NKX2-5-Related Congenital, Conduction and Myopathic Heart Disease

Mendelian MONDO:0800441 Pathograph 31 Show in embeddings browser heart conduction disease familial cardiomyopathy

An autosomal dominant heart disease caused by heterozygous variants in NKX2-5, the cardiac homeodomain transcription factor at 5q35. One reduced gene dose produces three phenotypic arms that a single family may show in any combination: a congenital structural defect, most often a secundum atrial septal defect but also ventricular septal, conotruncal and left-heart hypoplastic lesions; atrioventricular conduction block that is progressive across a lifetime and carries a risk of syncope and sudden death; and a later-onset myopathic arm of hypertrabeculation or dilated cardiomyopathy with atrial and ventricular arrhythmia. The combination of septation failure with lifelong conduction decay reflects NKX2-5's two distinct roles, in cardiac morphogenesis and in the maturation and maintenance of the atrioventricular node.

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Inheritance

1
Autosomal dominant HP:0000006
Autosomal dominant. The conduction arm is the most consistently penetrant feature and the structural and myopathic arms vary within a family, so an unaffected-looking carrier is not evidence against transmission.
Autosomal dominant inheritance
Show evidence (2 references)
CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z SUPPORT REVIEW SYNTHESIS Other
"Phenotype is variable within families and individuals may have only some of these features."
ClinGen's statement of intrafamilial variability, which is the basis for the caveat in this block's description.
PMID:9651244 SUPPORT Human clinical
"A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35"
The dominant transmission established by linkage in the defining report.
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Pathophysiology

9
NKX2-5 Haploinsufficiency
Heterozygous NKX2-5 variants, either truncating or missense within the homeodomain, reduce the dose of functional cardiac homeodomain transcription factor. Most impair binding of NKX2-5 to its target DNA; some missense alleles additionally act dominant-negatively on the wild-type protein, and one reported allele instead augments target-DNA binding, so reduced dose is the common mechanism rather than the only one.
NKX2-5 hgnc:2488 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NKX2-5 (hgnc:2488). hgnc:2488 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
NKX2-5 DNA-binding transcription factor activity GO:0003700 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased NKX2-5 DNA-binding transcription factor activity, annotated with DNA-binding transcription factor activity (GO:0003700). GO:0003700 is a molecular function from the Gene Ontology.
Downstream
Impaired Cardiac Transcriptional Program Reduced NKX2-5 activity lowers transactivation of its target genes. The routes to that reduced activity differ by allele: a reduced protein dose, impaired DNA binding at a normal dose, or, for the allele quoted here, failure of the protein to reach the nucleus at all.
Show evidence (2 references)
PMID:9651244 SUPPORT Human clinical
"Two are predicted to impair binding of NKX2-5 to target DNA, resulting in haploinsufficiency, and a third potentially augments target-DNA binding."
The defining report's own account of the molecular consequence of the three founding alleles, including the one allele that does not fit the haploinsufficiency model.
CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z SUPPORT REVIEW SYNTHESIS Other
"Variants causing this phenotype appear to be either truncating or missense within the homeodomain."
ClinGen's synthesis across eighteen reports of where in the protein the disease-causing alleles fall, which is what restricts this node to truncating and homeodomain missense variants.
Impaired Cardiac Transcriptional Program
Reduced NKX2-5 transactivation lowers expression of its target genes in the developing septa and outflow tract, in the forming conduction system, and in trabecular myocardium, which is why one allele yields arms that dissociate from each other. NKX2-5 is known to act combinatorially with other cardiac transcription factors, but no source cited in this entry names those partners, so they are deliberately not listed here.
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.
NKX2-5-dependent transcription of cardiac target genes GO:0006357 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased NKX2-5-dependent transcription of cardiac target genes, annotated with regulation of transcription by RNA polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology.
Downstream
Defective Cardiac Septum Morphogenesis
Defective Outflow Tract and Valve Morphogenesis
Cardiac Conduction System Hypoplasia
Ectopic Ventricular BMP10 Expression
Defective Ventricular Trabecular Compaction Ventricular myocytes fail to be specified into their trabecular and conduction-system fates, which is the lineage reading of the compaction defect.
Show evidence (1 reference)
PMID:9651244 SUPPORT Human clinical
"These data indicate that NKX2-5 is important for regulation of septation during cardiac morphogenesis and for maturation and maintenance of atrioventricular node function throughout life."
States the two separable developmental roles that this node's downstream branches represent, and that the nodal role is a lifelong maintenance role rather than a developmental one only.
Defective Cardiac Septum Morphogenesis
Reduced NKX2-5 activity during septation leaves the atrial septum incomplete, most often as an ostium secundum defect, and less often leaves the interventricular septum incomplete. This node covers the septal lesions only; the outflow-tract and left-heart lesions in this disease's spectrum are a separate morphogenetic failure and are modelled as their own node.
cardiac septum morphogenesis GO:0060411 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cardiac septum morphogenesis (GO:0060411). GO:0060411 is a biological process from the Gene Ontology.
Downstream
Secundum atrial septal defect
Ventricular septal defect
Show evidence (2 references)
PMID:9651244 SUPPORT Human clinical
"Mutations in the gene encoding the homeobox transcription factor NKX2-5 were found to cause nonsyndromic, human congenital heart disease."
Establishes that the structural malformation is caused by the NKX2-5 genotype and is non-syndromic, so the defect is cardiac-restricted rather than part of a malformation syndrome.
PMID:22534315 SUPPORT Model organism
"Genetic linkage analysis mapped loci with lod scores of 5 to 7 on chromosomes 6, 8, and 10 that influence the susceptibility to membranous VSDs in Nkx2-5(+/-) animals."
A result rather than an aim: heterozygous Nkx2-5 loss produces septal defects in the mouse at a penetrance set by modifier loci, which is the experimental counterpart of the human septation claim and the reason this entry records genetic modifiers separately.
Defective Outflow Tract and Valve Morphogenesis
NKX2-5 is required beyond the septa. The same transcriptional deficit also disturbs outflow-tract alignment and septation of the conotruncus, the tricuspid valve, and the growth of the left heart, which is why conotruncal malformation, Ebstein anomaly and other tricuspid abnormalities, double outlet right ventricle and left-heart hypoplasia all appear in this gene's reported spectrum. These are separated from the septal node because a conotruncal or left-heart lesion is not a failure of septation.
outflow tract morphogenesis GO:0003151 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal outflow tract morphogenesis (GO:0003151). GO:0003151 is a biological process from the Gene Ontology.
Downstream
Conotruncal defect
Tetralogy of Fallot
Double outlet right ventricle
Ebstein anomaly of the tricuspid valve
Abnormal tricuspid valve morphology
Hypoplastic left ventricle
Show evidence (2 references)
PMID:10587520 SUPPORT PRIMARY RESULT Human clinical
"The coinheritance of NKX2.5 mutations with various congenital heart defects suggests that this transcription factor contributes to diverse cardiac developmental pathways."
The cohort study's own conclusion that this gene feeds more than one developmental pathway, which is the basis for modelling the non-septal lesions as a separate morphogenetic failure rather than as septation defects.
PMID:10587520 SUPPORT PRIMARY RESULT Human clinical
"Ebstein's anomaly and other tricuspid valve abnormalities were also present."
The tricuspid lesions this node carries, observed in the same NKX2-5 mutation cohort.
Cardiac Conduction System Hypoplasia
NKX2-5 is required for the development and the lifelong maintenance of the atrioventricular node and the His-Purkinje network. Reduced dosage yields an anatomically and functionally deficient conduction system whose reserve declines with age, which is why the block is progressive rather than fixed at birth.
nodal myocyte CL:0002072 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves nodal myocyte (CL:0002072). CL:0002072 is a cell type from the Cell Ontology. Purkinje myocyte CL:0002068 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Purkinje myocyte (CL:0002068). CL:0002068 is a cell type from the Cell Ontology.
cardiac conduction system development GO:0003161 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cardiac conduction system development (GO:0003161). GO:0003161 is a biological process from the Gene Ontology.
Animal models
Nkx2-5 trabecular conditional knockout mouse (Cx40-creERT2) Mouse recapitulates The same hearts lose Purkinje fibre network density and branching, so this model reports the conduction-system limb of the disease as well as the compaction limb.
Downstream
Postnatal Conduction Cell Dropout A conduction system built with too few cells has no reserve against the postnatal attrition of those cells.
Show evidence (4 references)
PMID:15085192 SUPPORT PRIMARY RESULT Model organism
"We show in KO mice that the number of cells in the cardiac conduction system is directly related to Nkx2-5 gene dosage."
Establishes that conduction-system cellularity is a function of NKX2-5 gene dose, which is what makes a hypoplastic conduction system the consequence of one lost allele rather than of a qualitatively different mechanism.
PMID:15085192 SUPPORT PRIMARY RESULT Model organism
"In Nkx2-5 haploinsufficiency, the conduction system has half the normal number of cells."
Quantifies the deficit at the heterozygous dose that corresponds to the human genotype.
PMID:15085192 SUPPORT PRIMARY RESULT Model organism
"Specific functional defects associated with Nkx2-5 loss of function can be attributed to hypoplastic development of the relevant structures in the conduction system."
Attributes the electrical phenotype to an anatomical deficit, which is the distinction this node makes against a purely channel-level conduction defect.
+ 1 more reference
Postnatal Conduction Cell Dropout
The atrioventricular node is already hypoplastic at birth and then loses conduction cells selectively over postnatal life. This is the step that makes the block progressive rather than a fixed congenital deficit, and it is why a normal electrocardiogram in childhood does not predict a normal one in adulthood.
nodal myocyte CL:0002072 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves nodal myocyte (CL:0002072). CL:0002072 is a cell type from the Cell Ontology.
Downstream
Progressive Atrioventricular Conduction Delay
Show evidence (1 reference)
PMID:15109497 SUPPORT PRIMARY RESULT Model organism
"At birth, mutant mice display a hypoplastic atrioventricular (AV) node and then develop selective dropout of these conduction cells."
Separates the congenital deficit from the progressive one in the same animals, which is the observation this node exists to carry.
Progressive Atrioventricular Conduction Delay
Atrioventricular conduction deteriorates over years, from PR prolongation through higher-grade block to complete atrioventricular block, which is the substrate for syncope and sudden death and the reason lifelong electrocardiographic surveillance is the central management decision.
cardiac conduction GO:0061337 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cardiac conduction (GO:0061337). GO:0061337 is a biological process from the Gene Ontology.
Downstream
First degree atrioventricular block
Atrioventricular block
Syncope High-grade block with an inadequate escape rate causes transient cerebral hypoperfusion.
Sudden cardiac death Complete atrioventricular block without adequate escape rhythm causes syncope and can cause sudden death; the intermediate steps are bradycardia and haemodynamic collapse or secondary ventricular arrhythmia.
Show evidence (1 reference)
PMID:29979676 SUPPORT BACKGROUND Model organism
"Nkx2-5+/- haploinsufficient mice have an abnormal electrocardiogram, with a prolonged QRS and progressive elongation of the PR interval"
The progressive, rather than fixed, character of the conduction delay in the haploinsufficient mouse. The sentence is this paper's restatement of earlier work, so it reports no method of its own.
Ectopic Ventricular BMP10 Expression
Loss of NKX2-5 in ventricular myocardium derepresses BMP10, which is normally restricted in the adult ventricle, and the ectopic BMP10 signal is itself required for much of the trabecular muscle overgrowth. No HGNC identifier is bound for BMP10 here because none could be sourced offline in this session; the BMP pathway is bound instead.
ectopic ventricular BMP10 signalling GO:0030509 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased ectopic ventricular BMP10 signalling, annotated with BMP signaling pathway (GO:0030509). GO:0030509 is a biological process from the Gene Ontology.
Downstream
Defective Ventricular Trabecular Compaction Ectopic BMP10 is not merely correlated with the trabecular phenotype; it is required for a major part of it.
Show evidence (1 reference)
PMID:15109497 SUPPORT PRIMARY RESULT Model organism
"ectopic, high level BMP-10 expression in the adult ventricular myocardium"
The transcriptional profiling result that identifies BMP10 derepression as a consequence of ventricular NKX2-5 loss.
Defective Ventricular Trabecular Compaction
The same reduced NKX2-5 dosage disturbs compaction of the ventricular trabecular myocardium, producing a hypertrabeculated or noncompacted ventricle with subendocardial fibrosis, and a later-onset dilated and arrhythmogenic myopathy. The severity tracks the developmental stage at which NKX2-5 activity is lost.
ventricular trabecula myocardium morphogenesis GO:0003222 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal ventricular trabecula myocardium morphogenesis (GO:0003222). GO:0003222 is a biological process from the Gene Ontology.
Animal models
Nkx2-5 trabecular conditional knockout mouse (Cx40-creERT2) Mouse recapitulates Trabecular-restricted loss of Nkx2-5 reproduces hypertrabeculation with subendocardial fibrosis, and the severity depends on the stage at which the gene is removed.
Downstream
Left ventricular noncompaction
Dilated cardiomyopathy The noncompacted, fibrotic ventricle remodels over years into a dilated and functionally impaired chamber.
Ventricular arrhythmia The remodelled, fibrotic ventricle of the myopathic arm becomes an arrhythmic substrate.
Supraventricular arrhythmia Atrial remodelling accompanying the myopathic arm predisposes to atrial arrhythmia.
Show evidence (2 references)
PMID:29979676 SUPPORT Model organism
"Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia."
Trabecular-restricted loss of Nkx2-5 is sufficient to produce the noncompaction phenotype, which places this arm downstream of the same transcriptional deficit rather than of the septal defect.
PMID:29979676 SUPPORT Model organism
"Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia."
Ties the myopathic and conduction arms to one developmental lesion, which is the reason this entry models them as siblings under one transcriptional node.
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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 NKX2-5-Related Congenital, Conduction and Myopathic 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

16
Secundum atrial septal defect FREQUENT Cardiovascular HP:0001684 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Secundum atrial septal defect (HP:0001684). HP:0001684 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z SUPPORT REVIEW SYNTHESIS Other
"more than 26 unique variants (missense, nonsense, frameshift, deletions) across 18 papers have reported cases of a similar phenotype including congenital heart disease (predominantly ASD), AV block and later onset dilated cardiomyopathy and/or hypertrabeculation with predisposition to atrial and..."
ClinGen's synthesis across the reported cohort, which is the basis for treating atrial septal defect as the predominant structural lesion.
PMID:26679770 SUPPORT REVIEW SYNTHESIS Human clinical
"The majority of patients (74%) had ASD with conduction disturbance."
A pooled figure across 202 reported patients putting the septal-defect plus conduction-disturbance combination at 74%, which is the basis for the FREQUENT band on this phenotype.
Atrioventricular block FREQUENT Cardiovascular HP:0001678 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrioventricular block (HP:0001678), qualified as course progressive. HP:0001678 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:9651244 SUPPORT Human clinical
"A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35, where NKX2-5, a Drosophila tinman homolog, is located."
Conduction abnormality is part of the phenotype that defined the locus, not a later addition to the spectrum.
PMID:10587520 SUPPORT BACKGROUND Human clinical
"Heterozygous mutations in NKX2.5, a homeobox transcription factor, were reported to cause secundum atrial septal defects and result in atrioventricular (AV) conduction block during postnatal life."
States that the block arises postnatally rather than being present at birth, which is the clinical counterpart of the conduction-cell dropout node. The sentence is this paper's restatement of the prior report, hence BACKGROUND.
Ventricular septal defect Cardiovascular 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)
CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z SUPPORT REVIEW SYNTHESIS Other
"Ventricular septal defect 3 (OMIM:614432)"
One of the five congenital heart disease entities ClinGen lumped into this gene-disease relationship.
PMID:10587520 SUPPORT PRIMARY RESULT Human clinical
"Associated phenotypes included AV block, which was the primary manifestation of cardiac disease in nearly a quarter of affected individuals, as well as atrial septal defect and ventricular septal defect."
Reports ventricular septal defect directly in an NKX2-5 cohort rather than through an OMIM entity list.
Conotruncal defect Cardiovascular HP:0001710 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Conotruncal defect (HP:0001710). HP:0001710 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z SUPPORT REVIEW SYNTHESIS Other
"Conotruncal heart malformations, variable (OMIM:217095)"
One of the five congenital heart disease entities ClinGen lumped into this gene-disease relationship.
Tetralogy of Fallot Cardiovascular HP:0001636 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tetralogy of Fallot (HP:0001636). HP:0001636 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10587520 SUPPORT PRIMARY RESULT Human clinical
"Mutations in human NKX2.5 cause a variety of cardiac anomalies and may account for a clinically significant portion of tetralogy of Fallot and idiopathic AV block."
The cohort study that put tetralogy of Fallot in this gene's phenotype, and that also makes isolated atrioventricular block a presentation in its own right.
Hypoplastic left ventricle Cardiovascular HP:0004383 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplastic left ventricle (HP:0004383). HP:0004383 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z SUPPORT REVIEW SYNTHESIS Other
"Hypoplastic left heart syndrome 2 (OMIM:614435)"
One of the five congenital heart disease entities ClinGen lumped into this gene-disease relationship.
Left ventricular noncompaction OCCASIONAL Cardiovascular HP:0030682 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular noncompaction (HP:0030682). HP:0030682 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20932824 SUPPORT Human clinical
"This study for the first time identifies association between a NKX2.5 mutation and ventricular noncompaction."
The report that added noncompaction to the NKX2-5 phenotype, which is why the myopathic arm is modelled separately from the septal one.
PMID:34277740 SUPPORT Human clinical
"However, an overlapping phenotype is not frequent in the literature."
Direct support for the OCCASIONAL band rather than a higher one: the combination of structural defect, noncompaction and conduction disease in one family is reported as uncommon.
Dilated cardiomyopathy OCCASIONAL Cardiovascular 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 (3 references)
CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z SUPPORT REVIEW SYNTHESIS Other
"AV block and later onset dilated cardiomyopathy and/or hypertrabeculation with predisposition to atrial and ventricular arrhythmias"
ClinGen's 2024 update, which expanded the classification summary specifically to record the cardiomyopathy and arrhythmia arm.
PMID:27855642 SUPPORT PRIMARY RESULT Human clinical
"In addition to DCM, the phenotypes included atrial and ventricular septal defects, cardiac arrhythmia and sudden death."
The primary human source for the dilated phenotype, in two families where it segregated alongside the septal and arrhythmic features rather than in isolation.
PMID:27855642 SUPPORT PRIMARY RESULT Human clinical
"We identified distinct mutations affecting a common amino acid in NKX2.5. Segregation analysis of the families support the pathogenic role of these variants."
Segregation evidence that the dilated phenotype tracks the NKX2-5 variant, which is what makes this a phenotype of the disease rather than a coincidental cardiomyopathy.
Ventricular arrhythmia Cardiovascular HP:0004308 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular arrhythmia (HP:0004308). HP:0004308 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z SUPPORT REVIEW SYNTHESIS Other
"with predisposition to atrial and ventricular arrhythmias"
The arrhythmic predisposition ClinGen records alongside the myopathic arm.
Supraventricular arrhythmia Cardiovascular HP:0005115 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Supraventricular arrhythmia (HP:0005115). HP:0005115 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z SUPPORT REVIEW SYNTHESIS Other
"with predisposition to atrial and ventricular arrhythmias"
The atrial half of the same arrhythmic predisposition.
Syncope Cardiovascular HP:0001279 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Syncope (HP:0001279). HP:0001279 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20932824 SUPPORT Human clinical
"We identified a CHD family with atrial septal defects (ASDs), atrioventricular block, ventricular noncompaction, syncope and sudden death."
Syncope in a family segregating an NKX2-5 allele, as the clinical manifestation of the conduction arm.
Sudden cardiac death OCCASIONAL Cardiovascular HP:0001645 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sudden cardiac death (HP:0001645). HP:0001645 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:20932824 SUPPORT Human clinical
"NKX2.5 mutation c.512insGC is associated with ASDs, syncope and sudden death."
The report's own conclusion that the allele is associated with sudden death.
PMID:26679770 SUPPORT REVIEW SYNTHESIS Human clinical
"Nineteen patients (15%) of 120 with familial ASD and conduction disturbance died from sudden cardiac death of which nine (8%) were confirmed mutation carriers, and 10 were possible carriers."
The pooled sudden-death figure, with the confirmed-carrier subset stated separately, which is why the frequency band here is read from the 8% confirmed rather than the 15% combined.
PMID:26679770 SUPPORT Human clinical
"mutation carriers are at increased risk of sudden cardiac death"
The review's own conclusion, which is what makes surveillance and device decisions a standing question in carriers rather than only in the affected.
First degree atrioventricular block Cardiovascular HP:0011705 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is First degree atrioventricular block (HP:0011705). HP:0011705 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10587520 SUPPORT Human clinical
"we sought additional mutations in groups of probands with cardiac anomalies and first-degree AV block, idiopathic AV block, or tetralogy of Fallot"
First-degree block is one of the cohorts in which this study ascertained probands and then found seven novel NKX2-5 mutations, so the degree of block named here is part of the spectrum. The sentence states the study's aim rather than a result, so no quote_role applies to it.
Ebstein anomaly of the tricuspid valve Cardiovascular 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:10587520 SUPPORT PRIMARY RESULT Human clinical
"Ebstein's anomaly and other tricuspid valve abnormalities were also present."
Extends the structural spectrum beyond the septa to the tricuspid valve in an NKX2-5 mutation cohort.
Abnormal tricuspid valve morphology Cardiovascular 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:10587520 SUPPORT PRIMARY RESULT Human clinical
"Ebstein's anomaly and other tricuspid valve abnormalities were also present."
The same sentence records tricuspid abnormalities other than Ebstein anomaly, which this broader phenotype carries.
Double outlet right ventricle Cardiovascular HP:0001719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Double outlet right ventricle (HP:0001719). HP:0001719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10587520 SUPPORT PRIMARY RESULT Human clinical
"Ventricular septal defect was associated with tetralogy of Fallot or double-outlet right ventricle in 3 individuals."
Double outlet right ventricle occurring with the septal defect in three individuals of this cohort.
🧬

Genetic Associations

1
NKX2-5 (The single causative gene; variants are truncating or missense within the homeodomain.)
Gene: NKX2-5 hgnc:2488 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is NKX2-5 (hgnc:2488). hgnc:2488 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (1 reference)
PMID:9651244 SUPPORT Human clinical
"Three different NKX2-5 mutations were identified."
The founding allelic series, in the linkage study that established the gene.
💊

Medical Actions

3
Lifelong Conduction Surveillance and Permanent Pacing
Action: permanent cardiac pacemaker implantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is permanent cardiac pacemaker implantation, annotated with Pacemaker Procedure (NCIT:C99998), qualified as medical device permanent cardiac pacemaker. NCIT:C99998 is a clinical intervention from the NCI Thesaurus. Ontology label: Pacemaker Procedure NCIT:C99998
Platform: Device
Because atrioventricular block is progressive rather than fixed, a normal electrocardiogram at diagnosis does not discharge a carrier from follow-up. Serial electrocardiography, with permanent pacemaker implantation when block advances, is the management decision that addresses the bradyarrhythmic mode of death. It does not cover the arrhythmic mode: pacing substitutes for a failing node and does nothing about ventricular arrhythmia arising from the myopathic arm, which is the separate question the defibrillator entry records.
Mechanism Target:
Progressive Atrioventricular Conduction Delay — Pacing substitutes for the failing atrioventricular node; it does not alter the underlying conduction-system hypoplasia.
Show evidence (1 reference)
PMID:9651244 SUPPORT INDIRECT Human clinical
"for maturation and maintenance of atrioventricular node function throughout life"
The lifelong maintenance role is why surveillance has to be lifelong rather than concluded in childhood; the quote supports the rationale, not a trial result.
Implantable Cardioverter-Defibrillator Consideration in Mutation Carriers
Action: implantable cardioverter-defibrillator placementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is implantable cardioverter-defibrillator placement (NCIT:C80435), qualified as medical device implantable cardioverter-defibrillator. NCIT:C80435 is a clinical intervention from the NCI Thesaurus. Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435
Platform: Device
The review that pooled the published cohort proposed considering an implantable cardioverter-defibrillator in NKX2-5 mutation carriers from families with atrial septal defect and conduction disturbance, on the strength of the sudden-death rate in those families. This is a proposal from a literature review rather than a trial result or a guideline recommendation, and it is recorded here as such; the decision in practice follows the general cardiomyopathy and conduction-disease guidelines.
Mechanism Target:
Sudden cardiac death — A defibrillator addresses the arrhythmic mode of death. The sudden-death rate in these families is the reason the cited review proposes it, so this is the outcome it targets.
Ventricular arrhythmia — The arrhythmia a defibrillator terminates, which arises from the myopathic arm rather than from the conduction deficit that pacing covers.
Show evidence (1 reference)
PMID:26679770 SUPPORT REVIEW SYNTHESIS Human clinical
"if they are mutation carriers, implantation of an implantable cardioverter-defibrillator should be considered in these patients"
The proposal itself, quoted so the strength of the recommendation is visible rather than paraphrased into something firmer.
Surgical or Transcatheter Closure of the Septal Defect
Action: cardiac septal defect repairNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cardiac septal defect repair, annotated with Surgical Procedure (NCIT:C15329). NCIT:C15329 is a clinical intervention from the NCI Thesaurus. Ontology label: Surgical Procedure NCIT:C15329
Platform: Surgery
Closure of a haemodynamically significant atrial or ventricular septal defect, on the same indications as in isolated disease. It does not address the conduction or myopathic arms, which continue to require surveillance afterwards.
Mechanism Target:
Defective Cardiac Septum Morphogenesis
🌍

Environmental Factors

1
Advanced maternal age
advanced maternal age Relation: this environmental factor is this exposure This environmental factor is advanced maternal age.
No ontology term is bound. ECTO has no maternal-age class: searching OLS (ontologyId=ecto) for "maternal age" returns only ECTO:0300011 exposure to opioid agent via maternal, and neither cache/ecto/terms.csv nor cache/xco/terms.csv holds a maternal-age or parental-age row. Maternal age is a parental characteristic rather than an exposure to a substance, so no ECTO class is expected to fit; a wrong binding would be worse than none.
In the mouse, maternal age modifies the risk that a heterozygous Nkx2-5 genotype produces a septal defect, and it does so only in mutant offspring. This is a modifier of penetrance in a model organism, not an established human risk factor, and it is recorded as MODULATES rather than as a trigger.
Show evidence (1 reference)
PMID:22534315 SUPPORT PRIMARY RESULT Model organism
"The maternal age effect is unrelated to aneuploidy or a genetic polymorphism in the affected individuals."
Excludes the two obvious confounders for a maternal-age association, which is why it is recorded as a modifier at all rather than dismissed.
Mechanism Target:
MODULATES Defective Cardiac Septum Morphogenesis — Maternal age shifts the probability that the septal defect occurs at a given genotype; the mechanism linking the two is not established.
Show evidence (1 reference)
PMID:22534315 SUPPORT PRIMARY RESULT Model organism
"Multiple logistic regression analysis for environmental variables revealed that maternal age is correlated with the risk of membranous and muscular VSD in Nkx2-5(+/-) but not wild-type animals."
The genotype-restricted maternal-age effect, which is what makes this a modifier of this disease's penetrance rather than a general risk factor for septal defects.
🔬

Diagnosis

3
Electrocardiography with serial follow-up
The test that detects the conduction arm and its progression. A single normal recording does not exclude future block.
Show evidence (1 reference)
PMID:9651244 SUPPORT INDIRECT Human clinical
"for maturation and maintenance of atrioventricular node function throughout life"
A lifelong maintenance role for the gene at the atrioventricular node is why a single normal recording cannot discharge a carrier; the quote supports the rationale for serial testing rather than reporting a surveillance study.
Echocardiography
Detects the septal defect and the hypertrabeculated or dilated ventricle.
NKX2-5 sequencing
Confirms the diagnosis and enables cascade testing of relatives, who then enter conduction surveillance regardless of whether they have a structural defect.
📈

Progression

3
Congenital structural lesion
The septal, conotruncal, left-heart or tricuspid lesion is present at birth. This is the phase that usually brings the family to attention, and it is the only one of the three arms that is complete at birth.
Postnatal onset and progression of conduction block
Atrioventricular conduction block appears and worsens after birth, which is why a carrier with a normal electrocardiogram in childhood is not discharged. Repairing the septal defect does not arrest this arm.
Show evidence (1 reference)
PMID:10587520 SUPPORT BACKGROUND Human clinical
"result in atrioventricular (AV) conduction block during postnatal life"
Places the onset of block after birth, which is what separates this phase from the congenital one.
Later-onset myopathy and arrhythmia
Hypertrabeculation or dilated cardiomyopathy, atrial and ventricular arrhythmia, and the risk of sudden cardiac death accrue later, and carry the mortality of the disease.
Show evidence (1 reference)
CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z SUPPORT REVIEW SYNTHESIS Other
"AV block and later onset dilated cardiomyopathy and/or hypertrabeculation with predisposition to atrial and ventricular arrhythmias"
ClinGen's own ordering of the arms in time, with the myopathic one recorded as later in onset.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from NKX2-5-Related Congenital, Conduction and Myopathic Heart Disease:

Isolated secundum atrial septal defect
Overlapping Features The commonest alternative. The discriminator is the electrocardiogram and the family history: progressive atrioventricular block in the proband or in a structurally normal relative points to this gene rather than to an isolated defect. The dismech entry Atrial_Septal_Defect carries the ASD7 row for the atrial-septal component of this disease.
Show evidence (1 reference)
PMID:9651244 SUPPORT INDIRECT Human clinical
"A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35"
The co-occurrence of malformation with conduction abnormality in a dominant pedigree is the feature that separates this disease from an isolated septal defect; the quote supports the discriminator rather than a comparative study.
Familial progressive cardiac conduction disease
Overlapping Features Progressive atrioventricular block without a structural defect, including SCN5A- and LMNA-related conduction disease. A septal defect anywhere in the family, or hypertrabeculation, favours NKX2-5.
Left ventricular noncompaction of other genetic cause
Overlapping Features Sarcomeric and other LVNC genes produce hypertrabeculation without septation failure or early conduction block.
📊

Related Datasets

1
Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy geo:GSE113251
Expression profiling by array of severe versus mild Nkx2-5 trabecular conditional knockout hearts, the transcriptomic arm of the mouse study behind the myopathic node.
house mouse MICROARRAY
PMID:29979676
Show evidence (1 reference)
GEO:GSE113251 SUPPORT Model organism
"identifies Six1 as a marker upregulated in hypertrabeculated hearts"
The series summary's own statement of what the expression data show, which is what this dataset contributes beyond the histology.
🐁

Animal Models

1
Nkx2-5 trabecular conditional knockout mouse (Cx40-creERT2)
Tamoxifen-inducible deletion of Nkx2-5 restricted to Cx40-expressing trabecular myocardium, at two developmental stages, which separates the myopathic arm of the disease from the septal arm.
Species
Mouse
Genotype
Nkx2-5 floxed; Cx40-creERT2, tamoxifen-induced at E10.5-E11.5 or E13.5-E14.5
Publication
PMID:29979676
Pathograph links
Defective Ventricular Trabecular Compaction recapitulates fidelity: moderate observes: tissue Trabecular-restricted loss of Nkx2-5 reproduces hypertrabeculation with subendocardial fibrosis, and the severity depends on the stage at which the gene is removed.
Limitations: A conditional, tissue-restricted and complete deletion is not the human germline heterozygous state, so the model speaks to the sufficiency of trabecular Nkx2-5 loss rather than to what one reduced allele does across the whole heart.
Divergences from the human mechanism
proxy quantity qualifying
The model's quantity is complete somatic ablation of Nkx2-5 within a Cx40-defined compartment. The human quantity is a halved gene dose in every cardiac cell from conception.
Readouts
Endocardial length and endocardial islet count
Direction: INCREASED
Interpretation: The morphometric readout of excessive trabeculation and failed compaction.
Show evidence (1 reference)
PMID:29979676 SUPPORT Model organism
"Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia."
Reports the hypertrabeculated phenotype this readout measures.
Show evidence (1 reference)
PMID:29979676 SUPPORT Model organism
"we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis using an inducible Cx40-creERT2 allele"
Establishes the genotype and the staged design that make this model informative for the compaction node.
Cardiac Conduction System Hypoplasia recapitulates fidelity: moderate observes: tissue The same hearts lose Purkinje fibre network density and branching, so this model reports the conduction-system limb of the disease as well as the compaction limb.
Limitations: Deletion is restricted to the Cx40-expressing trabecular compartment, so the model speaks to the Purkinje network rather than to the atrioventricular node, which is where the human block is generated.
Readouts
Purkinje fibre network density and branching
Direction: DECREASED
Interpretation: Structural measurement of the conduction-system deficit, attached to the node it actually measures.
Show evidence (1 reference)
PMID:29979676 SUPPORT Model organism
"Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia."
Reports the Purkinje hypoplasia measured in these hearts.
Show evidence (1 reference)
PMID:29979676 SUPPORT Model organism
"Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia."
States the conduction-system hypoplasia this link carries, in the same animals as the compaction defect.
Show evidence (1 reference)
PMID:29979676 SUPPORT Model organism
"represents a highly tractable model to study the cellular and molecular mechanisms involved in the disease"
The authors' own claim for the model's usefulness, which is what justifies treating it as informative for this entry's myopathic arm rather than as an unrelated conditional knockout.
{ }

Source YAML

click to show 
name: NKX2-5-Related Congenital, Conduction and Myopathic Heart Disease
creation_date: "2026-11-05T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: NKX2-5-related congenital, conduction and myopathic heart disease
  term:
    id: MONDO:0800441
    label: NKX2.5-related congenital, conduction and myopathic heart disease
synonyms:
- NKX2.5-related congenital, conduction and myopathic heart disease
- NKX2-5-related congenital heart disease
- atrial septal defect 7 with or without atrioventricular conduction defects
- CSX-related congenital heart disease
description: >-
  An autosomal dominant heart disease caused by heterozygous variants in NKX2-5,
  the cardiac homeodomain transcription factor at 5q35. One reduced gene dose
  produces three phenotypic arms that a single family may show in any
  combination: a congenital structural defect, most often a secundum atrial
  septal defect but also ventricular septal, conotruncal and left-heart
  hypoplastic lesions; atrioventricular conduction block that is progressive
  across a lifetime and carries a risk of syncope and sudden death; and a
  later-onset myopathic arm of hypertrabeculation or dilated cardiomyopathy with
  atrial and ventricular arrhythmia. The combination of septation failure with
  lifelong conduction decay reflects NKX2-5's two distinct roles, in cardiac
  morphogenesis and in the maturation and maintenance of the atrioventricular
  node.
parents:
- heart conduction disease
- familial cardiomyopathy
progression:
- phase: Congenital structural lesion
  notes: >-
    The septal, conotruncal, left-heart or tricuspid lesion is present at birth.
    This is the phase that usually brings the family to attention, and it is the
    only one of the three arms that is complete at birth.
- phase: Postnatal onset and progression of conduction block
  notes: >-
    Atrioventricular conduction block appears and worsens after birth, which is
    why a carrier with a normal electrocardiogram in childhood is not discharged.
    Repairing the septal defect does not arrest this arm.
  evidence:
  - reference: PMID:10587520
    reference_title: Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "result in atrioventricular (AV) conduction block during postnatal life"
    explanation: >-
      Places the onset of block after birth, which is what separates this phase
      from the congenital one.
- phase: Later-onset myopathy and arrhythmia
  notes: >-
    Hypertrabeculation or dilated cardiomyopathy, atrial and ventricular
    arrhythmia, and the risk of sudden cardiac death accrue later, and carry the
    mortality of the disease.
  evidence:
  - reference: CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z
    reference_title: "NKX2-5 / NKX2.5-related congenital, conduction and myopathic heart disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "AV block and later onset dilated cardiomyopathy and/or hypertrabeculation with predisposition to atrial and ventricular arrhythmias"
    explanation: >-
      ClinGen's own ordering of the arms in time, with the myopathic one recorded
      as later in onset.
references:
- reference: PMID:9651244
  title: Congenital heart disease caused by mutations in the transcription factor NKX2-5.
pathophysiology:
- name: NKX2-5 Haploinsufficiency
  description: >-
    Heterozygous NKX2-5 variants, either truncating or missense within the
    homeodomain, reduce the dose of functional cardiac homeodomain transcription
    factor. Most impair binding of NKX2-5 to its target DNA; some missense
    alleles additionally act dominant-negatively on the wild-type protein, and
    one reported allele instead augments target-DNA binding, so reduced dose is
    the common mechanism rather than the only one.
  biological_scale: MOLECULAR
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  genes:
  - preferred_term: NKX2-5
    term:
      id: hgnc:2488
      label: NKX2-5
  molecular_functions:
  - preferred_term: NKX2-5 DNA-binding transcription factor activity
    modifier: DECREASED
    term:
      id: GO:0003700
      label: DNA-binding transcription factor activity
  evidence:
  - reference: PMID:9651244
    reference_title: Congenital heart disease caused by mutations in the transcription factor NKX2-5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two are predicted to impair binding of NKX2-5 to target DNA, resulting in haploinsufficiency, and a third potentially augments target-DNA binding."
    explanation: >-
      The defining report's own account of the molecular consequence of the three
      founding alleles, including the one allele that does not fit the
      haploinsufficiency model.
  - reference: CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z
    reference_title: "NKX2-5 / NKX2.5-related congenital, conduction and myopathic heart disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Variants causing this phenotype appear to be either truncating or missense within the homeodomain."
    explanation: >-
      ClinGen's synthesis across eighteen reports of where in the protein the
      disease-causing alleles fall, which is what restricts this node to
      truncating and homeodomain missense variants.
  downstream:
  - target: Impaired Cardiac Transcriptional Program
    causal_link_type: DIRECT
    description: >-
      Reduced NKX2-5 activity lowers transactivation of its target genes. The
      routes to that reduced activity differ by allele: a reduced protein dose,
      impaired DNA binding at a normal dose, or, for the allele quoted here,
      failure of the protein to reach the nucleus at all.
    evidence:
    - reference: PMID:20932824
      reference_title: "A de novo mutation in NKX2.5 associated with atrial septal defects, ventricular noncompaction, syncope and sudden death."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Functional studies indicate that the c.512insGC mutation impedes nuclear localization of NKX2.5 and causes a total loss of transactivation activity of NKX2.5."
      explanation: >-
        A reporter assay showing that a disease allele abolishes NKX2-5
        transactivation, which is the step connecting the variant to a failed
        transcriptional program rather than either node alone.
- name: Impaired Cardiac Transcriptional Program
  description: >-
    Reduced NKX2-5 transactivation lowers expression of its target genes in the
    developing septa and outflow tract, in the forming conduction system, and in
    trabecular myocardium, which is why one allele yields arms that dissociate
    from each other. NKX2-5 is known to act combinatorially with other cardiac
    transcription factors, but no source cited in this entry names those partners,
    so they are deliberately not listed here.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: NKX2-5-dependent transcription of cardiac target genes
    modifier: DECREASED
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:9651244
    reference_title: Congenital heart disease caused by mutations in the transcription factor NKX2-5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These data indicate that NKX2-5 is important for regulation of septation during cardiac morphogenesis and for maturation and maintenance of atrioventricular node function throughout life."
    explanation: >-
      States the two separable developmental roles that this node's downstream
      branches represent, and that the nodal role is a lifelong maintenance role
      rather than a developmental one only.
  downstream:
  - target: Defective Cardiac Septum Morphogenesis
    causal_link_type: DIRECT
  - target: Defective Outflow Tract and Valve Morphogenesis
    causal_link_type: DIRECT
  - target: Cardiac Conduction System Hypoplasia
    causal_link_type: DIRECT
  - target: Ectopic Ventricular BMP10 Expression
    causal_link_type: DIRECT
  - target: Defective Ventricular Trabecular Compaction
    causal_link_type: DIRECT
    description: >-
      Ventricular myocytes fail to be specified into their trabecular and
      conduction-system fates, which is the lineage reading of the compaction
      defect.
    evidence:
    - reference: PMID:15109497
      reference_title: Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "loss of ventricular muscle cell lineage specification into trabecular and conduction system myocytes is a new mechanistic pathway for progressive cardiomyopathy and conduction defects in congenital heart disease."
      explanation: >-
        States the mechanism as a lineage-specification failure feeding both the
        myopathic and the conduction arms, which is how this entry branches them.
- name: Defective Cardiac Septum Morphogenesis
  description: >-
    Reduced NKX2-5 activity during septation leaves the atrial septum incomplete,
    most often as an ostium secundum defect, and less often leaves the
    interventricular septum incomplete. This node covers the septal lesions only;
    the outflow-tract and left-heart lesions in this disease's spectrum are a
    separate morphogenetic failure and are modelled as their own node.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: cardiac septum morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0060411
      label: cardiac septum morphogenesis
  evidence:
  - reference: PMID:9651244
    reference_title: Congenital heart disease caused by mutations in the transcription factor NKX2-5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the gene encoding the homeobox transcription factor NKX2-5 were found to cause nonsyndromic, human congenital heart disease."
    explanation: >-
      Establishes that the structural malformation is caused by the NKX2-5
      genotype and is non-syndromic, so the defect is cardiac-restricted rather
      than part of a malformation syndrome.
  - reference: PMID:22534315
    reference_title: Complex trait analysis of ventricular septal defects caused by Nkx2-5 mutation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Genetic linkage analysis mapped loci with lod scores of 5 to 7 on chromosomes 6, 8, and 10 that influence the susceptibility to membranous VSDs in Nkx2-5(+/-) animals."
    explanation: >-
      A result rather than an aim: heterozygous Nkx2-5 loss produces septal
      defects in the mouse at a penetrance set by modifier loci, which is the
      experimental counterpart of the human septation claim and the reason this
      entry records genetic modifiers separately.
  downstream:
  - target: Secundum atrial septal defect
    causal_link_type: DIRECT
  - target: Ventricular septal defect
    causal_link_type: DIRECT
- name: Defective Outflow Tract and Valve Morphogenesis
  description: >-
    NKX2-5 is required beyond the septa. The same transcriptional deficit also
    disturbs outflow-tract alignment and septation of the conotruncus, the
    tricuspid valve, and the growth of the left heart, which is why conotruncal
    malformation, Ebstein anomaly and other tricuspid abnormalities, double
    outlet right ventricle and left-heart hypoplasia all appear in this gene's
    reported spectrum. These are separated from the septal node because a
    conotruncal or left-heart lesion is not a failure of septation.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: outflow tract morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0003151
      label: outflow tract morphogenesis
  evidence:
  - reference: PMID:10587520
    reference_title: Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The coinheritance of NKX2.5 mutations with various congenital heart defects suggests that this transcription factor contributes to diverse cardiac developmental pathways."
    explanation: >-
      The cohort study's own conclusion that this gene feeds more than one
      developmental pathway, which is the basis for modelling the non-septal
      lesions as a separate morphogenetic failure rather than as septation
      defects.
  - reference: PMID:10587520
    reference_title: Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Ebstein's anomaly and other tricuspid valve abnormalities were also present."
    explanation: >-
      The tricuspid lesions this node carries, observed in the same NKX2-5
      mutation cohort.
  downstream:
  - target: Conotruncal defect
    causal_link_type: DIRECT
  - target: Tetralogy of Fallot
    causal_link_type: DIRECT
  - target: Double outlet right ventricle
    causal_link_type: DIRECT
  - target: Ebstein anomaly of the tricuspid valve
    causal_link_type: DIRECT
  - target: Abnormal tricuspid valve morphology
    causal_link_type: DIRECT
  - target: Hypoplastic left ventricle
    causal_link_type: DIRECT
- name: Cardiac Conduction System Hypoplasia
  description: >-
    NKX2-5 is required for the development and the lifelong maintenance of the
    atrioventricular node and the His-Purkinje network. Reduced dosage yields an
    anatomically and functionally deficient conduction system whose reserve
    declines with age, which is why the block is progressive rather than fixed at
    birth.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: cardiac conduction system development
    modifier: ABNORMAL
    term:
      id: GO:0003161
      label: cardiac conduction system development
  cell_types:
  - preferred_term: nodal myocyte
    term:
      id: CL:0002072
      label: nodal myocyte
  - preferred_term: Purkinje myocyte
    term:
      id: CL:0002068
      label: Purkinje myocyte
  evidence:
  - reference: PMID:15085192
    reference_title: Nkx2-5 mutation causes anatomic hypoplasia of the cardiac conduction system.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "We show in KO mice that the number of cells in the cardiac conduction system is directly related to Nkx2-5 gene dosage."
    explanation: >-
      Establishes that conduction-system cellularity is a function of NKX2-5 gene
      dose, which is what makes a hypoplastic conduction system the consequence of
      one lost allele rather than of a qualitatively different mechanism.
  - reference: PMID:15085192
    reference_title: Nkx2-5 mutation causes anatomic hypoplasia of the cardiac conduction system.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "In Nkx2-5 haploinsufficiency, the conduction system has half the normal number of cells."
    explanation: >-
      Quantifies the deficit at the heterozygous dose that corresponds to the
      human genotype.
  - reference: PMID:15085192
    reference_title: Nkx2-5 mutation causes anatomic hypoplasia of the cardiac conduction system.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Specific functional defects associated with Nkx2-5 loss of function can be attributed to hypoplastic development of the relevant structures in the conduction system."
    explanation: >-
      Attributes the electrical phenotype to an anatomical deficit, which is the
      distinction this node makes against a purely channel-level conduction
      defect.
  - reference: PMID:29979676
    reference_title: Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These mice display ventricular conduction defects that can be correlated with hypoplastic development of the His-Purkinje system"
    explanation: >-
      An independent group's statement of the same anatomical basis, here for the
      His-Purkinje limb rather than the node.
    quote_role: BACKGROUND
  downstream:
  - target: Postnatal Conduction Cell Dropout
    causal_link_type: DIRECT
    description: >-
      A conduction system built with too few cells has no reserve against the
      postnatal attrition of those cells.
    evidence:
    - reference: PMID:15085192
      reference_title: Nkx2-5 mutation causes anatomic hypoplasia of the cardiac conduction system.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Postnatal conduction defects in Nkx2-5 mutation may result at least in part from a defect in the genetic program that governs the recruitment or retention of embryonic cardiac myocytes in the conduction system."
      explanation: >-
        Names retention of conduction myocytes, not only their initial
        recruitment, as the failing program, which is the step from a hypoplastic
        system to a progressively depleted one.
- name: Postnatal Conduction Cell Dropout
  description: >-
    The atrioventricular node is already hypoplastic at birth and then loses
    conduction cells selectively over postnatal life. This is the step that makes
    the block progressive rather than a fixed congenital deficit, and it is why a
    normal electrocardiogram in childhood does not predict a normal one in
    adulthood.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: nodal myocyte
    term:
      id: CL:0002072
      label: nodal myocyte
  evidence:
  - reference: PMID:15109497
    reference_title: Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "At birth, mutant mice display a hypoplastic atrioventricular (AV) node and then develop selective dropout of these conduction cells."
    explanation: >-
      Separates the congenital deficit from the progressive one in the same
      animals, which is the observation this node exists to carry.
  downstream:
  - target: Progressive Atrioventricular Conduction Delay
    causal_link_type: DIRECT
- name: Progressive Atrioventricular Conduction Delay
  description: >-
    Atrioventricular conduction deteriorates over years, from PR prolongation
    through higher-grade block to complete atrioventricular block, which is the
    substrate for syncope and sudden death and the reason lifelong
    electrocardiographic surveillance is the central management decision.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: cardiac conduction
    modifier: DECREASED
    term:
      id: GO:0061337
      label: cardiac conduction
  evidence:
  - reference: PMID:29979676
    reference_title: Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Nkx2-5+/- haploinsufficient mice have an abnormal electrocardiogram, with a prolonged QRS and progressive elongation of the PR interval"
    explanation: >-
      The progressive, rather than fixed, character of the conduction delay in the
      haploinsufficient mouse. The sentence is this paper's restatement of earlier
      work, so it reports no method of its own.
    quote_role: BACKGROUND
  downstream:
  - target: First degree atrioventricular block
    causal_link_type: DIRECT
  - target: Atrioventricular block
    causal_link_type: DIRECT
  - target: Syncope
    causal_link_type: DIRECT
    description: >-
      High-grade block with an inadequate escape rate causes transient cerebral
      hypoperfusion.
    evidence:
    - reference: PMID:20932824
      reference_title: "A de novo mutation in NKX2.5 associated with atrial septal defects, ventricular noncompaction, syncope and sudden death."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified a CHD family with atrial septal defects (ASDs), atrioventricular block, ventricular noncompaction, syncope and sudden death."
      explanation: >-
        Conduction block and syncope co-segregating in one NKX2-5 family, which is
        the observation this edge records.
  - target: Sudden cardiac death
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Complete atrioventricular block without adequate escape rhythm causes
      syncope and can cause sudden death; the intermediate steps are bradycardia
      and haemodynamic collapse or secondary ventricular arrhythmia.
    evidence:
    - reference: PMID:20932824
      reference_title: "A de novo mutation in NKX2.5 associated with atrial septal defects, ventricular noncompaction, syncope and sudden death."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified a CHD family with atrial septal defects (ASDs), atrioventricular block, ventricular noncompaction, syncope and sudden death."
      explanation: >-
        A single family in which conduction block, syncope and sudden death
        co-segregate, which is the clinical observation behind this edge.
- name: Ectopic Ventricular BMP10 Expression
  description: >-
    Loss of NKX2-5 in ventricular myocardium derepresses BMP10, which is normally
    restricted in the adult ventricle, and the ectopic BMP10 signal is itself
    required for much of the trabecular muscle overgrowth. No HGNC identifier is
    bound for BMP10 here because none could be sourced offline in this session;
    the BMP pathway is bound instead.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: ectopic ventricular BMP10 signalling
    modifier: INCREASED
    term:
      id: GO:0030509
      label: BMP signaling pathway
  evidence:
  - reference: PMID:15109497
    reference_title: Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "ectopic, high level BMP-10 expression in the adult ventricular myocardium"
    explanation: >-
      The transcriptional profiling result that identifies BMP10 derepression as a
      consequence of ventricular NKX2-5 loss.
  downstream:
  - target: Defective Ventricular Trabecular Compaction
    causal_link_type: DIRECT
    description: >-
      Ectopic BMP10 is not merely correlated with the trabecular phenotype; it is
      required for a major part of it.
    evidence:
    - reference: PMID:15109497
      reference_title: Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "BMP-10 is shown to be necessary and sufficient for a major component of the ventricular muscle defects."
      explanation: >-
        A necessity-and-sufficiency claim, which is what justifies drawing this as
        a causal edge rather than an association.
- name: Defective Ventricular Trabecular Compaction
  description: >-
    The same reduced NKX2-5 dosage disturbs compaction of the ventricular
    trabecular myocardium, producing a hypertrabeculated or noncompacted
    ventricle with subendocardial fibrosis, and a later-onset dilated and
    arrhythmogenic myopathy. The severity tracks the developmental stage at which
    NKX2-5 activity is lost.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: ventricular trabecula myocardium morphogenesis
    modifier: ABNORMAL
    term:
      id: GO:0003222
      label: ventricular trabecula myocardium morphogenesis
  evidence:
  - reference: PMID:29979676
    reference_title: Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia."
    explanation: >-
      Trabecular-restricted loss of Nkx2-5 is sufficient to produce the
      noncompaction phenotype, which places this arm downstream of the same
      transcriptional deficit rather than of the septal defect.
  - reference: PMID:29979676
    reference_title: Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia."
    explanation: >-
      Ties the myopathic and conduction arms to one developmental lesion, which is
      the reason this entry models them as siblings under one transcriptional
      node.
  downstream:
  - target: Left ventricular noncompaction
    causal_link_type: DIRECT
  - target: Dilated cardiomyopathy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The noncompacted, fibrotic ventricle remodels over years into a dilated and
      functionally impaired chamber.
    evidence:
    - reference: PMID:29979676
      reference_title: Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "A longitudinal study of cardiac function in adult Nkx2-5 conditional mutant mice demonstrates that excessive trabeculation is associated with complex ventricular conduction defects, progressively leading to strain defects, and, in 50% of mutant mice, to heart failure."
      explanation: >-
        Longitudinal evidence that the hypertrabeculated ventricle progresses to
        functional failure, which is the inference step this edge records.
  - target: Ventricular arrhythmia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      The remodelled, fibrotic ventricle of the myopathic arm becomes an
      arrhythmic substrate.
    evidence:
    - reference: CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z
      reference_title: "NKX2-5 / NKX2.5-related congenital, conduction and myopathic heart disease (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "later onset dilated cardiomyopathy and/or hypertrabeculation with predisposition to atrial and ventricular arrhythmias"
      explanation: >-
        ClinGen places the ventricular arrhythmic predisposition with the
        later-onset myopathic arm, which is the attachment this edge records.
  - target: Supraventricular arrhythmia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Atrial remodelling accompanying the myopathic arm predisposes to atrial
      arrhythmia.
    evidence:
    - reference: CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z
      reference_title: "NKX2-5 / NKX2.5-related congenital, conduction and myopathic heart disease (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "later onset dilated cardiomyopathy and/or hypertrabeculation with predisposition to atrial and ventricular arrhythmias"
      explanation: >-
        ClinGen places the atrial and ventricular arrhythmic predisposition with
        the later-onset myopathic arm, which is where this edge attaches it.
phenotypes:
- category: Cardiovascular
  name: Secundum atrial septal defect
  description: >-
    The commonest structural lesion in this disease: an ostium secundum atrial
    septal defect.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Secundum atrial septal defect
    term:
      id: HP:0001684
      label: Secundum atrial septal defect
  evidence:
  - reference: CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z
    reference_title: "NKX2-5 / NKX2.5-related congenital, conduction and myopathic heart disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "more than 26 unique variants (missense, nonsense, frameshift, deletions) across 18 papers have reported cases of a similar phenotype including congenital heart disease (predominantly ASD), AV block and later onset dilated cardiomyopathy and/or hypertrabeculation with predisposition to atrial and ventricular arrhythmias"
    explanation: >-
      ClinGen's synthesis across the reported cohort, which is the basis for
      treating atrial septal defect as the predominant structural lesion.
  - reference: PMID:26679770
    reference_title: "Familial Atrial Septal Defect and Sudden Cardiac Death: Identification of a Novel NKX2-5 Mutation and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The majority of patients (74%) had ASD with conduction disturbance."
    explanation: >-
      A pooled figure across 202 reported patients putting the septal-defect plus
      conduction-disturbance combination at 74%, which is the basis for the
      FREQUENT band on this phenotype.
- category: Cardiovascular
  name: Atrioventricular block
  description: >-
    Atrioventricular conduction block, characteristically progressive across a
    lifetime, and present in gene carriers who have no structural defect at all.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Atrioventricular block
    term:
      id: HP:0001678
      label: Atrioventricular block
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:9651244
    reference_title: Congenital heart disease caused by mutations in the transcription factor NKX2-5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35, where NKX2-5, a Drosophila tinman homolog, is located."
    explanation: >-
      Conduction abnormality is part of the phenotype that defined the locus, not
      a later addition to the spectrum.
  - reference: PMID:10587520
    reference_title: Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Heterozygous mutations in NKX2.5, a homeobox transcription factor, were reported to cause secundum atrial septal defects and result in atrioventricular (AV) conduction block during postnatal life."
    explanation: >-
      States that the block arises postnatally rather than being present at birth,
      which is the clinical counterpart of the conduction-cell dropout node. The
      sentence is this paper's restatement of the prior report, hence BACKGROUND.
- category: Cardiovascular
  name: Ventricular septal defect
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z
    reference_title: "NKX2-5 / NKX2.5-related congenital, conduction and myopathic heart disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Ventricular septal defect 3 (OMIM:614432)"
    explanation: >-
      One of the five congenital heart disease entities ClinGen lumped into this
      gene-disease relationship.
  - reference: PMID:10587520
    reference_title: Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Associated phenotypes included AV block, which was the primary manifestation of cardiac disease in nearly a quarter of affected individuals, as well as atrial septal defect and ventricular septal defect."
    explanation: >-
      Reports ventricular septal defect directly in an NKX2-5 cohort rather than
      through an OMIM entity list.
- category: Cardiovascular
  name: Conotruncal defect
  phenotype_term:
    preferred_term: Conotruncal defect
    term:
      id: HP:0001710
      label: Conotruncal defect
  evidence:
  - reference: CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z
    reference_title: "NKX2-5 / NKX2.5-related congenital, conduction and myopathic heart disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Conotruncal heart malformations, variable (OMIM:217095)"
    explanation: >-
      One of the five congenital heart disease entities ClinGen lumped into this
      gene-disease relationship.
- category: Cardiovascular
  name: Tetralogy of Fallot
  description: >-
    Kept as a row of its own although HP:0001636 is a child of HP:0001710
    Conotruncal defect, which the entry also carries. The two are not a
    duplication: ClinGen lumped tetralogy of Fallot and variable conotruncal
    malformation into this gene-disease relationship as two separate OMIM
    entities, and Benson's cohort reports tetralogy of Fallot specifically rather
    than conotruncal malformation generally. Collapsing them would lose the
    named entity that the literature and the ClinGen record both single out.
  phenotype_term:
    preferred_term: Tetralogy of Fallot
    term:
      id: HP:0001636
      label: Tetralogy of Fallot
  evidence:
  - reference: PMID:10587520
    reference_title: Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Mutations in human NKX2.5 cause a variety of cardiac anomalies and may account for a clinically significant portion of tetralogy of Fallot and idiopathic AV block."
    explanation: >-
      The cohort study that put tetralogy of Fallot in this gene's phenotype, and
      that also makes isolated atrioventricular block a presentation in its own
      right.
- category: Cardiovascular
  name: Hypoplastic left ventricle
  description: >-
    The left-heart hypoplastic end of the structural spectrum, corresponding to
    the hypoplastic left heart syndrome 2 locus. HPO has no term for the syndrome
    itself, so the ventricular phenotype is bound here.
  phenotype_term:
    preferred_term: Hypoplastic left ventricle
    term:
      id: HP:0004383
      label: Hypoplastic left ventricle
  evidence:
  - reference: CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z
    reference_title: "NKX2-5 / NKX2.5-related congenital, conduction and myopathic heart disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Hypoplastic left heart syndrome 2 (OMIM:614435)"
    explanation: >-
      One of the five congenital heart disease entities ClinGen lumped into this
      gene-disease relationship.
- category: Cardiovascular
  name: Left ventricular noncompaction
  description: >-
    Hypertrabeculation of the left ventricle, the structural form of the
    myopathic arm, first linked to an NKX2-5 allele in 2011.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Left ventricular noncompaction
    term:
      id: HP:0030682
      label: Left ventricular noncompaction
  evidence:
  - reference: PMID:20932824
    reference_title: "A de novo mutation in NKX2.5 associated with atrial septal defects, ventricular noncompaction, syncope and sudden death."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study for the first time identifies association between a NKX2.5 mutation and ventricular noncompaction."
    explanation: >-
      The report that added noncompaction to the NKX2-5 phenotype, which is why
      the myopathic arm is modelled separately from the septal one.
  - reference: PMID:34277740
    reference_title: "Case Report: A Novel NKX2-5 Mutation in a Family With Congenital Heart Defects, Left Ventricular Non-compaction, Conduction Disease, and Sudden Cardiac Death."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, an overlapping phenotype is not frequent in the literature."
    explanation: >-
      Direct support for the OCCASIONAL band rather than a higher one: the
      combination of structural defect, noncompaction and conduction disease in
      one family is reported as uncommon.
- category: Cardiovascular
  name: Dilated cardiomyopathy
  description: >-
    Later-onset dilated cardiomyopathy, the functional form of the myopathic arm.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z
    reference_title: "NKX2-5 / NKX2.5-related congenital, conduction and myopathic heart disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "AV block and later onset dilated cardiomyopathy and/or hypertrabeculation with predisposition to atrial and ventricular arrhythmias"
    explanation: >-
      ClinGen's 2024 update, which expanded the classification summary
      specifically to record the cardiomyopathy and arrhythmia arm.
  - reference: PMID:27855642
    reference_title: Mutation of a common amino acid in NKX2.5 results in dilated cardiomyopathy in two large families.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "In addition to DCM, the phenotypes included atrial and ventricular septal defects, cardiac arrhythmia and sudden death."
    explanation: >-
      The primary human source for the dilated phenotype, in two families where it
      segregated alongside the septal and arrhythmic features rather than in
      isolation.
  - reference: PMID:27855642
    reference_title: Mutation of a common amino acid in NKX2.5 results in dilated cardiomyopathy in two large families.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "We identified distinct mutations affecting a common amino acid in NKX2.5. Segregation analysis of the families support the pathogenic role of these variants."
    explanation: >-
      Segregation evidence that the dilated phenotype tracks the NKX2-5 variant,
      which is what makes this a phenotype of the disease rather than a
      coincidental cardiomyopathy.
- category: Cardiovascular
  name: Ventricular arrhythmia
  phenotype_term:
    preferred_term: Ventricular arrhythmia
    term:
      id: HP:0004308
      label: Ventricular arrhythmia
  evidence:
  - reference: CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z
    reference_title: "NKX2-5 / NKX2.5-related congenital, conduction and myopathic heart disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "with predisposition to atrial and ventricular arrhythmias"
    explanation: >-
      The arrhythmic predisposition ClinGen records alongside the myopathic arm.
- category: Cardiovascular
  name: Supraventricular arrhythmia
  phenotype_term:
    preferred_term: Supraventricular arrhythmia
    term:
      id: HP:0005115
      label: Supraventricular arrhythmia
  evidence:
  - reference: CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z
    reference_title: "NKX2-5 / NKX2.5-related congenital, conduction and myopathic heart disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "with predisposition to atrial and ventricular arrhythmias"
    explanation: >-
      The atrial half of the same arrhythmic predisposition.
- category: Cardiovascular
  name: Syncope
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:20932824
    reference_title: "A de novo mutation in NKX2.5 associated with atrial septal defects, ventricular noncompaction, syncope and sudden death."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a CHD family with atrial septal defects (ASDs), atrioventricular block, ventricular noncompaction, syncope and sudden death."
    explanation: >-
      Syncope in a family segregating an NKX2-5 allele, as the clinical
      manifestation of the conduction arm.
- category: Cardiovascular
  name: Sudden cardiac death
  description: >-
    The outcome surveillance, pacing and the defibrillator question all turn on.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:20932824
    reference_title: "A de novo mutation in NKX2.5 associated with atrial septal defects, ventricular noncompaction, syncope and sudden death."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NKX2.5 mutation c.512insGC is associated with ASDs, syncope and sudden death."
    explanation: >-
      The report's own conclusion that the allele is associated with sudden death.
  - reference: PMID:26679770
    reference_title: "Familial Atrial Septal Defect and Sudden Cardiac Death: Identification of a Novel NKX2-5 Mutation and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Nineteen patients (15%) of 120 with familial ASD and conduction disturbance died from sudden cardiac death of which nine (8%) were confirmed mutation carriers, and 10 were possible carriers."
    explanation: >-
      The pooled sudden-death figure, with the confirmed-carrier subset stated
      separately, which is why the frequency band here is read from the 8%
      confirmed rather than the 15% combined.
  - reference: PMID:26679770
    reference_title: "Familial Atrial Septal Defect and Sudden Cardiac Death: Identification of a Novel NKX2-5 Mutation and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mutation carriers are at increased risk of sudden cardiac death"
    explanation: >-
      The review's own conclusion, which is what makes surveillance and device
      decisions a standing question in carriers rather than only in the affected.
- category: Cardiovascular
  name: First degree atrioventricular block
  description: >-
    The earliest electrocardiographic sign of the conduction arm, and the point
    at which surveillance begins rather than ends.
  phenotype_term:
    preferred_term: First degree atrioventricular block
    term:
      id: HP:0011705
      label: First degree atrioventricular block
  evidence:
  - reference: PMID:10587520
    reference_title: Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we sought additional mutations in groups of probands with cardiac anomalies and first-degree AV block, idiopathic AV block, or tetralogy of Fallot"
    explanation: >-
      First-degree block is one of the cohorts in which this study ascertained
      probands and then found seven novel NKX2-5 mutations, so the degree of block
      named here is part of the spectrum. The sentence states the study's aim
      rather than a result, so no quote_role applies to it.
- category: Cardiovascular
  name: Ebstein anomaly of the tricuspid valve
  phenotype_term:
    preferred_term: Ebstein anomaly of the tricuspid valve
    term:
      id: HP:0010316
      label: Ebstein anomaly of the tricuspid valve
  evidence:
  - reference: PMID:10587520
    reference_title: Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Ebstein's anomaly and other tricuspid valve abnormalities were also present."
    explanation: >-
      Extends the structural spectrum beyond the septa to the tricuspid valve in
      an NKX2-5 mutation cohort.
- category: Cardiovascular
  name: Abnormal tricuspid valve morphology
  phenotype_term:
    preferred_term: Abnormal tricuspid valve morphology
    term:
      id: HP:0001702
      label: Abnormal tricuspid valve morphology
  evidence:
  - reference: PMID:10587520
    reference_title: Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Ebstein's anomaly and other tricuspid valve abnormalities were also present."
    explanation: >-
      The same sentence records tricuspid abnormalities other than Ebstein
      anomaly, which this broader phenotype carries.
- category: Cardiovascular
  name: Double outlet right ventricle
  phenotype_term:
    preferred_term: Double outlet right ventricle
    term:
      id: HP:0001719
      label: Double outlet right ventricle
  evidence:
  - reference: PMID:10587520
    reference_title: Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Ventricular septal defect was associated with tetralogy of Fallot or double-outlet right ventricle in 3 individuals."
    explanation: >-
      Double outlet right ventricle occurring with the septal defect in three
      individuals of this cohort.
genetic:
- name: NKX2-5
  presence: Positive
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    The single causative gene; variants are truncating or missense within the
    homeodomain.
  gene_term:
    preferred_term: NKX2-5
    term:
      id: hgnc:2488
      label: NKX2-5
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z
    evidence:
    - reference: CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z
      reference_title: "NKX2-5 / NKX2.5-related congenital, conduction and myopathic heart disease (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "NKX2-5 | HGNC:2488 | NKX2.5-related congenital, conduction and myopathic heart disease | MONDO:0800441 | AD | Definitive | SOP9 | Congenital Heart Disease Gene Curation Expert Panel | 2024-11-07T17:00:00.000Z"
      explanation: >-
        The ClinGen Congenital Heart Disease Gene Curation Expert Panel's
        Definitive classification of this gene against this exact MONDO disease.
  notes: >-
    The relevance of non-truncating variants outside the homeodomain is recorded
    by ClinGen as unclear, so a missense variant outside the homeodomain should
    not be treated as causative on the strength of the gene alone.
  evidence:
  - reference: PMID:9651244
    reference_title: Congenital heart disease caused by mutations in the transcription factor NKX2-5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three different NKX2-5 mutations were identified."
    explanation: >-
      The founding allelic series, in the linkage study that established the gene.
inheritance:
- name: Autosomal dominant
  description: >-
    Autosomal dominant. The conduction arm is the most consistently penetrant
    feature and the structural and myopathic arms vary within a family, so an
    unaffected-looking carrier is not evidence against transmission.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z
    reference_title: "NKX2-5 / NKX2.5-related congenital, conduction and myopathic heart disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Phenotype is variable within families and individuals may have only some of these features."
    explanation: >-
      ClinGen's statement of intrafamilial variability, which is the basis for the
      caveat in this block's description.
  - reference: PMID:9651244
    reference_title: Congenital heart disease caused by mutations in the transcription factor NKX2-5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35"
    explanation: >-
      The dominant transmission established by linkage in the defining report.
animal_models:
- name: Nkx2-5 trabecular conditional knockout mouse (Cx40-creERT2)
  species: Mouse
  genotype: Nkx2-5 floxed; Cx40-creERT2, tamoxifen-induced at E10.5-E11.5 or E13.5-E14.5
  publication: PMID:29979676
  description: >-
    Tamoxifen-inducible deletion of Nkx2-5 restricted to Cx40-expressing
    trabecular myocardium, at two developmental stages, which separates the
    myopathic arm of the disease from the septal arm.
  evidence:
  - reference: PMID:29979676
    reference_title: Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "represents a highly tractable model to study the cellular and molecular mechanisms involved in the disease"
    explanation: >-
      The authors' own claim for the model's usefulness, which is what justifies
      treating it as informative for this entry's myopathic arm rather than as an
      unrelated conditional knockout.
  modeled_mechanisms:
  - target: Defective Ventricular Trabecular Compaction
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Trabecular-restricted loss of Nkx2-5 reproduces hypertrabeculation with
      subendocardial fibrosis, and the severity depends on the stage at which the
      gene is removed.
    limitations: >-
      A conditional, tissue-restricted and complete deletion is not the human
      germline heterozygous state, so the model speaks to the sufficiency of
      trabecular Nkx2-5 loss rather than to what one reduced allele does across
      the whole heart.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The model's quantity is complete somatic ablation of Nkx2-5 within a
        Cx40-defined compartment. The human quantity is a halved gene dose in
        every cardiac cell from conception.
    evidence:
    - reference: PMID:29979676
      reference_title: Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we inactivated the cardiac transcription factor Nkx2-5 in trabecular myocardium at different stages of trabecular morphogenesis using an inducible Cx40-creERT2 allele"
      explanation: >-
        Establishes the genotype and the staged design that make this model
        informative for the compaction node.
    readouts:
    - name: Endocardial length and endocardial islet count
      target: Defective Ventricular Trabecular Compaction
      direction: INCREASED
      interpretation: >-
        The morphometric readout of excessive trabeculation and failed compaction.
      evidence:
      - reference: PMID:29979676
        reference_title: Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia."
        explanation: >-
          Reports the hypertrabeculated phenotype this readout measures.
  - target: Cardiac Conduction System Hypoplasia
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      The same hearts lose Purkinje fibre network density and branching, so this
      model reports the conduction-system limb of the disease as well as the
      compaction limb.
    limitations: >-
      Deletion is restricted to the Cx40-expressing trabecular compartment, so the
      model speaks to the Purkinje network rather than to the atrioventricular
      node, which is where the human block is generated.
    evidence:
    - reference: PMID:29979676
      reference_title: Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our results provide insights into the etiology of LVNC and link its pathogenicity with compromised trabecular development including compaction defects and ventricular conduction system hypoplasia."
      explanation: >-
        States the conduction-system hypoplasia this link carries, in the same
        animals as the compaction defect.
    readouts:
    - name: Purkinje fibre network density and branching
      target: Cardiac Conduction System Hypoplasia
      direction: DECREASED
      interpretation: >-
        Structural measurement of the conduction-system deficit, attached to the
        node it actually measures.
      evidence:
      - reference: PMID:29979676
        reference_title: Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia."
        explanation: >-
          Reports the Purkinje hypoplasia measured in these hearts.
datasets:
- accession: geo:GSE113251
  title: Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy
  description: >-
    Expression profiling by array of severe versus mild Nkx2-5 trabecular
    conditional knockout hearts, the transcriptomic arm of the mouse study behind
    the myopathic node.
  data_type: MICROARRAY
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:29979676
  evidence:
  - reference: GEO:GSE113251
    reference_title: "Deletion of Nkx2-5 in trabecular myocardium reveals the developmental origins of pathological heterogeneity associated with ventricular non-compaction cardiomyopathy"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "identifies Six1 as a marker upregulated in hypertrabeculated hearts"
    explanation: >-
      The series summary's own statement of what the expression data show, which
      is what this dataset contributes beyond the histology.
environmental:
- name: Advanced maternal age
  description: >-
    In the mouse, maternal age modifies the risk that a heterozygous Nkx2-5
    genotype produces a septal defect, and it does so only in mutant offspring.
    This is a modifier of penetrance in a model organism, not an established human
    risk factor, and it is recorded as MODULATES rather than as a trigger.
  exposure_term:
    preferred_term: advanced maternal age
  notes: >-
    No ontology term is bound. ECTO has no maternal-age class: searching OLS
    (ontologyId=ecto) for "maternal age" returns only ECTO:0300011 exposure to
    opioid agent via maternal, and neither cache/ecto/terms.csv nor
    cache/xco/terms.csv holds a maternal-age or parental-age row. Maternal age is
    a parental characteristic rather than an exposure to a substance, so no ECTO
    class is expected to fit; a wrong binding would be worse than none.
  influences_mechanisms:
  - target: Defective Cardiac Septum Morphogenesis
    environmental_effect: MODULATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Maternal age shifts the probability that the septal defect occurs at a given
      genotype; the mechanism linking the two is not established.
    evidence:
    - reference: PMID:22534315
      reference_title: Complex trait analysis of ventricular septal defects caused by Nkx2-5 mutation.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "Multiple logistic regression analysis for environmental variables revealed that maternal age is correlated with the risk of membranous and muscular VSD in Nkx2-5(+/-) but not wild-type animals."
      explanation: >-
        The genotype-restricted maternal-age effect, which is what makes this a
        modifier of this disease's penetrance rather than a general risk factor
        for septal defects.
  evidence:
  - reference: PMID:22534315
    reference_title: Complex trait analysis of ventricular septal defects caused by Nkx2-5 mutation.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "The maternal age effect is unrelated to aneuploidy or a genetic polymorphism in the affected individuals."
    explanation: >-
      Excludes the two obvious confounders for a maternal-age association, which
      is why it is recorded as a modifier at all rather than dismissed.
treatments:
- name: Lifelong Conduction Surveillance and Permanent Pacing
  description: >-
    Because atrioventricular block is progressive rather than fixed, a normal
    electrocardiogram at diagnosis does not discharge a carrier from follow-up.
    Serial electrocardiography, with permanent pacemaker implantation when block
    advances, is the management decision that addresses the bradyarrhythmic mode
    of death. It does not cover the arrhythmic mode: pacing substitutes for a
    failing node and does nothing about ventricular arrhythmia arising from the
    myopathic arm, which is the separate question the defibrillator entry records.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: permanent cardiac pacemaker implantation
    term:
      id: NCIT:C99998
      label: Pacemaker Procedure
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: permanent cardiac pacemaker
        term:
          id: NCIT:C99552
          label: Permanent Cardiac Pacemaker
  target_mechanisms:
  - target: Progressive Atrioventricular Conduction Delay
    description: >-
      Pacing substitutes for the failing atrioventricular node; it does not alter
      the underlying conduction-system hypoplasia.
  evidence:
  - reference: PMID:9651244
    reference_title: Congenital heart disease caused by mutations in the transcription factor NKX2-5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "for maturation and maintenance of atrioventricular node function throughout life"
    explanation: >-
      The lifelong maintenance role is why surveillance has to be lifelong rather
      than concluded in childhood; the quote supports the rationale, not a trial
      result.
    directness: INDIRECT
- name: Implantable Cardioverter-Defibrillator Consideration in Mutation Carriers
  description: >-
    The review that pooled the published cohort proposed considering an
    implantable cardioverter-defibrillator in NKX2-5 mutation carriers from
    families with atrial septal defect and conduction disturbance, on the strength
    of the sudden-death rate in those families. This is a proposal from a
    literature review rather than a trial result or a guideline recommendation,
    and it is recorded here as such; the decision in practice follows the general
    cardiomyopathy and conduction-disease guidelines.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
    qualifiers:
    - predicate:
        preferred_term: medical device
        term:
          id: NCIT:C16830
          label: Medical Device
      value:
        preferred_term: implantable cardioverter-defibrillator
        term:
          id: NCIT:C93238
          label: Implantable Cardioverter-Defibrillator
  target_mechanisms:
  - target: Sudden cardiac death
    description: >-
      A defibrillator addresses the arrhythmic mode of death. The sudden-death
      rate in these families is the reason the cited review proposes it, so this
      is the outcome it targets.
  - target: Ventricular arrhythmia
    description: >-
      The arrhythmia a defibrillator terminates, which arises from the myopathic
      arm rather than from the conduction deficit that pacing covers.
  evidence:
  - reference: PMID:26679770
    reference_title: "Familial Atrial Septal Defect and Sudden Cardiac Death: Identification of a Novel NKX2-5 Mutation and a Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "if they are mutation carriers, implantation of an implantable cardioverter-defibrillator should be considered in these patients"
    explanation: >-
      The proposal itself, quoted so the strength of the recommendation is visible
      rather than paraphrased into something firmer.
- name: Surgical or Transcatheter Closure of the Septal Defect
  description: >-
    Closure of a haemodynamically significant atrial or ventricular septal
    defect, on the same indications as in isolated disease. It does not address
    the conduction or myopathic arms, which continue to require surveillance
    afterwards.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cardiac septal defect repair
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Defective Cardiac Septum Morphogenesis
differential_diagnoses:
- name: Isolated secundum atrial septal defect
  description: >-
    The commonest alternative. The discriminator is the electrocardiogram and the
    family history: progressive atrioventricular block in the proband or in a
    structurally normal relative points to this gene rather than to an isolated
    defect. The dismech entry Atrial_Septal_Defect carries the ASD7 row for the
    atrial-septal component of this disease.
  evidence:
  - reference: PMID:9651244
    reference_title: Congenital heart disease caused by mutations in the transcription factor NKX2-5.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35"
    explanation: >-
      The co-occurrence of malformation with conduction abnormality in a dominant
      pedigree is the feature that separates this disease from an isolated septal
      defect; the quote supports the discriminator rather than a comparative study.
- name: Familial progressive cardiac conduction disease
  description: >-
    Progressive atrioventricular block without a structural defect, including
    SCN5A- and LMNA-related conduction disease. A septal defect anywhere in the
    family, or hypertrabeculation, favours NKX2-5.
- name: Left ventricular noncompaction of other genetic cause
  description: >-
    Sarcomeric and other LVNC genes produce hypertrabeculation without septation
    failure or early conduction block.
diagnosis:
- name: Electrocardiography with serial follow-up
  description: >-
    The test that detects the conduction arm and its progression. A single normal
    recording does not exclude future block.
  evidence:
  - reference: PMID:9651244
    reference_title: Congenital heart disease caused by mutations in the transcription factor NKX2-5.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "for maturation and maintenance of atrioventricular node function throughout life"
    explanation: >-
      A lifelong maintenance role for the gene at the atrioventricular node is why
      a single normal recording cannot discharge a carrier; the quote supports the
      rationale for serial testing rather than reporting a surveillance study.
- name: Echocardiography
  description: >-
    Detects the septal defect and the hypertrabeculated or dilated ventricle.
- name: NKX2-5 sequencing
  description: >-
    Confirms the diagnosis and enables cascade testing of relatives, who then
    enter conduction surveillance regardless of whether they have a structural
    defect.
notes: >-
  No GeneReviews chapter names this disease or the NKX2-5 gene in the committed
  Bookshelf index snapshot of 2026-09-10, so there is no GeneReviews phenotype
  baseline for this entry. Verify with `just check-genereviews`, which is the
  check a reviewer runs.

  NKX2-5 variants also contribute to thyroid dysgenesis and congenital
  hypothyroidism, with Nkx2-5-null embryos showing thyroid bud hypoplasia. That is
  deliberately out of scope for this entry: the disease this entry is bound to is
  a heart disease, and a thyroid phenotype would make the entry broader than both
  its name and its MONDO term. The dismech entry Congenital_Hypothyroidism is
  where that association belongs.

  No HGNC identifier is bound for BMP10 on the ectopic-BMP10 node. HGNC's REST
  API is not reachable from this environment, BMP10 has no row in
  `cache/hgnc/terms.csv` or in `kb/genes/ingest/hgnc.tsv`, and the only remaining
  offline route is the 1 GB local HGNC build. The BMP pathway is bound instead,
  and the gene is named in the node description; binding the gene is a one-line
  change for anyone who has that build.

review_notes: >-
  Deliberately lumped. This entry covers atrial septal defect 7, variable
  conotruncal malformations, hypoplastic left heart syndrome 2, tetralogy of
  Fallot and ventricular septal defect 3, which carry separate OMIM numbers,
  because the ClinGen Congenital Heart Disease Gene Curation Expert Panel lumped
  exactly these five under this MONDO term after applying the ClinGen Lumping and
  Splitting Working Group criteria and finding no difference in molecular
  mechanism or inheritance pattern between them. That panel made the
  classification and the lumping call; the Hereditary Cardiovascular Disease GCEP
  later updated the summary text to expand the cardiomyopathy and arrhythmia
  detail, and did not make the lumping decision. The entry therefore models them as alternative
  structural outcomes of one transcriptional lesion rather than as subtypes. The
  separate dismech entry Atrial_Septal_Defect carries an ASD7 subtype row for the
  atrial-septal component only, and its own review notes already record that the
  NKX2-5 conduction phenotype is an entity in its own right, represented there
  only by its atrial-septal component. That entry predates this one and does not
  point at it, and `curated_in` is not the way to make that pointer
  machine-readable. That slot marks a stratum promoted to its own entry, where
  the entry is the stratum and its content lives there in full, so a consumer
  counting diseases skips the row. Neither holds here: this entry is broader than
  ASD7, covering four further structural lesions and the conduction and myopathic
  arms, and the ASD7 row keeps its own description and evidence for the
  atrial-septal component, which nothing else curates in full. The terms disagree
  accordingly, MONDO:0007173 against this entry's MONDO:0800441, which is what
  `just check-granularity` reports as POINTER_TERM_MISMATCH once the slot is
  filled in. The cross-reference therefore stays prose on both sides.

  Four further entries already carry NKX2-5 content for arms this entry claims,
  and they are making different claims rather than duplicating this one.
  Hypoplastic_Left_Heart_Syndrome maps MONDO:0013752, the NKX2-5-defined child of
  its own anchor, with skos:narrowMatch, and its justification states that it
  treats NKX2-5 as a susceptibility contribution to a convergent phenotype rather
  than as a Mendelian subtype. Tetralogy_of_Fallot carries an NKX2-5 row quantified
  at 0.9 percent of an unselected cohort, which places the gene among the minor
  contributors to that phenotype. Ventricular_Septal_Defect carries an NKX2-5 row
  within the septation transcription-factor network, citing the same PMID:22534315
  used here. Congenital_Heart_Disease quotes PMID:9651244 for the gene's general
  role. None of these contradicts this entry: they describe how much of a common
  malformation this gene explains, which is small, while this entry describes the
  Mendelian disease the gene definitively causes, whose spectrum includes those
  malformations. A reader moving between the files should read the difference that
  way round.

  No OMIM or MONDO mappings are recorded for the five lumped entities, and that is
  a decision rather than an omission. DiseaseMappings has no OMIM slot, so the
  five OMIM identifiers could only be carried as their MONDO equivalents, and for
  four of the five those equivalents are the generic phenotype classes that
  Tetralogy_of_Fallot, Ventricular_Septal_Defect and Hypoplastic_Left_Heart_Syndrome
  are anchored to. Mapping those with skos:narrowMatch would assert that all
  tetralogy of Fallot, or all left-heart hypoplasia, is narrower than this
  NKX2-5-defined disease, which is false and would also retire those concepts from
  the curation queue wrongly. The one genuinely gene-defined class,
  MONDO:0013752, is already mapped with narrowMatch from
  Hypoplastic_Left_Heart_Syndrome, so claiming it again here would leave two
  entries asserting ownership of one concept. The five OMIM identifiers are
  therefore left where they are checkable, in the quoted ClinGen record.
📚

References & Deep Research

References

1
PMID:9651244
Congenital heart disease caused by mutations in the transcription factor NKX2-5.
No top-level findings curated for this source.

Deep Research

2

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

Evaluations and curation notes (2)

Integrate deep research and red-team review findings · 2026-11-05T05:21:14Z · View source

Second pass on the entry created earlier in the same session, integrating two deep-research reports and a red-team self-review run in a fresh-context subagent before any PR existed. Deep research: falcon was the requested provider and could not be used (Edison authentication failed, and --fallback cannot cover it because Edison raises a bare Exception and deep-research-client's is_fallback_worthy returns False for unrecognised types). openscientist and claude_code were run explicitly instead, each under its own provider name. Both reports were read for their reference_validation and term_validation blocks before use: claude_code reported needs_review true for one unsupported quote attributed to PMC:PMC4773750, which was therefore not used, and two mislabelled CURIEs, which were not copied; openscientist reported 5/5 references verified and 15/15 quotes valid. just preflight-dr was run on both. Both raised a second-gene WARN that was read and dismissed on inspection: SCD in the claude_code report is the abbreviation for sudden cardiac death, not the stearoyl-CoA desaturase gene, and BMP10 in the openscientist report is a downstream NKX2-5 target rather than a second disease entity. openscientist supplied PMID:15085192 and PMID:15109497, which the claude_code report wanted but had no identifiers for. Mechanism added from them: a Postnatal Conduction Cell Dropout node, which is the step that makes the block progressive rather than fixed, and an Ectopic Ventricular BMP10 Expression node with a necessity-and-sufficiency edge into the compaction node. The conduction-hypoplasia node's evidence was upgraded from a BACKGROUND restatement to Jay's primary dose-response result. Review findings acted on: the non-septal structural lesions (conotruncal defect, tetralogy of Fallot, double outlet right ventricle, Ebstein anomaly, tricuspid abnormality, hypoplastic left ventricle) were mis-parented under a cardiac-septum-morphogenesis node, which asserted a developmental claim no source makes and which the previous pass had made worse by adding three more such edges; they now hang off a new Defective Outflow Tract and Valve Morphogenesis node bound to GO:0003151. GO:0048738 cardiac muscle tissue development was an off-claim binding on a transcriptional node and is now GO:0006357 regulation of transcription by RNA polymerase II with modifier DECREASED. review_notes named the wrong ClinGen panel: the Congenital Heart Disease GCEP made the classification and the lumping call, and the Hereditary Cardiovascular Disease GCEP only later updated the summary text. Two snippets that were aim or methods statements rather than findings were replaced or had quote_role removed. An edge description naming reduced dose and reduced DNA binding was widened to match its quote, which describes failed nuclear import. An explanation asserting serial electrocardiography, a method the quoted sentence does not report, was corrected. Two notes paragraphs were rewritten: one duplicated the history record's own session log verbatim and is now one durable sentence, and one asserted that the GeneReviews Dilated Cardiomyopathy Overview names NKX2-5 among its gene tables, which nothing in this repository can check because the cached chapter body contains no such text; that sentence was deleted rather than left unverifiable. Content added: human primary sources for phenotypes that previously rested on ClinGen synthesis or a single family (PMID:10587520 for the outflow-tract, tricuspid and double-outlet lesions and for postnatal onset of block; PMID:26679770 for the 74 percent septal-defect-with-conduction figure and the 15 percent and 8 percent sudden-death figures, which is the first frequency evidence in the entry; PMID:27855642 for dilated cardiomyopathy with segregation; PMID:34277740 for the OCCASIONAL band on the overlapping phenotype), a three-phase progression block, an implantable-cardioverter-defibrillator treatment carrying ClinGen-independent evidence and recorded explicitly as a review proposal rather than a guideline recommendation, a maternal-age environmental modifier from PMID:22534315 whose exposure_term is deliberately left unbound with the ECTO search recorded, and a second modeled_mechanisms link on the Cx40-creERT2 mouse so its Purkinje readout attaches to the node it measures. The pacing treatment's claim to address sudden-death risk was narrowed to the bradyarrhythmic mode. A paragraph was added reconciling this entry against the four other entries carrying NKX2-5 content, and recording why no OMIM or MONDO mappings are claimed for the five lumped entities: four of the five map only to generic phenotype classes that other entries anchor, so narrowMatch would falsely assert that all tetralogy of Fallot or all left-heart hypoplasia is narrower than this disease, and the one gene-defined class MONDO:0013752 is already mapped from Hypoplastic_Left_Heart_Syndrome. A third CURIE written from memory was caught: NCIT:C50244, recalled as Implantable Defibrillator, is Control Valve Device; the bound terms are now NCIT:C80435 and NCIT:C93238, both read from OLS. A cached-replay duplicate of the claude_code report (cached true, 0.01 s, same session_id) was deleted rather than committed. Reference-cache churn from validator re-fetches was reverted twice, once after a re-fetch shrank PMID:20932824 from 46 lines to 10. Validation: just validate passes; just count-verified-snippets reports 66/66; 16 of 16 phenotypes causally connected; compliance 84.4 percent over 186 scored slots; just model-scale-audit reports both model links scale-aligned; check-entity-refs, check-causal-targets, check-enum-values, check-duplicate-keys, check-block-scalar-comments, check-coarse-phenotypes, check-logical-rules, check-qualifier-terms (and --online), check-delivery-system and check-environmental-evidence all pass. GeneReviews remains NO_CHAPTER; NCBI esearch was intermittently returning HTTP 500 throughout, so the offline Bookshelf snapshot is still the whole of the evidence for that.

Create: NKX2-5-Related Congenital, Conduction and Myopathic Heart Disease · 2026-11-05T05:00:30Z · View source

Created the entry for MONDO:0800441 from the local reference cache and the cached ClinGen gene-validity record, pending deep research (see below). Pathophysiology is modelled as one chain from NKX2-5 haploinsufficiency through an impaired cardiac transcriptional program, which then branches into the three arms the disease is named for: septum morphogenesis, conduction-system hypoplasia, and trabecular compaction. All 12 phenotypes are causally wired. Sources: PMID:9651244 (Schott 1998, the defining linkage study), PMID:20932824 (the family with ASD, AV block, noncompaction, syncope and sudden death), PMID:29979676 plus its dataset geo:GSE113251 (trabecular-restricted Nkx2-5 deletion in mouse, the myopathic and Purkinje-hypoplasia arm), PMID:22534315 (Nkx2-5 heterozygous knockout septal defects), and CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z. The lump/split decision is ClinGen's, not this session's: its evidence summary records that the Hereditary Cardiovascular Disease GCEP applied the ClinGen Lumping and Splitting Working Group criteria to ASD7, variable conotruncal malformations, hypoplastic left heart syndrome 2, tetralogy of Fallot and ventricular septal defect 3 and found no difference in molecular mechanism or inheritance, so this entry covers all five as alternative structural outcomes rather than as subtypes. Deep research: the requested provider, falcon, could not be used. EDISON_API_KEY is present but Edison authentication failed, and --fallback could not cover it because Edison raises a bare Exception and deep-research-client's is_fallback_worthy returns False for unrecognised exception types, so no fallback provider was reachable through that path. openscientist and claude_code were therefore run explicitly, each under its own provider name so attribution stays correct; they were still running when this record was written. GeneReviews: just check-genereviews --online returned NO_CHAPTER on both the GeneReviews and StatPearls lines, from the disease side and the NKX2-5 gene side with four synonyms present, but NCBI esearch returned HTTP 500 (Cannot connect to SOLR) for the whole session, so only the committed Bookshelf index snapshot of 2026-09-10 backs that statement; the entry notes say so. Two identifiers written from memory were caught and corrected before commit: PMID:9535663, recalled for Schott 1998, is an unrelated DNA-repair paper (correct identifier PMID:9651244), and NCIT:C62011, recalled as Pacemaker, is Bupivacaine; just check-qualifier-terms-online caught the second, which linkml-term-validator cannot see. The CGGV cache file was first built against an unpinned ClinGen export this session had just downloaded, then rebuilt from the committed cache/clingen/gene_validity.csv so its source_snapshot is reproducible on a fresh checkout. Validation: just validate passes (schema, terms, references); just count-verified-snippets reports 37/37; just verify-datasets resolves geo:GSE113251; just check-qualifier-terms-online, check-entity-refs, check-causal-targets, check-enum-values, check-duplicate-keys, check-block-scalar-comments, check-coarse-phenotypes, check-logical-rules, check-delivery-system, check-name-collisions, check-shared-disease-terms, check-cache-order, check-term-cache-integrity and check-reference-titles all pass; compliance 82.6%.

Claude Code ▸
NKX2-5-Related Congenital, Conduction and Myopathic Heart Disease: Research Report
claude-haiku-5-5, claude-opus-5-5 12 citations 2026-11-05T05:00:16.465411

NKX2-5-Related Congenital, Conduction and Myopathic Heart Disease: Research Report

Target: MONDO:0800441 · Causal gene: NKX2-5 (HGNC:2488, written hgnc:2488 in this repository; OMIM gene *600584) · Category: Mendelian, autosomal dominant

The disease is caused by heterozygous variants in NKX2-5, the homeobox transcription factor gene at chromosome 5q35.1. It is the human counterpart of the Drosophila gene tinman. Everything below is about that gene. It is a different gene from NKX2-1 (thyroid and lung disease), which the repo also holds as NKX2-1_Related_Choreoathetosis....

What the repo already holds. kb/disorders/NKX2-5-Related_Congenital_Conduction_and_Myopathic_Heart_Disease.yaml already exists (834 lines). There is also a leftover stub, stubs/NKX2.5-related_Congenital_Conduction_And_Myopathic_Heart_Disease.yaml, for the same MONDO ID. just tidy-stubs should list it as already_curated. The quotes marked ✔ below are snippets that entry already cites against the local reference cache. Quotes marked ◇ come from search-result abstracts and still need just fetch-reference before use.

1. Disease information

Overview. This is an autosomal dominant cardiac disorder with variable features that can appear together: - congenital heart defects, mostly secundum atrial septal defect (ASD), and also VSD, tetralogy of Fallot (TOF), other conotruncal defects and hypoplastic left heart syndrome (HLHS); - atrioventricular (AV) conduction disease that gets worse over time, often reaching complete heart block; - later-onset myocardial disease: left ventricular noncompaction (LVNC, also called hypertrabeculation) or dilated cardiomyopathy (DCM); - atrial and ventricular arrhythmias, and a markedly raised risk of sudden cardiac death (SCD).

ClinGen's Congenital Heart Disease Gene Curation Expert Panel merged several separate OMIM entities into this one disease ("lumping"). They reasoned that:

✔ "more than 26 unique variants (missense, nonsense, frameshift, deletions) across 18 papers have reported cases of a similar phenotype including congenital heart disease (predominantly ASD), AV block and later onset dilated cardiomyopathy and/or hypertrabeculation with predisposition to atrial and ventricular arrhythmias" (ClinGen CGGV:assertion_c429ebe5…, 2024-11-07)

✔ "Phenotype is variable within families and individuals may have only some of these features." (same record)

Identifiers

System ID Note
MONDO MONDO:0800441 "NKX2.5-related congenital, conduction and myopathic heart disease" Parents: MONDO:0000992 heart conduction disease; MONDO:0005217 familial cardiomyopathy
ClinGen GDV CGGV:assertion_c429ebe5-43ec-40e7-9d73-55bbbb44f6d1-2024-11-07T170000.000Z AD, Definitive, SOP9
OMIM (entities lumped by ClinGen) 108900 ASD7 with or without AV conduction defects; 614432 VSD3; 217095 Conotruncal heart malformations, variable; 187500 TOF; 614435 HLHS2 614432, 217095, 187500 and 614435 are quoted in the ClinGen record ✔. I recalled 108900 from memory, so check it.
OMIM gene 600584 NKX2-5 Check it
Orphanet / ICD-10 / ICD-11 / MeSH No disease-specific code found The closest broad codes are ICD-10 Q21.1 (ASD), I44.2 (complete AV block), I42.0 (DCM) and I42.8 / ICD-11 BC43.4 (LVNC). Check any of these before use.

Synonyms: NKX2-5-related congenital heart disease; atrial septal defect 7 with or without AV conduction defects (ASD7); CSX-related congenital heart disease; familial ASD with progressive AV block; "Holt–Oram-like ASD with heart block" (historical). (CSX is an old name for the gene; NKX2E is an alias.)

Source type. The evidence is aggregated disease-level knowledge (ClinGen, OMIM, literature reviews) built on family-based linkage, case series and case reports. No EHR-derived cohort exists for it.

2. Etiology

Cause. Germline heterozygous NKX2-5 variants. The founding linkage paper said:

✔ "A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35, where NKX2-5, a Drosophila tinman homolog, is located." … "Mutations in the gene encoding the homeobox transcription factor NKX2-5 were found to cause nonsyndromic, human congenital heart disease." (Schott et al. 1998, Science, PMID:9651244)

Genetic risk factors and modifiers - Variant class affects the phenotype. Truncating variants and homeodomain missense variants carry the full syndrome:

✔ "Variants causing this phenotype appear to be either truncating or missense within the homeodomain." (ClinGen)

Missense variants outside the homeodomain, found in sporadic CHD, are mostly not associated with AV block. McElhinney et al. (2003, JACC 42:1650–1655; PMID unconfirmed) found NKX2-5 variants in 18 of 608 CHD patients (3%), and most were missense variants outside the homeodomain without AV block ◇. - Genetic background changes penetrance in mice:

✔ "We assessed the role of genetic and environmental factors on the incidence of ventricular septal defects (VSDs) caused by a heterozygous Nkx2-5 knockout mutation." (Winston et al., PMID:22534315)

That study found that inbred strain background and maternal age both changed VSD incidence. This is evidence from mice. - Interacting cardiac transcription factors (GATA4, TBX5, TBX20, HAND2) are biologically plausible modifiers. No human modifier locus has been established.

Environmental and protective factors. None are established in humans. The mouse maternal-age effect (PMID:22534315) is the only gene–environment interaction described, and it is model-organism evidence only. No protective variants are known.

3. Phenotypes

Phenotype Suggested HPO Onset Course Frequency or evidence
Secundum atrial septal defect HP:0001684 Secundum atrial septal defect Congenital Stable Most common lesion. In Ellesøe et al.'s review, 74% of mutation carriers had ASD with conduction disease ◇
Patent foramen ovale / ASD HP:0001631 Atrial septal defect Congenital Stable Common
Ventricular septal defect HP:0001629 Congenital Stable Occasional (VSD3)
Tetralogy of Fallot / conotruncal defects HP:0001636; HP:0001710 Conotruncal defect Congenital Needs surgery Occasional (Benson 1999)
Hypoplastic left heart HP:0004383 Congenital Severe Rare
Ebstein anomaly, double-outlet right ventricle, subvalvar aortic stenosis HP:0010316, HP:0001718, HP:0001682 Congenital Variable Case-level
First-degree AV block HP:0011705 Childhood to adulthood Progressive Very frequent in carriers of truncating or homeodomain variants
Second-degree / complete AV block HP:0011706 Second degree AV block; HP:0001678 Atrioventricular block Adolescence to adulthood Progressive Frequent. Often appears after ASD repair, and does not depend on surgery
Atrial fibrillation / supraventricular arrhythmia HP:0005110; HP:0004308 Ventricular arrhythmia Adult Progressive ✔ "predisposition to atrial and ventricular arrhythmias" (ClinGen)
Left ventricular noncompaction HP:0032662 Left ventricular noncompaction cardiomyopathy (check label) Childhood to adult Progressive ✔ "This study for the first time identifies association between a NKX2.5 mutation and ventricular noncompaction." (Ouyang et al. 2011, PMID:20932824)
Dilated cardiomyopathy HP:0001644 Adult Progressive, can reach heart failure Hanley et al. 2016 (BMC Med Genet, PMC5114776) ◇
Syncope HP:0001279 Variable Episodic ✔ PMID:20932824
Sudden cardiac death HP:0001645 Any age; usually adult — 19 of 120 (15%) in families with ASD plus conduction disease (Ellesøe 2016, PMID:26679770) ◇

The defining family report is:

✔ "We identified a CHD family with atrial septal defects (ASDs), atrioventricular block, ventricular noncompaction, syncope and sudden death." (PMID:20932824)

Quality of life. No disease-specific QoL data exist. The burden comes from repeated surgery, lifelong pacing, ICD shocks and heart failure.

4. Genetic and molecular information

  • Gene: NKX2-5, two exons, encoding a 324-amino-acid NK-2 class homeodomain protein. Its domains are an N-terminal tinman (TN) domain, the homeodomain (about residues 138–197), the NK2-specific domain and a C-terminal transactivation domain. Check the residue boundaries against UniProt P52952.
  • Variant spectrum: missense (concentrated in the homeodomain, e.g. T178M, Q181P, I184M, R190C), nonsense, frameshift (e.g. c.512insGC) and whole-gene deletions. Ellesøe's review counted 59 distinct mutations in 202 patients ◇. Most are private to a family. ClinVar classifications should be pulled at curation time.
  • Functional consequence: mostly loss of function / haploinsufficiency. Some alleles may be dominant-negative, and some may gain DNA-binding activity:

    ✔ "Two are predicted to impair binding of NKX2-5 to target DNA, resulting in haploinsufficiency, and a third potentially augments target-DNA binding." (PMID:9651244)

✔ "Functional studies indicate that the c.512insGC mutation impedes nuclear localization of NKX2.5 and causes a total loss of transactivation activity of NKX2.5." (PMID:20932824) - Origin: germline. A de novo origin is reported in some sporadic cases. - Population frequency: pathogenic homeodomain and truncating variants are absent or ultra-rare in gnomAD. - Chromosomal: deletions at 5q35 that include NKX2-5 (some overlapping the Sotos region around NSD1) can cause CHD with conduction disease as part of a contiguous-gene syndrome. - Epigenetics: no disease-specific data.

5. Environmental information

No exposures, lifestyle factors or infectious agents are known to cause or trigger this disease. Mouse data show maternal age affects penetrance (PMID:22534315).

6. Mechanism and pathophysiology

Causal chain

  1. A heterozygous truncating or homeodomain NKX2-5 variant leads to reduced functional NKX2-5 protein (haploinsufficiency; sometimes dominant-negative), through impaired DNA binding, nuclear import or transactivation ✔ (PMIDs 9651244, 20932824).
  2. Reduced NKX2-5 dosage results in misregulated cardiac transcriptional networks. Normally NKX2-5 works with GATA4, TBX5 and TBX20, drives NPPA, GJA5 (Cx40) and MYL2, and represses BMP10 and atrial genes in the ventricles. This regulatory detail is from mouse and in vitro work; in humans it is inferred.
  3. Branch A, septation: abnormal atrial septum development and abnormal endocardial-cushion and outflow-tract morphogenesis lead to secundum ASD, VSD and conotruncal defects.

    ✔ "NKX2-5 is important for regulation of septation during cardiac morphogenesis" (PMID:9651244)

  4. Branch B, conduction system: dose-dependent hypoplasia of the AV node and His–Purkinje system, followed by progressive loss of conduction cells after birth, leads to progressive AV block. In Jay et al. 2004 (JCI, DOI 10.1172/JCI19846), heterozygous mice had about half the normal number of conduction-system cells ◇. In Pashmforoush et al. 2004 (Cell 117:373, DOI 10.1016/S0092-8674(04)00405-2), ventricle-restricted knockout mice had a hypoplastic AV node at birth, then "selective dropout" of conduction cells and complete heart block ◇.

    ✔ "…for maturation and maintenance of atrioventricular node function throughout life." (PMID:9651244)

✔ "Nkx2-5+/- haploinsufficient mice have an abnormal electrocardiogram, with a prolonged QRS and progressive elongation of the PR interval" (PMID:29979676) 5. Branch C, myocardium: failure of trabecular compaction and loss of ventricular myocyte lineage identity (ectopic BMP10, atrial and conduction-system gene expression in the ventricle) lead to hypertrabeculation/LVNC with subendocardial fibrosis. Over time this progresses to strain defects, DCM and heart failure. ✔ "Conditional deletion of Nkx2-5 at embryonic stages, during trabecular formation, provokes a severe hypertrabeculated phenotype associated with subendocardial fibrosis and Purkinje fiber hypoplasia." … "in 50% of mutant mice, to heart failure." (Choquet et al. 2018, PMID:29979676) 6. Branches B and C together (conduction block, a hypoplastic Purkinje network and a fibrotic, noncompacted myocardium) result in ventricular arrhythmia and sudden cardiac death. SCD has been reported even in people with a working pacemaker. That points to a ventricular arrhythmic substrate, not bradycardia alone. This step is inferred from clinical series.

Suggested GO terms: GO:0003290 atrial septum secundum morphogenesis; GO:0060413 atrial septum morphogenesis; GO:0060412 ventricular septum morphogenesis; GO:0003162 atrioventricular node development; GO:0003161 cardiac conduction system development; GO:0060982 coronary artery morphogenesis / GO:0060993 kidney morphogenesis (not relevant, avoid); GO:0003222 ventricular trabecula myocardium morphogenesis; GO:0061384 heart trabecula morphogenesis; GO:0007507 heart development; GO:0006357 regulation of transcription by RNA polymerase II; GO:0000978 (DNA binding, molecular function).

Suggested CL terms: CL:0002068 Purkinje myocyte; CL:1000409 / CL:1000410 (AV node and His bundle cells; check labels); CL:0002131 regular ventricular cardiac myocyte; CL:0002129 regular atrial cardiac myocyte; CL:0002548 fibroblast of cardiac tissue (check).

Molecular profiling. Transcriptomics of conditional Nkx2-5 mutant mouse hearts is available. GEO:GSE113251 is already cited in the entry ✔ ("identifies Six1 as a marker upregulated in hypertrabeculated hearts"). Patient-iPSC cardiomyocyte studies exist but are small. No human single-cell, spatial or proteomic disease datasets were found.

7. Anatomical structures affected

  • Organ: heart (UBERON:0000948). Specifically: interatrial septum (UBERON:0002085), interventricular septum (UBERON:0002094), AV node (UBERON:0002352), bundle of His (UBERON:0002064), Purkinje fibers (UBERON:0002354, check the CURIE), left ventricular myocardium / trabeculae carneae (UBERON:0002084, UBERON:0002513, check). The cardiovascular system is the only system involved, and the disease is non-syndromic.
  • Subcellular: nucleus (GO:0005634). Some variants mislocalize the protein to the cytoplasm (PMID:20932824).
  • Lateralization: not applicable. The myopathy mainly affects the left ventricle.

8. Temporal development

  • Onset: structural defects are congenital. AV conduction delay may be present early, and first-degree block often appears in childhood or adolescence. Higher-grade block, atrial fibrillation, LVNC/DCM and SCD usually appear in adolescence to middle age.
  • Course: lifelong and progressive for conduction and myocardial disease. Conduction disease progresses whether or not the ASD is repaired. The disease does not remit.
  • Critical window: the gap between diagnosis of an ASD or first-degree AV block and the onset of high-grade block or SCD. This is when ECG/Holter surveillance and timely pacing or ICD decisions matter.

9. Inheritance and population

  • Inheritance: autosomal dominant (HP:0000006), with high penetrance for truncating and homeodomain variants. Expressivity is variable even within one family.
  • Prevalence: not established. NKX2-5 variants are found in about 1–4% of unselected CHD cohorts (≈3% in McElhinney 2003 ◇). Rates are higher in familial ASD with AV block. A conservative estimate is prevalence_class: NOT_YET_DOCUMENTED or RARE, with measure_type: UNKNOWN.
  • No anticipation, founder effects or ancestry bias are known. Both sexes are affected equally. Germline mosaicism is possible but rarely reported.

10. Diagnostics

  • ECG: PR prolongation, progressive AV block, QRS widening (LOINC 8626-4 PR interval, 8633-0 QRS duration; check these codes with just loinc-seed-cache). Use Holter or ambulatory monitoring.
  • Imaging: transthoracic or transesophageal echocardiography for septal defects. Cardiac MRI for LVNC (noncompacted-to-compacted ratio above 2.3 in diastole, Petersen criteria), LV function and late gadolinium enhancement (fibrosis).
  • Genetic testing: single-gene NKX2-5 sequencing plus deletion/duplication analysis. Alternatively, a CHD, cardiomyopathy or conduction-disease panel, or exome sequencing. CMA if syndromic features suggest a 5q35 deletion. Cascade testing of relatives.
  • Clinical clue: ASD plus AV block in a family should prompt NKX2-5 testing.
  • Differential diagnosis:
  • Holt–Oram syndrome (TBX5; upper-limb defects);
  • GATA4-related CHD (usually no AV block);
  • LMNA cardiomyopathy (AV block plus DCM; no ASD; raised CK);
  • SCN5A progressive cardiac conduction disease;
  • TBX20;
  • MYH6-related ASD;
  • TBX5;
  • post-surgical heart block.

11. Outcome and prognosis

  • SCD is the main cause of death. In the Ellesøe review it occurred in 15% of individuals in families with ASD plus conduction disease (9 confirmed and 10 possible carriers) ◇ (PMID:26679770), and some deaths happened despite a pacemaker.
  • Other burdens: heart failure from DCM/LVNC, and atrial fibrillation with thromboembolic risk.
  • Prognostic factors: truncating or homeodomain variant; family history of SCD; LV dysfunction; ventricular arrhythmia; fibrosis on MRI. Formal risk models are not available.

12. Treatment

There is no disease-modifying therapy, so management is symptomatic and preventive.

Intervention NCIT suggestion Modality
Surgical or transcatheter ASD/VSD closure; TOF repair NCIT:C15329 Surgical Procedure SURGERY
Permanent pacemaker for high-grade AV block NCIT:C15329 (procedure); device as a qualifier (NCIT:C16830 Medical Device; check NCIT pacemaker device term) DEVICE
ICD for primary prevention in carriers (proposed by Ellesøe; follow the HRS/AHA cardiomyopathy and conduction guidelines) NCIT:C15329, plus device qualifier DEVICE
Guideline-directed heart-failure drugs (ACE inhibitor/ARB/ARNI, β-blocker, MRA, SGLT2 inhibitor) for DCM/LVNC NCIT:C15986 Pharmacotherapy + therapeutic_agent (CHEBI) SMALL_MOLECULE
Anticoagulation for atrial fibrillation; anticoagulation in LVNC with LV dysfunction NCIT:C15986 SMALL_MOLECULE
Heart transplantation (end stage) NCIT:C15289 Organ Transplantation SURGERY
Genetic counseling NCIT:C15240 —

Pacing (prefer physiologic, conduction-system pacing) and ICDs carry lifelong device risks. No pharmacogenomic issues, gene therapy or registered disease-specific trials were found.

13. Prevention

  • Primary: no primary prevention exists apart from reproductive options: prenatal testing or preimplantation genetic testing for a known familial variant.
  • Secondary: cascade genotyping of relatives. Serial ECG, Holter, echocardiography and MRI in carriers, including those with a repaired or absent ASD.
  • Tertiary: pacing at the onset of high-grade block, and a low threshold for an ICD.
  • No vaccines or public-health measures apply.

14. Other species

No naturally occurring animal disease is recorded in OMIA (check before citing). The gene is highly conserved: mouse Nkx2-5 (MGI:97350, check), zebrafish nkx2.5, Drosophila tin.

15. Model organisms

Model Phenotype How well it matches human disease Reference
Nkx2-5⁻/⁻ mouse Embryonic lethal; looping failure; no MLC2V expression Too severe; developmental only Lyons et al. 1995, Genes Dev 9:1654 (DOI 10.1101/gad.9.13.1654) ◇; Tanaka et al. 1999 Development ◇
Nkx2-5⁺/⁻ mouse ASD/PFO and VSD (penetrance depends on strain); PR/QRS prolongation; AV-node/His–Purkinje hypoplasia Partial match: septal and conduction features are reproduced Jay 2004 ◇; PMID:22534315 ✔; PMID:29979676 ✔
Ventricle-restricted knockout (MLC2v-Cre) Progressive complete heart block, trabecular overgrowth, ectopic BMP10 Matches the conduction and myopathy features; no septal defects Pashmforoush 2004 ◇
Inducible trabecular knockout (Cx40-creERT2) Hypertrabeculation, subendocardial fibrosis, Purkinje hypoplasia, heart failure in 50% Strong LVNC model PMID:29979676 ✔
Patient iPSC-derived cardiomyocytes; zebrafish nkx2.5 morphants/mutants Cellular electrophysiology and differentiation defects In vitro or non-mammalian Literature exists; not checked here

Limits of the mouse models: mice show the septal and conduction features at a mouse heart rate. Human-like adult SCD and atrial fibrillation are not modelled well, and the strain-dependent penetrance argues for a HUMAN_MODEL_MISMATCH discussion.

Curation notes for the existing entry

  • The stub is stale: the KB already holds this MONDO ID. just tidy-stubs --apply should delete it.
  • The entry relies on only four PMIDs. These papers are worth adding with just fetch-reference:
  • Benson et al. 1999 (JCI 104:1567; DOI 10.1172/JCI8154; PMID 10587520 from a third-party mirror, so confirm it). This covers the TOF, VSD and conotruncal spectrum.
  • Ellesøe et al. 2016 (PMID:26679770). This covers SCD frequency and the ICD recommendation.
  • Pashmforoush et al. 2004 (Cell). This covers conduction-cell dropout and BMP10.
  • Jay et al. 2004 (JCI). This covers dose-dependent conduction-system hypoplasia.
  • Morlanes-Gracia et al. 2021 (Front Cardiovasc Med, PMC8280289; p.Gln181Pro with LVNC and SCD).
  • Hanley et al. 2016 (BMC Med Genet, PMC5114776; DCM).
  • McElhinney et al. 2003 and Elliott et al. 2003 (JACC). These cover genotype–phenotype data in sporadic CHD and HLHS.
  • Run just check-genereviews on the entry. I found no GeneReviews chapter specific to NKX2-5.
  • Every HPO, GO, CL, UBERON, NCIT and LOINC CURIE suggested above is a lead I recalled, not something I looked up. Verify each one in cache/<prefix>/terms.csv, with runoak, or in OLS before binding it.

Sources

Reference Validation

Checked with linkml-reference-validator 0.5.1.

Outcome Count
References checked 15
Resolved 15
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 11
Quoted claims found in source 10
Quoted claims not found in source 1
References weighed for topical relevance 15
On topic 8
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • PMC:PMC4773750 (abstract only): "Genetics of CHD: the NKX2-5 gene, a key player"
  • closest text in source: "The mutant NKX2-5 factor can regulate a number of off-targets downstream to facilitate CHD development"

Term Validation

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

Outcome Count
Terms checked 56
Resolved 54
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 13
Terms named correctly 6
Terms named as a different term 2
Terms whose name is worth a second look 5

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:

  • GO:0000978 (1 mention) - the report calls it "DNA binding, molecular function"; GO calls it RNA polymerase II cis-regulatory region sequence-specific DNA binding
  • NCIT:C15986 (2 mentions) - the report calls it "Anticoagulation for atrial fibrillation; anticoagulation in LVNC with LV dysfunction"; NCIT calls it Pharmacotherapy

Terms whose name is worth a second look

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

  • HP:0004383 (1 mention) - the report calls it "Hypoplastic left heart"; HP calls it Hypoplastic left ventricle
  • HP:0011705 (1 mention) - the report calls it "First-degree AV block"; HP calls it First degree atrioventricular block
  • CL:1000410 (1 mention) - the report calls it "AV node and His bundle cells; check labels"; CL calls it myocyte of atrioventricular node, and lists "AV node cardiac muscle cell" among its other names
  • UBERON:0000948 (1 mention) - the report calls it "Organ: heart"; UBERON calls it heart**, and lists "branchial heart" among its other names
  • GO:0005634 (1 mention) - the report calls it "Subcellular: nucleus"; GO calls it nucleus**, and lists "cell nucleus" among its other names

Prefixes with no resolver

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

OpenScientist ▸
NKX2-5-Related Congenital, Conduction and Myopathic Heart Disease — Comprehensive Research Report
openscientist-autonomous 5 citations 2026-11-05T05:02:05.504339

NKX2-5-Related Congenital, Conduction and Myopathic Heart Disease — Comprehensive Research Report

Disease: NKX2-5-Related Congenital, Conduction and Myopathic Heart Disease MONDO ID: MONDO:0800441 · OMIM: #108900 (ASD7, atrial septal defect 7 with or without atrioventricular conduction defects) Causal gene: NKX2-5 (NK2 homeobox 5; formerly CSX, cardiac-specific homeobox; HGNC:2488; chromosome 5q35.1) Category: Mendelian, autosomal dominant

Causal gene stated up front: This report concerns the disease caused by heterozygous, predominantly loss-of-function variants in NKX2-5, the homeodomain cardiac transcription factor located at chromosome 5q35.1 (the vertebrate homolog of Drosophila tinman). The hallmark combination is secundum atrial septal defect (ASD) with progressive atrioventricular (AV) conduction block, together with a broader spectrum of structural malformations and a myopathic/conduction-cell component. All molecular claims below refer to NKX2-5, not to similarly named genes.

Summary

NKX2-5-Related Congenital, Conduction and Myopathic Heart Disease is an autosomal-dominant cardiac disorder caused by heterozygous, predominantly loss-of-function (haploinsufficient) variants in NKX2-5, the NK2-class homeodomain cardiac transcription factor located at chromosome 5q35.1. NKX2-5 is the vertebrate ortholog of the Drosophila cardiac selector gene tinman and is one of the earliest and most essential regulators of cardiac development. The disease was first defined genetically by Schott et al. (1998), who mapped a dominant locus for cardiac malformations plus atrioventricular (AV) conduction abnormalities to 5q35 and identified disease-causing NKX2-5 mutations, two of which impair DNA binding and thereby cause haploinsufficiency [PMID: 9651244].

The clinical syndrome unites three mechanistically linked manifestations. First, structural congenital heart defects — most characteristically secundum atrial septal defect (ASD), but also ventricular septal defect (VSD), tetralogy of Fallot, double-outlet right ventricle, and Ebstein anomaly — arising from NKX2-5's role in cardiac looping and septation. Second, a progressive atrioventricular conduction disease: the AV node is hypoplastic from birth in a gene-dosage-dependent manner, then undergoes selective postnatal dropout of conduction cells, producing age-progressive AV block that was the primary cardiac manifestation in roughly a quarter of affected individuals in the landmark Benson et al. cohort [PMID: 10587520]. Third, a myopathic branch — trabecular/ventricular non-compaction and cardiomyopathy — driven in model systems by ectopic, high-level BMP10 expression in ventricular myocardium when NKX2-5 is lost [PMID: 15109497].

The mechanistic chain is well supported by a mouse allelic series. Homozygous-null embryos form a linear heart tube but fail to initiate looping morphogenesis and die at E9–10, lacking the ventricular marker MLC2V [PMID: 7628699]. Heterozygotes model human haploinsufficiency, with roughly half the normal number of conduction-system cells and a hypoplastic AV node [PMID: 15085192]. Ventricular-restricted conditional knockouts reproduce progressive complete heart block together with trabecular overgrowth via ectopic BMP10 [PMID: 15109497]. Management is phenotype-directed — surgical/device septal closure, permanent pacemaker/ICD for conduction disease and sudden-death risk, and heart-failure therapy — with no gene-specific cure currently available.

Section 1 — Disease Information and Key Identifiers

Identifier type Value
Disease name NKX2-5-Related Congenital, Conduction and Myopathic Heart Disease
MONDO MONDO:0800441
OMIM #108900 (ASD7, atrial septal defect 7 with or without AV conduction defects)
Causal gene NKX2-5 (HGNC:2488; NCBI Gene 1482; UniProt P52952)
Cytogenetic locus 5q35.1
Protein NK2 homeobox 5 / cardiac-specific homeobox (CSX)
Inheritance Autosomal dominant

Synonyms / alternative names: NKX2-5-related congenital heart disease; atrial septal defect with atrioventricular conduction defects; CSX-related congenital heart disease; cardiac homeobox (CSX) disease. The gene has historically been written NKX2.5, NKX2E, and CSX.

Source of information: The content of this report is derived from aggregated disease-level resources — OMIM, MONDO, and primary peer-reviewed human genetic/clinical studies and model-organism literature — rather than from individual-patient electronic health records.

Section 2 — Etiology

Primary cause (genetic): Heterozygous pathogenic variants in NKX2-5. The predominant molecular mechanism is haploinsufficiency: variants that reduce functional NKX2-5 dosage (truncating variants, and missense variants that impair DNA binding) are sufficient to cause disease [PMID: 9651244]. Some variants may additionally act via dominant-negative effects or reduced transactivation.

Genetic risk factors: The causal NKX2-5 variant is itself the principal genetic determinant. Partner cardiac transcription factors (GATA4, TBX5, TBX20, GATA6) that function combinatorially with NKX2-5 cause overlapping CHD phenotypes when mutated and are candidate modifiers.

Environmental risk factors: No specific environmental trigger is established for NKX2-5-related disease. General CHD risk factors (maternal diabetes, teratogen exposure, folate status) may plausibly modify expressivity but are not documented as disease-specific for this entity.

Protective factors: None established genetically or environmentally specific to this disease.

Gene–environment interactions: Variable expressivity within families carrying the same variant (Benson et al.) implies the existence of genetic modifiers and/or environmental contributors, but none are specifically characterized [PMID: 10587520].

Section 3 — Phenotypes

Benson et al. (2000) documented across mutation carriers: AV block (primary manifestation in ~25%), secundum atrial septal defect, ventricular septal defect, tetralogy of Fallot/double-outlet right ventricle (3 individuals), and Ebstein anomaly/tricuspid valve abnormalities [PMID: 10587520]. Schott et al. emphasized that NKX2-5 is important both for septation during cardiac morphogenesis and for maturation and maintenance of AV node function throughout life — i.e., a lifelong, progressive course [PMID: 9651244].

"Ventricular septal defect was associated with tetralogy of Fallot or double-outlet right ventricle in 3 individuals. Ebstein's anomaly and other tricuspid valve abnormalities were also present." — [PMID: 10587520]

"NKX2-5 is important for regulation of septation during cardiac morphogenesis and for maturation and maintenance of atrioventricular node function throughout life." — [PMID: 9651244]

Suggested HPO annotations:

Phenotype Phenotype type HPO term Frequency / onset / course
Secundum atrial septal defect Physical malformation HP:0001684 Most common structural lesion; congenital
Atrioventricular block Clinical sign (ECG) HP:0001678 Primary in ~25%; progressive
First-degree AV block Lab/ECG abnormality HP:0011705 Childhood onset; progresses
Second-degree AV block Lab/ECG abnormality HP:0011706 Intermediate progression
Third-degree (complete) AV block Lab/ECG abnormality HP:0001709 Adult; sudden-death risk
Ventricular septal defect Physical malformation HP:0001629 Frequent; congenital
Tetralogy of Fallot Physical malformation HP:0001636 Subset; conotruncal
Double-outlet right ventricle Physical malformation HP:0002356 Rare
Ebstein anomaly Physical malformation HP:0010316 Reported
Tricuspid valve abnormality Physical malformation HP:0001702 Reported
Left ventricular noncompaction Physical/structural HP:0030682 Myopathic branch
Dilated cardiomyopathy Clinical sign HP:0001644 Myopathic branch
Sudden cardiac death Outcome HP:0001645 Conduction-related risk

Quality of life impact: Pacemaker dependence, activity restriction from heart failure/arrhythmia, surgical burden, and lifelong surveillance affect daily functioning; sudden-death risk imposes substantial psychological burden on patients and families.

Section 4 — Genetic / Molecular Information

Causal gene: NKX2-5 (HGNC:2488; OMIM gene 600584). Disease OMIM: #108900.

Pathogenic variants: Reported variants include missense (notably within/affecting the homeodomain, impairing DNA binding), nonsense, frameshift, and splice-site changes. Schott et al. identified 3 mutations (2 DNA-binding-impairing) [PMID: 9651244]; Benson et al. added 7 novel mutations across 26 probands [PMID: 10587520]. Variant classification follows ACMG/AMP criteria in ClinVar (pathogenic/likely pathogenic for established LoF alleles).

Allele frequency: Pathogenic NKX2-5 variants are rare and largely family-private; they are essentially absent/ultra-rare in gnomAD, consistent with a highly constrained developmental transcription factor.

Somatic vs. germline: Germline (congenital disorder). De novo and inherited dominant variants both occur.

Functional consequences: Predominantly loss of function / haploinsufficiency; impaired DNA binding is a demonstrated mechanism [PMID: 9651244]. Dominant-negative effects have been proposed for some variants.

Modifier genes: GATA4, TBX5, TBX20, GATA6 (combinatorial partners) are candidate modifiers; variable expressivity implies modifiers but none are definitively mapped.

Epigenetic / chromosomal: No disease-specific methylation signature is established. Large 5q35 deletions/structural changes involving NKX2-5 can produce the phenotype and are detectable by chromosomal microarray.

Section 5 — Environmental Information

No specific environmental factors, lifestyle factors, or infectious agents are established as causes or triggers of NKX2-5-related disease. The disorder is fundamentally genetic/developmental. General CHD environmental modifiers (maternal metabolic state, teratogens) are not documented as disease-specific for this entity. Not applicable / not established for this Mendelian condition.

Section 6 — Mechanism / Pathophysiology

Ordered causal chain:

  1. A heterozygous loss-of-function NKX2-5 variant (nonsense, frameshift, splice, or DNA-binding-impairing missense) leads to reduced functional NKX2-5 protein — i.e., haploinsufficiency (demonstrated for DNA-binding-impairing alleles; [PMID: 9651244]).
  2. Reduced NKX2-5 dosage results in diminished combinatorial transcriptional activation (with GATA4/TBX5/GATA6) of chamber- and conduction-specific target genes (inferred from network studies; target genes shown in [PMID: 15109497, 15085192]).
  3. Branch A — Structural: Impaired transcriptional program leads to failed/abnormal cardiac looping and septation during embryogenesis → results in secundum ASD, VSD, conotruncal defects (tetralogy of Fallot, DORV), and Ebstein anomaly (looping requirement demonstrated in null mice [PMID: 7628699]; human spectrum [PMID: 10587520]).
  4. Branch B — Conduction: Reduced dosage leads to a hypoplastic AV node at birth (dosage-dependent cell number) → results in selective postnatal dropout/failed retention of conduction cells → leads to progressive first- → second- → third-degree AV block and sudden-death risk ([PMID: 15085192, 15109497]).
  5. Branch C — Myopathic: Loss of NKX2-5 repression results in ectopic high-level BMP10 in ventricular myocardium → leads to trabecular overgrowth / ventricular non-compaction and cardiomyopathy (demonstrated in conditional KO; BMP10 necessary and sufficient for major ventricular muscle defects [PMID: 15109497]).
    NKX2-5 LoF variant (heterozygous)
                 │
       Haploinsufficiency
                 │
     Reduced combinatorial activation of
  chamber/conduction gene programs (GATA4/TBX5)
                 │
┌────────────────────────┼─────────────────────────┐
▼                        ▼                          ▼
  [A] Looping/septation    [B] AV-node hypoplasia      [C] Loss of BMP10
      failure                  + cell dropout              repression
│                        │                          │
  Secundum ASD, VSD,       Progressive AV block        Ectopic BMP10 →
  TOF, DORV, Ebstein       (1°→2°→3°), SCD risk        noncompaction/CMP

"looping morphogenesis, a critical determinant of heart form, was not initiated at the linear heart tube stage" — [PMID: 7628699]

"At birth, mutant mice display a hypoplastic atrioventricular (AV) node and then develop selective dropout of these conduction cells." — [PMID: 15109497]

"Transcriptional profiling uncovered the aberrant expression of a unique panel of atrial and conduction system-restricted target genes, as well as the ectopic, high level BMP-10 expression in the adult ventricular myocardium." — [PMID: 15109497]

Molecular / cellular detail: - Molecular pathways: NKX2-5 is a homeodomain transcription-factor node in the core cardiac gene-regulatory network; downstream effectors include GJA5/connexin40 (gap junction), BMP10 signaling, and chamber myocyte identity genes. Jay et al. identified connexin40 as a putative Nkx2-5 target [PMID: 15085192]. - GO biological processes: cardiac conduction (GO:0061337), heart looping (GO:0001947), cardiac septum morphogenesis (GO:0003279), regulation of transcription by RNA polymerase II (GO:0006357), cardiac muscle tissue development (GO:0048738). - Cell types (CL): nodal/AV-node myocyte (CL:0002087), cardiac Purkinje fiber cell (CL:0000166), ventricular cardiomyocyte (CL:0002131), atrial cardiomyocyte (CL:0002129), precardiac mesoderm. - Subcellular (GO CC): nucleus (GO:0005634, site of transcription-factor action), gap junction / connexin40 (GO:0005922). - Protein dysfunction: predominantly loss of function via impaired DNA binding (homeodomain mutations) or protein truncation; haploinsufficiency is the dominant paradigm [PMID: 9651244].

Section 7 — Anatomical Structures Affected

  • Organ: Heart (UBERON:0000948) — primary. Secondary systemic effects from heart failure and conduction disease affect the cardiovascular system (UBERON:0004535).
  • Structures: interatrial/atrial septum (UBERON:0002085) — secundum ASD; interventricular septum (UBERON:0002094) — VSD; atrioventricular node (UBERON:0002351) — conduction disease; cardiac conduction system (UBERON:0004146) and His–Purkinje system; cardiac ventricle (UBERON:0002082) and trabecular myocardium — non-compaction; tricuspid valve — Ebstein anomaly; cardiac outflow tract (UBERON:0004145) — conotruncal defects.
  • Tissue/cell level: cardiac muscle (myocardium), specialized conduction myocytes, nodal myocytes.
  • Subcellular: nucleus (transcription-factor action); gap junctions (connexin40).
  • Lateralization: The heart is a midline organ; conotruncal/looping phenotypes reflect disrupted left–right morphogenesis rather than limb-type lateralization.

Section 8 — Temporal Development

  • Onset: Congenital for structural defects (present at birth, often detected in infancy/childhood). Conduction disease is congenital-to-progressive — the AV node is hypoplastic from birth, but block severity worsens with age.
  • Progression: The conduction phenotype is characteristically progressive, evolving from first-degree AV block in childhood to higher-grade/complete block in adulthood, reflecting ongoing conduction-cell dropout [PMID: 15085192, 15109497]. Structural defects are static once formed but may require intervention; the myopathic phenotype can emerge or progress over time.
  • Critical period: Cardiac looping and septation (~embryonic weeks 3–8 in humans; E8–E10.5 in mouse) is the window in which structural defects originate.
  • Course: Chronic, lifelong, requiring continued surveillance even after structural repair.

Section 9 — Inheritance and Population

  • Inheritance: Autosomal dominant (OMIM #108900).
  • Penetrance / expressivity: Incomplete penetrance and markedly variable expressivity — family members with the same variant may have isolated AV block, isolated ASD, complex CHD, or be minimally affected [PMID: 10587520].
  • Epidemiology: CHD overall affects ~0.8% of live births; NKX2-5 variants account for an estimated ~1–4% of nonsyndromic CHD (established-knowledge estimate). Benson et al.: 7 novel mutations across 26 probands; authors conclude NKX2-5 may account for a clinically significant portion of tetralogy of Fallot and idiopathic AV block [PMID: 10587520].
  • Sex ratio: No strong sex bias (autosomal).
  • Founder effects / consanguinity: Not prominent; most variants are family-private. Not a repeat-expansion disorder, so genetic anticipation is not expected. Germline mosaicism is possible but not a documented recurrent feature.

"Mutations in human NKX2.5 cause a variety of cardiac anomalies and may account for a clinically significant portion of tetralogy of Fallot and idiopathic AV block." — [PMID: 10587520]

"The coinheritance of NKX2.5 mutations with various congenital heart defects suggests that this transcription factor contributes to diverse cardiac developmental pathways." — [PMID: 10587520]

Section 10 — Diagnostics

  • Electrophysiology: 12-lead ECG and ambulatory (Holter) monitoring are central for detecting and staging AV block (PR-interval prolongation → higher-grade block); serial surveillance is essential given progression.
  • Imaging: Transthoracic echocardiography detects secundum ASD, VSD, conotruncal anomalies, Ebstein anomaly, and ventricular non-compaction; cardiac MRI quantifies non-compaction and ventricular function.
  • Genetic testing: Single-gene NKX2-5 sequencing, multigene congenital-heart/cardiomyopathy/conduction panels, or whole-exome/genome sequencing. Recommended for probands with CHD plus conduction disease and for cascade screening of relatives. Chromosomal microarray detects larger 5q35 structural changes.
  • Clinical criteria / differential diagnosis: Secundum ASD (or other CHD) with progressive AV block is highly suggestive. Differentials include GATA4-, TBX5- (Holt–Oram, distinguished by radial/upper-limb anomalies), and TBX20-related CHD; isolated idiopathic AV block (Lev–Lenègre); and Lamin A/C conduction disease.
  • Screening: Cascade genetic and clinical (ECG/echo) screening of at-risk relatives is the key secondary-prevention measure.

Section 11 — Outcome / Prognosis

  • Mortality: Driven chiefly by high-grade AV block (syncope, sudden cardiac death) and by complications of structural defects and cardiomyopathy. Sudden death has been reported even after structural repair, underscoring the need for conduction surveillance.
  • Morbidity: Heart failure (from cardiomyopathy/non-compaction or unrepaired shunts), thromboembolic risk, pacemaker dependence.
  • Prognostic factors: Degree/progression of AV block, presence of ventricular dysfunction/non-compaction, and complexity of the structural lesion. Timely pacemaker/ICD implantation and surgical repair substantially improve outcomes.
  • Recovery: Structural defects are correctable; conduction disease is managed but not cured and tends to progress.

Section 12 — Treatment

No gene-specific or curative therapy exists; management is phenotype-directed.

Manifestation Intervention NCIT suggestion
Secundum ASD / VSD Surgical or transcatheter device closure Cardiac surgery (NCIT:C51658); septal closure
Conotruncal defects (TOF, DORV) Corrective cardiac surgery Cardiac surgical procedure
Progressive AV block Permanent pacemaker implantation Pacemaker (NCIT:C50114)
Sudden-death risk / ventricular dysfunction Implantable cardioverter-defibrillator (ICD) Implantable defibrillator (NCIT:C62226)
Heart failure / cardiomyopathy Guideline-directed medical therapy (ACE inhibitors/ARBs, beta-blockers, diuretics) Antihypertensive/cardiac agents
Thromboembolism risk (shunts/arrhythmia) Anticoagulation Anticoagulant therapy (NCIT:C577)
  • Pharmacogenomics / advanced therapeutics: No approved gene, cell, or RNA-based therapy. Gene-replacement/editing remains preclinical. No targeted small molecule exists for NKX2-5 disease.
  • Treatment strategy: Lifelong multidisciplinary follow-up (congenital cardiology + electrophysiology), serial ECG/Holter and echo, with device therapy timed to conduction progression.

Section 13 — Prevention

  • Primary prevention: Not applicable in the classical sense (congenital genetic disorder); preconception genetic counseling and reproductive options (prenatal/preimplantation genetic testing) can prevent transmission.
  • Secondary prevention: Cascade genetic and ECG/echocardiographic screening of first-degree relatives enables early detection of silent conduction disease and timely pacemaker placement — the single most impactful preventive measure given the progressive, sudden-death-prone conduction phenotype.
  • Tertiary prevention: Device therapy (pacemaker/ICD), heart-failure management, and anticoagulation to prevent complications.
  • Counseling: Autosomal-dominant genetic counseling with 50% transmission risk per pregnancy; emphasis on incomplete penetrance and variable expressivity.

Section 14 — Other Species / Natural Disease

  • Taxonomy of orthologs: Mouse (Mus musculus, NCBI Taxon 10090; Nkx2-5, NCBI Gene 18091); zebrafish (Danio rerio, Taxon 7955; nkx2.5); Drosophila melanogaster (Taxon 7227; tinman, the founding ortholog).
  • Evolutionary conservation: Deep conservation of cardiac selector function — tinman mutants in Drosophila lack a heart, establishing the ancestral role. NKX2-5 expression in precardiac mesoderm and myocardium is conserved [PMID: 7628699].
  • Natural disease in companion animals/wildlife: Not a prominently catalogued naturally occurring NKX2-5 disease in veterinary species (OMIA); conservation implies orthologous roles but spontaneous disease is not a documented entity. Not applicable / not established for veterinary natural disease.

Section 15 — Model Organisms

  • Mouse (Mus musculus; Nkx2-5): The definitive model system with a graded allelic series:
  • Homozygous knockout — embryonic-lethal (E9–10), failed cardiac looping, absent MLC2V [PMID: 7628699].
  • Heterozygotes — model human haploinsufficiency; hypoplastic AV node, ~50% reduction in conduction-system cellularity [PMID: 15085192].
  • Ventricular-restricted conditional knockout — progressive complete heart block, trabecular overgrowth / non-compaction via ectopic BMP10 [PMID: 15109497].
  • Phenotype recapitulation: Strong and dosage-graded, faithfully reproducing both the conduction and myopathic branches of human disease.
  • Limitations: Homozygous lethality prevents study of adult null hearts without conditional strategies; mouse–human differences in conduction-system anatomy.
  • Zebrafish (nkx2.5): Useful for developmental and regenerative cardiac studies.
  • Resources: MGI (mouse), ZFIN (zebrafish), FlyBase (tinman), Alliance of Genome Resources.

"In Nkx2-5 haploinsufficiency, the conduction system has half the normal number of cells." — [PMID: 15085192]

"The murine homeo box gene Nkx2-5 is expressed in precardiac mesoderm and in the myocardium of embryonic and fetal hearts." — [PMID: 7628699]

Key Findings (consolidated with evidence)

Finding 1 — NKX2-5 haploinsufficiency causes autosomal-dominant CHD with secundum ASD and progressive AV conduction block

Schott et al. (1998) mapped a dominant locus for cardiac malformations plus AV conduction abnormalities to 5q35 (NKX2-5) and identified 3 mutations, 2 impairing DNA binding → haploinsufficiency [PMID: 9651244]. Benson et al. (2000) found 7 novel mutations in 26 probands; AV block was the primary manifestation in ~25%, alongside ASD and VSD [PMID: 10587520].

"A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35, where NKX2-5, a Drosophila tinman homolog, is located." — [PMID: 9651244] "Two are predicted to impair binding of NKX2-5 to target DNA, resulting in haploinsufficiency" — [PMID: 9651244] "Associated phenotypes included AV block, which was the primary manifestation of cardiac disease in nearly a quarter of affected individuals, as well as atrial septal defect and ventricular septal defect." — [PMID: 10587520]

Finding 2 — AV block arises from gene-dosage-dependent AV-node hypoplasia and progressive cell dropout

Jay et al. (2004): conduction-system cell number is directly proportional to Nkx2-5 dosage; heterozygotes have ~half the normal cells and lose a connexin40(−)/connexin45(+) AV-node population [PMID: 15085192]. Pashmforoush et al. (2004): hypoplastic AV node at birth followed by selective dropout causes progressive complete heart block [PMID: 15109497].

"We show in KO mice that the number of cells in the cardiac conduction system is directly related to Nkx2-5 gene dosage." — [PMID: 15085192] "Postnatal conduction defects in Nkx2-5 mutation may result at least in part from a defect in the genetic program that governs the recruitment or retention of embryonic cardiac myocytes in the conduction system." — [PMID: 15085192]

Finding 3 — Nkx2-5 is essential for cardiac looping and ventricular myogenic specification

Lyons et al. (1995): null embryos form a linear tube but fail looping and die E9–10; MLC2V is absent [PMID: 7628699].

"this gene is a component of a genetic pathway required for myogenic specialization of the ventricles" — [PMID: 7628699]

Finding 4 — Broad phenotypic spectrum (ASD predominant, progressive AV block, VSD/conotruncal/Ebstein, myopathy)

Documented in Benson et al. and Schott et al. [PMID: 10587520, 9651244] (see Section 3 table).

Finding 5 — NKX2-5 acts in a combinatorial network; targets include GJA5/connexin40 and BMP10

Jay et al. (connexin40 target) [PMID: 15085192]; Pashmforoush et al. (ectopic BMP10, aberrant conduction/chamber target genes) [PMID: 15109497].

Finding 6 — Autosomal dominant with incomplete penetrance / variable expressivity

Benson et al.: diverse coinherited CHD phenotypes; clinically significant contribution to TOF and idiopathic AV block [PMID: 10587520].

Finding 7 — Mouse models recapitulate the disease dosage-dependently; mechanism is deeply conserved

Allelic series across [PMID: 7628699, 15085192, 15109497]; conserved from Drosophila tinman through zebrafish nkx2.5.

Evidence Base

PMID Study (year, journal) Evidence type Contribution
9651244 Schott et al., 1998, Science Human genetics Mapped locus to 5q35; identified NKX2-5 mutations; established haploinsufficiency; septation + lifelong AV-node roles
10587520 Benson et al., 2000, JCI Human genetics/clinical 7 novel mutations, 26 probands; AV block ~25% primary; ASD/VSD/TOF/DORV/Ebstein spectrum; variable expressivity
15085192 Jay et al., 2004, JCI Mouse model Gene-dosage dependence of conduction-system cellularity; connexin40 target; hypoplastic AV node
15109497 Pashmforoush et al., 2004, Cell Mouse model Progressive complete heart block (hypoplasia + dropout); ectopic BMP10 drives myopathic/non-compaction branch
7628699 Lyons et al., 1995, Genes Dev Mouse model Nkx2-5 required for cardiac looping and ventricular myogenic specification; absent MLC2V in nulls

The evidence base is internally consistent: human genetic studies define the phenotype and the haploinsufficiency mechanism, and the mouse allelic series supplies the mechanistic causal chain, dosage dependence, and molecular mediators (connexin40, BMP10). The mouse and human data are mutually reinforcing.

Limitations and Knowledge Gaps

  1. Quantitative penetrance/expressivity for each phenotype across large modern cohorts is incompletely captured; the Benson cohort (26 probands) is foundational but small.
  2. Genotype–phenotype correlation — whether DNA-binding-missense vs. truncating variants preferentially cause conduction vs. structural vs. myopathic disease — is not fully resolved.
  3. Modifier genes and gene–environment interactions are undefined despite clear variable expressivity.
  4. Human BMP10 confirmation: the myopathic/BMP10 mechanism is robustly shown in mouse but direct human ventricular-tissue confirmation is limited.
  5. Disease-specific prevalence as a standalone epidemiological figure was not individually retrieved; estimates derive from CHD-attributable-fraction literature.
  6. Literature-fetch limitation: A PubMed esearch outage during the investigation locked the citation base to a verified set of efetch-confirmed landmark papers rather than an exhaustive recent-literature sweep.

Proposed Follow-up Experiments / Actions

  1. Variant-stratified cohort analysis: Mine ClinVar/HGMD NKX2-5 variants and test genotype–phenotype correlation (truncating vs. homeodomain-missense vs. dominant-negative) against conduction, structural, and myopathic sub-phenotypes.
  2. iPSC-cardiomyocyte modeling: Patient-derived iPSC-CMs with isogenic correction to quantify dosage effects on conduction (GJA5) and BMP10 expression, bridging mouse mechanism to human cells.
  3. Natural-history registry query: Extract age-of-onset and progression-rate distributions for AV block to quantify the progressive-conduction model.
  4. Modifier screen: GWAS/exome analysis within NKX2-5 families to identify modifier loci explaining variable expressivity.
  5. BMP10 human validation: Examine BMP10 in explanted/biopsied ventricular myocardium from NKX2-5-mutant non-compaction patients.
  6. Prospective pacing study: Correlate genotype with timing/necessity of pacemaker implantation to inform surveillance intervals.

Consensus Answer

NKX2-5-Related Congenital, Conduction and Myopathic Heart Disease (MONDO:0800441; OMIM #108900, ASD7) is an autosomal-dominant disorder caused by heterozygous, mostly loss-of-function (haploinsufficient) variants in NKX2-5, the NK2-class homeodomain cardiac transcription factor at 5q35.1 (vertebrate homolog of Drosophila tinman). Reduced NKX2-5 dosage impairs its combinatorial activation (with GATA4/TBX5/GATA6) of chamber- and conduction-specific gene programs, producing three linked manifestations: structural defects (characteristically secundum ASD, plus VSD, tetralogy of Fallot, Ebstein anomaly) from disrupted looping/septation; a dosage-dependent hypoplastic AV node with progressive postnatal conduction-cell dropout causing age-progressive AV block and sudden-death risk; and a myopathic branch (ventricular non-compaction/cardiomyopathy) driven by ectopic BMP10. Management is phenotype-directed (septal closure, pacemaker/ICD, heart-failure therapy) with no gene-specific cure, and the mechanism is faithfully recapitulated dosage-dependently in mouse models.

Artifacts

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Terms the report names something else

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

  • MONDO:0800441 (3 mentions) - the report calls it "MONDO"; MONDO calls it NKX2.5-related congenital, conduction and myopathic heart disease
  • HP:0001684 (1 mention) - the report calls it "Physical malformation"; HP calls it Secundum atrial septal defect
  • HP:0001678 (1 mention) - the report calls it "Clinical sign (ECG)"; HP calls it Atrioventricular block
  • HP:0011705 (1 mention) - the report calls it "Lab/ECG abnormality"; HP calls it First degree atrioventricular block
  • HP:0011706 (1 mention) - the report calls it "Lab/ECG abnormality"; HP calls it Second degree atrioventricular block
  • HP:0001709 (1 mention) - the report calls it "Lab/ECG abnormality"; HP calls it Third degree atrioventricular block
  • HP:0001629 (1 mention) - the report calls it "Physical malformation"; HP calls it Ventricular septal defect
  • HP:0001636 (1 mention) - the report calls it "Physical malformation"; HP calls it Tetralogy of Fallot
  • HP:0002356 (1 mention) - the report calls it "Physical malformation"; HP calls it Writer's cramp
  • HP:0001702 (1 mention) - the report calls it "Physical malformation"; HP calls it Abnormal tricuspid valve morphology
  • HP:0030682 (1 mention) - the report calls it "Physical/structural"; HP calls it Left ventricular noncompaction
  • HP:0001644 (1 mention) - the report calls it "Clinical sign"; HP calls it Dilated cardiomyopathy
  • HP:0001645 (1 mention) - the report calls it "Outcome"; HP calls it Sudden cardiac death
  • NCIT:C51658 (1 mention) - the report calls it "Cardiac surgery"; NCIT calls it Gastric Antrectomy
  • NCIT:C50114 (1 mention) - the report calls it "Pacemaker"; NCIT calls it Power Module Device
  • NCIT:C62226 (1 mention) - the report calls it "Implantable defibrillator"; NCIT calls it Juvenile Lesion
  • NCIT:C577 (1 mention) - the report calls it "Anticoagulant therapy"; NCIT calls it Industrial Waste

Terms whose name is worth a second look

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

  • HP:0010316 (1 mention) - the report calls it "Physical malformation"; HP calls it Ebstein anomaly of the tricuspid valve, and lists "Ebstein's malformation" among its other names
  • GO:0061337 (1 mention) - the report calls it "GO biological processes: cardiac conduction"; GO calls it cardiac conduction**
  • UBERON:0000948 (1 mention) - the report calls it "Organ: Heart"; UBERON calls it heart**, and lists "branchial heart" among its other names
  • UBERON:0002085 (1 mention) - the report calls it "Structures: interatrial/atrial septum"; UBERON calls it interatrial septum**