MYPN-Related Cardiomyopathy

Genetic MONDO:0014100 Pathograph 20 Show in embeddings browser Cardiovascular Disease Genetic Disorder

Heterozygous variants in MYPN, encoding the Z-disc and I-band protein myopalladin, cause an inherited cardiomyopathy that is not confined to a single morphological pattern: the same gene produces dilated, hypertrophic and restrictive disease, and MONDO:0014100 is the single class carrying all three labels (CMD1KK, CMH22 and CMR4). This entry is curated at the gene level for that reason. Myopalladin is not a contractile protein. It is a scaffold and a messenger: it anchors the Z-disc by binding titin, alpha-actinin-2, nebulette and desmin, and it shuttles to the nucleus with the transcriptional cofactor CARP/ANKRD1, so a MYPN lesion damages both the mechanical integrity of the sarcomere and the stress-responsive gene program that reads its load. The branch point that decides which cardiomyopathy pattern a family develops is allelic and mechanistic rather than nosological: truncating and dominant-negative alleles that disturb myofibrillogenesis (Q529X) produce restrictive physiology, while an N-terminal allele that fails to reach the nucleus and binds CARP poorly (Y20C) produces hypertrophic remodelling, and haploinsufficiency alleles (I83fsX105) produce dilation. Because the pattern is downstream of a shared Z-disc lesion, splitting the concept across three morphology-named entries would separate branches of one pathograph. The gene-disease relationship is real but not strongly evidenced: ClinGen's Dilated Cardiomyopathy expert panel classifies MYPN-DCM as Limited, so a MYPN variant of uncertain significance does not by itself establish this diagnosis. Biallelic MYPN loss-of-function causes a distinct skeletal-muscle disease (nemaline/cap myopathy) and is out of scope here.

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1
Inheritance
8
Pathophys.
7
Phenotypes
3
Gaps
20
Pathograph
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Genes
4
Medical Actions
3
Subtypes
3
Differentials
3
Models
16
References
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Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
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Inheritance

1
Autosomal dominant HP:0000006
Cardiomyopathy-causing MYPN variants are heterozygous and cosegregate with disease in reported pedigrees. Penetrance is incomplete and age-dependent, and expressivity is variable both between families and within one allele — Y20C reaches hypertrophic disease in some carriers and dilated disease in others. Numerical penetrance has not been established. This dominant cardiac disease should not be conflated with the recessive, biallelic MYPN skeletal myopathy.
Autosomal dominant inheritance Penetrance: INCOMPLETE
Show evidence (1 reference)
PMID:22286171 SUPPORT Human Clinical
"Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM."
Documents variable expressivity of a single heterozygous allele across two cardiomyopathy patterns, the observation this inheritance block describes.
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Subtypes

3
Cardiomyopathy, dilated, 1KK
MYPN hgnc:23246 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MYPN (hgnc:23246). hgnc:23246 is a gene from the HUGO Gene Nomenclature Committee.
The dilated pattern, and the label MONDO uses for the whole class. Reported alleles include a frameshift (I83fsX105) whose mutant transcript is absent from patient mRNA, indicating haploinsufficiency, a familial missense allele (R1088H) with reduced myopalladin at the Z-band of explanted left ventricular myofibrils, and two sporadic missense alleles (P1112L, V1195M) that disorganise the sarcomere and kill neonatal rat cardiomyocytes on expression. Onset is adult in the discovery cohort, with wide variability. No mean age at diagnosis is stated here: the only figure available is in the deep-research artifact, attributed to a full text this repository holds only as an abstract, so it carries no verifiable snippet (see `notes`).
Show evidence (1 reference)
PMID:18006477 SUPPORT Human Clinical
"We identified four independent heterozygous mutations in two families (R1088H and I83fsX105) and two sporadic cases (V1195M, P1112L)."
Names the four alleles this subtype is built on and establishes that they were found in dilated cardiomyopathy probands, familial and sporadic.
Cardiomyopathy, hypertrophic, 22
MYPN hgnc:23246 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MYPN (hgnc:23246). hgnc:23246 is a gene from the HUGO Gene Nomenclature Committee.
The hypertrophic pattern, carried by MONDO:0014100 as a synonym rather than as a separate class. Its worked allele is Y20C, an N-terminal missense variant found in patients with either hypertrophic or dilated disease, which binds CARP poorly and fails to translocate to the nucleus; cardiac-restricted transgenic mice carrying it develop hypertrophy with disrupted intercalated discs. The dual human phenotype of this one allele is the clearest reason the gene, not the morphology, is the right level for this entry.
Show evidence (1 reference)
PMID:22286171 SUPPORT Human Clinical
"Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM."
Human genotype-phenotype evidence that one MYPN allele reaches both the hypertrophic and the dilated pattern, which is what this subtype records.
Cardiomyopathy, familial restrictive, 4
MYPN hgnc:23246 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in MYPN (hgnc:23246). hgnc:23246 is a gene from the HUGO Gene Nomenclature Committee.
The restrictive pattern, carried as a further synonym of MONDO:0014100 and also recorded in `Restrictive_Cardiomyopathy` as a gene arm rather than a subtype there. Its worked allele is the nonsense variant Q529X, found in a familial restrictive pedigree; expression in cardiomyocytes disturbs myofibrillogenesis with loss of alpha-actinin-2, desmin and CARP from the myofibril, and heterozygous knock-in mice develop diastolic dysfunction with preserved systolic function and interstitial fibrosis.
Show evidence (1 reference)
PMID:22286171 SUPPORT In Vitro
"Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X)"
The cellular mechanism attributed to the restrictive MYPN allele, measured in transfected neonatal rat cardiomyocytes, which is why this item is graded IN_VITRO.
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Discussions and Knowledge Gaps

3
Does the aggregate human genetic evidence support MYPN as a monogenic cause of cardiomyopathy, or only as a modifier or bystander?
KNOWLEDGE GAP mypn_gene_disease_validity_is_limited
Attached to
genetic#MYPN disease#MYPN-Related Cardiomyopathy
ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel rates MYPN-dilated cardiomyopathy as Limited. The mechanistic case in this entry is strong — human myocardium, cardiomyocyte assays, three independent mouse models — but the human genetic case rests on small pedigrees, historical control panels of 400 to 1,020 individuals, and variants classified before gnomAD existed. That is exactly the configuration in which a plausible mechanism outlives a gene-disease association. Resolving it requires reclassification of the historical alleles against contemporary population-frequency and ACMG/AMP criteria, plus new segregation data; case ascertainment through cardiomyopathy panels alone will not do it, because a panel that includes MYPN will keep finding MYPN variants at population frequency.
Is the mapping from MYPN allele class to cardiomyopathy pattern reliable enough to be predictive, or is it a post-hoc description of a handful of families?
KNOWLEDGE GAP mypn_allelic_branch_point_is_underdetermined
Attached to
pathophysiology#Ventricular Remodeling pathophysiology#Impaired CARP Nuclear Shuttling has_subtypes#CMH22
This entry is built on the claim that the pattern a family develops is determined at the allele level — haploinsufficiency to dilation, CARP-shuttling failure to hypertrophy, disturbed myofibrillogenesis to restriction. Each leg rests on one or two alleles, and Y20C itself breaks the rule by producing both hypertrophic and dilated disease in different human carriers. The branch point is therefore a mechanistic hypothesis with model support, not an established genotype-phenotype rule, and it should not be used to predict a phenotype from a novel allele. What would settle it is a MYPN variant registry with paired functional classification and imaging phenotype across many more families.
Do the mouse models of MYPN cardiomyopathy reproduce the human mechanism, or only a load-dependent caricature of it?
HUMAN MODEL MISMATCH mypn_human_mechanism_evidence_is_model_weighted
Attached to
pathophysiology#Impaired Contractile and Passive Mechanics pathophysiology#Disturbed Myofibrillogenesis and Sarcomere Disorganization animal_models#Mouse
All three mouse models diverge from human disease in a specific, stated way. The knockout is homozygous null, so it models haploinsufficiency at best and the dominant-negative alleles not at all; it is nearly normal at baseline and only becomes severe after transaortic constriction, an imposed second hit that human carriers do not necessarily have. The Y20C transgenic is overexpression-driven and is predominantly hypertrophic, whereas human Y20C carriers develop hypertrophic or dilated disease. Only the Q529X knock-in is heterozygous at endogenous expression, and it models one allele of one branch. The human side of the mechanism is thinner than it looks: two immunolabelling observations in explanted myocardium and a set of transfected neonatal rat cardiomyocyte assays. No patient-derived iPSC cardiomyocyte or engineered heart tissue model of a MYPN allele has been reported, which is the obvious missing rung between the rodent work and the human disease.
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Pathophysiology

8
MYPN Variant Altering Myopalladin
The initiating lesion is a heterozygous MYPN variant that either reduces the amount of normal myopalladin or introduces a protein that misbehaves in the Z-disc. Three mechanistic classes are evidenced. A frameshift allele (I83fsX105) yields no detectable mutant transcript in patient mRNA, so the cell is left haploinsufficient. Missense alleles in the C-terminal half (R1088H, P1112L, V1195M) are incorporated but mislocalise and behave dominant-negatively. An N-terminal allele (Y20C) leaves Z-disc targeting largely intact but breaks the protein's second job, nuclear shuttling with CARP. Which class an allele belongs to is what predicts the cardiomyopathy pattern the family develops.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
MYPN hgnc:23246 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYPN (hgnc:23246). hgnc:23246 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context allele_type: MIXED variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: UNKNOWN
Germline heterozygous alleles spanning haploinsufficiency (I83fsX105), dominant-negative missense (P1112L, V1195M), and a signalling-selective N-terminal missense allele (Y20C). Biallelic loss of function produces a different disease and is not modelled here.
Myocardium UBERON:0002349 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Myocardium (UBERON:0002349). UBERON:0002349 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Z-Disc and I-Band Scaffolding Failure Loss or malfunction of myopalladin removes a structural node of the Z-disc lattice.
Show evidence (2 references)
PMID:18006477 SUPPORT Human Clinical
"Allele-specific expression analysis of mRNA from a patient harbouring the I83fsX105 mutation indicated the absence of the mutated transcript, suggesting a haploinsufficiency mechanism."
Direct patient-derived evidence for the haploinsufficiency class of allele named in this node.
PMID:22286171 SUPPORT Human Clinical
"MYPN mutations cause various forms of cardiomyopathy via different protein-protein interactions."
States the allele-dependent-mechanism principle that makes this a single trigger node with divergent downstream branches.
Z-Disc and I-Band Scaffolding Failure
Myopalladin cross-links the Z-disc: it binds the titin Ig domains Z4-Z5, alpha-actinin-2, nebulette, the PDZ-LIM proteins, and CARP at the titin N2A region. Losing it, or replacing it with a mislocalised mutant, degrades the lattice that transmits force between sarcomeres and laterally to the sarcolemma, and simultaneously degrades the mechanosensory apparatus that reports load. Explanted left ventricular myocardium from an R1088H carrier shows reduced myopalladin at alpha-actinin-positive Z-bands, so this node is observed in human tissue and not only inferred from models.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Z disc GO:0030018 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves abnormal Z disc (GO:0030018). GO:0030018 is a cellular component from the Gene Ontology.
Downstream
Disturbed Myofibrillogenesis and Sarcomere Disorganization A degraded Z-disc lattice cannot template orderly myofibril assembly.
Impaired CARP Nuclear Shuttling The same lesion removes the shuttle that carries CARP between the I-band and the nucleus; the Y20C allele isolates this branch.
Show evidence (2 references)
PMID:18006477 SUPPORT Human Clinical
"Specific immunolabelling of heart tissue from a proband carrying the R1088H mutation showed a decreased localization of myopalladin at the Z-band area of left ventricular cardiac myofibrils."
Human myocardial evidence that a disease allele depletes myopalladin from the Z-band, which is the lesion this node names.
PMID:34558411 SUPPORT In Vitro
"In a yeast two-hybrid screening, MYPN was found to bind to titin in the Z-line, which was confirmed by microscale thermophoresis."
Identifies the titin interaction that makes myopalladin a load-bearing element of the Z-disc lattice rather than a passive passenger. Graded IN_VITRO because the measurement is a yeast two-hybrid and thermophoresis binding assay.
Disturbed Myofibrillogenesis and Sarcomere Disorganization
Cardiomyocytes expressing mutant myopalladin build disorganised sarcomeres. Q529X strips alpha-actinin-2, desmin and CARP from assembling myofibrils; P1112L and V1195M produce frank sarcomeric disorganisation followed by premature cell death. The structural failure is the route to the restrictive pattern in particular, because a stiff, poorly assembled myofibril raises resting tension before it lowers developed tension.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Myofibril Assembly GO:0030239 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Myofibril Assembly (GO:0030239). GO:0030239 is a biological process from the Gene Ontology. ⚠ ABNORMAL Sarcomere Organization GO:0045214 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Sarcomere Organization (GO:0045214). GO:0045214 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Impaired Contractile and Passive Mechanics A disorganised myofibril generates less active tension and resists stretch more at long sarcomere lengths.
Show evidence (2 references)
PMID:22286171 SUPPORT In Vitro
"Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X)"
The measured myofibrillogenesis defect this node names, in cardiomyocytes expressing the restrictive allele.
PMID:18006477 SUPPORT In Vitro
"Analysis of the effects of the mutations after transfection in rat neonate cardiomyocytes indicated sarcomere disorganization and premature cell death associated with the V1195M and P1112L myopalladin expression."
Extends the same cellular phenotype to the two sporadic dilated-cardiomyopathy missense alleles, and adds the cardiomyocyte death this node passes downstream.
Impaired CARP Nuclear Shuttling
Myopalladin binds CARP/ANKRD1, a transcriptional cofactor that moves between the titin N2A region and the nucleus and is strongly induced by mechanical stress. The Y20C allele binds CARP poorly and fails to translocate; the Q529X truncation does the opposite, persisting in the nucleus while total and nuclear CARP fall. Either way the load-reporting arm of the Z-disc is uncoupled from the transcriptional response to load, which is the branch that biases remodelling towards hypertrophy rather than dilation.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Protein Import Into Nucleus GO:0006606 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Protein Import Into Nucleus (GO:0006606). GO:0006606 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Ventricular Remodeling Loss of the CARP-dependent load-reporting arm biases the remodelling response, producing hypertrophic rather than dilated geometry for the Y20C allele.
Show evidence (2 references)
PMID:22286171 SUPPORT In Vitro
"Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems."
Direct measurement of the shuttling and CARP-binding defect this node names.
PMID:25541130 SUPPORT Model Organism
"Truncated Mypn(Q526X) protein was found to translocate to the nucleus."
The mirror-image nuclear handling of the restrictive allele in knock-in mice, which is why this node is described as uncoupling rather than simply abolishing the shuttle.
Impaired Contractile and Passive Mechanics
Myofibrils lacking myopalladin generate less isometric tension and develop more resting tension when stretched, and calcium release and reuptake are delayed. The combination is a myocyte that contracts weakly and relaxes poorly — the shared substrate from which the dilated and the restrictive presentations diverge. It is also load-sensitive: the deficit is mild at baseline and becomes severe under pressure overload.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Cardiac Muscle Contraction GO:0060048 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Cardiac Muscle Contraction (GO:0060048). GO:0060048 is a biological process from the Gene Ontology. ↓ DECREASED Intracellular Calcium Ion Homeostasis GO:0006874 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Intracellular Calcium Ion Homeostasis (GO:0006874). GO:0006874 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Myopalladin knockout mouse Mouse recapitulates Directly measures the reduced active tension, raised passive tension and delayed calcium handling that this node asserts.
Downstream
Neurohormonal Activation Falling stroke volume recruits the compensatory neurohormonal axes.
Ventricular Remodeling Sustained mechanical underperformance drives chamber geometry change directly as well as through neurohormonal signalling.
Show evidence (2 references)
PMID:34558411 SUPPORT Model Organism
"Cardiac analyses of MYPN knockout (MKO) mice showed the development of mild cardiac dilation and systolic dysfunction, associated with decreased myofibrillar isometric tension generation and increased resting tension at longer sarcomere lengths."
Measures both halves of this node — reduced active tension and raised passive tension — in myofibrils from myopalladin-null hearts.
PMID:34558411 SUPPORT Model Organism
"Cardiomyocyte analyses showed delayed Ca2+ release and reuptake in unstressed MKO mice as well as reduced Ca2+ spark amplitude post-TAC, suggesting that altered Ca2+ handling may contribute to the development of DCM in MKO mice."
The calcium-handling component of this node, and the authors' own hedge that it contributes to rather than explains the dilated phenotype.
Neurohormonal Activation
The renin-angiotensin-aldosterone and sympathetic axes are recruited to defend cardiac output. Nothing in this arm is MYPN-specific; it is the shared cardiomyopathy response, and it is the arm that current drug therapy for this disease actually targets. Myopalladin-null hearts under pressure overload show the transcriptional signature of that activation, with induction of the fetal gene program including Nppa and Nppb.
Downstream
Ventricular Remodeling Chronic neurohormonal drive converts a compensatory response into adverse remodelling.
Show evidence (1 reference)
PMID:34558411 SUPPORT Model Organism
"MKO mice exhibited a normal hypertrophic response to transaortic constriction (TAC), but rapidly developed severe cardiac dilation and systolic dysfunction, associated with fibrosis, increased fetal gene expression, higher intercalated disc fold amplitude, decreased calsequestrin-2 protein..."
Records the fetal gene program readout of stress activation in a myopalladin-null heart, and the load-dependence that makes this arm decisive rather than incidental.
Ventricular Remodeling
The point at which the three clinical patterns separate. Interstitial and perivascular fibroblast activation and matrix deposition are common to all three; the geometry differs. Haploinsufficiency and dominant-negative alleles give chamber dilation with wall thinning; the CARP-shuttling allele gives wall thickening; the restrictive allele gives fibrosis and a stiff, normally sized ventricle without overt hypertrophy. Because the divergence sits here rather than at the trigger, the three MONDO labels on this class are three outcomes of one chain.
Cardiac fibroblast CL:0002548 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiac fibroblast, annotated with fibroblast of cardiac tissue (CL:0002548). CL:0002548 is a cell type from the Cell Ontology. Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Myocardium UBERON:0002349 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Myocardium (UBERON:0002349). UBERON:0002349 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Myopalladin knockout mouse Mouse partially recapitulates Reproduces the dilated, fibrotic branch of this node, but only after pressure overload; the hypertrophic and restrictive branches are not reached by a null allele.
MYPN Y20C cardiac-restricted transgenic mouse Mouse partially recapitulates Reproduces the hypertrophic geometry and intercalated-disc disruption attributed to the CARP-shuttling allele.
MYPN Q529X knock-in mouse Mouse recapitulates Reproduces restrictive physiology — diastolic dysfunction with preserved systolic function and interstitial fibrosis without hypertrophy — at endogenous expression level and in the correct heterozygous state.
Downstream
Structural Cardiac Impairment and Heart Failure Remodelled, fibrotic myocardium cannot sustain output or filling.
Dilated cardiomyopathy Chamber dilation with reduced systolic contraction is the dilated outcome of this node.
Hypertrophic cardiomyopathy Wall thickening is the outcome of the CARP-shuttling branch.
Restrictive cardiomyopathy Fibrosis with a stiff, non-dilated, non-hypertrophied ventricle is the restrictive outcome.
Show evidence (2 references)
PMID:25541130 SUPPORT Model Organism
"Histology revealed interstitial and perivascular fibrosis without overt hypertrophic remodeling."
The restrictive branch of this node: fibrosis without hypertrophy in knock-in mice carrying the restrictive human allele.
PMID:22286171 SUPPORT Model Organism
"Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident."
The hypertrophic branch of the same node, in transgenic mice carrying the CARP-shuttling allele.
Structural Cardiac Impairment and Heart Failure
The convergent endpoint. Whichever geometry the family took, the remodelled ventricle ends in congestion, exercise limitation and the arrhythmic and thromboembolic risk of a structurally abnormal heart. No MYPN-specific event rate, transplantation rate or survival curve has been published, so the clinical course of this node is currently borrowed from cardiomyopathy in general.
Heart UBERON:0000948 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Heart (UBERON:0000948). UBERON:0000948 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Congestive heart failure Congestion and low output are the clinical expression of this node.
Arrhythmia Structural and fibrotic remodelling creates the substrate for atrial and ventricular arrhythmia and for conduction disease.
Show evidence (1 reference)
PMID:34558411 SUPPORT Model Organism
"MYPN gene mutations are causative for dilated (DCM), hypertrophic, and restrictive cardiomyopathy."
States that all three patterns are MYPN outcomes, which is what makes this a single convergent endpoint node rather than three.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for MYPN-Related Cardiomyopathy 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

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Cardiovascular 6
Dilated cardiomyopathy HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:18006477 SUPPORT Human Clinical
"Idiopathic dilated cardiomyopathy (DCM) is a cardiac disorder characterized by left ventricular dilatation and impaired systolic contraction."
Supplies the case definition of the dilated pattern in the series that identified MYPN as a dilated cardiomyopathy gene.
Hypertrophic cardiomyopathy HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22286171 SUPPORT Human Clinical
"Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM."
Human carriers of the Y20C allele developed hypertrophic cardiomyopathy, which is the claim this phenotype makes. The same sentence also records that Y20C carriers can instead develop the dilated pattern, which is why the allele-to-pattern mapping is curated as an open question in `mypn_allelic_branch_point_is_underdetermined` rather than as a rule.
PMID:22286171 SUPPORT INDIRECT Model Organism
"Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted intercalated discs"
Model-organism recapitulation of the hypertrophic pattern for the same allele. Marked INDIRECT because the human phenotype is asserted by the preceding item; this quote adds only the transgenic reproduction the description refers to.
Restrictive cardiomyopathy HP:0001723 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Restrictive cardiomyopathy (HP:0001723). HP:0001723 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25541130 SUPPORT Model Organism
"Echocardiographic and CMR imaging signs of diastolic dysfunction with preserved systolic function were identified in 12-week-old Mypn(WT/Q526X) mice."
Model-organism recapitulation of the restrictive physiology; the human pedigree evidence for this allele is carried on the CMR4 subtype and in `Restrictive_Cardiomyopathy`.
PMID:22286171 SUPPORT Human Clinical
"Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM."
Human evidence that the restrictive pattern occurs in a MYPN family, so this phenotype is not supported by the mouse alone.
Congestive heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34558411 SUPPORT INDIRECT Model Organism
"MKO mice exhibited a normal hypertrophic response to transaortic constriction (TAC), but rapidly developed severe cardiac dilation and systolic dysfunction, associated with fibrosis, increased fetal gene expression, higher intercalated disc fold amplitude, decreased calsequestrin-2 protein..."
Model-organism progression to decompensated dilation and fibrosis under load. Marked INDIRECT because the human heart-failure syndrome is inferred from the mouse phenotype rather than measured in MYPN carriers.
Arrhythmia HP:0011675 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arrhythmia (HP:0011675). HP:0011675 is a phenotype from the Human Phenotype Ontology.
Cardiac conduction abnormality HP:0031546 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiac conduction abnormality (HP:0031546). HP:0031546 is a phenotype from the Human Phenotype Ontology.
Respiratory 1
Dyspnea HP:0002094 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyspnea (HP:0002094), qualified as temporality chronic. HP:0002094 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
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Genetic Associations

1
MYPN
Gene: MYPN hgnc:23246 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYPN (hgnc:23246). hgnc:23246 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
CGGV:assertion_ffd924ad-55ce-4b05-8a91-584ef49b4e80-2025-03-05T050000.000Z SUPPORT Other
"MYPN | HGNC:23246 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
ClinGen's current classification of this gene-disease relationship, which is why the entry states the diagnosis cannot rest on a variant alone.
PMID:22286171 SUPPORT Human Clinical
"Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress."
The dual structural and signalling role of the gene product, which is what makes a single gene reach three cardiomyopathy patterns.
💊

Medical Actions

4
Guideline-Directed Medical Therapy for Heart Failure with Reduced Ejection Fraction
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: sacubitril CHEBI:134714 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses sacubitril (CHEBI:134714). CHEBI:134714 is a therapeutic agent from Chemical Entities of Biological Interest. valsartan CHEBI:9927 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses valsartan (CHEBI:9927). CHEBI:9927 is a therapeutic agent from Chemical Entities of Biological Interest. dapagliflozin CHEBI:85078 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses dapagliflozin (CHEBI:85078). CHEBI:85078 is a therapeutic agent from Chemical Entities of Biological Interest. carvedilol CHEBI:3441 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses carvedilol (CHEBI:3441). CHEBI:3441 is a therapeutic agent from Chemical Entities of Biological Interest. spironolactone CHEBI:9241 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses spironolactone (CHEBI:9241). CHEBI:9241 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Angiotensin receptor-neprilysin inhibition or ACE inhibition/ARB, an evidence-based beta blocker, a mineralocorticoid receptor antagonist, an SGLT2 inhibitor, and diuretics for congestion. There is no MYPN-specific trial and no MYPN pharmacogenomic rule; this is the general heart-failure evidence applied to a patient whose cardiomyopathy happens to be MYPN-related, and it targets the neurohormonal arm of the pathograph rather than the Z-disc lesion.
Mechanism Target:
Neurohormonal Activation — Neurohormonal blockade acts on this node; nothing in the regimen reaches the upstream Z-disc lesion.
Show evidence (2 references)
PMID:25176015 SUPPORT INDIRECT Human Clinical
"LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure."
Trial evidence for the neurohormonal arm of this regimen. Marked INDIRECT because the trial enrolled heart failure with reduced ejection fraction generally, not MYPN carriers.
PMID:31535829 SUPPORT INDIRECT Human Clinical
"the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes"
Trial evidence for the SGLT2-inhibitor component. Marked INDIRECT for the same reason: an unselected reduced-ejection-fraction population.
Implantable Cardioverter-Defibrillator
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
Considered on standard ejection-fraction, arrhythmic and syncope criteria. MYPN is not an established high-arrhythmic-risk genotype in the way LMNA and FLNC are, so it does not lower the threshold; a gene-specific device rule for MYPN would not be supported by anything published.
Mechanism Target:
Arrhythmia — Terminates ventricular arrhythmia arising on the remodelled, fibrotic substrate; it does not modify the substrate.
Heart Transplantation
Action: heart transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is heart transplantation, annotated with Organ Transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. Ontology label: Organ Transplantation NCIT:C15289
Platform: Surgery
The endpoint therapy for advanced heart failure that no longer responds to medical management, with mechanical circulatory support as a bridge. No MYPN-specific transplantation rate or listing criterion exists.
Mechanism Target:
Structural Cardiac Impairment and Heart Failure — Replaces the failing organ; it is the only intervention here that removes the whole pathograph rather than modulating one node of it.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Counselling of the proband and family about autosomal dominant transmission, variable expressivity across the dilated, hypertrophic and restrictive patterns, the recessive skeletal-myopathy phenotype that biallelic MYPN loss of function causes, and reproductive options. The counselling has to carry the ClinGen Limited classification honestly, which is what constrains what can be said about risk to relatives. The cascade testing and longitudinal surveillance that follow from it are curated under `diagnosis:` — screening an asymptomatic relative is a diagnostic activity, not a therapy.
Show evidence (1 reference)
DOI:10.3390/biomedicines12081643 SUPPORT INDIRECT Other
"Genetic variants that can be transmitted from one generation to another can be a significant contributor to causing family or sporadic hereditary DCM."
Supports the transmission risk that is the substance of the counselling session. Graded OTHER because the source is a narrative review rather than a primary study, and INDIRECT because it addresses inherited dilated cardiomyopathy generally rather than MYPN.
🔬

Diagnosis

6
Electrocardiography and Ambulatory Rhythm Monitoring
The first-line electrical study, and the cheapest. A cardiomyopathy-oriented reading looks for conduction disease, low QRS voltage, QRS fragmentation and repolarization change, and ambulatory monitoring adds the atrial and ventricular ectopy burden that a resting tracing misses. Nothing here is MYPN-specific: the discovery cohorts reported arrhythmia and conduction disease in a minority of patients without resolving it by genotype, so there is no MYPN electrocardiographic signature to look for and no gene-specific monitoring interval to recommend.
electrocardiography NCIT:C38053 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:37125300 SUPPORT Other
"electrocardiogram (ECG) continues to represent a reliable diagnostic tool, for specific work up of every single patient"
Establishes the ECG as a standing part of the dilated-cardiomyopathy workup, which is the claim this diagnostic entry makes. Graded OTHER because the source is an expert review built around four illustrative tracings rather than a cohort study.
PMID:37125300 SUPPORT Other
"the strength of electrocardiography lies in the ability to diagnose and prognostically stratify DCMs in order to accurately address second and third diagnostic investigations"
States what the ECG contributes that the later imaging and genetic steps do not, which is why it is curated as its own diagnostic entry rather than folded into echocardiography.
Echocardiography
The test that establishes the morphological pattern, and therefore which of this entry's three subtypes a family is in: ventricular dimensions and ejection fraction for the dilated pattern, wall thickness for the hypertrophic pattern, and diastolic filling with preserved systolic function for the restrictive pattern. The diagnosis remains a clinical one that requires excluding loading conditions and coronary disease sufficient to explain the findings. Nothing about the imaging is MYPN-specific.
transthoracic echocardiography NCIT:C16525 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:31073128 SUPPORT Other
"Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling"
Establishes echocardiography as the required modality for assessing the ventricular dysfunction and remodelling that this entry's pathograph terminates in.
PMID:31073128 SUPPORT Other
"Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease."
States the exclusion criteria that define the dilated diagnosis, which is what makes echocardiography necessary but not sufficient.
PMID:27339497 SUPPORT Other
"Measurement of LV size and ejection fraction remain central to diagnosis, risk stratification, and treatment"
Names the two echocardiographic measurements that carry the diagnosis, and places them ahead of the tissue characterisation that cardiac MRI adds.
Cardiac Magnetic Resonance Imaging
Adds what echocardiography cannot: tissue characterisation, and with it the risk stratification that drives management in nonischemic dilated cardiomyopathy. In a meta-analysis of 103 studies and 29,687 patients, late gadolinium enhancement — both its presence and its extent — was associated with higher all-cause and cardiovascular mortality, arrhythmic events and heart failure events, while ejection fraction was NOT associated with all-cause mortality or arrhythmic outcomes. That inversion matters here because the fibrosis this measures is the same remodelling endpoint the Mypn-null mouse develops under pressure overload. No MYPN carrier series with cardiac MRI has been published, so none of this is gene-specific.
cardiac magnetic resonance imaging NCIT:C137915 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:39298146 SUPPORT Human Clinical
"Late gadolinium enhancement (LGE) presence and extent (per 1%) were associated with higher all-cause mortality"
Establishes late gadolinium enhancement as a prognostic marker in nonischemic dilated cardiomyopathy, which is what cardiac MRI adds beyond echocardiography.
PMID:39298146 SUPPORT Human Clinical
"Left ventricular ejection fraction (LVEF) (per 1%) was not associated with all-cause mortality"
The negative result that makes cardiac MRI worth curating separately from echocardiography: the echo-derived measure does not carry the mortality signal that late gadolinium enhancement does.
PMID:27339497 SUPPORT Other
"Assessment of myocardial fibrosis predicts both risk of sudden cardiac death and likelihood of LV functional recovery"
Connects the imaging measurement to the two decisions it informs, one of which is device therapy — the point at which this entry declines to make a MYPN-specific recommendation.
Natriuretic Peptide and Troponin Testing
BNP or NT-proBNP and high-sensitivity troponin are drawn as part of the heart-failure workup, alongside blood count, electrolytes, and renal, liver, thyroid and iron studies aimed at the alternative causes that have to be excluded. They quantify the heart-failure state rather than identify its cause, and no MYPN-specific biomarker, cut-off or reference interval has been reported — which is why this entry carries no `biochemical:` block.
natriuretic peptide and troponin testing NCIT:C25294 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:31073128 SUPPORT INDIRECT Other
"new diagnostic tools, such as serum biomarkers, that enable early diagnosis and treatment"
The cited review treats serum biomarkers as a developing rather than established diagnostic route in dilated cardiomyopathy. Marked INDIRECT because it supports biomarker testing as part of the workup without establishing a diagnostic threshold, and no such threshold exists for MYPN.
Molecular Genetic Testing (Multigene Cardiomyopathy Panel)
A curated multigene cardiomyopathy panel with sequence plus deletion/duplication analysis, rather than isolated MYPN sequencing; exome or genome sequencing after a negative panel. Every reported MYPN proband was ascertained this way — the founding series screened MYPN across 900 hypertrophic, dilated and restrictive cardiomyopathy patients. THE RESULT MUST NOT BE OVER-READ. ClinGen classifies the MYPN-dilated cardiomyopathy relationship as Limited, so a MYPN variant should not on its own make or exclude a diagnosis, nor direct predictive testing of relatives, and a MYPN variant of uncertain significance carries no clinical action at all.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:22286171 SUPPORT Human Clinical
"MYPN was genetically screened in 900 patients with HCM, DCM and RCM"
Documents the ascertainment route by which MYPN variants reach patients: broad genetic screening across all three cardiomyopathy patterns, not a MYPN-directed test.
PMID:20301725 SUPPORT Other
"Provide an evaluation strategy to identify (when possible) the genetic cause of nonsyndromic HCM in a proband"
The GeneReviews hypertrophic-cardiomyopathy overview supplies the proband evaluation strategy that a gene-level entry such as this one sits inside. Graded OTHER because GeneReviews is an expert-authored review resource; note that the cached PubMed record for this chapter contains only its stated purpose, so no clinical-characteristics text could be mined from it.
DOI:10.3390/biomedicines12081643 SUPPORT INDIRECT Other
"It is crucial to select patients who are most probable to gain advantages from genetic testing."
Supports testing being offered selectively rather than reflexively, which is the caution a Limited-evidence gene requires. Marked INDIRECT because the source addresses inherited dilated cardiomyopathy generally rather than MYPN.
Cascade Testing and Cardiac Surveillance of At-Risk Relatives
First-degree relatives of a carrier of a pathogenic or likely pathogenic MYPN variant are offered cascade testing, and genotype-positive relatives then enter longitudinal electrocardiographic and imaging surveillance even while asymptomatic. Where no credible familial variant is identified, relatives still need phenotype screening, because a negative panel does not exclude inherited disease. The MYPN-specific caveats bite here: the ClinGen Limited classification means a MYPN variant of uncertain significance is not an indication for predictive testing, and no MYPN-specific screening interval or lifetime penetrance figure exists to quote, so the interval is the one used for inherited cardiomyopathy generally.
cascade screening of at-risk relatives NCIT:C15419 NCI Thesaurus (NCIT)
Show evidence (4 references)
PMID:20301486 SUPPORT Other
"Provide a basic view of genetic risk assessment of at-risk asymptomatic relatives of a proband with DCM to inform cardiac surveillance and allow early detection and treatment of DCM to improve long-term outcome"
The GeneReviews chapter's stated purpose for relatives of a proband: genetic risk assessment driving cardiac surveillance. This is the baseline practice this entry follows, with the caveat that a Limited-evidence gene cannot carry the risk assessment the recommendation depends on.
PMID:20301725 SUPPORT Other
"Inform genetic counseling of family members of an individual with nonsyndromic HCM"
The matching GeneReviews purpose on the hypertrophic side, cited because this entry spans both patterns and the family-screening obligation does not depend on which one a proband presented with.
PMID:27339497 SUPPORT Other
"Detection of pre-clinical DCM could substantially reduce morbidity and mortality by allowing early instigation of cardioprotective therapy."
States the rationale for surveillance of asymptomatic relatives, which is why this is a diagnostic activity rather than a treatment.
+ 1 more reference
📊

Prevalence

2
Cardiomyopathy patients screened for MYPN (HCM, DCM and RCM combined)
Unknown 1660.0 per 100,000 Unknown
1.66% of a 900-patient combined HCM/DCM/RCM screening series carried a MYPN variant. This is a yield within an ascertained cardiomyopathy cohort, not a population rate, and it predates current population-frequency databases and ACMG/AMP reclassification, so it is an upper bound on clinically established pathogenic variation.
Show evidence (1 reference)
PMID:22286171 SUPPORT Human Clinical
"Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%."
Source of the 1.66% cohort yield across the three cardiomyopathy patterns.
Dilated cardiomyopathy patients of European descent
Unknown 3500.0 per 100,000 Unknown
3-4% of 114 unrelated dilated cardiomyopathy probands in the original French discovery series. Recorded as the midpoint of the reported 3-4% range. Same caveat as above: a pre-gnomAD discovery-cohort yield, not a population prevalence, and no population prevalence of MYPN-related cardiomyopathy is established.
Show evidence (1 reference)
PMID:18006477 SUPPORT Human Clinical
"we identified a new gene associated with DCM and observed mutations in 3-4% of cases in a population of European descent"
Source of the 3-4% discovery-cohort yield in dilated cardiomyopathy.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from MYPN-Related Cardiomyopathy:

Biallelic MYPN nemaline and cap myopathy
Overlapping Features The same gene, the opposite inheritance mode, and a different organ. Biallelic loss-of-function MYPN variants cause a childhood- to adult-onset, slowly progressive skeletal myopathy with nemaline rods or caps, in which cardiac involvement is the exception rather than the defining feature. It has its own MONDO class and is deliberately not curated as a subtype here: the dominant cardiac disease and the recessive skeletal disease are allelic disorders of one gene, not one disease with two presentations. Confusing them would let a homozygous truncating variant be read as evidence for dominant cardiomyopathy.
Distinguishing Features
  • Biallelic (homozygous or compound heterozygous) truncating variants, not a single heterozygous allele.
  • Proximal skeletal muscle weakness and walking difficulty as the presenting problem, with cardiac involvement absent or secondary.
  • Nemaline rods, intranuclear rods, or caps on muscle biopsy, with myopalladin absent from the skeletal Z-line.
Show evidence (2 references)
PMID:28220527 SUPPORT Human Clinical
"Our data uncover that mutations in MYPN cause either a cardiac or a congenital skeletal muscle disorder through different modes of inheritance."
States the inheritance-mode split that this differential turns on.
PMID:28017374 SUPPORT Human Clinical
"Individuals with identified MYPN mutations in all four of these families have relatively mild, childhood- to adult-onset NM with slowly progressive muscle weakness."
Characterises the recessive skeletal phenotype so it can be separated from the dominant cardiac one at the bedside.
Dilated cardiomyopathy from a high-evidence gene MONDO:0005021
Overlapping Features TTN truncating variants, LMNA, and the desmosomal and FLNC arms account for a far larger share of genetic dilated cardiomyopathy than MYPN does and carry management consequences MYPN does not — LMNA and FLNC in particular drive arrhythmic risk stratification and device decisions. On a multigene panel a MYPN variant found alongside a variant in one of these genes is very unlikely to be the explanation. Curated as `Dilated_Cardiomyopathy`, where MYPN is listed as a gene arm with the same ClinGen Limited classification.
Distinguishing Features
  • A pathogenic or likely pathogenic variant in a gene ClinGen rates Moderate, Strong, or Definitive for dilated cardiomyopathy.
  • Gene-specific features such as early conduction disease and arrhythmia out of proportion to systolic dysfunction (LMNA), or ring-like subepicardial late gadolinium enhancement (FLNC).
  • Established gene-specific device and surveillance recommendations, which MYPN does not have.
Hypertrophic cardiomyopathy from a sarcomere gene MONDO:0005045
Overlapping Features MYH7 and MYBPC3 account for the large majority of genotype-positive hypertrophic cardiomyopathy. A MYPN allele reaching the hypertrophic pattern is rare enough that a thick-walled ventricle should prompt a full sarcomere panel before MYPN is accepted as the cause.
Distinguishing Features
  • Pathogenic variant in MYH7, MYBPC3, or another core sarcomere gene.
  • Asymmetric septal hypertrophy with left ventricular outflow tract obstruction, which has not been described as a MYPN-specific pattern.
🐁

Animal Models

3
Myopalladin knockout mouse
Constitutive whole-body Mypn-null mice. They develop mild spontaneous dilation and systolic dysfunction with reduced myofibrillar tension and delayed calcium handling, and decompensate severely under transaortic constriction.
Species
Mouse
Genotype
Mypn constitutive knockout (homozygous null)
Publication
PMID:34558411
Pathograph links
Impaired Contractile and Passive Mechanics recapitulates fidelity: moderate Directly measures the reduced active tension, raised passive tension and delayed calcium handling that this node asserts.
Limitations: A homozygous null models haploinsufficiency at best and does not model the dominant-negative or CARP-shuttling missense alleles at all; the mouse is also far milder at baseline than the human disease and only becomes severe when pressure-overloaded.
Readouts
Myofibrillar isometric tension and resting tension
Direction: DECREASED
Interpretation: Active tension falls while resting tension at long sarcomere lengths rises, the mechanical signature of this node.
Show evidence (1 reference)
PMID:34558411 SUPPORT Model Organism
"Cardiac analyses of MYPN knockout (MKO) mice showed the development of mild cardiac dilation and systolic dysfunction, associated with decreased myofibrillar isometric tension generation and increased resting tension at longer sarcomere lengths."
The measurement behind this readout.
Show evidence (1 reference)
PMID:34558411 SUPPORT Model Organism
"Cardiomyocyte analyses showed delayed Ca2+ release and reuptake in unstressed MKO mice as well as reduced Ca2+ spark amplitude post-TAC, suggesting that altered Ca2+ handling may contribute to the development of DCM in MKO mice."
Supports treating this model as informative for the contractile and calcium-handling node.
Ventricular Remodeling partially recapitulates fidelity: moderate Reproduces the dilated, fibrotic branch of this node, but only after pressure overload; the hypertrophic and restrictive branches are not reached by a null allele.
Limitations: Baseline remodelling is mild and requires transaortic constriction to become severe, so the model conflates the genetic lesion with an imposed haemodynamic second hit that human carriers do not necessarily have.
Show evidence (1 reference)
PMID:34558411 SUPPORT Model Organism
"MKO mice exhibited a normal hypertrophic response to transaortic constriction (TAC), but rapidly developed severe cardiac dilation and systolic dysfunction, associated with fibrosis, increased fetal gene expression, higher intercalated disc fold amplitude, decreased calsequestrin-2 protein..."
Documents both what the model reproduces (dilation, fibrosis) and the load-dependence recorded in the limitation.
MYPN Y20C cardiac-restricted transgenic mouse
Transgenic mice expressing the human N-terminal Y20C allele under a cardiac promoter, the model for the hypertrophic branch of this entity.
Species
Mouse
Genotype
Cardiac-restricted transgenic expression of human MYPN Y20C
Publication
PMID:22286171
Pathograph links
Ventricular Remodeling partially recapitulates fidelity: moderate Reproduces the hypertrophic geometry and intercalated-disc disruption attributed to the CARP-shuttling allele.
Limitations: Human Y20C carriers develop hypertrophic or dilated disease, but the mouse is predominantly hypertrophic, so the model does not capture the allele's human variability. Transgenic overexpression may also exaggerate the dominant effect relative to a heterozygous endogenous allele.
Show evidence (1 reference)
PMID:22286171 SUPPORT Model Organism
"Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident."
The remodelling phenotype and junctional disruption this link asserts.
MYPN Q529X knock-in mouse
Heterozygous knock-in of the mouse equivalent of the human restrictive allele, the closest available model of the restrictive branch and the only one of the three at endogenous expression level in heterozygous state.
Species
Mouse
Genotype
Mypn Q526X knock-in, heterozygous (human MYPN Q529X equivalent)
Publication
PMID:25541130
Pathograph links
Ventricular Remodeling recapitulates fidelity: high Reproduces restrictive physiology — diastolic dysfunction with preserved systolic function and interstitial fibrosis without hypertrophy — at endogenous expression level and in the correct heterozygous state.
Limitations: Models one allele of one branch; nothing about it speaks to the dilated or hypertrophic patterns, and the human pedigree behind Q529X is single.
Readouts
Diastolic function with preserved ejection fraction
Direction: ALTERED
Interpretation: Restrictive filling with preserved systolic function is the geometric outcome this branch of the node predicts.
Show evidence (1 reference)
PMID:25541130 SUPPORT Model Organism
"Echocardiographic and CMR imaging signs of diastolic dysfunction with preserved systolic function were identified in 12-week-old Mypn(WT/Q526X) mice."
The imaging measurement behind this readout.
Show evidence (1 reference)
PMID:25541130 SUPPORT Model Organism
"Heterozygote Mypn(WT/Q526X) knock-in mice develop RCM due to persistence of mutant Mypn(Q526X) protein in the nucleus."
Supports treating this model as informative for the restrictive branch of the remodelling node, and names the nuclear-persistence mechanism.
{ }

Source YAML

click to show 
name: MYPN-Related Cardiomyopathy
creation_date: "2026-09-02T00:00:00Z"
synonyms:
- dilated cardiomyopathy 1KK
- CMD1KK
- cardiomyopathy, dilated, 1KK
- cardiomyopathy, hypertrophic, 22
- cardiomyopathy, familial restrictive, 4
- MYPN dilated cardiomyopathy
- myopalladin-related cardiomyopathy
description: >-
  Heterozygous variants in MYPN, encoding the Z-disc and I-band protein
  myopalladin, cause an inherited cardiomyopathy that is not confined to a single
  morphological pattern: the same gene produces dilated, hypertrophic and
  restrictive disease, and MONDO:0014100 is the single class carrying all three
  labels (CMD1KK, CMH22 and CMR4). This entry is curated at the gene level for
  that reason. Myopalladin is not a contractile protein. It is a scaffold and a
  messenger: it anchors the Z-disc by binding titin, alpha-actinin-2, nebulette
  and desmin, and it shuttles to the nucleus with the transcriptional cofactor
  CARP/ANKRD1, so a MYPN lesion damages both the mechanical integrity of the
  sarcomere and the stress-responsive gene program that reads its load. The
  branch point that decides which cardiomyopathy pattern a family develops is
  allelic and mechanistic rather than nosological: truncating and dominant-negative
  alleles that disturb myofibrillogenesis (Q529X) produce restrictive
  physiology, while an N-terminal allele that fails to reach the nucleus and
  binds CARP poorly (Y20C) produces hypertrophic remodelling, and
  haploinsufficiency alleles (I83fsX105) produce dilation. Because the pattern is
  downstream of a shared Z-disc lesion, splitting the concept across three
  morphology-named entries would separate branches of one pathograph. The
  gene-disease relationship is real but not strongly evidenced: ClinGen's Dilated
  Cardiomyopathy expert panel classifies MYPN-DCM as Limited, so a MYPN variant of
  uncertain significance does not by itself establish this diagnosis. Biallelic
  MYPN loss-of-function causes a distinct skeletal-muscle disease (nemaline/cap
  myopathy) and is out of scope here.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: MYPN-related cardiomyopathy
  term:
    id: MONDO:0014100
    label: dilated cardiomyopathy 1KK
parents:
- Cardiovascular Disease
- Genetic Disorder
has_subtypes:
- name: CMD1KK
  display_name: Cardiomyopathy, dilated, 1KK
  description: >-
    The dilated pattern, and the label MONDO uses for the whole class. Reported
    alleles include a frameshift (I83fsX105) whose mutant transcript is absent
    from patient mRNA, indicating haploinsufficiency, a familial missense allele
    (R1088H) with reduced myopalladin at the Z-band of explanted left ventricular
    myofibrils, and two sporadic missense alleles (P1112L, V1195M) that
    disorganise the sarcomere and kill neonatal rat cardiomyocytes on expression.
    Onset is adult in the discovery cohort, with wide variability. No mean age
    at diagnosis is stated here: the only figure available is in the
    deep-research artifact, attributed to a full text this repository holds
    only as an abstract, so it carries no verifiable snippet (see `notes`).
  genes:
  - preferred_term: MYPN
    term:
      id: hgnc:23246
      label: MYPN
  evidence:
  - reference: PMID:18006477
    reference_title: Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified four independent heterozygous mutations in two families
      (R1088H and I83fsX105) and two sporadic cases (V1195M, P1112L).
    explanation: >-
      Names the four alleles this subtype is built on and establishes that they
      were found in dilated cardiomyopathy probands, familial and sporadic.
- name: CMH22
  display_name: Cardiomyopathy, hypertrophic, 22
  description: >-
    The hypertrophic pattern, carried by MONDO:0014100 as a synonym rather than
    as a separate class. Its worked allele is Y20C, an N-terminal missense variant
    found in patients with either hypertrophic or dilated disease, which binds
    CARP poorly and fails to translocate to the nucleus; cardiac-restricted
    transgenic mice carrying it develop hypertrophy with disrupted intercalated
    discs. The dual human phenotype of this one allele is the clearest reason the
    gene, not the morphology, is the right level for this entry.
  genes:
  - preferred_term: MYPN
    term:
      id: hgnc:23246
      label: MYPN
  evidence:
  - reference: PMID:22286171
    reference_title: Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas
      Q529X-MYPN was found in familial RCM.
    explanation: >-
      Human genotype-phenotype evidence that one MYPN allele reaches both the
      hypertrophic and the dilated pattern, which is what this subtype records.
- name: CMR4
  display_name: Cardiomyopathy, familial restrictive, 4
  description: >-
    The restrictive pattern, carried as a further synonym of MONDO:0014100 and
    also recorded in `Restrictive_Cardiomyopathy` as a gene arm rather than a
    subtype there. Its worked allele is the nonsense variant Q529X, found in a
    familial restrictive pedigree; expression in cardiomyocytes disturbs
    myofibrillogenesis with loss of alpha-actinin-2, desmin and CARP from the
    myofibril, and heterozygous knock-in mice develop diastolic dysfunction with
    preserved systolic function and interstitial fibrosis.
  genes:
  - preferred_term: MYPN
    term:
      id: hgnc:23246
      label: MYPN
  evidence:
  - reference: PMID:22286171
    reference_title: Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X)
    explanation: >-
      The cellular mechanism attributed to the restrictive MYPN allele, measured
      in transfected neonatal rat cardiomyocytes, which is why this item is
      graded IN_VITRO.
inheritance:
- name: Autosomal dominant
  description: >-
    Cardiomyopathy-causing MYPN variants are heterozygous and cosegregate with
    disease in reported pedigrees. Penetrance is incomplete and age-dependent, and
    expressivity is variable both between families and within one allele — Y20C
    reaches hypertrophic disease in some carriers and dilated disease in others.
    Numerical penetrance has not been established. This dominant cardiac disease
    should not be conflated with the recessive, biallelic MYPN skeletal myopathy.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  evidence:
  - reference: PMID:22286171
    reference_title: Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas
      Q529X-MYPN was found in familial RCM.
    explanation: >-
      Documents variable expressivity of a single heterozygous allele across two
      cardiomyopathy patterns, the observation this inheritance block describes.
prevalence:
- population: Cardiomyopathy patients screened for MYPN (HCM, DCM and RCM combined)
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  rate_per_100000: 1660.0
  notes: >-
    1.66% of a 900-patient combined HCM/DCM/RCM screening series carried a MYPN
    variant. This is a yield within an ascertained cardiomyopathy cohort, not a
    population rate, and it predates current population-frequency databases and
    ACMG/AMP reclassification, so it is an upper bound on clinically established
    pathogenic variation.
  evidence:
  - reference: PMID:22286171
    reference_title: Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two nonsense and 13 missense MYPN variants were identified in subjects with
      DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%.
    explanation: >-
      Source of the 1.66% cohort yield across the three cardiomyopathy patterns.
- population: Dilated cardiomyopathy patients of European descent
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  rate_per_100000: 3500.0
  notes: >-
    3-4% of 114 unrelated dilated cardiomyopathy probands in the original French
    discovery series. Recorded as the midpoint of the reported 3-4% range. Same
    caveat as above: a pre-gnomAD discovery-cohort yield, not a population
    prevalence, and no population prevalence of MYPN-related cardiomyopathy is
    established.
  evidence:
  - reference: PMID:18006477
    reference_title: Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified a new gene associated with DCM and observed mutations in 3-4%
      of cases in a population of European descent
    explanation: >-
      Source of the 3-4% discovery-cohort yield in dilated cardiomyopathy.
pathophysiology:
- name: MYPN Variant Altering Myopalladin
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The initiating lesion is a heterozygous MYPN variant that either reduces the
    amount of normal myopalladin or introduces a protein that misbehaves in the
    Z-disc. Three mechanistic classes are evidenced. A frameshift allele
    (I83fsX105) yields no detectable mutant transcript in patient mRNA, so the
    cell is left haploinsufficient. Missense alleles in the C-terminal half
    (R1088H, P1112L, V1195M) are incorporated but mislocalise and behave
    dominant-negatively. An N-terminal allele (Y20C) leaves Z-disc targeting
    largely intact but breaks the protein's second job, nuclear shuttling with
    CARP. Which class an allele belongs to is what predicts the cardiomyopathy
    pattern the family develops.
  genes:
  - preferred_term: MYPN
    term:
      id: hgnc:23246
      label: MYPN
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  genetic_context:
    allele_type: MIXED
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: UNKNOWN
    description: >-
      Germline heterozygous alleles spanning haploinsufficiency (I83fsX105),
      dominant-negative missense (P1112L, V1195M), and a signalling-selective
      N-terminal missense allele (Y20C). Biallelic loss of function produces a
      different disease and is not modelled here.
  evidence:
  - reference: PMID:18006477
    reference_title: Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Allele-specific expression analysis of mRNA from a patient harbouring the
      I83fsX105 mutation indicated the absence of the mutated transcript,
      suggesting a haploinsufficiency mechanism.
    explanation: >-
      Direct patient-derived evidence for the haploinsufficiency class of allele
      named in this node.
  - reference: PMID:22286171
    reference_title: Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MYPN mutations cause various forms of cardiomyopathy via different
      protein-protein interactions.
    explanation: >-
      States the allele-dependent-mechanism principle that makes this a single
      trigger node with divergent downstream branches.
  downstream:
  - target: Z-Disc and I-Band Scaffolding Failure
    causal_link_type: DIRECT
    description: >-
      Loss or malfunction of myopalladin removes a structural node of the Z-disc
      lattice.
- name: Z-Disc and I-Band Scaffolding Failure
  biological_scale: MOLECULAR
  description: >-
    Myopalladin cross-links the Z-disc: it binds the titin Ig domains Z4-Z5,
    alpha-actinin-2, nebulette, the PDZ-LIM proteins, and CARP at the titin N2A
    region. Losing it, or replacing it with a mislocalised mutant, degrades the
    lattice that transmits force between sarcomeres and laterally to the
    sarcolemma, and simultaneously degrades the mechanosensory apparatus that
    reports load. Explanted left ventricular myocardium from an R1088H carrier
    shows reduced myopalladin at alpha-actinin-positive Z-bands, so this node is
    observed in human tissue and not only inferred from models.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cellular_components:
  - preferred_term: Z disc
    term:
      id: GO:0030018
      label: Z disc
    modifier: ABNORMAL
  evidence:
  - reference: PMID:18006477
    reference_title: Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Specific immunolabelling of heart tissue from a proband carrying the R1088H
      mutation showed a decreased localization of myopalladin at the Z-band area
      of left ventricular cardiac myofibrils.
    explanation: >-
      Human myocardial evidence that a disease allele depletes myopalladin from
      the Z-band, which is the lesion this node names.
  - reference: PMID:34558411
    reference_title: Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In a yeast two-hybrid screening, MYPN was found to bind to titin in the
      Z-line, which was confirmed by microscale thermophoresis.
    explanation: >-
      Identifies the titin interaction that makes myopalladin a load-bearing
      element of the Z-disc lattice rather than a passive passenger. Graded
      IN_VITRO because the measurement is a yeast two-hybrid and thermophoresis
      binding assay.
  downstream:
  - target: Disturbed Myofibrillogenesis and Sarcomere Disorganization
    causal_link_type: DIRECT
    description: >-
      A degraded Z-disc lattice cannot template orderly myofibril assembly.
  - target: Impaired CARP Nuclear Shuttling
    causal_link_type: DIRECT
    description: >-
      The same lesion removes the shuttle that carries CARP between the I-band
      and the nucleus; the Y20C allele isolates this branch.
- name: Disturbed Myofibrillogenesis and Sarcomere Disorganization
  biological_scale: CELLULAR
  description: >-
    Cardiomyocytes expressing mutant myopalladin build disorganised sarcomeres.
    Q529X strips alpha-actinin-2, desmin and CARP from assembling myofibrils;
    P1112L and V1195M produce frank sarcomeric disorganisation followed by
    premature cell death. The structural failure is the route to the restrictive
    pattern in particular, because a stiff, poorly assembled myofibril raises
    resting tension before it lowers developed tension.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Myofibril Assembly
    term:
      id: GO:0030239
      label: myofibril assembly
    modifier: ABNORMAL
  - preferred_term: Sarcomere Organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:22286171
    reference_title: Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X)
    explanation: >-
      The measured myofibrillogenesis defect this node names, in cardiomyocytes
      expressing the restrictive allele.
  - reference: PMID:18006477
    reference_title: Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Analysis of the effects of the mutations after transfection in rat neonate
      cardiomyocytes indicated sarcomere disorganization and premature cell death
      associated with the V1195M and P1112L myopalladin expression.
    explanation: >-
      Extends the same cellular phenotype to the two sporadic dilated-cardiomyopathy
      missense alleles, and adds the cardiomyocyte death this node passes downstream.
  downstream:
  - target: Impaired Contractile and Passive Mechanics
    causal_link_type: DIRECT
    description: >-
      A disorganised myofibril generates less active tension and resists stretch
      more at long sarcomere lengths.
- name: Impaired CARP Nuclear Shuttling
  biological_scale: MOLECULAR
  description: >-
    Myopalladin binds CARP/ANKRD1, a transcriptional cofactor that moves between
    the titin N2A region and the nucleus and is strongly induced by mechanical
    stress. The Y20C allele binds CARP poorly and fails to translocate; the Q529X
    truncation does the opposite, persisting in the nucleus while total and
    nuclear CARP fall. Either way the load-reporting arm of the Z-disc is
    uncoupled from the transcriptional response to load, which is the branch that
    biases remodelling towards hypertrophy rather than dilation.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Protein Import Into Nucleus
    term:
      id: GO:0006606
      label: protein import into nucleus
    modifier: DECREASED
  evidence:
  - reference: PMID:22286171
    reference_title: Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were
      demonstrated using in vitro and in vivo systems.
    explanation: >-
      Direct measurement of the shuttling and CARP-binding defect this node names.
  - reference: PMID:25541130
    reference_title: "Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Truncated Mypn(Q526X) protein was found to translocate to the nucleus.
    explanation: >-
      The mirror-image nuclear handling of the restrictive allele in knock-in
      mice, which is why this node is described as uncoupling rather than simply
      abolishing the shuttle.
  downstream:
  - target: Ventricular Remodeling
    causal_link_type: DIRECT
    description: >-
      Loss of the CARP-dependent load-reporting arm biases the remodelling
      response, producing hypertrophic rather than dilated geometry for the Y20C
      allele.
- name: Impaired Contractile and Passive Mechanics
  biological_scale: CELLULAR
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Progressive Contractile Dysfunction"
  description: >-
    Myofibrils lacking myopalladin generate less isometric tension and develop
    more resting tension when stretched, and calcium release and reuptake are
    delayed. The combination is a myocyte that contracts weakly and relaxes
    poorly — the shared substrate from which the dilated and the restrictive
    presentations diverge. It is also load-sensitive: the deficit is mild at
    baseline and becomes severe under pressure overload.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cardiac Muscle Contraction
    term:
      id: GO:0060048
      label: cardiac muscle contraction
    modifier: DECREASED
  - preferred_term: Intracellular Calcium Ion Homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:34558411
    reference_title: Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cardiac analyses of MYPN knockout (MKO) mice showed the development of mild
      cardiac dilation and systolic dysfunction, associated with decreased
      myofibrillar isometric tension generation and increased resting tension at
      longer sarcomere lengths.
    explanation: >-
      Measures both halves of this node — reduced active tension and raised
      passive tension — in myofibrils from myopalladin-null hearts.
  - reference: PMID:34558411
    reference_title: Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cardiomyocyte analyses showed delayed Ca2+ release and reuptake in
      unstressed MKO mice as well as reduced Ca2+ spark amplitude post-TAC,
      suggesting that altered Ca2+ handling may contribute to the development of
      DCM in MKO mice.
    explanation: >-
      The calcium-handling component of this node, and the authors' own hedge
      that it contributes to rather than explains the dilated phenotype.
  downstream:
  - target: Neurohormonal Activation
    causal_link_type: DIRECT
    description: >-
      Falling stroke volume recruits the compensatory neurohormonal axes.
  - target: Ventricular Remodeling
    causal_link_type: DIRECT
    description: >-
      Sustained mechanical underperformance drives chamber geometry change
      directly as well as through neurohormonal signalling.
- name: Neurohormonal Activation
  biological_scale: ORGANISM
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Neurohormonal Activation"
  description: >-
    The renin-angiotensin-aldosterone and sympathetic axes are recruited to
    defend cardiac output. Nothing in this arm is MYPN-specific; it is the shared
    cardiomyopathy response, and it is the arm that current drug therapy for this
    disease actually targets. Myopalladin-null hearts under pressure overload show
    the transcriptional signature of that activation, with induction of the fetal
    gene program including Nppa and Nppb.
  evidence:
  - reference: PMID:34558411
    reference_title: Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      MKO mice exhibited a normal hypertrophic response to transaortic
      constriction (TAC), but rapidly developed severe cardiac dilation and
      systolic dysfunction, associated with fibrosis, increased fetal gene
      expression, higher intercalated disc fold amplitude, decreased
      calsequestrin-2 protein levels, and increased desmoplakin and SORBS2
      protein levels.
    explanation: >-
      Records the fetal gene program readout of stress activation in a
      myopalladin-null heart, and the load-dependence that makes this arm
      decisive rather than incidental.
  downstream:
  - target: Ventricular Remodeling
    causal_link_type: DIRECT
    description: >-
      Chronic neurohormonal drive converts a compensatory response into adverse
      remodelling.
- name: Ventricular Remodeling
  biological_scale: TISSUE
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    The point at which the three clinical patterns separate. Interstitial and
    perivascular fibroblast activation and matrix deposition are common to all
    three; the geometry differs. Haploinsufficiency and dominant-negative alleles
    give chamber dilation with wall thinning; the CARP-shuttling allele gives wall
    thickening; the restrictive allele gives fibrosis and a stiff, normally sized
    ventricle without overt hypertrophy. Because the divergence sits here rather
    than at the trigger, the three MONDO labels on this class are three outcomes
    of one chain.
  cell_types:
  - preferred_term: Cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:25541130
    reference_title: "Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Histology revealed interstitial and perivascular fibrosis without overt
      hypertrophic remodeling.
    explanation: >-
      The restrictive branch of this node: fibrosis without hypertrophy in
      knock-in mice carrying the restrictive human allele.
  - reference: PMID:22286171
    reference_title: Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted
      intercalated discs, with disturbed expression of desmin, desmoplakin,
      connexin43 and vinculin being evident.
    explanation: >-
      The hypertrophic branch of the same node, in transgenic mice carrying the
      CARP-shuttling allele.
  downstream:
  - target: Structural Cardiac Impairment and Heart Failure
    causal_link_type: DIRECT
    description: >-
      Remodelled, fibrotic myocardium cannot sustain output or filling.
  - target: Dilated cardiomyopathy
    causal_link_type: DIRECT
    description: >-
      Chamber dilation with reduced systolic contraction is the dilated outcome
      of this node.
  - target: Hypertrophic cardiomyopathy
    causal_link_type: DIRECT
    description: >-
      Wall thickening is the outcome of the CARP-shuttling branch.
  - target: Restrictive cardiomyopathy
    causal_link_type: DIRECT
    description: >-
      Fibrosis with a stiff, non-dilated, non-hypertrophied ventricle is the
      restrictive outcome.
- name: Structural Cardiac Impairment and Heart Failure
  biological_scale: ORGANISM
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >-
    The convergent endpoint. Whichever geometry the family took, the remodelled
    ventricle ends in congestion, exercise limitation and the arrhythmic and
    thromboembolic risk of a structurally abnormal heart. No MYPN-specific event
    rate, transplantation rate or survival curve has been published, so the
    clinical course of this node is currently borrowed from cardiomyopathy in
    general.
  locations:
  - preferred_term: Heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:34558411
    reference_title: Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      MYPN gene mutations are causative for dilated (DCM), hypertrophic, and
      restrictive cardiomyopathy.
    explanation: >-
      States that all three patterns are MYPN outcomes, which is what makes this
      a single convergent endpoint node rather than three.
  downstream:
  - target: Congestive heart failure
    causal_link_type: DIRECT
    description: >-
      Congestion and low output are the clinical expression of this node.
  - target: Arrhythmia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Structural and fibrotic remodelling creates the substrate for atrial and
      ventricular arrhythmia and for conduction disease.
phenotypes:
- name: Dilated cardiomyopathy
  category: Cardiovascular
  description: >-
    Left ventricular or biventricular dilation with impaired systolic
    contraction, the pattern for which MONDO:0014100 is named. Reported in both
    familial and sporadic MYPN probands.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:18006477
    reference_title: Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Idiopathic dilated cardiomyopathy (DCM) is a cardiac disorder characterized
      by left ventricular dilatation and impaired systolic contraction.
    explanation: >-
      Supplies the case definition of the dilated pattern in the series that
      identified MYPN as a dilated cardiomyopathy gene.
- name: Hypertrophic cardiomyopathy
  category: Cardiovascular
  description: >-
    Unexplained ventricular wall thickening, reached by the Y20C allele in human
    carriers and reproduced in cardiac-restricted transgenic mice. MONDO carries
    "cardiomyopathy, hypertrophic, 22" as a synonym of this entry's anchor class.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:22286171
    reference_title: Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas
      Q529X-MYPN was found in familial RCM.
    explanation: >-
      Human carriers of the Y20C allele developed hypertrophic cardiomyopathy,
      which is the claim this phenotype makes. The same sentence also records
      that Y20C carriers can instead develop the dilated pattern, which is why
      the allele-to-pattern mapping is curated as an open question in
      `mypn_allelic_branch_point_is_underdetermined` rather than as a rule.
  - reference: PMID:22286171
    reference_title: Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted
      intercalated discs
    explanation: >-
      Model-organism recapitulation of the hypertrophic pattern for the same
      allele. Marked INDIRECT because the human phenotype is asserted by the
      preceding item; this quote adds only the transgenic reproduction the
      description refers to.
- name: Restrictive cardiomyopathy
  category: Cardiovascular
  description: >-
    Restrictive filling with diastolic dysfunction and preserved systolic
    function, found with the Q529X allele in a familial pedigree and reproduced
    in heterozygous knock-in mice. Also curated as a MYPN gene arm in
    `Restrictive_Cardiomyopathy`.
  phenotype_term:
    preferred_term: Restrictive cardiomyopathy
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
  evidence:
  - reference: PMID:25541130
    reference_title: "Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Echocardiographic and CMR imaging signs of diastolic dysfunction with
      preserved systolic function were identified in 12-week-old Mypn(WT/Q526X)
      mice.
    explanation: >-
      Model-organism recapitulation of the restrictive physiology; the human
      pedigree evidence for this allele is carried on the CMR4 subtype and in
      `Restrictive_Cardiomyopathy`.
  - reference: PMID:22286171
    reference_title: Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas
      Q529X-MYPN was found in familial RCM.
    explanation: >-
      Human evidence that the restrictive pattern occurs in a MYPN family, so
      this phenotype is not supported by the mouse alone.
- name: Congestive heart failure
  category: Cardiovascular
  description: >-
    Exertional dyspnoea, fatigue, exercise intolerance and congestion follow once
    remodelling outstrips compensation. No MYPN-specific frequency, severity
    distribution or hospitalisation rate has been reported; the symptom set is
    that of cardiomyopathic heart failure generally.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:34558411
    reference_title: Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      MKO mice exhibited a normal hypertrophic response to transaortic
      constriction (TAC), but rapidly developed severe cardiac dilation and
      systolic dysfunction, associated with fibrosis, increased fetal gene
      expression, higher intercalated disc fold amplitude, decreased
      calsequestrin-2 protein levels, and increased desmoplakin and SORBS2
      protein levels.
    explanation: >-
      Model-organism progression to decompensated dilation and fibrosis under
      load. Marked INDIRECT because the human heart-failure syndrome is inferred
      from the mouse phenotype rather than measured in MYPN carriers.
- name: Dyspnea
  category: Cardiovascular
  description: >-
    Breathlessness on exertion, the usual presenting symptom of the heart-failure
    phase. Not quantified in MYPN carriers specifically.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
    temporality: CHRONIC
- name: Arrhythmia
  category: Cardiovascular
  description: >-
    Atrial and ventricular arrhythmia and conduction disease occurred in a
    minority of the discovery cohort, but were not resolved by MYPN genotype, so
    there is no MYPN-specific arrhythmic risk estimate and no basis for a
    gene-specific device threshold. As with `Cardiac conduction abnormality`,
    the minority figure sits in the full text of the discovery paper rather than
    its abstract, so this phenotype is curated without an evidence item rather
    than with a snippet that cannot be verified against the cached record.
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
- name: Cardiac conduction abnormality
  category: Cardiovascular
  description: >-
    Conduction disease was reported alongside arrhythmia in a minority of the
    broader screened cardiomyopathy cohort. Like the arrhythmia finding it was
    not resolved by MYPN genotype, and the figure sits in the full text of the
    discovery paper rather than its abstract, so this phenotype is curated
    without an evidence item rather than with a snippet that cannot be verified
    against the cached record. It is modeled separately from `Arrhythmia`
    because conduction disease and tachyarrhythmia carry different management
    consequences, and because the electrocardiographic surveillance curated
    under `diagnosis:` is looking for both.
  phenotype_term:
    preferred_term: Cardiac conduction abnormality
    term:
      id: HP:0031546
      label: Cardiac conduction abnormality
diagnosis:
- name: Electrocardiography and Ambulatory Rhythm Monitoring
  description: >-
    The first-line electrical study, and the cheapest. A cardiomyopathy-oriented
    reading looks for conduction disease, low QRS voltage, QRS fragmentation and
    repolarization change, and ambulatory monitoring adds the atrial and
    ventricular ectopy burden that a resting tracing misses. Nothing here is
    MYPN-specific: the discovery cohorts reported arrhythmia and conduction
    disease in a minority of patients without resolving it by genotype, so there
    is no MYPN electrocardiographic signature to look for and no gene-specific
    monitoring interval to recommend.
  diagnosis_term:
    preferred_term: electrocardiography
    term:
      id: NCIT:C38053
      label: Electrocardiography
  evidence:
  - reference: PMID:37125300
    reference_title: "Pragmatic electrocardiogram tracings in non-ischaemic dilated cardiomyopathy: diagnostic and prognostic role."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      electrocardiogram (ECG) continues to represent a reliable diagnostic tool,
      for specific work up of every single patient
    explanation: >-
      Establishes the ECG as a standing part of the dilated-cardiomyopathy
      workup, which is the claim this diagnostic entry makes. Graded OTHER
      because the source is an expert review built around four illustrative
      tracings rather than a cohort study.
  - reference: PMID:37125300
    reference_title: "Pragmatic electrocardiogram tracings in non-ischaemic dilated cardiomyopathy: diagnostic and prognostic role."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the strength of electrocardiography lies in the ability to diagnose and
      prognostically stratify DCMs in order to accurately address second and
      third diagnostic investigations
    explanation: >-
      States what the ECG contributes that the later imaging and genetic steps
      do not, which is why it is curated as its own diagnostic entry rather than
      folded into echocardiography.
- name: Echocardiography
  description: >-
    The test that establishes the morphological pattern, and therefore which of
    this entry's three subtypes a family is in: ventricular dimensions and
    ejection fraction for the dilated pattern, wall thickness for the
    hypertrophic pattern, and diastolic filling with preserved systolic function
    for the restrictive pattern. The diagnosis remains a clinical one that
    requires excluding loading conditions and coronary disease sufficient to
    explain the findings. Nothing about the imaging is MYPN-specific.
  diagnosis_term:
    preferred_term: transthoracic echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:31073128
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Echocardiography and other imaging techniques are required to assess
      ventricular dysfunction and adverse myocardial remodelling
    explanation: >-
      Establishes echocardiography as the required modality for assessing the
      ventricular dysfunction and remodelling that this entry's pathograph
      terminates in.
  - reference: PMID:31073128
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left
      ventricular or biventricular dilation and impaired contraction that is not
      explained by abnormal loading conditions (for example, hypertension and
      valvular heart disease) or coronary artery disease.
    explanation: >-
      States the exclusion criteria that define the dilated diagnosis, which is
      what makes echocardiography necessary but not sufficient.
  - reference: PMID:27339497
    reference_title: The Diagnosis and Evaluation of Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Measurement of LV size and ejection fraction remain central to diagnosis,
      risk stratification, and treatment
    explanation: >-
      Names the two echocardiographic measurements that carry the diagnosis, and
      places them ahead of the tissue characterisation that cardiac MRI adds.
- name: Cardiac Magnetic Resonance Imaging
  description: >-
    Adds what echocardiography cannot: tissue characterisation, and with it the
    risk stratification that drives management in nonischemic dilated
    cardiomyopathy. In a meta-analysis of 103 studies and 29,687 patients, late
    gadolinium enhancement — both its presence and its extent — was associated
    with higher all-cause and cardiovascular mortality, arrhythmic events and
    heart failure events, while ejection fraction was NOT associated with
    all-cause mortality or arrhythmic outcomes. That inversion matters here
    because the fibrosis this measures is the same remodelling endpoint the
    Mypn-null mouse develops under pressure overload. No MYPN carrier series
    with cardiac MRI has been published, so none of this is gene-specific.
  diagnosis_term:
    preferred_term: cardiac magnetic resonance imaging
    term:
      id: NCIT:C137915
      label: Magnetic Resonance Imaging of the Heart
  evidence:
  - reference: PMID:39298146
    reference_title: "Risk Stratification in Nonischemic Dilated Cardiomyopathy Using CMR Imaging: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Late gadolinium enhancement (LGE) presence and extent (per 1%) were
      associated with higher all-cause mortality
    explanation: >-
      Establishes late gadolinium enhancement as a prognostic marker in
      nonischemic dilated cardiomyopathy, which is what cardiac MRI adds beyond
      echocardiography.
  - reference: PMID:39298146
    reference_title: "Risk Stratification in Nonischemic Dilated Cardiomyopathy Using CMR Imaging: A Systematic Review and Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Left ventricular ejection fraction (LVEF) (per 1%) was not associated with
      all-cause mortality
    explanation: >-
      The negative result that makes cardiac MRI worth curating separately from
      echocardiography: the echo-derived measure does not carry the mortality
      signal that late gadolinium enhancement does.
  - reference: PMID:27339497
    reference_title: The Diagnosis and Evaluation of Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Assessment of myocardial fibrosis predicts both risk of sudden cardiac
      death and likelihood of LV functional recovery
    explanation: >-
      Connects the imaging measurement to the two decisions it informs, one of
      which is device therapy — the point at which this entry declines to make a
      MYPN-specific recommendation.
- name: Natriuretic Peptide and Troponin Testing
  description: >-
    BNP or NT-proBNP and high-sensitivity troponin are drawn as part of the
    heart-failure workup, alongside blood count, electrolytes, and renal, liver,
    thyroid and iron studies aimed at the alternative causes that have to be
    excluded. They quantify the heart-failure state rather than identify its
    cause, and no MYPN-specific biomarker, cut-off or reference interval has
    been reported — which is why this entry carries no `biochemical:` block.
  diagnosis_term:
    preferred_term: natriuretic peptide and troponin testing
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:31073128
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: >-
      new diagnostic tools, such as serum biomarkers, that enable early
      diagnosis and treatment
    explanation: >-
      The cited review treats serum biomarkers as a developing rather than
      established diagnostic route in dilated cardiomyopathy. Marked INDIRECT
      because it supports biomarker testing as part of the workup without
      establishing a diagnostic threshold, and no such threshold exists for
      MYPN.
- name: Molecular Genetic Testing (Multigene Cardiomyopathy Panel)
  description: >-
    A curated multigene cardiomyopathy panel with sequence plus
    deletion/duplication analysis, rather than isolated MYPN sequencing; exome
    or genome sequencing after a negative panel. Every reported MYPN proband was
    ascertained this way — the founding series screened MYPN across 900
    hypertrophic, dilated and restrictive cardiomyopathy patients. THE RESULT
    MUST NOT BE OVER-READ. ClinGen classifies the MYPN-dilated cardiomyopathy
    relationship as Limited, so a MYPN variant should not on its own make or
    exclude a diagnosis, nor direct predictive testing of relatives, and a MYPN
    variant of uncertain significance carries no clinical action at all.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:22286171
    reference_title: Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MYPN was genetically screened in 900 patients with HCM, DCM and RCM
    explanation: >-
      Documents the ascertainment route by which MYPN variants reach patients:
      broad genetic screening across all three cardiomyopathy patterns, not a
      MYPN-directed test.
  - reference: PMID:20301725
    reference_title: Nonsyndromic Hypertrophic Cardiomyopathy Overview.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Provide an evaluation strategy to identify (when possible) the genetic
      cause of nonsyndromic HCM in a proband
    explanation: >-
      The GeneReviews hypertrophic-cardiomyopathy overview supplies the proband
      evaluation strategy that a gene-level entry such as this one sits inside.
      Graded OTHER because GeneReviews is an expert-authored review resource;
      note that the cached PubMed record for this chapter contains only its
      stated purpose, so no clinical-characteristics text could be mined from it.
  - reference: DOI:10.3390/biomedicines12081643
    reference_title: "Risk Assessment and Personalized Treatment Options in Inherited Dilated Cardiomyopathies: A Narrative Review"
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: >-
      It is crucial to select patients who are most probable to gain advantages
      from genetic testing.
    explanation: >-
      Supports testing being offered selectively rather than reflexively, which
      is the caution a Limited-evidence gene requires. Marked INDIRECT because
      the source addresses inherited dilated cardiomyopathy generally rather
      than MYPN.
- name: Cascade Testing and Cardiac Surveillance of At-Risk Relatives
  description: >-
    First-degree relatives of a carrier of a pathogenic or likely pathogenic
    MYPN variant are offered cascade testing, and genotype-positive relatives
    then enter longitudinal electrocardiographic and imaging surveillance even
    while asymptomatic. Where no credible familial variant is identified,
    relatives still need phenotype screening, because a negative panel does not
    exclude inherited disease. The MYPN-specific caveats bite here: the ClinGen
    Limited classification means a MYPN variant of uncertain significance is not
    an indication for predictive testing, and no MYPN-specific screening
    interval or lifetime penetrance figure exists to quote, so the interval is
    the one used for inherited cardiomyopathy generally.
  diagnosis_term:
    preferred_term: cascade screening of at-risk relatives
    term:
      id: NCIT:C15419
      label: Disease Screening
  evidence:
  - reference: PMID:20301486
    reference_title: Dilated Cardiomyopathy Overview.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Provide a basic view of genetic risk assessment of at-risk asymptomatic
      relatives of a proband with DCM to inform cardiac surveillance and allow
      early detection and treatment of DCM to improve long-term outcome
    explanation: >-
      The GeneReviews chapter's stated purpose for relatives of a proband:
      genetic risk assessment driving cardiac surveillance. This is the baseline
      practice this entry follows, with the caveat that a Limited-evidence gene
      cannot carry the risk assessment the recommendation depends on.
  - reference: PMID:20301725
    reference_title: Nonsyndromic Hypertrophic Cardiomyopathy Overview.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Inform genetic counseling of family members of an individual with
      nonsyndromic HCM
    explanation: >-
      The matching GeneReviews purpose on the hypertrophic side, cited because
      this entry spans both patterns and the family-screening obligation does
      not depend on which one a proband presented with.
  - reference: PMID:27339497
    reference_title: The Diagnosis and Evaluation of Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Detection of pre-clinical DCM could substantially reduce morbidity and
      mortality by allowing early instigation of cardioprotective therapy.
    explanation: >-
      States the rationale for surveillance of asymptomatic relatives, which is
      why this is a diagnostic activity rather than a treatment.
  - reference: PMID:27339497
    reference_title: The Diagnosis and Evaluation of Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A rigorous work-up can exclude alternative causes of left ventricular (LV)
      dilation and dysfunction, identify etiologies that may respond to specific
      treatments, and guide family screening.
    explanation: >-
      Ties the proband workup curated in the preceding diagnostic entries to the
      family screening curated here.
genetic:
- name: MYPN
  gene_term:
    preferred_term: MYPN
    term:
      id: hgnc:23246
      label: MYPN
  relationship_type: CAUSATIVE
  frequency: >-
    The sole gene of this entity. MYPN encodes myopalladin, a striated-muscle
    Z-disc and I-band protein that also shuttles to the nucleus, so it acts as
    both a structural anchor and a mechanotransduction messenger. Yield in
    ascertained cardiomyopathy cohorts is 1.66% across HCM, DCM and RCM combined,
    and 3-4% in the original European dilated cardiomyopathy series.
  notes: >-
    Gene-disease validity is Limited, not Definitive. ClinGen's Dilated
    Cardiomyopathy Gene Curation Expert Panel classifies the MYPN-dilated
    cardiomyopathy relationship as Limited under an autosomal dominant model.
    That is a statement about the strength of the aggregate human genetic
    evidence, not a claim that the mechanism described in this entry is wrong —
    the cellular, myocardial and mouse work is substantial. In practice it means
    a MYPN variant of uncertain significance should not be used to make this
    diagnosis, to drive predictive cascade testing, or to justify irreversible
    management. The historical alleles below predate gnomAD and current ACMG/AMP
    criteria and need reclassification against contemporary population data
    before clinical use.
  evidence:
  - reference: CGGV:assertion_ffd924ad-55ce-4b05-8a91-584ef49b4e80-2025-03-05T050000.000Z
    reference_title: "MYPN / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYPN | HGNC:23246 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited"
    explanation: >-
      ClinGen's current classification of this gene-disease relationship, which
      is why the entry states the diagnosis cannot rest on a variant alone.
  - reference: PMID:22286171
    reference_title: Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and
      functions as a structural, signaling and gene expression regulating
      molecule in response to muscle stress.
    explanation: >-
      The dual structural and signalling role of the gene product, which is what
      makes a single gene reach three cardiomyopathy patterns.
animal_models:
- name: Myopalladin knockout mouse
  species: Mouse
  genotype: Mypn constitutive knockout (homozygous null)
  publication: PMID:34558411
  description: >-
    Constitutive whole-body Mypn-null mice. They develop mild spontaneous
    dilation and systolic dysfunction with reduced myofibrillar tension and
    delayed calcium handling, and decompensate severely under transaortic
    constriction.
  modeled_mechanisms:
  - target: Impaired Contractile and Passive Mechanics
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Directly measures the reduced active tension, raised passive tension and
      delayed calcium handling that this node asserts.
    limitations: >-
      A homozygous null models haploinsufficiency at best and does not model the
      dominant-negative or CARP-shuttling missense alleles at all; the mouse is
      also far milder at baseline than the human disease and only becomes severe
      when pressure-overloaded.
    readouts:
    - name: Myofibrillar isometric tension and resting tension
      target: Impaired Contractile and Passive Mechanics
      direction: DECREASED
      interpretation: >-
        Active tension falls while resting tension at long sarcomere lengths
        rises, the mechanical signature of this node.
      evidence:
      - reference: PMID:34558411
        reference_title: Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Cardiac analyses of MYPN knockout (MKO) mice showed the development of
          mild cardiac dilation and systolic dysfunction, associated with
          decreased myofibrillar isometric tension generation and increased
          resting tension at longer sarcomere lengths.
        explanation: >-
          The measurement behind this readout.
    evidence:
    - reference: PMID:34558411
      reference_title: Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Cardiomyocyte analyses showed delayed Ca2+ release and reuptake in
        unstressed MKO mice as well as reduced Ca2+ spark amplitude post-TAC,
        suggesting that altered Ca2+ handling may contribute to the development
        of DCM in MKO mice.
      explanation: >-
        Supports treating this model as informative for the contractile and
        calcium-handling node.
  - target: Ventricular Remodeling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the dilated, fibrotic branch of this node, but only after
      pressure overload; the hypertrophic and restrictive branches are not
      reached by a null allele.
    limitations: >-
      Baseline remodelling is mild and requires transaortic constriction to
      become severe, so the model conflates the genetic lesion with an imposed
      haemodynamic second hit that human carriers do not necessarily have.
    evidence:
    - reference: PMID:34558411
      reference_title: Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        MKO mice exhibited a normal hypertrophic response to transaortic
        constriction (TAC), but rapidly developed severe cardiac dilation and
        systolic dysfunction, associated with fibrosis, increased fetal gene
        expression, higher intercalated disc fold amplitude, decreased
        calsequestrin-2 protein levels, and increased desmoplakin and SORBS2
        protein levels.
      explanation: >-
        Documents both what the model reproduces (dilation, fibrosis) and the
        load-dependence recorded in the limitation.
- name: MYPN Y20C cardiac-restricted transgenic mouse
  species: Mouse
  genotype: Cardiac-restricted transgenic expression of human MYPN Y20C
  publication: PMID:22286171
  description: >-
    Transgenic mice expressing the human N-terminal Y20C allele under a cardiac
    promoter, the model for the hypertrophic branch of this entity.
  modeled_mechanisms:
  - target: Ventricular Remodeling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the hypertrophic geometry and intercalated-disc disruption
      attributed to the CARP-shuttling allele.
    limitations: >-
      Human Y20C carriers develop hypertrophic or dilated disease, but the mouse
      is predominantly hypertrophic, so the model does not capture the allele's
      human variability. Transgenic overexpression may also exaggerate the
      dominant effect relative to a heterozygous endogenous allele.
    evidence:
    - reference: PMID:22286171
      reference_title: Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted
        intercalated discs, with disturbed expression of desmin, desmoplakin,
        connexin43 and vinculin being evident.
      explanation: >-
        The remodelling phenotype and junctional disruption this link asserts.
- name: MYPN Q529X knock-in mouse
  species: Mouse
  genotype: Mypn Q526X knock-in, heterozygous (human MYPN Q529X equivalent)
  publication: PMID:25541130
  description: >-
    Heterozygous knock-in of the mouse equivalent of the human restrictive allele,
    the closest available model of the restrictive branch and the only one of the
    three at endogenous expression level in heterozygous state.
  modeled_mechanisms:
  - target: Ventricular Remodeling
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Reproduces restrictive physiology — diastolic dysfunction with preserved
      systolic function and interstitial fibrosis without hypertrophy — at
      endogenous expression level and in the correct heterozygous state.
    limitations: >-
      Models one allele of one branch; nothing about it speaks to the dilated or
      hypertrophic patterns, and the human pedigree behind Q529X is single.
    readouts:
    - name: Diastolic function with preserved ejection fraction
      target: Ventricular Remodeling
      direction: ALTERED
      interpretation: >-
        Restrictive filling with preserved systolic function is the geometric
        outcome this branch of the node predicts.
      evidence:
      - reference: PMID:25541130
        reference_title: "Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Echocardiographic and CMR imaging signs of diastolic dysfunction with
          preserved systolic function were identified in 12-week-old
          Mypn(WT/Q526X) mice.
        explanation: >-
          The imaging measurement behind this readout.
    evidence:
    - reference: PMID:25541130
      reference_title: "Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Heterozygote Mypn(WT/Q526X) knock-in mice develop RCM due to persistence
        of mutant Mypn(Q526X) protein in the nucleus.
      explanation: >-
        Supports treating this model as informative for the restrictive branch of
        the remodelling node, and names the nuclear-persistence mechanism.
differential_diagnoses:
- name: Biallelic MYPN nemaline and cap myopathy
  description: >-
    The same gene, the opposite inheritance mode, and a different organ. Biallelic
    loss-of-function MYPN variants cause a childhood- to adult-onset, slowly
    progressive skeletal myopathy with nemaline rods or caps, in which cardiac
    involvement is the exception rather than the defining feature. It has its own
    MONDO class and is deliberately not curated as a subtype here: the dominant
    cardiac disease and the recessive skeletal disease are allelic disorders of
    one gene, not one disease with two presentations. Confusing them would let a
    homozygous truncating variant be read as evidence for dominant cardiomyopathy.
  distinguishing_features:
  - Biallelic (homozygous or compound heterozygous) truncating variants, not a single heterozygous allele.
  - Proximal skeletal muscle weakness and walking difficulty as the presenting problem, with cardiac involvement absent or secondary.
  - Nemaline rods, intranuclear rods, or caps on muscle biopsy, with myopalladin absent from the skeletal Z-line.
  evidence:
  - reference: PMID:28220527
    reference_title: Recessive MYPN mutations cause cap myopathy with occasional nemaline rods.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data uncover that mutations in MYPN cause either a cardiac or a
      congenital skeletal muscle disorder through different modes of inheritance.
    explanation: >-
      States the inheritance-mode split that this differential turns on.
  - reference: PMID:28017374
    reference_title: "Biallelic Mutations in MYPN, Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with identified MYPN mutations in all four of these families
      have relatively mild, childhood- to adult-onset NM with slowly progressive
      muscle weakness.
    explanation: >-
      Characterises the recessive skeletal phenotype so it can be separated from
      the dominant cardiac one at the bedside.
- name: Dilated cardiomyopathy from a high-evidence gene
  description: >-
    TTN truncating variants, LMNA, and the desmosomal and FLNC arms account for a
    far larger share of genetic dilated cardiomyopathy than MYPN does and carry
    management consequences MYPN does not — LMNA and FLNC in particular drive
    arrhythmic risk stratification and device decisions. On a multigene panel a
    MYPN variant found alongside a variant in one of these genes is very unlikely
    to be the explanation. Curated as `Dilated_Cardiomyopathy`, where MYPN is
    listed as a gene arm with the same ClinGen Limited classification.
  distinguishing_features:
  - A pathogenic or likely pathogenic variant in a gene ClinGen rates Moderate, Strong, or Definitive for dilated cardiomyopathy.
  - Gene-specific features such as early conduction disease and arrhythmia out of proportion to systolic dysfunction (LMNA), or ring-like subepicardial late gadolinium enhancement (FLNC).
  - Established gene-specific device and surveillance recommendations, which MYPN does not have.
  disease_term:
    preferred_term: dilated cardiomyopathy
    term:
      id: MONDO:0005021
      label: dilated cardiomyopathy
- name: Hypertrophic cardiomyopathy from a sarcomere gene
  description: >-
    MYH7 and MYBPC3 account for the large majority of genotype-positive
    hypertrophic cardiomyopathy. A MYPN allele reaching the hypertrophic pattern
    is rare enough that a thick-walled ventricle should prompt a full sarcomere
    panel before MYPN is accepted as the cause.
  distinguishing_features:
  - Pathogenic variant in MYH7, MYBPC3, or another core sarcomere gene.
  - Asymmetric septal hypertrophy with left ventricular outflow tract obstruction, which has not been described as a MYPN-specific pattern.
  disease_term:
    preferred_term: hypertrophic cardiomyopathy
    term:
      id: MONDO:0005045
      label: hypertrophic cardiomyopathy
treatments:
- name: Guideline-Directed Medical Therapy for Heart Failure with Reduced Ejection Fraction
  description: >-
    Angiotensin receptor-neprilysin inhibition or ACE inhibition/ARB, an
    evidence-based beta blocker, a mineralocorticoid receptor antagonist, an
    SGLT2 inhibitor, and diuretics for congestion. There is no MYPN-specific
    trial and no MYPN pharmacogenomic rule; this is the general heart-failure
    evidence applied to a patient whose cardiomyopathy happens to be MYPN-related,
    and it targets the neurohormonal arm of the pathograph rather than the Z-disc
    lesion.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sacubitril
      term:
        id: CHEBI:134714
        label: sacubitril
    - preferred_term: valsartan
      term:
        id: CHEBI:9927
        label: valsartan
    - preferred_term: dapagliflozin
      term:
        id: CHEBI:85078
        label: dapagliflozin
    - preferred_term: carvedilol
      term:
        id: CHEBI:3441
        label: carvedilol
    - preferred_term: spironolactone
      term:
        id: CHEBI:9241
        label: spironolactone
  target_mechanisms:
  - target: Neurohormonal Activation
    description: >-
      Neurohormonal blockade acts on this node; nothing in the regimen reaches
      the upstream Z-disc lesion.
  evidence:
  - reference: PMID:25176015
    reference_title: Angiotensin-neprilysin inhibition versus enalapril in heart failure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      LCZ696 was superior to enalapril in reducing the risks of death and of
      hospitalization for heart failure.
    explanation: >-
      Trial evidence for the neurohormonal arm of this regimen. Marked INDIRECT
      because the trial enrolled heart failure with reduced ejection fraction
      generally, not MYPN carriers.
  - reference: PMID:31535829
    reference_title: Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      the risk of worsening heart failure or death from cardiovascular causes was
      lower among those who received dapagliflozin than among those who received
      placebo, regardless of the presence or absence of diabetes
    explanation: >-
      Trial evidence for the SGLT2-inhibitor component. Marked INDIRECT for the
      same reason: an unselected reduced-ejection-fraction population.
- name: Implantable Cardioverter-Defibrillator
  description: >-
    Considered on standard ejection-fraction, arrhythmic and syncope criteria.
    MYPN is not an established high-arrhythmic-risk genotype in the way LMNA and
    FLNC are, so it does not lower the threshold; a gene-specific device rule for
    MYPN would not be supported by anything published.
  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: Arrhythmia
    description: >-
      Terminates ventricular arrhythmia arising on the remodelled, fibrotic
      substrate; it does not modify the substrate.
- name: Heart Transplantation
  description: >-
    The endpoint therapy for advanced heart failure that no longer responds to
    medical management, with mechanical circulatory support as a bridge. No
    MYPN-specific transplantation rate or listing criterion exists.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  target_mechanisms:
  - target: Structural Cardiac Impairment and Heart Failure
    description: >-
      Replaces the failing organ; it is the only intervention here that removes
      the whole pathograph rather than modulating one node of it.
- name: Genetic Counseling
  description: >-
    Counselling of the proband and family about autosomal dominant transmission,
    variable expressivity across the dilated, hypertrophic and restrictive
    patterns, the recessive skeletal-myopathy phenotype that biallelic MYPN loss
    of function causes, and reproductive options. The counselling has to carry
    the ClinGen Limited classification honestly, which is what constrains what
    can be said about risk to relatives. The cascade testing and longitudinal
    surveillance that follow from it are curated under `diagnosis:` — screening
    an asymptomatic relative is a diagnostic activity, not a therapy.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: DOI:10.3390/biomedicines12081643
    reference_title: "Risk Assessment and Personalized Treatment Options in Inherited Dilated Cardiomyopathies: A Narrative Review"
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: >-
      Genetic variants that can be transmitted from one generation to another
      can be a significant contributor to causing family or sporadic hereditary
      DCM.
    explanation: >-
      Supports the transmission risk that is the substance of the counselling
      session. Graded OTHER because the source is a narrative review rather than
      a primary study, and INDIRECT because it addresses inherited dilated
      cardiomyopathy generally rather than MYPN.
discussions:
- discussion_id: mypn_gene_disease_validity_is_limited
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does the aggregate human genetic evidence support MYPN as a monogenic cause
    of cardiomyopathy, or only as a modifier or bystander?
  rationale: >-
    ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel rates
    MYPN-dilated cardiomyopathy as Limited. The mechanistic case in this entry is
    strong — human myocardium, cardiomyocyte assays, three independent mouse
    models — but the human genetic case rests on small pedigrees, historical
    control panels of 400 to 1,020 individuals, and variants classified before
    gnomAD existed. That is exactly the configuration in which a plausible
    mechanism outlives a gene-disease association. Resolving it requires
    reclassification of the historical alleles against contemporary
    population-frequency and ACMG/AMP criteria, plus new segregation data; case
    ascertainment through cardiomyopathy panels alone will not do it, because a
    panel that includes MYPN will keep finding MYPN variants at population
    frequency.
  attaches_to:
  - genetic#MYPN
  - disease#MYPN-Related Cardiomyopathy
- discussion_id: mypn_allelic_branch_point_is_underdetermined
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is the mapping from MYPN allele class to cardiomyopathy pattern reliable
    enough to be predictive, or is it a post-hoc description of a handful of
    families?
  rationale: >-
    This entry is built on the claim that the pattern a family develops is
    determined at the allele level — haploinsufficiency to dilation, CARP-shuttling
    failure to hypertrophy, disturbed myofibrillogenesis to restriction. Each leg
    rests on one or two alleles, and Y20C itself breaks the rule by producing both
    hypertrophic and dilated disease in different human carriers. The branch point
    is therefore a mechanistic hypothesis with model support, not an established
    genotype-phenotype rule, and it should not be used to predict a phenotype from
    a novel allele. What would settle it is a MYPN variant registry with paired
    functional classification and imaging phenotype across many more families.
  attaches_to:
  - pathophysiology#Ventricular Remodeling
  - pathophysiology#Impaired CARP Nuclear Shuttling
  - has_subtypes#CMH22
- discussion_id: mypn_human_mechanism_evidence_is_model_weighted
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Do the mouse models of MYPN cardiomyopathy reproduce the human mechanism, or
    only a load-dependent caricature of it?
  rationale: >-
    All three mouse models diverge from human disease in a specific, stated way.
    The knockout is homozygous null, so it models haploinsufficiency at best and
    the dominant-negative alleles not at all; it is nearly normal at baseline and
    only becomes severe after transaortic constriction, an imposed second hit that
    human carriers do not necessarily have. The Y20C transgenic is
    overexpression-driven and is predominantly hypertrophic, whereas human Y20C
    carriers develop hypertrophic or dilated disease. Only the Q529X knock-in is
    heterozygous at endogenous expression, and it models one allele of one branch.
    The human side of the mechanism is thinner than it looks: two immunolabelling
    observations in explanted myocardium and a set of transfected neonatal rat
    cardiomyocyte assays. No patient-derived iPSC cardiomyocyte or engineered
    heart tissue model of a MYPN allele has been reported, which is the obvious
    missing rung between the rodent work and the human disease.
  attaches_to:
  - pathophysiology#Impaired Contractile and Passive Mechanics
  - pathophysiology#Disturbed Myofibrillogenesis and Sarcomere Disorganization
  - animal_models#Mouse
notes: >-
  Scope and the lump/split decision (issues #10635 and #9865). This entry is
  curated at the gene level, as MYPN-related cardiomyopathy, rather than as
  "dilated cardiomyopathy 1KK", because MONDO:0014100 is not in fact a dilated
  cardiomyopathy class. It has three asserted parents — familial restrictive
  cardiomyopathy (MONDO:0016340), familial hypertrophic cardiomyopathy
  (MONDO:0024573) and familial isolated dilated cardiomyopathy (MONDO:0700335) —
  and carries "cardiomyopathy, hypertrophic, 22" and "cardiomyopathy, familial
  restrictive, 4" as synonyms alongside "cardiomyopathy, dilated, 1KK". The
  MONDO label is one of the three names of the class, not a statement that the
  class is dilated. Curating it under the dilated name would have made the entry
  contradict two of its own three parents.

  Why not a subtype. The alternative shapes were a `has_subtypes` entry on
  `Dilated_Cardiomyopathy`, on `Hypertrophic_Cardiomyopathy`, or on
  `Restrictive_Cardiomyopathy`. Each would have had to pick one of the three
  patterns and drop the other two, which is the specific error
  `Restrictive_Cardiomyopathy` declined to make when it recorded MYPN as a
  `genetic:` gene arm rather than as its RCM4 subtype and left the decision open
  in a note. That note has been updated to point here. MYPN is retained as a gene
  arm in both `Restrictive_Cardiomyopathy` and `Dilated_Cardiomyopathy`, which is
  correct: those entries are curated by morphological pattern and MYPN genuinely
  reaches both, while this entry is curated by gene and holds the mechanism that
  connects them.

  Why not a grouping. A `Grouping` unites existing curated Disease entries.
  There are no separate CMD1KK, CMH22 and CMR4 entries to unite — they are one
  MONDO class with one OMIM anchor (OMIM:615248) — so a grouping would have had
  no members. The three patterns are carried as `has_subtypes` here instead,
  without `subtype_term` bindings, because MONDO has no distinct class for any of
  them.

  The pathograph is one chain with a branch. A MYPN lesion degrades the Z-disc
  and I-band scaffold; the scaffold failure then splits into a structural arm
  (disturbed myofibrillogenesis) and a signalling arm (failed CARP nuclear
  shuttling), and the two recombine at ventricular remodelling, where the
  dilated, hypertrophic and restrictive geometries separate. Splitting the entry
  by morphology would have cut that graph across its branch point and duplicated
  the shared upstream half three times. The entry conforms to
  `cardiomyopathy_maladaptive_remodeling` at four nodes.

  Evidence weighting, stated plainly. The human genetic layer is the weakest part
  of this entity and the entry says so in two places — the `genetic:` block and
  the `mypn_gene_disease_validity_is_limited` discussion. ClinGen rates
  MYPN-dilated cardiomyopathy Limited. The mechanism layer is much better
  supported but is weighted towards models: three mouse lines and a body of
  transfected neonatal rat cardiomyocyte work, against two immunolabelling
  observations in explanted human myocardium. The
  `mypn_human_mechanism_evidence_is_model_weighted` discussion records that
  imbalance and names the missing rung, a patient-derived iPSC cardiomyocyte or
  engineered heart tissue model, which has not been reported for any MYPN allele.

  Out of scope. Biallelic MYPN loss of function causes a recessive skeletal
  myopathy (nemaline myopathy 11 / cap myopathy) that is a distinct allelic
  disorder with its own MONDO class. It is recorded as a differential diagnosis
  so the inheritance-mode boundary is stated rather than assumed, and is not
  curated as a subtype here.

  GeneReviews baseline, and what could be mined from it. There is no
  gene-specific GeneReviews chapter for MYPN. A PubMed E-utilities search on
  2026-09-02 for `MYPN AND GeneReviews[book]` returns exactly one record, and
  the same search on `myopalladin` returns the same one: PMID:20301725, the
  Nonsyndromic Hypertrophic Cardiomyopathy Overview, which is a pattern-level
  chapter that mentions MYPN among the genes screened in HCM rather than a
  chapter about this entity. That chapter and its dilated counterpart are
  therefore both cited and tagged `GeneReviews` in `references:` —
  PMID:20301486 (Dilated Cardiomyopathy Overview) and PMID:20301725 — and both
  are mined in the `diagnosis:` block for the proband
  evaluation strategy and the at-risk-relative surveillance recommendation that
  this entry's diagnostic entries follow. The mining is deliberately thin: both
  cached PubMed records are abstract-only stubs whose entire content is the
  chapter's "the purpose of this overview is to" enumeration, so no clinical
  characteristics, penetrance figures or surveillance intervals could be taken
  from them, and each quoted purpose statement says so in its `explanation`.
  Both chapters are pattern-level rather than gene-level, so they establish the
  practice this entry sits inside; they assert nothing about MYPN.

  No `onset:` age figures. The deep-research artifact reports a mean age at
  diagnosis of 40.2 years with a standard deviation of 18.3 years, attributed to
  the full text of PMID:18006477. That paper's cached record is abstract-only
  and its abstract carries neither number, so the figure cannot be curated with
  a verified snippet and is not asserted here — including in the subtype
  descriptions, which state adult onset with wide variability and stop there.
  That qualitative claim is the whole of what the abstract supports. (There is
  no `progression:` block in this entry to carry it either; see the
  deliberately-not-curated list below.) The same applies to the report's suggested binding for
  conduction disease: HP:0001678 is `Atrioventricular block`, not the
  `Abnormality of cardiac conduction` the report named it, so the conduction
  phenotype above is bound to HP:0031546 instead.

  Deliberately not curated. No `clinical_trials:` block: no trial of any
  intervention in a MYPN-selected population was found, and listing general
  heart-failure trials as this disease's trials would misrepresent them. No
  `datasets:` block: no MYPN-stratified transcriptomic, proteomic or single-cell
  dataset was identified, and a general dilated-cardiomyopathy dataset is not a
  dataset about this entity. No `progression:` block with numbers: no
  MYPN-specific survival, transplantation or event rate has been published, so
  the only honest statement is the absence recorded in the
  `Structural Cardiac Impairment and Heart Failure` node. No `environmental:`
  block: the pressure-overload sensitivity of Mypn-null mice is suggestive of a
  two-hit model, but no exposure has been shown to trigger or exacerbate disease
  in a human MYPN carrier, and an unevidenced exposure entry would be worse than
  none.
references:
- reference: PMID:20301486
  title: "Dilated Cardiomyopathy Overview."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:20301725
  title: "Nonsyndromic Hypertrophic Cardiomyopathy Overview."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:18006477
  title: "Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy."
  findings: []
- reference: PMID:22286171
  title: "Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations."
  findings: []
- reference: PMID:34558411
  title: "Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload."
  findings: []
- reference: PMID:25541130
  title: "Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy."
  findings: []
- reference: PMID:28017374
  title: "Biallelic Mutations in MYPN, Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy."
  findings: []
- reference: PMID:28220527
  title: "Recessive MYPN mutations cause cap myopathy with occasional nemaline rods."
  findings: []
- reference: PMID:27339497
  title: "The Diagnosis and Evaluation of Dilated Cardiomyopathy."
  findings: []
- reference: PMID:31073128
  title: "Dilated cardiomyopathy."
  findings: []
- reference: PMID:37125300
  title: "Pragmatic electrocardiogram tracings in non-ischaemic dilated cardiomyopathy: diagnostic and prognostic role."
  findings: []
- reference: PMID:39298146
  title: "Risk Stratification in Nonischemic Dilated Cardiomyopathy Using CMR Imaging: A Systematic Review and Meta-Analysis."
  findings: []
- reference: PMID:25176015
  title: "Angiotensin-neprilysin inhibition versus enalapril in heart failure."
  findings: []
- reference: PMID:31535829
  title: "Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction."
  findings: []
- reference: CGGV:assertion_ffd924ad-55ce-4b05-8a91-584ef49b4e80-2025-03-05T050000.000Z
  title: "MYPN / dilated cardiomyopathy (Limited)"
  findings: []
- reference: DOI:10.3390/biomedicines12081643
  title: "Risk Assessment and Personalized Treatment Options in Inherited Dilated Cardiomyopathies: A Narrative Review"
  findings: []
📚

References & Deep Research

References

16
PMID:20301486
Dilated Cardiomyopathy Overview.
No top-level findings curated for this source.
PMID:20301725
Nonsyndromic Hypertrophic Cardiomyopathy Overview.
No top-level findings curated for this source.
PMID:18006477
Mutations in the Z-band protein myopalladin gene and idiopathic dilated cardiomyopathy.
No top-level findings curated for this source.
PMID:22286171
Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.
No top-level findings curated for this source.
PMID:34558411
Myopalladin knockout mice develop cardiac dilation and show a maladaptive response to mechanical pressure overload.
No top-level findings curated for this source.
PMID:25541130
Disturbance in Z-disk mechanosensitive proteins induced by a persistent mutant myopalladin causes familial restrictive cardiomyopathy.
No top-level findings curated for this source.
PMID:28017374
Biallelic Mutations in MYPN, Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy.
No top-level findings curated for this source.
PMID:28220527
Recessive MYPN mutations cause cap myopathy with occasional nemaline rods.
No top-level findings curated for this source.
PMID:27339497
The Diagnosis and Evaluation of Dilated Cardiomyopathy.
No top-level findings curated for this source.
PMID:31073128
Dilated cardiomyopathy.
No top-level findings curated for this source.
PMID:37125300
Pragmatic electrocardiogram tracings in non-ischaemic dilated cardiomyopathy: diagnostic and prognostic role.
No top-level findings curated for this source.
PMID:39298146
Risk Stratification in Nonischemic Dilated Cardiomyopathy Using CMR Imaging: A Systematic Review and Meta-Analysis.
No top-level findings curated for this source.
PMID:25176015
Angiotensin-neprilysin inhibition versus enalapril in heart failure.
No top-level findings curated for this source.
PMID:31535829
Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction.
No top-level findings curated for this source.
No top-level findings curated for this source.
DOI:10.3390/biomedicines12081643
Risk Assessment and Personalized Treatment Options in Inherited Dilated Cardiomyopathies: A Narrative Review
No top-level findings curated for this source.