| 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. (pqac-00000000, pqac-00000002, pqac-00000007) |
| 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. (pqac-00000000, pqac-00000002) |
| 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. (pqac-00000003, pqac-00000009) |
| 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. (pqac-00000004) |
| 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. (pqac-00000003, pqac-00000004) |
| 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. (pqac-00000000) |
| 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. (pqac-00000004, pqac-00000007) |
| 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. (pqac-00000000, pqac-00000003) |
| 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. (pqac-00000009) |
| 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. (pqac-00000000, pqac-00000002, pqac-00000009) |
| 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. (pqac-00000003, pqac-00000005) |
| 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. (pqac-00000000) |
| 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. (pqac-00000009) |
| 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. (pqac-00000000, pqac-00000007, pqac-00000008) |
| 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. (pqac-00000008) |
| 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. (pqac-00000003, pqac-00000006) |
| 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. (pqac-00000007, pqac-00000008) |
| 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. (pqac-00000002, pqac-00000003, pqac-00000009) |
| 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. (pqac-00000000, pqac-00000006) |
| 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. (pqac-00000008, pqac-00000010) |
| 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. (pqac-00000006, pqac-00000008, pqac-00000010) |


*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.*