both male and female mice
      explanation: >-
        Establishes complete penetrance of the closure failure in this model.
diagnosis:
- name: Echocardiographic identification of ductal patency
  description: >-
    Transthoracic echocardiography establishes the presence of the duct and the
    magnitude of the shunt, including the left heart volume loading that drives the
    decision to close.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:23055849
    reference_title: "Patent ductus arteriosus: an overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Symptoms are not always present; therefore, diagnostic imaging is critical if a PDA is suspected on clinical grounds.
    explanation: >-
      States the necessity of imaging for diagnosis, which echocardiography provides
      for this lesion.
- name: PRDM6 sequencing
  description: >-
    Molecular confirmation of PDA3 requires demonstrating a heterozygous PRDM6
    variant. The causal gene was found by exome sequencing, and sequencing remains
    the route to the diagnosis in a term infant with isolated PDA and a suggestive
    family history.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:27181681
    reference_title: "Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using combined genome-wide linkage analysis and whole-exome sequencing (WES), we identified independent mutations in PRDM6
    explanation: >-
      Sequencing is the method by which PRDM6 variants are identified in affected
      individuals.
treatments:
- name: Transcatheter device closure
  description: >-
    Catheter-delivered coils or duct occluders close the duct and are the standard
    of care for most patients. Because PDA3 is a structural failure of ductal
    smooth muscle rather than a prostaglandin-mediated failure to constrict,
    mechanical closure, not pharmacological closure, is the definitive treatment.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: transcatheter ductal occlusion
    term:
      id: NCIT:C168283
      label: Interventional Cardiac Catheterization
  target_mechanisms:
  - target: Persistent Left-to-Right Aortopulmonary Shunt
    description: >-
      Occluding the duct abolishes the shunt; it does not correct the underlying
      smooth muscle defect.
  notes: >-
    The device itself is not bound as a qualifier: NCIT has no occluder or duct
    occluder term (searches for occluder, septal occluder device and vascular
    occlusion device return nothing usable), so the device convention in CLAUDE.md
    has nothing to attach. The devices are named in the evidence snippet instead.
  evidence:
  - reference: PMID:24560920
    reference_title: "Transcatheter closure of patent ductus arteriosus: past, present and future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transcatheter PDA closure is the standard of care in most cases and PDA closure is indicated in any patient with signs of left ventricular volume overload due to a ductus.
    explanation: >-
      Establishes transcatheter closure as standard of care and states the
      indication.
  - reference: PMID:24560920
    reference_title: "Transcatheter closure of patent ductus arteriosus: past, present and future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Coils and the Amplatzer Duct Occluder are used most frequently for PDA closure worldwide, with a high occlusion rate and few complications.
    explanation: >-
      Names the devices used and supports the efficacy and safety of the approach.
- name: Surgical ductal ligation
  description: >-
    Surgical ligation or division of the duct remains an option where transcatheter
    closure is not feasible, notably in very small infants in whom device delivery
    is technically difficult.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical ductal ligation
    term:
      id: NCIT:C15270
      label: Ligation
  target_mechanisms:
  - target: Persistent Left-to-Right Aortopulmonary Shunt
    description: >-
      Ligation interrupts the shunt at the duct.
  evidence:
  - reference: PMID:23055849
    reference_title: "Patent ductus arteriosus: an overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three management strategies are currently available for PDA: fluid restriction and diuretics (as clinically appropriate), medical intervention, and surgical ligation.
    explanation: >-
      Lists surgical ligation among the established management strategies for a
      persistent duct.
  - reference: PMID:24560920
    reference_title: "Transcatheter closure of patent ductus arteriosus: past, present and future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transcatheter PDA closure in preterm or low-bodyweight infants remains a highly challenging procedure and further device and catheter design development is indicated before transcatheter closure is the treatment of choice in this delicate patient population.
    explanation: >-
      Supports retaining a surgical option where the transcatheter route is
      technically challenging.
- name: Cyclooxygenase-inhibitor pharmacologic closure
  description: >-
    Indomethacin and ibuprofen close the duct in preterm infants by suppressing the
    prostaglandin E2 tone that maintains patency. They are recorded here for
    contrast rather than as a treatment for this disease: PDA3 is a defect of the
    ductal smooth muscle program rather than of the prostaglandin signal, and in the
    Prdm6-deficient mouse duct the same prostaglandin-inhibition manoeuvre that
    closes control ducts does nothing. No trial of pharmacologic closure in a PRDM6
    variant carrier has been reported.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: indomethacin
      term:
        id: CHEBI:49662
        label: indometacin
    - preferred_term: ibuprofen
      term:
        id: CHEBI:5855
        label: ibuprofen
  target_mechanisms:
  - target: Failure of Postnatal Ductal Closure
    description: >-
      The intended target is the prostaglandin tone holding the duct open. In PDA3
      the block sits downstream of that signal, which is why this link is recorded
      with refuting evidence rather than as a working treatment.
  evidence:
  - reference: PMID:23055849
    reference_title: "Patent ductus arteriosus: an overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pharmacologic closure can be achieved via administration of intravenous indomethacin or ibuprofen lysine.
    explanation: >-
      Establishes the pharmacologic closure option that exists for a persistent
      duct, the paradigm this entry is contrasting against.
  - reference: PMID:36749647
    reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      While this procedure resulted in premature DA closure in all littermate controls, it had no effect on DA closure in Wnt1Cre2 Prdm6fl/fl fetuses
    explanation: >-
      Refutes pharmacologic closure as a treatment route when the PRDM6-dependent
      ductal program is lost: prostaglandin inhibition closed control ducts and not
      Prdm6-deficient ones.
  - reference: PMID:36749647
    reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      As with indomethacin treatment, oxygen exposure for 1 hour did not stimulate DA closure in Wnt1Cre2 Prdm6fl/fl animals (data not shown).
    explanation: >-
      The second physiological closure trigger also fails, reinforcing that the
      block is downstream of the closure signals rather than in them.
  notes: >-
    The refuting evidence is from a homozygous conditional mouse null, not from
    human PRDM6 variant carriers, so it constrains the expected mechanism rather
    than reporting a failed human treatment.
- name: Supportive care for a symptomatic shunt
  description: >-
    Fluid restriction and diuretics manage the volume-loaded circulation of a large
    shunt while closure is arranged. This treats the hemodynamic consequence, not
    the duct.
  notes: >-
    No therapeutic_modality is tagged: this entry bundles a fluid-management measure
    with a drug class, and neither SMALL_MOLECULE nor BEHAVIORAL is true of both.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Persistent Left-to-Right Aortopulmonary Shunt
    description: >-
      Reducing circulating volume lessens the load the shunt imposes without
      altering the shunt itself.
  evidence:
  - reference: PMID:23055849
    reference_title: "Patent ductus arteriosus: an overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Three management strategies are currently available for PDA: fluid restriction and diuretics (as clinically appropriate), medical intervention, and surgical ligation.
    explanation: >-
      Lists fluid restriction and diuretics as one of the established management
      strategies for a persistent duct.
- name: Genetic counseling and cascade family evaluation
  description: >-
    Autosomal dominant transmission puts a 50 percent chance of inheriting the
    variant on each pregnancy of a carrier parent. That is the transmission risk and
    not the risk of disease: penetrance is incomplete, so a carrier child may never
    develop a patent duct, and counseling has to separate the two numbers. Expressivity
    among carriers ranges from isolated patent ductus arteriosus to patent ductus
    arteriosus with coarctation of the aorta. First-degree relatives of an affected
    individual warrant evaluation.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:27181681
    reference_title: "Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Using combined genome-wide linkage analysis and whole-exome sequencing (WES), we identified independent mutations in PRDM6
    explanation: >-
      Familial linkage transmission is what makes recurrence-risk counseling and
      relative evaluation applicable; the counseling recommendation follows from the
      inheritance pattern rather than being stated in the paper.
differential_diagnoses:
- name: Char syndrome
  description: >-
    The syndromic Mendelian form of PDA, caused by TFAP2B variants, in which ductal
    patency comes with facial dysmorphism and hand anomalies. PDA3 is by definition
    isolated and nonsyndromic, so the extracardiac features separate them.
  distinguishing_features:
  - Facial dysmorphism and fifth-finger anomalies absent in PDA3
  - TFAP2B rather than PRDM6 as the causal gene
  evidence:
  - reference: PMID:19955832
    reference_title: "Insights into the pathogenesis and genetic background of patency of the ductus arteriosus."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Genetic research has identified the cause of syndromic forms of PDA, such as the TFAP2B mutations in Char syndrome.
    explanation: >-
      Identifies Char syndrome and its causal gene as the syndromic genetic
      alternative to a nonsyndromic PRDM6-related duct.
- name: MYH11-related thoracic aortic aneurysm and dissection with patent ductus arteriosus
  description: >-
    A separate dominant smooth-muscle disorder in which patent ductus arteriosus
    comes with thoracic aortic aneurysm or dissection and marked aortic stiffness
    even in asymptomatic carriers. It shares the theme of a smooth-muscle
    contractile-protein lesion with PDA3 but is not confined to the duct, so an
    aortic assessment separates the two.
  distinguishing_features:
  - Thoracic aortic aneurysm or dissection, absent in PDA3
  - Aortic stiffness in asymptomatic carriers
  - MYH11 rather than PRDM6 as the causal gene
  evidence:
  - reference: PMID:16444274
    reference_title: "Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We have recently described two kindreds presenting thoracic aortic aneurysm and/or aortic dissection (TAAD) and patent ductus arteriosus (PDA) and mapped the disease locus to 16p12.2-p13.13
    explanation: >-
      Establishes the combined TAAD-plus-PDA entity that has to be told apart from
      an isolated genetic duct.
  - reference: PMID:16444274
    reference_title: "Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All individuals bearing the heterozygous mutations, even if asymptomatic, showed marked aortic stiffness.
    explanation: >-
      Aortic stiffness in asymptomatic carriers is the finding that makes aortic
      assessment discriminating here.
- name: Prematurity-associated patent ductus arteriosus
  description: >-
    Far the commonest cause of a persistent duct, in which failure to close follows
    immaturity of the oxygen- and prostaglandin-dependent closure mechanisms rather
    than an intrinsic genetic defect of the ductal wall. This form is often
    responsive to cyclooxygenase inhibition, which is not the treatment paradigm for
    PDA3.
  distinguishing_features:
  - Preterm gestation
  - Failure of the prostaglandin-dependent closure mechanism rather than a ductal smooth muscle gene defect
  evidence:
  - reference: PMID:23055849
    reference_title: "Patent ductus arteriosus: an overview."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PDA in term infants is usually associated with a functional defect, whereas in preterm infants it is associated with immaturity.
    explanation: >-
      Draws exactly the distinction that separates a genetic term-infant duct from
      the prematurity-associated form.
discussions:
- discussion_id: prdm6_direction_of_effect
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Does PRDM6 loss cause patent ductus arteriosus by releasing ductal smooth
    muscle cells into premature differentiation, or by failing to build their
    contractile identity in the first place?
  attaches_to:
  - pathophysiology#Deregulated Ductal Smooth Muscle Transcriptional Program
  - pathophysiology#Loss of Ductal Smooth Muscle Contractile Identity
  - pathophysiology#Premature Ductal Smooth Muscle Differentiation
  - mechanistic_hypotheses#prdm6_premature_differentiation
  - mechanistic_hypotheses#prdm6_smc_identity
  rationale: >-
    The two published models assign opposite signs to the same molecule. The human
    genetic study describes PRDM6 as a transcriptional suppressor of contractile
    proteins that holds ductal smooth muscle cells undifferentiated, so that loss of
    function produces premature differentiation. The conditional knockout study finds
    that loss of Prdm6 downregulates a ductus-enriched contractile gene program and
    reduces ductal tone, which is what a positive, identity-building role predicts.
    Both are supported by direct data, though not symmetrically: two independent
    conditional-knockout datasets report reduced contractile gene expression on
    Prdm6 loss, while the premature-differentiation model rests on an expression
    time course plus in vitro assays, and its reduced-proliferation corollary was
    subsequently refuted by Ki67 measurement. The entry carries both rather than
    silently retiring one. Resolving the direction of effect matters because it
    determines whether a therapeutic aimed at the ductal smooth muscle program would
    need to promote or restrain contractile differentiation.
  evidence:
  - reference: PMID:27181681
    reference_title: Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This dynamic change suggests that PRDM6 plays a key role in maintaining VSMCs in an undifferentiated stage in order to promote their proliferation and that its loss of activity results in premature differentiation and impaired remodeling of the DA.
    explanation: >-
      One side of the disagreement: PRDM6 restrains differentiation, so its loss
      causes premature differentiation.
  - reference: PMID:36749647
    reference_title: Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      RNA-Seq analyses on DA and ascending aorta samples at E18.5 identified a DA-enriched gene program that included many SMC-selective contractile associated proteins that was downregulated by Prdm6 depletion.
    explanation: >-
      The other side: Prdm6 loss reduces rather than releases contractile gene
      expression in the ductus.
  proposed_experiments:
  - experiment_id: prdm6_dose_matched_contractile_program
    name: Contractile gene program in dose-matched PRDM6 loss
    description: >-
      Profile the contractile gene program and the proliferative index of ductal
      smooth muscle across a PRDM6 dosage series (heterozygous patient-variant
      knock-in, heterozygous null, homozygous null) in the same ductal tissue and at
      matched developmental stages, so that the direction of effect is read from one
      comparable experiment rather than across two study designs.
    readouts:
    - name: Ductal contractile gene expression
      target: pathophysiology#Loss of Ductal Smooth Muscle Contractile Identity
      interpretation: >-
        Downregulation across the dosage series favors the identity-building model.
    - name: Ductal smooth muscle proliferative index
      target: pathophysiology#Premature Ductal Smooth Muscle Differentiation
      interpretation: >-
        An early fall in proliferation with early contractile marker gain favors the
        premature-differentiation model.
    would_support:
    - pathophysiology#Loss of Ductal Smooth Muscle Contractile Identity
    would_refute:
    - pathophysiology#Premature Ductal Smooth Muscle Differentiation
    supporting_outcome:
    - >-
      Ductal contractile gene expression falls with reducing PRDM6 dose while the
      proliferative index is unchanged or increased.
    refuting_outcome:
    - >-
      Contractile markers appear earlier than in wild-type ducts and the
      proliferative index falls, with medial cellularity reduced at term.
- discussion_id: prdm6_crest_versus_contractility
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Does the Prdm6-null duct stay open because neural crest cells never populate its
    media, or because the smooth muscle that does populate it cannot contract?
  attaches_to:
  - pathophysiology#Impaired Cardiac Neural Crest Cell Specification and Migration
  - pathophysiology#Loss of Ductal Smooth Muscle Contractile Identity
  - mechanistic_hypotheses#prdm6_cncc_specification
  - mechanistic_hypotheses#prdm6_smc_identity
  rationale: >-
    Two labs ran the same Wnt1-Cre2 Prdm6fl/fl cross and disagree on the finding the
    crest model rests on. One reports the ductal media dramatically depleted of
    neural-crest-derived cells by E17.5; the other reports investment and medial
    morphology indistinguishable from controls, finds no migration defect in
    outflow-tract smooth muscle culture, and points out that the same study's
    SM22-Cre model, in which Prdm6 goes only after crest migration is complete, also
    gives a patent duct. The two groups used different reporters and detection
    methods, which is the explanation offered for the discrepancy but has not been
    tested. This is a sharper disagreement than the direction-of-effect one, because
    the two positions predict different treatable steps: a cell-supply failure fixed
    before birth, or a contractile failure present in a normally built wall.
  evidence:
  - reference: PMID:35108221
    reference_title: "Prdm6 controls heart development by regulating neural crest cell differentiation and migration."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The examination of the DA of Prdm6fl/fl Wnt1-Cre2 ZsGreen1 mice at E17.5 showed dramatically reduced ZsGreen1-positive (NCC-derived) cells in the tunica media compared with those of the WT littermates
    explanation: >-
      The crest-depletion side of the disagreement.
  - reference: PMID:36749647
    reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      As shown in Figure 4, we did not detect differences in neural crest cell investment of the ductus or the morphology of the ductus medial SMC layer.
    explanation: >-
      The normal-investment side, from the same genotype.
  proposed_experiments:
  - experiment_id: prdm6_crest_investment_replication
    name: Reporter-matched replication of ductal neural crest investment
    description: >-
      Quantify neural-crest-derived cells in the ductal media of Wnt1-Cre2
      Prdm6fl/fl embryos at a fixed stage, with both reporters and both detection
      methods run side by side on the same litters, so the discrepancy is tested
      rather than attributed to methodology.
    readouts:
    - name: Neural-crest-derived cell fraction in the ductal tunica media
      target: pathophysiology#Impaired Cardiac Neural Crest Cell Specification and Migration
      interpretation: >-
        A deficit reproduced under both detection methods would settle the question
        for the crest model; a deficit visible under only one would locate the
        disagreement in the assay.
    would_support:
    - pathophysiology#Impaired Cardiac Neural Crest Cell Specification and Migration
    would_refute:
    - pathophysiology#Loss of Ductal Smooth Muscle Contractile Identity
    supporting_outcome:
    - >-
      Neural-crest-derived cells are reduced in the mutant ductal media under both
      reporters and both detection methods.
    refuting_outcome:
    - >-
      Investment is normal under both methods, leaving the contractile defect as the
      operative lesion.
- discussion_id: prdm6_human_tissue_gap
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Do the mouse ductal and neural crest phenotypes reflect what heterozygous PRDM6
    variants do in the human ductus arteriosus?
  attaches_to:
  - pathophysiology#Impaired Cardiac Neural Crest Cell Specification and Migration
  - pathophysiology#Impaired Ductal Contractile Tone
  rationale: >-
    Every mechanistic step below the variant itself rests on mouse models that delete
    Prdm6 homozygously in a lineage-restricted way and are perinatally lethal, while
    human PDA3 is a viable heterozygous condition. One of those models also produces
    ventricular noncompaction, which is not reported in PRDM6 variant carriers, so
    the models are not simply milder or stronger versions of the human disease.
    No human ductal tissue from a PRDM6 variant carrier has been profiled. The
    dosage mismatch is not merely quantitative: in the mouse, losing one copy of
    Prdm6 leaves ductal closure intact, whereas in humans a single altered copy is
    sufficient to cause disease.
  evidence:
  - reference: PMID:36749647
    reference_title: "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Taken together these data indicated that PRDM6 expression was absolutely required for DA closure, that Cre expression alone or deletion of 1 copy of PRDM6 had no effect on ductus closure, and that the floxed PRDM6 allele behaved in a manner similar to the WT allele.
    explanation: >-
      A heterozygous mouse deletion leaves ductal closure normal while human
      heterozygous variants cause disease, which is the dosage mismatch this
      discussion records.
  proposed_experiments:
  - experiment_id: prdm6_human_ductal_tissue
    name: Molecular profiling of ductal tissue from PRDM6 variant carriers
    description: >-
      Collect ductal tissue at the time of surgical ligation from patients with a
      confirmed heterozygous PRDM6 variant and profile smooth muscle contractile
      gene expression, medial cellularity, and intimal cushion formation against
      duct tissue from term infants closing without a PRDM6 variant.
    readouts:
    - name: Ductal medial smooth muscle contractile marker expression
      target: pathophysiology#Impaired Ductal Contractile Tone
      interpretation: >-
        Reduced contractile marker expression in human carrier tissue would carry the
        mouse finding across to the human duct.
    would_support:
    - pathophysiology#Impaired Ductal Contractile Tone
    supporting_outcome:
    - >-
      Carrier ductal tissue shows reduced contractile marker expression and absent
      intimal cushion formation relative to non-carrier term ductal tissue.
    refuting_outcome:
    - >-
      Carrier ductal tissue is indistinguishable from non-carrier term ductal tissue
      in contractile marker expression and medial structure.
datasets:
- accession: geo:GSE221004
  title: Effect of smooth muscle specific PRDM6 depletion on Aorta and Ductus Arterious (DA) development
  data_type: BULK_RNA_SEQ
  sample_count: 24
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  genes:
  - preferred_term: PRDM6
    term:
      id: hgnc:9350
      label: PRDM6
  publication: PMID:36749647
  notes: >-
    The RNA-seq comparison of ductus arteriosus against ascending aorta with and
    without Prdm6 depletion that identifies the downregulated ductus-enriched
    contractile gene program curated in this entry. Relevance triaged manually:
    the series is about the ductus arteriosus and the causal gene of this entry,
    not merely a PRDM6 gene-name match.
- accession: geo:GSE221094
  title: Determining the PRDM6 genomic binding sites in primary outflow tract smooth muscle cells
  data_type: CHIP_SEQ
  sample_count: 4
  organism:
    preferred_term: mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  genes:
  - preferred_term: PRDM6
    term:
      id: hgnc:9350
      label: PRDM6
  publication: PMID:36749647
  notes: >-
    The ChIP-seq series behind the finding that half the genes altered by Prdm6
    depletion carry Prdm6 binding sites, which is what supports a primary
    transcriptional mechanism in this entry rather than a secondary effect.
references:
- reference: PMID:27181681
  title: Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus.
- reference: PMID:36749647
  title: Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility.
- reference: PMID:35108221
  title: Prdm6 controls heart development by regulating neural crest cell differentiation and migration.
- reference: PMID:38071433
  title: Patent ductus arteriosus and coarctation of the aorta in association with PRDM6 variants.
- reference: PMID:16444274
  title: Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus.
- reference: PMID:23055849
  title: "Patent ductus arteriosus: an overview."
- reference: PMID:24560920
  title: "Transcatheter closure of patent ductus arteriosus: past, present and future."
- reference: PMID:19955832
  title: Insights into the pathogenesis and genetic background of patency of the ductus arteriosus.
mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:Q25.0
      label: Patent ductus arteriosus
    mapping_predicate: skos:broadMatch
    mapping_justification: semapv:ManualMappingCuration
    notes: >-
      A broadMatch, not an exact one. ICD-10-CM codes the lesion and not its cause,
      so Q25.0 covers prematurity-associated, syndromic, and PRDM6-related ducts
      alike; there is no PDA3-specific code.
review_notes: >-
  Three things in the primary report sit in the article body rather than in the
  abstract that is cached here, so they are handled without a snippet. Incomplete
  penetrance and variable expressivity are recorded as enum values on the
  inheritance block, which take no evidence. The three missense variants are
  recorded in `genetic[].variants` with their ClinVar accessions, each classified
  Pathogenic for patent ductus arteriosus 3; their domain assignments are described
  rather than cited. The in vitro histone-mark reversal and MYH11 suppression assays
  are still uncurated: they are substantive claims that would need a quote, and a
  curator with full-text access should add them. A second `just fetch-reference
  PMID:27181681` run against the PMC4908195 record after review still returned
  abstract_only, so the gap is in what the fetcher can reach, not an omission.
  The entry deliberately carries two live disagreements rather than resolving
  either. On direction of effect, the discovery paper and the conditional knockouts
  read PRDM6's role oppositely. On lesion location, two labs ran the same Wnt1-Cre2
  Prdm6fl/fl cross and disagree on whether the ductal media is populated normally.
  Nodes on both sides therefore carry REFUTE evidence alongside their support, which
  is intended, not an oversight.
📚

References & Deep Research

References

8
PMID:27181681
Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus.
No top-level findings curated for this source.
PMID:36749647
Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility.
No top-level findings curated for this source.
PMID:35108221
Prdm6 controls heart development by regulating neural crest cell differentiation and migration.
No top-level findings curated for this source.
PMID:38071433
Patent ductus arteriosus and coarctation of the aorta in association with PRDM6 variants.
No top-level findings curated for this source.
PMID:16444274
Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus.
No top-level findings curated for this source.
PMID:23055849
Patent ductus arteriosus: an overview.
No top-level findings curated for this source.
PMID:24560920
Transcatheter closure of patent ductus arteriosus: past, present and future.
No top-level findings curated for this source.
PMID:19955832
Insights into the pathogenesis and genetic background of patency of the ductus arteriosus.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (2)

Review response: repair corrupted description, revert HP:0031670, move rationale to notes · 2026-09-03T15:44:16Z · View source

Response to the ai4c-reviewer CHANGES_REQUESTED review on PR 10701 and to its follow-up approval. Correction to the earlier record in this directory. The 2026-09-03T100712Z record states 'HP:0030148 replaced by HP:0031670 Continuous heart murmur'. That change was reversed here: the word continuous appears in no reference cached for this entry, so the narrower term outran its snippet and the binding is back to HP:0030148 Heart murmur, with the node name, preferred_term and term label now agreeing. History records are append-only, so the earlier line stands as an accurate account of what that session did; this record is the correction. Blocking defect fixed. The top-level description had been corrupted during the previous session's edits: a copy of a biological_processes block landed inside the folded scalar and the intended prose was fused onto the end of a label: line. Because a >- scalar makes that one valid string, schema validation, term validation, snippet verification and every content gate passed while the rendered disease page would have shown a YAML fragment as the description. Restored, then every string value in the file was parsed and scanned for embedded keys (984 scalars, zero suspect), and the page was rendered to confirm the description comes out as prose. The root cause was blind string replacement on prose that shared wording with the block being edited, with no re-read of the file head afterwards; rendering the page and scanning scalars are now part of the loop rather than an afterthought. Other review items: dropped therapeutic_modality SMALL_MOLECULE from the supportive-care treatment, which bundles fluid restriction with diuretics so neither SMALL_MOLECULE nor BEHAVIORAL fits; gave Impaired Ductal Wall Remodeling the cell type and process its siblings carry (CL:0000359, GO:0048771 tissue remodeling, modifier DECREASED); retried just fetch-reference PMID:27181681 against PMC4908195, which still returns abstract_only, so the in vitro histone-mark, MYH11 suppression and no-dominant-negative claims stay uncurated and review_notes records the retry. Then, on the approving re-review's first two suggestions: curation rationale that had been written into reader-facing description fields was moved into notes. Affected the Heart murmur phenotype (why the narrower HP term was not used), the supportive-care treatment (why no modality is tagged), the top-level description (that the entry carries both readings of PRDM6's direction of effect, now in the entry notes), and the inheritance description (that penetrance and expressivity are enum values rather than cited claims, already covered in review_notes). Description fields now carry clinical prose only. Not acted on: the reviewer also noted the PR body's validation section is stale, still reporting the deep-research report's term-validation numbers including an obsolete GO:0034770 that appears nowhere in the entry. That body was generated by the PR-creation UI rather than by this session; the discrepancy was corrected in a PR comment, and editing the body itself is left to the PR author. Validation: just validate and just validate-disorders pass, 77/77 snippets verified, all content gates clean, full-file scalar scan clean. Model id omitted from this record for the same reason as the two earlier ones.

Create: Patent Ductus Arteriosus 3 (PRDM6, MONDO:0024266) · 2026-09-03T09:42:03Z · View source

New Mendelian entry for the PRDM6-caused, isolated nonsyndromic form of patent ductus arteriosus (PDA3). Deleted the matching stub. Deep research: 'just research-disorder falcon Patent_Ductus_Arteriosus_3' failed because EDISON_API_KEY is present but empty (403 ProviderAuthError). Re-run with the fallback mechanism rather than hand-substituting a provider. A first '--fallback' run selected openscientist, which hung with no output for ~40 minutes (OPENSCIENTIST_API_KEY is also empty) and was killed; the run was then repeated as 'just dr_fallback=--fallback-provider claude_code research-disorder falcon Patent_Ductus_Arteriosus_3', which produced research/Patent_Ductus_Arteriosus_3-deep-research-claude_code.md with fell_back/requested_provider/provider_attempts recorded in its frontmatter. Report validation read before use: reference_validation needs_review true, 14/15 verified, one unresolved identifier (PMC:PMC38071433, a malformed PMC id built from PMID 38071433 digits) and one off-topic DOI. Neither was cited; the underlying paper is cited as PMID:38071433, which resolves and is cached. term_validation needs_review true with three mislabelled terms, all placeholder text the report itself wrote ('verify', 'verify via OAK', 'Ontology identifier for PDA3'), plus obsolete GO:0034770 (histone H4-K20 methylation) which was not bound. The report also suggested UBERON:0002106 for ductus arteriosus, which is spleen; the entry binds UBERON:0005440 instead. GeneReviews: PubMed searches for 'PRDM6 GeneReviews[All Fields]' and 'patent ductus arteriosus GeneReviews[All Fields]' return no chapter for PDA3 or PRDM6. The only Mendelian-PDA chapter is Char Syndrome (TFAP2B, PDA1/PDA2), a different syndromic entity, curated here only as a differential diagnosis. Recorded in the entry notes. Lump/split: curated as a separate DISEASE rather than a subtype of Patent_Ductus_Arteriosus. That entry curates PRDM6 as a developmental susceptibility locus and states explicitly that it is not curated there as a deterministic Mendelian cause, so the Mendelian form had no home. Content: a nine-node causal chain from heterozygous PRDM6 loss of function to the left-to-right shunt, deliberately branching at the transcriptional-program node into three hypothesis groups because the literature disagrees about the direction of PRDM6's effect. Li 2016 (human genetics plus in vitro) has PRDM6 restraining differentiation, so loss causes premature differentiation; Zou 2023 (conditional knockout) has Prdm6 building contractile identity, so loss reduces contractile gene expression and ductal tone. Both are curated as ALTERNATIVE hypotheses with a CONTROVERSY discussion and a dose-matched experiment proposal rather than silently preferring one. A third EMERGING group carries the cardiac-neural-crest route from Hong 2022. A HUMAN_MODEL_MISMATCH discussion records that mouse heterozygous Prdm6 deletion leaves ductal closure intact while human heterozygous variants cause disease. Two animal models with modeled_mechanisms and five readouts, including ABOLISHED depolarization- and oxygen-induced ductal constriction. A pharmacotherapy entry carries two REFUTE evidence items: indomethacin and 100 percent oxygen both close control ducts and fail in the Prdm6-deficient duct, which is why mechanical closure and not COX inhibition is the treatment paradigm here. Datasets: geo:GSE221004 and geo:GSE221094 added after manual relevance triage (both are PRDM6 ductus arteriosus series from PMID:36749647). The PRDM6 medulloblastoma and generic zinc-finger series that discover-datasets surfaced were GENE_ONLY name matches and were excluded. Deliberately not curated, recorded in review_notes: incomplete penetrance, the three specific missense variants, and the in vitro histone-mark and MYH11 assays. All are in the Li 2016 article body, and only its abstract is in the reference cache, so citing them would mean a snippet that cannot be verified. Validation: just validate passes (schema, terms, 59/59 snippets verified); just validate-disorders passes; check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading and check-environmental-evidence all clean; just verify-datasets resolves both accessions; compliance 86.0 percent. No DOI-keyed evidence items, so the snippet audit needed no --unskip-prefix run. The model id field is omitted from this record because this session's configuration forbids writing a model identifier into repository artifacts; the session URL in links carries the provenance.

Claude Code ▸
Patent Ductus Arteriosus 3 (PDA3) — Disease Characteristics Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 22 citations 2026-09-03T09:22:20.919575

Patent Ductus Arteriosus 3 (PDA3) — Disease Characteristics Research Report

1. Disease Information

Overview. Patent ductus arteriosus 3 (PDA3) is an autosomal-dominant, non-syndromic (isolated) form of patent ductus arteriosus (PDA) caused by heterozygous loss-of-function mutation in PRDM6 (PR/SET domain 6; chromosome 5q23.2). The ductus arteriosus is the fetal vessel connecting the main pulmonary artery to the descending aorta that normally closes within hours to weeks of birth; in PDA3 the vessel remains patent because the vascular smooth muscle cells (VSMCs) of the ductus fail to differentiate and remodel normally, independent of prematurity or other congenital heart disease. PDA3 was defined by Li et al. (2016) after linkage mapping in a large African-American kindred (PDA-101) segregating autosomal-dominant PDA with incomplete penetrance, followed by whole-exome sequencing that identified PRDM6 mutations (Li et al. 2016, AJHG, PMID:27181681).

Key identifiers: - OMIM phenotype: #617039 – PATENT DUCTUS ARTERIOSUS 3; PDA3 (omim.org/entry/617039) - OMIM gene: 616982 – PR DOMAIN-CONTAINING PROTEIN 6; PRDM6 (omim.org/entry/616982) - MONDO: MONDO:0024266 – "patent ductus arteriosus 3," defined as "Any patent ductus arteriosus in which the cause of the disease is a mutation in the PRDM6 gene" - Orphanet (parent nosologic entity): ORPHA:466729 – Familial patent arterial duct (rare, non-syndromic, autosomal-dominant congenital anomaly of the great arteries) — note that PDA in general is not itself in the Orphanet rare-disease nomenclature (ORPHA:706, "non-rare in Europe"); it is the familial/genetic form that is classified as rare (Orphanet) - ICD-10-CM: Q25.0 – Patent ductus arteriosus (the general code; no PDA3-specific code exists) - Gene (HGNC): PRDM6, HGNC:9350, 5q23.2 (GeneCards) - Related loci for genetic heterogeneity of isolated PDA: PDA1 (OMIM 607411, reference/heterogeneity locus symbol), PDA2 (OMIM 617035, caused by TFAP2B, 6p12), PDA3 (OMIM 617039, PRDM6). TFAP2B is also the gene mutated in Char syndrome (syndromic PDA with facial dysmorphism and fifth-finger clinodactyly), and MYH11 mutations cause a distinct syndrome combining thoracic aortic aneurysm/dissection with PDA (not itself numbered "PDA3"). - Synonyms:* PRDM6-related patent ductus arteriosus; familial nonsyndromic patent ductus arteriosus (PRDM6 form)

Evidence basis. All data on PDA3 specifically derive from aggregated, family-based genetic studies (linkage + exome sequencing across pedigrees and unrelated probands) plus a small number of subsequent case reports, not large-scale EHR/individual-patient registries — reflecting its rarity (three known causal variants reported to date, expanded to a handful of additional cases in follow-up reports).

2. Etiology

Disease causal factor: Heterozygous, non-conservative missense mutation in PRDM6, acting via loss of function (impaired nuclear localization and/or altered histone methyltransferase activity), inherited in an autosomal-dominant pattern with incomplete penetrance.

Genetic risk factors (causal)

Three independent PRDM6 mutations have been reported, all in individuals/families with isolated (nonsyndromic) PDA and normal-term birth (i.e., not a prematurity-related PDA):

Variant (cDNA) Protein change Domain Family context
c.1646G>A p.Arg549Gln (R549Q) Fourth zinc-finger domain (nuclear localization) Large African-American kindred PDA-101 (9 affected across generations); segregated with disease, absent in unaffected relatives and all exome databases
c.788G>C p.Cys263Ser (C263S) SET domain (chromatin regulation) Proband whose deceased mother and maternal grandfather were also affected
c.1385A>G p.Gln462Arg (Q462R) — Affected mother and daughter; predicted deleterious by PolyPhen and SIFT

Statistical enrichment: recurrent independent PRDM6 mutations in this small sample were judged unlikely by chance (p < 4.74 × 10⁻⁶); no nonsynonymous PRDM6 variant was found among 2,000 healthy white control exomes (Li et al. 2016, PMID:27181681).

A subsequent case series identified additional/novel PRDM6 variants (including a previously unreported likely-pathogenic variant) in three patients presenting with both PDA and coarctation of the aorta, extending the phenotypic spectrum beyond isolated PDA (Stanley et al. 2024, Am J Med Genet A, PMID:38071433, PMC summary).

Gene-set enrichment analysis (GSEA) in the same cohort found that rare deleterious variants in broader histone-modification pathway genes were significantly associated with PDA in 15 of 32 affected individuals (estimated OR = 14.95), suggesting epigenetic dysregulation is a recurring theme in nonsyndromic PDA beyond PRDM6 alone.

Broader genetic landscape of isolated/nonsyndromic PDA (context, not PDA3-specific)

  • PDA1 (OMIM 607411) — reference locus for genetic heterogeneity of isolated PDA (originally mapped to 5q23 before renaming; a separate autosomal-recessive PDA locus on 12q24 had already used the "PDA1" symbol).
  • PDA2 (OMIM 617035) — TFAP2B, 6p12; also causal for Char syndrome (facial dysmorphism, PDA, 5th-finger clinodactyly) when haploinsufficient/dominant-negative missense.
  • MYH11 — smooth-muscle myosin heavy chain; mutations cause a syndrome combining thoracic aortic aneurysm/dissection (TAAD) with PDA (Pannu et al. 2007; Zhu et al. 2006, PMID:16444274).
  • Candidate/rare-variant genes from exome studies: NOTCH1, FOXC2, CITED2, and others identified via WES/CNV studies of nonsyndromic PDA cohorts (e.g., PMID:35734438, PMC7689032).
  • Chromosomal etiologies of PDA broadly: trisomy 21, trisomy 13, trisomy 18, and other aneuploidies/CNVs are well-documented non-Mendelian causes of PDA (not PDA3, but relevant differential).

Environmental / infectious risk factors (for PDA broadly, differential for PDA3)

  • Prematurity is the dominant risk factor for PDA in general (up to 30% of infants 500–1500 g by day 3; >70% in infants <1000 g) — this is mechanistically and clinically distinct from the genetic PDA3 form, which occurs in term infants.
  • Congenital rubella syndrome: maternal rubella infection in the first trimester is a classic teratogenic/infectious cause of PDA (histopathologically distinct — abnormal elastic tissue in the ductal wall) (PMID reviews on congenital rubella and PDA, PMC6863812).
  • High altitude, maternal factors, and other prematurity-associated exposures are risk factors for the sporadic/prematurity form but are not implicated in PDA3.

Protective factors

No specific genetic or environmental protective factors have been reported for PDA3. For prematurity-associated PDA generally, antenatal corticosteroids reduce PDA incidence indirectly by reducing prematurity-related morbidity; this is not disease-specific to PDA3.

Gene-environment interaction

Not established for PDA3; the mechanism is described as a cell-autonomous VSMC differentiation/epigenetic defect rather than gene-environment interaction.

3. Phenotypes

PDA3 presents as an essentially isolated cardiovascular malformation — the reported kindreds and cases are notable for the absence of syndromic features (no consistent facial dysmorphism, limb anomaly, or other organ-system involvement), distinguishing it from Char syndrome (TFAP2B/PDA2).

Phenotype Type HPO suggestion Onset Notes
Patent ductus arteriosus Congenital structural cardiac anomaly HP:0001643 (Patent ductus arteriosus) Congenital (present at birth in term infants) Core/defining feature; failure of ductal closure
Continuous ("machinery") heart murmur Clinical sign HP:0030148 (Heart murmur) — general term; a specific "continuous murmur" HPO term should be confirmed via OAK/HPO browser before use Infancy Classic auscultatory finding of a large PDA
Congestive heart failure (if large shunt) Clinical sign/complication HP:0001635 (Congestive heart failure) Infancy–childhood, dependent on shunt size Secondary to left-to-right shunt volume overload
Pulmonary arterial hypertension (if large, uncorrected shunt) Clinical sign/complication HP:0002092 (Pulmonary hypertension) Progresses over years if untreated ~50% of infants with large nonrestrictive PDA develop pulmonary hypertension by early childhood
Coarctation of the aorta (in some PRDM6-variant carriers) Congenital structural cardiac anomaly HP:0001680 (Coarctation of aorta) Congenital Reported co-occurring with PDA in 3 patients with PRDM6 variants (Stanley et al. 2024) — extends phenotype beyond "isolated PDA"
Reduced penetrance / asymptomatic carriers — — — Some obligate carriers in reported pedigrees do not manifest PDA, consistent with incomplete, age-independent penetrance

Severity/progression: Severity is determined by shunt size (small/moderate/large), not by genotype specifically; no PDA3-specific genotype-phenotype severity correlation has been established given the small number of reported families. Course is not episodic — an uncorrected large PDA follows a progressive trajectory toward pulmonary vascular disease if untreated, while a small PDA may remain stable or even undergo spontaneous late closure in rare cases (uncommon after infancy in term-born PDA).

Quality of life impact: Direct QOL data for PDA3 specifically are not available. For symptomatic PDA generally, unrepaired large shunts are associated with exercise intolerance, failure to thrive in infancy, and, if progressing to Eisenmenger physiology, cyanosis and severe functional limitation.

4. Genetic/Molecular Information

Causal gene: PRDM6 (PR domain-containing protein 6), HGNC:9350, chromosome 5q23.2. OMIM gene entry *616982.

Gene product/function: PRDM6 is a nuclear protein expressed selectively in vascular smooth muscle cells. It contains a SET (PR) domain with histone methyltransferase activity and zinc-finger DNA/protein-interaction domains. It acts as a transcriptional repressor of VSMC contractile genes (e.g., MYH11, α-smooth muscle actin) and cooperates with myocardin-related transcription factor-A (MRTF-A) and other SMC transcriptional regulators; it also epigenetically regulates neural-crest-cell specification genes (Wnt1, Tfap2b, Sox9) via H4K20 monomethylation, controlling G1–S progression needed for neural crest delamination/migration into the ductal wall (Zou et al. 2023, JCI Insight, PMID:36749647; additional neural-crest mechanistic paper, PMC8876496).

Variant classification (ACMG/AMP framework, as reported by original authors, not formally re-classified in ClinVar at time of writing):

Variant Type Predicted effect Population frequency
p.Arg549Gln Missense Loss of function — cytoplasmic mislocalization, altered methyltransferase output Absent from >2,000 control exomes and population databases (gnomAD not specifically reported in source, but described as absent from exome variant databases at publication)
p.Cys263Ser Missense (SET domain) Loss of function — retained nuclear localization but altered histone methylation activity Absent from controls
p.Gln462Arg Missense Predicted deleterious (PolyPhen, SIFT) Absent from controls

Zygosity/origin: All reported variants are heterozygous, germline, consistent with autosomal-dominant transmission (no somatic PDA3 cases reported; PDA is not a neoplastic condition).

Functional consequences (mechanistically loss-of-function, established in vitro): - Subcellular mislocalization: Wild-type PRDM6 and p.Cys263Ser localize normally to the nucleus in HEK293 cells and human aortic VSMCs; p.Arg549Gln is predominantly mislocalized to the cytoplasm, with co-staining excluding ER/Golgi/mitochondrial retention — consistent with impaired nuclear import via the disrupted zinc-finger domain. - Histone methyltransferase activity reversed: Wild-type PRDM6 reduces H3K9 dimethylation and increases H4K20 dimethylation; both p.Arg549Gln and p.Cys263Ser show completely opposite effects on these histone marks. - Failure to suppress contractile proteins: Wild-type PRDM6 overexpression suppresses MYH11 in human aortic VSMCs; both mutant proteins largely fail to reduce MYH11, and variant-expressing cells show higher steady-state MYH11 and α-SMA than wild-type. - No dominant-negative dimerization effect: Native PAGE excluded altered wild-type/variant heterodimerization as the mechanism — supporting simple haploinsufficiency-type loss of function rather than dominant-negative protein poisoning.

Modifier genes: None specifically established for PDA3; broader GSEA-level enrichment of histone-modification-pathway variants in the same cohort suggests a possible oligogenic/epigenetic modifier landscape, but no individual modifier gene has been validated.

Epigenetic information: PDA3 is fundamentally a disorder of epigenetic dysregulation — PRDM6 is itself a chromatin-modifying enzyme, and its variants alter H3K9me2/H4K20me2 marks at target loci controlling VSMC differentiation genes. This is the central molecular lesion, not a downstream epiphenomenon.

Chromosomal abnormalities: None reported for PDA3 specifically (contrast with PDA broadly, where trisomy 21/18/13 are well-known non-Mendelian causes).

Suggested ontology terms: - Gene: HGNC:9350 (PRDM6); note dismech convention uses lowercase hgnc:9350 - GO Molecular Function candidates (verify via OAK before binding): histone methyltransferase activity (GO:0042054/more specific child terms), histone H4-K20 methyltransferase activity (GO:0140945 or similar — verify), DNA-binding transcription repressor activity - GO Biological Process candidates: negative regulation of transcription (GO:0045892), histone H4-K20 methylation (GO:0034770), regulation of smooth muscle cell differentiation, neural crest cell migration (GO:0001755)

5. Environmental Information

PDA3 itself is a monogenic condition with no reported environmental modifiers of penetrance or expressivity in the literature. Environmental factors relevant to PDA as a broader clinical entity (but not specifically implicated in the PRDM6-driven form): - Congenital rubella syndrome (infectious/teratogenic) — classic non-genetic cause of PDA, histologically distinct (elastic tissue fragmentation in the ductal wall) from the genetic forms. - Prematurity/hypoxia/high altitude — drive the far more common, non-genetic "premature PDA," mechanistically related to immature oxygen-sensing and prostaglandin-clearance pathways rather than a structural/differentiation gene defect. - No infectious agent, toxin, or lifestyle factor has been linked causally to PDA3.

6. Mechanism / Pathophysiology

Causal chain (PDA3)

  1. Heterozygous loss-of-function mutation in PRDM6 (e.g., p.Arg549Gln, p.Cys263Ser, p.Gln462Arg) impairs PRDM6 nuclear localization and/or its histone methyltransferase activity (established in vitro, human/mouse cell systems).
  2. Loss of PRDM6 function reverses its normal epigenetic output at target loci: instead of reducing H3K9me2 and increasing H4K20me2, mutant protein produces the opposite chromatin changes (demonstrated in vitro).
  3. Altered chromatin state fails to repress VSMC contractile-differentiation genes (MYH11, α-SMA) in ductal smooth muscle cells during fetal life, when PRDM6 is normally highly expressed specifically in ductus arteriosus (but not aortic) smooth muscle (demonstrated by mouse immunofluorescence at E14.5, E17.5, P0.5).
  4. This leads to premature differentiation of ductal VSMCs and — paradoxically, despite higher contractile-protein levels — reduced VSMC proliferation and impaired subintimal cushion formation/remodeling of the ductus (the process that normally produces permanent anatomical closure); this step is inferred from the correlative in vitro/mouse expression data rather than directly demonstrated by lineage-tracing loss-of-function in the human variant carriers themselves.
  5. Failure of normal ductal wall remodeling results in persistent ductal patency after birth despite the normal postnatal drop in prostaglandin E2 and rise in oxygen tension (i.e., the general perinatal "closure trigger" signal may still occur, but the ductal wall cannot execute the anatomic remodeling response) — clinical PDA.
  6. If the ductus remains widely patent, sustained left-to-right shunting leads to pulmonary overcirculation, left heart volume overload, and, if uncorrected over years, progressive pulmonary vascular remodeling → pulmonary arterial hypertension → (in the most severe, longstanding, uncorrected cases) Eisenmenger physiology with shunt reversal and cyanosis.
  7. A parallel/branching pathway, shown specifically in mouse neural-crest-conditional Prdm6 knockouts (not yet directly confirmed as the operative mechanism in the human missense-variant carriers): loss of Prdm6-mediated H4K20 monomethylation impairs G1–S cell-cycle progression required for cardiac neural crest cell (CNCC) delamination and migration, via elevated Wnt1 signaling; this reduces CNCC contribution to the ductal smooth muscle layer, independently contributing to a PDA phenotype (Wnt1-Cre and SM22-Cre conditional Prdm6 knockout mice both show complete-penetrance PDA and perinatal lethality) (PMC8876496).

Molecular pathways

  • Histone methylation / chromatin remodeling (H3K9me2, H4K20me2) via the PRDM6 SET domain.
  • MRTF-A/SRF-dependent smooth-muscle gene transcription — PRDM6 physically interacts with the central and N-terminal actin-binding regions of MRTF-A (JCI Insight, PMC/Zou et al. 2023).
  • Downstream target genes altered in Prdm6-depleted mouse ductus arteriosus include the PGE2 receptor EP4 (Ptger4), and transcription factors Tfap2b, myocardin, Foxc1, Hand2; Notch pathway components Jag1, Notch3 are also altered.
  • A common non-coding PRDM6 variant (rs17149944) in an SMC-selective intronic enhancer (bound by SRF, RBPJ, TEAD) has separately been proposed as a causal SNP at a cardiovascular/hypertension GWAS locus, indicating a dose-sensitive relationship between PRDM6 expression level and vascular smooth muscle/blood-pressure phenotypes more broadly.

Cellular processes

  • Vascular smooth muscle cell (VSMC) differentiation and proliferation (dysregulated — premature differentiation, reduced proliferation).
  • Neural crest cell delamination, EMT, and migration (impaired in conditional knockout mice).
  • Intimal cushion formation via subendothelial VSMC migration/proliferation and extracellular matrix deposition (the normal anatomic-closure process that fails).
  • Contractile response: in a related Prdm6-depletion mouse model, DA segments showed reduced myogenic tone, absent contractile response to KCl, eliminated oxygen-induced constriction, and reduced thromboxane-agonist response (40% vs. 76% in controls) — directly linking loss of PRDM6-regulated SMC identity to failure of the ductal functional constriction response as well as anatomic remodeling.

Protein dysfunction

Loss-of-function via (a) impaired nuclear localization (p.Arg549Gln) and (b) altered catalytic/chromatin-binding output of the SET domain (p.Cys263Ser and, inferentially, p.Gln462Arg) — not dominant-negative dimerization.

Tissue damage mechanism

Not applicable in the classic sense (no cell death/fibrosis/oxidative injury described); the "tissue damage" analog is a developmental patterning failure — the ductal wall never acquires the mature, contractile, remodeling-competent VSMC phenotype needed for closure.

Immune system involvement

None reported.

Suggested GO/CL terms (verify exact IDs/labels via OAK before curating)

  • GO Biological Process: "smooth muscle cell differentiation," "positive regulation of vascular associated smooth muscle cell proliferation," "neural crest cell migration" (GO:0001755), "histone H4-K20 methylation"
  • GO Molecular Function: "histone methyltransferase activity," "chromatin binding"
  • Cell types (CL): vascular associated smooth muscle cell (CL:0000359 — verify), cardiac neural crest cell
  • GO Cellular Component: nucleus (GO:0005634) for wild-type PRDM6 localization; cytoplasm (GO:0005737) for the mislocalized p.Arg549Gln variant

7. Anatomical Structures Affected

Organ level: - Primary: Ductus arteriosus (fetal/perinatal vascular structure connecting main pulmonary artery to descending aorta, just distal to the left subclavian artery origin). - Secondary (downstream, shunt-dependent): Left atrium and left ventricle (volume overload/dilation), pulmonary arteries (pressure/flow overload → pulmonary vascular remodeling), and — in the co-occurring phenotype reported by Stanley et al. — the aortic arch (coarctation). - Body systems: Cardiovascular system primarily; pulmonary vascular bed secondarily if the shunt is large and uncorrected.

Tissue/cell level: - Ductus arteriosus smooth muscle cells (specifically — not aortic SMCs, which do not show the same PRDM6 developmental expression decline) are the principal cell population implicated. - Endothelial cells of the ductal intima participate in the normal anatomic remodeling process (subendothelial migration, cushion formation) that fails in PDA3. - Cardiac/vascular neural crest cells contribute to the ductal SMC layer during development; their delamination/migration is impaired in Prdm6-deficient mouse models.

Subcellular level: - Nucleus (site of normal PRDM6 chromatin-modifying activity; site of pathology when nuclear import is disrupted by p.Arg549Gln). - Chromatin/histones (H3K9, H4K20 methylation marks directly altered).

Localization: The ductus arteriosus is a midline, typically solitary structure — laterality is not applicable in the way it is for paired organs; it lies at the aortic isthmus, adjacent to the site where coarctation (also reported in some PRDM6-variant carriers) occurs.

Suggested UBERON term: ductus arteriosus (UBERON:0002106 — verify via OAK).

8. Temporal Development

Onset: Congenital — present from birth in structurally term-appropriate infants (as opposed to prematurity-related PDA, which is a consequence of gestational immaturity rather than a fixed structural anomaly). PDA3 pedigrees are explicitly described as comprising term-born affected individuals.

Onset pattern: The structural lesion is congenital, but clinical detection may occur at any point from the newborn period (murmur on routine exam) through adulthood (incidental finding, or presentation with heart failure/pulmonary hypertension symptoms in a previously undiagnosed adult).

Progression: - Untreated small PDA: often clinically silent and hemodynamically insignificant; may remain stable indefinitely. - Untreated large/moderate PDA: progressive — left heart volume overload → pulmonary overcirculation → progressive pulmonary vascular remodeling → pulmonary arterial hypertension (in ~50% of infants with large nonrestrictive PDA by early childhood) → potential Eisenmenger physiology (shunt reversal, cyanosis, arrhythmia, sudden death) if never closed. - Once anatomically closed (surgically or via catheter device), the ductal lesion itself is cured; any established pulmonary vascular disease may or may not regress depending on how long it was present before closure.

Critical period: The perinatal window (first hours to ~3 weeks after birth) is the critical period for normal anatomic closure (functional closure within hours; anatomic remodeling to a permanent fibrous seal over 2–3 weeks). This is precisely the window in which the PRDM6-dependent transcriptional/epigenetic program is disrupted in PDA3.

Remission: Spontaneous late closure of an isolated PDA in an otherwise term, structurally normal infant beyond early infancy is uncommon; treatment-induced closure (catheter device or surgical ligation) is the standard "remission" pathway.

9. Inheritance and Population

Epidemiology of PDA (general, not PDA3-specific): PDA occurs in 1 in 2,000–5,000 term/live births and accounts for 5–7% of all congenital heart defects; incidence is far higher in preterm infants (up to 70–80% in extremely low-birth-weight infants), but this preterm form is developmentally/mechanistically distinct from PDA3.

PDA3 specifically: Exceedingly rare — the literature to date comprises one large index kindred (PDA-101, 9 affected individuals) plus a small number of additional unrelated probands/families (2 further mutation-positive cases in the original report, plus 3 more recently reported patients with PDA/coarctation and PRDM6 variants). No formal population prevalence estimate exists; it should be considered an "ultra-rare"/"cases in literature" tier of the PrevalenceClassEnum sense.

Inheritance pattern: Autosomal dominant, with incomplete penetrance — explicitly demonstrated in the PDA-101 kindred, where some obligate mutation carriers did not manifest PDA, and further supported by the general finding that PDA has "great phenotypic variability" across TFAP2B/PRDM6 families.

Penetrance: Incomplete; not formally quantified numerically in the literature (unlike some Mendelian conditions with published penetrance percentages).

Expressivity: Variable — ranging from isolated PDA to PDA with coarctation of the aorta in different PRDM6-variant carriers (Stanley et al. 2024).

Genetic anticipation: Not reported/applicable (not a repeat-expansion disorder).

Germline mosaicism: Not specifically reported for PDA3.

Founder effects: Not established; the index kindred is African-American, and additional families are of Iranian and North American/white ancestry in the discovery cohort — suggesting independent mutational events rather than a single founder haplotype.

Consanguinity: Not reported as a feature (autosomal dominant, not recessive).

Carrier frequency: Not applicable in the traditional AR sense; population allele frequency of the specific PRDM6 missense variants is essentially zero in reference databases (absent from >2,000 control exomes at publication).

Population demographics: No specific ethnic/geographic enrichment beyond the ancestry of the reported families (African-American, Iranian, white/North American); sex ratio and detailed age-distribution data specific to PDA3 have not been published (too few cases). For PDA broadly, a female predominance (roughly 2:1 to 3:1) is well documented, but this figure should not be assumed to hold for the genetic PDA3 subtype without dedicated data.

10. Diagnostics

Clinical tests: - Auscultation: classic continuous ("machinery") murmur, best heard at the left infraclavicular/upper sternal border, in a hemodynamically significant PDA. - Echocardiography (2D with color-flow and spectral Doppler) is the primary diagnostic and confirmatory test, establishing ductal patency, direction/velocity of shunt flow, and chamber size/loading conditions. It is standard for both symptomatic detection and "clinically silent" PDA found incidentally on color-flow imaging. - Chest radiography: may show cardiomegaly and increased pulmonary vascular markings in a large shunt (nonspecific). - Cardiac catheterization: used both diagnostically (hemodynamic assessment, pulmonary vascular resistance calculation before intervention in older patients/pulmonary hypertension) and therapeutically (device closure).

Genetic testing: - No PDA3-specific clinical panel is described in the literature reviewed; given the described disease model, genetic evaluation of isolated/familial (rather than prematurity-associated) PDA would reasonably include a congenital heart disease gene panel (covering TFAP2B, PRDM6, NOTCH1, MYH11, FOXC2, etc.) or whole-exome sequencing, particularly when PDA occurs in a term infant with a family history of PDA/other CHD and no syndromic features. - Chromosomal microarray is indicated to exclude aneuploidy/CNV causes of PDA in the differential (trisomy 21/18/13, other CNVs) before attributing an isolated PDA to a monogenic cause like PRDM6. - Sanger confirmation of a candidate PRDM6 variant, with segregation analysis in the family, was the approach used in the discovery studies.

Clinical criteria / differential diagnosis: Differentiate PDA3 from: - Prematurity-associated PDA (gestational-age history is key). - Char syndrome (TFAP2B) — look for facial dysmorphism and 5th-finger clinodactyly/middle-phalanx hypoplasia. - Chromosomal syndromes (trisomy 21/18/13) via karyotype/microarray. - Congenital rubella syndrome — maternal infection history, additional classic triad features (cataracts, sensorineural hearing loss). - Other genetic CHD-PDA associations (e.g., MYH11-associated TAAD/PDA syndrome — screen for aortic aneurysm).

Screening: No population or targeted genetic screening program exists for PDA3 specifically; pulse oximetry newborn screening detects critical CHD generally but is not ductus-specific, and an isolated PDA (without other critical CHD) may not be reliably flagged by oximetry screening alone.

11. Outcome/Prognosis

Survival/mortality: With modern transcatheter or surgical closure, prognosis for isolated PDA (including the PDA3 genetic form) is excellent, with normalization of cardiac loading and low procedural mortality. Untreated large PDA carries substantial long-term morbidity/mortality risk via progression to pulmonary arterial hypertension and Eisenmenger syndrome, which is associated with arrhythmia and sudden cardiac death as late complications.

Morbidity: - Congestive heart failure and failure to thrive in infancy with a large untreated shunt. - Progressive pulmonary vascular disease (~50% of infants with large nonrestrictive PDA develop pulmonary hypertension by early childhood if uncorrected). - Increased risk of infective endarteritis of the ductal lesion (a recognized general PDA complication, though specific incidence data for PDA3 are not available). - In the subset of PRDM6-variant carriers with co-occurring coarctation of the aorta, additional morbidity from arch obstruction (hypertension, arch re-intervention risk) applies.

Recovery potential: Full anatomic and hemodynamic correction is achieved with device or surgical closure in the great majority of cases; pulmonary vascular changes that have already become fixed (established Eisenmenger physiology) may not fully reverse even after closure, and closure can be contraindicated in advanced Eisenmenger physiology (shunt reversal used for right-ventricular decompression).

Prognostic factors: Shunt size/hemodynamic significance, age/timing of diagnosis and closure, and presence of associated lesions (e.g., coarctation) are the operative prognostic variables; no PRDM6-genotype-specific prognostic marker has been established given the small case numbers.

12. Treatment

Pharmacotherapy: Pharmacologic ductal closure agents (indomethacin, ibuprofen, and increasingly paracetamol/acetaminophen — all COX inhibitors reducing PGE2 synthesis) are the mainstay for prematurity-associated PDA in neonates, effective in roughly 70–80% of extremely-low-birth-weight infants. This pharmacologic approach is not the relevant treatment paradigm for PDA3, since the lesion occurs in structurally mature, term infants with a fixed anatomic/developmental ductal-wall defect rather than a reversible prostaglandin-mediated patency — mechanical/procedural closure is expected to be the definitive treatment. - NCIT suggestion: NCIT:C15986 (Pharmacotherapy) as the generic action term, if pharmacologic closure is ever attempted; therapeutic agents indomethacin (CHEBI) or ibuprofen (CHEBI) as therapeutic_agent.

Surgical/interventional (primary treatment modality for PDA3): - Transcatheter device closure is now the treatment of choice for most children >1 year and many infants with favorable ductal anatomy — devices include the Amplatzer Duct Occluder and Amplatzer Piccolo Occluder (implant success ~95.5%, major complication rate ~2.1%, effective closure in ~99.4% at 6 months in one large series). - Surgical ligation/division remains preferred for infants <1 year with anatomy unfavorable for catheter closure. - NCIT suggestions: NCIT:C15329 (Surgical Procedure) for ligation; a device-specific qualifier pattern (per dismech convention) would bind the clinical action (e.g., NCIT:C15329) with a qualifiers predicate-value pair naming the occluder device, since NCIT device terms are not valid treatment_term bindings on their own.

Supportive care: Management of heart failure symptoms (diuretics, fluid management) in infants awaiting closure, or in those with a large symptomatic shunt.

Experimental/advanced therapeutics: No gene therapy, RNA-based therapy, or other advanced modality has been developed or trialed for PDA3; given the structural/anatomic nature of the lesion, mechanical closure rather than molecular correction is the applicable treatment paradigm.

Treatment outcomes: High closure success rates and low complication rates with modern transcatheter devices, as above; surgical ligation carries a low but real risk profile (recurrent laryngeal nerve injury, residual shunt, bleeding) typical of thoracic surgical procedures.

Genetic counseling: Because PDA3 is autosomal dominant with incomplete penetrance, genetic counseling for affected families should address a 50% transmission risk per pregnancy for a carrier parent, with the caveat that not all mutation carriers will manifest PDA (or may show variable expressivity, e.g., isolated PDA vs. PDA with coarctation).

13. Prevention

Primary prevention: No primary prevention exists for the underlying PRDM6 mutation (a de novo or inherited germline variant); genetic counseling and prenatal/preimplantation genetic testing could theoretically be offered in a family with a known pathogenic variant, though this has not been reported as clinical practice for PDA3 specifically given its rarity and generally favorable treatability.

Secondary prevention: Early echocardiographic detection (e.g., prompted by a family history of PDA, or postnatal murmur screening) allows early closure before pulmonary vascular disease develops — this is the principal "prevention" lever for PDA3's main morbidity (Eisenmenger progression).

Tertiary prevention: Timely device/surgical closure once diagnosed prevents progression to pulmonary arterial hypertension and Eisenmenger syndrome.

Screening/genetic counseling: Cascade screening (echocardiography ± targeted genetic testing) of first-degree relatives in a family with a confirmed PRDM6 variant would be a reasonable clinical approach given the autosomal-dominant inheritance, though no formal screening program is published.

Public health: Congenital rubella vaccination programs remain the relevant public-health primary-prevention measure for the infectious form of PDA (not PDA3).

14. Other Species / Natural Disease

Naturally occurring PDA in other species: PDA is a well-recognized, common congenital cardiac defect in dogs (e.g., over-represented in Poodles, Pomeranians, Maltese, and notably studied in the Dutch Stabyhoun breed, where epidemiology and population genetics have been characterized — PMC4906750) and other companion animals; it is generally regarded as heritable/polygenic in most affected dog breeds rather than tied to a PRDM6 ortholog specifically. No PRDM6-specific naturally-occurring veterinary PDA has been reported in the literature surveyed.

Orthologous gene: Prdm6 is conserved from mammals to lower vertebrates; the Li et al. 2016 study explicitly notes that Arg549 is "highly conserved in orthologs from humans to sea anemones," indicating deep evolutionary conservation of this residue/domain.

Comparative pathology: Mouse Prdm6 conditional-knockout studies (below) recapitulate complete-penetrance PDA, supporting cross-species conservation of the PRDM6-dependent ductal-closure mechanism; this is the primary comparative-biology evidence base for PDA3, rather than natural disease in other species.

Zoonotic potential: Not applicable (non-infectious, monogenic developmental disorder).

15. Model Organisms

Mouse models (the dominant model system for PDA3 mechanism):

  1. Prdm6fl/fl; Wnt1-Cre2* (neural-crest-specific conditional knockout) — complete-penetrance PDA with perinatal lethality (P0.5–P1.5) in both sexes; neural crest migration/delamination impaired via elevated Wnt1 signaling and reduced H4K20 monomethylation-dependent G1–S progression (PMC8876496).
  2. Prdm6fl/fl; SM22-Cre* (smooth-muscle-specific conditional knockout) — also complete-penetrance PDA with perinatal lethality, confirming a cell-autonomous requirement for Prdm6 in ductal SMC identity independent of the neural crest contribution pathway (same source).
  3. Prdm6 depletion models used by Zou et al. 2023 (JCI Insight, PMID:36749647) — demonstrated Prdm6's role in maintaining DA-specific SMC gene expression (319 of 519 DA-enriched genes downregulated on Prdm6 depletion), reduced myogenic tone, abolished KCl and oxygen-induced contractile responses, and reduced thromboxane-agonist response, directly linking Prdm6 loss to failure of both anatomic remodeling and functional ductal constriction. Pharmacologic (indomethacin) and oxygen stimulation both failed to induce closure in mutant embryos, unlike controls — a key translational finding showing that the standard postnatal closure triggers are insufficient to overcome the structural/differentiation defect.
  4. Immunofluorescence expression-mapping in wild-type mouse ductus arteriosus vs. aorta at E14.5, E17.5, and P0.5 established the developmental expression pattern underpinning the human disease model (high embryonic PRDM6 in DA SMCs, postnatal decline, contrasted with persistent aortic SMC expression) (Li et al. 2016).

Model characteristics: These conditional-knockout mouse models recapitulate the core human phenotype (PDA) with high fidelity and complete penetrance, and additionally reveal a functional-contractility deficit and a neural-crest-migration mechanism not yet directly demonstrated in human PDA3 carriers — representing a model-to-human translational gap: it remains unconfirmed whether the specific human missense variants (haploinsufficient/hypomorphic) produce the same degree of pathway disruption as the mouse complete conditional knockouts (a full biallelic tissue-specific null), which is a candidate HUMAN_MODEL_MISMATCH consideration for KB curation.

In vitro models: HEK293 cells and primary/immortalized human aortic vascular smooth muscle cells (VSMCs) transfected with wild-type or mutant PRDM6 constructs — used for subcellular localization, histone methylation (H3K9me2/H4K20me2), and MYH11/α-SMA suppression assays (Li et al. 2016).

Resources: No dedicated PDA3/PRDM6 mouse strain repository entry (e.g., MGI/IMSR ID) was identified in this search; strains described are custom conditional-knockout lines (Prdm6^fl/fl^ crossed to Wnt1-Cre2 or SM22-Cre) generated by the cited research groups rather than centrally banked at time of publication.

Summary Table of Key Citations

Citation Focus
Li N et al., Am J Hum Genet 2016, PMID:27181681 (PMC4908195) Discovery of PRDM6 as PDA3 gene; 3 mutations; functional assays; mouse expression mapping
Stanley HM et al., Am J Med Genet A 2024, PMID:38071433 PRDM6 variants with PDA + coarctation of the aorta; novel variant
Zou M et al., JCI Insight 2023, PMID:36749647 Prdm6 mechanism — MRTF-A interaction, SMC contractility, GWAS SNP rs17149944
Prdm6/neural crest paper, PMC8876496 Prdm6 controls cardiac neural crest differentiation/migration via Wnt1/H4K20me1
Guo DC / Pannu H et al. (MYH11-TAAD-PDA), PMID:16444274 Related but distinct MYH11-associated TAAD+PDA syndrome
Char syndrome (TFAP2B) GeneReviews, NCBI Bookshelf NBK1106; StatPearls NBK604201 PDA2/Char syndrome comparator
OMIM #617039 (PDA3), *616982 (PRDM6), #617035 (PDA2), #607411 (PDA1) Canonical disease/gene numbering
MONDO:0024266 Ontology identifier for PDA3
Orphanet ORPHA:466729 Familial patent arterial duct (parent nosologic entity)

Sources: - OMIM #617039 – PATENT DUCTUS ARTERIOSUS 3; PDA3 - OMIM *616982 – PRDM6 - OMIM #617035 – PATENT DUCTUS ARTERIOSUS 2; PDA2 - OMIM `607411 – PATENT DUCTUS ARTERIOSUS 1; PDA1 - Li N et al. 2016, "Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus" — PMC4908195 - Stanley HM et al. 2024, "Patent ductus arteriosus and coarctation of the aorta in association with PRDM6 variants" — PubMed 38071433 - Zou M et al. 2023, "Prdm6 drives ductus arteriosus closure by promoting ductus arteriosus smooth muscle cell identity and contractility" — JCI Insight - Prdm6 controls heart development by regulating neural crest cell differentiation and migration — PMC8876496 - Char Syndrome – GeneReviews, NCBI Bookshelf NBK1106 - Char Syndrome – StatPearls, NCBI Bookshelf NBK604201 - PRDM6 gene – GeneCards - Orphanet: Familial patent arterial duct (ORPHA:466729) - Orphanet: Patent arterial duct (ORPHA:706, non-rare in Europe) - Molecular and Mechanical Mechanisms Regulating Ductus Arteriosus Closure in Preterm Infants – PMC7477801 - Prostaglandin E2–Mediated Relaxation of the Ductus Arteriosus – Circulation - Patent Ductus Arteriosus – Merck Manual Professional Edition - Patent Ductus Arteriosus: A Contemporary Perspective – Journal of the American Heart Association - Catheter Closure of Clinically Silent PDA Using Amplatzer Duct Occluder II – PMC8465329 - Characteristics of Patent Ductus Arteriosus in Congenital Rubella Syndrome – PMC6863812 - Epidemiology, presentation and population genetics of patent ductus arteriosus (PDA) in the Dutch Stabyhoun dog – PMC4906750 - Zhu L et al. 2006, "Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus" – PubMed 16444274

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 15
Resolved 14
Unresolved (possible confabulation) 1
Unverifiable 0
References weighed for topical relevance 14
On topic 10
Off topic 1

Unresolved references

These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:

  • PMC:PMC38071433 (2 mentions) - NCBI reports no such accession in PMC

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

  • DOI:10.1161/01.cir.0000145159.16637.5d (2 mentions) - Prostaglandin E 2 —Mediated Relaxation of the Ductus Arteriosus
  • shared terms: ductus, arteriosus

Weighed against this report's own most characteristic terms: pda3, pda, prdm6, genetic, via, ductal, vascular, gene, variant, disease, closure, ductus, arteriosus, congenital, isolated, cell, specifically, syndrome, muscle, mutation.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 20
Resolved 16
Unresolved (possible confabulation) 0
Obsolete 1
Unverifiable 3
Terms whose name was checked 12
Terms named correctly 6
Terms named as a different term 3
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0024266 (2 mentions) - the report calls it "Ontology identifier for PDA3"; MONDO calls it patent ductus arteriosus 3
  • CL:0000359 (1 mention) - the report calls it "verify"; CL calls it vascular associated smooth muscle cell
  • UBERON:0002106 (1 mention) - the report calls it "verify via OAK"; UBERON calls it spleen

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0034770 (obsolete histone H4-K20 methylation) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0002092 (1 mention) - the report calls it "Pulmonary hypertension"; HP calls it Pulmonary arterial hypertension, and lists "Pulmonary artery hypertension" among its other names
  • GO:0045892 (1 mention) - the report calls it "GO Biological Process candidates: negative regulation of transcription"; GO calls it negative regulation of DNA-templated transcription
  • GO:0005634 (1 mention) - the report calls it "GO Cellular Component: nucleus"; GO calls it nucleus, and lists "cell nucleus" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.