Left Ventricular Noncompaction 10 (LVNC10): Disease-Characteristics Research Report

Executive summary and scope

Left ventricular noncompaction 10 (LVNC10) is the numbered, MYBPC3-associated form of left-ventricular noncompaction/hypertrabeculation. Its disease-specific identifier is MONDO:0014163; the broader LVNC concept is MONDO:0018901. Open Targets maps LVNC10 specifically to MYBPC3 (myosin-binding protein C3; Ensembl ENSG00000134571) and links the association to primary-literature PMIDs including 20186049 and 27532257. The historical variant underlying this numbered subtype is MYBPC3 p.Arg820Trp (R820W), although its present ClinVar classification and transcript-specific HGVS expression should be rechecked at the time of clinical interpretation. (OpenTargets Search: left ventricular noncompaction-MYBPC3)

A crucial curation distinction is that LVNC10 is a rare genetic disease entry, whereas left-ventricular hypertrabeculation is also a common, sometimes reversible imaging trait. The 2023 ESC framework treats noncompaction as a dynamic trait found in healthy hearts, other cardiomyopathies, congenital disease, anemia, renal disease, pregnancy, and athletes rather than automatically as a separate cardiomyopathy. Consequently, morphology alone must not be equated with MYBPC3-related LVNC10. (grasso2024thenew2023 pages 1-2, walsh2023thetroublewith pages 1-2)

The evidence is predominantly aggregated disease-level information from families, referral cohorts, systematic reviews, and registries—not individual-patient EHR data. Subtype-specific epidemiology, penetrance, prognosis, and treatment-response estimates are unavailable; broad-LVNC evidence is identified as such below.

Table: This table summarizes subtype-specific facts for Left Ventricular Noncompaction 10 alongside broader LVNC context needed for interpretation. It is designed as a compact curation aid for identifiers, mechanisms, phenotypes, diagnostics, treatment categories, and major evidence gaps.

1. Disease information

Definition

LVNC is morphologically characterized by prominent LV trabeculae, deep intertrabecular recesses communicating with the ventricular cavity, and a relatively thin compacted myocardial layer. A modern formulation requires excessive trabeculation plus clinically meaningful myocardial disease, such as ventricular dysfunction, fibrosis, arrhythmia, or a pathogenic genotype, rather than an imaging ratio alone. (arbustini2014leftventricularnoncompaction pages 1-2, mazzarotto2021systematiclargescaleassessment pages 1-2, walsh2023thetroublewith pages 1-2)

Direct source quotation (Walsh, published 29 November 2023): “Excessive trabeculation of the cardiac left ventricular wall is a complex phenotypic substrate associated with various physiological and pathological processes.” The same review concludes that uncertainty remains over whether hypertrabeculation causes disease or constitutes a distinct LVNC cardiomyopathy. DOI: https://doi.org/10.1007/s12265-023-10459-6. (walsh2023thetroublewith pages 1-2)

Identifiers and synonyms

• MONDO: LVNC10, MONDO:0014163; broad LVNC, MONDO:0018901.
• OMIM: LVNC10 is historically indexed as OMIM 615396. The disease number should not be confused with the MYBPC3 gene record.
• MeSH: Isolated Noncompaction of the Ventricular Myocardium, D056830. (NCT01470014 chunk 1)
• ICD-10/ICD-11: No retrieved evidence established a unique subtype-specific LVNC10 code. In practice it is generally coded under cardiomyopathy/other cardiomyopathy categories, with local coding-system variation.
• Synonyms: left ventricular noncompaction 10; LVNC10; MYBPC3-related left ventricular noncompaction; noncompaction cardiomyopathy due to MYBPC3. Broader terms include LVNC, left ventricular non-compaction cardiomyopathy, isolated ventricular myocardial noncompaction, spongy myocardium, and left ventricular hypertrabeculation.

2. Etiology, risk, protective factors, and gene–environment interaction

Causal factor

LVNC10 is a germline genetic sarcomeric cardiomyopathy caused by disease-associated variation in MYBPC3, which encodes cardiac myosin-binding protein C. Open Targets reports five supporting association items and an LVNC10–MYBPC3 score of approximately 0.797. (OpenTargets Search: left ventricular noncompaction-MYBPC3)

The historic p.Arg820Trp association is important for disease nomenclature, but MYBPC3 produces a broad allelic spectrum: missense, truncating, splice-altering, whole-gene deletion, and compound-heterozygous states can yield HCM, DCM, LVNC, or overlapping phenotypes. Therefore, MYBPC3 genotype does not uniquely predict LVNC morphology. Large-scale analysis of 840 LVNC cases and 125,748 gnomAD controls found extensive genetic overlap between LVNC, HCM, and DCM. (mazzarotto2021systematiclargescaleassessment pages 1-2)

Genetic risk and modifiers

• Most clinically recognized MYBPC3 cardiomyopathy is autosomal dominant, with incomplete, often age-dependent penetrance and variable expressivity.
• A second pathogenic allele can markedly increase severity. In a human cardiac-tissue study, a de novo p.Ser858Arg allele in trans with deletion of the entire MYBPC3 gene caused severe early cardiomyopathy with LVNC, approximately 80% lower protein and approximately 50% lower transcript than controls. (kolokotronis2019biallelicmutationin pages 1-2, kolokotronis2019biallelicmutationin pages 7-9)
• Broad LVNC polygenic architecture may modify morphology. A UK Biobank GWAS of 18,096 participants identified 16 loci, including TTN, TNNT2, PLN, MTSS1, and GOSR2; segmental SNP heritability was estimated at 20–25%. MIB1 loss-of-function variants have also been proposed as modifiers in patients carrying TTN truncating variants. These observations are not specific to LVNC10. (walsh2023thetroublewith pages 11-13)

Environmental and lifestyle factors

No toxin, infection, diet, smoking pattern, alcohol exposure, occupation, or medication has been shown to cause LVNC10. Likewise, no validated genetic or environmental protective factor has been identified.

Hemodynamic loading can, however, induce or amplify the hypertrabeculation phenotype and thereby confound diagnosis. Increased trabeculation has been documented with athletic training, pregnancy, and chronic anemia. In cited observational data, athletes had more hypertrabeculation than controls (18.3% versus 7.0%), and 8.1% met conventional echocardiographic LVNC criteria. During pregnancy, 25.4% developed increased trabeculation and 7.8% met Chin and Jenni criteria; prevalence was higher in Black than White women (46% versus 13%, p=0.0003). These are physiologic remodeling data, not evidence that exercise or pregnancy causes inherited LVNC10. (NCT02568072 chunk 1, NCT02568072 chunk 2)

Interpretive gene–environment model: an MYBPC3 variant may create a susceptible sarcomeric substrate, while developmental, polygenic, and loading conditions alter penetrance or the degree of trabeculation. Direct LVNC10-specific interaction studies are absent.

3. Phenotypes

The 2024 pediatric systematic review searched 4,531 records and analyzed 57 cases from prenatal life through age 18. It reported frequent conduction abnormalities, including Mobitz II and WPW; 9% displayed WPW, and 46% of mapped arrhythmias originated near the apex. Diagnostic methods were inconsistent in 66% of cases. These percentages reflect a selected case literature and should not be treated as population frequencies. DOI: https://doi.org/10.14814/phy2.16029. (fitzsimons2024electrophysiologicalphenotypingof pages 7-8, fitzsimons2024electrophysiologicalphenotypingof pages 1-3)

Direct abstract quotation (accepted 12 April 2024): the review found “abnormal left ventricular, atrioventricular node, and interventricular septal patterns, and specifically a high incidence of Mobitz type II and Wolff–Parkinson–White waveforms.” (fitzsimons2024electrophysiologicalphenotypingof pages 1-3)

Quality of life is impaired principally by heart-failure symptoms, exercise restriction, recurrent surveillance, arrhythmia anxiety, ICD shocks, embolic events, and hospitalization. No LVNC10-specific EQ-5D, SF-36, or PROMIS dataset was identified.

4. Genetic and molecular information

Gene and variants

• Gene: MYBPC3; approved name myosin binding protein C3; Ensembl ENSG00000134571. (OpenTargets Search: left ventricular noncompaction-MYBPC3)
• Origin: germline; somatic MYBPC3 disease is not established.
• Historical LVNC10 allele: p.Arg820Trp/R820W. PMID 20186049 is among the primary references linked to the MYBPC3–LVNC10 association. (OpenTargets Search: left ventricular noncompaction-MYBPC3)
• Variant interpretation: clinical classification must use transcript-correct HGVS, ClinVar/ClinGen evidence, ancestry-matched frequency, segregation, phenotype, and ACMG/AMP criteria. The old numbered disease assignment alone is insufficient to classify an allele as pathogenic.
• Population frequency: no reliable subtype-specific allele frequency was recovered. A genuinely penetrant severe dominant allele should be rare in gnomAD; exact variant frequencies should be retrieved directly from the current gnomAD release.

Functional consequences

MYBPC3 loss-of-function commonly acts through haploinsufficiency; missense alleles may impair protein stability, sarcomeric incorporation, or myosin/actin regulation. In the severe biallelic LVNC case, only about 20% of normal MYBPC3 protein remained in diseased myocardium. Histology showed cardiomyocyte misalignment, cytoplasmic vacuolization, and extensive fibrosis. (kolokotronis2019biallelicmutationin pages 1-2, kolokotronis2019biallelicmutationin pages 7-9)

No reproducible LVNC10-specific epigenetic alteration, chromosomal rearrangement, methylation signature, or validated modifier gene has been established. Whole-gene MYBPC3 deletion can contribute to severe biallelic disease, so copy-number analysis is clinically relevant in selected cases. (kolokotronis2019biallelicmutationin pages 7-9)

5. Environmental information

Environmental exposures are best understood as phenocopy or expression modifiers, not primary causes of LVNC10. High preload/afterload in pregnancy, endurance exercise, and chronic anemia can produce reversible or persistent hypertrabeculation. The completed MARATHON study, NCT02568072, prospectively examined 120 healthy first-time marathon runners with echocardiography and CMR; its registry notes that no remodeling was observed from baseline to post-marathon time points. (NCT02568072 chunk 1, NCT02568072 chunk 2)

No infectious agent, zoonosis, radiation exposure, pollutant, or occupational toxicant is implicated. Ordinary cardiovascular-health measures remain advisable but are not proven to prevent the genetic disease.

6. Mechanism and pathophysiology

Causal chain

1. Upstream germline event: pathogenic MYBPC3 variation alters the quantity, stability, or function of cardiac myosin-binding protein C.
2. Sarcomeric defect: impaired thick-filament regulation and sarcomere organization perturb cardiomyocyte force generation, relaxation, and mechanosensing.
3. Developmental/remodeling consequence: altered myocardial growth and contractile signaling may bias the balance between compact and trabecular layers or cause hypertrabeculation as a secondary cardiomyopathy phenotype.
4. Tissue remodeling: cardiomyocyte disarray, stretch, cell injury, and fibrosis impair systolic/diastolic function.
5. Clinical outputs: heart failure, conduction heterogeneity, re-entry/ventricular arrhythmia, stasis in deep recesses, thromboembolism, and sudden death.

Human genetic data argue against one universal “failure of embryonic compaction” mechanism. The 840-case study concluded that LVNC has “substantial genetic overlap” with HCM/DCM, although truncating MYH7, ACTN2, and PRDM16 variants and selected RYR2/HCN4 variants define more LVNC- or arrhythmia-specific etiologies. MYH7 truncating variants were 20-fold enriched in LVNC cases. These findings contextualize, but do not redefine, MYBPC3-associated LVNC10. (mazzarotto2021systematiclargescaleassessment pages 1-2)

Suggested ontology annotations

• GO biological process: sarcomere organization; cardiac muscle contraction; regulation of cardiac muscle contraction; ventricular cardiac muscle tissue morphogenesis; cardiac muscle cell development; response to mechanical stimulus.
• GO cellular component: sarcomere, A band, myosin filament, cardiac myofibril.
• Cell Ontology: cardiomyocyte; ventricular cardiac muscle cell; cardiac conduction cell where electrophysiologic disease is documented.
• Downstream processes: fibrosis, abnormal impulse propagation, and hemodynamic stasis. Immune activation is not an established primary LVNC10 mechanism.

Molecular profiling and advanced technology

Subtype-specific transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, and CRISPR-screen signatures were not identified. The strongest human molecular evidence is diseased cardiac tissue showing reduced MYBPC3 transcript/protein and structural disorganization. Broad-LVNC mitochondrial bioenergetics is an active research area, but it should not be imported as an established LVNC10 mechanism. (kolokotronis2019biallelicmutationin pages 7-9, mahendran2024emerginghallmarksof pages 6-10)

7. Anatomical structures affected

• Primary organ/system: heart/cardiovascular system.
• Primary site: LV myocardium, especially apical and mid-inferolateral endocardial regions.
• Layers: thick trabecular/noncompacted endocardial layer over a thinner compact epicardial layer; deep recesses communicate with the LV cavity, not the coronary circulation.
• Tissues/cells: cardiac muscle tissue and ventricular cardiomyocytes; conduction tissue is functionally involved in arrhythmic cases.
• Subcellular structures: sarcomere, thick filament, A band, myofibril.
• Secondary organs: brain and systemic organs may be injured by embolism; lungs, liver, and kidneys may be affected secondarily by advanced heart failure.
• Lateralization: left-sided by definition, although biventricular hypertrabeculation may occur in broader disease.
• Suggested UBERON: heart, left ventricle, myocardium, ventricular myocardium, endocardium.

8. Temporal development

Onset ranges from prenatal/infantile to late adulthood. Heterozygous MYBPC3 disease may remain asymptomatic for years because penetrance is incomplete and age dependent. Biallelic disease can present in infancy or childhood with rapidly progressive heart failure and transplantation. (kolokotronis2019biallelicmutationin pages 1-2)

Course categories include:

• stable asymptomatic morphology with preserved EF;
• slowly progressive HCM/DCM phenotype;
• episodic arrhythmia or embolism;
• advanced systolic failure requiring ICD/CRT, mechanical support, or transplantation.

Morphologic hypertrabeculation may regress when loading conditions normalize, especially after pregnancy; that reversibility supports an acquired trait rather than inherited LVNC10 in many imaging-positive individuals. In one reviewed pregnancy series, 73% showed complete postpartum resolution. (arbustini2014leftventricularnoncompaction pages 1-2)

9. Inheritance and population

Inheritance

The expected LVNC10 pattern is autosomal dominant, with variable expressivity and incomplete/age-dependent penetrance. Broad LVNC also includes X-linked, recessive, and mitochondrial disorders; those inheritance modes should not be assigned to LVNC10 without a second diagnosis. (sedaghathamedani2017clinicalgeneticsand pages 1-2)

No validated anticipation, common germline mosaicism rate, LVNC10 founder effect, carrier frequency, consanguinity effect, or sex ratio was identified. The R820W allele is notable in Ragdoll cats but this does not establish a human founder effect.

Epidemiology

A trustworthy incidence or prevalence for genetically confirmed LVNC10 is unavailable. Historical estimates for clinically diagnosed isolated LVNC were 0.05–0.24%, but imaging criteria substantially inflate apparent prevalence. Eight percent of healthy controls met at least one echocardiographic criterion in one study, while Petersen CMR criteria labeled 25.7% of one low-risk multiethnic cohort. More conservative modern summaries note that up to 15% of apparently healthy people exceed an NC/C threshold on sensitive CMR. (NCT02568072 chunk 1, mazzarotto2021systematiclargescaleassessment pages 1-2, walsh2023thetroublewith pages 1-2)

Pediatric LVNC has been estimated at approximately 2% of children with known congenital heart disease, while about 12% of diagnosed LVNC patients in one series had additional congenital heart disease. These broad-LVNC figures are not LVNC10 prevalence estimates. (fitzsimons2024electrophysiologicalphenotypingof pages 1-3)

10. Diagnostics

Clinical pathway

1. History and pedigree: heart failure, syncope, palpitations, embolism, sudden death, HCM/DCM, and neuromuscular/syndromic disease over at least three generations.
2. Examination and baseline testing: ECG, echocardiography, ambulatory rhythm monitoring, and laboratory evaluation for secondary cardiomyopathy; natriuretic peptides and troponin assess severity but are not specific.
3. CMR: quantify function and morphology and identify late gadolinium enhancement/fibrosis or thrombus.
4. Genetics: counseling followed by a curated cardiomyopathy panel including MYBPC3; test the familial variant in relatives when pathogenic/likely pathogenic.
5. Extended testing: deletion/duplication analysis, WES/WGS, and mitochondrial analysis when panel-negative, syndromic, or severe early-onset disease suggests another cause.

Imaging criteria and limitations

Common echocardiographic criteria include a two-layered myocardium, deep perfused recesses, and an end-systolic NC/C ratio >2. CMR commonly uses an end-diastolic NC/C ratio >2.3 or trabeculated-mass/fractal measures. No criterion is a gold standard, and methods differ by imaging plane and cardiac phase. (mahendran2024emerginghallmarksof pages 6-10, mazzarotto2021systematiclargescaleassessment pages 1-2)

The central diagnostic safeguard is to require concordance among morphology, ventricular function, tissue characterization, ECG/rhythm findings, family history, and genotype. The 2023 ESC interpretation explicitly calls LV noncompaction a dynamic trait, while advanced imaging and genetics are essential components of cardiomyopathy workup. DOI: https://doi.org/10.1093/eurheartjsupp/suae002; published April 2024. (grasso2024thenew2023 pages 1-2)

Differential diagnosis

• physiologic trabeculation in athletes or pregnancy;
• ancestry-associated normal variation;
• HCM or DCM with secondary hypertrabeculation;
• athlete’s heart;
• chronic anemia/sickle-cell remodeling;
• congenital heart disease;
• endocardial fibroelastosis, apical HCM, thrombus, or prominent papillary muscles;
• arrhythmogenic forms due to HCN4 or RYR2;
• syndromic/metabolic disease, including TAFAZZIN/Barth syndrome, LAMP2/Danon disease, mitochondrial disease, and neuromuscular disorders.

Screening

Population or newborn screening is not recommended. First-degree relatives should receive genetic counseling and phenotype screening with ECG and echocardiography; variant-positive relatives require age-appropriate longitudinal surveillance. A negative familial-variant test can usually release a relative from genotype-driven surveillance, provided the familial variant is securely pathogenic and no independent clinical abnormality exists.

11. Outcome and prognosis

No LVNC10-specific five- or ten-year survival estimate exists. In a human LVNC cohort of 95 patients followed for a median 61 months, LVNC was associated with more cardiovascular events than age-matched nonischemic DCM (hazard ratio 2.481, p=0.002); nuclear-envelope/RBM20 genotypes were especially adverse. This is broad-LVNC evidence and may reflect referral severity. (sedaghathamedani2017clinicalgeneticsand pages 1-2)

Conversely, morphology alone has weak prognostic value. In MESA, excessive trabeculation did not predict deterioration in LV volume or function over 10 years; in DCM cohorts, NC/C mass or length did not predict event-free survival over median 3.4 years. Preserved EF and otherwise normal apical architecture were associated with survival comparable to the general population. (walsh2023thetroublewith pages 1-2, fitzsimons2024electrophysiologicalphenotypingof pages 1-3)

Important adverse prognostic factors are reduced EF, ventricular dilation, heart-failure symptoms, myocardial fibrosis/LGE, ventricular arrhythmia, syncope, family history of sudden death, intracardiac thrombus/embolism, and high-risk genetic context. Major morbidities are heart failure, hospitalization, stroke, arrhythmia, device implantation, and transplantation. Validated LVNC10-specific prognostic biomarkers and quality-of-life estimates are lacking.

12. Treatment

There is no approved disease-modifying or MYBPC3-directed treatment specifically for LVNC10. Management follows the expressed cardiomyopathy phenotype:

• Heart failure: guideline-directed therapy for reduced EF—typically an ARNI/ACE inhibitor/ARB, evidence-based beta blocker, mineralocorticoid-receptor antagonist, and SGLT2 inhibitor as tolerated; diuretics for congestion.
• Arrhythmias: beta blockade or appropriate antiarrhythmic therapy, ambulatory monitoring, electrophysiology evaluation, and catheter ablation for suitable tachyarrhythmias.
• ICD: standard primary- or secondary-prevention indications based on EF, documented VT/VF, syncope, genotype/fibrosis, and overall risk—not trabeculation alone.
• CRT: standard electrical/mechanical dyssynchrony indications; individual severe pediatric cases have benefited, but this is not LVNC10-specific evidence. (mahendran2024emerginghallmarksof pages 6-10)
• Anticoagulation: indicated for atrial fibrillation, documented LV thrombus, previous systemic embolism, or other standard high-risk settings. Routine anticoagulation solely for trabeculation remains unsupported.
• Advanced failure: mechanical circulatory support and heart transplantation. Severe biallelic MYBPC3 LVNC has required transplantation. (kolokotronis2019biallelicmutationin pages 1-2)
• Exercise: individualized advice based on EF, arrhythmia, symptoms, fibrosis, and family history; morphology alone should not automatically disqualify an asymptomatic athlete.

Suggested NCIT intervention concepts include heart-failure therapy, anticoagulation therapy, catheter ablation, implantable cardioverter-defibrillator, cardiac resynchronization therapy, ventricular-assist device therapy, and heart transplantation. No LVNC10 pharmacogenomic rule or combination regimen has been validated.

Trials and real-world implementation

• NCT06024759, Predictors of Risk in Left Ventricular Non-Compaction: recruiting observational adult registry, target 500, started 1 September 2023, estimated completion 1 August 2033. It examines genetic mutations, LV strain, PVC burden, NSVT, LV dysfunction, and predictors of ICD implantation. https://clinicaltrials.gov/study/NCT06024759 (NCT06024759 chunk 1)
• NCT06607471: recruiting large nonischemic-cardiomyopathy registry that includes LVNC and tracks death, arrhythmia, AV block, transplantation, end-stage failure, and ventricular dysfunction over as long as 30 years. (NCT06607471 chunk 23)
• NCT01470014: completed prospective CT diagnostic study, actual enrollment 39. https://clinicaltrials.gov/study/NCT01470014 (NCT01470014 chunk 1)
• NCT02568072 (MARATHON): completed prospective physiologic-remodeling study, actual enrollment 120. https://clinicaltrials.gov/study/NCT02568072 (NCT02568072 chunk 1, NCT02568072 chunk 2)

No interventional gene, RNA, cell, CRISPR, or MYBPC3-targeted LVNC10 trial was identified.

13. Prevention

Primary prevention

Inherited LVNC10 cannot currently be prevented by lifestyle, medication, or immunization. Reproductive options after counseling include prenatal diagnosis and preimplantation genetic testing for a known familial pathogenic variant, with attention to incomplete penetrance and variable expressivity.

Secondary prevention

• cascade genetic and clinical screening;
• periodic ECG, echocardiography, and rhythm monitoring in at-risk relatives;
• CMR when echo is equivocal or fibrosis/thrombus assessment is needed;
• early treatment of ventricular dysfunction and clinically important arrhythmia.

Tertiary prevention

Optimize heart-failure therapy, control arrhythmias, anticoagulate for established indications, use ICD/CRT according to risk, and manage exercise and pregnancy through specialist cardiogenetic care. There is no LVNC-specific vaccine, chemoprophylaxis, or public-health environmental intervention.

14. Other species and natural disease

The MYBPC3 R820W allele is naturally associated with hypertrophic cardiomyopathy and cardiac death in Ragdoll cats; the homologous feline protein change is commonly reported as R820W/R818W depending on sequence convention. This provides comparative evidence for conserved MYBPC3 sarcomeric pathogenicity, but feline disease is principally HCM and is not a validated natural model of human LVNC10. A 2024 feline review identifies MYBPC3 R818W and A31P as pathogenic HCM variants. DOI: https://doi.org/10.3390/cimb46080517. No zoonotic transmission is possible because LVNC10 is inherited, not infectious.

Suggested taxonomy: Homo sapiens NCBI Taxon 9606; Felis catus NCBI Taxon 9685. A verified VBO identifier for Ragdoll was not recovered.

15. Model organisms and experimental systems

• Human cardiac tissue: strongest LVNC10-relevant mechanistic system; biallelic MYBPC3 disease demonstrated protein depletion, transcript reduction, cardiomyocyte disarray, vacuolization, and fibrosis. Limitation: end-stage tissue cannot separate primary developmental changes from secondary remodeling. (kolokotronis2019biallelicmutationin pages 7-9)
• Mybpc3 knockout/knock-in mice: widely used HCM models reproduce haploinsufficiency, hypertrophy, contractile dysfunction, and proteostasis abnormalities. Autophagy activation improved cardiomyopathy in one targeted knock-in model, but this is preclinical HCM evidence—not proof of efficacy or phenotype reversal in LVNC10.
• Cellular/iPSC systems: patient-specific iPSC cardiomyocytes are suitable for sarcomere assembly, calcium handling, contractility, and allele-correction studies, but no retrieved LVNC10-specific validated organoid or iPSC therapeutic dataset was found.
• Developmental LVNC models: mouse, zebrafish, and other models manipulating Notch/neuregulin, endocardial–myocardial signaling, mitochondrial function, or sarcomeric genes illuminate trabeculation. Their limitation is that developmental noncompaction may not reproduce adult MYBPC3 cardiomyopathy with secondary hypertrabeculation.

Relevant resources include MGI, IMPC, IMSR/MMRRC, ZFIN, Cellosaurus, and the Alliance of Genome Resources.

Evidence-quality assessment and knowledge-base cautions

1. High confidence: LVNC10–MYBPC3 association and MONDO:0014163; MYBPC3 is a causal cardiomyopathy gene. (OpenTargets Search: left ventricular noncompaction-MYBPC3)
2. Moderate confidence: MYBPC3 dosage/protein instability can produce severe LVNC morphology, especially in biallelic disease. (kolokotronis2019biallelicmutationin pages 1-2, kolokotronis2019biallelicmutationin pages 7-9)
3. Limited subtype-specific evidence: penetrance, prevalence, sex ratio, natural history, survival, treatment response, and quality of life.
4. Do not infer disease from morphology alone: up to 15% of apparently healthy people can exceed sensitive CMR NC/C thresholds, and physiologic remodeling may be reversible. (mazzarotto2021systematiclargescaleassessment pages 1-2, walsh2023thetroublewith pages 1-2)
5. Variant-level caution: the historic p.Arg820Trp/R820W association should be curated using current ClinVar/ClinGen and population-frequency evidence before being labeled pathogenic in a patient.
6. Unavailable/not established: specific protective alleles; toxins or infections; LVNC10 epigenetic, single-cell, spatial, proteomic, metabolomic, or lipidomic signatures; validated circulating biomarkers; genotype-specific pharmacotherapy; gene/RNA/cell therapy; and subtype-specific interventional trials.

References

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18. (fitzsimons2024electrophysiologicalphenotypingof pages 7-8): Lindsey A. Fitzsimons, Delanie M. Kneeland‐Barber, Gracie C. Hannigan, David A. Karpe, Lyman Wu, Michael Colon, Jess Randall, and Kerry L. Tucker. Electrophysiological phenotyping of left ventricular noncompaction cardiomyopathy in pediatric populations: a systematic review. Physiological Reports, Apr 2024. URL: https://doi.org/10.14814/phy2.16029, doi:10.14814/phy2.16029. This article has 3 citations and is from a peer-reviewed journal.

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