| Knowledge-base field | DCM1W essential annotation | Evidence / ontology suggestions |
|---|---|---|
| Disease identity and identifiers | **Dilated cardiomyopathy 1W (DCM1W)** is the historical Mendelian label for **VCL-associated dilated cardiomyopathy**, characterized by ventricular dilation and systolic dysfunction after exclusion of sufficient ischemic, loading, valvular, or congenital causes. A subtype-specific MONDO identifier was not verified; use broader **MONDO:0005021** (dilated cardiomyopathy) or **MONDO:0016333** (familial dilated cardiomyopathy) with a VCL qualifier rather than inventing an identifier. | Open Targets maps VCL to dilated and familial dilated cardiomyopathy (pqac-00000000). Suggested phenotype ontology: **HP:0001644 Dilated cardiomyopathy**. |
| Gene, protein, and locus | **VCL** encodes vinculin, a 117-kDa, 1,066-aa mechanosensitive actin-binding adaptor. The muscle-specific splice isoform **metavinculin** contains an additional 68 aa. Locus: **10q22.1–q23** in the foundational report; a later iPSC resource specifies **10q22.2**. Vinculin/metavinculin localize to cardiomyocyte costameres and intercalated-disc adherens junctions. | Vinculin links F-actin to integrin- and cadherin-associated adhesion complexes (pqac-00000017, pqac-00000019, pqac-00000020). Suggested GO: **GO:0005925 focal adhesion**, **GO:0005912 adherens junction**, **GO:0051015 actin filament binding**; CL: **CL:0000746 cardiac muscle cell**. |
| Foundational metavinculin variants | **p.Leu954del** (in-frame 3-bp deletion) and **p.Arg975Trp** (missense) were identified among 350 unrelated DCM patients, absent from 500 controls, and significantly altered metavinculin-mediated actin-filament cross-linking in vitro. The p.Arg975Trp carrier had grossly abnormal intercalated discs. | Human genetic plus in-vitro functional evidence supports impaired force transmission at the thin-filament/intercalated-disc interface (pqac-00000019). |
| VCL predicted loss-of-function variants | In 18,135 cardiomyopathy-test referrals, 30 heterozygous probands carried 26 unique pLOF variants: **12 nonsense, seven frameshift, six canonical splice-site, and one multi-exon duplication**. Rare pLOF variants were enriched in DCM: OR **9.01** (95% CI 4.93–16.45), rising to **11.33** (5.80–22.15) under stricter filtering. Population prevalence was approximately **0.0003–0.00046** in gnomAD, depending on filtering. | Human case-control evidence (pqac-00000003, pqac-00000004, pqac-00000006). Individual variants must be classified under ACMG/AMP criteria; many remain VUS. |
| Inheritance and penetrance | Usually modeled as **heterozygous/autosomal-dominant susceptibility**, but family data do not support uniformly sufficient, highly penetrant monogenic causation. Current evidence favors **reduced/incomplete penetrance**, variable expressivity, and a moderate-risk or modifier effect involving other genetic or environmental stressors. No convincing biallelic human series, anticipation, founder effect, or carrier-frequency estimate specific to DCM1W is established. | Family studies found no clear dominant segregation; possible modifiers include **MYH7, DSP, TPM1, LAMA4, SCN5A**, and **MYBPC3** (pqac-00000005, pqac-00000006, pqac-00000007). |
| Hallmark phenotype and onset | Hallmark disease is left-ventricular or biventricular dilation with reduced systolic function, often presenting as heart failure or arrhythmia. Among 32 VCL-pLOF probands, DCM/LV dilation occurred in **19/32 (59.4%)**; **22/32 (68.8%)** had onset before 20 years, **16/32 (50%)** by 10 years, and **13/32 (40.6%)** in infancy. In the DCM subgroup, **17/19 (89.5%)** had pediatric onset. Less-certain associated findings include LV noncompaction, hypertrophy, bradycardia, heart block, and ventricular tachycardia. | Human cohort evidence (pqac-00000006). Suggested HPO: **HP:0001644 Dilated cardiomyopathy**, **HP:0001635 Congestive heart failure**, **HP:0001711 Abnormality of left ventricular function**, **HP:0004756 Ventricular tachycardia**, **HP:0001678 Atrioventricular block**. |
| 2023 infant outcomes | Six infants with VCL LOF variants had median diagnosis age **2 months**, median LVEF **24%**, and median LV end-diastolic-diameter z-score **10.8**. With heart-failure medication, **5/6 (83%)** normalized LV function after 0.3–3.2 years (median recovery age **2.7 years**); **1/6** progressed to end-stage failure and transplantation. Five variants were VUS and one likely pathogenic, and four infants had additional cardiomyopathy-gene VUS. | Small human case series; estimates are not population-level rates and require replication (pqac-00000001, pqac-00000012). |
| Core mechanism | Pathogenic or risk-conferring VCL dysfunction **leads to** impaired vinculin/metavinculin binding and actin cross-linking; this **weakens** cadherin-based cell–cell and integrin-based cell–matrix anchorage; junctional instability **results in** defective force transmission and conduction; chronic mechanical stress **is inferred to cause** cardiomyocyte injury, adverse remodeling, ventricular dilation, systolic failure, and arrhythmia. Mouse knockout directly demonstrates reduced cadherin/β1-integrin, lateral connexin-43 redistribution, adherens-junction dissolution, intercalated-disc disruption, and disorganized mitochondria before dysfunction. | Human in-vitro and mouse evidence (pqac-00000002, pqac-00000017, pqac-00000019). Suggested GO: **GO:0007155 cell adhesion**, **GO:0007015 actin filament organization**, **GO:0072659 protein localization to plasma membrane**, **GO:0003012 muscle system process**. |
| Diagnostic approach | Establish the DCM phenotype with history and three-generation pedigree, examination, ECG/Holter, echocardiography, and CMR with late gadolinium enhancement; measure natriuretic peptides/troponin and exclude coronary disease, abnormal loading, valvular/congenital disease, toxins, infection, endocrine/metabolic disease, and sustained tachyarrhythmia. Use a curated cardiomyopathy multigene NGS panel including **VCL** with deletion/duplication analysis; WES/WGS or RNA studies may follow unresolved cases. Confirm candidate variants and perform segregation/cascade testing, but do not use a VCL VUS for predictive testing. Biopsy is reserved for selected suspected myocarditis, infiltrative, or inflammatory disease. | Contemporary DCM criteria and work-up (pqac-00000013, pqac-00000015, pqac-00000021). Genetic testing remains markedly underused: only **827/101,919 (0.8%)** newly diagnosed US DCM patients had recorded testing within six months (pqac-00000022). |
| Treatment and surveillance | No approved **VCL-specific** therapy exists. Treat the expressed phenotype according to DCM/HFrEF guidance: ARNI or ACE inhibitor/ARB, evidence-based β-blocker, mineralocorticoid-receptor antagonist, SGLT2 inhibitor, and diuretics for congestion; continue guideline-directed therapy after EF recovery because recovery may not represent resolution. Consider ICD/CRT according to LVEF, conduction, arrhythmia, CMR, and overall risk—not VCL genotype alone. Advanced disease may require LV assist support or transplantation. Genotype-positive relatives need longitudinal ECG/imaging surveillance. | The infant series used ACE inhibitors and β-blockers (pqac-00000012); contemporary HF guidance supports continued therapy in improved EF (pqac-00000023). Suggested NCIT concepts: **Angiotensin-Converting Enzyme Inhibitor**, **Beta-Adrenergic Blocker**, **Implantable Cardioverter Defibrillator**, **Cardiac Resynchronization Therapy**, **Heart Transplantation**. |
| Experimental and comparative models | **Mouse:** cardiac-specific Vcl knockout caused ventricular tachycardia/sudden death in **49% before 3 months**; survivors developed DCM and died before 6 months. Heterozygous mice showed conduction/junction abnormalities and stress-induced vulnerability. **Zebrafish:** vinculin knockdown produced impaired contractility, pericardial edema, and blood congestion. **Human iPSC:** line ZZUNEUi026-A, from a 65-year-old man with heterozygous **c.625A>T (p.Met209Leu)**, has a normal karyotype and can generate cardiomyocytes, but disease phenotyping was not reported. **Y822F mouse:** defective adhesion organization and cardiac dysfunction at 28 weeks implicate post-translational regulation. | Animal and cellular-resource evidence (pqac-00000002, pqac-00000007, pqac-00000017, pqac-00000018, pqac-00000020). Species: *Mus musculus* NCBI Taxon **10090**; *Danio rerio* **7955**; *Homo sapiens* **9606**. |
| Major evidence limitations | DCM1W is ultra-rare and genetically heterogeneous; no reliable subtype-specific prevalence, incidence, sex ratio, penetrance percentage, survival curve, founder effect, protective allele, epigenetic signature, single-cell/spatial/multi-omics profile, or validated prognostic biomarker exists. Foundational missense/in-frame variants and modern pLOF observations may represent different allelic mechanisms. Many reported variants are VUS, unaffected heterozygotes occur, pedigrees are small, oligogenic findings are common, and the favorable infant recovery estimate derives from only six patients. No VCL-directed clinical trial was identified. | Modern authors explicitly recommend distinguishing VCL pLOF alleles from conventional highly penetrant Mendelian variants (pqac-00000001, pqac-00000005, pqac-00000008). |


*Table: Compact evidence-based summary of VCL-associated dilated cardiomyopathy, including disease identity, variants, penetrance, phenotype, mechanism, diagnosis, management, models, ontology suggestions, and key uncertainties.*