PLD1-Related Congenital Heart Disease

Mendelian MONDO:0008913 Pathograph 37 Show in embeddings browser

PLD1-related congenital heart disease is the autosomal recessive disorder caused by biallelic loss-of-function variants in PLD1, which encodes phospholipase D1. The enzyme hydrolyses phosphatidylcholine to generate phosphatidic acid, a lipid second messenger; the disease alleles cluster in the regions encoding the catalytic core and reduce that activity. What makes the entity recognisable is where in the heart it lands. The lesions are overwhelmingly right-sided - severe tricuspid and pulmonary valve dysplasia, often with a hypoplastic right ventricle and hypoplastic pulmonary arteries - and Ebstein's anomaly is a recurring diagnosis. That topography follows from the mechanism rather than being incidental to it: phosphatidic acid is required for cardiac endothelial-to-mesenchymal transition, the step that supplies the mesenchyme and remodelled matrix of the endocardial cushions, and pharmacological PLD1 inhibition reduces that transition directly. The founding report also places the attenuated TGF-beta and hedgehog signalling that follows loss of phosphatidic acid behind the arterial pole defects specifically. A second presentation is cardiomyopathy, and it is not simply a consequence of the valve lesion. The delineating cohort associated recessive PLD1 variants with *isolated* neonatal cardiomyopathy, and dilated cardiomyopathy has since been reported in older patients alongside their valve disease. The fetal end of the spectrum is severe: hydrops fetalis, intrauterine death, and termination for a complex defect with poor prognosis all occur, so the liveborn phenotype is a survivorship-filtered view of the disorder. The nomenclature is the most confusing part of this entry, and the entry is deliberately not named after the term it is bound to. The label of MONDO:0008913, `cardiac valvular defect, developmental`, describes a condition that occurs without PLD1 at all - the X-linked FLNA form and the ADAMTS19 form are two of the other genetically defined cardiac valvular dysplasias, and most developmental valve disease is neither - so as an entry name it would be broader than the entry. Worse, it does not cover this disorder's isolated-cardiomyopathy arm, which the delineating cohort reports with no structural valve defect at all. The name used here is ClinGen's, which is also the label of MONDO:1010144: ClinGen curates this gene-disease relationship as PLD1-related congenital heart disease, and states that it lumped cardiac valvular dysplasia 1 and congenital heart disease into a single entity after finding no difference in mechanism, inheritance or phenotypic variability - which is why MONDO:1010144 is mapped here as an exact match rather than as a separate concept. The clinical and genetics literature mostly calls this cardiac valvular dysplasia 1 (CVDD1 or CVDP1); that name and the MONDO label are both kept in `synonyms`. The file name still follows the MONDO label, because dismech has not settled how a slug follows a rename (dismech#15894).

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Mappings

MONDO
MONDO:0008913 cardiac valvular defect, developmental
skos:exactMatch MONDO
Primary disease term for this entry.
MONDO:1010144 PLD1-related congenital heart disease
skos:exactMatch ClinGen
MONDO files the gene-centric ClinGen concept separately from the OMIM-derived MONDO:0008913, and neither is an ancestor of the other. They denote one entity: ClinGen's own Congenital Heart Disease GCEP record states that it lumped cardiac valvular dysplasia 1 and congenital heart disease into a single disease entity for PLD1 after finding no difference in molecular mechanism, inheritance pattern or phenotypic variability. The exact match is that published lumping decision, not an inference from the two labels. Note what MONDO's own placement does not cover: MONDO:0008913 sits under `cardiac valvular defect`, so the isolated neonatal cardiomyopathy arm - which this entry curates, and which the delineating cohort reports in the absence of any structural valve defect - falls inside MONDO:1010144 but arguably outside MONDO:0008913's parent. On MONDO's own axes 1010144 is therefore the broader class, and the exact match asserts a merge MONDO has not itself made.
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Inheritance

1
Autosomal recessive HP:0000007
Biallelic PLD1 genotypes - homozygous and compound heterozygous - across 21 unrelated families of different ancestries, with heterozygous parents unaffected.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:33645542 SUPPORT DIRECT Human clinical
"we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects"
Biallelic genotypes across 21 unrelated families establish recessive inheritance.
CGGV:assertion_d37e1c81-cb59-45db-9481-338149fa5064-2024-12-02T170000.000Z SUPPORT Other
"PLD1 | HGNC:9067 | PLD1-related congenital heart disease | MONDO:1010144 | AR | Definitive | SOP11 | Congenital Heart Disease Gene Curation Expert Panel"
ClinGen records the inheritance pattern as autosomal recessive in its Definitive validity assertion.
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Mechanistic Hypotheses

2
Arterial pole defects via attenuated TGF-beta and hedgehog signalling
pld1_tgfb_shh_route EMERGING
Evidence balance 1 support
The route from depleted phosphatidic acid to the arterial pole lesions, proposed by the delineating cohort. It is recorded as a hypothesis group rather than as settled main-chain mechanism because the supporting paragraph is hedged throughout and assembled from other work: the phosphatidic-acid-to-TGF-beta step is inferred from an adult myocardial-infarction study, the hedgehog step from the consequence of inhibiting hedgehog at the corresponding developmental stage, and nothing about either pathway was measured in this disease. The nodes are kept in the chain because the entry's phenotype distribution is otherwise unexplained, but the two edges into and out of them carry this group so the epistemic status travels with them - the same standard applied to the apoptosis route below.
Pathograph links
Depleted Phosphatidic Acid Signalling -> Attenuated TGF-beta and Hedgehog Signalling INDIRECT UNKNOWN INTERMEDIATES
Attenuated TGF-beta and Hedgehog Signalling -> Impaired Cardiac Endothelial-to-Mesenchymal Transition INDIRECT KNOWN INTERMEDIATES
Show evidence (1 reference)
PMID:33645542 SUPPORT INDIRECT BACKGROUND Model organism
"In the adult heart, loss of PLD1 can lead to a reduction in TGF-β signaling activity in the context of myocardial infarction"
The only empirical support for the phosphatidic-acid-to-TGF-beta step, and it comes from adult myocardial infarction rather than cardiac development - which is why this is a hypothesis group and not a settled edge.
Loss of developmentally programmed apoptosis in the valve primordia
pld1_apoptosis_route EMERGING
Evidence balance 1 support
An alternative to the endothelial-to-mesenchymal transition account. The original report noted that the chick PLD1 expression pattern follows the known dynamic patterning of apoptosis in the developing heart, and read this as consistent with PLD1's established role in promoting apoptosis - implying the valve defect arises because sculpting apoptosis fails rather than because cushion mesenchyme is not generated. The two accounts are not exclusive and neither has been tested against the other in cardiac tissue; the entry's main chain follows the transition route because that is the one with a direct perturbation experiment behind it.
Show evidence (1 reference)
PMID:27799408 SUPPORT INDIRECT Model organism
"This pattern of expression follows the known dynamic patterning of apoptosis in the developing heart, consistent with the known role of PLD1 in the promotion of apoptosis."
The observation and inference behind this hypothesis. Graded INDIRECT because it is an argument from a correlation between an expression pattern and a known developmental process, with no apoptosis measurement in PLD1-deficient hearts.
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Discussions and Knowledge Gaps

2
Is the cardiomyopathy in PLD1 disease a primary myocardial defect, or secondary to chronic valvular loading?
KNOWLEDGE GAP pld1_cardiomyopathy_primary_or_loading
Attached to
pathophysiology#Myocardial Dysfunction
The two reported forms point in opposite directions. Isolated neonatal cardiomyopathy without a structural valve defect argues for a primary myocardial requirement for phospholipase D1, which is plausible given that the enzyme is highly expressed in the heart and that phosphatidic acid signalling operates in cardiomyocytes. But the dilated cardiomyopathy reported in older patients arrives after years of valve disease and multiple operations, where loading is an adequate explanation on its own. Nothing yet separates the two, and the answer changes surveillance: a primary myocardial effect would mean echocardiographic follow-up is indicated even in a biallelic carrier whose valves look normal.
Proposed experiments
Myocardial phenotyping of PLD1-deficient hearts without valve obstruction
pld1_cardiomyocyte_specific_loss
Assess contractile function and chamber dimensions in a model in which PLD1 is lost in cardiomyocytes only, leaving valve development intact, so that any cardiomyopathy cannot be attributed to altered loading.
Would support
pathophysiology#Myocardial Dysfunction
Supporting outcome
  • Reduced systolic function and ventricular dilation in the absence of any valve lesion or outflow obstruction.
Refuting outcome
  • Normal contractile function and chamber dimensions throughout life when valve development is unaffected.
Show evidence (2 references)
PMID:33645542 SUPPORT DIRECT Human clinical
"We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy."
The isolated presentation that makes a primary myocardial defect the live possibility.
PMID:42591229 SUPPORT INDIRECT Human clinical
"with a history of cardiac valve disease for more than 17 years and three open-heart surgeries"
The other side of the gap: this patient's cardiomyopathy follows 17 years of valve disease and three operations, so loading is an adequate explanation here.
Why is the phenotype right-sided, when phosphatidic acid is required for endothelial-to-mesenchymal transition in both the inflow and outflow cushions?
KNOWLEDGE GAP pld1_right_sided_predominance
Attached to
pathophysiology#Impaired Cardiac Endothelial-to-Mesenchymal Transition pathophysiology#Right-Sided Valve Dysplasia
The mechanism as stated is not side-specific: the cushions supply both left and right heart structures, so a general reduction in the transition should damage the mitral and aortic valves as much as the tricuspid and pulmonary ones. It does not - the mitral valve is involved in a minority, two of 28 phenotyped patients, and aortic involvement is reported once. Three candidate explanations are on record and none has been tested against the others. The delineating cohort's own is that the two sides of the heart present different environments - cell populations, extracellular matrix, haemodynamics - so right-sided cells may be less able to compensate for the same disruption of EndoMT in the common cushions. The chick expression data suggest a simpler one: PLD1 transcription narrows specifically to the atrioventricular valves and the right ventricular outflow tract, making this a matter of where the gene is expressed. And the hedgehog dependence invoked for the arterial pole is itself regionalised. Resolving this would say whether the right-sided predominance is a property of the gene's expression domain, of differential pathway dependence, or of differential capacity to compensate.
Proposed experiments
Side-resolved transition assay across inflow and outflow cushions
pld1_side_resolved_endmt_assay
Quantify endothelial-to-mesenchymal transition separately in left- and right-sided cushion explants under graded PLD1 inhibition, to test whether the right-sided structures are more sensitive at equal inhibition or merely express more of the enzyme.
Would support
pathophysiology#Right-Sided Valve Dysplasia
Supporting outcome
  • Right-sided cushion explants lose the transition at lower degrees of PLD1 inhibition than left-sided explants from the same embryos.
Refuting outcome
  • Both sides lose the transition at the same degree of inhibition, locating the asymmetry in expression level rather than pathway dependence.
Show evidence (3 references)
PMID:33645542 SUPPORT DIRECT BACKGROUND Other
"In the endocardial cushions, EndoMT provides the mesenchymal cells and remodeled matrix essential for the formation of both left and right heart structures"
The side-neutral statement of the mechanism, which is what the right-sided clinical predominance sits awkwardly against.
PMID:33645542 SUPPORT INDIRECT BACKGROUND Other
"These differing contexts may underlie the susceptibility of the right side of the heart to loss of PLD1 activity."
The third candidate explanation, and the one the delineating cohort itself favours: the two sides of the heart differ in cell populations, matrix and haemodynamics, so right-sided cells may be less able to compensate for the same loss of EndoMT.
PMID:27799408 SUPPORT INDIRECT Model organism
"Thereafter its expression decreases, remaining only adjacent to the atrioventricular valves and the right ventricular outflow tract."
One of the two candidate explanations - a regionalised expression domain rather than regionalised pathway dependence.
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Pathophysiology

9
PLD1 Biallelic Loss of Function
Homozygous or compound heterozygous PLD1 variants - missense, nonsense, frameshift and splice - reduce phospholipase D1 activity. The missense alleles are concentrated in the regions encoding the catalytic core, and most of the mutant proteins show strongly reduced activity in a direct enzymatic assay, so this is a loss of catalytic function rather than a dominant-negative or gain-of-function mechanism.
PLD1 hgnc:9067 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PLD1 (hgnc:9067). hgnc:9067 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
phospholipase D1 catalytic activity GO:0004630 ⇓ LOSS OF FUNCTION Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves phospholipase D1 catalytic activity, annotated with D-type glycerophospholipase activity (GO:0004630), qualified as loss of function. GO:0004630 is a molecular function from the Gene Ontology.
Downstream
Depleted Phosphatidic Acid Signalling Phospholipase D1 is the enzyme that makes phosphatidic acid from phosphatidylcholine, so losing its catalytic activity removes the second messenger directly.
Show evidence (3 references)
PMID:33645542 SUPPORT DIRECT In vitro / ex vivo
"PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay."
Direct enzymatic evidence that the disease alleles reduce catalytic activity.
PMID:27799408 SUPPORT DIRECT In vitro / ex vivo
"the p.His442Pro mutation produced a strong loss of function phenotype in yeast homologous mutant strain"
Independent loss-of-function evidence for a disease allele in a heterologous assay.
PMID:32198492 SUPPORT INDIRECT In vitro / ex vivo
"The C terminus folds into and contributes part of the catalytic pocket, which harbors a phosphohistidine that mimics an intermediate stage of the catalytic cycle."
Structural account of the catalytic pocket, which is why missense alleles clustered in the regions encoding it abolish activity. Graded INDIRECT because the structure is of wild-type PLD1 and says nothing about the disease variants directly - it supplies the reason their position matters.
Depleted Phosphatidic Acid Signalling
Loss of phospholipase D1 activity depletes phosphatidic acid, the lipid second messenger the enzyme generates. Phosphatidic acid is the node through which the defect reaches morphogenetic signalling, and the founding cohort reads the downstream arterial pole defects as a consequence of reduced TGF-beta and hedgehog signalling.
Arterial pole defects via attenuated TGF-beta and hedgehog signalling
phosphatidic acid biosynthetic process GO:0006654 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased phosphatidic acid biosynthetic process (GO:0006654). GO:0006654 is a biological process from the Gene Ontology.
Downstream
Attenuated TGF-beta and Hedgehog Signalling Arterial pole defects via attenuated TGF-beta and hedgehog signalling
Myocardial Dysfunction The same enzymatic loss produces cardiomyopathy without a structural valve defect in some patients. How one lesion yields either outcome is explicitly unresolved, so the intermediates are recorded as unknown rather than guessed.
Impaired Cardiac Endothelial-to-Mesenchymal Transition Pharmacological PLD1 inhibition, which removes the same enzymatic product, reduces endothelial-to-mesenchymal transition.
Attenuated TGF-beta and Hedgehog Signalling
Reduced TGF-beta and sonic hedgehog signalling downstream of phosphatidic acid depletion. The founding cohort invokes this specifically for the arterial pole defects, noting that inhibiting hedgehog signalling at the corresponding developmental stage produces pulmonary atresia.
Arterial pole defects via attenuated TGF-beta and hedgehog signalling
transforming growth factor beta receptor signaling pathway GO:0007179 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased transforming growth factor beta receptor signaling pathway (GO:0007179). GO:0007179 is a biological process from the Gene Ontology. smoothened signaling pathway GO:0007224 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased smoothened signaling pathway (GO:0007224). GO:0007224 is a biological process from the Gene Ontology.
Downstream
Impaired Cardiac Endothelial-to-Mesenchymal Transition Arterial pole defects via attenuated TGF-beta and hedgehog signalling
Show evidence (1 reference)
PMID:33645542 SUPPORT INDIRECT BACKGROUND Other
"Inhibition of Shh signaling at this developmental stage leads to pulmonary atresia."
The developmental-biology premise the cohort borrows to connect reduced hedgehog signalling to the arterial pole lesions. It is a background statement about other work, not a measurement in this study or in these patients.
Impaired Cardiac Endothelial-to-Mesenchymal Transition
Endocardial cells fail to undergo the endothelial-to-mesenchymal transition that populates the endocardial cushions. This is the step PLD1 inhibition was shown to reduce, and it is the point at which a lipid signalling defect becomes a morphogenetic one.
endocardial cell CL:0002350 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endocardial cell (CL:0002350). CL:0002350 is a cell type from the Cell Ontology. endocardial cushion cell CL:0008022 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endocardial cushion cell (CL:0008022). CL:0008022 is a cell type from the Cell Ontology.
cardiac endothelial to mesenchymal transition GO:0140074 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cardiac endothelial to mesenchymal transition (GO:0140074). GO:0140074 is a biological process from the Gene Ontology.
Downstream
Deficient Endocardial Cushion Remodelling
Show evidence (1 reference)
PMID:33645542 SUPPORT DIRECT In vitro / ex vivo
"Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis."
Experimental demonstration that losing PLD1 activity reduces this transition.
Deficient Endocardial Cushion Remodelling
Without sufficient cushion mesenchyme and remodelled matrix, the inflow cushions that become the tricuspid and mitral valves and the outflow cushions that become the arterial valves fail to form normal leaflets. PLD1 expression in the developing chick heart narrows to exactly these sites - adjacent to the atrioventricular valves and the right ventricular outflow tract - as development proceeds.
mesenchymal cell CL:0008019 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves mesenchymal cell (CL:0008019). CL:0008019 is a cell type from the Cell Ontology.
endocardial cushion morphogenesis GO:0003203 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased endocardial cushion morphogenesis (GO:0003203). GO:0003203 is a biological process from the Gene Ontology. heart valve morphogenesis GO:0003179 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased heart valve morphogenesis (GO:0003179). GO:0003179 is a biological process from the Gene Ontology.
Animal models
Chick embryo PLD1 expression Chicken measures Maps where the gene is expressed during valvulogenesis, which is the structures that are malformed in patients.
Downstream
Right-Sided Valve Dysplasia
Right Ventricular and Pulmonary Arterial Hypoplasia Downstream chamber and great-artery hypoplasia follows the obstructed or dysplastic right-sided valve rather than being a separate primary defect.
Ventricular septal defect The same cushions that become the valve leaflets also build the septa, so septation defects are the other arm of the same failure rather than an incidental association.
Atrial septal defect The atrial arm of the same septation failure; the inflow cushions contribute to the atrioventricular septum.
Show evidence (2 references)
PMID:42600378 SUPPORT DIRECT REVIEW SYNTHESIS Other
"Improper morphogenesis of the endocardial cushion leads to septal and valvular abnormalities, which contribute to the largest proportion of congenital heart diseases (CHDs)."
Establishes that failed cushion morphogenesis is a route to valvular congenital heart disease generally, which is the step this node occupies.
PMID:27799408 SUPPORT INDIRECT Model organism
"Thereafter its expression decreases, remaining only adjacent to the atrioventricular valves and the right ventricular outflow tract."
The chick expression pattern localises PLD1 to the structures that are malformed, which is the spatial argument that this is where the defect acts.
Right-Sided Valve Dysplasia
Dysplastic, thickened or atretic tricuspid and pulmonary valves, with the tricuspid lesion frequently taking the form of Ebstein's anomaly. The mitral valve is involved in a minority. This right-sided predominance is the defining feature of the entity and distinguishes it from the other genetically defined cardiac valvular dysplasias.
Animal models
Pld1 knockout mouse Mouse partially recapitulates The knockout reproduces the right-sided distribution and, at histology, thickened and narrowed pulmonic leaflets - but the two sources disagree on whether it reproduces a structural malformation at all, which is why this is partial recapitulation rather than recapitulation.
Downstream
Abnormal tricuspid valve morphology
Abnormal pulmonary valve morphology
Ebstein anomaly of the tricuspid valve
Pulmonary valve atresia
Tricuspid atresia
Tricuspid regurgitation
Pulmonic stenosis
Show evidence (1 reference)
PMID:39553471 SUPPORT DIRECT BACKGROUND Other
"Patients with autosomal-recessive variants of PLD1 are predisposed to Cardiac Valvular Dysplasia-1 (CVDP1), which predominantly affects the right-sided heart valves, including the pulmonic, tricuspid, and mitral valves."
States the right-sided predominance this node asserts. BACKGROUND and OTHER because the sentence is this case report's introduction summarising five prior studies, not its own result. Note it lists the mitral valve among the "right-sided" valves, which is loose; the mitral minority is carried by the two-patient count on the Mitral regurgitation phenotype instead.
Right Ventricular and Pulmonary Arterial Hypoplasia
Hypoplastic right ventricle and hypoplastic pulmonary arteries, present in roughly half and over a third of phenotyped patients respectively. In the most severe hearts the right ventricular wall is extremely thin.
Downstream
Hypoplastic right ventricle
Pulmonary artery hypoplasia
Single ventricle Where right ventricular hypoplasia is severe enough that the chamber cannot support a circulation, the heart is functionally univentricular - the same lesion at its extreme rather than a distinct malformation.
Show evidence (1 reference)
PMID:33645542 SUPPORT DIRECT Human clinical
"These defects were characterized by severe tricuspid and/or pulmonary valve abnormalities (27 of 28), hypoplastic right ventricles (16 of 28), and/or hypoplastic pulmonary arteries (11 of 28)"
Cohort counts for both lesions this node covers.
Myocardial Dysfunction
Cardiomyopathy in PLD1 disease is recorded in two forms that must be kept apart. The delineating cohort associated recessive PLD1 variants with isolated neonatal cardiomyopathy - that is, cardiomyopathy without an accompanying structural valve defect - which is why this node is not drawn as a consequence of the valve lesion. Separately, dilated cardiomyopathy with left ventricular enlargement has been reported in older patients who also carry the valve disease, where a contribution from chronic valvular loading cannot be separated from a primary myocardial effect. Conforms to the primary-insult node of cardiomyopathy_maladaptive_remodeling. The module's generic node lists sarcomere organization alongside muscle contraction; PLD1 is not a sarcomere protein and no source implicates sarcomere assembly here, so only the contraction process is substituted. The module's downstream neurohormonal and remodelling chain is deliberately not reproduced: no source establishes it in PLD1 disease, and conforming further down would assert a cascade this entry cannot cite.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
muscle contraction GO:0006936 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased muscle contraction (GO:0006936). GO:0006936 is a biological process from the Gene Ontology.
Downstream
Fetal Cardiac Decompensation Where the myocardial disease presents in utero it decompensates into hydrops.
Cardiomyopathy
Dilated cardiomyopathy
Left ventricular dilatation
Mitral regurgitation The intermediate is ventricular dilation, which dilates the mitral annulus and produces functional regurgitation; the two are reported together.
Show evidence (2 references)
PMID:33645542 SUPPORT DIRECT Human clinical
"We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy."
The claim that the cardiomyopathy occurs in isolation, which is what makes it a parallel consequence of the gene defect rather than a sequela of the valve lesion.
PMID:42591229 SUPPORT DIRECT Human clinical
"PLD1 gene variants are postnatally associated with pulmonary stenosis, valvular regurgitation, left ventricular dilation and right ventricular hypoplasia."
Independent report placing left ventricular dilation in the postnatal PLD1 phenotype.
Fetal Cardiac Decompensation
The severe end of the spectrum presents before birth. Hydrops fetalis occurs secondary to cardiac failure, and intrauterine death and termination for a complex defect with poor prognosis are both documented, including recurrently within one family. The liveborn phenotype is therefore a survivorship-filtered view of the disorder. Intrauterine death is recorded in this node and its evidence rather than as a phenotype: HPO files Stillbirth (HP:0003826) under Clinical modifier and Mortality/Aging, not under Phenotypic abnormality, so it sits outside the PhenotypeTerm enum and cannot be bound in the phenotypes section.
Downstream
Hydrops fetalis
Show evidence (3 references)
PMID:33645542 SUPPORT DIRECT Human clinical
"A fetal ultrasound revealed hydrops fetalis due to severe cardiomyopathy, and an emergency delivery by caesarean section was performed."
Documents hydrops arising from the cardiac disease in an affected fetus.
PMID:37770978 SUPPORT DIRECT Human clinical
"intrauterine fetal death was confirmed at 14 weeks and 3 days of gestation"
Documents intrauterine death, which this node's description asserts and which neither of the other two items supports.
PMID:33645542 SUPPORT DIRECT Human clinical
"Six pregnancies were terminated because of a complex heart defect with poor prognosis"
The ascertainment loss behind reading the liveborn cohort as survivorship-filtered.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for PLD1-Related Congenital Heart Disease Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

17
Cardiovascular 16
Abnormal tricuspid valve morphology VERY_FREQUENT HP:0001702 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal tricuspid valve morphology (HP:0001702). HP:0001702 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33645542 SUPPORT DIRECT Human clinical
"These defects were characterized by severe tricuspid and/or pulmonary valve abnormalities (27 of 28), hypoplastic right ventricles (16 of 28), and/or hypoplastic pulmonary arteries (11 of 28)"
27 of 28 is 96%, which is VERY_FREQUENT. The count is for tricuspid and/or pulmonary valve abnormality as a combined category, so it is the same figure on both phenotypes rather than a tricuspid-specific one.
Abnormal pulmonary valve morphology VERY_FREQUENT HP:0001641 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal pulmonary valve morphology (HP:0001641). HP:0001641 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33645542 SUPPORT DIRECT Human clinical
"These defects were characterized by severe tricuspid and/or pulmonary valve abnormalities (27 of 28), hypoplastic right ventricles (16 of 28), and/or hypoplastic pulmonary arteries (11 of 28)"
The same combined 27 of 28 count; see the note on the tricuspid phenotype.
Ebstein anomaly of the tricuspid valve OCCASIONAL HP:0010316 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ebstein anomaly of the tricuspid valve (HP:0010316). HP:0010316 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33645542 SUPPORT DIRECT Human clinical
"Five of these 28 patients were diagnosed with Ebstein’s anomaly."
5 of 28 is 18%, which falls in the OCCASIONAL band.
Hypoplastic right ventricle FREQUENT HP:0010954 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplastic right ventricle (HP:0010954). HP:0010954 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33645542 SUPPORT DIRECT Human clinical
"These defects were characterized by severe tricuspid and/or pulmonary valve abnormalities (27 of 28), hypoplastic right ventricles (16 of 28), and/or hypoplastic pulmonary arteries (11 of 28)"
16 of 28 is 57%, which falls in the FREQUENT band.
Pulmonary artery hypoplasia FREQUENT HP:0004971 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary artery hypoplasia (HP:0004971). HP:0004971 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33645542 SUPPORT DIRECT Human clinical
"These defects were characterized by severe tricuspid and/or pulmonary valve abnormalities (27 of 28), hypoplastic right ventricles (16 of 28), and/or hypoplastic pulmonary arteries (11 of 28)"
11 of 28 is 39%, which falls in the FREQUENT band.
Pulmonary valve atresia HP:0010882 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary valve atresia (HP:0010882). HP:0010882 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33645542 SUPPORT DIRECT Human clinical
"This child also had pulmonary atresia."
Documents pulmonary atresia in a patient of the delineating cohort.
PMID:37770978 SUPPORT DIRECT Human clinical
"The second pregnancy was diagnosed as pulmonary atresia with intact ventricular septum with cardiomegaly"
Independent prenatal documentation of pulmonary atresia in a PLD1 family.
Tricuspid atresia HP:0011662 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tricuspid atresia (HP:0011662). HP:0011662 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42591229 SUPPORT DIRECT Human clinical
"Newborn: severe cyanosis, tricuspid/pulmonary atresia, single left ventricle, small pulmonary arteries, no extracardiac symptoms"
Tricuspid atresia in a named PLD1 patient. The delineating cohort's only mention of tricuspid atresia is its screening inclusion criterion, which attributes the lesion to no patient, so it is not cited here.
Tricuspid regurgitation HP:0005180 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tricuspid regurgitation (HP:0005180). HP:0005180 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37770978 SUPPORT DIRECT Human clinical
"fetal ultrasonography at 11 weeks and 5 days of gestation showed mild fetal hydrops and moderate tricuspid valve regurgitation"
Prenatal documentation of tricuspid regurgitation in a PLD1-affected fetus.
Dilated cardiomyopathy HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42591229 SUPPORT DIRECT Human clinical
"Echocardiography showed left ventricular enlargement, decreased ventricular wall motion amplitude, and mild tricuspid regurgitation."
Echocardiographic documentation of a dilated, hypokinetic left ventricle in a PLD1 patient. This is the direct support for the dilated form specifically.
PMID:33645542 SUPPORT INDIRECT Human clinical
"We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy."
Graded INDIRECT because the cohort says cardiomyopathy, not dilated cardiomyopathy: its two cases were severe left ventricular systolic dysfunction with mitral regurgitation, and a presentation read as histiocytoid cardiomyopathy, neither characterised as dilated. The undifferentiated presentation is carried by the separate Cardiomyopathy phenotype.
Left ventricular dilatation HP:4000141 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular dilatation (HP:4000141). HP:4000141 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42591229 SUPPORT DIRECT Human clinical
"PLD1 gene variants are postnatally associated with pulmonary stenosis, valvular regurgitation, left ventricular dilation and right ventricular hypoplasia."
Places left ventricular dilation in the postnatal phenotype of PLD1 variants.
Mitral regurgitation OCCASIONAL HP:0001653 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mitral regurgitation (HP:0001653). HP:0001653 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33645542 SUPPORT DIRECT Human clinical
"Two patients had dilated left ventricles and mitral regurgitation in addition to tricuspid and/or pulmonary valve defects."
Documents the minority with left-sided involvement alongside the right-sided lesion.
Pulmonic stenosis HP:0001642 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonic stenosis (HP:0001642). HP:0001642 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42591229 SUPPORT DIRECT Human clinical
"PLD1 gene variants are postnatally associated with pulmonary stenosis, valvular regurgitation, left ventricular dilation and right ventricular hypoplasia."
Names pulmonary stenosis as a postnatal feature of PLD1 variants.
Cardiomyopathy HP:0001638 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiomyopathy (HP:0001638). HP:0001638 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33645542 SUPPORT DIRECT Human clinical
"We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy."
The undifferentiated isolated cardiomyopathy this phenotype carries, which the dilated-cardiomyopathy term would overstate.
Ventricular septal defect HP:0001629 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular septal defect (HP:0001629). HP:0001629 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:42591229 SUPPORT DIRECT Human clinical
"Newborn: severe pulmonary stenosis, moderate RV hypoplasia, 3 medium VSDs, large ASD, no extracardiac symptoms"
Documents ventricular septal defects in a reported PLD1 patient.
PMID:39553471 SUPPORT INDIRECT BACKGROUND Other
"Additionally, these individuals exhibit structural cardiac anomalies such as atrial and ventricular septal defects, a single left ventricle, and a hypoplastic right ventricle"
Places septal defects in the PLD1 phenotype. BACKGROUND because the phrase sits in this report's introduction rather than in its own case description.
Atrial septal defect HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal defect (HP:0001631). HP:0001631 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42591229 SUPPORT DIRECT Human clinical
"Newborn: severe pulmonary stenosis, moderate RV hypoplasia, 3 medium VSDs, large ASD, no extracardiac symptoms"
Documents an atrial septal defect in a reported PLD1 patient.
Single ventricle HP:0001750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Single ventricle (HP:0001750). HP:0001750 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37770978 SUPPORT DIRECT Human clinical
"At 16 weeks and 5 days of gestation, the fetus was suspected to have a left ventricular-type single ventricle, trace right ventricle, pulmonary atresia with intact ventricular septum, or cardiomyopathy."
Documents univentricular physiology, with the vestigial right ventricle beside it, in an affected fetus.
PMID:42591229 SUPPORT DIRECT Human clinical
"Newborn: severe cyanosis, tricuspid/pulmonary atresia, single left ventricle, small pulmonary arteries, no extracardiac symptoms"
Independent documentation in a liveborn patient, in the same row that records this patient's tricuspid atresia.
Metabolism 1
Hydrops fetalis HP:0001789 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hydrops fetalis (HP:0001789). HP:0001789 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33645542 SUPPORT DIRECT Human clinical
"A fetal ultrasound revealed hydrops fetalis due to severe cardiomyopathy, and an emergency delivery by caesarean section was performed."
Documents hydrops attributable to the cardiac disease.
PMID:37770978 SUPPORT DIRECT Human clinical
"fetal ultrasonography at 11 weeks and 5 days of gestation showed mild fetal hydrops and moderate tricuspid valve regurgitation"
Independent prenatal documentation of hydrops in a PLD1 family.
🧬

Genetic Associations

1
PLD1 (Pathogenic Variants)
Gene: PLD1 hgnc:9067 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PLD1 (hgnc:9067). hgnc:9067 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:27799408 SUPPORT DIRECT Human clinical
"The findings support a role for PLD1 in normal heart valvulogenesis."
The original report's conclusion binding PLD1 to valve development.
PMID:33645542 SUPPORT DIRECT Human clinical
"we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects"
The cohort that established the gene-disease relationship at scale.
Variants (8)
p.Ile668Phe Pathogenic
Founder missense variant in the Ashkenazi Jewish population, at an allele frequency of about 2%. In a separate 5,424-proband congenital heart disease exome study, founder variants in GDF1 and PLD1 together accounted for most of the recessive-genotype contribution among Ashkenazi Jewish probands.
Population-specific effects
Ashkenazi Jewish probands with congenital heart disease
Ashkenazi Jewish HANCESTRO:0324 Human Ancestry Ontology (HANCESTRO) Relation: this population-specific finding was reported in this population This population-specific finding was reported in Ashkenazi Jewish, annotated with Ashkenazi Jew (HANCESTRO:0324). HANCESTRO:0324 is a population from the Human Ancestry Ontology.
Group defined by: genetically inferred Differs in: allele frequency n = 410
The variant is enriched to founder frequency in this population, so recessive PLD1 genotypes account for a disproportionate share of congenital heart disease there. Recorded as GENETICALLY_INFERRED rather than self-reported because the study defines the group by principal-component analysis of its own sequence data ("410 PCA-defined Ashkenazim"), not by reported ethnicity.
Show evidence (1 reference)
PMID:40030011 SUPPORT DIRECT Human clinical
"Founder variants in GDF1 and PLD1 accounted for 74% of the contribution of RGs among 410 Ashkenazi Jewish probands."
Quantifies the population-specific contribution in a cohort assembled independently of the delineating study.
Show evidence (1 reference)
PMID:33645542 SUPPORT DIRECT Human clinical
"we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%)"
Establishes the variant's founder status and allele frequency.
p.His442Pro Pathogenic
Missense variant at a highly conserved site, one of the three alleles in the original two-family report. It produced a strong loss-of-function phenotype when modelled in the homologous yeast gene.
Show evidence (1 reference)
PMID:27799408 SUPPORT DIRECT In vitro / ex vivo
"the p.His442Pro mutation produced a strong loss of function phenotype in yeast homologous mutant strain"
Functional evidence that this allele is loss of function.
p.Thr495fs32* Pathogenic
Frameshift variant from the original two-family report.
Show evidence (1 reference)
PMID:27799408 SUPPORT DIRECT Human clinical
"Three mutations, p.His442Pro, p.Thr495fs32* and c.2882+2T>C, were identified in the PLD1 gene."
Reports the allele in patients with severe valvular malformations.
c.2882+2T>C Pathogenic
Splice donor variant from the original two-family report.
Show evidence (1 reference)
PMID:27799408 SUPPORT DIRECT Human clinical
"Three mutations, p.His442Pro, p.Thr495fs32* and c.2882+2T>C, were identified in the PLD1 gene."
Reports the allele in patients with severe valvular malformations.
c.1062-59A>G Uncertain significance
Deep intronic variant that would normally be filtered out of a diagnostic pipeline. Transcript work on the fetus and mother showed it causes a 76-bp intronic insertion and skipping of exon 11, producing a frameshift and premature stop - so a non-canonical intronic PLD1 variant can be the second hit.
Show evidence (1 reference)
PMID:39553471 SUPPORT DIRECT Human clinical
"RT-PCR and TA clone sequencing revealed a 76-bp intronic insertion and exon 11 skipping in the proband and her mother's transcripts, causing a frameshift and premature stop codon in PLD1."
Transcript-level demonstration of the splicing consequence. Recorded as UNCERTAIN_SIGNIFICANCE because the authors classified it VUS under ACMG despite this functional result.
p.Arg993Ter and p.Trp487Ter Pathogenic
Compound heterozygous nonsense variants in a fetus with generalised oedema and complex cardiac malformation, neither previously reported. One of the three publications ClinGen scored for the Definitive classification.
Show evidence (1 reference)
PMID:38171566 SUPPORT DIRECT Human clinical
"Trio-WES revealed that it has harbored compound heterozygous variants of the PLD1 gene, namely c.2977C>T (p.R993*) and c.1460G>A (p.W487*), which were respectively inherited from its father and mother."
Reports the biallelic nonsense genotype and its parental phase.
p.Ile378fs and p.Arg391Cys Pathogenic
Compound heterozygous frameshift and missense variants found by exome sequencing of a fetus in a family with recurrent fetal congenital heart defects.
Show evidence (1 reference)
PMID:36923242 SUPPORT DIRECT Human clinical
"a compound heterozygous variation in PLD1 gene consisting of c.1132dupA (p.I378fs) and c.1171C>T (p.R391C) was identified in the fetus"
Reports the biallelic genotype in a recurrent-fetal-loss family.
p.Arg158Ter Pathogenic
Homozygous nonsense variant reported in an adult with cardiac valvular dysplasia complicated by dilated cardiomyopathy.
Show evidence (1 reference)
PMID:39681445 SUPPORT DIRECT Human clinical
"并通过高通量测序鉴定出PLD1基因纯合致病变异c.472C>T（p.Arg158Ter）"
Names the homozygous nonsense allele. The quote is in Chinese because this report has no English abstract in PubMed; the snippet is the variant designation itself, which is language-independent.
💊

Medical Actions

4
Cardiac valve surgery
Action: cardiac valve procedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cardiac valve procedure (NCIT:C99546). NCIT:C99546 is a clinical intervention from the NCI Thesaurus. Ontology label: Cardiac Valve Procedure NCIT:C99546
Platform: Surgery
Surgical repair or replacement of the dysplastic right-sided valves, and staged palliation where the right ventricle is hypoplastic. Reoperation is expected: one reported patient had three open-heart operations by the age of 16.
Show evidence (2 references)
PMID:33645542 SUPPORT DIRECT Human clinical
"most commonly the placement of a Blalock-Taussig shunt and bidirectional Glenn palliation"
The staged single-ventricle palliation this description asserts, which was previously unevidenced.
PMID:42591229 SUPPORT DIRECT Human clinical
"with a history of cardiac valve disease for more than 17 years and three open-heart surgeries"
Documents the surgical burden in a patient with this disorder.
Heart failure management
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
Platform: Other
Where cardiomyopathy supervenes, standard heart-failure care applies. The management point that follows from the mechanism is that cardiomyopathy can occur in isolation, so a normal valve study does not exclude myocardial disease in a PLD1 biallelic carrier.
Show evidence (1 reference)
PMID:33645542 SUPPORT INDIRECT Human clinical
"We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy."
Graded INDIRECT: the paper establishes that isolated cardiomyopathy occurs, from which the surveillance point follows, rather than evaluating any treatment.
Heart transplantation
Action: Heart TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Heart Transplantation (NCIT:C15246). NCIT:C15246 is a clinical intervention from the NCI Thesaurus. NCIT:C15246
Platform: Surgery
Orthotopic heart transplantation for end-stage myocardial failure. Documented in the neonatal period in this disorder, which is as early as this intervention goes.
Show evidence (1 reference)
PMID:33645542 SUPPORT DIRECT Human clinical
"One patient underwent an orthotopic heart transplantation at the age of 45 days because of worsening heart function (family S)."
Documents the intervention and its timing in a patient with this disorder.
Genetic counselling and reproductive options
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: Other
Recurrence risk is 25% for a sibling, and recurrent fetal loss within one family is documented, so counselling matters disproportionately here. Preimplantation genetic testing for monogenic disorders was used by one couple after a variant of uncertain significance was resolved by transcript studies, and they had an unaffected child.
Show evidence (1 reference)
PMID:39553471 SUPPORT DIRECT Human clinical
"the couple chose pre-implantation genetic testing for monogenic disorders (PGT-M) and had a healthy child"
Documents the reproductive option taken and its outcome in a PLD1 family.
🔬

Diagnosis

4
Echocardiography
Echocardiography defines the valve lesion and the right ventricular and pulmonary arterial hypoplasia, and is also how the cardiomyopathy is identified and followed.
Echocardiography Test NCIT:C16525 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:42591229 SUPPORT DIRECT Human clinical
"Echocardiography showed left ventricular enlargement, decreased ventricular wall motion amplitude, and mild tricuspid regurgitation."
Echocardiography establishing both the valve and myocardial findings in a patient.
Fetal echocardiography and ultrasonography
Because the severe end of the spectrum presents in utero, prenatal imaging is frequently the first diagnostic step - detecting the valve lesion, tricuspid regurgitation and hydrops from the first trimester onward.
Fetal Echocardiography Test NCIT:C114079 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:37770978 SUPPORT DIRECT Human clinical
"fetal ultrasonography at 11 weeks and 5 days of gestation showed mild fetal hydrops and moderate tricuspid valve regurgitation"
Prenatal imaging making the cardiac diagnosis in an affected fetus.
Carrier screening for the Ashkenazi founder allele
Proposed, not established. The delineating cohort suggests that carriership testing for the PLD1 founder variants could be used in population-based preconception and prenatal screening among people of Ashkenazi Jewish descent, where p.Ile668Phe reaches an allele frequency of about 2%. The entry records the proposal rather than a practice: no guideline, panel inclusion or screening programme is cited, and the source itself is hedged.
Mutation Carrier Screening NCIT:C62694 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:33645542 SUPPORT INDIRECT Human clinical
"Carriership testing for these variants could potentially be used in population-based preconception and prenatal carrier screening to assess the risk of congenital heart defects among descendants of Ashkenazi Jews."
The authors' proposal. Graded INDIRECT because the sentence recommends a use ("could potentially be used") rather than reporting a screening programme or its yield.
Exome sequencing
The diagnosis is molecular. Exome sequencing identified the gene in the original families and remains how biallelic PLD1 genotypes are found; note that a pathogenic second allele may be deep intronic and so missed by a pipeline that filters non-canonical splice variants, which in one family required transcript studies to resolve.
Whole Exome Sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:27799408 SUPPORT DIRECT Human clinical
"Whole-exome analysis was used to identify the mutations in five patients who suffered from severe valvular malformations involving the pulmonic, tricuspid and mitral valves."
The method that identified the causal gene.
📈

Progression

3
Fetal
The earliest and most severe phase. Complex malformation is detectable on first-trimester ultrasound, and the phase can end in hydrops, intrauterine death, or termination for poor prognosis - documented recurrently within single families. Patients who reach birth are a survivorship-filtered subset.
Show evidence (1 reference)
PMID:37770978 SUPPORT DIRECT Human clinical
"intrauterine fetal death was confirmed at 14 weeks and 3 days of gestation"
Documents the fetal-loss outcome that defines this phase.
Neonatal
Cyanosis and heart failure from the structural lesion, or isolated cardiomyopathy with no structural defect. This is where surgical palliation begins, and transplantation has been performed as early as 45 days of life.
Show evidence (1 reference)
PMID:33645542 SUPPORT DIRECT Human clinical
"One patient underwent an orthotopic heart transplantation at the age of 45 days because of worsening heart function (family S)."
The neonatal end-stage intervention that marks this phase.
Childhood and adult
Survivors live with repaired or palliated valve disease and accumulate reoperations; dilated cardiomyopathy may supervene years later. One reported patient had three open-heart operations and presented at 16 with left ventricular enlargement and reduced wall motion after 17 years of valve disease.
Show evidence (1 reference)
PMID:42591229 SUPPORT DIRECT Human clinical
"with a history of cardiac valve disease for more than 17 years and three open-heart surgeries"
The long-term reoperation course that defines this phase.
📊

Prevalence

1
Ashkenazi Jewish population
Prevalence at birth 40.0 per 100,000 live births 1–9 per 10,000 (births)
Predicted, not observed. The figure is the homozygote frequency the authors derive from the p.Ile668Phe allele frequency of 2.1% in 410 PCA-defined Ashkenazim - 1 in 2,500, which is 40 per 100,000. Two caveats follow from how it was obtained. It is a Hardy-Weinberg projection from an allele frequency measured in a congenital heart disease cohort rather than a count of patients in the population, and it covers only homozygotes for this one founder allele, so it omits compound heterozygotes carrying it with a second rare variant. Against that, fetal loss and termination are documented for this disorder, so the number of liveborn affected individuals would be lower than the genotype frequency predicts.
Show evidence (2 references)
PMID:40030011 SUPPORT DIRECT Human clinical
"Among 410 PCA-defined Ashkenazim in our cohort, the overall allele frequency of p.Ile668Phe was 2.1%, predicting a homozygote frequency of 1 in 2,500."
The allele frequency and the derived homozygote frequency this record normalizes.
PMID:33645542 SUPPORT DIRECT Human clinical
"this variant is estimated to occur homozygously in up to approximately 1 of 2500 births among Ashkenazi Jews"
The same figure reached independently from a population allele frequency rather than from an ascertained cohort, which is what keeps the estimate from resting only on case-cohort sampling.
🐁

Animal Models

2
Pld1 knockout mouse
Constitutive PLD1 knockout mice were examined by echocardiography and histology. They reproduce the right-sided valve lesion - tricuspid regurgitation with right atrial enlargement, and a narrowed pulmonic valve with thickened leaflets - which is the human phenotype's defining topography.
Species
Mouse
Genotype
PLD1 knockout
Publication
PMID:27799408
Pathograph links
Right-Sided Valve Dysplasia partially recapitulates fidelity: low observes: tissue The knockout reproduces the right-sided distribution and, at histology, thickened and narrowed pulmonic leaflets - but the two sources disagree on whether it reproduces a structural malformation at all, which is why this is partial recapitulation rather than recapitulation.
Limitations: The delineating cohort states that no overt structural cardiac defects were noted in these mice, only impaired valve function on echocardiography, and calls the human-versus-mouse difference in severity unexplained. The original report's histology does describe narrowed, thickened pulmonic leaflets, so the structural claim is contested rather than absent. Either way the mice show nothing like the atresia, Ebstein's anomaly, right ventricular hypoplasia or fetal loss that dominate the patient series, and a complete null does not model the hypomorphic missense alleles most patients carry.
Divergences from the human mechanism
boundary omission qualifying
The node is a structural valve malformation, and that lesion is outside what the model produces. What the mice reliably show is impaired pulmonary and tricuspid valve function on echocardiography, with the delineating cohort reporting no overt structural defect; the severe structural lesions that define the human disease are absent.
species mismatch qualifying
The mouse-versus-human difference in severity is explicitly unexplained in the literature, so the gap is not a known quantitative offset that can be corrected for when reading the model.
Readouts
Tricuspid regurgitation and pulmonic valve leaflet thickening on echocardiography
Direction: INCREASED
Interpretation: Structural and functional correlate of the human right-sided valve lesion.
Show evidence (1 reference)
PMID:27799408 SUPPORT DIRECT Model organism
"In hearts of PLD1 knockout mice, we detected marked tricuspid regurgitation, right atrial enlargement, and increased flow velocity, narrowing and thickened leaflets of the pulmonic valve."
The echocardiographic and histological measurements behind this readout.
Show evidence (2 references)
PMID:27799408 SUPPORT DIRECT Model organism
"In hearts of PLD1 knockout mice, we detected marked tricuspid regurgitation, right atrial enlargement, and increased flow velocity, narrowing and thickened leaflets of the pulmonic valve."
Supports treating the knockout as informative for the human valve lesion.
+ 1 more reference
Show evidence (1 reference)
PMID:27799408 SUPPORT DIRECT Model organism
"echocardiography and histological examination of hearts of PLD1 knockout mice"
Establishes that this model exists and names how it was characterised.
Chick embryo PLD1 expression
In situ hybridisation in the chick embryo localised PLD1 expression to the forming heart from E2 to E8, initially throughout the heart and later narrowing to the atrioventricular valves and the right ventricular outflow tract. This is an expression-mapping model, not a disease model: it supplies the spatial argument for where the defect acts, and does not itself produce a phenotype.
Species
Chicken
Genotype
Wild type
Publication
PMID:27799408
Pathograph links
Deficient Endocardial Cushion Remodelling measures fidelity: unknown observes: tissue Maps where the gene is expressed during valvulogenesis, which is the structures that are malformed in patients.
Limitations: Expression is not function - the model shows where PLD1 is transcribed, not that cushion remodelling fails without it. It is also a non-mammalian embryo, and the authors read the temporal pattern as tracking developmental apoptosis, which is a different proposed mechanism from the endothelial-to-mesenchymal transition the main chain follows.
Readouts
PLD1 transcript distribution in the developing heart
Interpretation: Localises the gene to the atrioventricular valves and right ventricular outflow tract, the sites of the human lesion.
Show evidence (1 reference)
PMID:27799408 SUPPORT DIRECT Model organism
"Here we show that in chick embryos PLD1 expression is confined to the forming heart (E2-E8) and homogeneously expressed all over the heart during days E2-E3."
The in situ hybridisation result behind this readout.
Show evidence (1 reference)
PMID:27799408 SUPPORT INDIRECT Model organism
"Thereafter its expression decreases, remaining only adjacent to the atrioventricular valves and the right ventricular outflow tract."
Supports treating this expression map as informative for where cushion remodelling fails. Graded INDIRECT because expression localisation is not a measurement of remodelling.
Show evidence (1 reference)
PMID:27799408 SUPPORT DIRECT Model organism
"Here we show that in chick embryos PLD1 expression is confined to the forming heart (E2-E8) and homogeneously expressed all over the heart during days E2-E3."
Establishes this model as a chick in-situ hybridisation study and states its basic result, that PLD1 expression in the embryo is cardiac-restricted. The readout below quotes the same sentence for the measurement itself.
{ }

Source YAML

click to show 
name: PLD1-Related Congenital Heart Disease
creation_date: "2026-10-30T00:00:00Z"
description: >-
  PLD1-related congenital heart disease is the autosomal recessive disorder caused by
  biallelic loss-of-function variants in PLD1, which encodes phospholipase D1. The
  enzyme hydrolyses phosphatidylcholine to generate phosphatidic acid, a lipid second
  messenger; the disease alleles cluster in the regions encoding the catalytic core
  and reduce that activity.

  What makes the entity recognisable is where in the heart it lands. The lesions are
  overwhelmingly right-sided - severe tricuspid and pulmonary valve dysplasia, often
  with a hypoplastic right ventricle and hypoplastic pulmonary arteries - and
  Ebstein's anomaly is a recurring diagnosis. That topography follows from the
  mechanism rather than being incidental to it: phosphatidic acid is required for
  cardiac endothelial-to-mesenchymal transition, the step that supplies the
  mesenchyme and remodelled matrix of the endocardial cushions, and pharmacological
  PLD1 inhibition reduces that transition directly. The founding report also places
  the attenuated TGF-beta and hedgehog signalling that follows loss of phosphatidic
  acid behind the arterial pole defects specifically.

  A second presentation is cardiomyopathy, and it is not simply a consequence of the
  valve lesion. The delineating cohort associated recessive PLD1 variants with
  *isolated* neonatal cardiomyopathy, and dilated cardiomyopathy has since been
  reported in older patients alongside their valve disease. The fetal end of the
  spectrum is severe: hydrops fetalis, intrauterine death, and termination for a
  complex defect with poor prognosis all occur, so the liveborn phenotype is a
  survivorship-filtered view of the disorder.

  The nomenclature is the most confusing part of this entry, and the entry is
  deliberately not named after the term it is bound to. The label of MONDO:0008913,
  `cardiac valvular defect, developmental`, describes a condition that occurs without
  PLD1 at all - the X-linked FLNA form and the ADAMTS19 form are two of the other
  genetically defined cardiac valvular dysplasias, and most developmental valve
  disease is neither - so as an entry name it would be broader than the entry.
  Worse, it does not cover this disorder's isolated-cardiomyopathy arm, which the
  delineating cohort reports with no structural valve defect at all. The name used
  here is ClinGen's, which is also the label of MONDO:1010144: ClinGen curates this
  gene-disease relationship as PLD1-related congenital heart disease, and states that
  it lumped cardiac valvular dysplasia 1 and congenital heart disease into a single
  entity after finding no difference in mechanism, inheritance or phenotypic
  variability - which is why MONDO:1010144 is mapped here as an exact match rather
  than as a separate concept. The clinical and genetics literature mostly calls this
  cardiac valvular dysplasia 1 (CVDD1 or CVDP1); that name and the MONDO label are
  both kept in `synonyms`. The file name still follows the MONDO label, because
  dismech has not settled how a slug follows a rename (dismech#15894).
category: Mendelian
synonyms:
- cardiac valvular defect, developmental
- CVDD
- CVDD1
- CVDP1
- cardiac valvular dysplasia 1
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0008913
      label: cardiac valvular defect, developmental
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary disease term for this entry.
  - term:
      id: MONDO:1010144
      label: PLD1-related congenital heart disease
    mapping_predicate: skos:exactMatch
    mapping_source: ClinGen
    mapping_justification: >-
      MONDO files the gene-centric ClinGen concept separately from the OMIM-derived
      MONDO:0008913, and neither is an ancestor of the other. They denote one entity:
      ClinGen's own Congenital Heart Disease GCEP record states that it lumped
      cardiac valvular dysplasia 1 and congenital heart disease into a single disease
      entity for PLD1 after finding no difference in molecular mechanism, inheritance
      pattern or phenotypic variability. The exact match is that published lumping
      decision, not an inference from the two labels. Note what MONDO's own placement
      does not cover: MONDO:0008913 sits under `cardiac valvular defect`, so the
      isolated neonatal cardiomyopathy arm - which this entry curates, and which the
      delineating cohort reports in the absence of any structural valve defect - falls
      inside MONDO:1010144 but arguably outside MONDO:0008913's parent. On MONDO's own
      axes 1010144 is therefore the broader class, and the exact match asserts a merge
      MONDO has not itself made.
disease_term:
  preferred_term: cardiac valvular defect, developmental
  term:
    id: MONDO:0008913
    label: cardiac valvular defect, developmental
notes: >-
  No GeneReviews chapter names this disease. `just check-genereviews --online` over
  this entry's name, its five synonyms and its disease_term returns NO_CHAPTER
  against the committed Bookshelf index (snapshot 2026-09-10, 958 chapters) and
  against a live PubMed `genereviews[book]` title search, so the mandatory phenotype
  baseline is unavailable and the cohort reports are the baseline instead. The
  phenotype frequencies here are therefore the delineating cohort's own counts rather
  than an expert-curated summary. The denominator is 28: the patients with a structural
  valve malformation, out of 30 biallelic patients in total, the other two having
  isolated cardiomyopathy. The bands are unchanged on either denominator.

  No dataset in GEO is about this disease. The only PLD1 series indexed there are
  oncology: geo:GSE166004 (PLD1 and MMP-13 in bladder cancer, mouse), geo:GSE55724 and
  geo:GSE55771 (PLD1-E2F1 and a PLD1 inhibitor in colon cancer lines). None involves
  cardiac tissue or valve development, so none is admissible here despite resolving
  cleanly against a search on the causal gene.
prevalence:
- population: Ashkenazi Jewish population
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 40.0
  rate_denominator: LIVE_BIRTHS
  notes: >-
    Predicted, not observed. The figure is the homozygote frequency the authors derive
    from the p.Ile668Phe allele frequency of 2.1% in 410 PCA-defined Ashkenazim - 1 in
    2,500, which is 40 per 100,000. Two caveats follow from how it was obtained. It is
    a Hardy-Weinberg projection from an allele frequency measured in a congenital heart
    disease cohort rather than a count of patients in the population, and it covers
    only homozygotes for this one founder allele, so it omits compound heterozygotes
    carrying it with a second rare variant. Against that, fetal loss and termination
    are documented for this disorder, so the number of liveborn affected individuals
    would be lower than the genotype frequency predicts.
  evidence:
  - reference: PMID:40030011
    reference_title: Recessive genetic contribution to congenital heart disease in 5,424 probands.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among 410 PCA-defined Ashkenazim in our cohort, the overall allele frequency of p.Ile668Phe was 2.1%, predicting a homozygote frequency of 1 in 2,500."
    explanation: The allele frequency and the derived homozygote frequency this record normalizes.
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "this variant is estimated to occur homozygously in up to approximately 1 of 2500 births among Ashkenazi Jews"
    explanation: >-
      The same figure reached independently from a population allele frequency rather
      than from an ascertained cohort, which is what keeps the estimate from resting
      only on case-cohort sampling.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic PLD1 genotypes - homozygous and compound heterozygous - across 21
    unrelated families of different ancestries, with heterozygous parents unaffected.
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects"
    explanation: Biallelic genotypes across 21 unrelated families establish recessive inheritance.
  - reference: CGGV:assertion_d37e1c81-cb59-45db-9481-338149fa5064-2024-12-02T170000.000Z
    reference_title: PLD1 / PLD1-related congenital heart disease (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PLD1 | HGNC:9067 | PLD1-related congenital heart disease | MONDO:1010144 | AR | Definitive | SOP11 | Congenital Heart Disease Gene Curation Expert Panel"
    explanation: ClinGen records the inheritance pattern as autosomal recessive in its Definitive validity assertion.
pathophysiology:
- name: PLD1 Biallelic Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Homozygous or compound heterozygous PLD1 variants - missense, nonsense, frameshift
    and splice - reduce phospholipase D1 activity. The missense alleles are
    concentrated in the regions encoding the catalytic core, and most of the mutant
    proteins show strongly reduced activity in a direct enzymatic assay, so this is a
    loss of catalytic function rather than a dominant-negative or gain-of-function
    mechanism.
  genes:
  - preferred_term: PLD1
    term:
      id: hgnc:9067
      label: PLD1
  molecular_functions:
  - preferred_term: phospholipase D1 catalytic activity
    term:
      id: GO:0004630
      label: D-type glycerophospholipase activity
    modifier: LOSS_OF_FUNCTION
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Depleted Phosphatidic Acid Signalling
    causal_link_type: DIRECT
    description: >-
      Phospholipase D1 is the enzyme that makes phosphatidic acid from
      phosphatidylcholine, so losing its catalytic activity removes the second
      messenger directly.
    evidence:
    - reference: PMID:33645542
      reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Recessive variants in PLD1, which encodes phospholipase D1, a signal transduction enzyme that hydrolyses the membrane lipid phosphatidylcholine to generate the lipid second messenger phosphatidic acid"
      explanation: States the enzymatic step this edge asserts, and that the disease variants are recessive variants in that enzyme.
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay."
    explanation: Direct enzymatic evidence that the disease alleles reduce catalytic activity.
  - reference: PMID:27799408
    reference_title: Congenital valvular defects associated with deleterious mutations in the PLD1 gene.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "the p.His442Pro mutation produced a strong loss of function phenotype in yeast homologous mutant strain"
    explanation: Independent loss-of-function evidence for a disease allele in a heterologous assay.
  - reference: PMID:32198492
    reference_title: "Crystal structure of human PLD1 provides insight into activation by PI(4,5)P(2) and RhoA."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: "The C terminus folds into and contributes part of the catalytic pocket, which harbors a phosphohistidine that mimics an intermediate stage of the catalytic cycle."
    explanation: >-
      Structural account of the catalytic pocket, which is why missense alleles
      clustered in the regions encoding it abolish activity. Graded INDIRECT because
      the structure is of wild-type PLD1 and says nothing about the disease variants
      directly - it supplies the reason their position matters.
- name: Depleted Phosphatidic Acid Signalling
  biological_scale: MOLECULAR
  description: >-
    Loss of phospholipase D1 activity depletes phosphatidic acid, the lipid second
    messenger the enzyme generates. Phosphatidic acid is the node through which the
    defect reaches morphogenetic signalling, and the founding cohort reads the
    downstream arterial pole defects as a consequence of reduced TGF-beta and
    hedgehog signalling.
  biological_processes:
  - preferred_term: phosphatidic acid biosynthetic process
    term:
      id: GO:0006654
      label: phosphatidic acid biosynthetic process
    modifier: DECREASED
  downstream:
  - target: Attenuated TGF-beta and Hedgehog Signalling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - pld1_tgfb_shh_route
    evidence:
    - reference: PMID:33645542
      reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: "Thus, a reduction in TGF-β and SSh signaling resulting from loss-of-function PLD1 variants might underlie the arterial pole defects seen in affected patients."
      explanation: >-
        The authors' own proposal for the signalling consequence of the
        loss-of-function variants. Nothing about TGF-beta or hedgehog was measured in
        this study, in patients or otherwise - the paragraph is assembled from other
        papers and hedged throughout ("could", "suggesting", "may", "might") - so the
        item is graded OTHER with quote_role BACKGROUND rather than HUMAN_CLINICAL,
        which would assert a human cohort measured it.
  - target: Myocardial Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The same enzymatic loss produces cardiomyopathy without a structural valve
      defect in some patients. How one lesion yields either outcome is explicitly
      unresolved, so the intermediates are recorded as unknown rather than guessed.
    evidence:
    - reference: PMID:33645542
      reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "The mechanism underlying this pleotropic effect of PLD1 loss of function, resulting in either valvular heart defects or isolated cardiomyopathy, is currently unknown."
      explanation: >-
        States that the myocardial outcome is a consequence of PLD1 loss of function
        and that the route is unknown - which is exactly what this edge claims and
        why its intermediates are typed unknown.
  - target: Impaired Cardiac Endothelial-to-Mesenchymal Transition
    causal_link_type: DIRECT
    description: >-
      Pharmacological PLD1 inhibition, which removes the same enzymatic product,
      reduces endothelial-to-mesenchymal transition.
    evidence:
    - reference: PMID:33645542
      reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: "Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis."
      explanation: The experiment that connects loss of PLD1 activity to the cellular transition this edge targets.
    - reference: PMID:33645542
      reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: "Similarly, siRNA constructs targeting chick PLD1 significantly decreased the number of transformed cells compared with a scrambled control"
      explanation: >-
        The genetic arm of the same experiment, in chick atrioventricular cushion
        explants. It matters independently of the pharmacological arm: knocking the
        transcript down reproduces the effect of the small-molecule inhibitors, so the
        result is not an off-target property of those compounds.
- name: Attenuated TGF-beta and Hedgehog Signalling
  biological_scale: MOLECULAR
  description: >-
    Reduced TGF-beta and sonic hedgehog signalling downstream of phosphatidic acid
    depletion. The founding cohort invokes this specifically for the arterial pole
    defects, noting that inhibiting hedgehog signalling at the corresponding
    developmental stage produces pulmonary atresia.
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: DECREASED
  - preferred_term: smoothened signaling pathway
    term:
      id: GO:0007224
      label: smoothened signaling pathway
    modifier: DECREASED
  downstream:
  - target: Impaired Cardiac Endothelial-to-Mesenchymal Transition
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - pld1_tgfb_shh_route
    evidence:
    - reference: PMID:33645542
      reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: "In the developing heart, TGF-β signaling is crucial for the EndoMT that generates the mesenchyme of the cardiac cushions essential for valve formation"
      explanation: >-
        The TGF-beta dependence of cushion EndoMT, which is the intermediate step this
        edge runs through. BACKGROUND because it is established developmental biology
        the paper restates, not its own finding.
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Inhibition of Shh signaling at this developmental stage leads to pulmonary atresia."
    explanation: >-
      The developmental-biology premise the cohort borrows to connect reduced hedgehog
      signalling to the arterial pole lesions. It is a background statement about
      other work, not a measurement in this study or in these patients.
- name: Impaired Cardiac Endothelial-to-Mesenchymal Transition
  biological_scale: CELLULAR
  description: >-
    Endocardial cells fail to undergo the endothelial-to-mesenchymal transition that
    populates the endocardial cushions. This is the step PLD1 inhibition was shown to
    reduce, and it is the point at which a lipid signalling defect becomes a
    morphogenetic one.
  cell_types:
  - preferred_term: endocardial cell
    term:
      id: CL:0002350
      label: endocardial cell
  - preferred_term: endocardial cushion cell
    term:
      id: CL:0008022
      label: endocardial cushion cell
  biological_processes:
  - preferred_term: cardiac endothelial to mesenchymal transition
    term:
      id: GO:0140074
      label: cardiac endothelial to mesenchymal transition
    modifier: DECREASED
  downstream:
  - target: Deficient Endocardial Cushion Remodelling
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33645542
      reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      quote_role: BACKGROUND
      snippet: "In the endocardial cushions, EndoMT provides the mesenchymal cells and remodeled matrix essential for the formation of both left and right heart structures"
      explanation: >-
        States the dependency this edge asserts - cushion mesenchyme and matrix are
        supplied by the transition, so losing it starves cushion remodelling.
    - reference: PMID:42600378
      reference_title: "The regulation of endothelial-to-mesenchymal transition in endocardial cushion development: Signaling pathways and transcription factors."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "The development and maturation of the endocardial cushion rely on endothelial-to-mesenchymal transition (EndMT), a process by which endocardial cells undergo morphological remodeling and develop into the endocardial cushion mesenchyme."
      explanation: >-
        Independent statement of the dependency, from the developmental-biology
        literature rather than from the PLD1 cohort that proposed it.
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: "Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis."
    explanation: Experimental demonstration that losing PLD1 activity reduces this transition.
- name: Deficient Endocardial Cushion Remodelling
  biological_scale: TISSUE
  description: >-
    Without sufficient cushion mesenchyme and remodelled matrix, the inflow cushions
    that become the tricuspid and mitral valves and the outflow cushions that become
    the arterial valves fail to form normal leaflets. PLD1 expression in the
    developing chick heart narrows to exactly these sites - adjacent to the
    atrioventricular valves and the right ventricular outflow tract - as development
    proceeds.
  cell_types:
  - preferred_term: mesenchymal cell
    term:
      id: CL:0008019
      label: mesenchymal cell
  biological_processes:
  - preferred_term: endocardial cushion morphogenesis
    term:
      id: GO:0003203
      label: endocardial cushion morphogenesis
    modifier: DECREASED
  - preferred_term: heart valve morphogenesis
    term:
      id: GO:0003179
      label: heart valve morphogenesis
    modifier: DECREASED
  downstream:
  - target: Right-Sided Valve Dysplasia
    causal_link_type: DIRECT
  - target: Right Ventricular and Pulmonary Arterial Hypoplasia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Downstream chamber and great-artery hypoplasia follows the obstructed or
      dysplastic right-sided valve rather than being a separate primary defect.
  - target: Ventricular septal defect
    causal_link_type: DIRECT
    description: >-
      The same cushions that become the valve leaflets also build the septa, so
      septation defects are the other arm of the same failure rather than an
      incidental association.
    evidence:
    - reference: PMID:42600378
      reference_title: "The regulation of endothelial-to-mesenchymal transition in endocardial cushion development: Signaling pathways and transcription factors."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Improper morphogenesis of the endocardial cushion leads to septal and valvular abnormalities, which contribute to the largest proportion of congenital heart diseases (CHDs)."
      explanation: >-
        Names septal abnormalities, alongside valvular ones, as the consequence of
        failed cushion morphogenesis - which is this edge.
  - target: Atrial septal defect
    causal_link_type: DIRECT
    description: >-
      The atrial arm of the same septation failure; the inflow cushions contribute to
      the atrioventricular septum.
  evidence:
  - reference: PMID:42600378
    reference_title: "The regulation of endothelial-to-mesenchymal transition in endocardial cushion development: Signaling pathways and transcription factors."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Improper morphogenesis of the endocardial cushion leads to septal and valvular abnormalities, which contribute to the largest proportion of congenital heart diseases (CHDs)."
    explanation: >-
      Establishes that failed cushion morphogenesis is a route to valvular congenital
      heart disease generally, which is the step this node occupies.
  - reference: PMID:27799408
    reference_title: Congenital valvular defects associated with deleterious mutations in the PLD1 gene.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Thereafter its expression decreases, remaining only adjacent to the atrioventricular valves and the right ventricular outflow tract."
    explanation: >-
      The chick expression pattern localises PLD1 to the structures that are
      malformed, which is the spatial argument that this is where the defect acts.
- name: Right-Sided Valve Dysplasia
  biological_scale: TISSUE
  description: >-
    Dysplastic, thickened or atretic tricuspid and pulmonary valves, with the
    tricuspid lesion frequently taking the form of Ebstein's anomaly. The mitral valve
    is involved in a minority. This right-sided predominance is the defining feature
    of the entity and distinguishes it from the other genetically defined cardiac
    valvular dysplasias.
  downstream:
  - target: Abnormal tricuspid valve morphology
    causal_link_type: DIRECT
  - target: Abnormal pulmonary valve morphology
    causal_link_type: DIRECT
  - target: Ebstein anomaly of the tricuspid valve
    causal_link_type: DIRECT
  - target: Pulmonary valve atresia
    causal_link_type: DIRECT
  - target: Tricuspid atresia
    causal_link_type: DIRECT
  - target: Tricuspid regurgitation
    causal_link_type: DIRECT
  - target: Pulmonic stenosis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:39553471
    reference_title: Prenatal detection of novel compound heterozygous variants of the PLD1 gene in a fetus with congenital heart disease.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Patients with autosomal-recessive variants of PLD1 are predisposed to Cardiac Valvular Dysplasia-1 (CVDP1), which predominantly affects the right-sided heart valves, including the pulmonic, tricuspid, and mitral valves."
    explanation: >-
      States the right-sided predominance this node asserts. BACKGROUND and OTHER
      because the sentence is this case report's introduction summarising five prior
      studies, not its own result. Note it lists the mitral valve among the
      "right-sided" valves, which is loose; the mitral minority is carried by the
      two-patient count on the Mitral regurgitation phenotype instead.
- name: Right Ventricular and Pulmonary Arterial Hypoplasia
  biological_scale: TISSUE
  description: >-
    Hypoplastic right ventricle and hypoplastic pulmonary arteries, present in roughly
    half and over a third of phenotyped patients respectively. In the most severe
    hearts the right ventricular wall is extremely thin.
  downstream:
  - target: Hypoplastic right ventricle
    causal_link_type: DIRECT
  - target: Pulmonary artery hypoplasia
    causal_link_type: DIRECT
  - target: Single ventricle
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Where right ventricular hypoplasia is severe enough that the chamber cannot
      support a circulation, the heart is functionally univentricular - the same lesion
      at its extreme rather than a distinct malformation.
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "These defects were characterized by severe tricuspid and/or pulmonary valve abnormalities (27 of 28), hypoplastic right ventricles (16 of 28), and/or hypoplastic pulmonary arteries (11 of 28)"
    explanation: Cohort counts for both lesions this node covers.
- name: Myocardial Dysfunction
  biological_scale: TISSUE
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    Cardiomyopathy in PLD1 disease is recorded in two forms that must be kept apart.
    The delineating cohort associated recessive PLD1 variants with isolated neonatal
    cardiomyopathy - that is, cardiomyopathy without an accompanying structural valve
    defect - which is why this node is not drawn as a consequence of the valve lesion.
    Separately, dilated cardiomyopathy with left ventricular enlargement has been
    reported in older patients who also carry the valve disease, where a contribution
    from chronic valvular loading cannot be separated from a primary myocardial
    effect.

    Conforms to the primary-insult node of cardiomyopathy_maladaptive_remodeling. The
    module's generic node lists sarcomere organization alongside muscle contraction;
    PLD1 is not a sarcomere protein and no source implicates sarcomere assembly here,
    so only the contraction process is substituted. The module's downstream
    neurohormonal and remodelling chain is deliberately not reproduced: no source
    establishes it in PLD1 disease, and conforming further down would assert a cascade
    this entry cannot cite.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: muscle contraction
    term:
      id: GO:0006936
      label: muscle contraction
    modifier: DECREASED
  downstream:
  - target: Fetal Cardiac Decompensation
    causal_link_type: DIRECT
    description: >-
      Where the myocardial disease presents in utero it decompensates into hydrops.
    evidence:
    - reference: PMID:33645542
      reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "A fetal ultrasound revealed hydrops fetalis due to severe cardiomyopathy, and an emergency delivery by caesarean section was performed."
      explanation: Attributes the fetal hydrops to the cardiomyopathy, which is this edge.
  - target: Cardiomyopathy
    causal_link_type: DIRECT
  - target: Dilated cardiomyopathy
    causal_link_type: DIRECT
  - target: Left ventricular dilatation
    causal_link_type: DIRECT
  - target: Mitral regurgitation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The intermediate is ventricular dilation, which dilates the mitral annulus and
      produces functional regurgitation; the two are reported together.
    evidence:
    - reference: PMID:33645542
      reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Two patients had dilated left ventricles and mitral regurgitation in addition to tricuspid and/or pulmonary valve defects."
      explanation: >-
        Reports the dilation and the regurgitation in the same patients. Graded
        INDIRECT because co-occurrence is not a demonstration that the dilation caused
        the regurgitation.
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy."
    explanation: >-
      The claim that the cardiomyopathy occurs in isolation, which is what makes it a
      parallel consequence of the gene defect rather than a sequela of the valve
      lesion.
  - reference: PMID:42591229
    reference_title: "Novel compound heterozygous variants in the PLD1 gene causing cardiac valve dysplasia 1 complicated with dilated cardiomyopathy: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "PLD1 gene variants are postnatally associated with pulmonary stenosis, valvular regurgitation, left ventricular dilation and right ventricular hypoplasia."
    explanation: Independent report placing left ventricular dilation in the postnatal PLD1 phenotype.
- name: Fetal Cardiac Decompensation
  biological_scale: ORGANISM
  description: >-
    The severe end of the spectrum presents before birth. Hydrops fetalis occurs
    secondary to cardiac failure, and intrauterine death and termination for a complex
    defect with poor prognosis are both documented, including recurrently within one
    family. The liveborn phenotype is therefore a survivorship-filtered view of the
    disorder.

    Intrauterine death is recorded in this node and its evidence rather than as a
    phenotype: HPO files Stillbirth (HP:0003826) under Clinical modifier and
    Mortality/Aging, not under Phenotypic abnormality, so it sits outside the
    PhenotypeTerm enum and cannot be bound in the phenotypes section.
  downstream:
  - target: Hydrops fetalis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "A fetal ultrasound revealed hydrops fetalis due to severe cardiomyopathy, and an emergency delivery by caesarean section was performed."
    explanation: Documents hydrops arising from the cardiac disease in an affected fetus.
  - reference: PMID:37770978
    reference_title: "Triple repeated fetal congenital heart disease linked to PLD1 mutation: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "intrauterine fetal death was confirmed at 14 weeks and 3 days of gestation"
    explanation: >-
      Documents intrauterine death, which this node's description asserts and which
      neither of the other two items supports.
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Six pregnancies were terminated because of a complex heart defect with poor prognosis"
    explanation: The ascertainment loss behind reading the liveborn cohort as survivorship-filtered.
phenotypes:
- name: Abnormal tricuspid valve morphology
  category: Cardiovascular
  description: >-
    Dysplastic tricuspid valve, with thickened or displaced leaflets. Counted together
    with pulmonary valve abnormalities in the delineating cohort, where the combined
    lesion was present in 27 of 28 phenotyped patients.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal tricuspid valve morphology
    term:
      id: HP:0001702
      label: Abnormal tricuspid valve morphology
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "These defects were characterized by severe tricuspid and/or pulmonary valve abnormalities (27 of 28), hypoplastic right ventricles (16 of 28), and/or hypoplastic pulmonary arteries (11 of 28)"
    explanation: >-
      27 of 28 is 96%, which is VERY_FREQUENT. The count is for tricuspid and/or
      pulmonary valve abnormality as a combined category, so it is the same figure on
      both phenotypes rather than a tricuspid-specific one.
- name: Abnormal pulmonary valve morphology
  category: Cardiovascular
  description: >-
    Dysplastic pulmonary valve, reported as narrowing with thickened leaflets in the
    knockout mouse and as pulmonary stenosis postnatally in patients.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Abnormal pulmonary valve morphology
    term:
      id: HP:0001641
      label: Abnormal pulmonary valve morphology
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "These defects were characterized by severe tricuspid and/or pulmonary valve abnormalities (27 of 28), hypoplastic right ventricles (16 of 28), and/or hypoplastic pulmonary arteries (11 of 28)"
    explanation: The same combined 27 of 28 count; see the note on the tricuspid phenotype.
- name: Ebstein anomaly of the tricuspid valve
  category: Cardiovascular
  description: >-
    Apical displacement of the tricuspid valve leaflets, diagnosed in 5 of 28
    phenotyped patients. In one family the Ebstein lesion accompanied an extremely
    thin-walled right ventricle and tricuspid regurgitation.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Ebstein anomaly of the tricuspid valve
    term:
      id: HP:0010316
      label: Ebstein anomaly of the tricuspid valve
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five of these 28 patients were diagnosed with Ebstein’s anomaly."
    explanation: 5 of 28 is 18%, which falls in the OCCASIONAL band.
- name: Hypoplastic right ventricle
  category: Cardiovascular
  description: Hypoplastic right ventricle, present in 16 of 28 phenotyped patients.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypoplastic right ventricle
    term:
      id: HP:0010954
      label: Hypoplastic right ventricle
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "These defects were characterized by severe tricuspid and/or pulmonary valve abnormalities (27 of 28), hypoplastic right ventricles (16 of 28), and/or hypoplastic pulmonary arteries (11 of 28)"
    explanation: 16 of 28 is 57%, which falls in the FREQUENT band.
- name: Pulmonary artery hypoplasia
  category: Cardiovascular
  description: Hypoplastic pulmonary arteries, present in 11 of 28 phenotyped patients.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Pulmonary artery hypoplasia
    term:
      id: HP:0004971
      label: Pulmonary artery hypoplasia
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "These defects were characterized by severe tricuspid and/or pulmonary valve abnormalities (27 of 28), hypoplastic right ventricles (16 of 28), and/or hypoplastic pulmonary arteries (11 of 28)"
    explanation: 11 of 28 is 39%, which falls in the FREQUENT band.
- name: Pulmonary valve atresia
  category: Cardiovascular
  description: >-
    Pulmonary atresia, documented both postnatally and prenatally, including pulmonary
    atresia with intact ventricular septum in an affected fetus.
  phenotype_term:
    preferred_term: Pulmonary valve atresia
    term:
      id: HP:0010882
      label: Pulmonary valve atresia
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "This child also had pulmonary atresia."
    explanation: Documents pulmonary atresia in a patient of the delineating cohort.
  - reference: PMID:37770978
    reference_title: "Triple repeated fetal congenital heart disease linked to PLD1 mutation: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The second pregnancy was diagnosed as pulmonary atresia with intact ventricular septum with cardiomegaly"
    explanation: Independent prenatal documentation of pulmonary atresia in a PLD1 family.
- name: Tricuspid atresia
  category: Cardiovascular
  description: >-
    Tricuspid atresia or stenosis, one of the severe right-sided valvular lesions used
    to ascertain patients for PLD1 screening.
  phenotype_term:
    preferred_term: Tricuspid atresia
    term:
      id: HP:0011662
      label: Tricuspid atresia
  evidence:
  - reference: PMID:42591229
    reference_title: "Novel compound heterozygous variants in the PLD1 gene causing cardiac valve dysplasia 1 complicated with dilated cardiomyopathy: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Newborn: severe cyanosis, tricuspid/pulmonary atresia, single left ventricle, small pulmonary arteries, no extracardiac symptoms"
    explanation: >-
      Tricuspid atresia in a named PLD1 patient. The delineating cohort's only
      mention of tricuspid atresia is its screening inclusion criterion, which
      attributes the lesion to no patient, so it is not cited here.
- name: Tricuspid regurgitation
  category: Cardiovascular
  description: >-
    Tricuspid regurgitation, documented in patients, in affected fetuses, and in the
    PLD1 knockout mouse.
  phenotype_term:
    preferred_term: Tricuspid regurgitation
    term:
      id: HP:0005180
      label: Tricuspid regurgitation
  evidence:
  - reference: PMID:37770978
    reference_title: "Triple repeated fetal congenital heart disease linked to PLD1 mutation: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "fetal ultrasonography at 11 weeks and 5 days of gestation showed mild fetal hydrops and moderate tricuspid valve regurgitation"
    explanation: Prenatal documentation of tricuspid regurgitation in a PLD1-affected fetus.
- name: Dilated cardiomyopathy
  category: Cardiovascular
  description: >-
    Dilated cardiomyopathy. Reported as isolated neonatal cardiomyopathy in the
    delineating cohort, and as dilated cardiomyopathy complicating the valve disease
    in older patients, including a 16-year-old after three open-heart operations and
    an adult with a homozygous nonsense variant.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:42591229
    reference_title: "Novel compound heterozygous variants in the PLD1 gene causing cardiac valve dysplasia 1 complicated with dilated cardiomyopathy: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Echocardiography showed left ventricular enlargement, decreased ventricular wall motion amplitude, and mild tricuspid regurgitation."
    explanation: >-
      Echocardiographic documentation of a dilated, hypokinetic left ventricle in a
      PLD1 patient. This is the direct support for the dilated form specifically.
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy."
    explanation: >-
      Graded INDIRECT because the cohort says cardiomyopathy, not dilated
      cardiomyopathy: its two cases were severe left ventricular systolic dysfunction
      with mitral regurgitation, and a presentation read as histiocytoid
      cardiomyopathy, neither characterised as dilated. The undifferentiated
      presentation is carried by the separate Cardiomyopathy phenotype.
- name: Left ventricular dilatation
  category: Cardiovascular
  description: Left ventricular dilation, recorded as part of the postnatal PLD1 phenotype.
  phenotype_term:
    preferred_term: Left ventricular dilatation
    term:
      id: HP:4000141
      label: Left ventricular dilatation
  evidence:
  - reference: PMID:42591229
    reference_title: "Novel compound heterozygous variants in the PLD1 gene causing cardiac valve dysplasia 1 complicated with dilated cardiomyopathy: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "PLD1 gene variants are postnatally associated with pulmonary stenosis, valvular regurgitation, left ventricular dilation and right ventricular hypoplasia."
    explanation: Places left ventricular dilation in the postnatal phenotype of PLD1 variants.
- name: Mitral regurgitation
  category: Cardiovascular
  description: >-
    Mitral regurgitation, reported with left ventricular dilatation in two of 28
    phenotyped patients. Which mechanism produces it is unresolved, and the graph
    draws only the route its source supports: the cohort reports the regurgitation
    alongside ventricular dilation, so the edge here is functional regurgitation on a
    dilated annulus. A structural, cushion-derived component is not excluded - the
    inflow cushions build both atrioventricular valves, and the literature lists the
    mitral valve among those this disorder affects - but no source attributes this
    cohort's mitral regurgitation to a developmental valve lesion, so no edge from
    cushion remodelling is drawn.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Mitral regurgitation
    term:
      id: HP:0001653
      label: Mitral regurgitation
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients had dilated left ventricles and mitral regurgitation in addition to tricuspid and/or pulmonary valve defects."
    explanation: Documents the minority with left-sided involvement alongside the right-sided lesion.
- name: Hydrops fetalis
  category: Cardiovascular
  description: >-
    Hydrops fetalis secondary to cardiac failure, documented in affected fetuses in two
    independent families.
  phenotype_term:
    preferred_term: Hydrops fetalis
    term:
      id: HP:0001789
      label: Hydrops fetalis
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "A fetal ultrasound revealed hydrops fetalis due to severe cardiomyopathy, and an emergency delivery by caesarean section was performed."
    explanation: Documents hydrops attributable to the cardiac disease.
  - reference: PMID:37770978
    reference_title: "Triple repeated fetal congenital heart disease linked to PLD1 mutation: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "fetal ultrasonography at 11 weeks and 5 days of gestation showed mild fetal hydrops and moderate tricuspid valve regurgitation"
    explanation: Independent prenatal documentation of hydrops in a PLD1 family.
- name: Pulmonic stenosis
  category: Cardiovascular
  description: >-
    Pulmonary valve stenosis, named first among the postnatal associations of PLD1
    variants and reported in the original two-family series.
  phenotype_term:
    preferred_term: Pulmonic stenosis
    term:
      id: HP:0001642
      label: Pulmonic stenosis
  evidence:
  - reference: PMID:42591229
    reference_title: "Novel compound heterozygous variants in the PLD1 gene causing cardiac valve dysplasia 1 complicated with dilated cardiomyopathy: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "PLD1 gene variants are postnatally associated with pulmonary stenosis, valvular regurgitation, left ventricular dilation and right ventricular hypoplasia."
    explanation: Names pulmonary stenosis as a postnatal feature of PLD1 variants.
- name: Cardiomyopathy
  category: Cardiovascular
  description: >-
    Cardiomyopathy as such, carried separately from the dilated form because the
    delineating cohort's two isolated cases were not characterised as dilated - one was
    severe left ventricular systolic dysfunction with mitral regurgitation, the other
    read as histiocytoid cardiomyopathy. This is the presentation that occurs with no
    structural valve defect at all.
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy."
    explanation: >-
      The undifferentiated isolated cardiomyopathy this phenotype carries, which the
      dilated-cardiomyopathy term would overstate.
- name: Ventricular septal defect
  category: Cardiovascular
  description: >-
    Ventricular septal defect. Predicted by the mechanism this entry models - the same
    endocardial cushions build the septa as well as the valves - and reported in
    patients.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:42591229
    reference_title: "Novel compound heterozygous variants in the PLD1 gene causing cardiac valve dysplasia 1 complicated with dilated cardiomyopathy: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Newborn: severe pulmonary stenosis, moderate RV hypoplasia, 3 medium VSDs, large ASD, no extracardiac symptoms"
    explanation: Documents ventricular septal defects in a reported PLD1 patient.
  - reference: PMID:39553471
    reference_title: Prenatal detection of novel compound heterozygous variants of the PLD1 gene in a fetus with congenital heart disease.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Additionally, these individuals exhibit structural cardiac anomalies such as atrial and ventricular septal defects, a single left ventricle, and a hypoplastic right ventricle"
    explanation: >-
      Places septal defects in the PLD1 phenotype. BACKGROUND because the phrase sits
      in this report's introduction rather than in its own case description.
- name: Atrial septal defect
  category: Cardiovascular
  description: Atrial septal defect, reported alongside the ventricular septal defects.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  evidence:
  - reference: PMID:42591229
    reference_title: "Novel compound heterozygous variants in the PLD1 gene causing cardiac valve dysplasia 1 complicated with dilated cardiomyopathy: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Newborn: severe pulmonary stenosis, moderate RV hypoplasia, 3 medium VSDs, large ASD, no extracardiac symptoms"
    explanation: Documents an atrial septal defect in a reported PLD1 patient.
- name: Single ventricle
  category: Cardiovascular
  description: >-
    Functionally univentricular heart, the severe end of right-heart hypoplasia - a
    single left ventricle with a vestigial right ventricle, reported in three
    consecutive affected pregnancies in one family and in a liveborn patient.
  phenotype_term:
    preferred_term: Single ventricle
    term:
      id: HP:0001750
      label: Single ventricle
  evidence:
  - reference: PMID:37770978
    reference_title: "Triple repeated fetal congenital heart disease linked to PLD1 mutation: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 16 weeks and 5 days of gestation, the fetus was suspected to have a left ventricular-type single ventricle, trace right ventricle, pulmonary atresia with intact ventricular septum, or cardiomyopathy."
    explanation: >-
      Documents univentricular physiology, with the vestigial right ventricle beside
      it, in an affected fetus.
  - reference: PMID:42591229
    reference_title: "Novel compound heterozygous variants in the PLD1 gene causing cardiac valve dysplasia 1 complicated with dilated cardiomyopathy: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Newborn: severe cyanosis, tricuspid/pulmonary atresia, single left ventricle, small pulmonary arteries, no extracardiac symptoms"
    explanation: >-
      Independent documentation in a liveborn patient, in the same row that records
      this patient's tricuspid atresia.
progression:
- phase: Fetal
  notes: >-
    The earliest and most severe phase. Complex malformation is detectable on
    first-trimester ultrasound, and the phase can end in hydrops, intrauterine death,
    or termination for poor prognosis - documented recurrently within single families.
    Patients who reach birth are a survivorship-filtered subset.
  evidence:
  - reference: PMID:37770978
    reference_title: "Triple repeated fetal congenital heart disease linked to PLD1 mutation: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "intrauterine fetal death was confirmed at 14 weeks and 3 days of gestation"
    explanation: Documents the fetal-loss outcome that defines this phase.
- phase: Neonatal
  notes: >-
    Cyanosis and heart failure from the structural lesion, or isolated cardiomyopathy
    with no structural defect. This is where surgical palliation begins, and
    transplantation has been performed as early as 45 days of life.
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient underwent an orthotopic heart transplantation at the age of 45 days because of worsening heart function (family S)."
    explanation: The neonatal end-stage intervention that marks this phase.
- phase: Childhood and adult
  notes: >-
    Survivors live with repaired or palliated valve disease and accumulate
    reoperations; dilated cardiomyopathy may supervene years later. One reported
    patient had three open-heart operations and presented at 16 with left ventricular
    enlargement and reduced wall motion after 17 years of valve disease.
  evidence:
  - reference: PMID:42591229
    reference_title: "Novel compound heterozygous variants in the PLD1 gene causing cardiac valve dysplasia 1 complicated with dilated cardiomyopathy: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "with a history of cardiac valve disease for more than 17 years and three open-heart surgeries"
    explanation: The long-term reoperation course that defines this phase.
genetic:
- name: PLD1
  gene_term:
    preferred_term: PLD1
    term:
      id: hgnc:9067
      label: PLD1
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  notes: >-
    Phospholipase D1, at 3q26.31. Biallelic loss-of-function variants are the cause of
    this disorder. Missense alleles are concentrated in the catalytic core and most
    reduce enzymatic activity directly, and nonsense, frameshift and splice alleles
    also occur, so the mechanism is loss of catalytic function. ClinGen's Congenital
    Heart Disease GCEP classifies the relationship Definitive under an autosomal
    recessive model, having reached the maximum genetic-evidence score; the record
    notes that further evidence exists beyond the publications it scored.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_d37e1c81-cb59-45db-9481-338149fa5064-2024-12-02T170000.000Z
    evidence:
    - reference: CGGV:assertion_d37e1c81-cb59-45db-9481-338149fa5064-2024-12-02T170000.000Z
      reference_title: PLD1 / PLD1-related congenital heart disease (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "PLD1 | HGNC:9067 | PLD1-related congenital heart disease | MONDO:1010144 | AR | Definitive | SOP11 | Congenital Heart Disease Gene Curation Expert Panel"
      explanation: >-
        The ClinGen validity row. Its MONDO term is MONDO:1010144, which this entry
        maps skos:exactMatch, so the assertion is for this entry's disease.
  variants:
  - name: p.Ile668Phe
    description: >-
      Founder missense variant in the Ashkenazi Jewish population, at an allele
      frequency of about 2%. In a separate 5,424-proband congenital heart disease
      exome study, founder variants in GDF1 and PLD1 together accounted for most of
      the recessive-genotype contribution among Ashkenazi Jewish probands.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:33645542
      reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%)"
      explanation: Establishes the variant's founder status and allele frequency.
    population_effects:
    - population: Ashkenazi Jewish probands with congenital heart disease
      ancestry_terms:
      - preferred_term: Ashkenazi Jewish
        term:
          id: HANCESTRO:0324
          label: Ashkenazi Jew
      ancestry_basis: GENETICALLY_INFERRED
      effect_differences:
      - ALLELE_FREQUENCY
      cohort_size: 410
      description: >-
        The variant is enriched to founder frequency in this population, so recessive
        PLD1 genotypes account for a disproportionate share of congenital heart
        disease there. Recorded as GENETICALLY_INFERRED rather than self-reported
        because the study defines the group by principal-component analysis of its own
        sequence data ("410 PCA-defined Ashkenazim"), not by reported ethnicity.
      evidence:
      - reference: PMID:40030011
        reference_title: Recessive genetic contribution to congenital heart disease in 5,424 probands.
        supports: SUPPORT
        directness: DIRECT
        evidence_source: HUMAN_CLINICAL
        snippet: "Founder variants in GDF1 and PLD1 accounted for 74% of the contribution of RGs among 410 Ashkenazi Jewish probands."
        explanation: >-
          Quantifies the population-specific contribution in a cohort assembled
          independently of the delineating study.
  - name: p.His442Pro
    description: >-
      Missense variant at a highly conserved site, one of the three alleles in the
      original two-family report. It produced a strong loss-of-function phenotype when
      modelled in the homologous yeast gene.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:27799408
      reference_title: Congenital valvular defects associated with deleterious mutations in the PLD1 gene.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: "the p.His442Pro mutation produced a strong loss of function phenotype in yeast homologous mutant strain"
      explanation: Functional evidence that this allele is loss of function.
  - name: p.Thr495fs32*
    description: Frameshift variant from the original two-family report.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:27799408
      reference_title: Congenital valvular defects associated with deleterious mutations in the PLD1 gene.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Three mutations, p.His442Pro, p.Thr495fs32* and c.2882+2T>C, were identified in the PLD1 gene."
      explanation: Reports the allele in patients with severe valvular malformations.
  - name: c.2882+2T>C
    description: Splice donor variant from the original two-family report.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:27799408
      reference_title: Congenital valvular defects associated with deleterious mutations in the PLD1 gene.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Three mutations, p.His442Pro, p.Thr495fs32* and c.2882+2T>C, were identified in the PLD1 gene."
      explanation: Reports the allele in patients with severe valvular malformations.
  - name: c.1062-59A>G
    description: >-
      Deep intronic variant that would normally be filtered out of a diagnostic
      pipeline. Transcript work on the fetus and mother showed it causes a 76-bp
      intronic insertion and skipping of exon 11, producing a frameshift and premature
      stop - so a non-canonical intronic PLD1 variant can be the second hit.
    clinical_significance: UNCERTAIN_SIGNIFICANCE
    evidence:
    - reference: PMID:39553471
      reference_title: Prenatal detection of novel compound heterozygous variants of the PLD1 gene in a fetus with congenital heart disease.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "RT-PCR and TA clone sequencing revealed a 76-bp intronic insertion and exon 11 skipping in the proband and her mother's transcripts, causing a frameshift and premature stop codon in PLD1."
      explanation: >-
        Transcript-level demonstration of the splicing consequence. Recorded as
        UNCERTAIN_SIGNIFICANCE because the authors classified it VUS under ACMG
        despite this functional result.
  - name: p.Arg993Ter and p.Trp487Ter
    description: >-
      Compound heterozygous nonsense variants in a fetus with generalised oedema and
      complex cardiac malformation, neither previously reported. One of the three
      publications ClinGen scored for the Definitive classification.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:38171566
      reference_title: "[Clinical phenotype and genetic analysis of a fetus with Cardiac valvular dysplasia type 1]."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "Trio-WES revealed that it has harbored compound heterozygous variants of the PLD1 gene, namely c.2977C>T (p.R993*) and c.1460G>A (p.W487*), which were respectively inherited from its father and mother."
      explanation: Reports the biallelic nonsense genotype and its parental phase.
  - name: p.Ile378fs and p.Arg391Cys
    description: >-
      Compound heterozygous frameshift and missense variants found by exome sequencing
      of a fetus in a family with recurrent fetal congenital heart defects.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:36923242
      reference_title: Detection of Novel Pathogenic Variants in Two Families with Recurrent Fetal Congenital Heart Defects.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "a compound heterozygous variation in PLD1 gene consisting of c.1132dupA (p.I378fs) and c.1171C>T (p.R391C) was identified in the fetus"
      explanation: Reports the biallelic genotype in a recurrent-fetal-loss family.
  - name: p.Arg158Ter
    description: >-
      Homozygous nonsense variant reported in an adult with cardiac valvular dysplasia
      complicated by dilated cardiomyopathy.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:39681445
      reference_title: "[A case of cardiac valvular dysplasia combined with dilated cardiomyopathy caused by a homozygous nonsense variant in PLD1]."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "并通过高通量测序鉴定出PLD1基因纯合致病变异c.472C>T（p.Arg158Ter）"
      explanation: >-
        Names the homozygous nonsense allele. The quote is in Chinese because this
        report has no English abstract in PubMed; the snippet is the variant
        designation itself, which is language-independent.
  evidence:
  - reference: PMID:27799408
    reference_title: Congenital valvular defects associated with deleterious mutations in the PLD1 gene.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The findings support a role for PLD1 in normal heart valvulogenesis."
    explanation: The original report's conclusion binding PLD1 to valve development.
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects"
    explanation: The cohort that established the gene-disease relationship at scale.
animal_models:
- name: Pld1 knockout mouse
  species: Mouse
  genotype: PLD1 knockout
  publication: PMID:27799408
  description: >-
    Constitutive PLD1 knockout mice were examined by echocardiography and histology.
    They reproduce the right-sided valve lesion - tricuspid regurgitation with right
    atrial enlargement, and a narrowed pulmonic valve with thickened leaflets - which
    is the human phenotype's defining topography.
  evidence:
  - reference: PMID:27799408
    reference_title: Congenital valvular defects associated with deleterious mutations in the PLD1 gene.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "echocardiography and histological examination of hearts of PLD1 knockout mice"
    explanation: Establishes that this model exists and names how it was characterised.
  modeled_mechanisms:
  - target: Right-Sided Valve Dysplasia
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      The knockout reproduces the right-sided distribution and, at histology,
      thickened and narrowed pulmonic leaflets - but the two sources disagree on
      whether it reproduces a structural malformation at all, which is why this is
      partial recapitulation rather than recapitulation.
    limitations: >-
      The delineating cohort states that no overt structural cardiac defects were
      noted in these mice, only impaired valve function on echocardiography, and calls
      the human-versus-mouse difference in severity unexplained. The original report's
      histology does describe narrowed, thickened pulmonic leaflets, so the structural
      claim is contested rather than absent. Either way the mice show nothing like the
      atresia, Ebstein's anomaly, right ventricular hypoplasia or fetal loss that
      dominate the patient series, and a complete null does not model the hypomorphic
      missense alleles most patients carry.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The node is a structural valve malformation, and that lesion is outside what
        the model produces. What the mice reliably show is
        impaired pulmonary and tricuspid valve function on echocardiography, with the
        delineating cohort reporting no overt structural defect; the severe structural
        lesions that define the human disease are absent.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The mouse-versus-human difference in severity is explicitly unexplained in the
        literature, so the gap is not a known quantitative offset that can be
        corrected for when reading the model.
    readouts:
    - name: Tricuspid regurgitation and pulmonic valve leaflet thickening on echocardiography
      target: Right-Sided Valve Dysplasia
      direction: INCREASED
      interpretation: Structural and functional correlate of the human right-sided valve lesion.
      evidence:
      - reference: PMID:27799408
        reference_title: Congenital valvular defects associated with deleterious mutations in the PLD1 gene.
        supports: SUPPORT
        directness: DIRECT
        evidence_source: MODEL_ORGANISM
        snippet: "In hearts of PLD1 knockout mice, we detected marked tricuspid regurgitation, right atrial enlargement, and increased flow velocity, narrowing and thickened leaflets of the pulmonic valve."
        explanation: The echocardiographic and histological measurements behind this readout.
    evidence:
    - reference: PMID:27799408
      reference_title: Congenital valvular defects associated with deleterious mutations in the PLD1 gene.
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "In hearts of PLD1 knockout mice, we detected marked tricuspid regurgitation, right atrial enlargement, and increased flow velocity, narrowing and thickened leaflets of the pulmonic valve."
      explanation: Supports treating the knockout as informative for the human valve lesion.
    - reference: PMID:33645542
      reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
      supports: REFUTE
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      quote_role: BACKGROUND
      snippet: "Although no overt structural cardiac defects were noted, mice lacking PLD1 (36) displayed impaired function of the pulmonary and tricuspid valves on echocardiography"
      explanation: >-
        The delineating cohort's reading of the same knockout denies the structural
        phenotype this node asserts, which is what caps the link at partial
        recapitulation. BACKGROUND because the sentence restates the earlier mouse
        work rather than reporting this paper's own result.
- name: Chick embryo PLD1 expression
  species: Chicken
  genotype: Wild type
  publication: PMID:27799408
  description: >-
    In situ hybridisation in the chick embryo localised PLD1 expression to the forming
    heart from E2 to E8, initially throughout the heart and later narrowing to the
    atrioventricular valves and the right ventricular outflow tract. This is an
    expression-mapping model, not a disease model: it supplies the spatial argument
    for where the defect acts, and does not itself produce a phenotype.
  evidence:
  - reference: PMID:27799408
    reference_title: Congenital valvular defects associated with deleterious mutations in the PLD1 gene.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we show that in chick embryos PLD1 expression is confined to the forming heart (E2-E8) and homogeneously expressed all over the heart during days E2-E3."
    explanation: >-
      Establishes this model as a chick in-situ hybridisation study and states its
      basic result, that PLD1 expression in the embryo is cardiac-restricted. The
      readout below quotes the same sentence for the measurement itself.
  modeled_mechanisms:
  - target: Deficient Endocardial Cushion Remodelling
    relationship: MEASURES
    fidelity: UNKNOWN
    model_scale: TISSUE
    description: >-
      Maps where the gene is expressed during valvulogenesis, which is the structures
      that are malformed in patients.
    limitations: >-
      Expression is not function - the model shows where PLD1 is transcribed, not that
      cushion remodelling fails without it. It is also a non-mammalian embryo, and the
      authors read the temporal pattern as tracking developmental apoptosis, which is a
      different proposed mechanism from the endothelial-to-mesenchymal transition the
      main chain follows.
    readouts:
    - name: PLD1 transcript distribution in the developing heart
      target: Deficient Endocardial Cushion Remodelling
      interpretation: >-
        Localises the gene to the atrioventricular valves and right ventricular
        outflow tract, the sites of the human lesion.
      evidence:
      - reference: PMID:27799408
        reference_title: Congenital valvular defects associated with deleterious mutations in the PLD1 gene.
        supports: SUPPORT
        directness: DIRECT
        evidence_source: MODEL_ORGANISM
        snippet: "Here we show that in chick embryos PLD1 expression is confined to the forming heart (E2-E8) and homogeneously expressed all over the heart during days E2-E3."
        explanation: The in situ hybridisation result behind this readout.
    evidence:
    - reference: PMID:27799408
      reference_title: Congenital valvular defects associated with deleterious mutations in the PLD1 gene.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Thereafter its expression decreases, remaining only adjacent to the atrioventricular valves and the right ventricular outflow tract."
      explanation: >-
        Supports treating this expression map as informative for where cushion
        remodelling fails. Graded INDIRECT because expression localisation is not a
        measurement of remodelling.
mechanistic_hypotheses:
- hypothesis_group_id: pld1_tgfb_shh_route
  hypothesis_label: Arterial pole defects via attenuated TGF-beta and hedgehog signalling
  status: EMERGING
  description: >-
    The route from depleted phosphatidic acid to the arterial pole lesions, proposed by
    the delineating cohort. It is recorded as a hypothesis group rather than as settled
    main-chain mechanism because the supporting paragraph is hedged throughout and
    assembled from other work: the phosphatidic-acid-to-TGF-beta step is inferred from
    an adult myocardial-infarction study, the hedgehog step from the consequence of
    inhibiting hedgehog at the corresponding developmental stage, and nothing about
    either pathway was measured in this disease. The nodes are kept in the chain
    because the entry's phenotype distribution is otherwise unexplained, but the two
    edges into and out of them carry this group so the epistemic status travels with
    them - the same standard applied to the apoptosis route below.
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "In the adult heart, loss of PLD1 can lead to a reduction in TGF-β signaling activity in the context of myocardial infarction"
    explanation: >-
      The only empirical support for the phosphatidic-acid-to-TGF-beta step, and it
      comes from adult myocardial infarction rather than cardiac development - which
      is why this is a hypothesis group and not a settled edge.
- hypothesis_group_id: pld1_apoptosis_route
  hypothesis_label: Loss of developmentally programmed apoptosis in the valve primordia
  status: EMERGING
  description: >-
    An alternative to the endothelial-to-mesenchymal transition account. The original
    report noted that the chick PLD1 expression pattern follows the known dynamic
    patterning of apoptosis in the developing heart, and read this as consistent with
    PLD1's established role in promoting apoptosis - implying the valve defect arises
    because sculpting apoptosis fails rather than because cushion mesenchyme is not
    generated. The two accounts are not exclusive and neither has been tested against
    the other in cardiac tissue; the entry's main chain follows the transition route
    because that is the one with a direct perturbation experiment behind it.
  evidence:
  - reference: PMID:27799408
    reference_title: Congenital valvular defects associated with deleterious mutations in the PLD1 gene.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "This pattern of expression follows the known dynamic patterning of apoptosis in the developing heart, consistent with the known role of PLD1 in the promotion of apoptosis."
    explanation: >-
      The observation and inference behind this hypothesis. Graded INDIRECT because it
      is an argument from a correlation between an expression pattern and a known
      developmental process, with no apoptosis measurement in PLD1-deficient hearts.
diagnosis:
- name: Echocardiography
  description: >-
    Echocardiography defines the valve lesion and the right ventricular and pulmonary
    arterial hypoplasia, and is also how the cardiomyopathy is identified and followed.
  diagnosis_term:
    preferred_term: Echocardiography Test
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:42591229
    reference_title: "Novel compound heterozygous variants in the PLD1 gene causing cardiac valve dysplasia 1 complicated with dilated cardiomyopathy: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Echocardiography showed left ventricular enlargement, decreased ventricular wall motion amplitude, and mild tricuspid regurgitation."
    explanation: Echocardiography establishing both the valve and myocardial findings in a patient.
- name: Fetal echocardiography and ultrasonography
  description: >-
    Because the severe end of the spectrum presents in utero, prenatal imaging is
    frequently the first diagnostic step - detecting the valve lesion, tricuspid
    regurgitation and hydrops from the first trimester onward.
  diagnosis_term:
    preferred_term: Fetal Echocardiography Test
    term:
      id: NCIT:C114079
      label: Fetal Echocardiography Test
  evidence:
  - reference: PMID:37770978
    reference_title: "Triple repeated fetal congenital heart disease linked to PLD1 mutation: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "fetal ultrasonography at 11 weeks and 5 days of gestation showed mild fetal hydrops and moderate tricuspid valve regurgitation"
    explanation: Prenatal imaging making the cardiac diagnosis in an affected fetus.
- name: Carrier screening for the Ashkenazi founder allele
  description: >-
    Proposed, not established. The delineating cohort suggests that carriership
    testing for the PLD1 founder variants could be used in population-based
    preconception and prenatal screening among people of Ashkenazi Jewish descent,
    where p.Ile668Phe reaches an allele frequency of about 2%. The entry records the
    proposal rather than a practice: no guideline, panel inclusion or screening
    programme is cited, and the source itself is hedged.
  diagnosis_term:
    preferred_term: Mutation Carrier Screening
    term:
      id: NCIT:C62694
      label: Mutation Carrier Screening
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Carriership testing for these variants could potentially be used in population-based preconception and prenatal carrier screening to assess the risk of congenital heart defects among descendants of Ashkenazi Jews."
    explanation: >-
      The authors' proposal. Graded INDIRECT because the sentence recommends a use
      ("could potentially be used") rather than reporting a screening programme or
      its yield.
- name: Exome sequencing
  description: >-
    The diagnosis is molecular. Exome sequencing identified the gene in the original
    families and remains how biallelic PLD1 genotypes are found; note that a
    pathogenic second allele may be deep intronic and so missed by a pipeline that
    filters non-canonical splice variants, which in one family required transcript
    studies to resolve.
  diagnosis_term:
    preferred_term: Whole Exome Sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:27799408
    reference_title: Congenital valvular defects associated with deleterious mutations in the PLD1 gene.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome analysis was used to identify the mutations in five patients who suffered from severe valvular malformations involving the pulmonic, tricuspid and mitral valves."
    explanation: The method that identified the causal gene.
treatments:
- name: Cardiac valve surgery
  description: >-
    Surgical repair or replacement of the dysplastic right-sided valves, and staged
    palliation where the right ventricle is hypoplastic. Reoperation is expected: one
    reported patient had three open-heart operations by the age of 16.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cardiac valve procedure
    term:
      id: NCIT:C99546
      label: Cardiac Valve Procedure
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "most commonly the placement of a Blalock-Taussig shunt and bidirectional Glenn palliation"
    explanation: >-
      The staged single-ventricle palliation this description asserts, which was
      previously unevidenced.
  - reference: PMID:42591229
    reference_title: "Novel compound heterozygous variants in the PLD1 gene causing cardiac valve dysplasia 1 complicated with dilated cardiomyopathy: a case report."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "with a history of cardiac valve disease for more than 17 years and three open-heart surgeries"
    explanation: Documents the surgical burden in a patient with this disorder.
- name: Heart failure management
  description: >-
    Where cardiomyopathy supervenes, standard heart-failure care applies. The
    management point that follows from the mechanism is that cardiomyopathy can occur
    in isolation, so a normal valve study does not exclude myocardial disease in a
    PLD1 biallelic carrier.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy."
    explanation: >-
      Graded INDIRECT: the paper establishes that isolated cardiomyopathy occurs, from
      which the surveillance point follows, rather than evaluating any treatment.
- name: Heart transplantation
  description: >-
    Orthotopic heart transplantation for end-stage myocardial failure. Documented in
    the neonatal period in this disorder, which is as early as this intervention goes.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Heart Transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient underwent an orthotopic heart transplantation at the age of 45 days because of worsening heart function (family S)."
    explanation: Documents the intervention and its timing in a patient with this disorder.
- name: Genetic counselling and reproductive options
  description: >-
    Recurrence risk is 25% for a sibling, and recurrent fetal loss within one family is
    documented, so counselling matters disproportionately here. Preimplantation genetic
    testing for monogenic disorders was used by one couple after a variant of uncertain
    significance was resolved by transcript studies, and they had an unaffected child.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:39553471
    reference_title: Prenatal detection of novel compound heterozygous variants of the PLD1 gene in a fetus with congenital heart disease.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "the couple chose pre-implantation genetic testing for monogenic disorders (PGT-M) and had a healthy child"
    explanation: Documents the reproductive option taken and its outcome in a PLD1 family.
discussions:
- discussion_id: pld1_cardiomyopathy_primary_or_loading
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is the cardiomyopathy in PLD1 disease a primary myocardial defect, or secondary to
    chronic valvular loading?
  attaches_to:
  - pathophysiology#Myocardial Dysfunction
  rationale: >-
    The two reported forms point in opposite directions. Isolated neonatal
    cardiomyopathy without a structural valve defect argues for a primary myocardial
    requirement for phospholipase D1, which is plausible given that the enzyme is
    highly expressed in the heart and that phosphatidic acid signalling operates in
    cardiomyocytes. But the dilated cardiomyopathy reported in older patients arrives
    after years of valve disease and multiple operations, where loading is an adequate
    explanation on its own. Nothing yet separates the two, and the answer changes
    surveillance: a primary myocardial effect would mean echocardiographic follow-up is
    indicated even in a biallelic carrier whose valves look normal.
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy."
    explanation: The isolated presentation that makes a primary myocardial defect the live possibility.
  - reference: PMID:42591229
    reference_title: "Novel compound heterozygous variants in the PLD1 gene causing cardiac valve dysplasia 1 complicated with dilated cardiomyopathy: a case report."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "with a history of cardiac valve disease for more than 17 years and three open-heart surgeries"
    explanation: >-
      The other side of the gap: this patient's cardiomyopathy follows 17 years of
      valve disease and three operations, so loading is an adequate explanation here.
  proposed_experiments:
  - experiment_id: pld1_cardiomyocyte_specific_loss
    name: Myocardial phenotyping of PLD1-deficient hearts without valve obstruction
    description: >-
      Assess contractile function and chamber dimensions in a model in which PLD1 is
      lost in cardiomyocytes only, leaving valve development intact, so that any
      cardiomyopathy cannot be attributed to altered loading.
    would_support:
    - pathophysiology#Myocardial Dysfunction
    supporting_outcome:
    - >-
      Reduced systolic function and ventricular dilation in the absence of any valve
      lesion or outflow obstruction.
    refuting_outcome:
    - >-
      Normal contractile function and chamber dimensions throughout life when valve
      development is unaffected.
- discussion_id: pld1_right_sided_predominance
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why is the phenotype right-sided, when phosphatidic acid is required for
    endothelial-to-mesenchymal transition in both the inflow and outflow cushions?
  attaches_to:
  - pathophysiology#Impaired Cardiac Endothelial-to-Mesenchymal Transition
  - pathophysiology#Right-Sided Valve Dysplasia
  rationale: >-
    The mechanism as stated is not side-specific: the cushions supply both left and
    right heart structures, so a general reduction in the transition should damage the
    mitral and aortic valves as much as the tricuspid and pulmonary ones. It does not -
    the mitral valve is involved in a minority, two of 28 phenotyped patients, and
    aortic involvement is reported once. Three candidate explanations are on record and
    none has been tested against the others. The delineating cohort's own is that the
    two sides of the heart present different environments - cell populations,
    extracellular matrix, haemodynamics - so right-sided cells may be less able to
    compensate for the same disruption of EndoMT in the common cushions. The chick
    expression data suggest a simpler one: PLD1 transcription narrows specifically to
    the atrioventricular valves and the right ventricular outflow tract, making this a
    matter of where the gene is expressed. And the hedgehog dependence invoked for the
    arterial pole is itself regionalised. Resolving this would say whether the
    right-sided predominance is a property of the gene's expression domain, of
    differential pathway dependence, or of differential capacity to compensate.
  evidence:
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "In the endocardial cushions, EndoMT provides the mesenchymal cells and remodeled matrix essential for the formation of both left and right heart structures"
    explanation: >-
      The side-neutral statement of the mechanism, which is what the right-sided
      clinical predominance sits awkwardly against.
  - reference: PMID:33645542
    reference_title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "These differing contexts may underlie the susceptibility of the right side of the heart to loss of PLD1 activity."
    explanation: >-
      The third candidate explanation, and the one the delineating cohort itself
      favours: the two sides of the heart differ in cell populations, matrix and
      haemodynamics, so right-sided cells may be less able to compensate for the same
      loss of EndoMT.
  - reference: PMID:27799408
    reference_title: Congenital valvular defects associated with deleterious mutations in the PLD1 gene.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Thereafter its expression decreases, remaining only adjacent to the atrioventricular valves and the right ventricular outflow tract."
    explanation: >-
      One of the two candidate explanations - a regionalised expression domain rather
      than regionalised pathway dependence.
  proposed_experiments:
  - experiment_id: pld1_side_resolved_endmt_assay
    name: Side-resolved transition assay across inflow and outflow cushions
    description: >-
      Quantify endothelial-to-mesenchymal transition separately in left- and
      right-sided cushion explants under graded PLD1 inhibition, to test whether the
      right-sided structures are more sensitive at equal inhibition or merely express
      more of the enzyme.
    would_support:
    - pathophysiology#Right-Sided Valve Dysplasia
    supporting_outcome:
    - >-
      Right-sided cushion explants lose the transition at lower degrees of PLD1
      inhibition than left-sided explants from the same embryos.
    refuting_outcome:
    - >-
      Both sides lose the transition at the same degree of inhibition, locating the
      asymmetry in expression level rather than pathway dependence.
references:
- reference: PMID:33645542
  title: Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
- reference: PMID:27799408
  title: Congenital valvular defects associated with deleterious mutations in the PLD1 gene.
- reference: CGGV:assertion_d37e1c81-cb59-45db-9481-338149fa5064-2024-12-02T170000.000Z
  title: PLD1 / PLD1-related congenital heart disease (Definitive)
📚

References & Deep Research

References

3
PMID:33645542
Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy.
No top-level findings curated for this source.
PMID:27799408
Congenital valvular defects associated with deleterious mutations in the PLD1 gene.
No top-level findings curated for this source.
CGGV:assertion_d37e1c81-cb59-45db-9481-338149fa5064-2024-12-02T170000.000Z
PLD1 / PLD1-related congenital heart disease (Definitive)
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 (1)

Create: Cardiac Valvular Defect, Developmental (PLD1) · 2026-10-30T03:40:33Z · View source

Created the entry for MONDO:0008913 (OMIM 212093), the autosomal recessive PLD1 congenital heart disease, claimed via issue #15968. Lump/split: curated as a separate Disease rather than a has_subtypes row on Congenital_Heart_Disease, which carries PLD1 only as one causal gene among many wired to a shared endocardial-cushion node. MONDO:0008913 appears nowhere else in kb/. Precedent followed is Congenital_Heart_Defects_Multiple_Types_2 (TAB2), a gene-defined entry sitting alongside the broad clinical one. Two MONDO classes denote this entity and neither is an ancestor of the other: MONDO:0008913 (OMIM-anchored, phenotype-named) and MONDO:1010144 (ClinGen gene-centric). Both are recorded in mappings.mondo_mappings as skos:exactMatch. The justification is external rather than inferred: ClinGen's Congenital Heart Disease GCEP record states it lumped cardiac valvular dysplasia 1 and congenital heart disease into one entity after finding no difference in mechanism, inheritance or phenotypic variability. That mapping is also what makes the Definitive ClinGen assertion (whose MONDO term is MONDO:1010144) attributable to this entry under the gene-disease-validity rule. Deep research: falcon was attempted first, as the default. It failed with 'Failed to authenticate' from the FutureHouse/Edison JWT endpoint despite EDISON_API_KEY being set. The recorded-fallback path was tried twice (--fallback, then --fallback with explicit --fallback-provider claude_code and openscientist) and does not recover this failure mode, because the auth exception escapes provider construction before the fallback chain engages, so no report with fell_back provenance could be produced. openscientist was then run directly and produced research/Cardiac_Valvular_Defect_Developmental-deep-research-openscientist.md. The substitution is therefore recorded here rather than in the report's frontmatter. Report validation: 21/21 references resolved, confabulation_rate 0.0, 14/14 quoted claims found in source, 0 off topic (11 of 21 scored on topic; the rest undecided, not off topic). term_validation carries needs_review: true for 5 mislabelled terms, inspected and all benign - the 'reported label' in each case is a table column header the extractor picked up ('Clinical sign', 'Outcome'), not a term name the report asserts, and none of those CURIEs is bound here. 2 unverifiable are OMIM, an unresolvable prefix. Named Entity Confusion: just preflight-dr passes (exit 0) with one WARN naming 'PA' as a second gene at 30 mentions. Inspected: PA is the report's abbreviation for phosphatidic acid, the lipid second messenger central to the mechanism, not a gene and not a second disease. OMIM agrees on both sides (MONDO 212093, report 212093) and PLD1 is mentioned 71 times with no competing causal gene (ADAMTS19, FLNA, GDF1, RPL3L all zero). Run without the local HGNC build, so the lexicon was heuristic. GeneReviews: no chapter exists. just check-genereviews --online returns NO_CHAPTER against the committed Bookshelf index (snapshot 2026-09-10) and a live PubMed genereviews[book] title search, run after the five synonyms were added so the check was not matching on name alone. Recorded in the entry's notes. Phenotype frequencies therefore come from the delineating cohort's own counts out of 28 phenotyped patients. Mechanism is built as a chain, not a list: PLD1 loss of function -> depleted phosphatidic acid -> (attenuated TGF-beta/hedgehog signalling) -> impaired cardiac endothelial-to-mesenchymal transition -> deficient endocardial cushion remodelling -> right-sided valve dysplasia, with right ventricular/pulmonary arterial hypoplasia downstream of the valve lesion. Myocardial Dysfunction is drawn as a parallel consequence of the gene defect, not a sequela of the valve lesion, because the delineating cohort reports isolated neonatal cardiomyopathy without a structural defect. Fetal Cardiac Decompensation captures the hydrops/intrauterine-death end of the spectrum. The apoptosis account from the original chick expression work is recorded as a mechanistic_hypotheses entry (status EMERGING) rather than as a node, because the main chain's route has a direct perturbation experiment behind it and the apoptosis route has only a correlation between an expression pattern and a known developmental process. Terms: three CURIEs were corrected against the source during curation rather than trusted. GO:0004630 is labelled 'D-type glycerophospholipase activity', not 'phospholipase D activity'. HANCESTRO:0017 is 'Oceanian ancestry'; the Ashkenazi Jewish term is HANCESTRO:0324 'Ashkenazi Jew'. NCIT:C101295 is Whole Exome Sequencing. The CGGV reference_title was also replaced with the cached title verbatim after a composed one failed the title check. References: 12 cited, all cached. Seven found by PubMed search before the report landed (including Ta-Shma 2017, PMID:27799408, the original two-family report that the report and ClinGen both treat as founding); three added from the report's own citations where they strengthened the chain (PMID:32198492 PLD1 crystal structure, PMID:42600378 cushion EndMT review, PMID:41173720 phosphatidic acid review). The two review-derived items carry quote_role: REVIEW_SYNTHESIS. PMID:39681445 is quoted in Chinese - it has no English abstract in PubMed and the quoted substring is the variant designation itself. datasets: deliberately absent. just discover-datasets returns three candidates, all GENE_ONLY PLD1 oncology studies (bladder and colon cancer); all rejected on relevance and the triage recorded in the entry's notes. Validation: just validate passes - schema, terms, and 65/65 snippets with 68 titles checked. Per-file gates pass (check-duplicate-keys, check-block-scalar-comments, check-enum-values, check-entity-refs, check-causal-targets, check-coarse-phenotypes, check-qualifier-terms, check-delivery-system). Whole-tree gates pass (check-folded-hyphens, check-title-snippets, check-reference-titles, check-retired-support-prose, check-shared-disease-terms, check-environmental-evidence, and check-snippet-grading, which CI skips on a kb-only PR). Compliance 89.0%. The residual gaps are the definitional node-to-phenotype causal edges, left uncited rather than given the parent node's citation.

OpenScientist ▸
Cardiac Valvular Defect, Developmental (CVDD) — Comprehensive Disease Report
openscientist-autonomous 21 citations 2026-10-30T03:31:53.985403

Cardiac Valvular Defect, Developmental (CVDD) — Comprehensive Disease Report

Disease: Cardiac Valvular Defect, Developmental (CVDD) Causal gene: PLD1 (Phospholipase D1; HGNC:9067; UniProt Q13393; chromosome 3q26.31) MONDO: MONDO:0008913 | OMIM: 212093 | Inheritance: Autosomal recessive Synonyms: CVDD; PLD1-related congenital heart disease; PLD1-related cardiac valvular dysplasia

Summary

Cardiac Valvular Defect, Developmental (CVDD) is a rare, autosomal-recessive Mendelian congenital heart disease caused by biallelic loss-of-function variants in PLD1 (Phospholipase D1). It is critical to anchor this entry to the gene: although the disease name ("cardiac valvular defect") is generic and could be confused with many non-genetic or differently-caused valve disorders, the MONDO:0008913 / OMIM:212093 entity is specifically the PLD1-driven recessive disorder. Affected individuals present predominantly with congenital right-sided cardiac valve defects — pulmonary and tricuspid valve stenosis, atresia, and dysplasia — and, in a distinct subset, with isolated neonatal cardiomyopathy. The phenotypic spectrum is broad, ranging from recurrent lethal intrauterine fetal demise with hydrops at one extreme to adult-survivable valve disease requiring multiple open-heart surgeries at the other.

Mechanistically, PLD1 is a lipid-signaling enzyme that hydrolyzes phosphatidylcholine to generate the second-messenger lipid phosphatidic acid (PA). Loss-of-function variants — concentrated in the catalytically critical regions of the protein — strongly reduce enzymatic activity, lowering PA production. Because PA signaling (acting through downstream nodes including mTOR, RAF/MEK/ERK, and S6 kinase) feeds into the pathways that drive endothelial-to-mesenchymal transition (EndMT), a pivotal early step in endocardial-cushion valvulogenesis, PLD1 deficiency impairs the formation of normal heart valves during embryogenesis. The landmark study established directly that PLD1 inhibition decreases EndMT, providing the mechanistic link between gene loss and valve malformation.

The disorder was first linked to congenital valve defects in 2017 (Ta-Shma et al.) and definitively established in a 30-patient, 21-family cohort in 2021 (Lahrouchi et al.). The missense variant p.I668F is an Ashkenazi Jewish founder allele with a carrier allele frequency of ~2%. Diagnosis rests on fetal/neonatal echocardiography combined with exome or targeted PLD1 sequencing; management is lesion-specific surgical and palliative cardiac care, as no gene-specific or disease-modifying therapy currently exists. Notably, the constitutive Pld1-knockout mouse is viable and models thrombosis/platelet phenotypes rather than the human congenital valve malformation — a key limitation of the available animal models.

Key Findings

Finding 1 — Biallelic loss-of-function PLD1 variants cause CVDD

The foundational genetic finding (Lahrouchi et al., 2021) identified 30 patients from 21 unrelated families of diverse ancestries carrying biallelic PLD1 variants, discovered through whole-exome sequencing of a cohort of 2,718 congenital heart disease (CHD) patients augmented by GeneMatcher-based international matchmaking. The phenotype was predominantly congenital cardiac valve defects, strongly biased to the right side of the heart (pulmonary and tricuspid valves). The authors wrote that they "identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects" (PMID: 33645542).

A second, distinct phenotype was also established: "We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy" (PMID: 33645542). This indicates that PLD1 deficiency can manifest either as a structural valvular defect or as a primary myocardial disorder in the neonatal period.

Crucially, the molecular consequence is loss of enzymatic function: "PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay" (PMID: 33645542). This establishes the loss-of-function mechanism and explains why the disorder is recessive — a single functional allele produces sufficient enzyme, while biallelic loss crosses a critical threshold during valvulogenesis. The inheritance is autosomal recessive; the disorder maps to OMIM 212093 and MONDO:0008913.

Finding 2 — Mechanism: PLD1 loss reduces EndMT and impairs valvulogenesis; p.I668F is an Ashkenazi Jewish founder variant

The same cohort study provided the central mechanistic demonstration. Using functional assays, the authors showed that "PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis" (PMID: 33645542). EndMT is the developmental process by which endocardial endothelial cells delaminate, migrate, and transform into the mesenchymal cells that populate the endocardial cushions — the primordia of the cardiac septa and valves. By connecting reduced PLD1 activity to reduced EndMT, this result links the biochemical defect (lowered phosphatidic acid production) to the developmental failure (abnormal valve formation).

The study also delineated the population genetics of one key variant: "we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%)" (PMID: 33645542). A carrier allele frequency of ~2% is high for a recessive disease allele and has direct implications for carrier screening and genetic counseling in the Ashkenazi Jewish population.

Finding 3 — PLD1 enzymology and regulation

PLD1 (UniProt Q13393; HGNC:9067; gene on chromosome 3q26.31) hydrolyzes phosphatidylcholine to generate the lipid second-messenger phosphatidic acid (PA). Structural studies of the human enzyme (Bowling et al., 2020; Metrick et al., 2020) revealed that PLD1 is directly and synergistically regulated by protein kinase C (PKC), the small GTPases Arf and Rho, and the membrane phosphoinositide PIP2. As stated: "phospholipase D1 (PLD1) hydrolyzes phosphatidylcholine to generate the lipid second-messenger phosphatidic acid, which plays roles in disease processes such as thrombosis and cancer. PLD1 is directly and synergistically regulated by protein kinase C, Arf and Rho GTPases" (PMID: 32198492).

The product, PA, is a pleiotropic signaling lipid: "Mammalian phospholipase D (PLD) generates phosphatidic acid, a dynamic lipid secondary messenger involved with a broad spectrum of cellular functions including but not limited to metabolism, migration, and exocytosis" (PMID: 33495125). The relevance to EndMT is the involvement in cell migration, a core feature of the endocardial-cushion transformation. PA exerts its effects through downstream effectors including mTOR and the RAF/MEK/ERK cascade: the pathway maps "mechanistic connections to disease through mTOR and RAF/MEK/ERK signaling" (PMID: 41173720). These nodes intersect the canonical signaling arms governing valve development (see Mechanistic Model below).

Finding 4 — Pld1-knockout mice model thrombosis, not congenital valve defects

A key translational caveat emerges from the mouse literature. Constitutive Pld1(−/−) mice (Elvers et al., 2010) are viable and fertile and display platelet/thrombosis phenotypes rather than overt congenital valve malformation: "platelets from Pld1(-/-) mice displayed impaired alpha(IIb)beta(3) integrin activation in response to major agonists and defective glycoprotein Ib-dependent aggregate formation under high shear conditions. These defects resulted in protection from thrombosis and ischemic brain infarction without affecting tail bleeding times" (PMID: 20051593).

Pharmacologic PLD inhibition reproduces the anti-thrombotic protection: "pharmacological PLD inhibition might provide a safe therapeutic strategy to prevent arterial thrombosis and ischemic stroke" (PMID: 23868933). PLD1 also regulates platelet-mediated inflammation (PMID: 28711718) and TNF-α/sepsis responses (PMID: 29968773). The absence of a reported congenital valve phenotype in the knockout mouse — despite the clear human valvulogenesis defect — points to species differences in developmental robustness or redundancy and is an important limitation for mechanistic and preclinical work.

Finding 5 — First linkage (2017) and the full allelic/phenotypic spectrum

PLD1 was first linked to congenital valve malformations in 2017 by Ta-Shma et al., who studied two families and identified p.His442Pro, p.Thr495fs32*, and the splice variant c.2882+2T>C, affecting pulmonic, tricuspid, and mitral valves, with functional support from a yeast PLD sporulation assay: "Three mutations, p.His442Pro, p.Thr495fs32* and c.2882+2T>C, were identified in the" families, and "The findings support a role for PLD1 in normal heart valvulogenesis" (PMID: 27799408).

The 2021 Lahrouchi study expanded the cohort to 30 patients across 21 families (PMID: 33645542). The phenotypic spectrum is wide: - Most severe / lethal: recurrent intrauterine fetal demise and non-immune fetal hydrops, including a remarkable report of three consecutive affected fetuses with homozygous PLD1 variants and recurrent right-ventricular valve dysplasia (PMID: 37770978). - Adult-survivable: a 2026 case report of a proband with a 17-year history of valve disease who underwent three open-heart surgeries, carrying novel compound heterozygous PLD1 variants (PMID: 42591229).

The broader recessive contribution to CHD was quantified in a large exome study of 5,424 probands: "Rare damaging RGs were estimated to contribute to at least 2.2% of CHD, with greater enrichment among laterality phenotypes (5.4%) versus other subsets (1.4%)" (PMID: 40030011), situating PLD1 within the recessive-gene category of congenital heart disease.

Finding 6 — PLD1/PA intersects the canonical endocardial-cushion EndMT network

The endocardial cushions, derived from the atrioventricular canal and the outflow tract, are the primordia of the cardiac septa and valves. EndMT converts endocardial cells into cushion mesenchyme and is governed by a well-defined network. As summarized in a 2026 review: "Various signaling pathways, including TGFβ/BMP, Wnt, Notch, Hippo/YAP, PI3K/AKT, VEGF, and mechanical stress, are involved in the modulation of endocardial cell proliferation, migration, and mesenchymal transition. Transcription factors, such as SMAD, SNAIL, TWIST, TBX2, SOX9, KLF2/4, and NFATc1, exert distinct effects on endocardial EndMT" (PMID: 42600378). Importantly, "Improper morphogenesis of the endocardial cushion leads to septal and valvular abnormalities, which contribute to the largest proportion of congenital heart diseases" (PMID: 42600378) — precisely the CVDD phenotype.

PLD1-derived PA signals through mTOR and RAF/MEK/ERK (PMID: 41173720) and via S6 kinase, where PA "acts as a leukocyte chemoattractant … through S6 kinase signaling" and drives actin polymerization and chemotaxis (PMID: 20304930). These nodes map onto the PI3K/AKT/mTOR and MAPK arms of the EndMT network, providing a plausible molecular bridge from PLD1 loss to defective EndMT. A human iPSC valve-differentiation platform demonstrates that other CHD genes (e.g., Noonan-syndrome RAS/MAPK variants) cause EndMT defects biased toward specific valve interstitial-cell subtypes (PMID: 41648231), offering a validated model approach directly applicable to PLD1.

Mechanistic Model / Interpretation

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Biallelic loss-of-function variants in PLD1 (missense in catalytic regions, frameshift, nonsense, or splice variants) lead to strongly reduced PLD1 catalytic activity (demonstrated in enzymatic assays — PMID: 33645542).
  2. Reduced PLD1 activity results in diminished hydrolysis of phosphatidylcholine and therefore lower production of phosphatidic acid (PA) (enzymology established — PMID: 32198492, PMID: 33495125).
  3. Lowered PA leads to attenuated signaling through PA-dependent effectors — mTOR, RAF/MEK/ERK, and S6 kinase — nodes that drive cell migration and the mesenchymal program (PA→S6K/migration demonstrated in leukocytes, PMID: 20304930; PA→mTOR/ERK mapping PMID: 41173720 — inferred for cardiac endocardium).
  4. Reduced PA-dependent signaling results in decreased endothelial-to-mesenchymal transition (EndMT) in the endocardium (directly demonstrated: PLD1 inhibition decreased EndMT — PMID: 33645542).
  5. Impaired EndMT leads to defective population and remodeling of the endocardial cushions of the atrioventricular canal and outflow tract (EndMT is the pivotal early step in valvulogenesis — PMID: 33645542, PMID: 42600378).
  6. Abnormal endocardial-cushion morphogenesis results in structural cardiac valve malformations, predominantly right-sided (pulmonary/tricuspid stenosis, atresia, dysplasia). Branch: in a distinct subset the same lesion results in isolated neonatal cardiomyopathy rather than a structural valve defect (both phenotypes documented — PMID: 33645542).
  7. Depending on lesion severity, the valve malformation leads to a spectrum of outcomes: lethal intrauterine fetal demise / hydrops (PMID: 37770978) at the severe extreme, through neonatal heart failure, to adult-survivable valve disease requiring repeated surgery (PMID: 42591229).

Schematic

 PLD1 biallelic LoF variants
│  (reduced catalytic activity — demonstrated)
▼
 ↓ Phosphatidylcholine → Phosphatidic acid (PA)
│  (PA second-messenger pool falls)
▼
 ↓ PA-dependent signaling ── mTOR ── RAF/MEK/ERK ── S6K
│  (intersects PI3K/AKT/mTOR + MAPK arms of EndMT network)
▼
 ↓ EndMT in endocardium  ◄── TGFβ/BMP, Notch, Wnt, Hippo/YAP, VEGF
│                      TFs: SNAIL, TWIST, SOX9, NFATc1, TBX2
▼
 Defective endocardial-cushion morphogenesis (AV canal + outflow tract)
│
├────────────► Right-sided valve defects (pulmonary/tricuspid)
└────────────► Isolated neonatal cardiomyopathy  [BRANCH]
│
▼
 Spectrum: fetal demise/hydrops ── neonatal heart failure ── adult valve disease

Upstream vs downstream, cells, and processes

  • Upstream: the PLD1 mutation and the resulting PA deficit are the proximal, gene-specific lesions.
  • Downstream / convergent: the EndMT machinery (TGFβ/BMP, Notch, Wnt, Hippo/YAP, PI3K/AKT, VEGF; transcription factors SNAIL, TWIST, SOX9, NFATc1) is shared with many other CHD genes, explaining phenotypic overlap with other valve disorders.
  • Cell types involved: endocardial endothelial cells (CL:0002350 endocardial cell / CL:0000115 endothelial cell) undergoing transition to cushion mesenchymal cells / valve interstitial cells (CL:0000057 fibroblast lineage).
  • Biological processes (GO): endothelial-to-mesenchymal transition (GO:0003198 cardiac epithelial-to-mesenchymal transition / GO:0001837 EMT), heart valve morphogenesis (GO:0003179), phosphatidic acid biosynthetic process (GO:0006654), phospholipase D activity (GO:0004630).
  • Anatomy (UBERON): cardiac valves, specifically pulmonary valve (UBERON:0002146) and tricuspid valve (UBERON:0002147); endocardial cushion (UBERON:0002062); cardiac outflow tract (UBERON:0004145); myocardium (UBERON:0002349).

Comprehensive Section-by-Section Content

1. Disease Information

CVDD is a rare autosomal-recessive congenital heart disease of the cardiac valves caused by biallelic PLD1 loss-of-function variants. Identifiers: OMIM 212093; MONDO:0008913; gene PLD1 (HGNC:9067). The disease is captured at the disease level in aggregated resources (OMIM, MONDO) and has been characterized from individual patient/family case series and a multi-family cohort (human clinical evidence). Synonyms: CVDD; PLD1-related congenital heart disease; PLD1-related cardiac valvular dysplasia. ICD-10 maps broadly to congenital malformations of cardiac valves (Q22 for pulmonary/tricuspid valve anomalies; Q24 other). Information is derived from aggregated disease-level resources and primary case/cohort literature rather than EHR mining.

2. Etiology

Primary cause: genetic — biallelic (homozygous or compound heterozygous) loss-of-function variants in PLD1 (PMID: 33645542, PMID: 27799408). Genetic risk factors: carrier status for pathogenic PLD1 variants; the p.I668F founder allele (~2% in Ashkenazi Jews) markedly raises risk in that population; consanguinity increases homozygosity risk. Environmental/infectious factors: none established as causal for this Mendelian disorder. Protective factors: none specifically identified; a single functional PLD1 allele is protective (recessive disease, carriers unaffected). Gene–environment interactions: not characterized for CVDD.

3. Phenotypes

Phenotype Type Suggested HPO Onset Frequency Severity/Course
Pulmonary valve stenosis/atresia/dysplasia Clinical sign (structural) HP:0001642 / HP:0010450 Congenital/fetal Predominant (right-sided) Severe; progressive without intervention
Tricuspid valve dysplasia/regurgitation/atresia Clinical sign (structural) HP:0010446 / HP:0005180 Congenital/fetal Common Variable; can be severe
Mitral valve involvement Clinical sign HP:0001633 Congenital Less common Variable
Neonatal cardiomyopathy Clinical sign HP:0001638 Neonatal Distinct subset Severe
Non-immune fetal hydrops Physical manifestation HP:0001790 Fetal Severe cases Often lethal
Intrauterine fetal demise / stillbirth Outcome HP:0001560 Fetal Severe cases Lethal
Right ventricular hypoplasia / single-ventricle physiology Clinical sign HP:0001667 Congenital Severe cases Severe

Severity is variable (lethal fetal to adult-survivable). Quality-of-life impact: substantial in survivors — repeated cardiac surgery, chronic heart-failure risk, and lifelong cardiology follow-up (PMID: 42591229). Disease-specific QoL instruments have not been applied in published CVDD cohorts.

4. Genetic / Molecular Information

Causal gene: PLD1 (HGNC:9067; chromosome 3q26.31; UniProt Q13393). Variant types reported: missense (e.g., p.His442Pro, p.Ile668Phe, p.Arg816Pro, p.Arg391Cys), frameshift (p.Thr495fs32*), splice-site (c.2882+2T>C; c.1062-59A>G), and compound heterozygous combinations (PMID: 27799408, PMID: 33645542, PMID: 33142350, PMID: 39553471). Classification: pathogenic/likely pathogenic per ACMG, supported by functional enzymatic assays showing reduced activity. Functional consequence: loss of function (reduced catalysis); missense variants cluster in catalytic regions (PMID: 33645542). Allele frequency: p.I668F ~2% in Ashkenazi Jews (founder); other variants rare/novel in gnomAD. Origin: germline. Modifier genes / epigenetics / chromosomal abnormalities: not established for CVDD; note that 3q26 microdeletions potentially unmasking PLD1 were considered but not confirmed as a CHD mechanism in one report (PMID: 36345653).

5. Environmental Information

No environmental, lifestyle, or infectious agents are established as causal or contributory to CVDD. It is a monogenic recessive disorder. (Not applicable.)

6. Mechanism / Pathophysiology

See the Mechanistic Model section above for the full ordered causal chain and diagram. In brief: PLD1 LoF → ↓phosphatidic acid → ↓PA-dependent signaling (mTOR, RAF/MEK/ERK, S6K) → ↓EndMT → defective endocardial-cushion morphogenesis → valve malformation (or, as a branch, neonatal cardiomyopathy). Key GO terms: GO:0004630 (phospholipase D activity), GO:0003198/GO:0001837 (EndMT/EMT), GO:0003179 (heart valve morphogenesis). Cell types: endocardial endothelial cells (CL:0002350), valve interstitial cells.

7. Anatomical Structures Affected

Primary organ: heart — specifically the cardiac valves, with right-sided predominance (pulmonary valve UBERON:0002146; tricuspid valve UBERON:0002147; mitral valve UBERON:0002135 less commonly). Developmental origin: endocardial cushions (UBERON:0002062), atrioventricular canal, and outflow tract (UBERON:0004145). Secondary involvement: myocardium (UBERON:0002349) in the cardiomyopathy subset; systemic effects of heart failure/hydrops (fetal serous effusions). Body system: cardiovascular. Tissue/cell level: endocardial endothelium and cushion-derived mesenchyme/valve interstitial cells. Lateralization: right-sided predominant, but can be bilateral/multivalvular.

8. Temporal Development

Onset: congenital, with lesions arising during embryonic valvulogenesis; detectable prenatally by fetal echocardiography (as early as the late first/second trimester) (PMID: 37770978). Onset pattern: structural and present at birth (or fetal). Course: ranges from lethal fetal demise to chronic lifelong valve disease; progression in survivors can require staged/repeated surgical intervention (PMID: 42591229). Critical period: embryonic endocardial-cushion EndMT is the vulnerable window — a developmental event not amenable to postnatal correction of the underlying biology.

9. Inheritance and Population

Inheritance: autosomal recessive. Penetrance: appears high when biallelic LoF present, with variable expressivity (fetal-lethal to adult-survivable, even within the same variant class). Founder effect: p.I668F in Ashkenazi Jews (~2% allele frequency) (PMID: 33645542). Consanguinity: increases risk of homozygosity (several families reported with homozygous variants). Carrier frequency: elevated in Ashkenazi Jews due to the founder allele; rare elsewhere. Epidemiology: CVDD is a rare disease without precise prevalence/incidence estimates; it represents a small fraction of CHD (recessive genes contribute ≥2.2% of CHD overall — PMID: 40030011). Sex ratio: no strong sex bias reported (autosomal). Geographic/variant distribution: founder variant concentrated in Ashkenazi Jewish populations; other variants reported across diverse ancestries including Chinese and Japanese cohorts (PMID: 33142350, PMID: 37770978).

10. Diagnostics

Imaging: fetal and neonatal echocardiography is the primary diagnostic modality, revealing right-sided valve stenosis/atresia/dysplasia, regurgitation, ventricular hypoplasia, and cardiomyopathy (PMID: 37770978). Genetic testing: diagnosis confirmed by whole-exome sequencing (WES) or targeted PLD1 sequencing; WES is recommended for CHD fetuses without aneuploidy/pathogenic CNV on chromosomal microarray (CMA) (PMID: 33142350). CMA/CNV-seq is first-line to exclude aneuploidy and 22q11.2 deletion, then WES (PMID: 39205944). Prenatal diagnosis with Sanger confirmation of parental carrier status and splice-variant RT-PCR validation has been reported (PMID: 39553471). Functional confirmation: enzymatic activity assays and yeast sporulation assays support variant pathogenicity (PMID: 33645542, PMID: 27799408). Differential diagnosis: other causes of right-sided congenital valve disease and non-immune fetal hydrops, including Ebstein's anomaly and other monogenic/oligogenic CHD (PMID: 38884760); aneuploidies and 22q11.2 deletion syndrome. Screening: carrier screening for p.I668F is relevant in Ashkenazi Jewish populations; cascade testing of relatives once a familial variant is known.

11. Outcome / Prognosis

Prognosis is highly variable and lesion-dependent. At the severe end, CVDD causes recurrent intrauterine fetal demise and non-immune hydrops (lethal) (PMID: 37770978). Neonatal cardiomyopathy carries high morbidity/mortality. Survivors with structural valve disease can reach adulthood but typically require multiple open-heart surgeries and face chronic heart-failure risk (e.g., a proband with a 17-year disease history and three surgeries) (PMID: 42591229). No validated prognostic biomarkers are established; severity of the structural lesion and presence of cardiomyopathy/hydrops are the main prognostic factors. Formal survival statistics for CVDD specifically are not available (rare disease).

12. Treatment

There is no gene-specific or disease-modifying therapy. Management is lesion-specific surgical and interventional cardiac care: balloon valvuloplasty, surgical valvotomy/valve repair or replacement, and staged palliation for single-ventricle physiology, as dictated by the anatomic defect (PMID: 42591229). Supportive care includes standard heart-failure management for the cardiomyopathy subset. Suggested NCIT intervention concepts: cardiac valve repair/replacement surgery, balloon valvuloplasty, supportive/palliative cardiac care. No pharmacogenomic, gene-therapy, RNA-based, or targeted molecular therapies are currently available or in trials for CVDD. Pharmacologic PLD inhibitors exist (developed for thrombosis/cancer) but are not therapeutic here — the disease is caused by loss of PLD1 function.

13. Prevention

Primary prevention: genetic counseling and carrier screening (notably for p.I668F in Ashkenazi Jewish couples); for at-risk couples, preimplantation genetic testing (PGT) or prenatal diagnosis (CVS/amniocentesis with targeted variant testing) enables informed reproductive decisions (PMID: 39553471, PMID: 36923242). Secondary prevention: early fetal echocardiographic detection permits delivery planning at centers with pediatric cardiac surgery. Tertiary prevention: structured cardiology follow-up to manage valve dysfunction and heart failure. No vaccine or environmental interventions apply.

14. Other Species / Natural Disease

Orthologs: Pld1 is conserved across mammals (mouse NCBI Gene 18805), with functional orthologs in zebrafish, Drosophila, and yeast (the yeast PLD sporulation assay was used for functional validation — PMID: 27799408). A naturally occurring canine model of tricuspid valve malformation exists and is discussed in the context of tricuspid valve developmental disease, though not specifically attributed to PLD1 (PMID: 38884760). No zoonotic potential (non-infectious genetic disease).

15. Model Organisms

Mouse: constitutive Pld1-knockout mice are viable/fertile and exhibit platelet/thrombosis phenotypes (impaired αIIbβ3 activation, protection from arterial thrombosis and ischemic stroke) rather than congenital valve malformation (PMID: 20051593, PMID: 23868933); they also model platelet-mediated inflammation (PMID: 28711718) and TNF-α/sepsis responses (PMID: 29968773). Limitation: the knockout does not recapitulate the human congenital valve phenotype, limiting its utility for CVDD mechanism and therapy. Yeast: PLD sporulation assay provides a functional readout for variant pathogenicity (PMID: 27799408). Human iPSC valve-differentiation platforms generate valve interstitial-cell subtypes and model EndMT defects for other CHD genes (PMID: 41648231) — a promising, directly applicable system for PLD1 that has not yet been formally deployed for CVDD.

Evidence Base

PMID Title (abbrev.) Evidence type Role in this report
33645542 Biallelic LoF variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy Human cohort (30 pts/21 families) + functional Primary/landmark: gene, phenotype, LoF mechanism, EndMT link, p.I668F founder
27799408 Congenital valvular defects associated with deleterious mutations in PLD1 Human (2 families) + yeast assay First linkage of PLD1 to valvulogenesis (2017)
32198492 Crystal structure of human PLD1 … activation by PIP2 Structural/in vitro PLD1 enzymology and regulation (PKC, Arf, Rho, PIP2)
33495125 Structure and regulation of human phospholipase D Review/structural PA as pleiotropic second messenger (migration)
41173720 Phosphatidic acid at the crossroads of membrane dynamics Review PA downstream signaling via mTOR, RAF/MEK/ERK
20304930 Phosphatidic acid … acts through S6 kinase signaling In vitro PA → S6K → migration/chemotaxis (EndMT-relevant)
42600378 Regulation of EndMT in endocardial cushion development Review Canonical EndMT network PLD1/PA intersects
41648231 Dysregulated TGFβ-ERK … Noonan-associated PVS iPSC model EndMT/valve-differentiation model approach
20051593 Impaired αIIbβ3 … in mice lacking PLD1 Mouse model Pld1-KO models thrombosis, not valve defect
23868933 Pharmacological inhibition of PLD protects mice from thrombosis Mouse/pharmacology PLD inhibition → anti-thrombotic phenotype
37770978 Triple repeated fetal CHD linked to PLD1 mutation Human case report Severe fetal-lethal end of spectrum
42591229 Novel compound het PLD1 variants (2026) Human case report Adult-survivable end of spectrum
40030011 Recessive genetic contribution to CHD in 5,424 probands Human cohort Recessive-gene contribution context
33142350 CMA + ES in fetuses with CHD Human cohort Diagnostic yield, novel PLD1 variants
39553471 Prenatal detection of compound het PLD1 variants Human case Prenatal diagnosis, splice variant
38884760 Molecular Pathways and Animal Models of Ebstein's Anomaly Review Differential dx / canine tricuspid model

Consistency: All primary human genetic studies (2017 → 2026) converge on biallelic PLD1 LoF causing right-sided congenital valve disease, with functional assays uniformly showing reduced enzymatic activity. The EndMT mechanism is supported by one direct functional demonstration (PMID: 33645542) and is biologically coherent with the independently characterized EndMT network (PMID: 42600378) and PA signaling literature. The main tension in the evidence base is between the clear human valve phenotype and the mouse knockout, which shows thrombosis rather than valve malformation — unresolved and flagged as a limitation.

Limitations and Knowledge Gaps

  1. No faithful animal model. The constitutive Pld1-knockout mouse does not reproduce congenital valve defects (PMID: 20051593), leaving the in-vivo developmental mechanism without a validated mammalian model. Whether conditional/endocardial-specific or compound Pld1/Pld2 mouse models would reveal valve phenotypes is unknown.
  2. EndMT mechanism partly inferred. The direct evidence is that PLD1 inhibition decreases EndMT; the specific downstream PA effectors operative in endocardial cells (mTOR vs RAF/MEK/ERK vs S6K) are extrapolated from other cell types and not yet dissected in cardiac tissue.
  3. Genotype–phenotype correlation incomplete. The determinants of the fetal-lethal vs adult-survivable spectrum, and of the valve-defect vs cardiomyopathy branch, are not understood. Residual enzymatic activity, modifier genes, and environmental factors are all unmeasured.
  4. Epidemiology unquantified. Precise prevalence/incidence of CVDD are unavailable outside the founder population; carrier frequencies in non-Ashkenazi populations are not well defined.
  5. No disease-specific QoL, natural-history, or survival data. Outcomes derive from scattered case reports rather than systematic cohorts.
  6. No therapeutics beyond surgery. No molecular or gene-directed treatment exists or is in trial.

Proposed Follow-up Experiments / Actions

  1. Generate an endocardial/endothelial-specific conditional Pld1 mouse (e.g., Tie2-Cre or Nfatc1-Cre driven) and assess endocardial-cushion EndMT and valve morphogenesis — directly tests whether tissue-specific loss reproduces the human phenotype absent in the constitutive knockout.
  2. Deploy the human iPSC valve-differentiation platform for PLD1 (PMID: 41648231): CRISPR-engineer patient variants (p.I668F, p.His442Pro, frameshift) and quantify EndMT efficiency, valve interstitial-cell subtype specification, and PA levels; attempt rescue with exogenous phosphatidic acid.
  3. Lipidomic/phospho-signaling dissection in patient-derived endocardial cells to define which PA effectors (mTOR, ERK, S6K) are attenuated — closing the inferred steps of the causal chain.
  4. Assemble an international CVDD registry to quantify penetrance, expressivity, genotype–phenotype correlations, natural history, surgical outcomes, and survival.
  5. Formalize carrier-screening recommendations for p.I668F in Ashkenazi Jewish reproductive-genetics panels, and define carrier frequencies in additional populations via gnomAD/targeted screening.
  6. Test PA-pathway modulation as a proof-of-concept rescue in iPSC and organoid valve models (e.g., PA supplementation or downstream pathway stimulation) to explore whether any node is pharmacologically tractable.

Evidence source legend: human clinical = patient/family cohorts and case reports; model organism = mouse/yeast; in vitro = enzymatic/structural/cell assays; computational = variant prediction. This report integrates 6 confirmed findings and 36 reviewed papers across 5 iterations.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome Count
References checked 21
Resolved 21
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 14
Quoted claims found in source 14
Quoted claims not found in source 0
References weighed for topical relevance 21
On topic 11
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 26
Resolved 24
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 8
Terms named correctly 1
Terms named as a different term 5
Terms whose name is worth a second look 2

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:

  • HP:0001633 (1 mention) - the report calls it "Clinical sign"; HP calls it Abnormal mitral valve morphology
  • HP:0001638 (1 mention) - the report calls it "Clinical sign"; HP calls it Cardiomyopathy
  • HP:0001790 (1 mention) - the report calls it "Physical manifestation"; HP calls it Nonimmune hydrops fetalis
  • HP:0001560 (1 mention) - the report calls it "Outcome"; HP calls it Abnormality of the amniotic fluid
  • HP:0001667 (1 mention) - the report calls it "Clinical sign"; HP calls it Right ventricular hypertrophy

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:

  • GO:0001837 (2 mentions) - the report calls it "EndMT/EMT"; GO calls it epithelial to mesenchymal transition, and lists "EMT" among its other names
  • GO:0004630 (2 mentions) - the report calls it "phospholipase D activity"; GO calls it D-type glycerophospholipase activity, and lists "phospholipase D activity" 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: OMIM.