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:

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

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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.

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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.

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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.

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