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 1U (PSEN1-associated dilated cardiomyopathy, CMD1U)
• MONDO ID: MONDO:0013371 (if available)
• Category: Mendelian

Research Objectives

Please provide a comprehensive research report on dilated cardiomyopathy 1U (PSEN1-associated dilated cardiomyopathy, CMD1U) 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 1U (PSEN1-associated DCM; CMD1U)

Executive summary and evidence caveat

CMD1U is a proposed autosomal-dominant Mendelian form of dilated cardiomyopathy (DCM) associated with PSEN1, principally on the basis of one family carrying PSEN1 p.Asp333Gly (D333G) reported in 2006. That study screened 315 DCM index cases and found the variant in one pedigree; it segregated with aggressive adult DCM, was absent from 413 controls, and carrier fibroblasts had abnormal intracellular calcium signaling. No independent CMD1U pedigree or second convincingly causal PSEN1 variant was identified in the retrieved literature. Thus, CMD1U should be represented in a knowledge base as a historically reported, very-low-evidence gene–disease relationship, not as equivalent to DCM caused by well-validated genes such as TTN, LMNA, FLNC, DSP, BAG3, RBM20, or PLN. Open Targets contains five PSEN1–DCM evidence records and an aggregate association score of approximately 0.72, but several records cite overlapping literature and do not represent five independent families (OpenTargets Search: dilated cardiomyopathy-PSEN1, li2006mutationsofpresenilin pages 7-8, li2006mutationsofpresenilin pages 1-3).

The evidence hierarchy used below is: (A) direct CMD1U human evidence; (B) functional evidence involving D333G or carrier cells; (C) broader PSEN1 cardiac models; and (D) general DCM evidence. Categories C and D must not be interpreted as proof that D333G causes cardiomyopathy.

Table: This table grades the current evidence base for PSEN1-associated dilated cardiomyopathy (CMD1U), separating direct human findings from inferred mechanisms and general DCM management guidance. It is useful because the condition appears to rest on a very limited primary literature base despite ongoing mention in databases and reviews.

1. Disease information

Definition

DCM is ventricular—usually left-ventricular—dilatation with impaired systolic function that is not adequately explained by coronary artery disease, hypertension, valve disease, congenital heart disease, or another abnormal loading condition. CMD1U denotes the proposed PSEN1-associated familial subtype. The reported family had progressive ventricular enlargement, systolic dysfunction, heart failure, transplantation, and death (li2006mutationsofpresenilin pages 3-5, li2006mutationsofpresenilin pages 1-3, sorella2025diagnosisandmanagement pages 1-2).

Identifiers and synonyms

• MONDO: MONDO:0013371, dilated cardiomyopathy 1U (identifier supplied in the query; users should verify current MONDO release status).
• OMIM phenotype: commonly indexed as DCM1U/CMD1U, OMIM 613694; causal-gene entry PSEN1, OMIM 104311.
• Broader MONDO concepts: dilated cardiomyopathy MONDO:0005021; familial DCM MONDO:0016333; familial isolated DCM MONDO:0700335 (OpenTargets Search: dilated cardiomyopathy-PSEN1).
• ICD-10-CM: I42.0, dilated cardiomyopathy. This is not CMD1U-specific.
• ICD-11: BC43.0, dilated cardiomyopathy; no PSEN1-specific code.
• MeSH: Cardiomyopathy, Dilated (D002311).
• Likely synonyms: dilated cardiomyopathy 1U; DCM1U; CMD1U; PSEN1-related dilated cardiomyopathy; PSEN1-associated familial dilated cardiomyopathy.
• Orphanet: no confidently verified CMD1U-specific ORPHA identifier was found; broader familial/genetic DCM records should not be treated as a unique CMD1U identifier.

The evidence is predominantly aggregated disease-level information derived from one published pedigree, not longitudinal EHR data or a disease registry. The 2006 report is primary patient/family evidence (PMID 17186461; published December 2006; DOI/URL: https://doi.org/10.1086/509900) (li2006mutationsofpresenilin pages 7-8, li2006mutationsofpresenilin pages 1-3).

2. Etiology

Causal and genetic factors

The sole reported CMD1U candidate lesion is a heterozygous germline PSEN1 missense variant, p.Asp333Gly, reported in the original article as 1539A>G in exon 10. Because transcript conventions have changed, that historical nucleotide description should not be converted automatically into modern HGVS without transcript-level confirmation. Asp333 is conserved, and substitution of acidic aspartate by neutral glycine was predicted to alter protein structure/function. The variant occurred in all reported affected relatives, was absent from 413 controls—206 White and 207 African American—and the proband did not carry variants in the other genes tested at that time: LMNA, MYH7, TNNT2, SCN5A, CSRP3, or PLN (li2006mutationsofpresenilin pages 3-5).

The initial study described “full penetrance” among clinically evaluable affected adult carriers, but phenotype-negative carriers younger than 35 years were also reported. The defensible interpretation is therefore apparently high but age-dependent penetrance in one family, with an imprecise lifetime estimate (li2006mutationsofpresenilin pages 7-8, li2006mutationsofpresenilin pages 1-3).

Environmental, lifestyle, and infectious factors

No CMD1U-specific toxin, diet, infection, occupation, smoking exposure, alcohol threshold, or exercise interaction has been demonstrated. For genetic DCM generally, alcohol, cardiotoxic chemotherapy, pregnancy, sustained tachyarrhythmia, viral myocarditis, and metabolic stress can act as additional myocardial insults, but their interaction with PSEN1 D333G is inferred, not established.

Protective factors and modifiers

No PSEN1-specific protective allele, modifier gene, diet, medication, or exposure has been identified. General avoidance of cardiotoxins and early treatment may reduce downstream heart-failure risk but cannot prevent inheritance. A 2024 study identified BAG3 p.Cys151Arg as a modifier in broader DCM—not CMD1U—illustrating the emerging concept of penetrance modifiers but providing no evidence that it modifies PSEN1 disease.

3. Phenotypes

The disease-specific phenotype catalogue is small and should not be assigned population frequencies beyond “reported in the original family.”

• Left-ventricular dilatation — clinical sign/imaging abnormality; adult onset in reported affected carriers; progressive and severe. Suggested HPO: HP:0001644, Dilated cardiomyopathy and HP:0001711, Abnormality of the left ventricle.
• Left-ventricular systolic dysfunction / reduced ejection fraction — imaging/functional sign; the study used LV enlargement plus ejection fraction ≤0.50 in phenotyping. HPO: HP:0005162, Abnormal left ventricular function; HP:0012664, Reduced left ventricular ejection fraction.
• Heart failure — symptoms/signs may include exertional dyspnea, fatigue, edema, and exercise limitation, although complete symptom-by-subject frequencies were not retrieved. HPO: HP:0001635, Congestive heart failure, HP:0002094, Dyspnea, HP:0012378, Fatigue, HP:0000969, Edema.
• Electrocardiographic anteroseptal abnormalities — reported in pedigree descriptions; exact frequency and specificity unavailable. HPO: HP:0003115, Abnormal EKG.
• End-stage disease requiring transplantation or causing death — severe outcome in older affected relatives; HPO: HP:0033676, Heart transplantation may be represented as an intervention/history rather than an intrinsic phenotype.
• Neurological phenotype: one family member was described in the later review as having Alzheimer disease, but the relationship between that case, genotype, and cardiac phenotype is insufficiently resolved. Neurodegeneration is therefore not an established CMD1U feature (yang2023presenilin1(psen1)mutations pages 9-10).

Reported affected ages were approximately 35–80 years; carriers younger than 35 could be phenotype-negative. Severity ranged from preclinical carrier status to transplantation or death. No validated phenotype-specific quality-of-life study exists. By analogy with symptomatic DCM, dyspnea, fatigue, hospitalization, activity restriction, anxiety, and transplant/device burden are expected to impair SF-36, EQ-5D, or Kansas City Cardiomyopathy Questionnaire scores, but no CMD1U measurements are available (li2006mutationsofpresenilin pages 7-8, li2006mutationsofpresenilin pages 3-5).

4. Genetic and molecular information

• Gene: PSEN1, presenilin 1; HGNC HGNC:9508; Ensembl ENSG00000080815; chromosome 14q24.2; protein is the catalytic presenilin component of the γ-secretase complex (OpenTargets Search: dilated cardiomyopathy-PSEN1, li2006mutationsofpresenilin pages 1-3).
• Variant: heterozygous germline missense p.Asp333Gly (D333G). The historical report’s “1539A>G” should be retained verbatim with a transcript-warning until validated against MANE Select.
• Classification: historically called a disease-causing mutation. Under present ACMG/AMP practice, segregation, rarity in 413 controls, conservation, and carrier-cell functional evidence support pathogenicity, but the absence of independent families, modern population-frequency confirmation, variant-specific cardiomyocyte evidence, and formal PSEN1–DCM clinical-validity consensus materially weaken interpretation. A contemporary laboratory could reasonably classify it as VUS or possibly likely pathogenic only with strong family-specific evidence; this report does not assert a current ClinVar consensus.
• Population frequency: absent from the original 413 controls. A reliable current gnomAD allele count/frequency was not retrieved and should be populated directly from the current gnomAD release rather than inferred from old controls.
• Origin: germline; no somatic CMD1U mechanism is reported.
• Functional consequence: unknown. Carrier fibroblasts showed abnormal calcium signaling, while D333G expressed in HEK293 cells did not change Aβ42/Aβ40, arguing against a simple Alzheimer-type amyloid mechanism (yang2023presenilin1(psen1)mutations pages 9-10, li2006mutationsofpresenilin pages 7-8).
• Modifier genes/epigenetics: none established for CMD1U.
• Chromosomal abnormalities: no recurrent deletion, duplication, translocation, or aneuploidy defines CMD1U.

5. Environmental information

No environmental cause is part of the disease definition. Alcohol excess, cocaine/amphetamine exposure, anthracyclines, trastuzumab, nutritional deficiencies, endocrine disease, sustained tachycardia, and myocarditis should be assessed because they can cause or aggravate a DCM phenotype independently of PSEN1. No infectious agent is necessary or sufficient for CMD1U, and the disease is neither contagious nor zoonotic.

Practical lifestyle considerations follow general cardiomyopathy guidance: avoid smoking and recreational stimulants, avoid excess alcohol, control blood pressure and metabolic disease, maintain vaccination and infection prevention, and individualize exercise after arrhythmic and functional risk assessment. These are secondary-risk measures, not proven PSEN1-directed prevention.

6. Mechanism and pathophysiology

Ordered causal chain

1. A heterozygous PSEN1 p.Asp333Gly allele is proposed to alter presenilin-1 structure/function; this initiating molecular effect is predicted rather than directly demonstrated in human cardiomyocytes.
2. Altered PSEN1 function leads to disturbed intracellular Ca²⁺ regulation; increased basal and histamine-evoked Ca²⁺ was demonstrated in carrier fibroblasts, but myocardial translation is inferred (li2006mutationsofpresenilin pages 7-8).
3. Ca²⁺ dysregulation is inferred to cause abnormal excitation–contraction coupling and cellular stress in cardiomyocytes, reducing efficient contraction and relaxation.
4. In parallel, altered γ-secretase-dependent Notch/cadherin signaling and β-catenin regulation may lead to abnormal cardiomyocyte development or maintenance; this branch is biologically plausible and model-supported but not demonstrated for D333G myocardium (yang2023presenilin1(psen1)mutations pages 9-10, li2006mutationsofpresenilin pages 1-3).
5. A second inferred branch—proteostasis failure, oxidative stress, or mitochondrial dysfunction—may lead to cardiomyocyte injury, but evidence comes from broader failing-heart or APP/PS1 models, not CMD1U.
6. Chronic cardiomyocyte dysfunction/injury leads to adverse ventricular remodeling, including chamber dilatation, wall stress, neurohormonal activation, and possible fibrosis.
7. Remodeling results in reduced ejection fraction and progressive heart failure, with arrhythmia, transplantation, or death in severe disease.

Mechanistic detail and evidence level

PSEN1 forms γ-secretase with nicastrin, APH1, and PEN2 and processes APP, Notch, ErbB4, and cadherins. Notch and β-catenin are important in cardiac development. Psen1-null developmental models exhibit ventricular septal defects and double-outlet right ventricle, supporting cardiac relevance but not reproducing adult heterozygous D333G DCM (yang2023presenilin1(psen1)mutations pages 9-10, li2006mutationsofpresenilin pages 1-3).

D333G carrier fibroblasts had elevated resting intracellular calcium and increased maximal/AUC responses to histamine. This is the strongest disease-linked functional observation, although fibroblasts are not contractile cardiomyocytes. HEK293 D333G experiments found no altered Aβ42/Aβ40 ratio, favoring an amyloid-independent mechanism (yang2023presenilin1(psen1)mutations pages 9-10, li2006mutationsofpresenilin pages 7-8).

Suggested GO biological-process terms: γ-secretase activity/Notch receptor processing; GO:0007219 Notch signaling pathway; GO:0006816 calcium ion transport; GO:0055008 cardiac muscle tissue development; GO:0003015 heart process; GO:0006979 response to oxidative stress; GO:0007005 mitochondrion organization; GO:0006457 protein folding. Suggested cell types: CL:0000746 cardiac muscle cell/cardiomyocyte, CL:0002543 cardiac fibroblast, CL:0000115 endothelial cell, CL:0000235 macrophage. Only the cardiomyocyte is a primary mechanistic target; fibroblasts were the experimentally sampled human cells.

No CMD1U-specific single-cell, spatial-transcriptomic, proteomic, metabolomic, lipidomic, methylomic, CRISPR-screen, or multi-omics dataset was identified.

7. Anatomical structures affected

• Primary organ: heart, especially left ventricular myocardium. UBERON: UBERON:0000948 heart, UBERON:0002084 heart left ventricle, UBERON:0002349 myocardium.
• Tissues/cells: cardiac muscle tissue and cardiomyocytes; interstitial fibroblasts and vascular/immune cells probably participate in secondary remodeling.
• Secondary systems: lungs through pulmonary congestion; kidneys and liver through low output/venous congestion; skeletal muscle through deconditioning; brain through embolic events or hypoperfusion in advanced DCM. These complications were not quantified for CMD1U.
• Subcellular compartments: PSEN1/γ-secretase is associated with endoplasmic-reticulum/Golgi/endosomal membranes; calcium-related hypotheses implicate ER/sarcoplasmic reticulum. Suggested GO-CC: GO:0005783 endoplasmic reticulum, GO:0016529 sarcoplasmic reticulum, GO:0000139 Golgi membrane, GO:0005886 plasma membrane, and GO:0005739 mitochondrion for downstream stress.
• Lateralization: not applicable; ventricular disease is not unilateral.

8. Temporal development

The reported pattern is insidious adult-onset, chronic, and progressive. A useful knowledge-base staging model is:

1. Genotype-positive/phenotype-negative: normal examination and imaging, particularly in younger carriers.
2. Early phenotype: subtle ECG/Holter, strain, or CMR abnormalities; mild LV enlargement or dysfunction.
3. Overt DCM: LV dilatation plus reduced systolic function.
4. Symptomatic heart failure/arrhythmic phase: exercise intolerance, congestion, hospitalization, ventricular arrhythmia.
5. Advanced/end-stage disease: refractory heart failure, mechanical support, transplantation, or death.

No CMD1U-specific conversion rate, remission probability, or critical therapeutic window has been measured. The presence of unaffected carriers under 35 makes periodic surveillance preferable to a one-time normal assessment (li2006mutationsofpresenilin pages 7-8).

9. Inheritance and population

Inheritance in the original pedigree was consistent with autosomal dominant transmission. Penetrance was described as complete in affected/evaluable adult carriers but was clearly age-dependent because younger carriers were unaffected. Expressivity was variable by age and severity. Anticipation, germline mosaicism, consanguinity, a founder effect, and sex bias have not been demonstrated (li2006mutationsofpresenilin pages 7-8, li2006mutationsofpresenilin pages 1-3).

There is no disease-specific prevalence, incidence, carrier frequency, ethnicity distribution, geographic distribution, or male:female ratio. One variant in one pedigree among 315 screened index cases corresponds to a discovery frequency of approximately 0.32% of that selected cohort, not population prevalence and not a stable estimate of the contribution of PSEN1 to DCM. For DCM generally, a recent guideline review reports prevalence estimates of approximately 1:250–1:400, familial disease in 30–50%, and an identifiable genetic cause in roughly 30–40% of familial cases (sorella2025diagnosisandmanagement pages 1-2).

10. Diagnostics

Clinical evaluation

A suspected case requires a three-generation pedigree, cardiovascular examination, 12-lead ECG, ambulatory ECG/Holter, transthoracic echocardiography, and preferably cardiac MRI. Echocardiography measures chamber size, ejection fraction, valves, and hemodynamics; CMR characterizes biventricular function, edema, scar/fibrosis, and alternative etiologies. BNP/NT-proBNP and high-sensitivity troponin assist severity and prognosis. CBC, electrolytes, renal/liver function, TSH, iron indices, CK, glucose/HbA1c, and tests targeted to infection, autoimmunity, or metabolic disease help identify competing causes. Endomyocardial biopsy is reserved for situations in which myocarditis, infiltrative/storage disease, or another treatable diagnosis is suspected (sorella2025diagnosisandmanagement pages 1-2, sorella2025diagnosisandmanagement pages 2-3).

Genetic testing

1. Begin with genetic counseling and a curated cardiomyopathy panel containing clinically validated DCM genes.
2. PSEN1 should not displace core genes. If included, interpretation must acknowledge the limited gene–disease validity and should not call an unrelated PSEN1 VUS diagnostic.
3. Confirm a candidate D333G result by an orthogonal method; verify transcript/HGVS; review current ClinVar/gnomAD; perform segregation and deep phenotyping.
4. WES/WGS can be considered when panel testing is negative, the phenotype is syndromic, or structural/noncoding variants are suspected. RNA sequencing may resolve splice variants but is not established for D333G.
5. CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion tests are not routine CMD1U tests unless another phenotype indicates them.

Cascade genetic testing is clinically appropriate only after a variant has been judged pathogenic/likely pathogenic in the family. With a PSEN1 VUS, relatives should undergo phenotype-based screening rather than predictive testing being treated as definitive (sorella2025diagnosisandmanagement pages 12-13).

Differential diagnosis

Exclude ischemic cardiomyopathy, hypertensive/valvular disease, myocarditis, alcohol- or drug-induced cardiomyopathy, tachycardia-mediated disease, peripartum cardiomyopathy, endocrine/metabolic/nutritional causes, neuromuscular disease, and validated genetic DCM. Cardiac amyloidosis usually produces increased wall thickness/restrictive physiology rather than classic DCM; Alzheimer-associated PSEN1 variants are not automatically CMD1U variants.

11. Outcome and prognosis

The only family-specific evidence indicates an aggressive course in affected adults, with transplantation or death in some relatives. No reliable five- or ten-year survival rate, median life expectancy, hospitalization rate, sudden-death rate, or treatment-response percentage exists for CMD1U (li2006mutationsofpresenilin pages 7-8, li2006mutationsofpresenilin pages 1-3).

General adverse DCM prognostic factors include advanced NYHA class, low LVEF, right-ventricular dysfunction, persistent congestion, renal dysfunction, elevated natriuretic peptides/troponin, ventricular arrhythmia, conduction disease, and extensive CMR late gadolinium enhancement. Recovery/remodeling is possible with treatment in DCM generally, but its probability in D333G carriers is unknown. Morbidity includes exercise limitation, repeated hospitalization, arrhythmia, thromboembolism, device therapy, and transplantation.

12. Treatment

There is no PSEN1-directed approved treatment and no evidence that γ-secretase or Alzheimer-directed therapies benefit CMD1U.

Standard DCM/HFrEF care

• ARNI (sacubitril/valsartan) or ACE inhibitor/ARB: suppresses maladaptive renin–angiotensin signaling.
• Evidence-based β-blocker: carvedilol, metoprolol succinate, or bisoprolol.
• Mineralocorticoid-receptor antagonist: spironolactone or eplerenone.
• SGLT2 inhibitor: dapagliflozin or empagliflozin.
• Loop diuretic: for congestion; improves symptoms rather than disease-specific survival.
• Selected patients may require hydralazine/isosorbide dinitrate, ivabradine, digoxin, anticoagulation for atrial fibrillation/intracardiac thrombus, or antiarrhythmic therapy.

Suggested NCIt intervention concepts include pharmacotherapy (C1909), angiotensin-receptor–neprilysin inhibition, beta-adrenergic blockade, mineralocorticoid-receptor antagonism, sodium-glucose cotransporter-2 inhibition, diuretic therapy, implantable cardioverter-defibrillator therapy, cardiac resynchronization therapy, ventricular-assist-device therapy, and heart transplantation. Exact NCIt identifiers should be validated against the current NCIt release before database loading.

ICD and CRT decisions follow LVEF, symptoms, QRS morphology/duration, scar, arrhythmias, and genotype-informed risk—not PSEN1 status alone. Refractory NYHA III–IV disease may require mechanical circulatory support and transplantation (sorella2025diagnosisandmanagement pages 12-13).

Experimental treatment

No CMD1U-specific gene therapy, CRISPR therapy, RNA therapy, cell therapy, or registered interventional trial was retrieved. AAV-PSEN1 or calcium-handling interventions in experimental cardiac models are hypothesis-generating and not clinical recommendations. No validated PSEN1 pharmacogenomic rule exists.

13. Prevention

• Primary prevention: inheritance cannot be prevented by lifestyle. Reproductive options include genetic counseling and, where the familial variant is accepted as pathogenic, prenatal diagnosis or preimplantation genetic testing. The uncertain clinical validity of PSEN1–DCM must be disclosed.
• Secondary prevention: cascade evaluation of first-degree relatives with history, examination, ECG, echocardiography, and periodic reassessment; Holter, strain imaging, and CMR as indicated. Early detection permits treatment before advanced remodeling.
• Tertiary prevention: guideline-directed therapy, vaccination, sodium/fluid advice when congested, exercise prescription, avoidance of cardiotoxins, arrhythmia surveillance, and timely ICD/CRT/transplant referral.
• Newborn/population screening: not recommended specifically for CMD1U; evidence is far below that required for a population screening program.
• Immunization/prophylaxis: no disease-specific vaccine. Routine respiratory vaccination is reasonable in heart failure.

14. Other species and natural disease

Orthologues include mouse Psen1 (Mus musculus, NCBI Taxon 10090), rat Psen1 (Rattus norvegicus, 10116), zebrafish psen1 (Danio rerio, 7955), and Drosophila Psn (Drosophila melanogaster, 7227). Presenilin function is evolutionarily conserved, especially γ-secretase/Notch biology.

No naturally occurring PSEN1 D333G-equivalent cardiomyopathy, breed association, OMIA syndrome, veterinary prevalence, or cross-species transmission was identified. Naturally occurring canine DCM is genetically heterogeneous and is not a CMD1U counterpart. Zoonotic potential is not applicable.

15. Model organisms and experimental systems

• Carrier-derived fibroblasts: directly disease-linked; reproduce abnormal intracellular Ca²⁺ signaling but not cardiomyocyte contraction (li2006mutationsofpresenilin pages 7-8).
• HEK293 D333G expression: useful for APP-processing assays; unchanged Aβ42/Aβ40 argues against a simple amyloid mechanism but the cells are non-cardiac (yang2023presenilin1(psen1)mutations pages 9-10).
• Psen1 knockout/conditional mouse models: demonstrate roles in cardiac development and calcium regulation; limitations include developmental lethality/structural defects and a genotype unlike heterozygous adult D333G disease.
• APPswe/PS1ΔE9 mice: exhibit cardiomyocyte mechanical and calcium abnormalities with oxidative stress in some studies, but combine APP and an Alzheimer-associated PSEN1 allele and therefore do not model CMD1U.
• Drosophila presenilin cardiac manipulation: supports conserved cardiac effects but has substantial anatomical and physiological differences from human ventricles.
• Human iPSC cardiomyocytes carrying PSEN1 ΔE9: 2024 work reported sarcoplasmic-reticulum calcium leak and altered intracellular Ca²⁺ distribution; this is valuable cardiac human-cell evidence for another PSEN1 allele, not proof for D333G/CMD1U.

The highest-priority future model would be an isogenic CRISPR-corrected pair of human iPSC cardiomyocytes carrying D333G, evaluated for calcium transients, RyR2/SERCA/phospholamban function, force generation, electrophysiology, mitochondrial respiration, proteostasis, and rescue by allele correction.

Recent developments and authoritative interpretation

A 2023 PSEN1 review stated: “Asp333Gly was reported in a family with dilated cardiomyopathy”—appropriately singular—and emphasized that next-generation sequencing and biomarker work are needed to distinguish atypical PSEN1 phenotypes (published May 2023; https://doi.org/10.3390/ijms24098417) (yang2023presenilin1(psen1)mutations pages 9-10).

A 2024 genetic review summarized the broader field as follows: “While over 200 genes have been associated with DCM, the evidence supporting pathogenicity for most remains limited.” This is particularly relevant to PSEN1, for which the retrieved evidence remains one-family deep (published October 2024; https://doi.org/10.3390/ijms252111460). Current guideline synthesis likewise recommends concentrating clinical testing on genes strongly associated with the phenotype rather than treating all historically published genes as equivalent (sorella2025diagnosisandmanagement pages 12-13).

The 2025 guideline systematic review found consensus on BNP/troponin, multimodality imaging, genetic counseling, and advanced-disease management, but highlighted continuing gaps in the natural history of genetic DCM and aetiology-directed treatments (published online from a 2024 DOI record; https://doi.org/10.1093/ehjqcco/qcae109) (sorella2025diagnosisandmanagement pages 1-2, sorella2025diagnosisandmanagement pages 2-3).

Knowledge-base conclusion

Recommended assertion: “PSEN1 p.Asp333Gly has been reported to segregate with autosomal-dominant, adult-onset, aggressive DCM in one family, with abnormal calcium signaling in carrier fibroblasts. Independent replication and definitive gene–disease validation are lacking.”

Accordingly, populate CMD1U with limited evidence, preserve the original family and PMID 17186461 as the principal evidence item, avoid assigning precise prevalence or penetrance, and do not use an incidental PSEN1 variant as a molecular diagnosis without stringent variant-level, segregation, and phenotype review. Clinical care should follow contemporary DCM guidelines rather than an unvalidated PSEN1-specific pathway.

References

1. (OpenTargets Search: dilated cardiomyopathy-PSEN1): Open Targets Query (dilated cardiomyopathy-PSEN1, 6 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

2. (li2006mutationsofpresenilin pages 7-8): Duanxiang Li, Sharie B. Parks, Jessica D. Kushner, Deirdre Nauman, Donna Burgess, Susan Ludwigsen, Julie Partain, Randal R. Nixon, Charles N. Allen, Robert P. Irwin, Petra M. Jakobs, Michael Litt, and Ray E. Hershberger. Mutations of presenilin genes in dilated cardiomyopathy and heart failure. American journal of human genetics, 79 6:1030-9, Dec 2006. URL: https://doi.org/10.1086/509900, doi:10.1086/509900. This article has 233 citations and is from a highest quality peer-reviewed journal.

3. (li2006mutationsofpresenilin pages 1-3): Duanxiang Li, Sharie B. Parks, Jessica D. Kushner, Deirdre Nauman, Donna Burgess, Susan Ludwigsen, Julie Partain, Randal R. Nixon, Charles N. Allen, Robert P. Irwin, Petra M. Jakobs, Michael Litt, and Ray E. Hershberger. Mutations of presenilin genes in dilated cardiomyopathy and heart failure. American journal of human genetics, 79 6:1030-9, Dec 2006. URL: https://doi.org/10.1086/509900, doi:10.1086/509900. This article has 233 citations and is from a highest quality peer-reviewed journal.

4. (li2006mutationsofpresenilin pages 3-5): Duanxiang Li, Sharie B. Parks, Jessica D. Kushner, Deirdre Nauman, Donna Burgess, Susan Ludwigsen, Julie Partain, Randal R. Nixon, Charles N. Allen, Robert P. Irwin, Petra M. Jakobs, Michael Litt, and Ray E. Hershberger. Mutations of presenilin genes in dilated cardiomyopathy and heart failure. American journal of human genetics, 79 6:1030-9, Dec 2006. URL: https://doi.org/10.1086/509900, doi:10.1086/509900. This article has 233 citations and is from a highest quality peer-reviewed journal.

5. (yang2023presenilin1(psen1)mutations pages 9-10): Youngsoon Yang, Eva Bagyinszky, and Seong Soo A. An. Presenilin-1 (psen1) mutations: clinical phenotypes beyond alzheimer’s disease. International Journal of Molecular Sciences, 24:8417, May 2023. URL: https://doi.org/10.3390/ijms24098417, doi:10.3390/ijms24098417. This article has 73 citations.

6. (sorella2025diagnosisandmanagement pages 1-2): Anna Sorella, Kristian Galanti, Lorena Iezzi, Sabina Gallina, Selma F Mohammed, Neha Sekhri, Mohammed Majid Akhtar, Sanjay K Prasad, Choudhary Anwar Ahmed Chahal, Fabrizio Ricci, and Mohammed Yunus Khanji. Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations. European Heart Journal. Quality of Care & Clinical Outcomes, 11:206-222, Dec 2025. URL: https://doi.org/10.1093/ehjqcco/qcae109, doi:10.1093/ehjqcco/qcae109. This article has 45 citations.

7. (sorella2025diagnosisandmanagement pages 2-3): Anna Sorella, Kristian Galanti, Lorena Iezzi, Sabina Gallina, Selma F Mohammed, Neha Sekhri, Mohammed Majid Akhtar, Sanjay K Prasad, Choudhary Anwar Ahmed Chahal, Fabrizio Ricci, and Mohammed Yunus Khanji. Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations. European Heart Journal. Quality of Care & Clinical Outcomes, 11:206-222, Dec 2025. URL: https://doi.org/10.1093/ehjqcco/qcae109, doi:10.1093/ehjqcco/qcae109. This article has 45 citations.

8. (sorella2025diagnosisandmanagement pages 12-13): Anna Sorella, Kristian Galanti, Lorena Iezzi, Sabina Gallina, Selma F Mohammed, Neha Sekhri, Mohammed Majid Akhtar, Sanjay K Prasad, Choudhary Anwar Ahmed Chahal, Fabrizio Ricci, and Mohammed Yunus Khanji. Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations. European Heart Journal. Quality of Care & Clinical Outcomes, 11:206-222, Dec 2025. URL: https://doi.org/10.1093/ehjqcco/qcae109, doi:10.1093/ehjqcco/qcae109. This article has 45 citations.

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Reference Validation

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All extracted references resolved successfully.

Term Validation

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Terms the report names something else

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

• MONDO:0013371 (2 mentions) - the report calls it "if available"; MONDO calls it dilated cardiomyopathy 1U

Terms whose name is worth a second look

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

• MONDO:0700335 (1 mention) - the report calls it "OpenTargets Search: dilated cardiomyopathy-PSEN1"; MONDO calls it familial isolated dilated cardiomyopathy, and lists "familial or idiopathic dilated cardiomyopathy" among its other names