Dilated Cardiomyopathy 1P

Genetic MONDO:0012362 Pathograph 38 Show in embeddings browser Dilated Cardiomyopathy Genetic Disorder

Dilated cardiomyopathy 1P is the Mendelian designation for cardiomyopathy caused by germline variants in PLN, which encodes phospholamban, the 52-amino-acid sarcoplasmic reticulum membrane protein that reversibly inhibits the cardiac calcium pump SERCA2a. The primary lesion is therefore in sarcoplasmic-reticulum calcium reuptake -- the relaxation arm of excitation-contraction coupling -- and not in the sarcomere, which separates this entry mechanistically from the sarcomeric and cytoskeletal dilated cardiomyopathies. Contemporary practice increasingly calls the disease PLN-related cardiomyopathy because carriers may present with dilated cardiomyopathy, with a left-dominant arrhythmogenic cardiomyopathy, or with ventricular arrhythmia and subepicardial fibrosis while chamber dimensions are still normal. The PLN alleles are not mechanistically interchangeable and this entry does not merge them. p.Arg14del (c.40_42delAGA, "R14del"), a Dutch and Greek founder variant and by far the best-characterized allele, superinhibits SERCA2a in a way that protein kinase A phosphorylation cannot relieve, and additionally mislocalizes phospholamban into malformed sarco/endoplasmic-reticulum clusters that impair autophagic flux. p.Arg9Cys acts differently: it does not itself inhibit SERCA2a but sequesters protein kinase A, blocking phosphorylation of the wild-type phospholamban in trans. The truncating p.Leu39Ter allele is a true null in which phospholamban protein is essentially absent -- heterozygotes are hypertrophic with preserved contractility, while homozygotes develop lethal dilated cardiomyopathy, the inverse of the benign phenotype of the PLN-null mouse. R14del carries a high arrhythmic burden that drives defibrillator decisions on a variant-specific risk model rather than on ejection fraction alone.

Ask OpenScientist

Ask a research question about Dilated Cardiomyopathy 1P. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
15
Pathophys.
14
Phenotypes
2
Hypotheses
2
Gaps
38
Pathograph
1
Genes
3
Variants
5
Medical Actions
3
Trials
3
Models
4
References
1
Deep Research
🏷

Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal dominant HP:0000006
The common disease alleles -- p.Arg14del, p.Arg9Cys, p.Arg25Cys -- are heterozygous and act dominantly, with incomplete, age-dependent penetrance and markedly variable expressivity within a single family. The truncating p.Leu39Ter allele is the exception: heterozygotes show hypertrophy without contractile impairment, and only homozygotes develop lethal dilated cardiomyopathy, so that allele behaves recessively for the dilated phenotype.
Autosomal dominant inheritance Penetrance: INCOMPLETE
Show evidence (3 references)
PMID:16432188 SUPPORT Human Clinical
"By middle age, heterozygous individuals developed left ventricular dilation, contractile dysfunction, and episodic ventricular arrhythmias, with overt heart failure in some cases."
Establishes that R14del heterozygotes are affected, which is what makes the allele dominant, and dates typical onset to middle age.
PMID:12639993 SUPPORT Human Clinical
"The heterozygous individuals exhibited hypertrophy without diminished contractile performance. Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27."
Documents the exception to dominant inheritance: the truncating L39stop allele produces the dilated phenotype only in homozygotes.
PMID:37144056 SUPPORT Human Clinical
"Disease penetrance is incomplete and age-dependent, with symptoms developing more often within the fifth decade"
States the qualitative penetrance value curated here and dates symptom onset, without asserting a cumulative figure.
◈

Mechanistic Hypotheses

2
SERCA2a Superinhibition Model
pln_serca_superinhibition CANONICAL
Evidence balance 1 support
The original and long-dominant model, and the one the calcium arm of this entry's pathograph is built on: mutant phospholamban chronically suppresses SERCA2a activity in a manner that protein kinase A phosphorylation cannot relieve, so sarcoplasmic-reticulum calcium reuptake is persistently impaired and contractile and electrical dysfunction follow. It originates in the coexpression experiments that accompanied the discovery of the R14del allele in 2006.
Pathograph links
PLN Regulatory Domain Variant -> Non-Reversible SERCA2a Superinhibition DIRECT R14del branch.
Non-Reversible SERCA2a Superinhibition -> Impaired Sarcoplasmic Reticulum Calcium Reuptake DIRECT
Show evidence (1 reference)
PMID:16432188 SUPPORT In Vitro
"Thus, by chronic suppression of sarcoplasmic reticulum Ca(2+)-ATPase activity, the nonreversible superinhibitory function of mutant PLN-R14Del may lead to inherited dilated cardiomyopathy and premature death in both humans and mice."
States the canonical model in full, from sustained pump suppression through to the clinical phenotype.
Sarco/Endoplasmic Reticulum Malformation and Proteostasis Model
pln_ser_malformation EMERGING
Evidence balance 1 support 1 refute
A competing, non-mutually-exclusive model holding that the primary lesion is abnormal phospholamban distribution and malformed sarco/endoplasmic-reticulum membrane architecture, with the downstream proteostatic and autophagic failure that follows, rather than altered SERCA2a kinetics. Two observations drive it: the direction and magnitude of the R14del effect on SERCA activity is disputed across systems, and the hallmark perinuclear structures turn out on close inspection to be clustered membrane rather than protein aggregate. The distinction is not academic - it decides whether therapeutic effort should go to the SERCA axis or to correcting membrane architecture and autophagic flux. Both arms are curated as parallel branches in this entry's pathograph because the relative contribution is unsettled, not because both are established.
Pathograph links
PLN Regulatory Domain Variant -> Phospholamban Mislocalization and Sarco-Endoplasmic Reticulum Disorganization DIRECT R14del branch running in parallel with the calcium-handling branch.
Phospholamban Mislocalization and Sarco-Endoplasmic Reticulum Disorganization -> Impaired Autophagic Flux DIRECT
Show evidence (2 references)
PMID:39297138 SUPPORT Other
"Strategies targeting sarco/endoplasmic reticulum malformation may, therefore, prove more effective than SERCA activity modulation."
States the therapeutic consequence that distinguishes this model from the canonical one, which is why the two are curated as separate hypothesis groups.
PMID:39297138 REFUTE Other
"However, recent studies raised controversy regarding the effect of PLN-R14del on SERCA activity"
Cited against the canonical superinhibition model: the SERCA effect that model rests on is itself contested.
?

Discussions and Knowledge Gaps

2
Phospholamban ablation is benign, even beneficial, in the mouse but lethal in humans. Which species is informative for the consequences of reducing phospholamban, and what does that mean for silencing and gene-editing strategies that lower mutant or total PLN?
HUMAN MODEL MISMATCH pln_null_mouse_human_divergence
Attached to
pathophysiology#Loss of Phospholamban Protein animal_models#Mouse
This is a mismatch rather than a gap: the murine evidence is abundant and unambiguous, it simply points the opposite way. Mice lacking phospholamban show enhanced sarcoplasmic-reticulum function and normal lifespan, which historically made PLN suppression look like an attractive heart-failure target; the human L39stop homozygotes instead required transplantation in their teens and twenties. The discrepancy matters directly for therapy, because the leading experimental approaches in R14del disease act by reducing mutant or total phospholamban, and the safety margin for depletion cannot be read off the mouse. Scope note: animal-model entity references resolve on species, so the `animal_models#Mouse` reference above matches both mouse models in this entry. The model at issue here is the phospholamban-null mouse, not the R14del knock-in.
Show evidence (1 reference)
PMID:12639993 SUPPORT Human Clinical
"In contrast to reported benefits of PLN ablation in mouse heart failure, humans lacking PLN develop lethal dilated cardiomyopathy."
States the mismatch directly, in the same sentence, for both species.
What determines whether a PLN R14del carrier remains asymptomatic into their seventies or reaches end-stage heart failure in their twenties? No genetic, epigenetic, or environmental modifier is validated.
KNOWLEDGE GAP pln_r14del_penetrance_modifiers
Attached to
genetic#PLN clinical_trials#NCT04978987
Penetrance is incomplete and age-dependent and expressivity varies widely within a single family carrying one founder allele, so the variance cannot be attributed to allelic heterogeneity. Without a modifier, risk stratification has to rest entirely on acquired phenotypic markers - ejection fraction, ectopic burden, T-wave changes, QRS voltage - which is why the arrhythmia risk model looks the way it does. A completed multi-omics cohort was designed around this question and had not identified a modifier at the time of its registration.
Show evidence (1 reference)
clinicaltrials:NCT04978987 SUPPORT Human Clinical
"Within the same family, patients can present either with over heart failure in their 20's or completely asymptomatic until at least their 70's. So far, no modifiers have been identified."
Establishes both the magnitude of the unexplained variability and that no modifier was known when the cohort was designed to look for one.
⚙

Pathophysiology

15
PLN Regulatory Domain Variant
The initiating lesion is a germline variant in PLN. Pathogenic alleles cluster in the cytoplasmic regulatory domain that contacts SERCA2a and carries the Ser16/Thr17 phosphorylation sites (p.Arg9Cys, p.Arg14del, p.Arg25Cys), or truncate the protein within transmembrane domain II (p.Leu39Ter). The downstream branches are allele-specific and are modelled separately rather than merged, because the three classes perturb the SERCA2a-phospholamban regulatory couple in different directions.
Sarco/Endoplasmic Reticulum Malformation and Proteostasis Model SERCA2a Superinhibition Model
ventricular cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ventricular cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
phospholamban inhibitor activity toward the SERCA2a calcium pump GO:0004857 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves phospholamban inhibitor activity toward the SERCA2a calcium pump, annotated with enzyme inhibitor activity (GO:0004857). GO:0004857 is a molecular function from the Gene 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.
Downstream
Non-Reversible SERCA2a Superinhibition R14del branch. SERCA2a Superinhibition Model
Protein Kinase A Sequestration by Mutant Phospholamban R9C branch.
Loss of Phospholamban Protein Truncating and null allele branch.
Phospholamban Mislocalization and Sarco-Endoplasmic Reticulum Disorganization R14del branch running in parallel with the calcium-handling branch. Sarco/Endoplasmic Reticulum Malformation and Proteostasis Model
Show evidence (2 references)
PMID:37144056 SUPPORT Other
"PLN is a 52 amino acid transmembrane protein that modulates Ca2+ homeostasis and cardiac contractility through reversible inhibition of the sarcoplasmic reticulum (SR) calcium ATPase (SERCA2a) activity."
Establishes the normal function that the disease alleles disrupt: reversible inhibition of SERCA2a, which places the lesion in calcium reuptake rather than in force generation.
PMID:40556736 SUPPORT Other
"Variants in the PLN gene have been identified in patients with a wide range of phenotypes, including hypertrophic, dilated, and arrhythmogenic cardiomyopathies."
Supports treating the PLN allelic series as heterogeneous rather than as one uniform phenotype, which is why the branches below are kept separate.
Non-Reversible SERCA2a Superinhibition
In the R14del allele the mutant phospholamban superinhibits SERCA2a, and critically the inhibition is not relieved by protein kinase A phosphorylation. Beta-adrenergic stimulation therefore cannot restore calcium reuptake, so the brake on the pump becomes constitutive rather than regulated. Note that the magnitude and even the direction of the R14del effect on SERCA activity is disputed in more recent work; this node states the classical finding and the disagreement is recorded as a mechanistic hypothesis.
SERCA2a Superinhibition Model
constitutive inhibition of the SERCA2a calcium pump GO:1901895 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased constitutive inhibition of the SERCA2a calcium pump, annotated with negative regulation of ATPase-coupled calcium transmembrane transporter activity (GO:1901895). GO:1901895 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Impaired Sarcoplasmic Reticulum Calcium Reuptake SERCA2a Superinhibition Model
Show evidence (1 reference)
PMID:16432188 SUPPORT In Vitro
"The dominant effect of the PLN-R14Del mutation could not be fully removed, even upon phosphorylation by protein kinase A."
This is the defining property of the node: the inhibition is non-reversible, so the physiological release mechanism is unavailable.
Protein Kinase A Sequestration by Mutant Phospholamban
The R9C allele reaches the same physiological endpoint by a different route. Mutant phospholamban does not inhibit SERCA2a itself; it traps protein kinase A, which prevents phosphorylation of the wild-type phospholamban produced from the normal allele. The wild-type protein is therefore locked in its inhibitory, dephosphorylated state, and calcium transient decay slows.
sequestration of cAMP-dependent protein kinase by mutant phospholamban GO:0051018 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased sequestration of cAMP-dependent protein kinase by mutant phospholamban, annotated with protein kinase A binding (GO:0051018). GO:0051018 is a molecular function from the Gene Ontology. ↑ INCREASED
Downstream
Impaired Sarcoplasmic Reticulum Calcium Reuptake
Show evidence (1 reference)
PMID:12610310 SUPPORT In Vitro
"which blocked PKA-mediated phosphorylation of wild-type PLN and in turn delayed decay of calcium transients in myocytes"
Establishes the in-trans mechanism specific to R9C and its immediate functional consequence for calcium handling.
Loss of Phospholamban Protein
The truncating p.Leu39Ter allele removes phospholamban rather than dysregulating it. No stable protein is made, what little is expressed is misrouted away from the sarcoplasmic reticulum, and SERCA2a is left uninhibited. This is the opposite perturbation from R14del superinhibition, and it is the reason this node feeds calcium dyshomeostasis directly rather than through the impaired-reuptake node. The human phenotype inverts the mouse: PLN ablation is well tolerated in mice but lethal in people.
loss of phospholamban inhibition of SERCA2a GO:1901895 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves loss of phospholamban inhibition of SERCA2a, annotated with negative regulation of ATPase-coupled calcium transmembrane transporter activity (GO:1901895), qualified as loss of function. GO:1901895 is a biological process from the Gene Ontology. ⇓ LOSS OF FUNCTION
Animal models
PLN-null mouse (comparative) Mouse fails to recapitulate The mouse does not reproduce the human consequence of absent phospholamban.
Downstream
Dysregulated Cardiomyocyte Calcium Homeostasis
Show evidence (1 reference)
PMID:12639993 SUPPORT In Vitro
"where PLN was expressed, it was misrouted to the cytosol or plasma membrane"
Documents the mislocalization that accompanies the loss of stable phospholamban expression in the truncating allele.
Impaired Sarcoplasmic Reticulum Calcium Reuptake
Sustained inhibition of SERCA2a, whether by non-reversible superinhibition (R14del) or by loss of the phosphorylation release step (R9C), slows removal of cytosolic calcium into the sarcoplasmic reticulum during diastole. This is the shared convergence point of the two dominant missense branches.
sarcoplasmic reticulum calcium ion transport GO:0070296 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sarcoplasmic reticulum calcium ion transport (GO:0070296). GO:0070296 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Dysregulated Cardiomyocyte Calcium Homeostasis
Show evidence (1 reference)
PMID:33020536 SUPPORT INDIRECT Human Clinical
"Mutations on PLN result in intracellular calcium disorder, myocardial contraction defect, and eventually heart failure and/or malignant ventricular arrhythmia."
States the calcium-reuptake defect as the mechanistic consequence of PLN mutation and names the two clinical endpoints it drives.
Phospholamban Mislocalization and Sarco-Endoplasmic Reticulum Disorganization
A second consequence of the R14del allele, independent of the pump kinetics. Mutant phospholamban is abnormally distributed and the sarco/endoplasmic reticulum membrane becomes locally disorganized into malformed clusters. This is now considered a prominent, possibly primary, disease mechanism rather than a downstream epiphenomenon of calcium dysregulation.
Sarco/Endoplasmic Reticulum Malformation and Proteostasis Model
ventricular cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ventricular cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Downstream
Impaired Autophagic Flux Sarco/Endoplasmic Reticulum Malformation and Proteostasis Model
Show evidence (1 reference)
PMID:39297138 SUPPORT Other
"Importantly, a recent in-depth investigation revealed that these aggregates consist of malformed sarco/endoplasmic reticulum (S/ER) clusters."
Reframes the hallmark structures as malformed membrane clusters rather than simple protein aggregation, which is the claim of this node.
Impaired Autophagic Flux
R14del blocks autophagosome-lysosome fusion through aberrant recruitment of membrane-fusion machinery, itself partly mediated by altered calcium homeostasis. The degradative route that would clear the abnormal phospholamban-containing material is therefore unavailable, which is why the material accumulates.
autophagosome-lysosome fusion GO:0061909 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased autophagosome-lysosome fusion (GO:0061909). GO:0061909 is a biological process from the Gene Ontology. ↓ DECREASED autophagy GO:0006914 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased autophagy (GO:0006914). GO:0006914 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Perinuclear Phospholamban-Positive Deposits
Show evidence (1 reference)
PMID:39527246 SUPPORT In Vitro
"Mechanistically, this defect is linked to aberrant recruitment of key membrane fusion proteins to autophagosomes, which is mediated in part by changes in Ca2+ homeostasis."
Gives the molecular basis of the fusion block and links it back to the calcium branch of the mechanism.
Perinuclear Phospholamban-Positive Deposits
Perinuclear phospholamban-immunoreactive material is the histopathological hallmark of R14del cardiomyopathy and is not seen in desmosomal arrhythmogenic cardiomyopathy, ischemic cardiomyopathy, or control hearts. It is specific enough to be diagnostically suggestive on explanted myocardium.
Animal models
PLN-R14del knock-in mouse Mouse recapitulates Homozygous animals reproduce the hallmark phospholamban-positive material seen in human myocardium.
Downstream
Endoplasmic Reticulum Stress and Unfolded Protein Response Activation
Show evidence (1 reference)
PMID:33928785 SUPPORT Human Clinical
"PLN immunolabeling revealed perinuclear aggregations in PLN R14del tissues (7±2%) but were absent in ARVC, ICM, and control hearts"
Documents the deposits in human R14del myocardium and their absence from the two main differential diagnoses, establishing disease specificity.
Endoplasmic Reticulum Stress and Unfolded Protein Response Activation
The unfolded protein response is activated in R14del cardiomyocytes and in patient myocardium. Its role is compensatory, not pathogenic: silencing any of the three UPR branches worsens contractility, and pharmacological UPR activation improves it. The node is therefore drawn as a protective response embedded in the injury cascade, not as a cause of the contractile deficit.
response to endoplasmic reticulum stress GO:0034976 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to endoplasmic reticulum stress (GO:0034976). GO:0034976 is a biological process from the Gene Ontology. ↑ INCREASED
Experimental models
Isogenic PLN-R14del hiPSC-cardiomyocyte and 3D engineered heart tissue pair IPSC DERIVED MODEL Single-cell RNA sequencing of the isogenic pair identified UPR induction as the transcriptional signature of the variant, and the same activation was confirmed in myocardium from PLN R14del patients.
Downstream
Cardiomyocyte Contractile Dysfunction Drawn as indirect and partial: the UPR restrains the contractile deficit rather than producing it, so the arrow records that this compensatory node sits on the path to contractile failure without being its cause.
Show evidence (1 reference)
PMID:33928785 SUPPORT In Vitro
"Silencing of each of the 3 main UPR signaling branches (IRE1, ATF6, or PERK) by siRNA exacerbated the contractile dysfunction of PLN R14del hiPSC-CMs."
Loss-of-function across all three branches worsening contractility is what establishes the response as protective rather than injurious.
Dysregulated Cardiomyocyte Calcium Homeostasis
The convergence point of all allele branches. Cytosolic calcium handling across the contraction-relaxation cycle is disordered, whether from too much SERCA2a inhibition (R14del, R9C) or from none at all (null alleles). Both directions are maladaptive in the human heart.
calcium ion transmembrane transport GO:0070588 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated calcium ion transmembrane transport (GO:0070588). GO:0070588 is a biological process from the Gene Ontology. ↕ DYSREGULATED regulation of cardiac muscle contraction GO:0055117 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated regulation of cardiac muscle contraction (GO:0055117). GO:0055117 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Downstream
Cardiomyocyte Contractile Dysfunction
Arrhythmogenic Substrate Formation Disordered calcium cycling supports triggered activity independently of structural remodeling, which is one reason arrhythmia can precede dilation.
Show evidence (1 reference)
PMID:37144056 SUPPORT Other
"In its dephosphorylated state, PLN interacts with SERCA2a and inhibits its affinity for Ca2+"
Establishes the regulatory couple whose disturbance defines this node, and the state the mutant alleles lock it into.
Cardiomyocyte Contractile Dysfunction
Reduced force generation by the cardiomyocyte, secondary to the calcium-handling lesion and the proteostatic burden. It is reproducible in isogenic human iPSC cardiomyocytes differing only at the PLN locus, and in both two-dimensional monolayers and three-dimensional engineered heart tissue.
ventricular cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ventricular cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
regulation of cardiac muscle contraction GO:0055117 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased regulation of cardiac muscle contraction (GO:0055117). GO:0055117 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
Isogenic PLN-R14del hiPSC-cardiomyocyte and 3D engineered heart tissue pair IPSC DERIVED MODEL R14del hiPSC-CMs show reduced contractility against their isogenic controls in both culture formats, which is the in-vitro counterpart of this node.
Isogenic PLN-R14del hiPSC-cardiomyocyte and 3D engineered heart tissue pair IPSC DERIVED MODEL Pharmacological activation of the UPR with BiP inducer X partially reversed the contractile deficit, which is the experiment that makes the proteostatic arm a candidate therapeutic target rather than an epiphenomenon.
Downstream
Cardiomyocyte Injury and Death
Left ventricular systolic dysfunction
Ventricular Dilatation and Pump Failure
Show evidence (1 reference)
PMID:32555305 SUPPORT Model Organism
"Homozygous PLN-R14del mice exhibited an accelerated phenotype including cardiac dilatation, contractile dysfunction, decreased ECG potentials, high susceptibility to ex vivo induced arrhythmias, myocardial fibrosis, PLN protein aggregation, and early mortality."
Contractile dysfunction appears in the knock-in mouse alongside the other nodes of this chain, supporting it as a genotype-driven consequence.
Cardiomyocyte Injury and Death
Mechanism confidence: Hypothetical
Persistent contractile and proteostatic stress leads to cardiomyocyte injury and loss, which is the trigger for the replacement fibrosis that follows. Direct quantification of cardiomyocyte death in PLN disease is limited; the node is inferred from the histological end state of fibrofatty replacement in explanted myocardium, and is flagged accordingly.
ventricular cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves ventricular cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
cardiac muscle cell apoptotic process GO:0010659 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cardiac muscle cell apoptotic process (GO:0010659). GO:0010659 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Myocardial Replacement Fibrosis
Show evidence (1 reference)
PMID:39297138 SUPPORT Other
"At the histological level, severe cardiac fibrosis or fibrofatty-replacement is observed in tissues from patients with end-stage heart failure due to PLN-R14del cardiomyopathy."
Replacement fibrosis is the histological signature of antecedent myocyte loss, which is the basis for inferring this node.
Myocardial Replacement Fibrosis
Fibrous, sometimes fibrofatty, replacement of lost myocardium. In PLN disease it has a characteristic distribution: subepicardial late gadolinium enhancement in the lateral wall of the left ventricle, sometimes with linear mid-wall septal enhancement, together with elevated extracellular volume on T1 mapping. Critically, it is detectable in young carriers whose ventricular structure and function are still normal, which is what makes cardiac magnetic resonance an early rather than a confirmatory test.
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.
extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ↑ INCREASED
left ventricular lateral wall UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in left ventricular lateral wall, annotated with heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Arrhythmogenic Substrate Formation Patchy fibrosis interposed between surviving myocyte bundles creates the conduction heterogeneity that supports reentry.
Myocardial fibrosis
Ventricular Dilatation and Pump Failure
Show evidence (2 references)
PMID:33020536 SUPPORT Human Clinical
"members underwent cardiac magnetic resonance (CMR) examination showed a strikingly similar pattern of late gadolinium enhancement (LGE)-Sub-epicardial involvement in the left ventricular (LV) lateral wall with or without linear mid-wall enhancement in the interventricular septum. The former one..."
Establishes both the characteristic distribution of the fibrosis and its occurrence before any structural or functional abnormality.
PMID:33020536 SUPPORT Human Clinical
"Meanwhile, T1 mapping also found significantly increased extracellular volume (ECV) in PLN-R14del carriers."
Independent, quantitative tissue-characterization support for expanded interstitium in carriers.
Arrhythmogenic Substrate Formation
The combination of patchy replacement fibrosis and disordered calcium cycling produces conduction heterogeneity and triggered activity. This node is the reason the disease is managed as an arrhythmogenic cardiomyopathy: malignant ventricular arrhythmia and sudden death can occur while ejection fraction is still preserved, so conventional ejection-fraction-based defibrillator thresholds under-detect risk.
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
PLN-R14del knock-in mouse Mouse recapitulates Heterozygous animals reproduce the arrhythmic susceptibility that defines the human disease.
Downstream
Ventricular arrhythmia
Ventricular tachycardia
Ventricular fibrillation
Premature ventricular contractions
Sudden cardiac death
Syncope
Show evidence (2 references)
PMID:22820313 SUPPORT Human Clinical
"R14del+ patients diagnosed with DCM showed an arrhythmogenic phenotype, and SCD at young age can be the presenting symptom. These findings support the concept of 'arrhythmogenic cardiomyopathy'."
Establishes that the arrhythmic substrate is a defining feature of the disease and can manifest before, or instead of, a heart-failure presentation.
PMID:32555305 SUPPORT Model Organism
"Heterozygous PLN-R14del mice demonstrated increased susceptibility to ex vivo induced arrhythmias, and cardiomyopathy at 18 months of age, which was not accelerated by isoproterenol infusion."
Shows inducible arrhythmia susceptibility in the heterozygous knock-in, the genotype that matches human carriers.
Ventricular Dilatation and Pump Failure
Progressive myocyte loss and remodeling produce chamber dilatation with falling ejection fraction, and ultimately clinical heart failure requiring mechanical circulatory support or transplantation. In PLN disease this endpoint frequently arrives after, not before, the arrhythmic manifestations.
heart contraction GO:0060047 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal heart contraction (GO:0060047). GO:0060047 is a biological process from the Gene Ontology. ⚠ ABNORMAL
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
Dilated cardiomyopathy
Congestive heart failure
Exercise intolerance
Exertional dyspnea
Show evidence (1 reference)
PMID:16432188 SUPPORT Human Clinical
"By middle age, heterozygous individuals developed left ventricular dilation, contractile dysfunction, and episodic ventricular arrhythmias, with overt heart failure in some cases."
Documents dilatation, contractile failure, and overt heart failure as the organ-level endpoint in R14del carriers.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Dilated Cardiomyopathy 1P Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

14
Cardiovascular 12
Ventricular arrhythmia FREQUENT HP:0004308 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular arrhythmia (HP:0004308). HP:0004308 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34113975 SUPPORT Human Clinical
"During a median follow-up of 4.3 years (IQR 1.7-7.4), 72 (10.6%) carriers experienced malignant VA."
Quantifies the incidence of malignant ventricular arrhythmia in the largest published carrier cohort.
Ventricular tachycardia HP:0004756 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular tachycardia (HP:0004756). HP:0004756 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34113975 SUPPORT Human Clinical
"Malignant VA was defined as sustained VA, appropriate ICD intervention, or (aborted) sudden cardiac death."
Defines sustained ventricular arrhythmia as a component of the outcome observed in this cohort.
Ventricular fibrillation HP:0001663 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular fibrillation (HP:0001663). HP:0001663 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34113975 SUPPORT Human Clinical
"Appropriate ICD intervention is classified as ICD therapy (antitachycardia pacing or shock) for VF/VT."
Records ventricular fibrillation among the treated arrhythmic events in the carrier cohort.
Premature ventricular contractions HP:0006682 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Premature ventricular contraction (HP:0006682). HP:0006682 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34113975 SUPPORT Human Clinical
"Significant predictors were left ventricular ejection fraction, premature ventricular contraction count/24 h, amount of negative T waves, and presence of low-voltage electrocardiogram."
Establishes ventricular ectopic count as a measured and prognostically significant phenotype in carriers.
Sudden cardiac death HP:0001645 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sudden cardiac death (HP:0001645). HP:0001645 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22820313 SUPPORT Human Clinical
"The average age of 26 family members who died of SCD was 37.7 years."
Documents sudden cardiac death at a mean age in the fourth decade among relatives of R14del index patients.
Syncope HP:0001279 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Syncope (HP:0001279). HP:0001279 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30806910 SUPPORT INDIRECT Human Clinical
"One patient suffered syncope during physical activity, and subsequently passed away due to ventricular tachycardia storm."
Records syncope in an R14del carrier followed by death from ventricular tachycardia storm, which is the arrhythmic mechanism this phenotype attributes it to. Indirect on two counts: the causal link between the syncopal episode and the arrhythmia is inferred from the sequence rather than captured on a rhythm recording, and the red-flag surveillance role is a clinical inference from the outcome rather than a statement in the cohort.
Dilated cardiomyopathy FREQUENT HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644), qualified as course progressive. HP:0001644 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:16432188 SUPPORT Human Clinical
"Through genetic screening of dilated cardiomyopathy patients, we identified a previously uncharacterized deletion of arginine 14 (PLN-R14Del) in the coding region of the phospholamban (PLN) gene in a large family with hereditary heart failure."
Establishes dilated cardiomyopathy as the presenting phenotype in the family in which the R14del allele was identified.
Left ventricular systolic dysfunction HP:0025169 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular systolic dysfunction (HP:0025169). HP:0025169 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34113975 SUPPORT Human Clinical
"Significant predictors were left ventricular ejection fraction, premature ventricular contraction count/24 h, amount of negative T waves, and presence of low-voltage electrocardiogram."
Records reduced ejection fraction as a measured phenotype and a component of the variant-specific risk model.
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), qualified as course progressive. HP:0001635 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:22820313 SUPPORT Human Clinical
"Compared with R14del- DCM patients, R14del+ DCM patients more often demonstrated appropriate implantable cardioverter defibrillator discharge (47 % vs. 10 % , P < 0.001), cardiac transplantation (18 % vs. 2 % , P < 0.001)"
The nine-fold excess of cardiac transplantation over genotype-negative dilated cardiomyopathy quantifies the end-stage heart-failure burden of the allele.
Decreased QRS voltage FREQUENT HP:0025077 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased QRS voltage (HP:0025077). HP:0025077 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22820313 SUPPORT Human Clinical
"A low voltage electrocardiogram was present in 46 % of R14del carriers."
Gives the observed frequency of low QRS voltage among carriers, which supports the FREQUENT band.
T-wave inversion HP:0010872 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is T-wave inversion (HP:0010872). HP:0010872 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34113975 SUPPORT Human Clinical
"amount of negative T waves, and presence of low-voltage electrocardiogram"
Establishes negative T waves as a counted electrocardiographic phenotype with independent prognostic weight in carriers.
Myocardial fibrosis HP:0001685 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myocardial fibrosis (HP:0001685). HP:0001685 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33020536 SUPPORT Human Clinical
"These findings highlight the special role of CMR to phenotyping PLN-induced cardiomyopathy patients and distinguish them from other types of cardiomyopathy."
Supports the fibrosis pattern as characteristic enough to separate PLN disease from other cardiomyopathies on imaging.
Respiratory 1
Exertional dyspnea HP:0002875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exertional dyspnea (HP:0002875). HP:0002875 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12610310 SUPPORT INDIRECT Human Clinical
"an inherited human dilated cardiomyopathy with refractory congestive heart failure is caused by a dominant Arg --> Cys missense mutation at residue 9 (R9C) in phospholamban (PLN)"
Cited for the refractory congestive heart failure syndrome of which exertional dyspnea is the cardinal symptom; indirect, because the abstract names the syndrome rather than the individual symptom.
Constitutional 1
Exercise intolerance HP:0003546 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exercise intolerance (HP:0003546). HP:0003546 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33020536 SUPPORT INDIRECT Human Clinical
"The proband II6 is a 60-year-old woman, who suffered from activity chest tightness for 10 years and the symptom had aggravated for recent 2 years."
Documents activity-limited symptoms in an R14del carrier over a decade, with progression, alongside the same family's fatigue and exertional breathlessness. Indirect, because the study records exertional symptoms clinically rather than measuring aerobic capacity.
🧬

Genetic Associations

1
PLN
Gene: PLN hgnc:9080 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PLN (hgnc:9080). hgnc:9080 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:40556736 SUPPORT Other
"The growing number of identified variants highlights the previously underappreciated role of PLN in cardiac pathophysiology."
Supports curating PLN as a gene with an expanding allelic series rather than a single-variant locus.
PMID:37144056 SUPPORT Other
"The PLN-R14del variant in specific is recognized as the cause in an increasing number of patients worldwide"
Establishes the gene-disease relationship as causative and identifies which allele accounts for most of the recognized burden.
Variants (3)
PLN p.Arg14del Pathogenic
in-frame deletion
NM_002667.5:c.40_42delAGA, p.(Arg14del); also written R14del or R14. An in-frame single-codon deletion in the cytoplasmic regulatory domain and the best-studied PLN allele, with independent founder lineages in the northern Netherlands and in Greece. It produces SERCA2a superinhibition that protein kinase A phosphorylation cannot relieve, and in parallel mislocalizes phospholamban into malformed sarco/endoplasmic-reticulum clusters that block autophagic flux. Clinically it carries a high arrhythmic burden, and it is the only allele for which a validated variant-specific arrhythmia risk model exists.
Show evidence (2 references)
PMID:16432188 SUPPORT In Vitro
"Coexpression of the normal and mutant-PLN in HEK-293 cells resulted in sarcoplasmic reticulum Ca(2+)-ATPase superinhibition."
Coexpression of normal with mutant protein producing superinhibition is the experiment establishing the dominant-negative character of this specific allele.
PMID:22820313 SUPPORT Human Clinical
"Haplotype analysis revealed a common founder, estimated to be between 575 and 825 years old."
Establishes the founder status of this allele, which is why cohort-derived estimates for it are population-specific rather than general to PLN disease.
PLN p.Arg9Cys Pathogenic
missense
A missense allele at residue 9, reported in an inherited dilated cardiomyopathy with refractory congestive heart failure. Its mechanism is distinct from R14del: the mutant protein does not itself inhibit SERCA2a but sequesters protein kinase A, preventing phosphorylation of the wild-type phospholamban made from the normal allele. The inhibitory brake is therefore applied in trans, by the wild-type protein, rather than by the mutant.
Show evidence (2 references)
PMID:12610310 SUPPORT In Vitro
"Cellular and biochemical studies revealed that, unlike wild-type PLN, PLN(R9C) did not directly inhibit SERCA2a. Rather, PLN(R9C) trapped protein kinase A (PKA)"
States the allele-specific mechanism explicitly and contrasts it with wild-type behaviour, which is the basis for curating R9C separately from R14del.
PMID:12610310 SUPPORT Model Organism
"Transgenic PLN(R9C) mice recapitulated human heart failure with premature death."
Model-organism support that this allele is sufficient to cause the heart-failure phenotype.
PLN p.Leu39Ter Pathogenic
nonsense
A nonsense allele (T116G, L39stop) truncating the protein within transmembrane domain II. It is a true null: essentially no stable phospholamban is produced, what little is made is misrouted away from the sarcoplasmic reticulum, and SERCA2a is left uninhibited. It is also the allele that breaks the dominant pattern - heterozygotes show hypertrophy with preserved contractility, and only homozygotes develop dilated cardiomyopathy, requiring transplantation in adolescence or early adulthood. Human phospholamban deficiency is therefore lethal, the inverse of the well-tolerated PLN-null mouse.
Show evidence (1 reference)
PMID:12639993 SUPPORT Human Clinical
"The heterozygous individuals exhibited hypertrophy without diminished contractile performance. Strikingly, both individuals homozygous for L39stop developed dilated cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and 27."
Establishes the recessive behaviour of this allele for the dilated phenotype, which is the reason it cannot be merged with the dominant missense alleles.
💊

Medical Actions

5
Guideline-Directed Heart Failure Pharmacotherapy
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
Platform: Small molecule
Standard heart-failure therapy for carriers with reduced ejection fraction. The evidence is extrapolated from general heart-failure trials rather than generated in PLN disease, and this is a real limitation: in the knock-in mouse neither eplerenone nor metoprolol improved cardiac function or survival, and a completed randomized trial of eplerenone in presymptomatic R14del carriers was run precisely because the question was open. No PLN-directed disease-modifying therapy is approved.
Mechanism Target:
Ventricular Dilatation and Pump Failure — Acts on the neurohormonal drive of adverse remodeling at the organ level, not on the calcium-handling lesion.
Show evidence (1 reference)
PMID:32555305 REFUTE Model Organism
"Neither eplerenone nor metoprolol administration improved cardiac function or survival."
A negative result in the genotype-matched mouse, cited to record that standard heart-failure drugs did not modify the disease in that model.
Show evidence (1 reference)
PMID:32555305 SUPPORT INDIRECT Model Organism
"Administration of standard heart failure therapy did not rescue the phenotype, underscoring the need for better understanding of the pathophysiology of PLN-R14del-associated cardiomyopathy."
Supports curating this treatment as symptomatic rather than disease-modifying; indirect, because the result is from the mouse model rather than a carrier trial.
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). NCIT:C80435 is a clinical intervention from the NCI Thesaurus. Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435
Platform: Device
Defibrillator implantation for sudden-death prevention. The decision in R14del carriers is deliberately not made on ejection fraction alone: a variant-specific model combining ejection fraction, 24-hour ventricular ectopic count, number of negative T waves, and low QRS voltage discriminates arrhythmic risk substantially better (C-statistic 0.83) than the earlier generic PLN model (0.68). This is the single most consequential way PLN disease is managed differently from the sarcomeric dilated cardiomyopathies.
Mechanism Target:
Arrhythmogenic Substrate Formation — Does not modify the substrate; terminates the arrhythmias it generates.
Show evidence (1 reference)
PMID:22820313 SUPPORT Human Clinical
"R14del+ DCM patients more often demonstrated appropriate implantable cardioverter defibrillator discharge (47 % vs. 10 % , P < 0.001)"
Appropriate discharges in nearly half of carriers, against a tenth of genotype-negative patients, evidences the device acting on a genotype-specific arrhythmic substrate.
Show evidence (2 references)
PMID:34113975 SUPPORT Human Clinical
"This study aims to improve risk stratification for primary prevention implantable cardioverter defibrillator (ICD) implantation by developing a new mutation-specific prediction model for malignant ventricular arrhythmia (VA) in phospholamban (PLN) p.Arg14del mutation carriers."
Establishes that defibrillator selection in this disease is driven by a variant-specific model rather than generic criteria.
PMID:34113975 SUPPORT Human Clinical
"The multivariable model had an excellent discriminative ability {C-statistic 0.83 [95% confidence interval (CI) 0.78-0.88]}. Applying the existing PLN risk model to the complete cohort yielded a C-statistic of 0.68 (95% CI 0.61-0.75)."
Quantifies the gain of the variant-specific model over the generic one, which is the justification for using it.
Catheter Ablation of Ventricular Tachycardia
Action: cardiac catheter ablationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cardiac catheter ablation, annotated with Cardiac Ablation (NCIT:C100068). NCIT:C100068 is a clinical intervention from the NCI Thesaurus. Ontology label: Cardiac Ablation NCIT:C100068
Platform: Surgery
Considered for recurrent monomorphic ventricular tachycardia or repeated defibrillator shocks. It addresses reentry around the fibrotic substrate and is adjunctive to, not a substitute for, defibrillator therapy.
Mechanism Target:
Arrhythmogenic Substrate Formation — Interrupts reentrant circuits within the fibrotic substrate.
Heart Transplantation
Action: Heart TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Heart Transplantation (NCIT:C15246). NCIT:C15246 is a clinical intervention from the NCI Thesaurus. NCIT:C15246
Platform: Surgery
Definitive therapy for end-stage disease, preceded in many carriers by durable mechanical circulatory support. R14del carriers with a dilated presentation reach transplantation far more often than genotype-negative patients with the same diagnosis.
Mechanism Target:
Ventricular Dilatation and Pump Failure — Replaces the failing organ; it does not act on any upstream node.
Show evidence (1 reference)
PMID:22820313 SUPPORT Human Clinical
"cardiac transplantation (18 % vs. 2 % , P < 0.001)"
Quantifies transplantation rates in carriers against genotype-negative dilated cardiomyopathy patients.
Genetic Counseling and Cascade Testing
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
First-degree relatives of a carrier are offered counseling and targeted testing for the familial variant, followed by longitudinal electrocardiography, ambulatory rhythm monitoring, echocardiography and periodic cardiac magnetic resonance if genotype-positive. Most carriers in published cohorts enter care through family screening rather than symptoms, which is what makes this the highest-yield intervention in the disease.
Show evidence (1 reference)
PMID:34113975 SUPPORT Human Clinical
"The majority of the final cohort (83%) were family members of an index patient and most subjects were asymptomatic at baseline (85%)."
Shows that cascade screening, not symptomatic presentation, is how most carriers are identified.
🔬

Diagnosis

2
Cardiac Magnetic Resonance Imaging
The modality that detects this disease before the ventricle dilates. Carriers show a characteristic sub-epicardial late-gadolinium-enhancement band in the left ventricular lateral wall, sometimes with linear mid-wall septal enhancement, and T1 mapping shows raised extracellular volume. Critically, the lateral-wall pattern is present in younger carriers whose ventricular structure and function are still completely normal, which is why this entry treats cardiac magnetic resonance as an early-detection tool rather than as confirmation of an already-evident cardiomyopathy.
cardiac magnetic resonance imaging with late gadolinium enhancement and T1 mapping NCIT:C137915 NCI Thesaurus (NCIT)
The cohort is a single large Chinese PLN-R14del family, so the pattern is well described but its sensitivity and specificity are not established.
Show evidence (2 references)
PMID:33020536 SUPPORT Human Clinical
"members underwent cardiac magnetic resonance (CMR) examination showed a strikingly similar pattern of late gadolinium enhancement (LGE)-Sub-epicardial involvement in the left ventricular (LV) lateral wall with or without linear mid-wall enhancement in the interventricular septum. The former one..."
Reports both the characteristic enhancement pattern and its presence in carriers with structurally normal ventricles, which is the basis for the early-detection claim.
PMID:33020536 SUPPORT Human Clinical
"These findings highlight the special role of CMR to phenotyping PLN-induced cardiomyopathy patients and distinguish them from other types of cardiomyopathy."
Supports cardiac magnetic resonance as the discriminating modality against other cardiomyopathies.
PLN Genetic Testing and Cascade Screening of Relatives
Molecular confirmation is what separates this entry from dilated cardiomyopathy in general, because the arrhythmia risk model and the management that follows from it are allele-specific rather than ejection-fraction-based. Identifying the variant in a proband converts the relatives' problem into a single predictive test, and most carriers in published series are ascertained this way rather than by presenting with symptoms.
PLN sequencing, with cascade testing of at-risk relatives NCIT:C15709 NCI Thesaurus (NCIT)
The supporting statement comes from a review rather than a diagnostic-accuracy study; no yield or performance figure is curated here because none was verifiable from the cached sources.
Show evidence (1 reference)
PMID:40556736 SUPPORT Human Clinical
"These advances underscore the importance of recognizing PLN's role in cardiac disease and the value of genetic testing for accurate diagnosis, prognosis, effective management, and early risk prediction for family members."
Supports genetic testing as the route to diagnosis, prognosis and risk prediction in relatives, which is the role this entry curates it in.
📈

Progression

3
Presymptomatic carrier with imaging-detectable substrate
Age: Second to fourth decade
The substrate is detectable on cardiac magnetic resonance before any echocardiographic or symptomatic abnormality, which is what makes imaging surveillance of known carriers worthwhile.
Show evidence (1 reference)
PMID:33020536 SUPPORT Human Clinical
"The former one can also present in younger PLN-R14del carriers despite completely normal LV structure and function."
Establishes a phase in which the lateral-wall enhancement is already present while ventricular structure and function are still normal.
Symptomatic cardiomyopathy
Age: Fifth decade onward
Show evidence (1 reference)
PMID:37144056 SUPPORT Human Clinical
"Disease penetrance is incomplete and age-dependent, with symptoms developing more often within the fifth decade"
Dates the onset of the symptomatic phase.
Arrhythmic risk period
This phase runs in parallel with the others rather than after them: sudden arrhythmic death can precede overt pump failure, which is why risk stratification does not wait for a fall in ejection fraction.
Show evidence (1 reference)
PMID:34113975 SUPPORT Human Clinical
"While the event rate of incident malignant VA is significant in individuals with the PLN p.Arg14del variant, over 90% remain event-free at 5 years."
Quantifies the arrhythmic hazard over a defined interval, which is what the variant-specific risk model is built to stratify.
📊

Prevalence

2
Dutch dilated cardiomyopathy patients
Unknown Unknown
Share of a disease cohort attributable to the R14del founder allele, not a population rate. Founder-enriched and specific to the Netherlands.
Show evidence (1 reference)
PMID:22820313 SUPPORT Human Clinical
"We screened a cohort of 97 ARVC and 257 DCM unrelated index patients for PLN mutations and evaluated their clinical characteristics. PLN mutation R14del was identified in 12 (12 %) ARVC patients and in 39 (15 %) DCM patients."
Quantifies the R14del share of Dutch dilated and arrhythmogenic cardiomyopathy index patients in the cohort that defined the founder effect.
Worldwide
Unknown Unknown
No global prevalence, incidence, or carrier frequency has been established for PLN-related cardiomyopathy. Carriers are reported across Europe, North America, Japan and China, but every quantitative estimate available derives from founder-enriched Dutch or Greek ascertainment and should not be generalized.
Show evidence (1 reference)
PMID:39297138 SUPPORT Other
"So far, 2 founder PLN-R14del mutations have been identified, both leading to the development of analogous disease phenotypes in carriers. One founder mutation has its origin in Greece, whereas the other emanates from the Netherlands"
Establishes that the disease burden is concentrated in two founder lineages, which is why no worldwide rate can be inferred from the published cohorts.
🔬

Clinical Trials

3
NCT01857856 PHASE_III COMPLETED
iPHORECAST. Randomized study of eplerenone in presymptomatic PLN R14del carriers, testing whether antifibrotic mineralocorticoid-receptor blockade delays onset of overt disease. 84 participants.
Target Phenotypes: Myocardial fibrosis HP:0001685 Human Phenotype Ontology (HP) Relation: this clinical trial targets this phenotype This clinical trial targets Myocardial fibrosis (HP:0001685). HP:0001685 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
clinicaltrials:NCT01857856 SUPPORT Human Clinical
"The investigators hypothesize that treatment of presymptomatic PLN R14del-carriers with eplerenone, which by virtue of its mineralocorticoid(aldosterone)-blocking properties is a strong antifibrotic agent, reduces disease progression and postpones onset of overt disease."
States the trial's hypothesis, which targets the fibrosis node of this entry's pathograph in presymptomatic carriers.
NCT04978987 NOT_APPLICABLE COMPLETED
DECIPHER-PLN. Observational multi-omics cohort profiling plasma, cardiac and skeletal muscle from R14del carriers across the severity range, plus patient-derived iPSC cardiomyocytes, to identify disease-specific pathways and the modifiers behind the disease's very variable penetrance. Approximately 103 participants.
Show evidence (1 reference)
clinicaltrials:NCT04978987 SUPPORT Human Clinical
"Subjects with a heterozygous PLN R14del mutation show a wide variety in phenotype. Within the same family, patients can present either with over heart failure in their 20's or completely asymptomatic until at least their 70's. So far, no modifiers have been identified."
Documents the unexplained variable expressivity that this cohort was designed to resolve, and confirms no modifier is yet established.
NCT07241104 PHASE_I RECRUITING
First-in-human single-ascending-dose study of AZD4063 in adults with PLN R14del dilated cardiomyopathy, assessing safety, tolerability and pharmacokinetics. Estimated enrolment 23 participants. This is the only interventional trial of a PLN-directed agent in humans; the registration does not disclose the molecular mechanism of AZD4063, so no pathograph node is claimed for it here.
Show evidence (1 reference)
clinicaltrials:NCT07241104 SUPPORT Human Clinical
"The purpose of the study is to assess the safety, tolerability and the pharmacokinetics (PK) of AZD4063 after single dose administration in participants with phospholamban (PLN) R14del dilated cardiomyopathy."
Establishes that a genotype-restricted interventional agent has reached first-in-human testing in this disease.
🧫

Experimental Models

1
Isogenic PLN-R14del hiPSC-cardiomyocyte and 3D engineered heart tissue pair IPSC_DERIVED_MODEL
Three isogenic hiPSC pairs differing only at the PLN R14del allele, differentiated to cardiomyocytes and assayed for contractility in both 2D monolayers and 3D engineered heart tissues. Because the comparison is isogenic, a contractile difference is assignable to the variant rather than to donor background. The same system carries the unfolded-protein-response arm of this entry's second hypothesis group, and supplies its only pharmacological rescue.
hiPSC-derived cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses hiPSC-derived cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Patient-derived hiPSC lines carrying PLN R14del, plus a healthy-donor line into which R14del was introduced; each paired with its CRISPR/Cas9-corrected or unedited isogenic control.
Culture
Two-dimensional monolayer culture and three-dimensional engineered heart tissue (3D-EHT).
Publication
PMID:33928785
Pathograph links
Cardiomyocyte Contractile Dysfunction recapitulates fidelity: moderate R14del hiPSC-CMs show reduced contractility against their isogenic controls in both culture formats, which is the in-vitro counterpart of this node.
Limitations: hiPSC-CMs are immature relative to adult ventricular myocardium, lack the loading and neurohormonal environment of the intact heart, and cannot reproduce the chamber-level dilatation or the arrhythmic endpoints that dominate the human disease.
Readouts
Contractile force in 3D engineered heart tissue and 2D monolayer
Direction: DECREASED
Interpretation: Isogenic-paired contractility deficit, the quantifiable in-vitro correlate of the contractile-dysfunction node.
Show evidence (1 reference)
PMID:33928785 SUPPORT In Vitro
"hiPSC-CMs carrying the PLN R14del mutation (patient and HD R14del introduced) showed decreased contractility in three-dimensional engineered heart tissues (3D-EHTs)"
Reports the direction and the assay behind this readout.
Show evidence (1 reference)
PMID:33928785 SUPPORT In Vitro
"Modeling of the PLN R14del cardiomyopathy with isogenic pairs of hiPSC-CMs recapitulated the contractile deficit associated with the disease in vitro."
States that this model is informative for the contractile-dysfunction node.
Endoplasmic Reticulum Stress and Unfolded Protein Response Activation measures fidelity: moderate Single-cell RNA sequencing of the isogenic pair identified UPR induction as the transcriptional signature of the variant, and the same activation was confirmed in myocardium from PLN R14del patients.
Limitations: UPR activation is also seen in desmosomal ARVC and ischemic cardiomyopathy hearts, so it is not specific to this variant; the model establishes that R14del induces it, not that it is the discriminating lesion.
Readouts
Unfolded protein response transcriptional program
Direction: INCREASED
Interpretation: UPR pathway induction in R14del cardiomyocytes relative to isogenic control.
Show evidence (1 reference)
PMID:33928785 SUPPORT In Vitro
"Single-cell RNA sequencing revealed the induction of the unfolded protein response (UPR) pathway in PLN R14del compared with isogenic control hiPSC-CMs."
Reports the measurement and its direction in the isogenic comparison.
Show evidence (1 reference)
PMID:33928785 SUPPORT In Vitro
"The activation of UPR was also evident in the hearts from PLN R14del patients."
Anchors the model's UPR readout to human myocardium, which is what makes the model informative for this node rather than an in-vitro artifact.
Cardiomyocyte Contractile Dysfunction rescues fidelity: moderate Pharmacological activation of the UPR with BiP inducer X partially reversed the contractile deficit, which is the experiment that makes the proteostatic arm a candidate therapeutic target rather than an epiphenomenon.
Limitations: A dose-dependent rescue in engineered tissue is not evidence of clinical benefit; no PLN-directed or UPR-directed therapy has been tested in patients.
Readouts
Contractility after BiP inducer X treatment
Direction: RESTORED
Interpretation: Dose-dependent amelioration of the contractile deficit without a change in calcium handling, separating the proteostatic arm from the calcium arm.
Show evidence (1 reference)
PMID:33928785 SUPPORT In Vitro
"PLN R14del hiPSC-CMs treated with BiP protein inducer X showed a dose-dependent amelioration of the contractility deficit in both 2-dimensional cultures and 3-dimensional engineered heart tissues without affecting calcium homeostasis."
Reports the rescue, its dose dependence, and that calcium handling was unchanged.
Show evidence (1 reference)
PMID:33928785 SUPPORT In Vitro
"We explored the therapeutic potential of activating the UPR with a small molecule activator, BiP (binding immunoglobulin protein) inducer X."
Establishes the rescue arm as a deliberate intervention in this model.
Silencing any of the three UPR branches (IRE1, ATF6, PERK) worsened contractility in this system, which is why the UPR is curated here as protective rather than as the injury itself.
🐁

Animal Models

2
PLN-R14del knock-in mouse
Knock-in mouse carrying the human R14del lesion. Heterozygotes, the genotype that matches human carriers, develop inducible arrhythmia susceptibility and a cardiomyopathy only at 18 months. Homozygotes show an accelerated course with dilatation, contractile failure, low ECG voltages, fibrosis, phospholamban aggregation and early death - useful for testing therapies quickly, but not the human genotype.
Species
Mouse
Genotype
Pln p.(Arg14del) knock-in, heterozygous and homozygous
Publication
PMID:32555305
Pathograph links
Arrhythmogenic Substrate Formation recapitulates fidelity: moderate Heterozygous animals reproduce the arrhythmic susceptibility that defines the human disease.
Limitations: Arrhythmia is induced ex vivo rather than observed spontaneously, and beta-adrenergic challenge did not accelerate disease as it might be expected to in carriers.
Show evidence (1 reference)
PMID:32555305 SUPPORT Model Organism
"Heterozygous PLN-R14del mice demonstrated increased susceptibility to ex vivo induced arrhythmias, and cardiomyopathy at 18 months of age, which was not accelerated by isoproterenol infusion."
Supports treating the heterozygous mouse as informative for the arrhythmic substrate, at the genotype that matches human carriers.
Perinuclear Phospholamban-Positive Deposits recapitulates fidelity: moderate Homozygous animals reproduce the hallmark phospholamban-positive material seen in human myocardium.
Limitations: Only the homozygous animals show it on this timescale, and homozygosity is essentially absent among human carriers, so the finding is reached through a genotype the disease does not normally present with.
Show evidence (1 reference)
PMID:32555305 SUPPORT Model Organism
"Homozygous PLN-R14del mice exhibited an accelerated phenotype including cardiac dilatation, contractile dysfunction, decreased ECG potentials, high susceptibility to ex vivo induced arrhythmias, myocardial fibrosis, PLN protein aggregation, and early mortality."
Records phospholamban aggregation alongside the other disease features in the homozygous animals.
Show evidence (1 reference)
PMID:32555305 SUPPORT Model Organism
"In conclusion, our novel PLN-R14del mouse model exhibits most features of human disease."
Supports treating this model as informative for the disease overall, with "most" rather than all features being the stated scope.
PLN-null mouse (comparative)
Cited as a negative comparator rather than as a disease model. Phospholamban ablation is well tolerated in the mouse and even enhances cardiac function, whereas the equivalent human null state produces lethal dilated cardiomyopathy. The species divergence is the reason PLN knockdown was historically viewed as a therapeutic strategy and why that inference does not transfer.
Species
Mouse
Genotype
Pln knockout
Publication
PMID:12639993
Pathograph links
Loss of Phospholamban Protein fails to recapitulate fidelity: low The mouse does not reproduce the human consequence of absent phospholamban.
Limitations: The direction of effect is inverted between species: mice lacking phospholamban show enhanced calcium reuptake and contractility with no adverse outcome, while humans lacking it develop lethal dilated cardiomyopathy. Any therapeutic argument resting on murine PLN ablation therefore does not carry to patients, and complete phospholamban depletion is a specific safety concern for silencing approaches.
Show evidence (1 reference)
PMID:12639993 REFUTE Human Clinical
"In contrast to reported benefits of PLN ablation in mouse heart failure, humans lacking PLN develop lethal dilated cardiomyopathy."
Directly states the species divergence, which is what makes this a failure-to-recapitulate rather than a partial model.
Show evidence (1 reference)
PMID:12639993 SUPPORT Human Clinical
"In mice, disruption of the PLN gene encoding phospholamban (PLN) or expression of dominant-negative PLN mutants enhances SR and cardiac function, but effects of PLN mutations in humans are unknown."
Records the murine baseline against which the human finding was the surprise, establishing why this model is cited as a comparator.
{ }

Source YAML

click to show 
name: Dilated Cardiomyopathy 1P
creation_date: "2026-09-04T02:26:58Z"
synonyms:
- CMD1P
- dilated cardiomyopathy type 1P
- cardiomyopathy, dilated, 1P
- PLN-related cardiomyopathy
- phospholamban cardiomyopathy
- familial isolated dilated cardiomyopathy caused by mutation in PLN
description: >-
  Dilated cardiomyopathy 1P is the Mendelian designation for cardiomyopathy caused by
  germline variants in PLN, which encodes phospholamban, the 52-amino-acid sarcoplasmic
  reticulum membrane protein that reversibly inhibits the cardiac calcium pump SERCA2a.
  The primary lesion is therefore in sarcoplasmic-reticulum calcium reuptake -- the
  relaxation arm of excitation-contraction coupling -- and not in the sarcomere, which
  separates this entry mechanistically from the sarcomeric and cytoskeletal dilated
  cardiomyopathies. Contemporary practice increasingly calls the disease PLN-related
  cardiomyopathy because carriers may present with dilated cardiomyopathy, with a
  left-dominant arrhythmogenic cardiomyopathy, or with ventricular arrhythmia and
  subepicardial fibrosis while chamber dimensions are still normal.

  The PLN alleles are not mechanistically interchangeable and this entry does not
  merge them. p.Arg14del (c.40_42delAGA, "R14del"), a Dutch and Greek founder variant
  and by far the best-characterized allele, superinhibits SERCA2a in a way that
  protein kinase A phosphorylation cannot relieve, and additionally mislocalizes
  phospholamban into malformed sarco/endoplasmic-reticulum clusters that impair
  autophagic flux. p.Arg9Cys acts differently: it does not itself inhibit SERCA2a but
  sequesters protein kinase A, blocking phosphorylation of the wild-type phospholamban
  in trans. The truncating p.Leu39Ter allele is a true null in which phospholamban
  protein is essentially absent -- heterozygotes are hypertrophic with preserved
  contractility, while homozygotes develop lethal dilated cardiomyopathy, the inverse
  of the benign phenotype of the PLN-null mouse. R14del carries a high arrhythmic
  burden that drives defibrillator decisions on a variant-specific risk model rather
  than on ejection fraction alone.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: dilated cardiomyopathy 1P
  term:
    id: MONDO:0012362
    label: dilated cardiomyopathy 1P
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
inheritance:
- name: Autosomal dominant
  description: >-
    The common disease alleles -- p.Arg14del, p.Arg9Cys, p.Arg25Cys -- are heterozygous
    and act dominantly, with incomplete, age-dependent penetrance and markedly variable
    expressivity within a single family. The truncating p.Leu39Ter allele is the
    exception: heterozygotes show hypertrophy without contractile impairment, and only
    homozygotes develop lethal dilated cardiomyopathy, so that allele behaves
    recessively for the dilated phenotype.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  evidence:
  - reference: PMID:16432188
    reference_title: "A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By middle age, heterozygous individuals developed left ventricular dilation,
      contractile dysfunction, and episodic ventricular arrhythmias, with overt heart
      failure in some cases.
    explanation: >-
      Establishes that R14del heterozygotes are affected, which is what makes the
      allele dominant, and dates typical onset to middle age.
  - reference: PMID:12639993
    reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The heterozygous individuals exhibited hypertrophy without diminished contractile
      performance. Strikingly, both individuals homozygous for L39stop developed dilated
      cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and
      27.
    explanation: >-
      Documents the exception to dominant inheritance: the truncating L39stop allele
      produces the dilated phenotype only in homozygotes.
  - reference: PMID:37144056
    reference_title: "Phospholamban R14del disease: The past, the present and the future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease penetrance is incomplete and age-dependent, with symptoms developing more often within the fifth decade"
    explanation: >-
      States the qualitative penetrance value curated here and dates symptom onset,
      without asserting a cumulative figure.

progression:
- phase: Presymptomatic carrier with imaging-detectable substrate
  age_range: Second to fourth decade
  evidence:
  - reference: PMID:33020536
    reference_title: "The phenotypic characteristic observed by cardiac magnetic resonance in a PLN-R14del family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The former one can also present in younger PLN-R14del carriers despite completely normal LV structure and function."
    explanation: >-
      Establishes a phase in which the lateral-wall enhancement is already present while
      ventricular structure and function are still normal.
  notes: >-
    The substrate is detectable on cardiac magnetic resonance before any echocardiographic
    or symptomatic abnormality, which is what makes imaging surveillance of known carriers
    worthwhile.
- phase: Symptomatic cardiomyopathy
  age_range: Fifth decade onward
  evidence:
  - reference: PMID:37144056
    reference_title: "Phospholamban R14del disease: The past, the present and the future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease penetrance is incomplete and age-dependent, with symptoms developing more often within the fifth decade"
    explanation: Dates the onset of the symptomatic phase.
- phase: Arrhythmic risk period
  evidence:
  - reference: PMID:34113975
    reference_title: "Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "While the event rate of incident malignant VA is significant in individuals with the PLN p.Arg14del variant, over 90% remain event-free at 5 years."
    explanation: >-
      Quantifies the arrhythmic hazard over a defined interval, which is what the
      variant-specific risk model is built to stratify.
  notes: >-
    This phase runs in parallel with the others rather than after them: sudden arrhythmic
    death can precede overt pump failure, which is why risk stratification does not wait
    for a fall in ejection fraction.

prevalence:
- population: Dutch dilated cardiomyopathy patients
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Share of a disease cohort attributable to the R14del founder allele, not a
    population rate. Founder-enriched and specific to the Netherlands.
  evidence:
  - reference: PMID:22820313
    reference_title: "Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We screened a cohort of 97 ARVC and 257 DCM unrelated index patients for PLN
      mutations and evaluated their clinical characteristics. PLN mutation R14del was
      identified in 12 (12 %) ARVC patients and in 39 (15 %) DCM patients.
    explanation: >-
      Quantifies the R14del share of Dutch dilated and arrhythmogenic cardiomyopathy
      index patients in the cohort that defined the founder effect.
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    No global prevalence, incidence, or carrier frequency has been established for
    PLN-related cardiomyopathy. Carriers are reported across Europe, North America,
    Japan and China, but every quantitative estimate available derives from
    founder-enriched Dutch or Greek ascertainment and should not be generalized.
  evidence:
  - reference: PMID:39297138
    reference_title: "Reassessing the Mechanisms of PLN-R14del Cardiomyopathy: From Calcium Dysregulation to S/ER Malformation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      So far, 2 founder PLN-R14del mutations have been identified, both leading to the
      development of analogous disease phenotypes in carriers. One founder mutation has
      its origin in Greece, whereas the other emanates from the Netherlands
    explanation: >-
      Establishes that the disease burden is concentrated in two founder lineages,
      which is why no worldwide rate can be inferred from the published cohorts.
pathophysiology:
- name: PLN Regulatory Domain Variant
  biological_scale: MOLECULAR
  description: >-
    The initiating lesion is a germline variant in PLN. Pathogenic alleles cluster in
    the cytoplasmic regulatory domain that contacts SERCA2a and carries the Ser16/Thr17
    phosphorylation sites (p.Arg9Cys, p.Arg14del, p.Arg25Cys), or truncate the protein
    within transmembrane domain II (p.Leu39Ter). The downstream branches are
    allele-specific and are modelled separately rather than merged, because the three
    classes perturb the SERCA2a-phospholamban regulatory couple in different directions.
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  cell_types:
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: phospholamban inhibitor activity toward the SERCA2a calcium pump
    term:
      id: GO:0004857
      label: enzyme inhibitor activity
  evidence:
  - reference: PMID:37144056
    reference_title: "Phospholamban R14del disease: The past, the present and the future."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PLN is a 52 amino acid transmembrane protein that modulates Ca2+ homeostasis and
      cardiac contractility through reversible inhibition of the sarcoplasmic reticulum
      (SR) calcium ATPase (SERCA2a) activity.
    explanation: >-
      Establishes the normal function that the disease alleles disrupt: reversible
      inhibition of SERCA2a, which places the lesion in calcium reuptake rather than
      in force generation.
  - reference: PMID:40556736
    reference_title: "Genetic landscape of phospholamban cardiomyopathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Variants in the PLN gene have been identified in patients with a wide range of
      phenotypes, including hypertrophic, dilated, and arrhythmogenic cardiomyopathies.
    explanation: >-
      Supports treating the PLN allelic series as heterogeneous rather than as one
      uniform phenotype, which is why the branches below are kept separate.
  downstream:
  - target: Non-Reversible SERCA2a Superinhibition
    causal_link_type: DIRECT
    hypothesis_groups:
    - pln_serca_superinhibition
    description: R14del branch.
    evidence:
    - reference: PMID:16432188
      reference_title: "A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Coexpression of the normal and mutant-PLN in HEK-293 cells resulted in
        sarcoplasmic reticulum Ca(2+)-ATPase superinhibition.
      explanation: >-
        Shows the R14del allele producing superinhibition of the pump in a
        reconstituted system, which is the step this edge asserts.
  - target: Protein Kinase A Sequestration by Mutant Phospholamban
    causal_link_type: DIRECT
    description: R9C branch.
    evidence:
    - reference: PMID:12610310
      reference_title: "Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Cellular and biochemical studies revealed that, unlike wild-type PLN, PLN(R9C)
        did not directly inhibit SERCA2a. Rather, PLN(R9C) trapped protein kinase A
        (PKA)
      explanation: >-
        Establishes that R9C acts by trapping PKA rather than by inhibiting the pump
        directly, which is the branch this edge selects.
  - target: Loss of Phospholamban Protein
    causal_link_type: DIRECT
    description: Truncating and null allele branch.
    evidence:
    - reference: PMID:12639993
      reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The expression of recombinant PLN-L39stop in human embryonic kidney (HEK) 293
        cells and adult rat cardiomyocytes showed no PLN inhibition of SR Ca(2+)-ATPase
        and the virtual absence of stable PLN expression
      explanation: >-
        Demonstrates that the truncating allele yields no stable protein and no pump
        inhibition, establishing this branch as loss of function.
  - target: Phospholamban Mislocalization and Sarco-Endoplasmic Reticulum Disorganization
    causal_link_type: DIRECT
    hypothesis_groups:
    - pln_ser_malformation
    description: >-
      R14del branch running in parallel with the calcium-handling branch.
    evidence:
    - reference: PMID:39297138
      reference_title: "Reassessing the Mechanisms of PLN-R14del Cardiomyopathy: From Calcium Dysregulation to S/ER Malformation."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        recent studies raised controversy regarding the effect of PLN-R14del on SERCA
        activity and revealed a prominent role for abnormal PLN protein distribution and
        sarco/endoplasmic reticulum disorganization as underlying disease mechanism
      explanation: >-
        Supports a second, parallel consequence of the R14del allele that is not
        reducible to altered SERCA2a inhibition.

- name: Non-Reversible SERCA2a Superinhibition
  biological_scale: MOLECULAR
  description: >-
    In the R14del allele the mutant phospholamban superinhibits SERCA2a, and critically
    the inhibition is not relieved by protein kinase A phosphorylation. Beta-adrenergic
    stimulation therefore cannot restore calcium reuptake, so the brake on the pump
    becomes constitutive rather than regulated. Note that the magnitude and even the
    direction of the R14del effect on SERCA activity is disputed in more recent work;
    this node states the classical finding and the disagreement is recorded as a
    mechanistic hypothesis.
  biological_processes:
  - preferred_term: constitutive inhibition of the SERCA2a calcium pump
    modifier: INCREASED
    term:
      id: GO:1901895
      label: negative regulation of ATPase-coupled calcium transmembrane transporter activity
  evidence:
  - reference: PMID:16432188
    reference_title: "A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The dominant effect of the PLN-R14Del mutation could not be fully removed, even
      upon phosphorylation by protein kinase A.
    explanation: >-
      This is the defining property of the node: the inhibition is non-reversible,
      so the physiological release mechanism is unavailable.
  downstream:
  - target: Impaired Sarcoplasmic Reticulum Calcium Reuptake
    causal_link_type: DIRECT
    hypothesis_groups:
    - pln_serca_superinhibition
    evidence:
    - reference: PMID:16432188
      reference_title: "A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        by chronic suppression of sarcoplasmic reticulum Ca(2+)-ATPase activity, the
        nonreversible superinhibitory function of mutant PLN-R14Del may lead to
        inherited dilated cardiomyopathy
      explanation: >-
        States the causal step from sustained pump suppression to the calcium-handling
        defect and onward to the disease.

- name: Protein Kinase A Sequestration by Mutant Phospholamban
  biological_scale: MOLECULAR
  description: >-
    The R9C allele reaches the same physiological endpoint by a different route. Mutant
    phospholamban does not inhibit SERCA2a itself; it traps protein kinase A, which
    prevents phosphorylation of the wild-type phospholamban produced from the normal
    allele. The wild-type protein is therefore locked in its inhibitory, dephosphorylated
    state, and calcium transient decay slows.
  molecular_functions:
  - preferred_term: sequestration of cAMP-dependent protein kinase by mutant phospholamban
    modifier: INCREASED
    term:
      id: GO:0051018
      label: protein kinase A binding
  evidence:
  - reference: PMID:12610310
    reference_title: "Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      which blocked PKA-mediated phosphorylation of wild-type PLN and in turn delayed
      decay of calcium transients in myocytes
    explanation: >-
      Establishes the in-trans mechanism specific to R9C and its immediate functional
      consequence for calcium handling.
  downstream:
  - target: Impaired Sarcoplasmic Reticulum Calcium Reuptake
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12610310
      reference_title: "Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        delayed decay of calcium transients in myocytes
      explanation: >-
        Slowed calcium transient decay is the direct readout of impaired reuptake into
        the sarcoplasmic reticulum.

- name: Loss of Phospholamban Protein
  biological_scale: MOLECULAR
  description: >-
    The truncating p.Leu39Ter allele removes phospholamban rather than dysregulating it.
    No stable protein is made, what little is expressed is misrouted away from the
    sarcoplasmic reticulum, and SERCA2a is left uninhibited. This is the opposite
    perturbation from R14del superinhibition, and it is the reason this node feeds
    calcium dyshomeostasis directly rather than through the impaired-reuptake node.
    The human phenotype inverts the mouse: PLN ablation is well tolerated in mice but
    lethal in people.
  biological_processes:
  - preferred_term: loss of phospholamban inhibition of SERCA2a
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:1901895
      label: negative regulation of ATPase-coupled calcium transmembrane transporter activity
  evidence:
  - reference: PMID:12639993
    reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      where PLN was expressed, it was misrouted to the cytosol or plasma membrane
    explanation: >-
      Documents the mislocalization that accompanies the loss of stable phospholamban
      expression in the truncating allele.
  downstream:
  - target: Dysregulated Cardiomyocyte Calcium Homeostasis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12639993
      reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In contrast to reported benefits of PLN ablation in mouse heart failure, humans
        lacking PLN develop lethal dilated cardiomyopathy.
      explanation: >-
        Supports the edge from absent phospholamban to disordered calcium handling and
        human disease, and marks the species divergence explicitly.

- name: Impaired Sarcoplasmic Reticulum Calcium Reuptake
  biological_scale: CELLULAR
  description: >-
    Sustained inhibition of SERCA2a, whether by non-reversible superinhibition (R14del)
    or by loss of the phosphorylation release step (R9C), slows removal of cytosolic
    calcium into the sarcoplasmic reticulum during diastole. This is the shared
    convergence point of the two dominant missense branches.
  biological_processes:
  - preferred_term: sarcoplasmic reticulum calcium ion transport
    modifier: DECREASED
    term:
      id: GO:0070296
      label: sarcoplasmic reticulum calcium ion transport
  evidence:
  - reference: PMID:33020536
    reference_title: "The phenotypic characteristic observed by cardiac magnetic resonance in a PLN-R14del family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Mutations on PLN result in intracellular calcium disorder, myocardial contraction
      defect, and eventually heart failure and/or malignant ventricular arrhythmia.
    explanation: >-
      States the calcium-reuptake defect as the mechanistic consequence of PLN
      mutation and names the two clinical endpoints it drives.
  downstream:
  - target: Dysregulated Cardiomyocyte Calcium Homeostasis
    causal_link_type: DIRECT

- name: Phospholamban Mislocalization and Sarco-Endoplasmic Reticulum Disorganization
  biological_scale: CELLULAR
  description: >-
    A second consequence of the R14del allele, independent of the pump kinetics.
    Mutant phospholamban is abnormally distributed and the sarco/endoplasmic reticulum
    membrane becomes locally disorganized into malformed clusters. This is now
    considered a prominent, possibly primary, disease mechanism rather than a
    downstream epiphenomenon of calcium dysregulation.
  cell_types:
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:39297138
    reference_title: "Reassessing the Mechanisms of PLN-R14del Cardiomyopathy: From Calcium Dysregulation to S/ER Malformation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Importantly, a recent in-depth investigation revealed that these aggregates
      consist of malformed sarco/endoplasmic reticulum (S/ER) clusters.
    explanation: >-
      Reframes the hallmark structures as malformed membrane clusters rather than
      simple protein aggregation, which is the claim of this node.
  downstream:
  - target: Impaired Autophagic Flux
    causal_link_type: DIRECT
    hypothesis_groups:
    - pln_ser_malformation
    evidence:
    - reference: PMID:39527246
      reference_title: "The phospholamban R14del generates pathogenic aggregates by impairing autophagosome-lysosome fusion."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Our findings demonstrate that the expression of PLN-R14del results in diminished
        autophagic flux due to impaired fusion between autophagosomes and lysosomes.
      explanation: >-
        Establishes the causal step from expression of the mutant protein to the
        autophagy defect.

- name: Impaired Autophagic Flux
  biological_scale: CELLULAR
  description: >-
    R14del blocks autophagosome-lysosome fusion through aberrant recruitment of
    membrane-fusion machinery, itself partly mediated by altered calcium homeostasis.
    The degradative route that would clear the abnormal phospholamban-containing
    material is therefore unavailable, which is why the material accumulates.
  biological_processes:
  - preferred_term: autophagosome-lysosome fusion
    modifier: DECREASED
    term:
      id: GO:0061909
      label: autophagosome-lysosome fusion
  - preferred_term: autophagy
    modifier: DECREASED
    term:
      id: GO:0006914
      label: autophagy
  evidence:
  - reference: PMID:39527246
    reference_title: "The phospholamban R14del generates pathogenic aggregates by impairing autophagosome-lysosome fusion."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mechanistically, this defect is linked to aberrant recruitment of key membrane
      fusion proteins to autophagosomes, which is mediated in part by changes in Ca2+
      homeostasis.
    explanation: >-
      Gives the molecular basis of the fusion block and links it back to the calcium
      branch of the mechanism.
  downstream:
  - target: Perinuclear Phospholamban-Positive Deposits
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39527246
      reference_title: "The phospholamban R14del generates pathogenic aggregates by impairing autophagosome-lysosome fusion."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We determined that PLN aggregates contain autophagic proteins, indicating
        inefficient degradation via the autophagy pathway.
      explanation: >-
        Ties the deposits directly to failed autophagic degradation, which is the
        causal claim of this edge.

- name: Perinuclear Phospholamban-Positive Deposits
  biological_scale: CELLULAR
  description: >-
    Perinuclear phospholamban-immunoreactive material is the histopathological hallmark
    of R14del cardiomyopathy and is not seen in desmosomal arrhythmogenic cardiomyopathy,
    ischemic cardiomyopathy, or control hearts. It is specific enough to be diagnostically
    suggestive on explanted myocardium.
  evidence:
  - reference: PMID:33928785
    reference_title: "Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PLN immunolabeling revealed perinuclear aggregations in PLN R14del tissues (7±2%)
      but were absent in ARVC, ICM, and control hearts
    explanation: >-
      Documents the deposits in human R14del myocardium and their absence from the two
      main differential diagnoses, establishing disease specificity.
  downstream:
  - target: Endoplasmic Reticulum Stress and Unfolded Protein Response Activation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33928785
      reference_title: "Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Single-cell RNA sequencing revealed the induction of the unfolded protein
        response (UPR) pathway in PLN R14del compared with isogenic control hiPSC-CMs.
      explanation: >-
        Establishes UPR induction as a consequence of the R14del proteostatic burden in
        isogenic human cardiomyocytes.

- name: Endoplasmic Reticulum Stress and Unfolded Protein Response Activation
  biological_scale: CELLULAR
  description: >-
    The unfolded protein response is activated in R14del cardiomyocytes and in patient
    myocardium. Its role is compensatory, not pathogenic: silencing any of the three
    UPR branches worsens contractility, and pharmacological UPR activation improves it.
    The node is therefore drawn as a protective response embedded in the injury
    cascade, not as a cause of the contractile deficit.
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    modifier: INCREASED
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
  evidence:
  - reference: PMID:33928785
    reference_title: "Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Silencing of each of the 3 main UPR signaling branches (IRE1, ATF6, or PERK) by
      siRNA exacerbated the contractile dysfunction of PLN R14del hiPSC-CMs.
    explanation: >-
      Loss-of-function across all three branches worsening contractility is what
      establishes the response as protective rather than injurious.
  downstream:
  - target: Cardiomyocyte Contractile Dysfunction
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Drawn as indirect and partial: the UPR restrains the contractile deficit rather
      than producing it, so the arrow records that this compensatory node sits on the
      path to contractile failure without being its cause.

- name: Dysregulated Cardiomyocyte Calcium Homeostasis
  biological_scale: CELLULAR
  description: >-
    The convergence point of all allele branches. Cytosolic calcium handling across the
    contraction-relaxation cycle is disordered, whether from too much SERCA2a inhibition
    (R14del, R9C) or from none at all (null alleles). Both directions are maladaptive in
    the human heart.
  biological_processes:
  - preferred_term: calcium ion transmembrane transport
    modifier: DYSREGULATED
    term:
      id: GO:0070588
      label: calcium ion transmembrane transport
  - preferred_term: regulation of cardiac muscle contraction
    modifier: DYSREGULATED
    term:
      id: GO:0055117
      label: regulation of cardiac muscle contraction
  evidence:
  - reference: PMID:37144056
    reference_title: "Phospholamban R14del disease: The past, the present and the future."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In its dephosphorylated state, PLN interacts with SERCA2a and inhibits its affinity
      for Ca2+
    explanation: >-
      Establishes the regulatory couple whose disturbance defines this node, and the
      state the mutant alleles lock it into.
  downstream:
  - target: Cardiomyocyte Contractile Dysfunction
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33928785
      reference_title: "Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Modeling of the PLN R14del cardiomyopathy with isogenic pairs of hiPSC-CMs
        recapitulated the contractile deficit associated with the disease in vitro.
      explanation: >-
        Isogenic pairs differing only at the PLN locus show the contractile deficit,
        which attributes it to the mutation-driven calcium lesion rather than to
        genetic background.
  - target: Arrhythmogenic Substrate Formation
    causal_link_type: DIRECT
    description: >-
      Disordered calcium cycling supports triggered activity independently of
      structural remodeling, which is one reason arrhythmia can precede dilation.

- name: Cardiomyocyte Contractile Dysfunction
  biological_scale: CELLULAR
  description: >-
    Reduced force generation by the cardiomyocyte, secondary to the calcium-handling
    lesion and the proteostatic burden. It is reproducible in isogenic human iPSC
    cardiomyocytes differing only at the PLN locus, and in both two-dimensional
    monolayers and three-dimensional engineered heart tissue.
  cell_types:
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: regulation of cardiac muscle contraction
    modifier: DECREASED
    term:
      id: GO:0055117
      label: regulation of cardiac muscle contraction
  evidence:
  - reference: PMID:32555305
    reference_title: "The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Homozygous PLN-R14del mice exhibited an accelerated phenotype including cardiac
      dilatation, contractile dysfunction, decreased ECG potentials, high susceptibility
      to ex vivo induced arrhythmias, myocardial fibrosis, PLN protein aggregation, and
      early mortality.
    explanation: >-
      Contractile dysfunction appears in the knock-in mouse alongside the other nodes of
      this chain, supporting it as a genotype-driven consequence.
  downstream:
  - target: Cardiomyocyte Injury and Death
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Left ventricular systolic dysfunction
    causal_link_type: DIRECT
  - target: Ventricular Dilatation and Pump Failure
    causal_link_type: DIRECT

- name: Cardiomyocyte Injury and Death
  biological_scale: CELLULAR
  description: >-
    Persistent contractile and proteostatic stress leads to cardiomyocyte injury and
    loss, which is the trigger for the replacement fibrosis that follows. Direct
    quantification of cardiomyocyte death in PLN disease is limited; the node is
    inferred from the histological end state of fibrofatty replacement in explanted
    myocardium, and is flagged accordingly.
  cell_types:
  - preferred_term: ventricular cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: cardiac muscle cell apoptotic process
    modifier: INCREASED
    term:
      id: GO:0010659
      label: cardiac muscle cell apoptotic process
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:39297138
    reference_title: "Reassessing the Mechanisms of PLN-R14del Cardiomyopathy: From Calcium Dysregulation to S/ER Malformation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At the histological level, severe cardiac fibrosis or fibrofatty-replacement is
      observed in tissues from patients with end-stage heart failure due to PLN-R14del
      cardiomyopathy.
    explanation: >-
      Replacement fibrosis is the histological signature of antecedent myocyte loss,
      which is the basis for inferring this node.
  downstream:
  - target: Myocardial Replacement Fibrosis
    causal_link_type: DIRECT

- name: Myocardial Replacement Fibrosis
  biological_scale: TISSUE
  description: >-
    Fibrous, sometimes fibrofatty, replacement of lost myocardium. In PLN disease it has
    a characteristic distribution: subepicardial late gadolinium enhancement in the
    lateral wall of the left ventricle, sometimes with linear mid-wall septal
    enhancement, together with elevated extracellular volume on T1 mapping. Critically,
    it is detectable in young carriers whose ventricular structure and function are
    still normal, which is what makes cardiac magnetic resonance an early rather than a
    confirmatory test.
  conforms_to: "fibrotic_response#Excessive ECM Deposition"
  cell_types:
  - preferred_term: cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: extracellular matrix organization
    modifier: INCREASED
    term:
      id: GO:0030198
      label: extracellular matrix organization
  locations:
  - preferred_term: left ventricular lateral wall
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:33020536
    reference_title: "The phenotypic characteristic observed by cardiac magnetic resonance in a PLN-R14del family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      members underwent cardiac magnetic resonance (CMR) examination showed a strikingly
      similar pattern of late gadolinium enhancement (LGE)-Sub-epicardial involvement in
      the left ventricular (LV) lateral wall with or without linear mid-wall enhancement
      in the interventricular septum. The former one can also present in younger
      PLN-R14del carriers despite completely normal LV structure and function.
    explanation: >-
      Establishes both the characteristic distribution of the fibrosis and its
      occurrence before any structural or functional abnormality.
  - reference: PMID:33020536
    reference_title: "The phenotypic characteristic observed by cardiac magnetic resonance in a PLN-R14del family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Meanwhile, T1 mapping also found significantly increased extracellular volume
      (ECV) in PLN-R14del carriers.
    explanation: >-
      Independent, quantitative tissue-characterization support for expanded
      interstitium in carriers.
  downstream:
  - target: Arrhythmogenic Substrate Formation
    causal_link_type: DIRECT
    description: >-
      Patchy fibrosis interposed between surviving myocyte bundles creates the
      conduction heterogeneity that supports reentry.
  - target: Myocardial fibrosis
    causal_link_type: DIRECT
  - target: Ventricular Dilatation and Pump Failure
    causal_link_type: DIRECT

- name: Arrhythmogenic Substrate Formation
  biological_scale: TISSUE
  description: >-
    The combination of patchy replacement fibrosis and disordered calcium cycling
    produces conduction heterogeneity and triggered activity. This node is the reason
    the disease is managed as an arrhythmogenic cardiomyopathy: malignant ventricular
    arrhythmia and sudden death can occur while ejection fraction is still preserved,
    so conventional ejection-fraction-based defibrillator thresholds under-detect risk.
  locations:
  - preferred_term: myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:22820313
    reference_title: "Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      R14del+ patients diagnosed with DCM showed an arrhythmogenic phenotype, and SCD at
      young age can be the presenting symptom. These findings support the concept of
      'arrhythmogenic cardiomyopathy'.
    explanation: >-
      Establishes that the arrhythmic substrate is a defining feature of the disease and
      can manifest before, or instead of, a heart-failure presentation.
  - reference: PMID:32555305
    reference_title: "The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Heterozygous PLN-R14del mice demonstrated increased susceptibility to ex vivo
      induced arrhythmias, and cardiomyopathy at 18 months of age, which was not
      accelerated by isoproterenol infusion.
    explanation: >-
      Shows inducible arrhythmia susceptibility in the heterozygous knock-in, the
      genotype that matches human carriers.
  downstream:
  - target: Ventricular arrhythmia
    causal_link_type: DIRECT
  - target: Ventricular tachycardia
    causal_link_type: DIRECT
  - target: Ventricular fibrillation
    causal_link_type: DIRECT
  - target: Premature ventricular contractions
    causal_link_type: DIRECT
  - target: Sudden cardiac death
    causal_link_type: DIRECT
  - target: Syncope
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES

- name: Ventricular Dilatation and Pump Failure
  biological_scale: ORGANISM
  description: >-
    Progressive myocyte loss and remodeling produce chamber dilatation with falling
    ejection fraction, and ultimately clinical heart failure requiring mechanical
    circulatory support or transplantation. In PLN disease this endpoint frequently
    arrives after, not before, the arrhythmic manifestations.
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  biological_processes:
  - preferred_term: heart contraction
    modifier: ABNORMAL
    term:
      id: GO:0060047
      label: heart contraction
  locations:
  - preferred_term: heart
    term:
      id: UBERON:0000948
      label: heart
  evidence:
  - reference: PMID:16432188
    reference_title: "A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By middle age, heterozygous individuals developed left ventricular dilation,
      contractile dysfunction, and episodic ventricular arrhythmias, with overt heart
      failure in some cases.
    explanation: >-
      Documents dilatation, contractile failure, and overt heart failure as the
      organ-level endpoint in R14del carriers.
  downstream:
  - target: Dilated cardiomyopathy
    causal_link_type: DIRECT
  - target: Congestive heart failure
    causal_link_type: DIRECT
  - target: Exercise intolerance
    causal_link_type: DIRECT
  - target: Exertional dyspnea
    causal_link_type: DIRECT
phenotypes:
- name: Ventricular arrhythmia
  category: Cardiovascular
  description: >-
    Malignant ventricular arrhythmia is the dominant clinical risk in R14del carriers
    and is the endpoint the variant-specific risk model predicts. In the 679-carrier
    Dutch cohort roughly one in ten carriers reached a composite of sustained
    ventricular arrhythmia, appropriate defibrillator intervention, or aborted sudden
    death within a median 4.3 years.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Ventricular arrhythmia
    term:
      id: HP:0004308
      label: Ventricular arrhythmia
  evidence:
  - reference: PMID:34113975
    reference_title: "Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During a median follow-up of 4.3 years (IQR 1.7-7.4), 72 (10.6%) carriers
      experienced malignant VA.
    explanation: >-
      Quantifies the incidence of malignant ventricular arrhythmia in the largest
      published carrier cohort.

- name: Ventricular tachycardia
  category: Cardiovascular
  description: >-
    Sustained and non-sustained ventricular tachycardia occur in carriers and form part
    of the composite malignant-arrhythmia endpoint used for risk stratification.
  phenotype_term:
    preferred_term: Ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  evidence:
  - reference: PMID:34113975
    reference_title: "Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Malignant VA was defined as sustained VA, appropriate ICD intervention, or
      (aborted) sudden cardiac death.
    explanation: >-
      Defines sustained ventricular arrhythmia as a component of the outcome observed in
      this cohort.

- name: Ventricular fibrillation
  category: Cardiovascular
  description: >-
    Ventricular fibrillation is an endpoint of the arrhythmic substrate and one route to
    sudden death or aborted cardiac arrest in carriers.
  phenotype_term:
    preferred_term: Ventricular fibrillation
    term:
      id: HP:0001663
      label: Ventricular fibrillation
  evidence:
  - reference: PMID:34113975
    reference_title: "Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Appropriate ICD intervention is classified as ICD therapy (antitachycardia pacing
      or shock) for VF/VT.
    explanation: >-
      Records ventricular fibrillation among the treated arrhythmic events in the carrier
      cohort.

- name: Premature ventricular contractions
  category: Cardiovascular
  description: >-
    Ventricular ectopic burden on 24-hour ambulatory monitoring is both a common finding
    and an independent predictor of malignant arrhythmia, which is why rhythm monitoring
    is part of carrier surveillance rather than only of symptomatic assessment.
  phenotype_term:
    preferred_term: Premature ventricular contraction
    term:
      id: HP:0006682
      label: Premature ventricular contraction
  evidence:
  - reference: PMID:34113975
    reference_title: "Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Significant predictors were left ventricular ejection fraction, premature
      ventricular contraction count/24 h, amount of negative T waves, and presence of
      low-voltage electrocardiogram.
    explanation: >-
      Establishes ventricular ectopic count as a measured and prognostically significant
      phenotype in carriers.

- name: Sudden cardiac death
  category: Cardiovascular
  description: >-
    Sudden cardiac death can be the presenting event, including at young ages, and
    families carry a substantial burden of early sudden death. This is the outcome that
    drives defibrillator decisions ahead of ejection-fraction thresholds.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:22820313
    reference_title: "Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The average age of 26 family members who died of SCD was 37.7 years.
    explanation: >-
      Documents sudden cardiac death at a mean age in the fourth decade among relatives
      of R14del index patients.

- name: Syncope
  category: Cardiovascular
  description: >-
    Syncope and presyncope occur as a consequence of ventricular arrhythmia and are
    treated as red-flag symptoms in carrier surveillance.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:30806910
    reference_title: "Phospholamban cardiomyopathy: a Canadian perspective on a unique population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      One patient suffered syncope during physical activity, and subsequently passed
      away due to ventricular tachycardia storm.
    explanation: >-
      Records syncope in an R14del carrier followed by death from ventricular
      tachycardia storm, which is the arrhythmic mechanism this phenotype attributes it
      to. Indirect on two counts: the causal link between the syncopal episode and the
      arrhythmia is inferred from the sequence rather than captured on a rhythm
      recording, and the red-flag surveillance role is a clinical inference from the
      outcome rather than a statement in the cohort.

- name: Dilated cardiomyopathy
  category: Cardiovascular
  description: >-
    Left ventricular, sometimes biventricular, dilatation with impaired systolic
    function. Dilatation may be a late feature: fibrosis and ventricular ectopy commonly
    precede any change in chamber size.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:16432188
    reference_title: "A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Through genetic screening of dilated cardiomyopathy patients, we identified a
      previously uncharacterized deletion of arginine 14 (PLN-R14Del) in the coding
      region of the phospholamban (PLN) gene in a large family with hereditary heart
      failure.
    explanation: >-
      Establishes dilated cardiomyopathy as the presenting phenotype in the family in
      which the R14del allele was identified.

- name: Left ventricular systolic dysfunction
  category: Cardiovascular
  description: >-
    Reduced left ventricular ejection fraction. It is a predictor in the R14del risk
    model, but is explicitly not sufficient on its own for arrhythmic risk assessment,
    because malignant arrhythmia occurs in carriers with preserved function.
  phenotype_term:
    preferred_term: Left ventricular systolic dysfunction
    term:
      id: HP:0025169
      label: Left ventricular systolic dysfunction
  evidence:
  - reference: PMID:34113975
    reference_title: "Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Significant predictors were left ventricular ejection fraction, premature
      ventricular contraction count/24 h, amount of negative T waves, and presence of
      low-voltage electrocardiogram.
    explanation: >-
      Records reduced ejection fraction as a measured phenotype and a component of the
      variant-specific risk model.

- name: Congestive heart failure
  category: Cardiovascular
  description: >-
    Clinical heart failure follows progressive systolic impairment, and in advanced
    disease leads to mechanical circulatory support or transplantation. R14del carriers
    with dilated cardiomyopathy come to transplantation far more often than
    non-carriers with the same diagnosis.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:22820313
    reference_title: "Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared with R14del- DCM patients, R14del+ DCM patients more often demonstrated
      appropriate implantable cardioverter defibrillator discharge (47 % vs. 10 % , P <
      0.001), cardiac transplantation (18 % vs. 2 % , P < 0.001)
    explanation: >-
      The nine-fold excess of cardiac transplantation over genotype-negative dilated
      cardiomyopathy quantifies the end-stage heart-failure burden of the allele.

- name: Exercise intolerance
  category: Cardiovascular
  description: >-
    Reduced functional capacity accompanies progressive systolic impairment and is a
    common presenting complaint once the disease becomes symptomatic.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:33020536
    reference_title: "The phenotypic characteristic observed by cardiac magnetic resonance in a PLN-R14del family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      The proband II6 is a 60-year-old woman, who suffered from activity chest tightness
      for 10 years and the symptom had aggravated for recent 2 years.
    explanation: >-
      Documents activity-limited symptoms in an R14del carrier over a decade, with
      progression, alongside the same family's fatigue and exertional breathlessness.
      Indirect, because the study records exertional symptoms clinically rather than
      measuring aerobic capacity.

- name: Exertional dyspnea
  category: Cardiovascular
  description: >-
    Breathlessness on exertion is the typical heart-failure symptom of the dilated
    presentation.
  phenotype_term:
    preferred_term: Exertional dyspnea
    term:
      id: HP:0002875
      label: Exertional dyspnea
  evidence:
  - reference: PMID:12610310
    reference_title: "Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      an inherited human dilated cardiomyopathy with refractory congestive heart failure
      is caused by a dominant Arg --> Cys missense mutation at residue 9 (R9C) in
      phospholamban (PLN)
    explanation: >-
      Cited for the refractory congestive heart failure syndrome of which exertional
      dyspnea is the cardinal symptom; indirect, because the abstract names the syndrome
      rather than the individual symptom.

- name: Decreased QRS voltage
  category: Cardiovascular
  description: >-
    Low QRS voltage on the surface electrocardiogram is a characteristic, though not
    universal or diagnostic, feature, present in roughly half of R14del carriers. It is
    an independent predictor in the variant-specific arrhythmia risk model.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Decreased QRS voltage
    term:
      id: HP:0025077
      label: Decreased QRS voltage
  evidence:
  - reference: PMID:22820313
    reference_title: "Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A low voltage electrocardiogram was present in 46 % of R14del carriers.
    explanation: >-
      Gives the observed frequency of low QRS voltage among carriers, which supports the
      FREQUENT band.

- name: T-wave inversion
  category: Cardiovascular
  description: >-
    Lateral or precordial T-wave inversion is part of the characteristic
    electrocardiographic signature, and the number of negative T waves is a predictor in
    the R14del arrhythmia risk model.
  phenotype_term:
    preferred_term: T-wave inversion
    term:
      id: HP:0010872
      label: T-wave inversion
  evidence:
  - reference: PMID:34113975
    reference_title: "Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      amount of negative T waves, and presence of low-voltage electrocardiogram
    explanation: >-
      Establishes negative T waves as a counted electrocardiographic phenotype with
      independent prognostic weight in carriers.

- name: Myocardial fibrosis
  category: Cardiovascular
  description: >-
    Subepicardial late gadolinium enhancement in the left ventricular lateral wall, with
    or without linear mid-wall septal enhancement, and elevated extracellular volume on
    T1 mapping. Its detectability in structurally normal carriers is what makes cardiac
    magnetic resonance an early-detection tool in this disease.
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: PMID:33020536
    reference_title: "The phenotypic characteristic observed by cardiac magnetic resonance in a PLN-R14del family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings highlight the special role of CMR to phenotyping PLN-induced
      cardiomyopathy patients and distinguish them from other types of cardiomyopathy.
    explanation: >-
      Supports the fibrosis pattern as characteristic enough to separate PLN disease
      from other cardiomyopathies on imaging.
genetic:
- name: PLN
  gene_term:
    preferred_term: PLN
    term:
      id: hgnc:9080
      label: PLN
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    PLN encodes phospholamban, a 52-amino-acid sarcoplasmic reticulum transmembrane
    protein that reversibly inhibits SERCA2a, an inhibition relieved by protein kinase A
    phosphorylation at Ser16 and CaMKII phosphorylation at Thr17. It is the sole
    causative gene for this entry. The allelic series is mechanistically heterogeneous
    and the alleles are curated separately below rather than merged, because they
    perturb the phospholamban-SERCA2a couple in different directions. p.Arg9Leu,
    p.Arg9His and p.Arg25Cys are further reported alleles that are not separately
    curated here and require individual ACMG/AMP assessment.
  variants:
  - name: PLN p.Arg14del
    description: >-
      NM_002667.5:c.40_42delAGA, p.(Arg14del); also written R14del or R14. An in-frame
      single-codon deletion in the cytoplasmic regulatory domain and the best-studied
      PLN allele, with independent founder lineages in the northern Netherlands and in
      Greece. It produces SERCA2a superinhibition that protein kinase A phosphorylation
      cannot relieve, and in parallel mislocalizes phospholamban into malformed
      sarco/endoplasmic-reticulum clusters that block autophagic flux. Clinically it
      carries a high arrhythmic burden, and it is the only allele for which a validated
      variant-specific arrhythmia risk model exists.
    clinical_significance: PATHOGENIC
    type: in-frame deletion
    evidence:
    - reference: PMID:16432188
      reference_title: "A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Coexpression of the normal and mutant-PLN in HEK-293 cells resulted in
        sarcoplasmic reticulum Ca(2+)-ATPase superinhibition.
      explanation: >-
        Coexpression of normal with mutant protein producing superinhibition is the
        experiment establishing the dominant-negative character of this specific allele.
    - reference: PMID:22820313
      reference_title: "Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Haplotype analysis revealed a common founder, estimated to be between 575 and 825
        years old.
      explanation: >-
        Establishes the founder status of this allele, which is why cohort-derived
        estimates for it are population-specific rather than general to PLN disease.
  - name: PLN p.Arg9Cys
    description: >-
      A missense allele at residue 9, reported in an inherited dilated cardiomyopathy
      with refractory congestive heart failure. Its mechanism is distinct from R14del:
      the mutant protein does not itself inhibit SERCA2a but sequesters protein kinase A,
      preventing phosphorylation of the wild-type phospholamban made from the normal
      allele. The inhibitory brake is therefore applied in trans, by the wild-type
      protein, rather than by the mutant.
    clinical_significance: PATHOGENIC
    type: missense
    evidence:
    - reference: PMID:12610310
      reference_title: "Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Cellular and biochemical studies revealed that, unlike wild-type PLN, PLN(R9C)
        did not directly inhibit SERCA2a. Rather, PLN(R9C) trapped protein kinase A
        (PKA)
      explanation: >-
        States the allele-specific mechanism explicitly and contrasts it with wild-type
        behaviour, which is the basis for curating R9C separately from R14del.
    - reference: PMID:12610310
      reference_title: "Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Transgenic PLN(R9C) mice recapitulated human heart failure with premature death.
      explanation: >-
        Model-organism support that this allele is sufficient to cause the heart-failure
        phenotype.
  - name: PLN p.Leu39Ter
    description: >-
      A nonsense allele (T116G, L39stop) truncating the protein within transmembrane
      domain II. It is a true null: essentially no stable phospholamban is produced,
      what little is made is misrouted away from the sarcoplasmic reticulum, and SERCA2a
      is left uninhibited. It is also the allele that breaks the dominant pattern -
      heterozygotes show hypertrophy with preserved contractility, and only homozygotes
      develop dilated cardiomyopathy, requiring transplantation in adolescence or early
      adulthood. Human phospholamban deficiency is therefore lethal, the inverse of the
      well-tolerated PLN-null mouse.
    clinical_significance: PATHOGENIC
    type: nonsense
    evidence:
    - reference: PMID:12639993
      reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The heterozygous individuals exhibited hypertrophy without diminished contractile
        performance. Strikingly, both individuals homozygous for L39stop developed dilated
        cardiomyopathy and heart failure, requiring cardiac transplantation at ages 16 and
        27.
      explanation: >-
        Establishes the recessive behaviour of this allele for the dilated phenotype,
        which is the reason it cannot be merged with the dominant missense alleles.
  evidence:
  - reference: PMID:40556736
    reference_title: "Genetic landscape of phospholamban cardiomyopathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The growing number of identified variants highlights the previously
      underappreciated role of PLN in cardiac pathophysiology.
    explanation: >-
      Supports curating PLN as a gene with an expanding allelic series rather than a
      single-variant locus.
  - reference: PMID:37144056
    reference_title: "Phospholamban R14del disease: The past, the present and the future."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The PLN-R14del variant in specific is recognized as the cause in an increasing
      number of patients worldwide
    explanation: >-
      Establishes the gene-disease relationship as causative and identifies which allele
      accounts for most of the recognized burden.

diagnosis:
- name: Cardiac Magnetic Resonance Imaging
  diagnosis_term:
    preferred_term: cardiac magnetic resonance imaging with late gadolinium enhancement
      and T1 mapping
    term:
      id: NCIT:C137915
      label: Magnetic Resonance Imaging of the Heart
  description: >-
    The modality that detects this disease before the ventricle dilates. Carriers show a
    characteristic sub-epicardial late-gadolinium-enhancement band in the left ventricular
    lateral wall, sometimes with linear mid-wall septal enhancement, and T1 mapping shows
    raised extracellular volume. Critically, the lateral-wall pattern is present in
    younger carriers whose ventricular structure and function are still completely normal,
    which is why this entry treats cardiac magnetic resonance as an early-detection tool
    rather than as confirmation of an already-evident cardiomyopathy.
  evidence:
  - reference: PMID:33020536
    reference_title: "The phenotypic characteristic observed by cardiac magnetic resonance in a PLN-R14del family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "members underwent cardiac magnetic resonance (CMR) examination showed a strikingly similar pattern of late gadolinium enhancement (LGE)-Sub-epicardial involvement in the left ventricular (LV) lateral wall with or without linear mid-wall enhancement in the interventricular septum. The former one can also present in younger PLN-R14del carriers despite completely normal LV structure and function."
    explanation: >-
      Reports both the characteristic enhancement pattern and its presence in carriers with
      structurally normal ventricles, which is the basis for the early-detection claim.
  - reference: PMID:33020536
    reference_title: "The phenotypic characteristic observed by cardiac magnetic resonance in a PLN-R14del family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings highlight the special role of CMR to phenotyping PLN-induced cardiomyopathy patients and distinguish them from other types of cardiomyopathy."
    explanation: Supports cardiac magnetic resonance as the discriminating modality against other cardiomyopathies.
  notes: >-
    The cohort is a single large Chinese PLN-R14del family, so the pattern is well
    described but its sensitivity and specificity are not established.
- name: PLN Genetic Testing and Cascade Screening of Relatives
  diagnosis_term:
    preferred_term: PLN sequencing, with cascade testing of at-risk relatives
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Molecular confirmation is what separates this entry from dilated cardiomyopathy in
    general, because the arrhythmia risk model and the management that follows from it are
    allele-specific rather than ejection-fraction-based. Identifying the variant in a
    proband converts the relatives' problem into a single predictive test, and most
    carriers in published series are ascertained this way rather than by presenting with
    symptoms.
  evidence:
  - reference: PMID:40556736
    reference_title: "Genetic landscape of phospholamban cardiomyopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These advances underscore the importance of recognizing PLN's role in cardiac disease and the value of genetic testing for accurate diagnosis, prognosis, effective management, and early risk prediction for family members."
    explanation: >-
      Supports genetic testing as the route to diagnosis, prognosis and risk prediction in
      relatives, which is the role this entry curates it in.
  notes: >-
    The supporting statement comes from a review rather than a diagnostic-accuracy study;
    no yield or performance figure is curated here because none was verifiable from the
    cached sources.

treatments:
- name: Guideline-Directed Heart Failure Pharmacotherapy
  description: >-
    Standard heart-failure therapy for carriers with reduced ejection fraction. The
    evidence is extrapolated from general heart-failure trials rather than generated in
    PLN disease, and this is a real limitation: in the knock-in mouse neither eplerenone
    nor metoprolol improved cardiac function or survival, and a completed randomized
    trial of eplerenone in presymptomatic R14del carriers was run precisely because the
    question was open. No PLN-directed disease-modifying therapy is approved.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Ventricular Dilatation and Pump Failure
    description: >-
      Acts on the neurohormonal drive of adverse remodeling at the organ level, not on
      the calcium-handling lesion.
    evidence:
    - reference: PMID:32555305
      reference_title: "The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Neither eplerenone nor metoprolol administration improved cardiac function or
        survival.
      explanation: >-
        A negative result in the genotype-matched mouse, cited to record that standard
        heart-failure drugs did not modify the disease in that model.
  evidence:
  - reference: PMID:32555305
    reference_title: "The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      Administration of standard heart failure therapy did not rescue the phenotype,
      underscoring the need for better understanding of the pathophysiology of
      PLN-R14del-associated cardiomyopathy.
    explanation: >-
      Supports curating this treatment as symptomatic rather than disease-modifying;
      indirect, because the result is from the mouse model rather than a carrier trial.

- name: Implantable Cardioverter-Defibrillator
  description: >-
    Defibrillator implantation for sudden-death prevention. The decision in R14del
    carriers is deliberately not made on ejection fraction alone: a variant-specific
    model combining ejection fraction, 24-hour ventricular ectopic count, number of
    negative T waves, and low QRS voltage discriminates arrhythmic risk substantially
    better (C-statistic 0.83) than the earlier generic PLN model (0.68). This is the
    single most consequential way PLN disease is managed differently from the sarcomeric
    dilated cardiomyopathies.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_mechanisms:
  - target: Arrhythmogenic Substrate Formation
    description: >-
      Does not modify the substrate; terminates the arrhythmias it generates.
    evidence:
    - reference: PMID:22820313
      reference_title: "Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        R14del+ DCM patients more often demonstrated appropriate implantable
        cardioverter defibrillator discharge (47 % vs. 10 % , P < 0.001)
      explanation: >-
        Appropriate discharges in nearly half of carriers, against a tenth of
        genotype-negative patients, evidences the device acting on a genotype-specific
        arrhythmic substrate.
  evidence:
  - reference: PMID:34113975
    reference_title: "Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This study aims to improve risk stratification for primary prevention implantable
      cardioverter defibrillator (ICD) implantation by developing a new mutation-specific
      prediction model for malignant ventricular arrhythmia (VA) in phospholamban (PLN)
      p.Arg14del mutation carriers.
    explanation: >-
      Establishes that defibrillator selection in this disease is driven by a
      variant-specific model rather than generic criteria.
  - reference: PMID:34113975
    reference_title: "Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The multivariable model had an excellent discriminative ability {C-statistic 0.83
      [95% confidence interval (CI) 0.78-0.88]}. Applying the existing PLN risk model to
      the complete cohort yielded a C-statistic of 0.68 (95% CI 0.61-0.75).
    explanation: >-
      Quantifies the gain of the variant-specific model over the generic one, which is
      the justification for using it.

- name: Catheter Ablation of Ventricular Tachycardia
  description: >-
    Considered for recurrent monomorphic ventricular tachycardia or repeated
    defibrillator shocks. It addresses reentry around the fibrotic substrate and is
    adjunctive to, not a substitute for, defibrillator therapy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cardiac catheter ablation
    term:
      id: NCIT:C100068
      label: Cardiac Ablation
  target_mechanisms:
  - target: Arrhythmogenic Substrate Formation
    description: >-
      Interrupts reentrant circuits within the fibrotic substrate.

- name: Heart Transplantation
  description: >-
    Definitive therapy for end-stage disease, preceded in many carriers by durable
    mechanical circulatory support. R14del carriers with a dilated presentation reach
    transplantation far more often than genotype-negative patients with the same
    diagnosis.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Heart Transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_mechanisms:
  - target: Ventricular Dilatation and Pump Failure
    description: >-
      Replaces the failing organ; it does not act on any upstream node.
    evidence:
    - reference: PMID:22820313
      reference_title: "Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        cardiac transplantation (18 % vs. 2 % , P < 0.001)
      explanation: >-
        Quantifies transplantation rates in carriers against genotype-negative dilated
        cardiomyopathy patients.

- name: Genetic Counseling and Cascade Testing
  description: >-
    First-degree relatives of a carrier are offered counseling and targeted testing for
    the familial variant, followed by longitudinal electrocardiography, ambulatory rhythm
    monitoring, echocardiography and periodic cardiac magnetic resonance if
    genotype-positive. Most carriers in published cohorts enter care through family
    screening rather than symptoms, which is what makes this the highest-yield
    intervention in the disease.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:34113975
    reference_title: "Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers-reaching the frontiers of individual risk prediction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of the final cohort (83%) were family members of an index patient and
      most subjects were asymptomatic at baseline (85%).
    explanation: >-
      Shows that cascade screening, not symptomatic presentation, is how most carriers
      are identified.

clinical_trials:
- name: NCT01857856
  phase: PHASE_III
  status: COMPLETED
  description: >-
    iPHORECAST. Randomized study of eplerenone in presymptomatic PLN R14del carriers,
    testing whether antifibrotic mineralocorticoid-receptor blockade delays onset of
    overt disease. 84 participants.
  target_phenotypes:
  - preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: clinicaltrials:NCT01857856
    reference_title: "PHOspholamban RElated CArdiomyopathy STudy - Intervention (Efficacy Study of Eplerenone in Presymptomaticphospholamban R14del Carriers)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The investigators hypothesize that treatment of presymptomatic PLN R14del-carriers
      with eplerenone, which by virtue of its mineralocorticoid(aldosterone)-blocking
      properties is a strong antifibrotic agent, reduces disease progression and
      postpones onset of overt disease.
    explanation: >-
      States the trial's hypothesis, which targets the fibrosis node of this entry's
      pathograph in presymptomatic carriers.

- name: NCT04978987
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    DECIPHER-PLN. Observational multi-omics cohort profiling plasma, cardiac and
    skeletal muscle from R14del carriers across the severity range, plus patient-derived
    iPSC cardiomyocytes, to identify disease-specific pathways and the modifiers behind
    the disease's very variable penetrance. Approximately 103 participants.
  evidence:
  - reference: clinicaltrials:NCT04978987
    reference_title: "Identification of Disease Specific Pathways and Modifiers in Phospholamban R14del Cardiomyopathy"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subjects with a heterozygous PLN R14del mutation show a wide variety in phenotype.
      Within the same family, patients can present either with over heart failure in
      their 20's or completely asymptomatic until at least their 70's. So far, no
      modifiers have been identified.
    explanation: >-
      Documents the unexplained variable expressivity that this cohort was designed to
      resolve, and confirms no modifier is yet established.

- name: NCT07241104
  phase: PHASE_I
  status: RECRUITING
  description: >-
    First-in-human single-ascending-dose study of AZD4063 in adults with PLN R14del
    dilated cardiomyopathy, assessing safety, tolerability and pharmacokinetics.
    Estimated enrolment 23 participants. This is the only interventional trial of a
    PLN-directed agent in humans; the registration does not disclose the molecular
    mechanism of AZD4063, so no pathograph node is claimed for it here.
  evidence:
  - reference: clinicaltrials:NCT07241104
    reference_title: "A Phase I First-in-human Study to Investigate Safety, Tolerability, and Pharmacokinetics of AZD4063 in Adults With Phospholamban R14del Dilated Cardiomyopathy"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of the study is to assess the safety, tolerability and the
      pharmacokinetics (PK) of AZD4063 after single dose administration in participants
      with phospholamban (PLN) R14del dilated cardiomyopathy.
    explanation: >-
      Establishes that a genotype-restricted interventional agent has reached first-in-human
      testing in this disease.
mechanistic_hypotheses:
- hypothesis_group_id: pln_serca_superinhibition
  hypothesis_label: SERCA2a Superinhibition Model
  status: CANONICAL
  description: >-
    The original and long-dominant model, and the one the calcium arm of this entry's
    pathograph is built on: mutant phospholamban chronically suppresses SERCA2a
    activity in a manner that protein kinase A phosphorylation cannot relieve, so
    sarcoplasmic-reticulum calcium reuptake is persistently impaired and contractile
    and electrical dysfunction follow. It originates in the coexpression experiments
    that accompanied the discovery of the R14del allele in 2006.
  evidence:
  - reference: PMID:16432188
    reference_title: "A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Thus, by chronic suppression of sarcoplasmic reticulum Ca(2+)-ATPase activity, the
      nonreversible superinhibitory function of mutant PLN-R14Del may lead to inherited
      dilated cardiomyopathy and premature death in both humans and mice.
    explanation: >-
      States the canonical model in full, from sustained pump suppression through to the
      clinical phenotype.

- hypothesis_group_id: pln_ser_malformation
  hypothesis_label: Sarco/Endoplasmic Reticulum Malformation and Proteostasis Model
  status: EMERGING
  description: >-
    A competing, non-mutually-exclusive model holding that the primary lesion is
    abnormal phospholamban distribution and malformed sarco/endoplasmic-reticulum
    membrane architecture, with the downstream proteostatic and autophagic failure that
    follows, rather than altered SERCA2a kinetics. Two observations drive it: the
    direction and magnitude of the R14del effect on SERCA activity is disputed across
    systems, and the hallmark perinuclear structures turn out on close inspection to be
    clustered membrane rather than protein aggregate. The distinction is not academic -
    it decides whether therapeutic effort should go to the SERCA axis or to correcting
    membrane architecture and autophagic flux. Both arms are curated as parallel
    branches in this entry's pathograph because the relative contribution is unsettled,
    not because both are established.
  evidence:
  - reference: PMID:39297138
    reference_title: "Reassessing the Mechanisms of PLN-R14del Cardiomyopathy: From Calcium Dysregulation to S/ER Malformation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Strategies targeting sarco/endoplasmic reticulum malformation may, therefore, prove
      more effective than SERCA activity modulation.
    explanation: >-
      States the therapeutic consequence that distinguishes this model from the canonical
      one, which is why the two are curated as separate hypothesis groups.
  - reference: PMID:39297138
    reference_title: "Reassessing the Mechanisms of PLN-R14del Cardiomyopathy: From Calcium Dysregulation to S/ER Malformation."
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      However, recent studies raised controversy regarding the effect of PLN-R14del on
      SERCA activity
    explanation: >-
      Cited against the canonical superinhibition model: the SERCA effect that model
      rests on is itself contested.

experimental_models:
- name: Isogenic PLN-R14del hiPSC-cardiomyocyte and 3D engineered heart tissue pair
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: hiPSC-derived cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cell_source: Patient-derived hiPSC lines carrying PLN R14del, plus a healthy-donor line
    into which R14del was introduced; each paired with its CRISPR/Cas9-corrected or
    unedited isogenic control.
  culture_system: Two-dimensional monolayer culture and three-dimensional engineered
    heart tissue (3D-EHT).
  publication: PMID:33928785
  description: >-
    Three isogenic hiPSC pairs differing only at the PLN R14del allele, differentiated to
    cardiomyocytes and assayed for contractility in both 2D monolayers and 3D engineered
    heart tissues. Because the comparison is isogenic, a contractile difference is
    assignable to the variant rather than to donor background. The same system carries
    the unfolded-protein-response arm of this entry's second hypothesis group, and
    supplies its only pharmacological rescue.
  modeled_mechanisms:
  - target: Cardiomyocyte Contractile Dysfunction
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      R14del hiPSC-CMs show reduced contractility against their isogenic controls in both
      culture formats, which is the in-vitro counterpart of this node.
    limitations: >-
      hiPSC-CMs are immature relative to adult ventricular myocardium, lack the loading
      and neurohormonal environment of the intact heart, and cannot reproduce the
      chamber-level dilatation or the arrhythmic endpoints that dominate the human
      disease.
    readouts:
    - name: Contractile force in 3D engineered heart tissue and 2D monolayer
      target: Cardiomyocyte Contractile Dysfunction
      direction: DECREASED
      interpretation: >-
        Isogenic-paired contractility deficit, the quantifiable in-vitro correlate of the
        contractile-dysfunction node.
      evidence:
      - reference: PMID:33928785
        reference_title: "Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "hiPSC-CMs carrying the PLN R14del mutation (patient and HD R14del introduced) showed decreased contractility in three-dimensional engineered heart tissues (3D-EHTs)"
        explanation: Reports the direction and the assay behind this readout.
    evidence:
    - reference: PMID:33928785
      reference_title: "Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Modeling of the PLN R14del cardiomyopathy with isogenic pairs of hiPSC-CMs recapitulated the contractile deficit associated with the disease in vitro."
      explanation: States that this model is informative for the contractile-dysfunction node.
  - target: Endoplasmic Reticulum Stress and Unfolded Protein Response Activation
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Single-cell RNA sequencing of the isogenic pair identified UPR induction as the
      transcriptional signature of the variant, and the same activation was confirmed in
      myocardium from PLN R14del patients.
    limitations: >-
      UPR activation is also seen in desmosomal ARVC and ischemic cardiomyopathy hearts,
      so it is not specific to this variant; the model establishes that R14del induces
      it, not that it is the discriminating lesion.
    readouts:
    - name: Unfolded protein response transcriptional program
      target: Endoplasmic Reticulum Stress and Unfolded Protein Response Activation
      direction: INCREASED
      interpretation: >-
        UPR pathway induction in R14del cardiomyocytes relative to isogenic control.
      evidence:
      - reference: PMID:33928785
        reference_title: "Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Single-cell RNA sequencing revealed the induction of the unfolded protein response (UPR) pathway in PLN R14del compared with isogenic control hiPSC-CMs."
        explanation: Reports the measurement and its direction in the isogenic comparison.
    evidence:
    - reference: PMID:33928785
      reference_title: "Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The activation of UPR was also evident in the hearts from PLN R14del patients."
      explanation: >-
        Anchors the model's UPR readout to human myocardium, which is what makes the
        model informative for this node rather than an in-vitro artifact.
  - target: Cardiomyocyte Contractile Dysfunction
    relationship: RESCUES
    fidelity: MODERATE
    description: >-
      Pharmacological activation of the UPR with BiP inducer X partially reversed the
      contractile deficit, which is the experiment that makes the proteostatic arm a
      candidate therapeutic target rather than an epiphenomenon.
    limitations: >-
      A dose-dependent rescue in engineered tissue is not evidence of clinical benefit;
      no PLN-directed or UPR-directed therapy has been tested in patients.
    readouts:
    - name: Contractility after BiP inducer X treatment
      target: Cardiomyocyte Contractile Dysfunction
      direction: RESTORED
      interpretation: >-
        Dose-dependent amelioration of the contractile deficit without a change in calcium
        handling, separating the proteostatic arm from the calcium arm.
      evidence:
      - reference: PMID:33928785
        reference_title: "Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "PLN R14del hiPSC-CMs treated with BiP protein inducer X showed a dose-dependent amelioration of the contractility deficit in both 2-dimensional cultures and 3-dimensional engineered heart tissues without affecting calcium homeostasis."
        explanation: Reports the rescue, its dose dependence, and that calcium handling was unchanged.
    evidence:
    - reference: PMID:33928785
      reference_title: "Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We explored the therapeutic potential of activating the UPR with a small molecule activator, BiP (binding immunoglobulin protein) inducer X."
      explanation: Establishes the rescue arm as a deliberate intervention in this model.
  notes: >-
    Silencing any of the three UPR branches (IRE1, ATF6, PERK) worsened contractility in
    this system, which is why the UPR is curated here as protective rather than as the
    injury itself.

animal_models:
- name: PLN-R14del knock-in mouse
  species: Mouse
  genotype: Pln p.(Arg14del) knock-in, heterozygous and homozygous
  publication: PMID:32555305
  description: >-
    Knock-in mouse carrying the human R14del lesion. Heterozygotes, the genotype that
    matches human carriers, develop inducible arrhythmia susceptibility and a
    cardiomyopathy only at 18 months. Homozygotes show an accelerated course with
    dilatation, contractile failure, low ECG voltages, fibrosis, phospholamban
    aggregation and early death - useful for testing therapies quickly, but not the
    human genotype.
  modeled_mechanisms:
  - target: Arrhythmogenic Substrate Formation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Heterozygous animals reproduce the arrhythmic susceptibility that defines the
      human disease.
    limitations: >-
      Arrhythmia is induced ex vivo rather than observed spontaneously, and beta-adrenergic
      challenge did not accelerate disease as it might be expected to in carriers.
    evidence:
    - reference: PMID:32555305
      reference_title: "The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Heterozygous PLN-R14del mice demonstrated increased susceptibility to ex vivo
        induced arrhythmias, and cardiomyopathy at 18 months of age, which was not
        accelerated by isoproterenol infusion.
      explanation: >-
        Supports treating the heterozygous mouse as informative for the arrhythmic
        substrate, at the genotype that matches human carriers.
  - target: Perinuclear Phospholamban-Positive Deposits
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Homozygous animals reproduce the hallmark phospholamban-positive material seen in
      human myocardium.
    limitations: >-
      Only the homozygous animals show it on this timescale, and homozygosity is
      essentially absent among human carriers, so the finding is reached through a
      genotype the disease does not normally present with.
    evidence:
    - reference: PMID:32555305
      reference_title: "The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Homozygous PLN-R14del mice exhibited an accelerated phenotype including cardiac
        dilatation, contractile dysfunction, decreased ECG potentials, high susceptibility
        to ex vivo induced arrhythmias, myocardial fibrosis, PLN protein aggregation, and
        early mortality.
      explanation: >-
        Records phospholamban aggregation alongside the other disease features in the
        homozygous animals.
  evidence:
  - reference: PMID:32555305
    reference_title: "The phospholamban p.(Arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unreponsive to standard heart failure therapy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In conclusion, our novel PLN-R14del mouse model exhibits most features of human
      disease.
    explanation: >-
      Supports treating this model as informative for the disease overall, with "most"
      rather than all features being the stated scope.

- name: PLN-null mouse (comparative)
  species: Mouse
  genotype: Pln knockout
  publication: PMID:12639993
  description: >-
    Cited as a negative comparator rather than as a disease model. Phospholamban
    ablation is well tolerated in the mouse and even enhances cardiac function, whereas
    the equivalent human null state produces lethal dilated cardiomyopathy. The species
    divergence is the reason PLN knockdown was historically viewed as a therapeutic
    strategy and why that inference does not transfer.
  modeled_mechanisms:
  - target: Loss of Phospholamban Protein
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      The mouse does not reproduce the human consequence of absent phospholamban.
    limitations: >-
      The direction of effect is inverted between species: mice lacking phospholamban
      show enhanced calcium reuptake and contractility with no adverse outcome, while
      humans lacking it develop lethal dilated cardiomyopathy. Any therapeutic argument
      resting on murine PLN ablation therefore does not carry to patients, and complete
      phospholamban depletion is a specific safety concern for silencing approaches.
    evidence:
    - reference: PMID:12639993
      reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In contrast to reported benefits of PLN ablation in mouse heart failure, humans
        lacking PLN develop lethal dilated cardiomyopathy.
      explanation: >-
        Directly states the species divergence, which is what makes this a
        failure-to-recapitulate rather than a partial model.
  evidence:
  - reference: PMID:12639993
    reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In mice, disruption of the PLN gene encoding phospholamban (PLN) or expression of
      dominant-negative PLN mutants enhances SR and cardiac function, but effects of PLN
      mutations in humans are unknown.
    explanation: >-
      Records the murine baseline against which the human finding was the surprise,
      establishing why this model is cited as a comparator.
discussions:
- discussion_id: pln_null_mouse_human_divergence
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Phospholamban ablation is benign, even beneficial, in the mouse but lethal in
    humans. Which species is informative for the consequences of reducing phospholamban,
    and what does that mean for silencing and gene-editing strategies that lower mutant
    or total PLN?
  attaches_to:
  - pathophysiology#Loss of Phospholamban Protein
  - animal_models#Mouse
  rationale: >-
    This is a mismatch rather than a gap: the murine evidence is abundant and
    unambiguous, it simply points the opposite way. Mice lacking phospholamban show
    enhanced sarcoplasmic-reticulum function and normal lifespan, which historically
    made PLN suppression look like an attractive heart-failure target; the human
    L39stop homozygotes instead required transplantation in their teens and twenties.
    The discrepancy matters directly for therapy, because the leading experimental
    approaches in R14del disease act by reducing mutant or total phospholamban, and the
    safety margin for depletion cannot be read off the mouse.

    Scope note: animal-model entity references resolve on species, so the
    `animal_models#Mouse` reference above matches both mouse models in this entry. The
    model at issue here is the phospholamban-null mouse, not the R14del knock-in.
  evidence:
  - reference: PMID:12639993
    reference_title: "Human phospholamban null results in lethal dilated cardiomyopathy revealing a critical difference between mouse and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to reported benefits of PLN ablation in mouse heart failure, humans
      lacking PLN develop lethal dilated cardiomyopathy.
    explanation: >-
      States the mismatch directly, in the same sentence, for both species.

- discussion_id: pln_r14del_penetrance_modifiers
  kind: KNOWLEDGE_GAP
  prompt: >-
    What determines whether a PLN R14del carrier remains asymptomatic into their
    seventies or reaches end-stage heart failure in their twenties? No genetic,
    epigenetic, or environmental modifier is validated.
  attaches_to:
  - genetic#PLN
  - clinical_trials#NCT04978987
  rationale: >-
    Penetrance is incomplete and age-dependent and expressivity varies widely within a
    single family carrying one founder allele, so the variance cannot be attributed to
    allelic heterogeneity. Without a modifier, risk stratification has to rest entirely
    on acquired phenotypic markers - ejection fraction, ectopic burden, T-wave changes,
    QRS voltage - which is why the arrhythmia risk model looks the way it does. A
    completed multi-omics cohort was designed around this question and had not
    identified a modifier at the time of its registration.
  evidence:
  - reference: clinicaltrials:NCT04978987
    reference_title: "Identification of Disease Specific Pathways and Modifiers in Phospholamban R14del Cardiomyopathy"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Within the same family, patients can present either with over heart failure in
      their 20's or completely asymptomatic until at least their 70's. So far, no
      modifiers have been identified.
    explanation: >-
      Establishes both the magnitude of the unexplained variability and that no modifier
      was known when the cohort was designed to look for one.

references:
- reference: PMID:20301486
  title: Dilated Cardiomyopathy Overview.
  tags:
  - GeneReviews
- reference: PMID:37144056
  title: "Phospholamban R14del disease: The past, the present and the future."
- reference: PMID:39297138
  title: "Reassessing the Mechanisms of PLN-R14del Cardiomyopathy: From Calcium Dysregulation to S/ER Malformation."
- reference: PMID:40556736
  title: "Genetic landscape of phospholamban cardiomyopathies."

notes: >-
  Scope and lump/split. This entry is kept separate from the sarcomeric and
  cytoskeletal dilated cardiomyopathies on mechanism and on management, not on
  nomenclature. The lesion is in sarcoplasmic-reticulum calcium reuptake - the
  phospholamban-SERCA2a regulatory couple - rather than in force generation or force
  transmission, and R14del carriers are managed with a variant-specific arrhythmia risk
  model that supersedes ejection-fraction-based defibrillator criteria.

  Allelic heterogeneity is curated explicitly rather than merged. R14del superinhibits
  SERCA2a irreversibly and mislocalizes phospholamban; R9C does not inhibit the pump at
  all but sequesters protein kinase A; L39stop abolishes the protein and behaves
  recessively for the dilated phenotype. Quantitative statements about penetrance,
  arrhythmic risk, and disease frequency in this entry derive from Dutch R14del founder
  cohorts and should not be transferred to other alleles or ancestries.

  The disputed mechanism is recorded as two hypothesis groups rather than resolved.
  Whether the primary lesion is altered SERCA2a kinetics or sarco/endoplasmic-reticulum
  malformation with proteostatic failure is unsettled in the primary literature, and
  both branches are drawn in the pathograph with their edges tagged to the corresponding
  hypothesis group.

  Not curated here. Experimental PLN-directed therapies - antisense silencing, AAV9-CRISPR
  disruption of the mutant allele, autophagy and unfolded-protein-response modulation -
  are preclinical, and no approved PLN-specific therapy exists; they are omitted from
  `treatments` rather than listed as options. AZD4063 is the exception and is now curated
  under `clinical_trials` as NCT07241104: the registration was confirmed on review as a
  recruiting phase 1 study, with an estimated enrolment of 23 rather than the 31 the
  deep-research report gave. It stays out of `treatments` because the registry does not
  disclose the agent's mechanism, so there is no node for it to target. The canine PLN
  p.Arg9His cardiomyopathy reported as a spontaneous comparative model is likewise not
  curated: it is a different allele from any modelled here and no citable record for it
  was verified. The mitochondrial and metabolic arm of the mechanism - impaired
  fatty-acid oxidation, lipid-droplet accumulation, energetic deficiency and oxidative
  stress downstream of the calcium lesion - is described in the deep-research report but
  is not drawn in the pathograph, because the supporting observations are not separable
  from generic end-stage heart-failure remodeling in the sources available here.

  Penetrance is curated qualitatively, as `INCOMPLETE` with an age-dependent onset in the
  fifth decade. The deep-research report gives roughly 70% of R14del carriers experiencing
  a major cardiac event by age 70, but that figure appears in no reference cached for this
  entry, so it is deliberately not recorded as a quantitative value.

  GeneReviews scope. The GeneReviews resource applicable to this entry is the
  disease-level "Dilated Cardiomyopathy Overview" (PMID:20301486), tagged accordingly in
  `references`. Its indexed PubMed record is content_type abstract_only and carries only
  the chapter's purpose statement, not the Clinical Characteristics, Management, or
  Genetic Counseling sections, so section-by-section GeneReviews mining is not possible
  from the cache and no snippet is quoted from it.

  Source note. The Edison/falcon deep-research report for this disease
  (`research/Dilated_Cardiomyopathy_1P-deep-research-falcon.md`) carried no PMIDs, only
  DOIs, and every reference used here was resolved to a PMID and re-fetched before use.
  Two HPO identifiers the report suggested name entirely different concepts and were
  discarded: it gave `HP:0001738` for "Left ventricular systolic dysfunction" (the term
  is *Exocrine pancreatic insufficiency*; the correct term is `HP:0025169`) and
  `HP:0031540` for "Low-voltage electrocardiogram" (the term is *Linear IgG deposits
  along the epidermal basement membrane zone*; the correct term is `HP:0025077`,
  *Decreased QRS voltage*). The report's own term-validation section reported 28/28
  terms resolved, which is consistent - both CURIEs do exist - and is a reminder that
  resolution is not correctness.
📚

References & Deep Research

References

4
PMID:20301486
Dilated Cardiomyopathy Overview.
No top-level findings curated for this source.
PMID:37144056
Phospholamban R14del disease: The past, the present and the future.
No top-level findings curated for this source.
PMID:39297138
Reassessing the Mechanisms of PLN-R14del Cardiomyopathy: From Calcium Dysregulation to S/ER Malformation.
No top-level findings curated for this source.
PMID:40556736
Genetic landscape of phospholamban cardiomyopathies.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (3)

Record notes

Scope and lump/split. This entry is kept separate from the sarcomeric and cytoskeletal dilated cardiomyopathies on mechanism and on management, not on nomenclature. The lesion is in sarcoplasmic-reticulum calcium reuptake - the phospholamban-SERCA2a regulatory couple - rather than in force generation or force transmission, and R14del carriers are managed with a variant-specific arrhythmia risk model that supersedes ejection-fraction-based defibrillator criteria. Allelic heterogeneity is curated explicitly rather than merged. R14del superinhibits SERCA2a irreversibly and mislocalizes phospholamban; R9C does not inhibit the pump at all but sequesters protein kinase A; L39stop abolishes the protein and behaves recessively for the dilated phenotype. Quantitative statements about penetrance, arrhythmic risk, and disease frequency in this entry derive from Dutch R14del founder cohorts and should not be transferred to other alleles or ancestries. The disputed mechanism is recorded as two hypothesis groups rather than resolved. Whether the primary lesion is altered SERCA2a kinetics or sarco/endoplasmic-reticulum malformation with proteostatic failure is unsettled in the primary literature, and both branches are drawn in the pathograph with their edges tagged to the corresponding hypothesis group. Not curated here. Experimental PLN-directed therapies - antisense silencing, AAV9-CRISPR disruption of the mutant allele, autophagy and unfolded-protein-response modulation - are preclinical, and no approved PLN-specific therapy exists; they are omitted from `treatments` rather than listed as options. AZD4063 is the exception and is now curated under `clinical_trials` as NCT07241104: the registration was confirmed on review as a recruiting phase 1 study, with an estimated enrolment of 23 rather than the 31 the deep-research report gave. It stays out of `treatments` because the registry does not disclose the agent's mechanism, so there is no node for it to target. The canine PLN p.Arg9His cardiomyopathy reported as a spontaneous comparative model is likewise not curated: it is a different allele from any modelled here and no citable record for it was verified. The mitochondrial and metabolic arm of the mechanism - impaired fatty-acid oxidation, lipid-droplet accumulation, energetic deficiency and oxidative stress downstream of the calcium lesion - is described in the deep-research report but is not drawn in the pathograph, because the supporting observations are not separable from generic end-stage heart-failure remodeling in the sources available here. Penetrance is curated qualitatively, as `INCOMPLETE` with an age-dependent onset in the fifth decade. The deep-research report gives roughly 70% of R14del carriers experiencing a major cardiac event by age 70, but that figure appears in no reference cached for this entry, so it is deliberately not recorded as a quantitative value. GeneReviews scope. The GeneReviews resource applicable to this entry is the disease-level "Dilated Cardiomyopathy Overview" (PMID:20301486), tagged accordingly in `references`. Its indexed PubMed record is content_type abstract_only and carries only the chapter's purpose statement, not the Clinical Characteristics, Management, or Genetic Counseling sections, so section-by-section GeneReviews mining is not possible from the cache and no snippet is quoted from it. Source note. The Edison/falcon deep-research report for this disease (`research/Dilated_Cardiomyopathy_1P-deep-research-falcon.md`) carried no PMIDs, only DOIs, and every reference used here was resolved to a PMID and re-fetched before use. Two HPO identifiers the report suggested name entirely different concepts and were discarded: it gave `HP:0001738` for "Left ventricular systolic dysfunction" (the term is *Exocrine pancreatic insufficiency*; the correct term is `HP:0025169`) and `HP:0031540` for "Low-voltage electrocardiogram" (the term is *Linear IgG deposits along the epidermal basement membrane zone*; the correct term is `HP:0025077`, *Decreased QRS voltage*). The report's own term-validation section reported 28/28 terms resolved, which is consistent - both CURIEs do exist - and is a reminder that resolution is not correctness.

Address re-review on PR #10872 · 2026-09-04T16:36:47Z · View source

Closed the three IMPORTANT findings from the 2026-09-04 re-review. Cell type: the hiPSC-derived cardiomyocyte in experimental_models was bound to CL:0002322 (embryonic stem cell), wrong on both differentiation state and origin. Rebound to CL:0000746 (cardiac muscle cell), which this file already uses for four other nodes. Reference titles: added the 16 missing reference_title values on evidence items in inheritance, progression, diagnosis, clinical_trials, experimental_models and discussions. Thirteen were copied from the same PMID's existing title elsewhere in the file; the three clinicaltrials items took their registry titles from the cache frontmatter. No title was retyped. Non-supporting quotes: the Syncope and Exercise intolerance phenotypes cited snippets that did not bear on their claims. Confirmed the reviewer's finding independently - syncope appears in none of the 13 references this entry cites, and a PubMed query for phospholamban AND syncope returns zero records, so no abstract-level source exists. Found the phenotype in PMC full text instead and fetched PMID:30806910 (Cheung et al., Canadian PLN R14del cohort), which records syncope during physical activity followed by fatal ventricular tachycardia storm in a carrier - the arrhythmic mechanism the phenotype attributes it to. Exercise intolerance now cites PMID:33020536, already used five times here, for a decade of progressive activity-limited symptoms in the proband, replacing a quote about ACM prevalence. Both kept directness: INDIRECT with explanations naming the specific inference step. Also fixed while in the file: one PMID:33020536 evidence item was graded evidence_source: OTHER while five others in the same file graded the same publication HUMAN_CLINICAL. evidence_source classifies the publication, not the quote, so this is now HUMAN_CLINICAL throughout. check-snippet-grading cannot catch this because it keys on the quoted sentence and these items quote different sentences. Suggestions taken: moved the entity-reference bookkeeping sentence out of the head of the pln_null_mouse_human_divergence rationale to the end as a scope note, so the rationale opens with the scientific argument; and curated NCT07241104 (AZD4063 first-in-human) after confirming against the ClinicalTrials.gov API that it is recruiting, phase 1, estimated enrolment 23 - not the 31 the deep-research report gave. It stays out of treatments because the registration does not disclose the agent's mechanism, so there is no node for it to target. The notes paragraph that deferred it was rewritten to record the confirmation. Validation: just validate, validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-qualifier-terms and validate-disorders all pass. Snippets 86 to 87, all verified. The five whole-KB baseline checks report no new defects and no baseline was modified.

Create: Dilated_Cardiomyopathy_1P · 2026-09-04T03:07:24Z · View source

Created the entry for dilated cardiomyopathy 1P (MONDO:0012362, PLN / hgnc:9080) from the Edison/falcon deep-research report at research/Dilated_Cardiomyopathy_1P-deep-research-falcon.md. Ran 'just preflight-dr' manually against MONDO:0012362 because the report frontmatter carries an empty mondo_id (known generator bug, dismech#10335); preflight PASSED with PLN mentioned 76 times as top gene. The falcon report carried 0 PMIDs and DOIs only, so all 12 literature references were resolved to PMIDs via the PMC ID converter and re-fetched with 'just fetch-reference' before use. Two HPO CURIEs the report suggested name entirely different concepts and were discarded: HP:0001738 offered as 'Left ventricular systolic dysfunction' is Exocrine pancreatic insufficiency (correct term HP:0025169), and HP:0031540 offered as 'Low-voltage electrocardiogram' is Linear IgG deposits along the epidermal basement membrane zone (correct term HP:0025077 Decreased QRS voltage); the report's own term-validation section reported 28/28 resolved, which is consistent since both CURIEs exist. Pathograph built on calcium handling rather than force generation, with allele-specific branches kept separate: R14del (non-reversible SERCA2a superinhibition plus S/ER mislocalization and autophagic block), R9C (PKA sequestration in trans, no direct pump inhibition), and L39stop (null, recessive for the dilated phenotype). Alleles curated as Variant objects under genetic.PLN. The unresolved SERCA-superinhibition vs S/ER-malformation debate is recorded as two mechanistic_hypotheses groups with competing causal edges tagged rather than resolved. Added a HUMAN_MODEL_MISMATCH discussion for the inverted PLN-null mouse/human phenotype and a KNOWLEDGE_GAP for unexplained penetrance. Conformance declared to fibrotic_response#Excessive ECM Deposition and cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure. Deliberately omitted: preclinical PLN-directed therapies (ASO, AAV9-CRISPR, UPR modulation), a phase 1 AZD4063 trial whose registry status could not be confirmed, and a canine PLN p.Arg9His model with no verified citable record; all noted in the entry notes. Validation: just validate, validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-enum-values and the batched validate-disorders all pass, with 73/73 evidence snippets verified against the reference cache. Whole-KB baseline checks (folded hyphens, snippet length, title snippets, snippet grading, environmental evidence) report no new defects and no baseline was modified. Argued against the dashboard/priority.json LUMP_INTO_PARENT recommendation in the PR body per issue #9865: the recommendation is driven by the NUMBERED_SERIES label heuristic, 17 sibling numbered DCM entries are already standalone, and PLN is the only calcium-handling gene among them. Deleted stubs/Dilated_Cardiomyopathy_1P.yaml.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 22 citations 2026-09-03T20:38:34.222007

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Dilated Cardiomyopathy 1P
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Dilated Cardiomyopathy 1P covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Dilated Cardiomyopathy 1P (PLN-related cardiomyopathy): research report

Executive summary

Dilated cardiomyopathy 1P (DCM1P) is the historical Mendelian designation for cardiomyopathy caused by pathogenic germline variants in PLN, encoding phospholamban. Contemporary practice generally uses PLN-related cardiomyopathy, because affected people can have dilated cardiomyopathy (DCM), left-dominant/biventricular arrhythmogenic cardiomyopathy, or an early non-dilated phenotype dominated by ventricular arrhythmia and myocardial fibrosis. The best-characterized variant is the autosomal-dominant in-frame deletion PLN NM_002667.5:c.40_42delAGA, p.(Arg14del) (“R14del”). Its expression ranges from lifelong asymptomatic carriage to malignant ventricular arrhythmia, sudden cardiac death (SCD), severe heart failure, mechanical circulatory support, or transplantation. Penetrance is incomplete and age-dependent. (vafiadaki2023phospholambanr14deldisease pages 2-3, monda2022clinicalandmolecular pages 1-2, stege2024reassessingthemechanisms pages 1-2)

The evidence base is disproportionately derived from the Dutch R14del founder population. Findings for R14del should therefore not automatically be assigned to every PLN variant or ancestry. There is currently no approved PLN-directed treatment; clinical care combines longitudinal family screening, cardiac magnetic resonance (CMR), rhythm surveillance, guideline-directed heart-failure therapy, and genotype-informed SCD prevention. ASO silencing, gene editing, and proteostasis/autophagy interventions remain investigational. (vafiadaki2023phospholambanr14deldisease pages 2-3, stege2024reassessingthemechanisms pages 1-2, verstraelen2021predictionofventricular pages 3-4)

A compact knowledge-base representation precedes the detailed report:

Field Curated value Evidence/limitations
Disease mapping Dilated cardiomyopathy 1P (DCM1P) is the historical Mendelian label for PLN-related cardiomyopathy. Current classification recognizes overlapping dilated, arrhythmogenic, and non-dilated left-ventricular phenotypes. Ventricular arrhythmia and fibrosis may precede dilation or systolic dysfunction; retain both DCM1P and PLN-related/arrhythmogenic cardiomyopathy mappings. (vafiadaki2023phospholambanr14deldisease pages 2-3, monda2022clinicalandmolecular pages 1-2, stege2024reassessingthemechanisms pages 1-2)
Identifiers OMIM: DCM1P record should be verified directly before ingestion. MONDO: no disease-specific ID was confidently verified. ICD-10-CM: I42.0, dilated cardiomyopathy, is not genotype-specific. MeSH: Dilated Cardiomyopathy. Unverified ontology identifiers are deliberately not supplied; map provisionally to inherited DCM and PLN-related cardiomyopathy parents.
Synonyms Dilated cardiomyopathy 1P; DCM1P; phospholamban-related cardiomyopathy; PLN-related cardiomyopathy; PLN cardiomyopathy; PLN-R14del cardiomyopathy; phospholamban R14del disease; PLN-related arrhythmogenic cardiomyopathy. PLN-R14del cardiomyopathy is variant-specific and is not synonymous with every PLN-associated phenotype. (vafiadaki2023phospholambanr14deldisease pages 2-3, monda2022clinicalandmolecular pages 1-2)
Evidence granularity Aggregated disease-level evidence from cohorts, pedigrees, guidelines, human myocardium, iPSC-derived cardiomyocytes, biochemical studies, and animal models—not individual-patient EHR data. Founder-enriched cohorts and small pedigrees may not generalize to all variants or populations. (jiang2020thephenotypiccharacteristic pages 3-5, verstraelen2021predictionofventricular pages 3-4)
Causal gene and protein PLN, encoding phospholamban, a 52-amino-acid sarcoplasmic-reticulum membrane regulator that reversibly inhibits cardiac SERCA2a. Human genetic, biochemical, cellular, and animal evidence supports causality. (vafiadaki2023phospholambanr14deldisease pages 1-2)
Principal pathogenic variant PLN c.40_42delAGA, p.(Arg14del), also R14del or R14Δ; an in-frame deletion and established founder variant. Other reported variants include p.Arg9Cys, p.Arg9Leu, p.Arg9His, p.Leu39Ter, and p.Arg25Cys. Evidence is strongest for p.Arg14del. Each variant requires ACMG/AMP assessment; population frequencies were not directly verified in gnomAD. (jiang2020thephenotypiccharacteristic pages 3-5, vafiadaki2023phospholambanr14deldisease pages 1-2)
Inheritance Predominantly autosomal dominant, germline, with a 50% transmission probability from a heterozygous parent; penetrance is incomplete and age-dependent, and expressivity is variable. Symptoms commonly emerge in middle age, but malignant arrhythmia or sudden death can occur earlier. Anticipation is not established. (vafiadaki2023phospholambanr14deldisease pages 2-3)
Epidemiology Dutch p.Arg14del founder disease is concentrated in the northern Netherlands; more than 1,500 carriers have been reported. Estimates include approximately 12% of Dutch arrhythmogenic cardiomyopathy and 15% of Dutch DCM. Founder-enriched estimates are not global prevalence. Worldwide prevalence and incidence are unknown. (vafiadaki2023phospholambanr14deldisease pages 1-2, stege2024reassessingthemechanisms pages 1-2)
Structural and heart-failure phenotypes LV dilation and systolic dysfunction, sometimes biventricular, with exertional dyspnea, fatigue, exercise intolerance, edema, and advanced heart failure. Suggested HPO: Dilated cardiomyopathy (HP:0001644), Left ventricular systolic dysfunction (HP:0001738), Congestive heart failure (HP:0001635), Exercise intolerance (HP:0003546). Phenotype ranges from asymptomatic carrier status to LVAD- or transplant-requiring disease; dilation may occur late. (vafiadaki2023phospholambanr14deldisease pages 2-3, jiang2020thephenotypiccharacteristic pages 3-5)
Arrhythmic phenotype Frequent PVCs, nonsustained or sustained VT, VF, syncope, appropriate ICD therapy, and sudden cardiac death. Suggested HPO: Ventricular arrhythmia (HP:0004308), Ventricular tachycardia (HP:0004756), Sudden cardiac death (HP:0001645), Syncope (HP:0001279). In a 679-carrier cohort, baseline NSVT occurred in 10%, and more than 500 PVCs/24 h occurred in 31% of evaluable carriers. (verstraelen2021predictionofventricular pages 3-4)
ECG phenotype Low QRS voltage, reduced R-wave amplitudes, lateral/precordial T-wave inversion, conduction abnormalities, and ventricular ectopy. Suggested HPO: Low-voltage electrocardiogram (HP:0031540) and T-wave inversion (HP:0010872). Characteristic but neither universal nor diagnostic. Low voltage and negative T waves contribute to variant-specific risk prediction. (vafiadaki2023phospholambanr14deldisease pages 2-3, monda2022clinicalandmolecular pages 1-2, verstraelen2021predictionofventricular pages 3-4)
CMR/fibrosis phenotype Non-ischemic subepicardial inferolateral or lateral-wall LGE, sometimes linear mid-wall septal enhancement, and elevated extracellular volume. Suggested HPO: Myocardial fibrosis (HP:0001685). Fibrosis may precede reduced LVEF. In one family, ECV ranged from 24.5% in a structurally normal carrier to 42.4–43.2% in symptomatic members; these are pedigree data, not population frequencies. (jiang2020thephenotypiccharacteristic pages 3-5, jiang2020thephenotypiccharacteristic pages 5-6)
Temporal course and prognosis Chronic, insidious, and highly variable. Electrical abnormalities and fibrosis can precede chamber dilation; overt symptoms are often reported in the fifth decade. Up to approximately 70% of p.Arg14del carriers have been reported to experience a major cardiac event by age 70. Outcomes include malignant ventricular arrhythmia, sudden death, progressive heart failure, LVAD implantation, transplantation, and heart-failure death. The penetrance estimate is variant- and population-specific. (vafiadaki2023phospholambanr14deldisease pages 2-3)
Risk prediction The p.Arg14del malignant-arrhythmia model uses LVEF, 24-hour PVC count, number of negative T waves, and low QRS voltage. In 679 carriers, median age was 42 years; 17% had LVEF below 45%, 10% RV dysfunction, and 29% of those imaged had LGE at baseline. Development evidence is predominantly from Dutch founder carriers; ancestry-diverse external validation is limited. (verstraelen2021predictionofventricular pages 3-4)
Mechanistic chain p.Arg14del leads to abnormal PLN conformation/localization and disturbed SERCA2a regulation; this results in altered SR Ca²⁺ handling. In parallel, mutant PLN leads to malformed sarco/endoplasmic-reticulum membranes and impaired proteostasis/autophagic flux; these changes result in perinuclear PLN-positive material, mitochondrial/metabolic dysfunction, cardiomyocyte injury, inflammation, and fibrosis; remodeling creates an arrhythmogenic substrate and leads to ventricular arrhythmias, dilation, contractile failure, and sudden death. Constitutive SERCA inhibition is the historical model; newer expert analysis emphasizes S/ER disorganization and proteotoxicity. Relative contributions remain unsettled. (vafiadaki2023phospholambanr14deldisease pages 2-3, stege2024reassessingthemechanisms pages 1-2, feyen2021unfoldedproteinresponse pages 1-3)
Molecular processes Suggested GO: autophagy (GO:0006914), autophagosome–lysosome fusion (GO:0061909), response to ER stress (GO:0034976), protein folding (GO:0006457), calcium-ion transmembrane transport (GO:0070588), and regulation of cardiac muscle contraction (GO:0055117). R14del impairs autophagosome–lysosome fusion. UPR activation appears compensatory: silencing IRE1, ATF6, or PERK worsened iPSC contractility, whereas BiP inducer X improved it in vitro. (feyen2021unfoldedproteinresponse pages 1-3)
Anatomy and cell ontology Primary sites: heart and ventricular myocardium; suggested UBERON:0000948 heart, UBERON:0002084 left ventricle, UBERON:0002080 right ventricle, and UBERON:0002349 myocardium. Principal cell: ventricular cardiomyocyte; suggested CL:0000746 cardiac muscle cell. Fibroblasts and immune cells participate downstream in fibrosis and inflammation. Exact ontology terms should be release-validated. (jiang2020thephenotypiccharacteristic pages 3-5, eijgenraam2020thephospholambanp.(arg14del) pages 2-4)
Subcellular ontology Sarcoplasmic/endoplasmic reticulum, SERCA complex, autophagosome, lysosome, mitochondrion, intercalated disc, and perinuclear region. Suggested GO-CC: GO:0016529, GO:0005783, GO:0005776, GO:0005764, GO:0005739, and GO:0014704, respectively where applicable. PLN-positive structures may be malformed S/ER membrane clusters rather than simple protein aggregates. (stege2024reassessingthemechanisms pages 1-2, feyen2021unfoldedproteinresponse pages 1-3)
Diagnostics Three-generation pedigree; examination; 12-lead ECG; ambulatory rhythm monitoring; echocardiography; CMR with LGE, T1 mapping, and ECV; BNP/NT-proBNP and troponin when indicated; exclusion of ischemic, hypertensive, valvular, toxic, infectious, inflammatory, and metabolic causes. No single finding is pathognomonic. CMR can reveal fibrosis before overt structural disease. (monda2022clinicalandmolecular pages 1-2, jiang2020thephenotypiccharacteristic pages 3-5, verstraelen2021predictionofventricular pages 3-4)
Genetic testing and screening Use a validated cardiomyopathy multigene panel including PLN, with sequencing and deletion/duplication analysis. Test the familial pathogenic variant directly in relatives; use WES/WGS when panel testing is negative or the phenotype is atypical. Genotype-positive relatives require longitudinal ECG, rhythm monitoring, echocardiography, and periodic CMR. A VUS should not direct predictive testing or irreversible intervention. CMA, karyotype, FISH, mtDNA, and repeat-expansion testing are not routine for isolated DCM1P unless another diagnosis is suspected.
Established treatment No approved PLN-specific therapy. Treat heart failure with guideline-directed therapy as clinically indicated; manage arrhythmias with beta-blockers/antiarrhythmics, catheter ablation in selected patients, and ICD placement using phenotype- and genotype-informed risk assessment. Advanced disease may require CRT, LVAD, or transplantation. Evidence for standard HF drugs is largely extrapolated from general HF trials; mouse p.Arg14del disease was not rescued by metoprolol or eplerenone. Suggested NCIT concepts: pharmacotherapy, ICD implantation, catheter ablation, mechanical circulatory support, and heart transplantation. (vafiadaki2023phospholambanr14deldisease pages 2-3, eijgenraam2020thephospholambanp.(arg14del) pages 2-4)
Trials and real-world research NCT01857856 (iPHORECAST): completed interventional eplerenone study, 84 participants. NCT04978987 (DECIPHER-PLN): completed observational multi-omics cohort, approximately 103 participants. NCT07241104: recruiting phase 1 study of AZD4063 in PLN-R14del DCM, planned enrollment 31. Trial status and enrollment were retrieved from ClinicalTrials.gov search records; efficacy conclusions should await posted results or peer-reviewed reports.
Experimental therapies PLN-targeting antisense oligonucleotides halted progression, prolonged survival, and resolved PLN-positive material in mouse models; AAV9-CRISPR disruption of the mutant allele improved volumes and increased the VT-induction threshold in humanized mice; UPR/autophagy modulation and SERCA-axis approaches remain experimental. No gene-editing, ASO, or autophagy-directed treatment is approved for patients. Evidence is preclinical or in vitro. (feyen2021unfoldedproteinresponse pages 1-3, eskandr2026molecularandfunctional pages 153-153)
Models Engineered heterozygous and homozygous PLN-R14del mice; humanized p.Arg14del mice; patient-derived and isogenic iPSC cardiomyocytes; 2D/3D engineered cardiac tissues; explanted human myocardium. A spontaneous canine PLN-R9H model has also been reported. Homozygous mice develop accelerated severe disease unlike typical heterozygous human carriers; iPSC cardiomyocytes are developmentally immature. Models reproduce complementary rather than complete aspects of human disease. (eijgenraam2020thephospholambanp.(arg14del) pages 2-4, feyen2021unfoldedproteinresponse pages 1-3, eskandr2026molecularandfunctional pages 153-153)

Table: Compact curation of Dilated Cardiomyopathy 1P as PLN-related cardiomyopathy, covering disease mapping, phenotypes, mechanisms, diagnostics, prognosis, management, trials, and models. Unverified ontology identifiers and evidence limitations are explicitly flagged.

1. Disease information

Definition and nomenclature

DCM1P is an inherited myocardial disease in which pathogenic PLN variants cause electrical instability, myocardial injury and fibrosis, and variably ventricular dilation and systolic dysfunction. The label “DCM1P” is narrower than the recognized disease spectrum: R14del is associated with both DCM and arrhythmogenic cardiomyopathy (ACM), and fibrosis or arrhythmia may precede dilation. (vafiadaki2023phospholambanr14deldisease pages 2-3, monda2022clinicalandmolecular pages 1-2, stege2024reassessingthemechanisms pages 1-2)

Synonyms: DCM1P; dilated cardiomyopathy type 1P; phospholamban-related cardiomyopathy; PLN-related cardiomyopathy; phospholamban cardiomyopathy; PLN-R14del cardiomyopathy; phospholamban R14del disease; PLN-related arrhythmogenic cardiomyopathy. “PLN-R14del cardiomyopathy” is variant-specific and should not be treated as synonymous with all PLN disease.

Identifiers and coding

  • OMIM: DCM1P has historically been linked to the PLN disease record, but the exact current OMIM phenotype number should be verified directly before database ingestion.
  • MONDO: a DCM1P-specific MONDO identifier was not reliably retrieved. A provisional mapping should use the MONDO parent for inherited dilated cardiomyopathy plus a PLN-related disease annotation rather than inventing an identifier.
  • ICD-10-CM: I42.0, dilated cardiomyopathy; not genotype-specific.
  • ICD-11: code under dilated cardiomyopathy/inherited cardiomyopathy; release-specific code should be verified.
  • MeSH: Cardiomyopathy, Dilated.
  • Orphanet: no confidently verified DCM1P-specific number was obtained.

The report integrates aggregated disease-level resources, pedigrees, cohorts, human myocardial tissue, iPSC-derived cardiomyocytes, engineered tissues, biochemical experiments, and animal models. It is not based on individual-patient EHR extraction.

2. Etiology

Causal and genetic factors

The primary cause is a heterozygous pathogenic germline variant in PLN. R14del is c.40_42delAGA, p.(Arg14del), an in-frame deletion in the cytoplasmic regulatory region. Other reported PLN variants include p.Arg9Cys, p.Arg9Leu, p.Arg9His, p.Leu39Ter and p.Arg25Cys, but their pathogenicity, mechanism, and phenotype must be evaluated individually. (jiang2020thephenotypiccharacteristic pages 3-5, vafiadaki2023phospholambanr14deldisease pages 1-2)

PLN encodes a 52-amino-acid sarcoplasmic-reticulum membrane protein that inhibits the Ca²⁺ pump SERCA2a when dephosphorylated. Physiologically, PKA/CaMKII-mediated PLN phosphorylation relieves this inhibition during adrenergic stimulation. (vafiadaki2023phospholambanr14deldisease pages 1-2)

Risk, protective, and modifying factors

Established clinical risk markers in R14del carriers include reduced LVEF, high 24-hour premature ventricular contraction (PVC) burden, more negative T waves, and low QRS voltage. In a 679-carrier cohort, baseline NSVT was present in 10%, >500 PVCs/24 h in 31% of evaluable participants, LVEF <45% in 17%, RV dysfunction in 10%, and LGE in 29% of those imaged. (verstraelen2021predictionofventricular pages 3-4)

Modifier evidence is preliminary. Variable disease within families and incomplete penetrance imply polygenic, epigenetic, sex-related, and environmental modification. A 2023 population study reported that some older carriers remained asymptomatic and examined polygenic predisposition to QRS duration, but no modifier is sufficiently validated for routine clinical prediction. No reproducible protective PLN allele or environmental exposure that prevents DCM1P has been established.

Environmental and gene–environment interactions

Alcohol excess, cardiotoxic chemotherapy, myocarditis, uncontrolled hypertension, ischemia, and other myocardial stressors can independently produce or aggravate cardiomyopathy and should be minimized, but PLN-specific interaction effect sizes are unavailable. Adrenergic stress can expose arrhythmia susceptibility in models, although pressure overload or isoproterenol has not consistently accelerated R14del disease. Thus, a “second-hit” model is plausible but not proven. Competitive/high-intensity exercise is a potential arrhythmogenic stressor in inherited ACM; recommendations should be individualized rather than extrapolated uncritically to every asymptomatic carrier.

3. Phenotypes

The phenotype is usually absent in childhood, subtle in early adulthood, and clinically apparent in middle age, but adolescence or young adulthood can be complicated by malignant arrhythmia or SCD. Severity and progression are highly variable. Symptoms impair exercise, employment, driving, independence, and psychological well-being; ICD shocks and fear of SCD add substantial quality-of-life burden. Formal DCM1P-specific EQ-5D/SF-36 data are sparse. (vafiadaki2023phospholambanr14deldisease pages 2-3)

  • Ventricular ectopy/arrhythmia: PVCs, NSVT, sustained VT, VF, palpitations, presyncope/syncope, appropriate ICD treatment, or SCD. Often precedes severe LV dysfunction. Suggested HPO: Ventricular arrhythmia HP:0004308; Ventricular tachycardia HP:0004756; Sudden cardiac death HP:0001645; Syncope HP:0001279. (vafiadaki2023phospholambanr14deldisease pages 2-3, verstraelen2021predictionofventricular pages 3-4)
  • DCM/systolic dysfunction: LV or biventricular dilation, reduced LVEF, impaired strain, progressive heart failure. Suggested HPO: Dilated cardiomyopathy HP:0001644; Left ventricular systolic dysfunction HP:0001738; Congestive heart failure HP:0001635. (jiang2020thephenotypiccharacteristic pages 3-5, eijgenraam2020thephospholambanp.(arg14del) pages 2-4)
  • Heart-failure symptoms: exertional dyspnea, fatigue, exercise intolerance, orthopnea, edema, and reduced functional capacity. Suggested HPO: Exercise intolerance HP:0003546, plus dyspnea/edema terms after release validation.
  • ECG phenotype: low QRS voltage/reduced R waves, lateral or precordial T-wave inversion, conduction delay, and ventricular ectopy. Suggested HPO: Low-voltage electrocardiogram HP:0031540; T-wave inversion HP:0010872. These are clues, not individually diagnostic. (vafiadaki2023phospholambanr14deldisease pages 2-3, monda2022clinicalandmolecular pages 1-2)
  • Myocardial fibrosis: inferolateral/lateral subepicardial LGE, sometimes linear mid-wall septal LGE; fibrosis may be detectable before dilation. Suggested HPO: Myocardial fibrosis HP:0001685. In one family, ECV ranged from 24.5% in a structurally normal carrier to 42.4–43.2% in symptomatic relatives; these values are pedigree observations, not population frequencies. (jiang2020thephenotypiccharacteristic pages 3-5, jiang2020thephenotypiccharacteristic pages 5-6)
  • Histopathology: replacement fibrosis, possible fibrofatty replacement, cardiomyocyte injury/disarray, and characteristic perinuclear PLN-positive material. (vafiadaki2023phospholambanr14deldisease pages 2-3, stege2024reassessingthemechanisms pages 1-2)

4. Genetic and molecular information

Gene: PLN; protein phospholamban. R14del is germline and usually heterozygous. Inheritance is autosomal dominant, implying a 50% transmission probability from a heterozygous parent. Penetrance is incomplete and age-dependent; expressivity is markedly variable. Anticipation, a consistent founder-independent sex ratio, and clinically important germline mosaicism have not been established. (vafiadaki2023phospholambanr14deldisease pages 2-3)

R14del has historically been described as causing abnormal phosphorylation/SERCA regulation and a dominant-negative effect. Current mechanistic analysis cautions that calcium dysregulation alone is inadequate: abnormal PLN localization and malformed sarco/endoplasmic-reticulum (S/ER) membrane structures may be central. (jiang2020thephenotypiccharacteristic pages 3-5, stege2024reassessingthemechanisms pages 1-2)

For curation, variant assertions should be taken from a current ClinVar/ClinGen submission and interpreted under ACMG/AMP criteria. R14del is an established pathogenic founder variant; a VUS must not be used for predictive family testing or irreversible intervention. Exact gnomAD/TOPMed allele frequencies and HGNC/NCBI identifiers should be retrieved directly from current database releases. Large chromosomal abnormalities are not characteristic of DCM1P. Disease-specific DNA methylation or histone signatures are not sufficiently validated for diagnosis.

5. Environmental information

No infectious agent, toxin, occupational exposure, radiation source, dietary deficiency, or lifestyle behavior is a primary cause of DCM1P. Such factors instead enter the differential diagnosis or may add myocardial stress. Recommended risk reduction includes avoiding cocaine/amphetamines, anabolic drugs, excessive alcohol, and unnecessary cardiotoxic exposure; controlling blood pressure and metabolic disease; and promptly assessing suspected myocarditis. Smoking cessation, vaccination against routine respiratory pathogens, and appropriate aerobic activity support general cardiovascular health but are not proven to alter PLN penetrance.

6. Mechanism and pathophysiology

Ordered causal chain

  1. A pathogenic heterozygous PLN variant, especially p.Arg14del, leads to altered phospholamban conformation, phosphorylation behavior, intermolecular interactions, and intracellular localization.
  2. Altered PLN leads to disturbed regulation of SERCA2a and SR Ca²⁺ reuptake; the magnitude and direction of this effect are model-dependent and remain partly disputed. (vafiadaki2023phospholambanr14deldisease pages 1-2, stege2024reassessingthemechanisms pages 1-2)
  3. In a parallel upstream branch, mutant PLN leads to abnormal S/ER membrane organization and perinuclear PLN-positive structures, now interpreted in part as malformed membrane clusters rather than merely insoluble aggregates. (stege2024reassessingthemechanisms pages 1-2)
  4. S/ER disruption and altered Ca²⁺ homeostasis lead to proteostasis stress and impaired autophagic flux; R14del specifically impairs autophagosome–lysosome fusion through abnormal recruitment of membrane-fusion machinery. This step is demonstrated in cellular systems and supported by patient tissue.
  5. Proteostasis stress results in a compensatory unfolded-protein response (UPR). In isogenic human iPSC cardiomyocytes, silencing IRE1, ATF6, or PERK worsened contractile dysfunction, whereas BiP inducer X improved contractility, indicating that UPR activation is initially protective rather than simply pathogenic. (feyen2021unfoldedproteinresponse pages 1-3)
  6. S/ER/proteostasis injury leads to mitochondrial dysfunction, impaired fatty-acid oxidation, lipid-droplet accumulation, energetic deficiency, oxidative stress, and altered intercalated-disc complexes; some links are inferred primarily from mouse omics and explanted myocardium. (vafiadaki2023phospholambanr14deldisease pages 2-3)
  7. Persistent cardiomyocyte dysfunction and death result in inflammatory/remodeling responses, fibroblast activation, replacement fibrosis, and sometimes fibrofatty change.
  8. Fibrosis plus abnormal Ca²⁺ cycling creates conduction heterogeneity and triggered activity, which lead to PVCs, VT/VF, ICD therapies, and SCD, sometimes before severe systolic dysfunction.
  9. Progressive myocyte loss and remodeling lead to ventricular dilation, reduced contractility, chronic heart failure, and ultimately LVAD implantation, transplantation, or death.

Ontology suggestions

Relevant GO biological processes include calcium-ion transmembrane transport (GO:0070588), regulation of cardiac muscle contraction (GO:0055117), autophagy (GO:0006914), autophagosome–lysosome fusion (GO:0061909), response to endoplasmic-reticulum stress (GO:0034976), protein folding (GO:0006457), mitochondrial organization, inflammatory response, and extracellular-matrix organization. Principal cells are ventricular cardiomyocytes (CL:0000746 cardiac muscle cell); fibroblasts, endothelial cells, macrophages, and other immune cells are downstream participants.

Molecular profiling and advanced technologies

RNA-seq/proteomics in R14del mice identified proteostasis and PLN aggregation before functional disease, followed by remodeling, inflammation, and metabolic abnormalities. Human iPSC-CM single-cell RNA-seq demonstrated UPR activation and enabled isogenic functional testing. Human myocardium confirms UPR activation and abnormal PLN localization. Multi-omics cohorts are being developed to identify circulating biomarkers and modifiers, but no transcriptomic, proteomic, metabolomic, or lipidomic signature is clinically validated. (eijgenraam2020thephospholambanp.(arg14del) pages 2-4, feyen2021unfoldedproteinresponse pages 1-3)

A representative abstract statement is: “Single-cell RNA sequencing revealed the induction of the unfolded protein response (UPR) pathway in PLN R14del compared with isogenic control hiPSC-CMs.” Feyen et al., Circulation, published 3 August 2021, DOI: https://doi.org/10.1161/CIRCULATIONAHA.120.049844. (feyen2021unfoldedproteinresponse pages 1-3)

7. Anatomical structures affected

The primary organ is the heart (UBERON:0000948). Disease predominantly affects ventricular myocardium, especially the left ventricle (UBERON:0002084) and inferolateral/lateral LV wall, but the right ventricle (UBERON:0002080) and septum can be involved. Secondary systemic involvement—lungs, kidneys, liver, skeletal muscle perfusion, and brain—reflects advanced heart failure, congestion, thromboembolism, or resuscitated cardiac arrest rather than primary PLN pathology. No lateralization applies. (jiang2020thephenotypiccharacteristic pages 3-5, eijgenraam2020thephospholambanp.(arg14del) pages 2-4)

At the subcellular level, relevant compartments are the sarcoplasmic/endoplasmic reticulum, SERCA2a–PLN complex, autophagosome, lysosome, mitochondrion, intercalated disc, and perinuclear region. Release-validating exact GO cellular-component identifiers is advisable before ingestion.

8. Temporal development

The disease is chronic, insidious, and lifelong. A practical trajectory is: genotype-positive/phenotype-negative carrier → electrical abnormalities or focal CMR fibrosis → ventricular ectopy/NSVT and subtle strain dysfunction → overt arrhythmogenic or dilated cardiomyopathy → sustained VA and/or symptomatic HF → end-stage HF. These are overlapping states, not mandatory stages. (vafiadaki2023phospholambanr14deldisease pages 2-3, verstraelen2021predictionofventricular pages 3-4)

Clinical manifestations become more frequent in the fifth decade, but fatal events can occur earlier. In one 679-carrier cohort, median presentation age was 42 years (IQR 27–55), and 85% entered through family screening rather than symptoms. (vafiadaki2023phospholambanr14deldisease pages 2-3, verstraelen2021predictionofventricular pages 3-4)

Apparent remission can follow suppression of arrhythmia or reverse remodeling on HF therapy, but the germline lesion and arrhythmic substrate remain. Critical intervention windows are before fibrosis, sustained VA, or irreversible ventricular failure—hence cascade testing and surveillance of asymptomatic carriers.

9. Inheritance and population

Inheritance is autosomal dominant with incomplete, age-dependent penetrance and variable expressivity. Up to approximately 70% of R14del carriers have been reported to experience a major cardiac event by age 70, although this estimate is variant-, ascertainment-, and population-dependent. (vafiadaki2023phospholambanr14deldisease pages 2-3)

R14del has Dutch and Greek founder lineages and is now reported in Europe, North America, Japan, and China. More than 1,500 Dutch carriers have been described; R14del accounts for approximately 12% of Dutch ACM and 15% of Dutch DCM in founder-enriched series. These are not worldwide prevalence estimates. (vafiadaki2023phospholambanr14deldisease pages 1-2, stege2024reassessingthemechanisms pages 1-2)

Global incidence, prevalence per 100,000, carrier frequency, and sex ratio are unknown. A Dutch population cohort previously found 6 heterozygotes among 8,267 people (0.07%), but this regional estimate should not be generalized internationally. Consanguinity is not a major factor in dominant heterozygous disease. Homozygous disease is expected to be more severe but is exceptionally rare.

10. Diagnostics

Clinical evaluation

Evaluation should include a three-generation pedigree, physical examination, 12-lead ECG, ambulatory monitoring, echocardiography with LV/RV size, LVEF and strain, and CMR with LGE, T1 mapping, and ECV. CMR is especially useful because lateral subepicardial fibrosis can occur in young carriers with preserved dimensions and LVEF. (jiang2020thephenotypiccharacteristic pages 3-5, jiang2020thephenotypiccharacteristic pages 5-6)

Laboratory testing includes BNP/NT-proBNP and troponin when indicated, plus tests directed at reversible DCM causes: blood count, electrolytes, renal/liver/thyroid function, iron studies, and infectious, inflammatory, or metabolic testing guided by context. Endomyocardial biopsy is not routine; it is reserved for suspected myocarditis, infiltrative/storage disease, or unexplained rapidly progressive cardiomyopathy.

Genetic testing

Use a curated cardiomyopathy panel including PLN with sequence and copy-number analysis. If a familial pathogenic variant is known, targeted testing is most efficient. WES/WGS is useful after a negative panel, in atypical disease, or when blended diagnoses/structural variants are suspected. RNA sequencing may resolve selected splice variants but is not routine. CMA, karyotyping, FISH, mtDNA, and repeat-expansion assays are not first-line for isolated DCM1P.

First-degree relatives should receive genetic counseling and cascade testing. Genotype-positive relatives require periodic ECG, ambulatory monitoring, echocardiography, and CMR tailored to age and phenotype. A VUS must not be used for predictive testing.

Differential diagnosis

Exclude ischemic, hypertensive, valvular, congenital, toxic/alcohol-related, inflammatory/myocarditic, tachycardia-mediated, peripartum, endocrine/metabolic, mitochondrial, and nutritional cardiomyopathy. Genetic differentials with high arrhythmic risk include LMNA, FLNC, RBM20, DSP and other desmosomal cardiomyopathies. Sarcoidosis and prior myocarditis can mimic the subepicardial LGE pattern.

11. Outcome and prognosis

Prognosis ranges from normal longevity to early SCD or transplantation. Adverse outcomes include sustained VT/VF, appropriate ICD therapy, sudden death, progressive systolic failure, recurrent hospitalization, LVAD implantation, and transplant. No reliable DCM1P-specific 5- or 10-year survival estimate applies across variants and populations. (vafiadaki2023phospholambanr14deldisease pages 2-3)

The 2021 R14del risk-model cohort comprised 679 carriers. During median 4.3-year follow-up, 72 (10.6%) developed malignant VA in the published abstract; model predictors were LVEF, 24-hour PVC count, number of negative T waves, and low-voltage ECG, with C-statistic 0.83. A 2024 landmark analysis of 268 event-free carriers found 28 major VA events (10%) after the landmark, an annual rate of 2.6% (95% CI 1.6–3.6), with C-statistic 0.83 and calibration slope 0.97. These tools support—not replace—shared ICD decisions and require caution outside Dutch R14del cohorts.

Quality-of-life burden arises from HF limitations, arrhythmia symptoms, ICD shocks, driving/employment restrictions, reproductive uncertainty, and anxiety among asymptomatic carriers. DCM1P-specific patient-reported outcome statistics remain limited.

12. Treatment

Established treatment

There is no approved disease-modifying PLN-specific therapy. Treat overt HFrEF using current guideline-directed therapy as tolerated: ARNI/ACE inhibitor/ARB, evidence-based beta-blocker, mineralocorticoid-receptor antagonist, and SGLT2 inhibitor; add diuretics for congestion. These treatments are extrapolated largely from general HF trials, not proven to correct the PLN lesion.

Rhythm management includes beta-blockade, selected antiarrhythmics, catheter ablation for recurrent monomorphic VT or ICD shocks, and ICD implantation based on prior VA plus integrated phenotype/genotype risk. Because PLN disease can cause VA before LVEF falls to conventional thresholds, decisions should incorporate PVC burden, NSVT, ECG changes, CMR fibrosis, family history, and the validated R14del risk model. Advanced HF may require CRT when standard criteria are met, LVAD, or transplantation. (vafiadaki2023phospholambanr14deldisease pages 2-3, verstraelen2021predictionofventricular pages 3-4)

Suggested NCIT intervention concepts include Pharmacotherapy, Implantable Cardioverter-Defibrillator Implantation, Cardiac Catheter Ablation, Cardiac Resynchronization Therapy, Mechanical Circulatory Support, and Heart Transplantation; exact NCIT codes should be release-validated.

Trials and emerging therapies

  • NCT01857856, iPHORECAST: completed interventional study of eplerenone in PLN-related cardiomyopathy; 84 participants. Mouse R14del disease was not rescued by eplerenone or metoprolol, so clinical benefit cannot be presumed. (eijgenraam2020thephospholambanp.(arg14del) pages 2-4)
  • NCT04978987, DECIPHER-PLN: completed observational cohort, approximately 103 participants, integrating deep phenotyping, biospecimens, iPSC cardiomyocytes and multi-omics to identify modifiers and biomarkers.
  • NCT07241104: recruiting phase 1 AstraZeneca study of AZD4063 in PLN-R14del DCM, planned enrollment 31. Trial status should be rechecked before curation.

PLN-targeting ASOs halted progression and eliminated most PLN-positive material in severe mouse disease; AAV9-CRISPR disruption of the mutant allele improved ventricular volumes and increased the ex-vivo VT-induction threshold in humanized mice. UPR activation, restoration of autophagic flux, correction of S/ER architecture, and SERCA-axis modulation are additional experimental strategies. None is approved for humans, and cardiac delivery, off-target editing, immune responses, dose durability, and the consequences of excessive PLN depletion remain translational concerns. (feyen2021unfoldedproteinresponse pages 1-3, eskandr2026molecularandfunctional pages 153-153)

13. Prevention

Primary prevention of the mutation itself is possible only through reproductive choice: preconception genetic counseling, PGT-M for a known familial pathogenic variant, prenatal diagnosis, donor gametes, or natural conception with informed testing. These options require nondirective counseling.

Secondary prevention is central: identify relatives by cascade testing, begin longitudinal ECG/rhythm/imaging surveillance, detect fibrosis or ectopy before symptoms, and perform individualized SCD risk assessment. Population or newborn screening is not currently recommended. Tertiary prevention comprises guideline-directed HF therapy, ICD treatment in high-risk carriers, arrhythmia control, vaccination and infection prevention in HF, rehabilitation, and timely referral for LVAD/transplant evaluation.

There is no vaccine or chemoprophylaxis for PLN disease. Avoiding cardiotoxins and excessive alcohol, controlling conventional cardiovascular risks, and individualized exercise counseling are prudent but not proven to prevent penetrance.

14. Other species and natural disease

PLN and SERCA regulation are evolutionarily conserved across vertebrates. A spontaneous canine PLN p.Arg9His cardiomyopathy with high penetrance and sudden death has been reported, providing comparative evidence that naturally occurring PLN dysfunction can cause DCM outside humans. It is not the same allele as human R14del and should not be labeled DCM1P without qualification.

Dogs are Canis lupus familiaris, NCBI Taxonomy 9615; mouse is Mus musculus, Taxonomy 10090; zebrafish is Danio rerio, Taxonomy 7955. No zoonotic transmission exists: these are inherited, noninfectious diseases. Breed-specific VBO mapping and ortholog NCBI Gene IDs should be retrieved directly from current veterinary and NCBI resources.

15. Model organisms and experimental systems

  • Knock-in R14del mice: heterozygotes model delayed/incomplete disease; homozygotes develop accelerated dilation, low ECG voltage, fibrosis, PLN-positive material, arrhythmia susceptibility, and early death. In one model, homozygous maximum lifespan was 54–61 days, whereas heterozygotes survived through 20 months. The accelerated homozygous course is useful for treatment testing but differs from typical human heterozygosity. (eijgenraam2020thephospholambanp.(arg14del) pages 2-4)
  • Humanized R14del mice: reproduce biventricular dilation and stress/pacing-induced VT and have supported AAV9-CRISPR proof-of-concept. Species-specific electrophysiology, vector dose, and immune biology limit direct translation. (eskandr2026molecularandfunctional pages 153-153)
  • Patient-derived/isogenic iPSC cardiomyocytes: reproduce contractile deficiency, UPR activation, Ca²⁺/S/ER and proteostasis abnormalities and permit CRISPR correction or pathway perturbation. Their fetal-like maturity and simplified cellular environment are limitations. (feyen2021unfoldedproteinresponse pages 1-3)
  • Engineered heart tissues and 3D constructs: improve mechanical loading and functional readouts; BiP inducer X improved R14del contractility in both 2D and 3D systems. (feyen2021unfoldedproteinresponse pages 1-3)
  • Human explanted myocardium: confirms fibrosis, abnormal PLN localization, proteostasis/UPR and metabolic abnormalities, but represents late-stage disease and is affected by treatment and terminal HF.
  • Omics models: staged mouse RNA-seq/proteomics indicate that PLN-positive material and proteostasis abnormalities precede overt dysfunction; subsequent changes include inflammation, remodeling and metabolic failure. (eijgenraam2020thephospholambanp.(arg14del) pages 2-4)

Evidence limitations and curation recommendations

The strongest quantitative evidence concerns Dutch R14del carriers; other PLN alleles and ancestries remain underrepresented. “Aggregation,” altered SERCA inhibition, and S/ER malformation are not mutually exclusive, but their causal hierarchy remains debated. No validated blood biomarker, epigenetic signature, modifier gene, protective allele, or PLN-specific pharmacogenomic rule is ready for clinical use. Database identifiers, ontology codes, ClinVar classifications, allele frequencies, trial status, and PMIDs should be rechecked against live primary databases immediately before knowledge-base release.

Selected recent authoritative sources

  1. Vafiadaki E, et al. Phospholamban R14del disease: the past, the present and the future. Front Cardiovasc Med. Published 18 April 2023. DOI/URL: https://doi.org/10.3389/fcvm.2023.1162205. (vafiadaki2023phospholambanr14deldisease pages 2-3, vafiadaki2023phospholambanr14deldisease pages 1-2)
  2. Stege NM, et al. Reassessing the Mechanisms of PLN-R14del Cardiomyopathy. JACC Basic Transl Sci. Published August 2024;9:1041–1052. DOI/URL: https://doi.org/10.1016/j.jacbts.2024.02.017. (stege2024reassessingthemechanisms pages 1-2)
  3. Vafiadaki E, et al. The phospholamban R14del generates pathogenic aggregates by impairing autophagosome–lysosome fusion. Cell Mol Life Sci. Published November 2024;81:450. DOI/URL: https://doi.org/10.1007/s00018-024-05471-1. (vafiadaki2025geneticlandscapeof pages 17-17)
  4. Verstraelen TE, et al. Prediction of ventricular arrhythmia in phospholamban p.Arg14del mutation carriers. Eur Heart J. Published June 2021. DOI/URL: https://doi.org/10.1093/eurheartj/ehab294. (verstraelen2021predictionofventricular pages 3-4)
  5. Feyen DAM, et al. Unfolded Protein Response as a Compensatory Mechanism and Potential Therapeutic Target in PLN R14del Cardiomyopathy. Circulation. Published 3 August 2021;144:382–392. DOI/URL: https://doi.org/10.1161/CIRCULATIONAHA.120.049844. (feyen2021unfoldedproteinresponse pages 1-3)
  6. Jiang X, et al. The phenotypic characteristic observed by cardiac magnetic resonance in a PLN-R14del family. Sci Rep. Published October 2020. DOI/URL: https://doi.org/10.1038/s41598-020-73359-8. (jiang2020thephenotypiccharacteristic pages 3-5, jiang2020thephenotypiccharacteristic pages 5-6)

PMIDs were not consistently present in the retrieved full-text metadata; rather than risk assigning an incorrect PMID, DOI URLs are provided as persistent primary-source links.

References

  1. (vafiadaki2023phospholambanr14deldisease pages 2-3): Elizabeth Vafiadaki, Pieter C. Glijnis, Pieter A. Doevendans, Evangelia G. Kranias, and Despina Sanoudou. Phospholamban r14del disease: the past, the present and the future. Frontiers in Cardiovascular Medicine, Apr 2023. URL: https://doi.org/10.3389/fcvm.2023.1162205, doi:10.3389/fcvm.2023.1162205. This article has 31 citations and is from a peer-reviewed journal.

  2. (monda2022clinicalandmolecular pages 1-2): Emanuele Monda, Ettore Blasi, Antonio De Pasquale, Alessandro Di Vilio, Federica Amodio, Martina Caiazza, Gaetano Diana, Michele Lioncino, Alessia Perna, Federica Verrillo, Maria Martucci, Orlando Munciguerra, Andrea Vergara, and Giuseppe Limongelli. Clinical and molecular characteristics of patients with pln r14del cardiomyopathy: state-of-the-art review. Cardiogenetics, 12:112-121, Mar 2022. URL: https://doi.org/10.3390/cardiogenetics12010012, doi:10.3390/cardiogenetics12010012. This article has 1 citations.

  3. (stege2024reassessingthemechanisms pages 1-2): Nienke M. Stege, Rudolf A. de Boer, Catherine A. Makarewich, Peter van der Meer, and Herman H.W. Silljé. Reassessing the mechanisms of pln-r14del cardiomyopathy. Aug 2024. URL: https://doi.org/10.1016/j.jacbts.2024.02.017, doi:10.1016/j.jacbts.2024.02.017. This article has 29 citations.

  4. (verstraelen2021predictionofventricular pages 3-4): Tom E Verstraelen, Freyja H M van Lint, Laurens P Bosman, Remco de Brouwer, Virginnio M Proost, Bob G S Abeln, Karim Taha, Aeilko H Zwinderman, Cathelijne Dickhoff, Toon Oomen, Bas A Schoonderwoerd, Gerardus P Kimman, Arjan C Houweling, Juan R Gimeno-Blanes, Folkert W Asselbergs, Paul A van der Zwaag, Rudolf A de Boer, Maarten P van den Berg, J Peter van Tintelen, and Arthur A M Wilde. Prediction of ventricular arrhythmia in phospholamban p.arg14del mutation carriers–reaching the frontiers of individual risk prediction. Jun 2021. URL: https://doi.org/10.1093/eurheartj/ehab294, doi:10.1093/eurheartj/ehab294. This article has 183 citations and is from a highest quality peer-reviewed journal.

  5. (jiang2020thephenotypiccharacteristic pages 3-5): Xincheng Jiang, Yuanwei Xu, Jiayu Sun, Lili Wang, Xinli Guo, and Yucheng Chen. The phenotypic characteristic observed by cardiac magnetic resonance in a pln-r14del family. Scientific Reports, Oct 2020. URL: https://doi.org/10.1038/s41598-020-73359-8, doi:10.1038/s41598-020-73359-8. This article has 30 citations and is from a peer-reviewed journal.

  6. (vafiadaki2023phospholambanr14deldisease pages 1-2): Elizabeth Vafiadaki, Pieter C. Glijnis, Pieter A. Doevendans, Evangelia G. Kranias, and Despina Sanoudou. Phospholamban r14del disease: the past, the present and the future. Frontiers in Cardiovascular Medicine, Apr 2023. URL: https://doi.org/10.3389/fcvm.2023.1162205, doi:10.3389/fcvm.2023.1162205. This article has 31 citations and is from a peer-reviewed journal.

  7. (jiang2020thephenotypiccharacteristic pages 5-6): Xincheng Jiang, Yuanwei Xu, Jiayu Sun, Lili Wang, Xinli Guo, and Yucheng Chen. The phenotypic characteristic observed by cardiac magnetic resonance in a pln-r14del family. Scientific Reports, Oct 2020. URL: https://doi.org/10.1038/s41598-020-73359-8, doi:10.1038/s41598-020-73359-8. This article has 30 citations and is from a peer-reviewed journal.

  8. (feyen2021unfoldedproteinresponse pages 1-3): Dries A.M. Feyen, Isaac Perea-Gil, Renee G.C. Maas, Magdalena Harakalova, Alexandra A. Gavidia, Jennifer Arthur Ataam, Ting-Hsuan Wu, Aryan Vink, Jiayi Pei, Nirmal Vadgama, Albert J. Suurmeijer, Wouter P. te Rijdt, Michelle Vu, Prashila L. Amatya, Maricela Prado, Yuan Zhang, Logan Dunkenberger, Joost P.G. Sluijter, Karim Sallam, Folkert W. Asselbergs, Mark Mercola, and Ioannis Karakikes. Unfolded protein response as a compensatory mechanism and potential therapeutic target in pln r14del cardiomyopathy. Aug 2021. URL: https://doi.org/10.1161/circulationaha.120.049844, doi:10.1161/circulationaha.120.049844. This article has 86 citations and is from a highest quality peer-reviewed journal.

  9. (eijgenraam2020thephospholambanp.(arg14del) pages 2-4): Tim R. Eijgenraam, Bastiaan J. Boukens, Cornelis J. Boogerd, E. Marloes Schouten, Cees W. A. van de Kolk, Nienke M. Stege, Wouter P. te Rijdt, Edgar T. Hoorntje, Paul A. van der Zwaag, Eva van Rooij, J. Peter van Tintelen, Maarten P. van den Berg, Peter van der Meer, Jolanda van der Velden, Herman H. W. Silljé, and Rudolf A. de Boer. The phospholamban p.(arg14del) pathogenic variant leads to cardiomyopathy with heart failure and is unresponsive to standard heart failure therapy. Scientific Reports, Jun 2020. URL: https://doi.org/10.1038/s41598-020-66656-9, doi:10.1038/s41598-020-66656-9. This article has 83 citations and is from a peer-reviewed journal.

  10. (eskandr2026molecularandfunctional pages 153-153): M Eskandr. Molecular and functional determinants of arrhythmias in genetic heart diseases: from pln-r14del cardiomyopathy to long qt syndrome. Unknown journal, 2026.

  11. (vafiadaki2025geneticlandscapeof pages 17-17): Elizabeth Vafiadaki, Ishita Chaudhari, Keisha Mireia Soliman, Aristides G. Eliopoulos, Evangelia G. Kranias, and Despina Sanoudou. Genetic landscape of phospholamban cardiomyopathies. Frontiers in Cell and Developmental Biology, Jun 2025. URL: https://doi.org/10.3389/fcell.2025.1626242, doi:10.3389/fcell.2025.1626242. This article has 4 citations.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 10
Resolved 10
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 10
On topic 6
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 28
Resolved 28
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0

Every term resolved, and every label the report gave matched.