| Domain | Subtype-specific finding | Evidence level/source type | Ontology/identifier suggestions | Caveat |
|---|---|---|---|---|
| Disease identity | Dilated cardiomyopathy 1KK (DCM1KK), a proposed MYPN-associated inherited DCM subtype characterized by ventricular dilation and systolic dysfunction. | Curated disease–target association and historical human case-series evidence (pqac-00000000, pqac-00000001) | MONDO:0014100; broader phenotype: dilated cardiomyopathy; MeSH: Cardiomyopathy, Dilated | No dedicated ICD-10, ICD-11, or Orphanet subtype code was identified; broader DCM coding is appropriate. |
| Causal gene/protein | MYPN encodes myopalladin, a striated-muscle protein localized to the sarcomeric Z-disc, I-band, and nucleus at chromosome 10q21.3. (pqac-00000000, pqac-00000006) | Human genetic association supported by cellular and mouse experiments | MYPN; OMIM gene 608517; historical transcript NM_032578; protein: myopalladin | MYPN has historically had limited evidence for monogenic DCM relative to core ClinGen-validated genes; interpret variants cautiously. |
| Inheritance | Familial variants were heterozygous and cosegregated with DCM, supporting likely autosomal-dominant inheritance with age-dependent, incomplete, or variable penetrance. (pqac-00000002) | Small pedigrees; human observational evidence | Autosomal dominant inheritance; HPO concept: incomplete penetrance | Numerical penetrance, anticipation, germline-mosaicism rate, founder effects, and carrier frequency are unavailable. |
| Historical variant | MYPN I83fsX105, described as exon-2 ins/del_T735, produced no detectable premature-termination transcript, supporting nonsense-mediated decay or haploinsufficiency. (pqac-00000003, pqac-00000005) | Familial segregation and patient-derived RNA assay | Sequence Ontology: frameshift variant; loss-of-function mechanism | Historical nomenclature may not conform to current HGVS; transcript/build normalization and current ClinVar/ACMG classification are required. |
| Historical variant | MYPN R1088H cosegregated with familial DCM; linkage was suggestive with LOD 2.1 at theta 0, and left-ventricular tissue showed reduced myopalladin at alpha-actinin-positive Z-discs. (pqac-00000002, pqac-00000003) | Familial human and myocardial-tissue functional evidence | Sequence Ontology: missense variant; GO: Z disc | Absent from 400 historical controls, but current population frequency and formal ACMG/AMP classification were not established. |
| Historical variants | MYPN P1112L and V1195M occurred in apparently sporadic DCM; expression in neonatal rat cardiomyocytes caused mislocalization, sarcomeric disorganization, and increased cell death. (pqac-00000001, pqac-00000003, pqac-00000005) | Human cases and in-vitro functional evidence | Sequence Ontology: missense variant; GO: sarcomere organization | Overexpression assays do not independently establish human pathogenicity; modern ClinVar, gnomAD, segregation, and ACMG reassessment are necessary. |
| Pleiotropic variant | MYPN Y20C was reported in DCM and hypertrophic cardiomyopathy, altered CARP binding and nuclear shuttling, and produced predominantly hypertrophic disease in transgenic mice. (pqac-00000004, pqac-00000006, pqac-00000007) | Human cases, in-vitro assays, and transgenic-mouse evidence | dbSNP rs140148105; Sequence Ontology: missense variant; GO concepts: protein binding and nuclear transport | Historical 1000 Genomes frequency was approximately 0.001; pleiotropy and model–human discordance weaken DCM1KK specificity. |
| Variant spectrum | Four variants were found among 114 unrelated DCM probands: 2 of 65 familial cases and 2 of 49 sporadic cases; mean diagnosis age among carriers was 40.2 ± 18.3 years. (pqac-00000001, pqac-00000002) | Historical European-descent DCM cohort | HPO concept: adult onset | The 3–4% cohort frequency is era- and cohort-dependent and is not contemporary population prevalence. |
| Core structural phenotype | Left-ventricular or biventricular dilation with reduced systolic contraction is the defining phenotype. (pqac-00000001) | Human clinical phenotype | HPO: Dilated cardiomyopathy, HP:0001644; ventricular dilatation; decreased ejection fraction | Variant-level frequencies and standardized imaging measurements were not reported. |
| Heart-failure phenotype | Progressive systolic dysfunction may cause exertional dyspnea, fatigue, exercise intolerance, edema, and advanced heart failure, as in DCM generally. | General DCM extrapolation; not systematically demonstrated in DCM1KK | HPO: Heart failure, HP:0001635; Dyspnea, HP:0002094; fatigue; exercise intolerance; peripheral edema | Symptom prevalence, severity, quality-of-life scores, hospitalization rates, and survival are unavailable for DCM1KK. |
| Electrical phenotype | Conduction abnormalities or arrhythmias occurred in a minority of the broader discovery cohort, but MYPN-variant-specific frequencies were not established. (pqac-00000002) | Human cohort; weak subtype specificity | HPO: Cardiac arrhythmia, HP:0011675; Abnormal cardiac conduction, HP:0001678 | No MYPN-specific sudden-death or ventricular-arrhythmia estimate supports genotype-specific ICD decisions. |
| Anatomy | Primary involvement is myocardium, particularly left-ventricular cardiomyocytes and sarcomeric I–Z–I regions; biventricular disease may involve the right ventricle. (pqac-00000003, pqac-00000006) | Patient myocardium and experimental models | UBERON: heart, UBERON:0000948; left ventricle; right ventricle; myocardium; cardiac muscle tissue | No lateralization applies; skeletal-muscle disease from other MYPN genotypes should not automatically be assigned to DCM1KK. |
| Upstream mechanism | MYPN loss or dysfunctional missense protein disrupts Z-disc/I-band scaffolding and interactions with titin, alpha-actinin-2, CARP/ANKRD1, desmin, and nebulette. (pqac-00000003, pqac-00000004, pqac-00000006) | Patient tissue, biochemical assays, and cellular models | GO: Z disc, GO:0030018; sarcomere, GO:0030017; I band; actin binding; titin binding; CL: cardiomyocyte | Mechanisms differ by variant: haploinsufficiency is supported for I83fsX105, while dominant-negative effects are proposed for some missense variants. |
| Downstream mechanism | Sarcomeric disorganization leads to reduced force and abnormal mechanotransduction; altered calcium handling is inferred to compound dysfunction, followed by dilation, fibrosis, and heart failure. (pqac-00000003) | Mechanistic inference based mainly on cellular and MYPN-knockout mouse studies | GO concepts: cardiac muscle contraction, calcium-ion homeostasis, response to mechanical stimulus, extracellular-matrix organization; CL: ventricular cardiomyocyte and cardiac fibroblast | Calcium-handling and fibrotic mechanisms have not been demonstrated directly in carriers of the historical DCM1KK variants. |
| Diagnostic testing | Evaluation includes pedigree, ECG, ambulatory rhythm monitoring, echocardiography, cardiac MRI, BNP or NT-proBNP, and troponin where clinically indicated. | General DCM guideline practice; not MYPN-specific | Phenotyping concepts: ventricular volume, ejection fraction, late gadolinium enhancement | No test uniquely identifies DCM1KK apart from a credible MYPN genotype in a compatible phenotype. |
| Genetic testing | Use a curated cardiomyopathy multigene panel with deletion/duplication analysis; consider WES or WGS if panel testing is negative, and confirm variants by segregation analysis. | Current inherited-DCM practice informed by limited MYPN evidence | MYPN plus high-evidence DCM genes; ACMG/AMP; ClinVar; gnomAD | A MYPN VUS must not establish DCM1KK, direct predictive testing, or guide irreversible treatment. |
| Family screening | For a confirmed pathogenic or likely pathogenic familial variant, offer genetic counseling and cascade testing; carriers require longitudinal ECG and imaging. | General genetic-DCM practice plus familial MYPN segregation | HPO concept: asymptomatic; genetic counseling; cascade screening | MYPN-specific screening intervals and lifetime penetrance are not established. |
| Pharmacotherapy | Treat symptomatic HFrEF with guideline-directed therapy: ARNI or ACE inhibitor/ARB, evidence-based beta blocker, mineralocorticoid-receptor antagonist, SGLT2 inhibitor, and diuretics for congestion. | Extrapolated from randomized HFrEF evidence; no MYPN-specific trials | NCIT categories: Pharmacologic Therapy; Angiotensin Receptor–Neprilysin Inhibitor Therapy; Beta Blocker Therapy; SGLT2 Inhibitor Therapy; Diuretic Therapy | No drug is approved specifically for DCM1KK, and no established MYPN pharmacogenomic rule exists. |
| Device and surgical treatment | ICD, cardiac resynchronization, ventricular-assist device, and transplantation are considered using standard arrhythmic, conduction, ejection-fraction, and advanced-heart-failure criteria. | General DCM implementation | NCIT categories: Implantable Cardioverter-Defibrillator Therapy; Cardiac Resynchronization Therapy; Ventricular Assist Device; Heart Transplantation | MYPN is not an established high-arrhythmic-risk genotype and does not justify gene-specific device thresholds. |
| Advanced therapeutics | No MYPN-directed gene replacement, genome editing, antisense, siRNA, mRNA, or cell therapy has established clinical efficacy or an identified disease-specific trial. | Explicit evidence gap | NCIT categories: Gene Therapy; Genetic Engineering; RNA Therapy; Cell Therapy | Experimental concepts must not be represented as available treatment. |
| Prevention | Primary genetic prevention is unavailable; general risk reduction includes avoiding cardiotoxic alcohol, illicit stimulants, unnecessary cardiotoxic drugs, uncontrolled hypertension, and inappropriate extreme exercise. | General DCM risk-management extrapolation | Genetic counseling; reproductive counseling; cardiovascular surveillance | No exposure has been proven to trigger DCM specifically in MYPN carriers, although stress sensitivity is biologically plausible. |
| Mouse model | Mypn-knockout mice develop mild dilation, systolic dysfunction, reduced myofibrillar tension, abnormal passive tension and calcium handling, and severe dilation and fibrosis after pressure overload. | Genetic animal model | NCBI Taxon: Mus musculus, 10090; GO concepts: response to mechanical stimulus, cardiac muscle contraction, calcium-ion transport | The knockout models haploinsufficiency better than individual heterozygous missense variants and does not reproduce full human natural history. |
| Variant-specific model | Cardiac-restricted Y20C transgenic mice show Z-disc and intercalated-disc abnormalities, altered junctional proteins, hypertrophy, and reduced ejection fraction. (pqac-00000008, pqac-00000009) | Transgenic mouse model | NCBI Taxon: Mus musculus, 10090; GO concepts: intercalated disc and cell–cell junction organization | Predominantly HCM-like remodeling limits fidelity as a DCM1KK model. |
| Cellular models | Neonatal rat cardiomyocytes expressing historical variants reproduce myopalladin mislocalization, defective myofibrillogenesis, sarcomeric disruption, and cell death. (pqac-00000001, pqac-00000005) | In-vitro overexpression model | CL: cardiomyocyte; GO concepts: myofibril assembly, sarcomere organization, programmed cell death | Immature rodent cells and overexpression may exaggerate effects; no validated patient-derived MYPN-DCM iPSC or organoid model was identified. |
| Natural disease in other species | No convincing naturally occurring orthologous MYPN-associated DCM1KK syndrome was identified in companion animals or wildlife. | Explicit evidence gap | NCBI Taxonomy and VBO terms: not assignable | Canine and feline DCM should not be attributed to MYPN without variant-specific evidence. |
| Molecular profiling | No DCM1KK-specific single-cell, spatial-transcriptomic, proteomic, metabolomic, lipidomic, or epigenomic signature has been established. | Explicit evidence gap | GEO, PRIDE, MetaboLights, and ENCODE: no subtype-specific term assignable | General DCM fibroblast, immune, fibrotic, and metabolic signatures cannot be assumed to be MYPN-specific. |
| Epidemiology and prognosis | Population prevalence, incidence, sex ratio, geographic distribution, survival, transplantation, recovery, and validated prognostic biomarkers are unknown for DCM1KK. | Explicit evidence gap; evidence is limited to small cohorts and families | Orphan-disease epidemiology fields: unavailable | Store general DCM statistics separately and label them as extrapolated rather than subtype-specific. |
| Data provenance | Evidence is aggregated from disease databases, published pedigrees, myocardial tissue, cellular assays, and engineered animals rather than individual EHR records. (pqac-00000000, pqac-00000001, pqac-00000004) | Aggregated disease-level evidence | Evidence categories: human genetic; human tissue; in vitro; model organism | Patient-level EHR frequencies, standardized longitudinal outcomes, and contemporary reinterpretations were unavailable. |


*Table: Concise disease, gene, variant, phenotype, mechanism, diagnostic, treatment, and model annotations for MYPN-associated Dilated Cardiomyopathy 1KK. Subtype-specific findings are separated from general DCM extrapolations and explicit evidence gaps.*