Hypertrophic Cardiomyopathy 15 (HCM15): Comprehensive Disease-Characteristics Report

Executive summary and evidence boundary

Hypertrophic cardiomyopathy 15 (HCM15) is a historically catalogued, extremely rare Mendelian hypertrophic-cardiomyopathy subtype attributed to heterozygous germline variants in VCL, which encodes vinculin and its muscle-specific splice isoform metavinculin. The supplied disease identifier is MONDO:0013200. Because disease numbering and gene–disease assertions can change between ontology releases, this identifier and the HCM15–VCL relationship should be checked against the current MONDO, OMIM, ClinGen, and ClinVar releases before production use. Open Targets supports a VCL–HCM association and points to human literature including PMIDs 16712796, 20052757, 21779496, 22826437, and 24937142, but this is gene-level evidence rather than proof that every rare VCL variant causes HCM15. (OpenTargets Search: hypertrophic cardiomyopathy-VCL)

The central limitation is that published HCM15-specific human data are too sparse to estimate penetrance, age-specific onset, phenotype frequencies, incidence, prognosis, or treatment response. Consequently, this report distinguishes:

• Subtype-specific evidence: human VCL association and experimental Vcl biology.
• Parent-disease evidence: contemporary phenotype-defined HCM criteria, surveillance, prognosis, and treatment, which guide management but must not be encoded as VCL-specific outcomes.

Table: This table separates VCL/HCM15-specific findings from parent-level HCM evidence used only for clinical context. It highlights which claims can be encoded directly and which must not be represented as VCL-specific frequencies, treatment responses, or outcomes.

1. Disease information

Definition

HCM15 is a proposed autosomal-dominant, VCL-associated form of familial hypertrophic cardiomyopathy. At the parent-disease level, HCM is defined by increased left-ventricular wall thickness that is not explained solely by loading conditions or another cardiac, systemic, metabolic, infiltrative, or storage disorder. Contemporary adult criteria are maximal end-diastolic LV wall thickness ≥15 mm, or ≥13 mm in a first-degree relative of an affected person or in a carrier of a confirmed disease-causing variant. (verheyen2024austrianconsensusstatement pages 6-7, verheyen2024austrianconsensusstatement pages 1-2)

Identifiers and terminology

• MONDO: MONDO:0013200, as supplied; verify against the live release.
• Preferred name: hypertrophic cardiomyopathy 15.
• Synonyms: HCM15; familial hypertrophic cardiomyopathy 15; VCL-related hypertrophic cardiomyopathy; vinculin-related cardiomyopathy.
• Parent disease: hypertrophic cardiomyopathy, MONDO:0005045 in Open Targets. (OpenTargets Search: hypertrophic cardiomyopathy-VCL)
• OMIM: the subtype has historically been associated with the VCL locus; the exact current phenotype record should be confirmed directly in OMIM because numbered HCM assignments are periodically revised.
• ICD-10-CM: I42.1, obstructive HCM; I42.2, other HCM. These codes do not distinguish HCM15.
• ICD-11: cardiomyopathy hierarchy, hypertrophic-cardiomyopathy category; no VCL-specific code.
• MeSH: Cardiomyopathy, Hypertrophic.

This is an aggregated disease-level synthesis, not an individual EHR record. The foundational subtype evidence derives from small human genetic observations; modern diagnostic and therapeutic statements derive predominantly from aggregated HCM cohorts, trials, and guidelines.

2. Etiology

Causal factor

The initiating lesion is a heterozygous germline VCL variant with sufficient pathogenic evidence. Vinculin is an actin-binding adhesion protein concentrated at cardiomyocyte costameres and intercalated discs; metavinculin is a muscle-enriched alternatively spliced isoform. VCL links the actin cytoskeleton and contractile apparatus to cell–matrix and cell–cell adhesion systems. Complete cardiomyocyte loss in mice demonstrates that this function is essential for junctional and electrical integrity. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2, zemljicharpf2007cardiacmyocytespecificexcisionof pages 2-3)

A rare VCL variant should not automatically be considered causal. A defensible molecular diagnosis requires ACMG/AMP classification, phenotype concordance, segregation, population rarity, and ideally variant-specific functional evidence. A VUS does not establish HCM15.

Risk factors

Genetic:

• A pathogenic/likely pathogenic VCL allele is the principal proposed risk factor.
• Autosomal-dominant transmission implies a 50% probability of allele transmission, not 50% certainty of clinical disease, because penetrance is likely incomplete and age dependent.
• Family history of HCM or sudden cardiac death increases clinical suspicion, but absence of family history does not exclude disease because of reduced penetrance or a de novo variant. General monogenic HCM shows variable penetrance and expressivity. (verheyen2024austrianconsensusstatement pages 11-12, verheyen2024austrianconsensusstatement pages 9-11)
• No validated HCM15-specific modifier gene, polygenic score, founder allele, carrier frequency, or ancestry-specific susceptibility estimate is available.

Environmental and physiologic modifiers:

Hypertension, obesity, valvular disease, ischemia, pregnancy-related hemodynamic loading, and intense exercise may alter hypertrophy, symptoms, or arrhythmic burden in HCM generally, but none is established as a cause of VCL-HCM15. Hypertension and athlete’s heart are especially important diagnostic confounders. In mild-to-moderate hypertension, LV thickness ≥15 mm is uncommon, reported in under 5% in the cited consensus. (verheyen2024austrianconsensusstatement pages 11-12)

Protective factors and gene–environment interaction

No replicated VCL-specific protective allele, diet, medication, or exposure is known to prevent disease penetrance. Control of hypertension and other cardiovascular comorbidities, avoidance of dehydration in obstructive physiology, and individualized exercise are prudent tertiary-risk measures rather than primary prevention of the mutation.

Vinculin is load responsive: mechanical stress alters adhesion-complex recruitment. Therefore, a VCL defect plausibly interacts with hemodynamic load through impaired mechanotransduction, but a quantitative human VCL × environment interaction has not been demonstrated. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 2-3)

3. Phenotypes

Published evidence does not support HCM15-specific percentages. The following are expected HCM phenotypes, to be recorded as observed rather than assumed in a VCL carrier.

HCM quality-of-life impairment is driven by dyspnea, fatigue, exercise limitation, anxiety about SCD, medication effects, and activity restrictions. The 2024 Austrian consensus states that HCM can cause a “substantial reduction in quality of life,” but no HCM15-specific EQ-5D, SF-36, KCCQ, or HCMSQ data exist. (verheyen2024austrianconsensusstatement pages 1-2)

4. Genetic and molecular information

Causal gene

• Gene: VCL, vinculin.
• Ensembl: ENSG00000035403. (OpenTargets Search: hypertrophic cardiomyopathy-VCL)
• Gene product: ubiquitous vinculin and muscle-specific metavinculin.
• Origin: germline for inherited HCM15; somatic VCL mutation is not an established cause.
• Inheritance: proposed autosomal dominant.

Pathogenic variants

The accessible evidence did not provide a sufficiently verified, current list of HCM15 variants with transcript, HGVS expression, ClinVar assertion, gnomAD frequency, segregation, and functional status. A knowledge-base implementation should therefore import variants directly from current ClinVar/ClinGen and retain:

1. reference transcript and genome build;
2. genomic, coding, and protein HGVS;
3. submitter/date and review status;
4. ACMG/AMP class;
5. gnomAD ancestry-specific frequency;
6. segregation and phenotype;
7. functional-assay type;
8. whether vinculin, metavinculin, or both are affected.

Reported VCL cardiomyopathy alleles have included missense and splice/isoform-affecting variants, but the disease spectrum includes both hypertrophic and dilated cardiomyopathy. Thus, variant-specific evidence is essential. Open Targets’ supporting literature includes PMIDs 16712796, 20052757, 21779496, 22826437, and 24937142. (OpenTargets Search: hypertrophic cardiomyopathy-VCL)

Functional consequence

Possible mechanisms include loss of function, altered actin binding, disturbed head–tail autoinhibition, defective recruitment to costameres/intercalated discs, or altered mechanosensing. Complete Vcl deletion is clearly loss of function, but it must not be assumed that every human heterozygous missense allele acts identically.

Modifiers, epigenetics, and chromosomal abnormalities

• Modifier genes: none validated specifically for HCM15.
• Epigenetics: no reproducible VCL-HCM15 methylation, chromatin, or histone signature identified.
• Structural variants: no recurrent HCM15-associated deletion, duplication, inversion, or translocation established.
• Anticipation: not established; VCL disease is not a repeat-expansion disorder.
• Mosaicism: theoretically possible but not quantified.

5. Environmental information

No toxin, pollutant, radiation exposure, occupation, or infectious agent is known to cause HCM15. Viral myocarditis and other acquired myocardial diseases can mimic or aggravate cardiomyopathy but are not defining etiologies. Smoking, excess alcohol, obesity, hypertension, sleep apnea, and sedentary behavior should be managed for overall cardiovascular health; none has demonstrated VCL-specific penetrance modification.

Lifestyle advice should be phenotype based. Low-to-moderate recreational exercise is generally safe and beneficial. High-intensity sport should be assessed through shared decision-making, particularly when there is prior cardiac arrest, unexplained syncope, exercise-induced arrhythmia, significant LVOTO, or elevated SCD risk. (verheyen2024austrianconsensusstatement pages 19-21)

6. Mechanism and pathophysiology

Ordered causal chain

1. A pathogenic heterozygous VCL lesion leads to deficient or abnormal vinculin/metavinculin localization or function at cardiomyocyte costameres and intercalated discs; this first step is established for Vcl loss but remains variant-specific in humans.
2. Abnormal vinculin leads to impaired linkage of actin/myofibrils to integrin-containing cell–matrix adhesions and cadherin-containing cell–cell junctions.
3. Impaired adhesion results in defective force transmission, mechanosensing, and intercalated-disc stability; conditional Vcl-null mouse hearts show reduced cadherin and β1D-integrin, myofibril detachment, and abnormal discs. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 8-11, zemljicharpf2007cardiacmyocytespecificexcisionof pages 11-12)
4. Junctional disruption leads to connexin-43 redistribution, heterogeneous coupling, local conduction slowing, ventricular ectopy, polymorphic VT, and sudden death in the knockout model. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 8-11, zemljicharpf2007cardiacmyocytespecificexcisionof pages 12-14)
5. Mechanical branch—partly inferred for human HCM15: chronic force-transmission inefficiency and load-responsive focal-adhesion signaling lead to compensatory cardiomyocyte hypertrophy, energetic stress, and maladaptive remodeling.
6. Structural branch: repeated mechanical injury results in myocyte loss, replacement fibrosis, and altered ventricular compliance.
7. Hypertrophy, disarray, fibrosis, and small-vessel/energetic dysfunction lead to diastolic dysfunction, microvascular ischemia, dynamic LVOTO, atrial enlargement, and heart-failure symptoms.
8. Fibrosis plus electrical uncoupling results in atrial and ventricular arrhythmia and creates the substrate for SCD.
9. In advanced disease, progressive myocyte loss and remodeling may lead to systolic dysfunction, dilation, or a restrictive end-stage phenotype; the direct Vcl-null model predominantly evolves toward DCM rather than faithfully reproducing heterozygous HCM15.

Molecular and cellular detail

Vinculin occupies costameres, which align with Z-discs and transmit sarcomeric force to extracellular matrix, and intercalated discs, which provide end-to-end mechanical and electrical coupling. Relevant signaling context includes integrin–FAK/Src, PI3K–AKT, Wnt/β-catenin, cytoskeletal tension, and hypertrophic gene programs. These pathways are biologically relevant to focal-adhesion mechanotransduction but have not been demonstrated as a complete allele-to-phenotype chain in HCM15.

In conditional cardiomyocyte Vcl-knockout mice, structural abnormalities preceded overt dysfunction: serrated, less electron-dense intercalated discs, separation of myofibrils, disorganized mitochondria, reduced cadherin/β1D-integrin, and lateralized connexin-43 were observed. Telemetry showed heart block and polymorphic VT; 86% of isolated knockout hearts had spontaneous ventricular ectopy. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 8-11, zemljicharpf2007cardiacmyocytespecificexcisionof pages 11-12)

Suggested GO biological processes:

• GO:0007155 cell adhesion
• GO:0007160 cell–matrix adhesion
• GO:0007156 homophilic cell adhesion
• GO:0055002 striated-muscle-cell development
• GO:0007512 adult heart development
• GO:0006936 muscle contraction
• GO:0003015 heart process
• GO:0006979 response to oxidative stress
• GO:0060048 cardiac muscle contraction
• GO:0007507 heart development
• GO:0035994 response to muscle stretch

Suggested GO cellular components: focal adhesion (GO:0005925), cell–substrate junction (GO:0030055), adherens junction (GO:0005912), intercalated disc (GO:0014704), costamere (GO:0043034), actin cytoskeleton (GO:0015629), Z disc (GO:0030018), mitochondrion (GO:0005739).

Suggested Cell Ontology terms: cardiomyocyte (CL:0000746), ventricular cardiomyocyte (CL:0002129), cardiac fibroblast, vascular endothelial cell (CL:0000115), vascular smooth-muscle cell (CL:0000359), cardiac conduction cell where appropriate.

Molecular profiling and advanced technologies

No HCM15-specific bulk transcriptomic, single-cell, spatial, proteomic, metabolomic, lipidomic, methylomic, or CRISPR-screen signature was identified. A 2023 spatial multiomic atlas mapped cellular niches across eight normal human heart regions, and a 2024 review emphasized that single-cell/spatial technologies now resolve cardiac cellular diversity, but these resources do not establish a VCL-HCM15 molecular signature. Therefore, such evidence should be treated as enabling context, not disease-specific annotation.

7. Anatomical structures affected

Primary organ: heart, principally the left-ventricular myocardium and interventricular septum.

Structures:

• left ventricle — UBERON:0002084;
• interventricular septum — UBERON:0002094;
• myocardium — UBERON:0002349;
• papillary muscles and mitral-valve apparatus when SAM/LVOTO is present;
• left atrium secondarily from elevated filling pressure;
• right ventricle occasionally through hypertrophy, loading, or advanced disease.

Tissue/cell level: striated cardiac muscle, ventricular cardiomyocytes, interstitial fibroblasts, intramural coronary microvasculature, conduction-system cells.

Subcellular level: intercalated discs, fascia adherens, costameres, focal adhesions, actin cytoskeleton, sarcomere/Z-disc interfaces, gap junctions, and secondarily mitochondria. The Vcl-knockout study directly showed abnormal intercalated discs, myofibril detachment, connexin-43 redistribution, and mitochondrial disorganization. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 8-11, zemljicharpf2007cardiacmyocytespecificexcisionof pages 11-12)

HCM is usually diffuse or regionally asymmetric rather than unilateral; lateralization is not applicable.

8. Temporal development

HCM15-specific onset is unknown. General inherited HCM may be detectable in childhood, adolescence, adulthood, or late life; onset is often insidious and penetrance is age dependent. A genotype-positive person may remain phenotype negative for years.

A practical temporal model is:

1. Preclinical: pathogenic-variant carrier, normal wall thickness; subtle ECG, strain, crypt, or CMR abnormalities may occur.
2. Early phenotype: localized or mild LV hypertrophy, preserved LVEF, few symptoms.
3. Established HCM: greater hypertrophy with diastolic dysfunction, possible LVOTO/SAM, symptoms, AF or ventricular ectopy.
4. Advanced disease: fibrosis, atrial enlargement, recurrent arrhythmia, heart failure, apical aneurysm, or LVEF <50%.
5. End stage: restrictive or dilated/systolic phenotype, transplantation consideration.

The course is chronic and lifelong but highly variable, not classically relapsing–remitting. There is no established spontaneous molecular remission. Obstruction and symptoms can improve with treatment.

Genotype-positive/phenotype-negative children and adolescents should generally undergo ECG and imaging every 1–2 years, and adults every 3–5 years. Stable phenotype-positive patients generally receive clinical review, ECG/Holter, and echocardiography every 1–2 years, with earlier reassessment after symptom change. (verheyen2024austrianconsensusstatement pages 21-22, verheyen2024austrianconsensusstatement pages 19-21)

9. Inheritance and population

Inheritance

• Pattern: autosomal dominant.
• Transmission risk: 50% per pregnancy from a heterozygous parent.
• Penetrance: insufficiently characterized for VCL; likely incomplete and age dependent by analogy with inherited HCM.
• Expressivity: variable; VCL variation has been associated with a cardiomyopathy spectrum rather than one invariant morphology.
• Anticipation: not established.
• Germline mosaicism: possible in principle, unquantified.
• Consanguinity: not expected to be a principal factor in dominant HCM15.
• Founder effects/carrier frequency: unknown.

Epidemiology

No HCM15-specific prevalence or incidence estimate exists. Parent-level phenotype-defined unexplained LV thickening affects approximately 0.16–0.23% of adults; inclusion of genotype-positive/phenotype-negative people may raise general HCM prevalence toward 0.6%. These values must not be assigned to HCM15. (verheyen2024austrianconsensusstatement pages 1-2)

No reliable HCM15-specific sex ratio, age distribution, ancestry enrichment, or geographic clustering is known. General cohorts can show referral-related male predominance, which should not be interpreted as Mendelian sex limitation.

10. Diagnostics

Clinical diagnostic pathway

1. Obtain symptoms, blood pressure, loading conditions, medications, and a three-generation pedigree including HCM, heart failure, unexplained death, and SCD.
2. Perform 12-lead ECG, transthoracic echocardiography, and 24–48-hour ambulatory ECG. Longer monitoring is appropriate for intermittent palpitations, presyncope, or suspected AF/VT. (verheyen2024austrianconsensusstatement pages 6-7)
3. Measure maximal LV thickness in all segments and assess systolic/diastolic function, left-atrial size, mitral anatomy, SAM, and resting/provoked LVOT gradient.
4. Use Valsalva, standing, squat-to-stand, or exercise provocation when resting obstruction is absent; dobutamine stress is not recommended for this purpose. (verheyen2024austrianconsensusstatement pages 6-7)
5. Obtain CMR when echocardiography is incomplete or to define morphology, apical disease/aneurysm, crypts, LVEF, and fibrosis by LGE/T1/ECV.
6. Conduct exercise testing or cardiopulmonary exercise testing for latent obstruction, symptoms, blood-pressure response, functional capacity, and advanced-heart-failure assessment.
7. Exclude phenocopies and alternative loading causes.
8. Offer genetic counselling and a curated cardiomyopathy panel. Molecular HCM15 requires a P/LP VCL variant plus a compatible phenotype or robust familial evidence.

CMR detects focal fibrosis; LGE is reported in approximately 50–60% of general HCM, and involvement of ≥15% of LV mass is an additional SCD-risk marker. CMR can be repeated every 3–5 years when useful for risk reassessment. (verheyen2024austrianconsensusstatement pages 9-11, verheyen2024austrianconsensusstatement pages 21-22)

Laboratory and biomarkers

No diagnostic enzyme assay or VCL-specific circulating biomarker exists. Useful phenotype/severity biomarkers include NT-proBNP/BNP and high-sensitivity troponin, but neither establishes HCM15. Baseline renal, liver, thyroid, iron, CK, and metabolic testing is selected according to differential diagnosis and treatment.

Genetic testing

• Preferred first line: phenotype-focused multigene cardiomyopathy panel containing validated HCM genes, phenocopy genes, and VCL with deletion/duplication analysis where validated.
• Single-gene VCL testing: reasonable when a familial P/LP VCL variant is already known.
• WES/WGS: useful after a negative panel in strongly familial disease, for structural/noncoding variants, blended phenotypes, or research reanalysis; interpretation remains the limiting step.
• CMA/karyotype/FISH: not routine for isolated HCM; use when syndromic features suggest a chromosomal disorder.
• mtDNA/repeat-expansion tests: not routine unless the phenotype suggests mitochondrial or repeat-expansion disease.
• RNA sequencing: potentially resolves splice variants but is not a standard HCM15 diagnostic and cardiac tissue is rarely available.

Cascade testing should target the known familial P/LP variant. Genotype-negative relatives can usually be released from serial familial surveillance when the familial variant is definitively causal; VUS-based predictive testing should not be used for reassurance or irreversible decisions.

Differential diagnosis

Hypertensive remodeling, aortic stenosis, athlete’s heart, transthyretin or AL amyloidosis, Fabry disease, Danon disease, Pompe disease, PRKAG2 glycogenosis, mitochondrial disease, Noonan/RASopathy, Friedreich ataxia, and cardiac tumors or subaortic membrane should be considered. Morphology, extracardiac features, ECG voltage, strain, CMR, biomarkers, and molecular testing distinguish these entities. (verheyen2024austrianconsensusstatement pages 11-12, verheyen2024austrianconsensusstatement pages 6-7)

11. Outcome and prognosis

There are no valid HCM15-specific 5- or 10-year survival estimates, annual SCD rate, transplant rate, or life-expectancy figures. Prognosis must be individualized from phenotype rather than VCL status alone.

General adverse outcomes include AF and stroke, ventricular arrhythmia/SCD, progressive heart failure, apical aneurysm/thrombus, end-stage systolic dysfunction, and need for septal reduction or transplantation. Apical aneurysm occurs in approximately 2% of general HCM and was associated in cited data with annual SCD and thromboembolism rates of 4.7% and 1.1%, respectively. (verheyen2024austrianconsensusstatement pages 9-11)

SCD assessment includes age, maximal wall thickness, LVOT gradient, left-atrial diameter, family history, unexplained syncope, and nonsustained VT. Additional markers include LVEF <50%, apical aneurysm, extensive LGE, and selected pathogenic sarcomeric variants. The ESC framework considers an ICD at a 5-year risk ≥6% and may consider it at 4–<6%; the AHA/ACC approach emphasizes major risk markers such as prior arrest/sustained VT, early familial SCD, wall thickness ≥30 mm, recent unexplained syncope, apical aneurysm, and LVEF <50%. (seferovic2023stateoftheartdocumenton pages 13-13)

A 2024 German cohort of 283 adults observed 14 SCD-equivalent events over median 5.77 years; adding genetic status improved model AUC to 0.76, but this was not VCL specific. Conversely, a separate 2024 international cohort of 1,468 patients found genotype-positive status was not independently predictive of mortality, heart-failure progression, or SCD. Genotype alone should therefore not dictate prognosis.

12. Treatment

No VCL-specific approved therapy or validated pharmacogenomic algorithm exists. Management is driven by obstruction, symptoms, arrhythmia, heart-failure state, and SCD risk.

Pharmacotherapy

• Nonvasodilating β-blocker: first-line symptom/gradient control in obstructive HCM; NCIT concept: beta-adrenergic blocker therapy.
• Verapamil or diltiazem: alternatives when β-blockers are ineffective or not tolerated, with caution in severe obstruction/hypotension; NCIT: calcium-channel-blocker therapy.
• Disopyramide: negative inotrope added in selected symptomatic obstruction, with QT and anticholinergic monitoring; NCIT: antiarrhythmic-agent therapy.
• Mavacamten: selective allosteric cardiac-myosin ATPase inhibitor for eligible symptomatic obstructive HCM; reduces excessive actin–myosin cross-bridging. NCIT: cardiac myosin inhibitor therapy.
• AF: rate/rhythm management and anticoagulation because HCM-associated AF has clinically important embolic risk; NCIT: anticoagulant therapy/catheter ablation as applicable.
• Advanced LVEF <50%: guideline-directed reduced-EF heart-failure therapy; discontinue negative inotropes when inappropriate and assess for CRT/transplantation.

In EXPLORER-HCM, 37% receiving mavacamten versus 17% receiving placebo met the primary functional endpoint; 65% versus 31% improved at least one NYHA class, and postexercise LVOT gradient fell by 36 mmHg. Transient LVEF <50% occurred in 6% and resolved after withdrawal. (seferovic2023stateoftheartdocumenton pages 11-12)

In VALOR-HCM, 17.9% of mavacamten-treated versus 76.8% of placebo-treated patients met criteria for or underwent septal reduction at 16 weeks. These are general obstructive-HCM data, not evidence of VCL-specific response. (pagel2025advancesincardiovascular pages 5-6)

Mavacamten requires serial echocardiographic LVEF/gradient surveillance and careful review of CYP2C19/CYP3A4 interactions because excessive myosin inhibition can cause systolic dysfunction.

Surgical and interventional treatment

• Surgical septal myectomy: preferred at experienced centers for severe, drug-refractory symptomatic LVOTO, especially with complex mitral/subvalvular anatomy; NCIT: ventricular septal myectomy.
• Alcohol septal ablation: catheter alternative in selected adults with suitable septal-perforator anatomy or elevated surgical risk; NCIT: alcohol septal ablation.
• ICD: secondary prevention after arrest/sustained VT and primary prevention after individualized risk assessment; NCIT: implantable cardioverter-defibrillator placement.
• Pacemaker/CRT, AF ablation, transplantation: phenotype-specific indications.

Exercise and rehabilitation

A 2023 randomized trial enrolled 15 completers. Five months of moderate- or progressive high-intensity training improved peak VO₂ by 1.3 mL/kg/min overall (P=0.009), without serious arrhythmia or adverse cardiac events, although it was underpowered for safety. A 2024 systematic review of five studies and 235 participants reported functional-capacity improvements up to 46% and no sustained tachyarrhythmia, ICD discharge, or SCD during the studied programs. These data support supervised, individualized rehabilitation rather than universal inactivity.

Experimental therapy and trials

Gene replacement, allele-specific silencing, base/prime editing, and RNA therapies are preclinical concepts for inherited HCM; none has demonstrated benefit for VCL-HCM15. Current HCM implementation studies include the multinational real-world COLLIGO-HCM, NCT06372457 (331 participants) and phase-3 mavacamten studies such as NCT05414175. Aficamten trials are active across obstructive and nonobstructive phenotypes. Trial eligibility is phenotype based, not VCL specific.

13. Prevention

Primary prevention

The germline variant cannot currently be prevented pharmacologically. Reproductive options after identification of a familial P/LP variant include genetic counselling, prenatal diagnosis, and preimplantation genetic testing for monogenic disease. These require discussion of uncertain penetrance and variable severity.

Secondary prevention

• Cascade genetic testing and clinical screening of first-degree relatives.
• ECG and imaging every 1–2 years in genotype-positive children/adolescents and every 3–5 years in genotype-positive adults without phenotype. (verheyen2024austrianconsensusstatement pages 21-22)
• Prompt assessment of exertional syncope, palpitations, chest pain, or family SCD.
• Periodic Holter monitoring, exercise testing, and CMR-based fibrosis/morphology assessment.

Tertiary prevention

• Treat obstruction, AF, hypertension, and heart failure.
• Anticoagulate clinically documented AF according to HCM recommendations.
• Use an ICD for secondary prevention and selected high-risk primary prevention.
• Maintain hydration and avoid unmonitored drugs that markedly reduce preload/afterload in severe obstruction.
• Encourage individualized low-to-moderate exercise and shared decisions regarding vigorous sport. (verheyen2024austrianconsensusstatement pages 19-21)

Vaccination has no disease-specific preventive role, although routine immunization reduces general infectious risk. Population newborn screening is not recommended because HCM15 is exceptionally rare and no validated biochemical marker exists.

14. Other species and natural disease

• Human: Homo sapiens, NCBI Taxonomy 9606.
• Mouse model species: Mus musculus, NCBI Taxonomy 10090; orthologue Vcl.

Naturally occurring HCM is recognized in cats and occurs in other animals, but no well-established naturally occurring veterinary disease was identified that is specifically caused by an orthologous VCL allele and faithfully corresponds to human HCM15. Accordingly, cat HCM should not be annotated automatically as VCL-HCM15. No zoonotic or transmissible potential exists.

Vinculin’s adhesion and mechanotransduction functions are evolutionarily conserved, supporting comparative study. Species differences in heart rate, loading, isoform expression, and remodeling limit direct translation.

15. Model organisms and experimental systems

Conditional cardiomyocyte Vcl-knockout mouse

The strongest direct model is the ventricular-cardiomyocyte-specific Vcl knockout created by Cre-mediated exon-3 excision. Vinculin/metavinculin were lost from cardiomyocytes while remaining in nonmyocytes and vessels. Before overt physiological dysfunction, animals developed abnormal intercalated discs, detachment of myofibrils, mitochondrial disorganization, reduced cadherin and β1D-integrin, and connexin-43 redistribution. Electrical mapping showed irregular wavefronts and local conduction slowing; telemetry documented heart block and polymorphic VT. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 8-11, zemljicharpf2007cardiacmyocytespecificexcisionof pages 11-12, zemljicharpf2007cardiacmyocytespecificexcisionof pages 3-4)

The abstract-level result is especially informative: “49% died suddenly before 3 months, despite preserved contractile function”; surviving animals subsequently developed DCM and died before six months. At 14 weeks, male survival was 51% and female survival 71%; no males survived beyond 32 weeks. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2, zemljicharpf2007cardiacmyocytespecificexcisionof pages 7-8)

Recapitulated features: cardiomyocyte junctional disease, conduction defects, ventricular arrhythmia, sudden death, early mild hypertrophy, fibrosis, and progressive cardiomyopathy.

Limitations: near-complete cardiomyocyte knockout is more severe than a heterozygous human missense allele; the dominant late phenotype is DCM, not isolated HCM; mouse timing and lethality cannot be transferred to humans.

Citation: Zemljic-Harpf et al., Molecular and Cellular Biology, November 2007; DOI: 10.1128/MCB.00728-07. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 8-11, zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2)

Other model systems

Human iPSC-derived cardiomyocytes carrying rigorously classified VCL variants, engineered heart tissues, and isogenic CRISPR-corrected controls would be the most informative future systems for variant-specific contractility, adhesion, conduction, and mechanoload studies. No sufficiently validated HCM15-specific iPSC, organoid, zebrafish, Drosophila, or large-animal model was identified in the retrieved evidence.

Knowledge-base recommendations

1. Store HCM15–VCL as a historically reported gene–disease assertion with provenance and periodic re-evaluation, not as an unconditional fact for every VCL variant.
2. Separate genotype, HCM phenotype, and molecular diagnosis fields.
3. Do not assign general-HCM phenotype frequencies, prevalence, prognosis, or mavacamten response to HCM15.
4. Encode mechanistic steps as demonstrated in Vcl-loss mouse versus inferred in heterozygous human HCM15.
5. Require P/LP status for cascade testing; retain VUS as non-diagnostic.
6. Mark HCM15-specific penetrance, incidence, sex ratio, carrier frequency, protective factors, omics signatures, natural veterinary disease, and treatment response as not currently available.

Key recent and foundational sources

• Verheyen N, et al. “Austrian consensus statement on the diagnosis and management of hypertrophic cardiomyopathy.” Published October 2024. DOI/URL: 10.1007/s00508-024-02442-1. (verheyen2024austrianconsensusstatement pages 11-12, verheyen2024austrianconsensusstatement pages 6-7, verheyen2024austrianconsensusstatement pages 1-2)
• Seferović PM, et al. “State-of-the-Art Document on Optimal Contemporary Management of Cardiomyopathies.” Published September 2023. DOI/URL: 10.1002/ejhf.2979. (seferovic2023stateoftheartdocumenton pages 11-12, seferovic2023stateoftheartdocumenton pages 13-13)
• MacNamara JP, et al. Randomized moderate- versus high-intensity exercise trial in HCM. Published October 2023. DOI/URL: 10.1161/JAHA.123.031399.
• Braunwald E, et al. “Mavacamten: a first-in-class myosin inhibitor for obstructive hypertrophic cardiomyopathy.” Published October 2023. DOI/URL: 10.1093/eurheartj/ehad637.
• Zemljic-Harpf AE, et al. “Cardiac-Myocyte-Specific Excision of the Vinculin Gene Disrupts Cellular Junctions, Causing Sudden Death or Dilated Cardiomyopathy.” Published November 2007. DOI/URL: 10.1128/MCB.00728-07. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 8-11, zemljicharpf2007cardiacmyocytespecificexcisionof pages 1-2)

Overall, HCM15 is best treated as a rare, incompletely validated VCL-associated HCM entity embedded within the broader clinical HCM framework. The most secure biology concerns vinculin’s role in cardiomyocyte adhesion, force transmission, intercalated-disc integrity, and conduction; the least secure domains are variant-level causality, penetrance, epidemiology, and genotype-specific therapeutic response.

References

1. (OpenTargets Search: hypertrophic cardiomyopathy-VCL): Open Targets Query (hypertrophic cardiomyopathy-VCL, 7 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

2. (verheyen2024austrianconsensusstatement pages 11-12): Nicolas Verheyen, Johannes Auer, Nikolaos Bonaros, Tamara Buchacher, Daniel Dalos, Michael Grimm, Agnes Mayr, Anna Rab, Sebastian Reinstadler, Daniel Scherr, Gabor G Toth, Thomas Weber, David K. Zach, Marc-Michael Zaruba, Daniel Zimpfer, Peter P Rainer, and Gerhard Pölzl. Austrian consensus statement on the diagnosis and management of hypertrophic cardiomyopathy. Wiener Klinische Wochenschrift, 136:571-597, Oct 2024. URL: https://doi.org/10.1007/s00508-024-02442-1, doi:10.1007/s00508-024-02442-1. This article has 6 citations and is from a peer-reviewed journal.

3. (verheyen2024austrianconsensusstatement pages 9-11): Nicolas Verheyen, Johannes Auer, Nikolaos Bonaros, Tamara Buchacher, Daniel Dalos, Michael Grimm, Agnes Mayr, Anna Rab, Sebastian Reinstadler, Daniel Scherr, Gabor G Toth, Thomas Weber, David K. Zach, Marc-Michael Zaruba, Daniel Zimpfer, Peter P Rainer, and Gerhard Pölzl. Austrian consensus statement on the diagnosis and management of hypertrophic cardiomyopathy. Wiener Klinische Wochenschrift, 136:571-597, Oct 2024. URL: https://doi.org/10.1007/s00508-024-02442-1, doi:10.1007/s00508-024-02442-1. This article has 6 citations and is from a peer-reviewed journal.

4. (verheyen2024austrianconsensusstatement pages 6-7): Nicolas Verheyen, Johannes Auer, Nikolaos Bonaros, Tamara Buchacher, Daniel Dalos, Michael Grimm, Agnes Mayr, Anna Rab, Sebastian Reinstadler, Daniel Scherr, Gabor G Toth, Thomas Weber, David K. Zach, Marc-Michael Zaruba, Daniel Zimpfer, Peter P Rainer, and Gerhard Pölzl. Austrian consensus statement on the diagnosis and management of hypertrophic cardiomyopathy. Wiener Klinische Wochenschrift, 136:571-597, Oct 2024. URL: https://doi.org/10.1007/s00508-024-02442-1, doi:10.1007/s00508-024-02442-1. This article has 6 citations and is from a peer-reviewed journal.

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6. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 2-3): Alice E. Zemljic-Harpf, Joel C. Miller, Scott A. Henderson, Adam T. Wright, Ana Maria Manso, Laila Elsherif, Nancy D. Dalton, Andrea K. Thor, Guy A. Perkins, Andrew D. McCulloch, and Robert S. Ross. Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy. Molecular and Cellular Biology, 27:7522-7537, Nov 2007. URL: https://doi.org/10.1128/mcb.00728-07, doi:10.1128/mcb.00728-07. This article has 245 citations and is from a domain leading peer-reviewed journal.

7. (verheyen2024austrianconsensusstatement pages 1-2): Nicolas Verheyen, Johannes Auer, Nikolaos Bonaros, Tamara Buchacher, Daniel Dalos, Michael Grimm, Agnes Mayr, Anna Rab, Sebastian Reinstadler, Daniel Scherr, Gabor G Toth, Thomas Weber, David K. Zach, Marc-Michael Zaruba, Daniel Zimpfer, Peter P Rainer, and Gerhard Pölzl. Austrian consensus statement on the diagnosis and management of hypertrophic cardiomyopathy. Wiener Klinische Wochenschrift, 136:571-597, Oct 2024. URL: https://doi.org/10.1007/s00508-024-02442-1, doi:10.1007/s00508-024-02442-1. This article has 6 citations and is from a peer-reviewed journal.

8. (pagel2025advancesincardiovascular pages 5-6): Paul S. Pagel, Dustin Hang, Julie K. Freed, and George J. Crystal. Advances in cardiovascular pharmacotherapy. i. cardiac myosin inhibitors. Journal of cardiothoracic and vascular anesthesia, Feb 2025. URL: https://doi.org/10.1053/j.jvca.2025.02.009, doi:10.1053/j.jvca.2025.02.009. This article has 3 citations and is from a peer-reviewed journal.

9. (seferovic2023stateoftheartdocumenton pages 11-12): Petar M. Seferović, Marija Polovina, Giuseppe Rosano, Biykem Bozkurt, Marco Metra, Stephane Heymans, Wilfried Mullens, Johann Bauersachs, Karen Sliwa, Rudolf A. de Boer, Dimitrios Farmakis, Thomas Thum, Iacopo Olivotto, Claudio Rapezzi, Aleš Linhart, Domenico Corrado, Carsten Tschöpe, Ivan Milinković, Antoni Bayes Genis, Gerasimos Filippatos, Andre Keren, Milika Ašanin, Gordana Krljanac, Ružica Maksimović, Hadi Skouri, Tuvia Ben Gal, Brenda Moura, Maurizio Volterrani, Magdy Abdelhamid, Yuri Lopatin, Ovidiu Chioncel, and Andrew J.S. Coats. State-of-the-art document on optimal contemporary management of cardiomyopathies. Sep 2023. URL: https://doi.org/10.1002/ejhf.2979, doi:10.1002/ejhf.2979. This article has 18 citations and is from a highest quality peer-reviewed journal.

10. (seferovic2023stateoftheartdocumenton pages 13-13): Petar M. Seferović, Marija Polovina, Giuseppe Rosano, Biykem Bozkurt, Marco Metra, Stephane Heymans, Wilfried Mullens, Johann Bauersachs, Karen Sliwa, Rudolf A. de Boer, Dimitrios Farmakis, Thomas Thum, Iacopo Olivotto, Claudio Rapezzi, Aleš Linhart, Domenico Corrado, Carsten Tschöpe, Ivan Milinković, Antoni Bayes Genis, Gerasimos Filippatos, Andre Keren, Milika Ašanin, Gordana Krljanac, Ružica Maksimović, Hadi Skouri, Tuvia Ben Gal, Brenda Moura, Maurizio Volterrani, Magdy Abdelhamid, Yuri Lopatin, Ovidiu Chioncel, and Andrew J.S. Coats. State-of-the-art document on optimal contemporary management of cardiomyopathies. Sep 2023. URL: https://doi.org/10.1002/ejhf.2979, doi:10.1002/ejhf.2979. This article has 18 citations and is from a highest quality peer-reviewed journal.

11. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 8-11): Alice E. Zemljic-Harpf, Joel C. Miller, Scott A. Henderson, Adam T. Wright, Ana Maria Manso, Laila Elsherif, Nancy D. Dalton, Andrea K. Thor, Guy A. Perkins, Andrew D. McCulloch, and Robert S. Ross. Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy. Molecular and Cellular Biology, 27:7522-7537, Nov 2007. URL: https://doi.org/10.1128/mcb.00728-07, doi:10.1128/mcb.00728-07. This article has 245 citations and is from a domain leading peer-reviewed journal.

12. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 11-12): Alice E. Zemljic-Harpf, Joel C. Miller, Scott A. Henderson, Adam T. Wright, Ana Maria Manso, Laila Elsherif, Nancy D. Dalton, Andrea K. Thor, Guy A. Perkins, Andrew D. McCulloch, and Robert S. Ross. Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy. Molecular and Cellular Biology, 27:7522-7537, Nov 2007. URL: https://doi.org/10.1128/mcb.00728-07, doi:10.1128/mcb.00728-07. This article has 245 citations and is from a domain leading peer-reviewed journal.

13. (verheyen2024austrianconsensusstatement pages 19-21): Nicolas Verheyen, Johannes Auer, Nikolaos Bonaros, Tamara Buchacher, Daniel Dalos, Michael Grimm, Agnes Mayr, Anna Rab, Sebastian Reinstadler, Daniel Scherr, Gabor G Toth, Thomas Weber, David K. Zach, Marc-Michael Zaruba, Daniel Zimpfer, Peter P Rainer, and Gerhard Pölzl. Austrian consensus statement on the diagnosis and management of hypertrophic cardiomyopathy. Wiener Klinische Wochenschrift, 136:571-597, Oct 2024. URL: https://doi.org/10.1007/s00508-024-02442-1, doi:10.1007/s00508-024-02442-1. This article has 6 citations and is from a peer-reviewed journal.

14. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 12-14): Alice E. Zemljic-Harpf, Joel C. Miller, Scott A. Henderson, Adam T. Wright, Ana Maria Manso, Laila Elsherif, Nancy D. Dalton, Andrea K. Thor, Guy A. Perkins, Andrew D. McCulloch, and Robert S. Ross. Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy. Molecular and Cellular Biology, 27:7522-7537, Nov 2007. URL: https://doi.org/10.1128/mcb.00728-07, doi:10.1128/mcb.00728-07. This article has 245 citations and is from a domain leading peer-reviewed journal.

15. (verheyen2024austrianconsensusstatement pages 21-22): Nicolas Verheyen, Johannes Auer, Nikolaos Bonaros, Tamara Buchacher, Daniel Dalos, Michael Grimm, Agnes Mayr, Anna Rab, Sebastian Reinstadler, Daniel Scherr, Gabor G Toth, Thomas Weber, David K. Zach, Marc-Michael Zaruba, Daniel Zimpfer, Peter P Rainer, and Gerhard Pölzl. Austrian consensus statement on the diagnosis and management of hypertrophic cardiomyopathy. Wiener Klinische Wochenschrift, 136:571-597, Oct 2024. URL: https://doi.org/10.1007/s00508-024-02442-1, doi:10.1007/s00508-024-02442-1. This article has 6 citations and is from a peer-reviewed journal.

16. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 3-4): Alice E. Zemljic-Harpf, Joel C. Miller, Scott A. Henderson, Adam T. Wright, Ana Maria Manso, Laila Elsherif, Nancy D. Dalton, Andrea K. Thor, Guy A. Perkins, Andrew D. McCulloch, and Robert S. Ross. Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy. Molecular and Cellular Biology, 27:7522-7537, Nov 2007. URL: https://doi.org/10.1128/mcb.00728-07, doi:10.1128/mcb.00728-07. This article has 245 citations and is from a domain leading peer-reviewed journal.

17. (zemljicharpf2007cardiacmyocytespecificexcisionof pages 7-8): Alice E. Zemljic-Harpf, Joel C. Miller, Scott A. Henderson, Adam T. Wright, Ana Maria Manso, Laila Elsherif, Nancy D. Dalton, Andrea K. Thor, Guy A. Perkins, Andrew D. McCulloch, and Robert S. Ross. Cardiac-myocyte-specific excision of the vinculin gene disrupts cellular junctions, causing sudden death or dilated cardiomyopathy. Molecular and Cellular Biology, 27:7522-7537, Nov 2007. URL: https://doi.org/10.1128/mcb.00728-07, doi:10.1128/mcb.00728-07. This article has 245 citations and is from a domain leading peer-reviewed journal.

Artifacts

• Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

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:0013200 (4 mentions) - the report calls it "if available"; MONDO calls it hypertrophic cardiomyopathy 15