Left Ventricular Noncompaction 10

Genetic MONDO:0014163 Pathograph 11 Show in embeddings browser Left Ventricular Noncompaction Genetic Disorder

Left ventricular noncompaction 10 (LVNC10) is the MYBPC3-specific form of left ventricular noncompaction (LVNC): any LVNC in which the disease-causing lesion is a variant in MYBPC3, the gene encoding cardiac myosin-binding protein C (cMyBP-C). MYBPC3 is best known as the single most frequently mutated gene in hypertrophic cardiomyopathy (see Hypertrophic Cardiomyopathy 4 / CMH4), where a single truncating allele produces adult-onset cMyBP-C haploinsufficiency and predominantly hypertrophic remodeling. The noncompaction phenotype captured by LVNC10 is most robustly documented at the opposite end of the allelic-dose spectrum: homozygous or compound heterozygous truncating MYBPC3 variants that abolish cMyBP-C almost entirely and produce a severe, usually lethal, neonatal cardiomyopathy with hypertrabeculated/noncompacted myocardium and congenital septal defects. Milder, monoallelic MYBPC3 variants have also been documented producing or co-segregating with a noncompaction phenotype, particularly in families that also carry an unambiguous hypertrophic cardiomyopathy phenotype in relatives. OMIM groups this entity with "cardiomyopathy, dilated, 1MM" (CMD1MM) under the same MIM number (615396), and MONDO likewise classifies LVNC10 as a subtype of both left ventricular noncompaction and familial isolated dilated cardiomyopathy, consistent with the broader LVNC-DCM-HCM phenotypic continuum already described for other MYBPC3 disease presentations. This entry models the MYBPC3-specific genetic and molecular mechanism; the shared downstream LVNC consequences (arrhythmia, ventricular dysfunction, thromboembolic risk) are modeled in the umbrella kb/disorders/Left_Ventricular_Noncompaction.yaml (MONDO:0018901) and are not re-derived here.

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2
Inheritance
5
Pathophys.
8
Phenotypes
1
Gaps
11
Pathograph
1
Genes
2
Variants
3
Medical Actions
2
Subtypes
2
Differentials
5
References
1
Deep Research
🏷

Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
👪

Inheritance

2
Autosomal recessive (biallelic truncating variants) HP:0000007
The severe neonatal LVNC10 phenotype segregates as autosomal recessive at the level of disease severity: two truncating MYBPC3 alleles (homozygous or compound heterozygous) are required, while heterozygous parents are typically asymptomatic or only mildly affected obligate carriers. Because the heterozygous state is itself the classic dominant CMH4 disease allele, this is a dose-dependent threshold effect rather than true biological recessivity.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:25335496 SUPPORT Human Clinical
"All patients with biallelic truncating pathogenic mutations in MYBPC3 reported so far (n=21) were diagnosed with severe cardiomyopathy and/or died within the first few months of life."
Establishes the biallelic requirement and uniform severity that defines the recessive-severity threshold of LVNC10.
Autosomal dominant (monoallelic variants, incomplete/variable penetrance) HP:0000006
A single heterozygous MYBPC3 variant can also be associated with a noncompaction phenotype in some kindreds, particularly those in which relatives carrying the same allele have an unambiguous hypertrophic cardiomyopathy phenotype, consistent with the incompletely penetrant, variably expressive autosomal dominant inheritance already established for MYBPC3-associated hypertrophic cardiomyopathy (CMH4).
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:30947911 SUPPORT Human Clinical
"NCCM with HCM (4%) was associated with MYBPC3 and HCM without NCCM in relatives (p < 0.001)."
PARTIAL support: identifies the MYBPC3-associated NCCM+HCM subgroup within a family-screening cohort in which relatives carrying the variant show variable, incompletely penetrant cardiac phenotypes.
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Subtypes

2
Biallelic (homozygous/compound heterozygous) MYBPC3 LVNC
Homozygous or compound heterozygous truncating MYBPC3 variants abolish cMyBP-C almost completely. This allelic configuration is the best-documented cause of LVNC10: a case series of four unrelated neonates, combined with a literature review totaling 21 reported patients with biallelic truncating MYBPC3 mutations, found that all were diagnosed with severe cardiomyopathy and/or died within the first few months of life, with noncompaction features in three of the four newly reported cases and septal defects or a patent ductus arteriosus in 62% of the pooled cohort. Obligate heterozygous parents are typically asymptomatic or only mildly affected, so the phenotype behaves recessively at this severity threshold even though the single-allele state is itself the classic dominant CMH4 disease allele.
Show evidence (3 references)
PMID:25335496 SUPPORT Human Clinical
"All patients with biallelic truncating pathogenic mutations in MYBPC3 reported so far (n=21) were diagnosed with severe cardiomyopathy and/or died within the first few months of life."
Establishes that biallelic truncating MYBPC3 mutations are uniformly severe across the full reported literature cohort, defining this subtype.
PMID:25335496 SUPPORT Human Clinical
"In contrast to heterozygous pathogenic mutations, homozygous or compound heterozygous truncating pathogenic MYBPC3 mutations cause severe neonatal cardiomyopathy with features of left ventricular noncompaction and septal defects in approximately 60% of patients."
Directly states the mono- versus bi-allelic contrast and defines the biallelic subtype as severe neonatal cardiomyopathy with noncompaction features and septal defects.
PMID:30924982 SUPPORT Human Clinical
"In contrast, haploinsufficiency in MYBPC3 results in a severe early-onset ventricular noncompaction phenotype requiring heart transplantation when combined with a de novo missense variant on the second allele."
Independent case series confirming the compound-heterozygous (loss-of-function plus missense) route to severe, transplant-requiring LVNC in MYBPC3.
Monoallelic (heterozygous) MYBPC3 LVNC
A single heterozygous MYBPC3 variant - the same class of allele that underlies hypertrophic cardiomyopathy 4 (CMH4) - can also present with, or co-segregate with, a noncompaction phenotype rather than pure hypertrophy, particularly in families that also carry an unambiguous HCM phenotype in relatives. In a family-screening study of 143 noncompaction cardiomyopathy index cases, the specific subgroup with noncompaction co-occurring with left ventricular hypertrophy was significantly associated with MYBPC3 variants and with hypertrophic cardiomyopathy (without noncompaction) in relatives, distinguishing it from the MYH7-associated noncompaction-with-dilation subgroup. Case reports also document a single truncating MYBPC3 allele producing hypertrophic, noncompaction, and restrictive phenotypes across different members of one family.
Show evidence (3 references)
PMID:30947911 SUPPORT Human Clinical
"NCCM with HCM (4%) was associated with MYBPC3 and HCM without NCCM in relatives (p < 0.001)."
Directly establishes the MYBPC3-associated NCCM+HCM cardiac-phenotype subgroup this subtype description refers to, and the co-occurrence of HCM without NCCM in relatives.
PMID:36011256 SUPPORT Human Clinical
"We present a case of familial sarcomeric cardiomyopathy caused by heterozygous truncating pathogenic variant p.Q1233* in cardiac myosin-binding protein C (MyBPC3) gene. The proband was first diagnosed with restrictive cardiomyopathy combined with left ventricular noncompaction (LVNC) and..."
Direct case demonstration that the identical heterozygous truncating MYBPC3 allele produces an LVNC-containing phenotype in one family member and a classic HCM phenotype in his adult children.
PMID:37963751 SUPPORT Human Clinical
"The proband carried a heterozygous variation of the MYBPC3 gene c.C2827T and the MYH7 gene c.G2221C. The proband's sister carried heterozygous variation of MYBPC3 gene c.C2827T."
PARTIAL, not full, support: despite the article's own title using "biallelic" to mean two genes (MYBPC3 plus MYH7), the genotype described is digenic rather than biallelic within MYBPC3 itself - the proband carries a heterozygous MYBPC3 variant together with a separate heterozygous MYH7 variant, and her sister carries only the heterozygous MYBPC3 variant. It is curated here, not under the biallelic subtype, as further evidence that a single heterozygous MYBPC3 allele (optionally alongside a second cardiomyopathy-gene variant) associates with an LVNC phenotype in a family setting, consistent with the genetic-heterogeneity picture this subtype already documents.
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Discussions and Knowledge Gaps

1
Why does near-complete biallelic loss of cMyBP-C converge on a developmental compaction-failure phenotype, while partial monoallelic haploinsufficiency of the same protein converges on hypertrophic remodeling (CMH4)?
KNOWLEDGE GAP OPEN lvnc10_dose_phenotype_divergence
Attached to
pathophysiology#Dose-Dependent Failure of Myocardial Compaction
The clinical genetics literature robustly documents the correlation between MYBPC3 allelic dose and phenotype (biallelic loss to severe neonatal noncompaction; monoallelic loss to adult hypertrophic disease), but the mechanistic step converting a quantitative cMyBP-C deficit into a qualitatively different developmental outcome (failure of fetal myocardial compaction, rather than postnatal hypertrophic remodeling) is not established in the cited literature. This differs from the CMH4 myosin super-relaxed-state mechanism, which explains hypercontractility from partial haploinsufficiency but has not been shown to explain the developmental compaction defect at near-complete loss.
Proposed experiments
Graded cMyBP-C dosage time-course of cardiac compaction
lvnc10_dose_dependent_compaction_study
In an iPSC-derived cardiac organoid or animal model system, titrate cMyBP-C dosage across a graded range from full-length wild-type to near-null and compare myofibrillogenesis and trabecular-to-compact remodeling outcomes across the dose range, to determine whether a distinct low-dose threshold specifically produces a compaction failure phenotype rather than a hypertrophic one.
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Pathophysiology

5
MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion
MYBPC3 encodes cardiac myosin-binding protein C (cMyBP-C), a thick-filament accessory protein of the sarcomeric A band. As in CMH4, most MYBPC3 disease alleles are truncating (frameshift, nonsense, or splice variants), the truncated peptide is not stably detected in patient myocardium, and the operative consequence is reduced functional cMyBP-C protein rather than a dominant-negative poison peptide (see kb/disorders/Hypertrophic_Cardiomyopathy_4.yaml for the detailed nonsense-mediated-decay/proteasomal-degradation mechanism, which is shared with this entry). What differs in LVNC10 is allelic dose: a single truncating allele produces the classic CMH4 haploinsufficiency state (roughly 50% residual protein), while two loss-of-function alleles, or a loss-of-function allele combined with a destabilizing missense allele on the second copy, can reduce residual cMyBP-C to as little as ~20% of normal.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
MYBPC3 hgnc:7551 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MYBPC3 (hgnc:7551). hgnc:7551 is a gene from the HUGO Gene Nomenclature Committee.
Sarcomere Organization GO:0045214 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Sarcomere Organization (GO:0045214). GO:0045214 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Sarcomeric A band GO:0031672 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Sarcomeric A band, annotated with A band (GO:0031672). GO:0031672 is a cellular component from the Gene Ontology.
Downstream
Dose-Dependent Failure of Myocardial Compaction Near-complete biallelic loss of cMyBP-C is the allelic state most consistently linked to failure of normal trabecular-to-compact myocardial remodeling.
Dose-Dependent Congenital Septal and Ductal Structural Defects The same near-complete biallelic loss of cMyBP-C is also associated with co-occurring congenital septal and ductal structural anomalies.
Monoallelic cMyBP-C Deficiency and Noncompaction-Hypertrophy Phenotypic Overlap A single truncating allele produces a milder gene-dosage state that in some kindreds manifests as, or co-segregates in relatives with, a noncompaction phenotype rather than pure hypertrophy.
Show evidence (2 references)
PMID:25335496 SUPPORT Human Clinical
"Two patients were compound heterozygotes for the pathogenic c.2373dup p.(Trp792fs) and c.2827C>T p.(Arg943*) mutations, and two were homozygous for the c.2373dup and c.2827C>T mutations."
Documents the specific truncating variant class and biallelic genotypes (homozygous and compound heterozygous) underlying LVNC10.
PMID:30924982 SUPPORT Human Clinical
"In addition, the missense variant may lead to an unstable protein, as overall only 20% of the MYBPC3 protein remain detectable in affected cardiac tissue compared to control tissue."
Directly quantifies residual cMyBP-C protein (~20% of control) in affected cardiac tissue from a compound heterozygous MYBPC3 LVNC case, grounding the dose-dependence claim.
Dose-Dependent Failure of Myocardial Compaction
When cMyBP-C is reduced to a small fraction of normal by biallelic truncating (or loss-of-function-plus-missense) MYBPC3 genotypes, the fetal myocardium fails to complete the normal trabecular-to-compact remodeling process, leaving a persistently noncompacted, hypertrabeculated ventricular wall. The precise molecular step by which near-complete cMyBP-C loss diverts the myocardium toward a noncompaction phenotype, rather than toward the hypertrophic remodeling seen with partial (monoallelic) haploinsufficiency in CMH4, is not established (see the discussion below).
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Myofibril Assembly GO:0030239 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Myofibril Assembly (GO:0030239). GO:0030239 is a biological process from the Gene Ontology. ⚠ ABNORMAL Cardiac Muscle Tissue Morphogenesis GO:0055008 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Cardiac Muscle Tissue Morphogenesis (GO:0055008). GO:0055008 is a biological process from the Gene Ontology. ⚠ ABNORMAL
left ventricle myocardium UBERON:0006566 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in left ventricle myocardium (UBERON:0006566). UBERON:0006566 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Neonatal Structural Cardiac Failure The noncompacted myocardium produces early, severe heart failure in the newborn period.
Show evidence (1 reference)
PMID:25335496 SUPPORT Human Clinical
"Features of left ventricular noncompaction were diagnosed in three patients. In the fourth, hypertrabeculation was not a clear feature, but could not be excluded."
Direct echocardiographic/clinical documentation of noncompaction features in the founding biallelic MYBPC3 case series.
Dose-Dependent Congenital Septal and Ductal Structural Defects
The same severe biallelic MYBPC3 genotype that produces compaction failure is also strongly associated with co-occurring congenital structural anomalies of the cardiac septum and the ductus arteriosus, which accompanied cardiomyopathy in the majority of the pooled biallelic literature cohort. The founding case series and its pooled literature review report these anomalies jointly ("septal defects or a patent ductus arteriosus") without distinguishing atrial from ventricular septal involvement, so this node is deliberately not more specific than the cited evidence supports.
Cardiac Septum Development GO:0003279 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Cardiac Septum Development (GO:0003279). GO:0003279 is a biological process from the Gene Ontology. ⚠ ABNORMAL
cardiac septum UBERON:0002099 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cardiac septum (UBERON:0002099). UBERON:0002099 is an anatomical location from the Uberon multi-species anatomy ontology. ductus arteriosus UBERON:0005440 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in ductus arteriosus (UBERON:0005440). UBERON:0005440 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Neonatal Structural Cardiac Failure The co-occurring septal and ductal structural anomalies add hemodynamic burden that contributes to the newborn heart-failure presentation.
Show evidence (2 references)
PMID:25335496 SUPPORT Human Clinical
"All of them had septal defects."
Documents septal defects as a near-universal co-occurring congenital anomaly in the founding biallelic MYBPC3 case series.
PMID:25335496 SUPPORT Human Clinical
"In 62% (13/21), septal defects or a patent ductus arteriosus accompanied cardiomyopathy."
Quantifies the co-occurrence of septal defects and patent ductus arteriosus across the full pooled literature cohort of biallelic truncating MYBPC3 cases.
Monoallelic cMyBP-C Deficiency and Noncompaction-Hypertrophy Phenotypic Overlap
A single truncating MYBPC3 allele - the CMH4 haploinsufficiency mechanism - produces a milder gene-dosage state that, in a subset of families, is associated with a noncompaction phenotype instead of, or together with, hypertrophic remodeling, and unaffected or hypertrophic-only relatives can carry the identical allele. This phenotypic plasticity supports a continuum-of-sarcomeric-cardiomyopathies model in which the same MYBPC3 lesion can manifest as hypertrophic, noncompaction, or restrictive disease depending on modifying genetic or environmental factors.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Sarcomere Organization GO:0045214 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Sarcomere Organization (GO:0045214). GO:0045214 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (2 references)
PMID:30947911 SUPPORT Human Clinical
"NCCM with HCM (4%) was associated with MYBPC3 and HCM without NCCM in relatives (p < 0.001)."
Directly establishes the MYBPC3-associated NCCM+HCM subgroup in this family-screening cohort, with HCM-without-NCCM co-occurring in relatives.
PMID:36011256 SUPPORT Human Clinical
"This report confirms the concept of the phenotypic continuum of sarcomeric cardiomyopathies and describes possible phenotypic patterns and their transformation over time."
States the phenotypic-continuum interpretation directly, grounded in a family in which one identical MYBPC3 truncating allele produced LVNC in one carrier and HCM in his children.
Neonatal Structural Cardiac Failure
The severe biallelic MYBPC3-cMyBP-C-deficient phenotype presents in the newborn period with feeding difficulties, failure to thrive, and dyspnea, and progresses to fatal cardiac failure within the first few months of life in the founding case series; heart transplantation has been used as a salvage therapy in an independently reported compound heterozygous case.
Show evidence (2 references)
PMID:25335496 SUPPORT Human Clinical
"All four children presented with feeding difficulties, failure to thrive, and dyspnea. They died from cardiac failure before age 13 weeks."
Direct clinical description of the neonatal presentation and near-uniform early mortality in the founding biallelic MYBPC3 LVNC case series.
PMID:30924982 SUPPORT Human Clinical
"In contrast, haploinsufficiency in MYBPC3 results in a severe early-onset ventricular noncompaction phenotype requiring heart transplantation when combined with a de novo missense variant on the second allele."
Documents heart transplantation as the clinical endpoint of the severe biallelic phenotype in an independent case series.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Left Ventricular Noncompaction 10 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

8
Cardiovascular 3
Patent ductus arteriosus HP:0001643 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Patent ductus arteriosus (HP:0001643). HP:0001643 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25335496 SUPPORT Human Clinical
"In 62% (13/21), septal defects or a patent ductus arteriosus accompanied cardiomyopathy."
Directly supports patent ductus arteriosus as a documented co-occurring structural anomaly in the pooled biallelic MYBPC3 literature cohort.
Congestive heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25335496 SUPPORT Human Clinical
"They died from cardiac failure before age 13 weeks."
Supports progression to fatal cardiac failure as the clinical outcome of the severe biallelic MYBPC3 LVNC subtype.
PMID:30924982 SUPPORT Human Clinical
"haploinsufficiency in MYBPC3 results in a severe early-onset ventricular noncompaction phenotype requiring heart transplantation when combined with a de novo missense variant on the second allele."
Supports progression to end-stage heart failure requiring transplantation as a clinical outcome of severe MYBPC3-associated LVNC.
Hypertrophic cardiomyopathy HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36011256 SUPPORT Human Clinical
"His 39-year-old son and 35-year-old daughter have identical non-obstructive asymmetric hypertrophic cardiomyopathy."
Documents hypertrophic cardiomyopathy co-occurring in relatives carrying the identical MYBPC3 truncating allele, supporting the noncompaction-hypertrophy phenotypic overlap of the monoallelic subtype.
Digestive 1
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25335496 SUPPORT Human Clinical
"All four children presented with feeding difficulties, failure to thrive, and dyspnea."
Supports feeding difficulties as a core presenting phenotype of the neonatal biallelic MYBPC3 LVNC subtype.
Respiratory 1
Dyspnea HP:0002094 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dyspnea (HP:0002094). HP:0002094 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25335496 SUPPORT Human Clinical
"All four children presented with feeding difficulties, failure to thrive, and dyspnea."
Supports dyspnea as a core presenting phenotype of the neonatal biallelic MYBPC3 LVNC subtype.
Growth 1
Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25335496 SUPPORT Human Clinical
"All four children presented with feeding difficulties, failure to thrive, and dyspnea."
Supports failure to thrive as a core presenting phenotype of the neonatal biallelic MYBPC3 LVNC subtype.
Other 2
Left ventricular noncompaction cardiomyopathy HP:0011664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular noncompaction cardiomyopathy (HP:0011664). HP:0011664 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25335496 SUPPORT Human Clinical
"Features of left ventricular noncompaction were diagnosed in three patients. In the fourth, hypertrabeculation was not a clear feature, but could not be excluded."
Directly supports left ventricular noncompaction cardiomyopathy as the defining phenotype of this entity, diagnosed in three of the four founding biallelic MYBPC3 cases and not excluded in the fourth.
Heart septal defect Abnormal cardiac septum morphology HP:0001671 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Heart septal defect, annotated with Abnormal cardiac septum morphology (HP:0001671). HP:0001671 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25335496 SUPPORT Human Clinical
"All of them had septal defects."
Supports a heart septal defect as a near-universal co-occurring congenital anomaly in the founding biallelic MYBPC3 case series. The source does not distinguish atrial from ventricular septal involvement (a grep of the cached abstract for "atrial"/"ventricular septal"/"VSD"/"ASD" returns no hits, and its MeSH indexing is the generic "Heart Septal Defects"), so this entry is deliberately curated at the general HP:0001671 level rather than as a specific VSD or ASD.
PMID:25335496 SUPPORT Human Clinical
"In 62% (13/21), septal defects or a patent ductus arteriosus accompanied cardiomyopathy."
Quantifies the co-occurrence of septal defects across the full pooled literature cohort of biallelic truncating MYBPC3 cases.
🧬

Genetic Associations

1
MYBPC3
Gene: MYBPC3 hgnc:7551 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MYBPC3 (hgnc:7551). hgnc:7551 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:25335496 SUPPORT Human Clinical
"In contrast to heterozygous pathogenic mutations, homozygous or compound heterozygous truncating pathogenic MYBPC3 mutations cause severe neonatal cardiomyopathy with features of left ventricular noncompaction and septal defects in approximately 60% of patients."
Establishes MYBPC3 as causative for this LVNC entity and gives the dose-dependent contrast between the mono- and bi-allelic states.
PMID:33500567 SUPPORT Human Clinical
"In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC etiology."
Documents that MYBPC3 was not among the genes found to be uniquely/ LVNC-specifically enriched in this 840-case vs. 125,748-control rare-variant burden analysis, a qualification on the CAUSATIVE relationship modeled here (see notes above for how this is reconciled with the directly reported biallelic pedigree evidence). PARTIAL because it qualifies rather than refutes the gene-disease relationship.
🔬

Variants

2
MYBPC3 c.2373dup (p.Trp792fs) and c.2827C>T (p.Arg943*) - Dutch founder variants Pathogenic
Gene: MYBPC3 hgnc:7551 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MYBPC3 (hgnc:7551). hgnc:7551 is a gene from the HUGO Gene Nomenclature Committee.
Two Dutch founder truncating alleles - the same c.2373dup allele responsible for roughly a quarter of Dutch heterozygous CMH4 cases, and c.2827C>T - were found together as compound heterozygotes, or each in the homozygous state, in the four neonates of the founding LVNC10 case series, all of whom died of cardiac failure or had severe cardiomyopathy with noncompaction features and septal defects.
Show evidence (1 reference)
PMID:25335496 SUPPORT Human Clinical
"Two patients were compound heterozygotes for the pathogenic c.2373dup p.(Trp792fs) and c.2827C>T p.(Arg943*) mutations, and two were homozygous for the c.2373dup and c.2827C>T mutations."
Documents the specific compound heterozygous and homozygous genotypes in the founding LVNC10 case series.
MYBPC3 loss-of-function allele in trans with a de novo missense allele (Kolokotronis 2019) Pathogenic
Gene: MYBPC3 hgnc:7551 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in MYBPC3 (hgnc:7551). hgnc:7551 is a gene from the HUGO Gene Nomenclature Committee.
An independently reported compound heterozygous genotype: a loss-of-function MYBPC3 allele combined in trans with a de novo missense variant on the second allele. The missense allele was associated with an unstable protein product, reducing overall residual cMyBP-C to approximately 20% of control levels in affected cardiac tissue, and produced a severe early-onset noncompaction phenotype that required heart transplantation. The reporting study also recommends considering copy-number variants as an additional route to the same biallelic-dose mechanism, though no specific CNV genotype is documented for this MYBPC3 case in the cited literature.
Show evidence (2 references)
PMID:30924982 SUPPORT Human Clinical
"In addition, the missense variant may lead to an unstable protein, as overall only 20% of the MYBPC3 protein remain detectable in affected cardiac tissue compared to control tissue."
Quantifies residual cMyBP-C protein (~20% of control) for this specific compound heterozygous loss-of-function-plus-missense MYBPC3 genotype.
PMID:30924982 SUPPORT Human Clinical
"In conclusion, in patients with early disease onset and atypical clinical course, biallelic inheritance or more complex variants including copy number variations and de novo mutations should be considered."
Documents the study's own recommendation to consider copy-number variants as part of the same biallelic-dose LVNC10 mechanism, alongside the truncating and de novo missense alleles curated elsewhere in this entry.
💊

Medical Actions

3
Guideline-directed heart failure pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
As in the broader LVNC umbrella entry, no disease-modifying therapy reverses the MYBPC3-driven compaction defect, so treatment focuses on standard heart-failure pharmacotherapy for the resulting ventricular dysfunction.
Mechanism Target:
Neonatal Structural Cardiac Failure — Symptomatic pharmacotherapy is directed at the heart failure produced by the noncompacted, structurally defective myocardium.
Target Phenotypes: Congestive heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37215603 SUPPORT Other
"Currently, no effective treatment strategy exists to reduce its incidence or severity, and symptomatic treatment is the only clinical treatment strategy."
Supports symptom-directed rather than disease-reversing pharmacotherapy as the current treatment paradigm, including for pediatric-onset LVNC such as the neonatal MYBPC3 form.
Heart transplantation
Action: heart transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is heart transplantation (NCIT:C15246). NCIT:C15246 is a clinical intervention from the NCI Thesaurus. Ontology label: Heart Transplantation NCIT:C15246
Heart transplantation is used as salvage therapy for the severe biallelic MYBPC3 LVNC phenotype when medical therapy cannot sustain cardiac function.
Mechanism Target:
Dose-Dependent Failure of Myocardial Compaction — Transplantation replaces the structurally noncompacted, functionally failing myocardium once medical management is exhausted.
Target Phenotypes: Congestive heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30924982 SUPPORT Human Clinical
"haploinsufficiency in MYBPC3 results in a severe early-onset ventricular noncompaction phenotype requiring heart transplantation when combined with a de novo missense variant on the second allele."
Directly documents heart transplantation as the clinical outcome for a compound heterozygous MYBPC3 LVNC case.
Genetic testing and reproductive counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Because biallelic MYBPC3 truncating genotypes are associated with severe, often lethal neonatal disease while single-allele carriers (including obligate-carrier parents) are typically unaffected or mildly affected, identification of a truncating MYBPC3 variant in one parent should prompt partner and family cascade testing to assess recurrence risk in future pregnancies.
Show evidence (1 reference)
PMID:30924982 SUPPORT Human Clinical
"In conclusion, in patients with early disease onset and atypical clinical course, biallelic inheritance or more complex variants including copy number variations and de novo mutations should be considered."
Directly supports the clinical recommendation to consider biallelic MYBPC3 inheritance, and therefore parental carrier and reproductive counseling, in early-onset atypical cardiomyopathy.
🔬

Diagnosis

2
Echocardiographic and cardiac MRI diagnosis of trabeculated two-layer myocardium
As in the broader LVNC umbrella, echocardiography and cardiac MRI are the primary imaging modalities used to identify the noncompacted and compacted myocardial layers; in the neonatal MYBPC3 form these are combined with assessment for co-occurring septal defects.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Imaging caveat: LV hypertrabeculation is not specific for pathological LVNC. Up to 15% of the general population exceeds conventional echocardiographic/CMR noncompaction-to-compaction ratio thresholds as a normal variant, and current (2023 ESC) guidance frames excessive trabeculation as a dynamic morphological trait that can occur physiologically (e.g., pregnancy, athletic training) rather than always indicating a distinct cardiomyopathy. In LVNC10, imaging findings should therefore be interpreted alongside the MYBPC3 genotype and, in the biallelic subtype, the co-occurring clinical and structural picture (feeding difficulties, failure to thrive, heart septal defects), not on morphology alone.
Show evidence (2 references)
PMID:25335496 SUPPORT Human Clinical
"Features of left ventricular noncompaction were diagnosed in three patients. In the fourth, hypertrabeculation was not a clear feature, but could not be excluded."
Supports echocardiographic/imaging assessment of noncompaction features as the diagnostic basis for this entity in the founding case series.
PMID:38019448 SUPPORT Other
"It commonly occurs as a normal variant in apparently healthy individuals, with up to 15% of the population exceeding the diagnostic NC/C ratio when detected by sensitive cardiac magnetic resonance (CMR) imaging"
Supports the imaging-overdiagnosis caveat that excessive trabeculation by NC/C-ratio criteria alone is not specific for pathological LVNC. PARTIAL because this is general LVNC-imaging-trait evidence, not MYBPC3/LVNC10-specific; evidence source is OTHER because this is a narrative review, not a primary clinical study.
Genetic testing for biallelic versus monoallelic MYBPC3 genotype
Molecular genetic testing distinguishes the severe biallelic (homozygous/compound heterozygous) MYBPC3 genotype from the monoallelic genotype, which is prognostically critical because the two states predict markedly different clinical courses and inform parental carrier and reproductive counseling.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:30924982 SUPPORT Human Clinical
"in patients with early disease onset and atypical clinical course, biallelic inheritance or more complex variants including copy number variations and de novo mutations should be considered."
Directly supports the clinical value of genetic testing to identify biallelic MYBPC3 genotypes in early-onset, atypical cardiomyopathy presentations.
📊

Prevalence

1
Reported in the literature (biallelic MYBPC3 genotype)
Cases In Literature Not yet documented
No population-based prevalence estimate exists for LVNC10. As of the 2015 founding case series and literature review, only 21 patients with biallelic truncating MYBPC3 mutations had been reported worldwide, underscoring extreme rarity.
Show evidence (1 reference)
PMID:25335496 SUPPORT Human Clinical
"All patients with biallelic truncating pathogenic mutations in MYBPC3 reported so far (n=21) were diagnosed with severe cardiomyopathy and/or died within the first few months of life."
Gives the total literature count (n=21) of biallelic MYBPC3 patients as of this 2015 review, supporting the ultra-rare/not-yet-documented population prevalence classification.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Left Ventricular Noncompaction 10:

Hypertrophic Cardiomyopathy 4 MONDO:0007268
Overlapping Features Hypertrophic cardiomyopathy 4 (CMH4) is caused by the same gene, MYBPC3, and the two entities sit at opposite ends of the same allelic-dose spectrum: monoallelic truncating variants classically produce the adult-onset hypertrophic phenotype of CMH4, while biallelic variants that abolish cMyBP-C more completely produce the severe neonatal noncompaction phenotype of LVNC10. Some monoallelic carriers and their relatives show overlapping or divergent hypertrophic/noncompaction phenotypes within the same family.
Distinguishing Features
  • Biallelic (homozygous/compound heterozygous) MYBPC3 genotype and severe neonatal onset in LVNC10, versus the classic monoallelic, adult-onset CMH4 presentation
  • Predominant imaging phenotype is noncompacted/hypertrabeculated myocardium in LVNC10 versus discrete left ventricular hypertrophy in CMH4
  • LVNC10 frequently co-occurs with congenital septal defects, which are not a feature of typical monoallelic CMH4
Show evidence (1 reference)
PMID:25335496 SUPPORT Human Clinical
"In contrast to heterozygous pathogenic mutations, homozygous or compound heterozygous truncating pathogenic MYBPC3 mutations cause severe neonatal cardiomyopathy with features of left ventricular noncompaction and septal defects in approximately 60% of patients."
Directly contrasts the heterozygous CMH4 genotype/phenotype with the biallelic LVNC10 genotype/phenotype in the same MYBPC3 gene.
Left Ventricular Noncompaction (idiopathic/other genetic causes) MONDO:0018901
Overlapping Features The broader LVNC umbrella entry captures noncompaction cardiomyopathy caused by other sarcomeric, mitochondrial, and cytoskeletal genes (MYH7, TAFAZZIN, NRAP, and others). LVNC10 is distinguished from these by the identification of a causative MYBPC3 variant, most often biallelic, on molecular genetic testing.
Distinguishing Features
  • Requires molecular confirmation of a causative MYBPC3 variant
  • Biallelic MYBPC3 genotypes are associated with a distinctively severe, early neonatal-lethal course and co-occurring septal defects not typically emphasized in other genetic causes of LVNC
Show evidence (1 reference)
PMID:30947911 SUPPORT Human Clinical
"NCCM with HCM (4%) was associated with MYBPC3 and HCM without NCCM in relatives (p < 0.001)."
Establishes that MYBPC3 (versus MYH7) marks a genetically and phenotypically distinguishable NCCM subgroup within the broader LVNC umbrella, supporting the need for molecular confirmation to distinguish LVNC10 from other genetic causes.
{ }

Source YAML

click to show 
name: Left Ventricular Noncompaction 10
creation_date: "2026-08-17T00:00:00Z"
synonyms:
- LVNC10
- left ventricular noncompaction type 10
- MYBPC3 left ventricular noncompaction
- left ventricular noncompaction caused by mutation in MYBPC3
- cardiomyopathy, dilated, 1MM
description: >-
  Left ventricular noncompaction 10 (LVNC10) is the MYBPC3-specific form of
  left ventricular noncompaction (LVNC): any LVNC in which the disease-causing
  lesion is a variant in MYBPC3, the gene encoding cardiac myosin-binding
  protein C (cMyBP-C). MYBPC3 is best known as the single most frequently
  mutated gene in hypertrophic cardiomyopathy (see Hypertrophic Cardiomyopathy
  4 / CMH4), where a single truncating allele produces adult-onset cMyBP-C
  haploinsufficiency and predominantly hypertrophic remodeling. The
  noncompaction phenotype captured by LVNC10 is most robustly documented at
  the opposite end of the allelic-dose spectrum: homozygous or compound
  heterozygous truncating MYBPC3 variants that abolish cMyBP-C almost entirely
  and produce a severe, usually lethal, neonatal cardiomyopathy with
  hypertrabeculated/noncompacted myocardium and congenital septal defects.
  Milder, monoallelic MYBPC3 variants have also been documented producing or
  co-segregating with a noncompaction phenotype, particularly in families that
  also carry an unambiguous hypertrophic cardiomyopathy phenotype in relatives.
  OMIM groups this entity with "cardiomyopathy, dilated, 1MM" (CMD1MM) under
  the same MIM number (615396), and MONDO likewise classifies LVNC10 as a
  subtype of both left ventricular noncompaction and familial isolated dilated
  cardiomyopathy, consistent with the broader LVNC-DCM-HCM phenotypic
  continuum already described for other MYBPC3 disease presentations. This
  entry models the MYBPC3-specific genetic and molecular mechanism; the shared
  downstream LVNC consequences (arrhythmia, ventricular dysfunction,
  thromboembolic risk) are modeled in the umbrella
  kb/disorders/Left_Ventricular_Noncompaction.yaml (MONDO:0018901) and are not
  re-derived here.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: left ventricular noncompaction 10
  term:
    id: MONDO:0014163
    label: left ventricular noncompaction 10
parents:
- Left Ventricular Noncompaction
- Genetic Disorder
has_subtypes:
- name: Biallelic MYBPC3 LVNC
  display_name: Biallelic (homozygous/compound heterozygous) MYBPC3 LVNC
  description: >-
    Homozygous or compound heterozygous truncating MYBPC3 variants abolish
    cMyBP-C almost completely. This allelic configuration is the
    best-documented cause of LVNC10: a case series of four unrelated neonates,
    combined with a literature review totaling 21 reported patients with
    biallelic truncating MYBPC3 mutations, found that all were diagnosed with
    severe cardiomyopathy and/or died within the first few months of life,
    with noncompaction features in three of the four newly reported cases and
    septal defects or a patent ductus arteriosus in 62% of the pooled cohort.
    Obligate heterozygous parents are typically asymptomatic or only mildly
    affected, so the phenotype behaves recessively at this severity threshold
    even though the single-allele state is itself the classic dominant CMH4
    disease allele.
  evidence:
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients with biallelic truncating pathogenic mutations in MYBPC3
      reported so far (n=21) were diagnosed with severe cardiomyopathy and/or
      died within the first few months of life.
    explanation: >-
      Establishes that biallelic truncating MYBPC3 mutations are uniformly
      severe across the full reported literature cohort, defining this
      subtype.
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to heterozygous pathogenic mutations, homozygous or compound
      heterozygous truncating pathogenic MYBPC3 mutations cause severe
      neonatal cardiomyopathy with features of left ventricular noncompaction
      and septal defects in approximately 60% of patients.
    explanation: >-
      Directly states the mono- versus bi-allelic contrast and defines the
      biallelic subtype as severe neonatal cardiomyopathy with noncompaction
      features and septal defects.
  - reference: PMID:30924982
    reference_title: "Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, haploinsufficiency in MYBPC3 results in a severe
      early-onset ventricular noncompaction phenotype requiring heart
      transplantation when combined with a de novo missense variant on the
      second allele.
    explanation: >-
      Independent case series confirming the compound-heterozygous
      (loss-of-function plus missense) route to severe, transplant-requiring
      LVNC in MYBPC3.
- name: Monoallelic MYBPC3 LVNC
  display_name: Monoallelic (heterozygous) MYBPC3 LVNC
  description: >-
    A single heterozygous MYBPC3 variant - the same class of allele that
    underlies hypertrophic cardiomyopathy 4 (CMH4) - can also present with, or
    co-segregate with, a noncompaction phenotype rather than pure hypertrophy,
    particularly in families that also carry an unambiguous HCM phenotype in
    relatives. In a family-screening study of 143 noncompaction cardiomyopathy
    index cases, the specific subgroup with noncompaction co-occurring with
    left ventricular hypertrophy was significantly associated with MYBPC3
    variants and with hypertrophic cardiomyopathy (without noncompaction) in
    relatives, distinguishing it from the MYH7-associated
    noncompaction-with-dilation subgroup. Case reports also document a single
    truncating MYBPC3 allele producing hypertrophic, noncompaction, and
    restrictive phenotypes across different members of one family.
  evidence:
  - reference: PMID:30947911
    reference_title: "Cardiac Phenotypes, Genetics, and Risks in Familial Noncompaction Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NCCM with HCM (4%) was associated with MYBPC3 and HCM without NCCM in
      relatives (p < 0.001).
    explanation: >-
      Directly establishes the MYBPC3-associated NCCM+HCM cardiac-phenotype
      subgroup this subtype description refers to, and the co-occurrence of
      HCM without NCCM in relatives.
  - reference: PMID:36011256
    reference_title: "Different Phenotypes of Sarcomeric MyBPC3-Cardiomyopathy in the Same Family: Hypertrophic, Left Ventricular Noncompaction and Restrictive Phenotypes (in Association with Sarcoidosis)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We present a case of familial sarcomeric cardiomyopathy caused by
      heterozygous truncating pathogenic variant p.Q1233* in cardiac
      myosin-binding protein C (MyBPC3) gene. The proband was first diagnosed
      with restrictive cardiomyopathy combined with left ventricular
      noncompaction (LVNC) and sarcoidosis at the age of 64. ... His 39-year-old
      son and 35-year-old daughter have identical non-obstructive asymmetric
      hypertrophic cardiomyopathy.
    explanation: >-
      Direct case demonstration that the identical heterozygous truncating
      MYBPC3 allele produces an LVNC-containing phenotype in one family member
      and a classic HCM phenotype in his adult children.
  - reference: PMID:37963751
    reference_title: "[Clinical phenotype and genetic analysis of patients with left ventricular noncompaction caused by the biallelic mutation of MYBPC3 and MYH7]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The proband carried a heterozygous variation of the MYBPC3 gene
      c.C2827T and the MYH7 gene c.G2221C. The proband's sister carried
      heterozygous variation of MYBPC3 gene c.C2827T.
    explanation: >-
      PARTIAL, not full, support: despite the article's own title using
      "biallelic" to mean two genes (MYBPC3 plus MYH7), the genotype
      described is digenic rather than biallelic within MYBPC3 itself - the
      proband carries a heterozygous MYBPC3 variant together with a separate
      heterozygous MYH7 variant, and her sister carries only the heterozygous
      MYBPC3 variant. It is curated here, not under the biallelic subtype, as
      further evidence that a single heterozygous MYBPC3 allele (optionally
      alongside a second cardiomyopathy-gene variant) associates with an LVNC
      phenotype in a family setting, consistent with the genetic-heterogeneity
      picture this subtype already documents.
pathophysiology:
- name: MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    MYBPC3 encodes cardiac myosin-binding protein C (cMyBP-C), a thick-filament
    accessory protein of the sarcomeric A band. As in CMH4, most MYBPC3
    disease alleles are truncating (frameshift, nonsense, or splice variants),
    the truncated peptide is not stably detected in patient myocardium, and
    the operative consequence is reduced functional cMyBP-C protein rather
    than a dominant-negative poison peptide (see
    kb/disorders/Hypertrophic_Cardiomyopathy_4.yaml for the detailed
    nonsense-mediated-decay/proteasomal-degradation mechanism, which is shared
    with this entry). What differs in LVNC10 is allelic dose: a single
    truncating allele produces the classic CMH4 haploinsufficiency state
    (roughly 50% residual protein), while two loss-of-function alleles, or a
    loss-of-function allele combined with a destabilizing missense allele on
    the second copy, can reduce residual cMyBP-C to as little as ~20% of
    normal.
  genes:
  - preferred_term: MYBPC3
    term:
      id: hgnc:7551
      label: MYBPC3
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Sarcomere Organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: Sarcomeric A band
    term:
      id: GO:0031672
      label: A band
  evidence:
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two patients were compound heterozygotes for the pathogenic c.2373dup
      p.(Trp792fs) and c.2827C>T p.(Arg943*) mutations, and two were
      homozygous for the c.2373dup and c.2827C>T mutations.
    explanation: >-
      Documents the specific truncating variant class and biallelic genotypes
      (homozygous and compound heterozygous) underlying LVNC10.
  - reference: PMID:30924982
    reference_title: "Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, the missense variant may lead to an unstable protein, as
      overall only 20% of the MYBPC3 protein remain detectable in affected
      cardiac tissue compared to control tissue.
    explanation: >-
      Directly quantifies residual cMyBP-C protein (~20% of control) in
      affected cardiac tissue from a compound heterozygous MYBPC3 LVNC case,
      grounding the dose-dependence claim.
  downstream:
  - target: Dose-Dependent Failure of Myocardial Compaction
    causal_link_type: DIRECT
    description: >-
      Near-complete biallelic loss of cMyBP-C is the allelic state most
      consistently linked to failure of normal trabecular-to-compact
      myocardial remodeling.
  - target: Dose-Dependent Congenital Septal and Ductal Structural Defects
    causal_link_type: DIRECT
    description: >-
      The same near-complete biallelic loss of cMyBP-C is also associated
      with co-occurring congenital septal and ductal structural anomalies.
  - target: Monoallelic cMyBP-C Deficiency and Noncompaction-Hypertrophy Phenotypic Overlap
    causal_link_type: DIRECT
    description: >-
      A single truncating allele produces a milder gene-dosage state that in
      some kindreds manifests as, or co-segregates in relatives with, a
      noncompaction phenotype rather than pure hypertrophy.
- name: Dose-Dependent Failure of Myocardial Compaction
  biological_scale: TISSUE
  role: effector
  description: >-
    When cMyBP-C is reduced to a small fraction of normal by biallelic
    truncating (or loss-of-function-plus-missense) MYBPC3 genotypes, the fetal
    myocardium fails to complete the normal trabecular-to-compact remodeling
    process, leaving a persistently noncompacted, hypertrabeculated ventricular
    wall. The precise molecular step by which near-complete cMyBP-C loss
    diverts the myocardium toward a noncompaction phenotype, rather than
    toward the hypertrophic remodeling seen with partial (monoallelic)
    haploinsufficiency in CMH4, is not established (see the discussion
    below).
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Myofibril Assembly
    term:
      id: GO:0030239
      label: myofibril assembly
    modifier: ABNORMAL
  - preferred_term: Cardiac Muscle Tissue Morphogenesis
    term:
      id: GO:0055008
      label: cardiac muscle tissue morphogenesis
    modifier: ABNORMAL
  locations:
  - preferred_term: left ventricle myocardium
    term:
      id: UBERON:0006566
      label: left ventricle myocardium
  evidence:
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Features of left ventricular noncompaction were diagnosed in three
      patients. In the fourth, hypertrabeculation was not a clear feature, but
      could not be excluded.
    explanation: >-
      Direct echocardiographic/clinical documentation of noncompaction
      features in the founding biallelic MYBPC3 case series.
  downstream:
  - target: Neonatal Structural Cardiac Failure
    causal_link_type: DIRECT
    description: >-
      The noncompacted myocardium produces early, severe heart failure in
      the newborn period.
- name: Dose-Dependent Congenital Septal and Ductal Structural Defects
  biological_scale: TISSUE
  role: effector
  description: >-
    The same severe biallelic MYBPC3 genotype that produces compaction
    failure is also strongly associated with co-occurring congenital
    structural anomalies of the cardiac septum and the ductus arteriosus,
    which accompanied cardiomyopathy in the majority of the pooled biallelic
    literature cohort. The founding case series and its pooled literature
    review report these anomalies jointly ("septal defects or a patent
    ductus arteriosus") without distinguishing atrial from ventricular
    septal involvement, so this node is deliberately not more specific than
    the cited evidence supports.
  biological_processes:
  - preferred_term: Cardiac Septum Development
    term:
      id: GO:0003279
      label: cardiac septum development
    modifier: ABNORMAL
  locations:
  - preferred_term: cardiac septum
    term:
      id: UBERON:0002099
      label: cardiac septum
  - preferred_term: ductus arteriosus
    term:
      id: UBERON:0005440
      label: ductus arteriosus
  evidence:
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All of them had septal defects.
    explanation: >-
      Documents septal defects as a near-universal co-occurring congenital
      anomaly in the founding biallelic MYBPC3 case series.
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 62% (13/21), septal defects or a patent ductus arteriosus
      accompanied cardiomyopathy.
    explanation: >-
      Quantifies the co-occurrence of septal defects and patent ductus
      arteriosus across the full pooled literature cohort of biallelic
      truncating MYBPC3 cases.
  downstream:
  - target: Neonatal Structural Cardiac Failure
    causal_link_type: DIRECT
    description: >-
      The co-occurring septal and ductal structural anomalies add
      hemodynamic burden that contributes to the newborn heart-failure
      presentation.
- name: Monoallelic cMyBP-C Deficiency and Noncompaction-Hypertrophy Phenotypic Overlap
  biological_scale: CELLULAR
  role: modulator
  description: >-
    A single truncating MYBPC3 allele - the CMH4 haploinsufficiency mechanism
    - produces a milder gene-dosage state that, in a subset of families, is
    associated with a noncompaction phenotype instead of, or together with,
    hypertrophic remodeling, and unaffected or hypertrophic-only relatives can
    carry the identical allele. This phenotypic plasticity supports a
    continuum-of-sarcomeric-cardiomyopathies model in which the same MYBPC3
    lesion can manifest as hypertrophic, noncompaction, or restrictive disease
    depending on modifying genetic or environmental factors.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Sarcomere Organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:30947911
    reference_title: "Cardiac Phenotypes, Genetics, and Risks in Familial Noncompaction Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NCCM with HCM (4%) was associated with MYBPC3 and HCM without NCCM in
      relatives (p < 0.001).
    explanation: >-
      Directly establishes the MYBPC3-associated NCCM+HCM subgroup in this
      family-screening cohort, with HCM-without-NCCM co-occurring in
      relatives.
  - reference: PMID:36011256
    reference_title: "Different Phenotypes of Sarcomeric MyBPC3-Cardiomyopathy in the Same Family: Hypertrophic, Left Ventricular Noncompaction and Restrictive Phenotypes (in Association with Sarcoidosis)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This report confirms the concept of the phenotypic continuum of
      sarcomeric cardiomyopathies and describes possible phenotypic patterns
      and their transformation over time.
    explanation: >-
      States the phenotypic-continuum interpretation directly, grounded in a
      family in which one identical MYBPC3 truncating allele produced LVNC in
      one carrier and HCM in his children.
- name: Neonatal Structural Cardiac Failure
  biological_scale: ORGANISM
  role: effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >-
    The severe biallelic MYBPC3-cMyBP-C-deficient phenotype presents in the
    newborn period with feeding difficulties, failure to thrive, and dyspnea,
    and progresses to fatal cardiac failure within the first few months of
    life in the founding case series; heart transplantation has been used as
    a salvage therapy in an independently reported compound heterozygous
    case.
  evidence:
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All four children presented with feeding difficulties, failure to
      thrive, and dyspnea. They died from cardiac failure before age 13
      weeks.
    explanation: >-
      Direct clinical description of the neonatal presentation and
      near-uniform early mortality in the founding biallelic MYBPC3 LVNC case
      series.
  - reference: PMID:30924982
    reference_title: "Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, haploinsufficiency in MYBPC3 results in a severe
      early-onset ventricular noncompaction phenotype requiring heart
      transplantation when combined with a de novo missense variant on the
      second allele.
    explanation: >-
      Documents heart transplantation as the clinical endpoint of the severe
      biallelic phenotype in an independent case series.
phenotypes:
- name: Left ventricular noncompaction cardiomyopathy
  category: Cardiovascular
  phenotype_term:
    preferred_term: Left ventricular noncompaction cardiomyopathy
    term:
      id: HP:0011664
      label: Left ventricular noncompaction cardiomyopathy
  evidence:
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Features of left ventricular noncompaction were diagnosed in three
      patients. In the fourth, hypertrabeculation was not a clear feature, but
      could not be excluded.
    explanation: >-
      Directly supports left ventricular noncompaction cardiomyopathy as the
      defining phenotype of this entity, diagnosed in three of the four
      founding biallelic MYBPC3 cases and not excluded in the fourth.
- name: Feeding difficulties
  category: Constitutional
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  subtype: Biallelic MYBPC3 LVNC
  evidence:
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All four children presented with feeding difficulties, failure to
      thrive, and dyspnea.
    explanation: >-
      Supports feeding difficulties as a core presenting phenotype of the
      neonatal biallelic MYBPC3 LVNC subtype.
- name: Failure to thrive
  category: Constitutional
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  subtype: Biallelic MYBPC3 LVNC
  evidence:
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All four children presented with feeding difficulties, failure to
      thrive, and dyspnea.
    explanation: >-
      Supports failure to thrive as a core presenting phenotype of the
      neonatal biallelic MYBPC3 LVNC subtype.
- name: Dyspnea
  category: Respiratory
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  subtype: Biallelic MYBPC3 LVNC
  evidence:
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All four children presented with feeding difficulties, failure to
      thrive, and dyspnea.
    explanation: >-
      Supports dyspnea as a core presenting phenotype of the neonatal
      biallelic MYBPC3 LVNC subtype.
- name: Heart septal defect
  category: Cardiovascular
  phenotype_term:
    preferred_term: Heart septal defect
    term:
      id: HP:0001671
      label: Abnormal cardiac septum morphology
  subtype: Biallelic MYBPC3 LVNC
  evidence:
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All of them had septal defects.
    explanation: >-
      Supports a heart septal defect as a near-universal co-occurring
      congenital anomaly in the founding biallelic MYBPC3 case series. The
      source does not distinguish atrial from ventricular septal
      involvement (a grep of the cached abstract for "atrial"/"ventricular
      septal"/"VSD"/"ASD" returns no hits, and its MeSH indexing is the
      generic "Heart Septal Defects"), so this entry is deliberately curated
      at the general HP:0001671 level rather than as a specific VSD or ASD.
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 62% (13/21), septal defects or a patent ductus arteriosus
      accompanied cardiomyopathy.
    explanation: >-
      Quantifies the co-occurrence of septal defects across the full pooled
      literature cohort of biallelic truncating MYBPC3 cases.
- name: Patent ductus arteriosus
  category: Cardiovascular
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  subtype: Biallelic MYBPC3 LVNC
  evidence:
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 62% (13/21), septal defects or a patent ductus arteriosus
      accompanied cardiomyopathy.
    explanation: >-
      Directly supports patent ductus arteriosus as a documented co-occurring
      structural anomaly in the pooled biallelic MYBPC3 literature cohort.
- name: Congestive heart failure
  category: Cardiovascular
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      They died from cardiac failure before age 13 weeks.
    explanation: >-
      Supports progression to fatal cardiac failure as the clinical outcome
      of the severe biallelic MYBPC3 LVNC subtype.
  - reference: PMID:30924982
    reference_title: "Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      haploinsufficiency in MYBPC3 results in a severe early-onset ventricular
      noncompaction phenotype requiring heart transplantation when combined
      with a de novo missense variant on the second allele.
    explanation: >-
      Supports progression to end-stage heart failure requiring
      transplantation as a clinical outcome of severe MYBPC3-associated LVNC.
- name: Hypertrophic cardiomyopathy
  category: Cardiovascular
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  subtype: Monoallelic MYBPC3 LVNC
  evidence:
  - reference: PMID:36011256
    reference_title: "Different Phenotypes of Sarcomeric MyBPC3-Cardiomyopathy in the Same Family: Hypertrophic, Left Ventricular Noncompaction and Restrictive Phenotypes (in Association with Sarcoidosis)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His 39-year-old son and 35-year-old daughter have identical
      non-obstructive asymmetric hypertrophic cardiomyopathy.
    explanation: >-
      Documents hypertrophic cardiomyopathy co-occurring in relatives carrying
      the identical MYBPC3 truncating allele, supporting the
      noncompaction-hypertrophy phenotypic overlap of the monoallelic
      subtype.
genetic:
- name: MYBPC3
  gene_term:
    preferred_term: MYBPC3
    term:
      id: hgnc:7551
      label: MYBPC3
  relationship_type: CAUSATIVE
  notes: >-
    MYBPC3 encodes cardiac myosin-binding protein C and is the defining gene
    of this MONDO entity. It is the single most frequently mutated gene in
    hypertrophic cardiomyopathy (see Hypertrophic Cardiomyopathy 4); the
    LVNC10 phenotype is most consistently associated with biallelic
    (homozygous or compound heterozygous) truncating variants that produce a
    much greater loss of functional protein than the monoallelic
    haploinsufficiency state that typically causes CMH4.

    Qualification: a large rare-variant case-control study (840 LVNC cases
    vs. 125,748 gnomAD population controls) did not find MYBPC3 among the
    genes showing LVNC-specific enrichment - only truncating variants in
    MYH7, ACTN2, and PRDM16 were uniquely associated with LVNC in that
    analysis. This is consistent with the LVNC phenotype seen in MYBPC3
    carriers more often reflecting the well-established MYBPC3-HCM
    relationship "showing through" as a noncompaction-type imaging finding,
    rather than MYBPC3 driving a population-validated, distinct LVNC etiology
    the way MYH7/ACTN2/PRDM16 do. It does not contradict the biallelic-dose
    evidence directly documenting near-complete cMyBP-C loss causing severe
    neonatal noncompaction (Wessels 2015; Kolokotronis 2019) - those are
    individually reported biallelic/compound-heterozygous pedigrees, a
    different allelic regime from a heterozygous-carrier case-control burden
    test - but it is a genuine caveat against treating monoallelic MYBPC3 as
    an LVNC-specific gene in the same sense as MYH7/ACTN2/PRDM16.
  evidence:
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to heterozygous pathogenic mutations, homozygous or compound
      heterozygous truncating pathogenic MYBPC3 mutations cause severe
      neonatal cardiomyopathy with features of left ventricular noncompaction
      and septal defects in approximately 60% of patients.
    explanation: >-
      Establishes MYBPC3 as causative for this LVNC entity and gives the
      dose-dependent contrast between the mono- and bi-allelic states.
  - reference: PMID:33500567
    reference_title: "Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were
      uniquely associated with LVNC and may reflect a distinct LVNC
      etiology.
    explanation: >-
      Documents that MYBPC3 was not among the genes found to be uniquely/
      LVNC-specifically enriched in this 840-case vs. 125,748-control
      rare-variant burden analysis, a qualification on the CAUSATIVE
      relationship modeled here (see notes above for how this is reconciled
      with the directly reported biallelic pedigree evidence). PARTIAL
      because it qualifies rather than refutes the gene-disease relationship.
variants:
- name: MYBPC3 c.2373dup (p.Trp792fs) and c.2827C>T (p.Arg943*) - Dutch founder variants
  gene:
    preferred_term: MYBPC3
    term:
      id: hgnc:7551
      label: MYBPC3
  description: >-
    Two Dutch founder truncating alleles - the same c.2373dup allele
    responsible for roughly a quarter of Dutch heterozygous CMH4 cases, and
    c.2827C>T - were found together as compound heterozygotes, or each in the
    homozygous state, in the four neonates of the founding LVNC10 case
    series, all of whom died of cardiac failure or had severe cardiomyopathy
    with noncompaction features and septal defects.
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two patients were compound heterozygotes for the pathogenic c.2373dup
      p.(Trp792fs) and c.2827C>T p.(Arg943*) mutations, and two were
      homozygous for the c.2373dup and c.2827C>T mutations.
    explanation: >-
      Documents the specific compound heterozygous and homozygous genotypes
      in the founding LVNC10 case series.
- name: MYBPC3 loss-of-function allele in trans with a de novo missense allele (Kolokotronis 2019)
  gene:
    preferred_term: MYBPC3
    term:
      id: hgnc:7551
      label: MYBPC3
  description: >-
    An independently reported compound heterozygous genotype: a loss-of-function
    MYBPC3 allele combined in trans with a de novo missense variant on the
    second allele. The missense allele was associated with an unstable
    protein product, reducing overall residual cMyBP-C to approximately 20%
    of control levels in affected cardiac tissue, and produced a severe
    early-onset noncompaction phenotype that required heart transplantation.
    The reporting study also recommends considering copy-number variants as
    an additional route to the same biallelic-dose mechanism, though no
    specific CNV genotype is documented for this MYBPC3 case in the cited
    literature.
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:30924982
    reference_title: "Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, the missense variant may lead to an unstable protein, as
      overall only 20% of the MYBPC3 protein remain detectable in affected
      cardiac tissue compared to control tissue.
    explanation: >-
      Quantifies residual cMyBP-C protein (~20% of control) for this specific
      compound heterozygous loss-of-function-plus-missense MYBPC3 genotype.
  - reference: PMID:30924982
    reference_title: "Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, in patients with early disease onset and atypical
      clinical course, biallelic inheritance or more complex variants
      including copy number variations and de novo mutations should be
      considered.
    explanation: >-
      Documents the study's own recommendation to consider copy-number
      variants as part of the same biallelic-dose LVNC10 mechanism, alongside
      the truncating and de novo missense alleles curated elsewhere in this
      entry.
inheritance:
- name: Autosomal recessive (biallelic truncating variants)
  description: >-
    The severe neonatal LVNC10 phenotype segregates as autosomal recessive at
    the level of disease severity: two truncating MYBPC3 alleles (homozygous
    or compound heterozygous) are required, while heterozygous parents are
    typically asymptomatic or only mildly affected obligate carriers. Because
    the heterozygous state is itself the classic dominant CMH4 disease allele,
    this is a dose-dependent threshold effect rather than true biological
    recessivity.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients with biallelic truncating pathogenic mutations in MYBPC3
      reported so far (n=21) were diagnosed with severe cardiomyopathy and/or
      died within the first few months of life.
    explanation: >-
      Establishes the biallelic requirement and uniform severity that defines
      the recessive-severity threshold of LVNC10.
- name: Autosomal dominant (monoallelic variants, incomplete/variable penetrance)
  description: >-
    A single heterozygous MYBPC3 variant can also be associated with a
    noncompaction phenotype in some kindreds, particularly those in which
    relatives carrying the same allele have an unambiguous hypertrophic
    cardiomyopathy phenotype, consistent with the incompletely penetrant,
    variably expressive autosomal dominant inheritance already established
    for MYBPC3-associated hypertrophic cardiomyopathy (CMH4).
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:30947911
    reference_title: "Cardiac Phenotypes, Genetics, and Risks in Familial Noncompaction Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NCCM with HCM (4%) was associated with MYBPC3 and HCM without NCCM in
      relatives (p < 0.001).
    explanation: >-
      PARTIAL support: identifies the MYBPC3-associated NCCM+HCM subgroup
      within a family-screening cohort in which relatives carrying the
      variant show variable, incompletely penetrant cardiac phenotypes.
prevalence:
- population: Reported in the literature (biallelic MYBPC3 genotype)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population-based prevalence estimate exists for LVNC10. As of the 2015
    founding case series and literature review, only 21 patients with biallelic
    truncating MYBPC3 mutations had been reported worldwide, underscoring
    extreme rarity.
  evidence:
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients with biallelic truncating pathogenic mutations in MYBPC3
      reported so far (n=21) were diagnosed with severe cardiomyopathy and/or
      died within the first few months of life.
    explanation: >-
      Gives the total literature count (n=21) of biallelic MYBPC3 patients as
      of this 2015 review, supporting the ultra-rare/not-yet-documented
      population prevalence classification.
environmental: []
treatments:
- name: Guideline-directed heart failure pharmacotherapy
  description: >-
    As in the broader LVNC umbrella entry, no disease-modifying therapy
    reverses the MYBPC3-driven compaction defect, so treatment focuses on
    standard heart-failure pharmacotherapy for the resulting ventricular
    dysfunction.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  target_mechanisms:
  - target: Neonatal Structural Cardiac Failure
    description: >-
      Symptomatic pharmacotherapy is directed at the heart failure produced by
      the noncompacted, structurally defective myocardium.
  evidence:
  - reference: PMID:37215603
    reference_title: "Advances in symptomatic therapy for left ventricular non-compaction in children."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Currently, no effective treatment strategy exists to reduce its
      incidence or severity, and symptomatic treatment is the only clinical
      treatment strategy.
    explanation: >-
      Supports symptom-directed rather than disease-reversing pharmacotherapy
      as the current treatment paradigm, including for pediatric-onset LVNC
      such as the neonatal MYBPC3 form.
- name: Heart transplantation
  description: >-
    Heart transplantation is used as salvage therapy for the severe biallelic
    MYBPC3 LVNC phenotype when medical therapy cannot sustain cardiac
    function.
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_phenotypes:
  - preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  target_mechanisms:
  - target: Dose-Dependent Failure of Myocardial Compaction
    description: >-
      Transplantation replaces the structurally noncompacted, functionally
      failing myocardium once medical management is exhausted.
  evidence:
  - reference: PMID:30924982
    reference_title: "Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      haploinsufficiency in MYBPC3 results in a severe early-onset
      ventricular noncompaction phenotype requiring heart transplantation
      when combined with a de novo missense variant on the second allele.
    explanation: >-
      Directly documents heart transplantation as the clinical outcome for a
      compound heterozygous MYBPC3 LVNC case.
- name: Genetic testing and reproductive counseling
  description: >-
    Because biallelic MYBPC3 truncating genotypes are associated with severe,
    often lethal neonatal disease while single-allele carriers (including
    obligate-carrier parents) are typically unaffected or mildly affected,
    identification of a truncating MYBPC3 variant in one parent should prompt
    partner and family cascade testing to assess recurrence risk in future
    pregnancies.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:30924982
    reference_title: "Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, in patients with early disease onset and atypical
      clinical course, biallelic inheritance or more complex variants
      including copy number variations and de novo mutations should be
      considered.
    explanation: >-
      Directly supports the clinical recommendation to consider biallelic
      MYBPC3 inheritance, and therefore parental carrier and reproductive
      counseling, in early-onset atypical cardiomyopathy.
diagnosis:
- name: Echocardiographic and cardiac MRI diagnosis of trabeculated two-layer myocardium
  description: >-
    As in the broader LVNC umbrella, echocardiography and cardiac MRI are the
    primary imaging modalities used to identify the noncompacted and compacted
    myocardial layers; in the neonatal MYBPC3 form these are combined with
    assessment for co-occurring septal defects.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
    qualifiers:
    - predicate:
        preferred_term: diagnostic procedure
        term:
          id: NCIT:C18020
          label: Diagnostic Procedure
      value:
        preferred_term: echocardiography test
        term:
          id: NCIT:C16525
          label: Echocardiography Test
  notes: >-
    Imaging caveat: LV hypertrabeculation is not specific for pathological
    LVNC. Up to 15% of the general population exceeds conventional
    echocardiographic/CMR noncompaction-to-compaction ratio thresholds as a
    normal variant, and current (2023 ESC) guidance frames excessive
    trabeculation as a dynamic morphological trait that can occur
    physiologically (e.g., pregnancy, athletic training) rather than always
    indicating a distinct cardiomyopathy. In LVNC10, imaging findings should
    therefore be interpreted alongside the MYBPC3 genotype and, in the
    biallelic subtype, the co-occurring clinical and structural picture
    (feeding difficulties, failure to thrive, heart septal defects), not on
    morphology alone.
  evidence:
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Features of left ventricular noncompaction were diagnosed in three
      patients. In the fourth, hypertrabeculation was not a clear feature, but
      could not be excluded.
    explanation: >-
      Supports echocardiographic/imaging assessment of noncompaction features
      as the diagnostic basis for this entity in the founding case series.
  - reference: PMID:38019448
    reference_title: "The Trouble with Trabeculation: How Genetics Can Help to Unravel a Complex and Controversial Phenotype."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It commonly occurs as a normal variant in apparently healthy
      individuals, with up to 15% of the population exceeding the diagnostic
      NC/C ratio when detected by sensitive cardiac magnetic resonance (CMR)
      imaging
    explanation: >-
      Supports the imaging-overdiagnosis caveat that excessive trabeculation
      by NC/C-ratio criteria alone is not specific for pathological LVNC.
      PARTIAL because this is general LVNC-imaging-trait evidence, not
      MYBPC3/LVNC10-specific; evidence source is OTHER because this is a
      narrative review, not a primary clinical study.
- name: Genetic testing for biallelic versus monoallelic MYBPC3 genotype
  description: >-
    Molecular genetic testing distinguishes the severe biallelic
    (homozygous/compound heterozygous) MYBPC3 genotype from the monoallelic
    genotype, which is prognostically critical because the two states predict
    markedly different clinical courses and inform parental carrier and
    reproductive counseling.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
    qualifiers:
    - predicate:
        preferred_term: diagnostic procedure
        term:
          id: NCIT:C18020
          label: Diagnostic Procedure
      value:
        preferred_term: genetic testing
        term:
          id: NCIT:C15709
          label: Genetic Testing
  evidence:
  - reference: PMID:30924982
    reference_title: "Biallelic mutation in MYH7 and MYBPC3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in patients with early disease onset and atypical clinical course,
      biallelic inheritance or more complex variants including copy number
      variations and de novo mutations should be considered.
    explanation: >-
      Directly supports the clinical value of genetic testing to identify
      biallelic MYBPC3 genotypes in early-onset, atypical cardiomyopathy
      presentations.
differential_diagnoses:
- name: Hypertrophic Cardiomyopathy 4
  disease_term:
    preferred_term: hypertrophic cardiomyopathy 4
    term:
      id: MONDO:0007268
      label: hypertrophic cardiomyopathy 4
  description: >-
    Hypertrophic cardiomyopathy 4 (CMH4) is caused by the same gene, MYBPC3,
    and the two entities sit at opposite ends of the same allelic-dose
    spectrum: monoallelic truncating variants classically produce the
    adult-onset hypertrophic phenotype of CMH4, while biallelic variants that
    abolish cMyBP-C more completely produce the severe neonatal noncompaction
    phenotype of LVNC10. Some monoallelic carriers and their relatives show
    overlapping or divergent hypertrophic/noncompaction phenotypes within the
    same family.
  distinguishing_features:
  - Biallelic (homozygous/compound heterozygous) MYBPC3 genotype and severe
    neonatal onset in LVNC10, versus the classic monoallelic, adult-onset
    CMH4 presentation
  - Predominant imaging phenotype is noncompacted/hypertrabeculated myocardium
    in LVNC10 versus discrete left ventricular hypertrophy in CMH4
  - LVNC10 frequently co-occurs with congenital septal defects, which are not
    a feature of typical monoallelic CMH4
  evidence:
  - reference: PMID:25335496
    reference_title: "Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to heterozygous pathogenic mutations, homozygous or compound
      heterozygous truncating pathogenic MYBPC3 mutations cause severe
      neonatal cardiomyopathy with features of left ventricular noncompaction
      and septal defects in approximately 60% of patients.
    explanation: >-
      Directly contrasts the heterozygous CMH4 genotype/phenotype with the
      biallelic LVNC10 genotype/phenotype in the same MYBPC3 gene.
- name: Left Ventricular Noncompaction (idiopathic/other genetic causes)
  disease_term:
    preferred_term: left ventricular noncompaction
    term:
      id: MONDO:0018901
      label: left ventricular noncompaction
  description: >-
    The broader LVNC umbrella entry captures noncompaction cardiomyopathy
    caused by other sarcomeric, mitochondrial, and cytoskeletal genes (MYH7,
    TAFAZZIN, NRAP, and others). LVNC10 is distinguished from these by the
    identification of a causative MYBPC3 variant, most often biallelic, on
    molecular genetic testing.
  distinguishing_features:
  - Requires molecular confirmation of a causative MYBPC3 variant
  - Biallelic MYBPC3 genotypes are associated with a distinctively severe,
    early neonatal-lethal course and co-occurring septal defects not
    typically emphasized in other genetic causes of LVNC
  evidence:
  - reference: PMID:30947911
    reference_title: "Cardiac Phenotypes, Genetics, and Risks in Familial Noncompaction Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      NCCM with HCM (4%) was associated with MYBPC3 and HCM without NCCM in
      relatives (p < 0.001).
    explanation: >-
      Establishes that MYBPC3 (versus MYH7) marks a genetically and
      phenotypically distinguishable NCCM subgroup within the broader LVNC
      umbrella, supporting the need for molecular confirmation to distinguish
      LVNC10 from other genetic causes.
discussions:
- discussion_id: lvnc10_dose_phenotype_divergence
  prompt: >-
    Why does near-complete biallelic loss of cMyBP-C converge on a
    developmental compaction-failure phenotype, while partial monoallelic
    haploinsufficiency of the same protein converges on hypertrophic
    remodeling (CMH4)?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Dose-Dependent Failure of Myocardial Compaction
  rationale: >-
    The clinical genetics literature robustly documents the correlation
    between MYBPC3 allelic dose and phenotype (biallelic loss to severe
    neonatal noncompaction; monoallelic loss to adult hypertrophic disease),
    but the mechanistic step converting a quantitative cMyBP-C deficit into a
    qualitatively different developmental outcome (failure of fetal
    myocardial compaction, rather than postnatal hypertrophic remodeling) is
    not established in the cited literature. This differs from the CMH4
    myosin super-relaxed-state mechanism, which explains hypercontractility
    from partial haploinsufficiency but has not been shown to explain the
    developmental compaction defect at near-complete loss.
  proposed_experiments:
  - experiment_id: lvnc10_dose_dependent_compaction_study
    name: Graded cMyBP-C dosage time-course of cardiac compaction
    description: >-
      In an iPSC-derived cardiac organoid or animal model system, titrate
      cMyBP-C dosage across a graded range from full-length wild-type to
      near-null and compare myofibrillogenesis and trabecular-to-compact
      remodeling outcomes across the dose range, to determine whether a
      distinct low-dose threshold specifically produces a compaction
      failure phenotype rather than a hypertrophic one.
clinical_trials: []
datasets: []
references:
- reference: PMID:29447731
  title: "Genetics, Clinical Features, and Long-Term Outcome of Noncompaction Cardiomyopathy."
- reference: PMID:31771441
  title: "Systematic Review of Genotype-Phenotype Correlations in Noncompaction Cardiomyopathy."
- reference: PMID:30980206
  title: "Clinical and genetic insights into non-compaction: a meta-analysis and systematic review on 7598 individuals."
- reference: PMID:29029073
  title: "Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy."
- reference: PMID:25443708
  title: "Left ventricular noncompaction: a distinct cardiomyopathy or a trait shared by different cardiac diseases?"
notes: >-
  These five references were consulted during curation (from the falcon
  deep-research pass and follow-up literature search) but are not individually
  mined for quoted evidence items: each is a broad LVNC genetics/outcome
  cohort, systematic review, or meta-analysis (van Waning 2018 JACC;
  van Waning 2019 systematic review; Kayvanpour 2019 meta-analysis;
  Sedaghat-Hamedani 2017; Arbustini 2014) that documents the general LVNC
  genetic-architecture and phenotype landscape summarized in the umbrella
  Left_Ventricular_Noncompaction.yaml entry, rather than a claim specific to
  MYBPC3/LVNC10 modeled in this entry. They are carried here for provenance
  and to record that they were reviewed and found non-contradictory to the
  MYBPC3-specific claims curated above. PMID:33500567 (Mazzarotto 2021,
  840 LVNC cases vs. 125,748 gnomAD controls) is mined for a direct
  MYBPC3-specific qualifying evidence item instead and so is cited in the
  `genetic` section, not repeated here.
📚

References & Deep Research

References

5
PMID:29447731
Genetics, Clinical Features, and Long-Term Outcome of Noncompaction Cardiomyopathy.
No top-level findings curated for this source.
PMID:31771441
Systematic Review of Genotype-Phenotype Correlations in Noncompaction Cardiomyopathy.
No top-level findings curated for this source.
PMID:30980206
Clinical and genetic insights into non-compaction: a meta-analysis and systematic review on 7598 individuals.
No top-level findings curated for this source.
PMID:29029073
Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy.
No top-level findings curated for this source.
PMID:25443708
Left ventricular noncompaction: a distinct cardiomyopathy or a trait shared by different cardiac diseases?
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Left Ventricular Noncompaction 10 (LVNC10): Disease-Characteristics Research Report
Edison Scientific Literature 26 citations 2026-08-17T21:17:14.671483

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.

Domain LVNC10-specific fact Broad LVNC / contextual evidence Suggested ontology terms Key citation(s)
Identity / identifiers Left Ventricular Noncompaction 10 (LVNC10); disease-specific MONDO: 0014163; subtype linked to MYBPC3 Broad left ventricular noncompaction MONDO: 0018901; phenotype/trait remains conceptually debated across cardiomyopathies MONDO:0014163; MONDO:0018901 (OpenTargets Search: left ventricular noncompaction-MYBPC3, walsh2023thetroublewith pages 1-2)
Synonyms / naming Numbered subtype name: Left ventricular noncompaction 10 LVNC, left ventricular non-compaction, left ventricular hypertrabeculation/noncompaction; recent ESC framing treats LV non-compaction as a dynamic trait rather than always a distinct cardiomyopathy HPO phenotype label suggestion: Left ventricular noncompaction cardiomyopathy (grasso2024thenew2023 pages 1-2, walsh2023thetroublewith pages 1-2)
Data granularity Evidence is primarily aggregated disease-level and family/cohort literature, not EHR-derived in the retrieved sources Large cohorts, reviews, and registries dominate current evidence — (sedaghathamedani2017clinicalgeneticsand pages 1-2, NCT06024759 chunk 1)
Causal gene MYBPC3 (myosin binding protein C3) is the mapped causal gene for LVNC10 MYBPC3 is one of several recurrent LVNC-associated genes; most validated LVNC genes overlap with HCM/DCM architecture HGNC gene symbol: MYBPC3; Ensembl: ENSG00000134571 (OpenTargets Search: left ventricular noncompaction-MYBPC3, mazzarotto2021systematiclargescaleassessment pages 1-2)
Canonical historical variant Historical human association includes p.Arg820Trp / R820W in MYBPC3 for LVNC10; current variant classification should be checked in ClinVar before reuse MYBPC3 disease can also involve truncating, missense, de novo, deletion, and biallelic combinations with severe phenotypes HGVS protein suggestion: p.Arg820Trp (OpenTargets Search: left ventricular noncompaction-MYBPC3, kolokotronis2019biallelicmutationin pages 7-9)
Inheritance Most consistent expectation for LVNC10 due to MYBPC3 is autosomal dominant with variable expressivity and incomplete penetrance; severe early disease may occur with biallelic/compound heterozygous states Broad LVNC familial transmission is often AD, but X-linked and maternal patterns also occur in other genetic forms HPO inheritance term suggestion: Autosomal dominant inheritance (sedaghathamedani2017clinicalgeneticsand pages 1-2, kolokotronis2019biallelicmutationin pages 1-2, kolokotronis2019biallelicmutationin pages 7-9)
Principal phenotypes MYBPC3-related LVNC10 is expected to feature LV noncompaction/hypertrabeculation and may overlap with HCM/DCM phenotypes Heart failure, ventricular dysfunction, arrhythmia, thromboembolism, sudden cardiac death risk, and ECG abnormalities are recurrent LVNC manifestations HPO suggestions: Left ventricular noncompaction cardiomyopathy; Arrhythmia; Ventricular tachycardia; Heart failure; Reduced ejection fraction; Sudden cardiac death (sedaghathamedani2017clinicalgeneticsand pages 1-2, arbustini2014leftventricularnoncompaction pages 1-2, fitzsimons2024electrophysiologicalphenotypingof pages 1-3)
Age at onset / course Variable; can be childhood or adult-onset in heterozygous disease; early severe onset reported with biallelic MYBPC3 states Pediatric to adult presentation occurs broadly; prognosis is heterogeneous HPO onset suggestions: Childhood onset; Adult onset; Infantile onset (for severe cases) (kolokotronis2019biallelicmutationin pages 1-2, fitzsimons2024electrophysiologicalphenotypingof pages 1-3)
Anatomy Primary structure affected: left ventricular myocardium, especially apical/trabecular endocardial regions with noncompacted and compacted layers Broad LVNC definitions emphasize prominent trabeculae, deep recesses, thin compacted layer UBERON suggestions: left ventricle; ventricular myocardium; endocardium (arbustini2014leftventricularnoncompaction pages 1-2, mazzarotto2021systematiclargescaleassessment pages 1-2, fitzsimons2024electrophysiologicalphenotypingof pages 1-3)
Cell type Disease-relevant cell type is primarily cardiomyocyte Arrhythmic manifestations imply conduction-system involvement as secondary physiology CL suggestion: cardiomyocyte (kolokotronis2019biallelicmutationin pages 1-2, fitzsimons2024electrophysiologicalphenotypingof pages 8-10)
Mechanism MYBPC3-associated mechanism is most consistent with sarcomeric dysfunction / haploinsufficiency / protein instability; severe biallelic cases showed marked reduction of MYBPC3 protein in tissue LVNC broadly reflects overlap of sarcomeric cardiomyopathy biology with abnormal trabeculation/compaction; modifier and developmental influences likely GO suggestions: sarcomere organization; cardiac muscle contraction; regulation of cardiac muscle cell contraction; ventricular cardiac muscle tissue morphogenesis (kolokotronis2019biallelicmutationin pages 1-2, kolokotronis2019biallelicmutationin pages 7-9, mazzarotto2021systematiclargescaleassessment pages 1-2)
Pathophysiology chain MYBPC3 variant → altered sarcomeric protein dosage/function → impaired contractile mechanics / myocardial architecture → excessive trabeculation or noncompaction phenotype ± systolic dysfunction/arrhythmia Broad LVNC may represent either a distinct developmental/noncompaction mechanism or a phenotypic expression of other cardiomyopathies GO suggestions as above (kolokotronis2019biallelicmutationin pages 1-2, mazzarotto2021systematiclargescaleassessment pages 1-2, walsh2023thetroublewith pages 1-2)
Diagnostics No LVNC10-only diagnostic test identified; diagnosis relies on clinical imaging + cardiogenetics Echo and CMR use NC/C ratio-based criteria; overdiagnosis is a major issue, especially when relying on morphology alone HPO suggestion: Abnormal left ventricular morphology (grasso2024thenew2023 pages 1-2, mazzarotto2021systematiclargescaleassessment pages 1-2, walsh2023thetroublewith pages 1-2)
Imaging criteria LVNC10 uses the same imaging framework as LVNC generally Typical thresholds cited in retrieved sources: NC/C ratio >2 to 2.3; CMR may label up to 15% of healthy individuals by ratio criteria alone — (mazzarotto2021systematiclargescaleassessment pages 1-2, walsh2023thetroublewith pages 1-2, mahendran2024emerginghallmarksof pages 6-10)
Genetic testing Recommended practical approach: cardiomyopathy gene panel including MYBPC3; consider exome/genome in unresolved or syndromic/early severe cases Genetic testing is most useful for diagnosis clarification, family screening, and differential diagnosis rather than proving morphology alone is pathologic — (grasso2024thenew2023 pages 1-2, mazzarotto2021systematiclargescaleassessment pages 1-2, NCT06024759 chunk 1)
Differential diagnosis Distinguish LVNC10 from HCM/DCM with secondary hypertrabeculation, athlete’s heart, pregnancy-related trabeculation, anemia/sickle-cell-associated trabeculation, congenital heart disease, and syndromic cardiomyopathy ESC 2023 explicitly frames LV non-compaction as a trait that can occur in many settings — (grasso2024thenew2023 pages 1-2, walsh2023thetroublewith pages 1-2, NCT02568072 chunk 1)
Prognosis No LVNC10-specific survival estimate identified Prognosis in LVNC depends more on ventricular dysfunction, arrhythmia burden, fibrosis/genotype context than trabeculation extent alone; LVNC cohort had more cardiovascular events than age-matched nonischemic DCM in one study HPO suggestions: Sudden cardiac death; Thromboembolism (sedaghathamedani2017clinicalgeneticsand pages 1-2, walsh2023thetroublewith pages 1-2, fitzsimons2024electrophysiologicalphenotypingof pages 1-3)
Treatment categories No LVNC10 genotype-specific approved therapy identified Treat according to phenotype: guideline-directed heart failure therapy, arrhythmia surveillance/management, anticoagulation when indicated, ICD/CRT in selected patients, transplant in end-stage disease NCIT suggestions: Heart Failure Therapy; Anticoagulation Therapy; Implantable Cardioverter-Defibrillator; Cardiac Resynchronization Therapy; Heart Transplantation (kolokotronis2019biallelicmutationin pages 1-2, mahendran2024emerginghallmarksof pages 6-10, NCT06024759 chunk 1)
Prevention / screening Cascade family screening and genetic counseling are relevant for MYBPC3-related disease Registry studies are actively evaluating mutation status, strain, PVC burden, NSVT, and ICD outcomes in LVNC — (NCT06024759 chunk 1, grasso2024thenew2023 pages 1-2)
Real-world implementation No LVNC10-specific interventional trial identified Active observational registry: NCT06024759 (recruiting; target n=500) studying genetics, LV strain, PVC burden, NSVT, ICD predictors; broader nonischemic cardiomyopathy registry NCT06607471 also includes LVNC NCT terms may be mapped separately in a trial table (NCT06024759 chunk 1, NCT06607471 chunk 23)
Evidence gaps No retrieved LVNC10-specific prevalence/incidence, penetrance estimate, protective variants, environmental triggers, epigenomic signature, single-cell/spatial profile, validated biomarker, or targeted MYBPC3-LVNC therapy Broad LVNC evidence is heterogeneous and often confounded by phenocopies and imaging overdiagnosis — (grasso2024thenew2023 pages 1-2, walsh2023thetroublewith pages 1-2)

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

Phenotype Type and characteristics Suggested HPO term
LV noncompaction/hypertrabeculation Imaging/structural sign; usually apical and mid-ventricular; severity variable HP:0011664, Left ventricular noncompaction cardiomyopathy
Cardiomyopathy overlap HCM, DCM, or mixed morphology; congenital through adult onset Hypertrophic cardiomyopathy; Dilated cardiomyopathy
LV systolic dysfunction Clinical/imaging sign; may be absent, progressive, or severe Reduced left ventricular ejection fraction
Heart failure Dyspnea, fatigue, exercise intolerance, edema, growth compromise in children; variable progression Heart failure; Exercise intolerance; Dyspnea
Arrhythmia/conduction disease PVCs, VT/VF, bradycardia, AV block, WPW; episodic and potentially fatal Arrhythmia; Ventricular tachycardia; Wolff–Parkinson–White syndrome; Atrioventricular block
Thromboembolism Stroke/systemic embolism, particularly with LV dysfunction, atrial fibrillation, or intracardiac thrombus Thromboembolism; Stroke
Sudden cardiac death Uncommon but major severe outcome, associated with malignant arrhythmia and dysfunction Sudden cardiac death

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

  1. (OpenTargets Search: left ventricular noncompaction-MYBPC3): Open Targets Query (left ventricular noncompaction-MYBPC3, 4 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (grasso2024thenew2023 pages 1-2): Maurizia Grasso, Davide Bondavalli, Viviana Vilardo, Claudia Cavaliere, Ilaria Gatti, Alessandro Di Toro, Lorenzo Giuliani, Mario Urtis, Michela Ferrari, Barbara Cattadori, Alessandra Serio, Carlo Pellegrini, and Eloisa Arbustini. The new 2023 esc guidelines for the management of cardiomyopathies: a guiding path for cardiologist decisions. European Heart Journal Supplements : Journal of the European Society of Cardiology, 26:i1-i5, Apr 2024. URL: https://doi.org/10.1093/eurheartjsupp/suae002, doi:10.1093/eurheartjsupp/suae002. This article has 18 citations.

  3. (walsh2023thetroublewith pages 1-2): Roddy Walsh. The trouble with trabeculation: how genetics can help to unravel a complex and controversial phenotype. Journal of cardiovascular translational research, 16:1310-1324, Nov 2023. URL: https://doi.org/10.1007/s12265-023-10459-6, doi:10.1007/s12265-023-10459-6. This article has 11 citations and is from a peer-reviewed journal.

  4. (sedaghathamedani2017clinicalgeneticsand pages 1-2): Farbod Sedaghat-Hamedani, Jan Haas, Feng Zhu, Christian Geier, Elham Kayvanpour, Martin Liss, Alan Lai, Karen Frese, Regina Pribe-Wolferts, Ali Amr, Daniel Tian Li, Omid Shirvani Samani, Avisha Carstensen, Diana Martins Bordalo, Marion Müller, Christine Fischer, Jing Shao, Jing Wang, Ming Nie, Li Yuan, Sabine Haßfeld, Christine Schwartz, Min Zhou, Zihua Zhou, Yanwen Shu, Min Wang, Kai Huang, Qiutang Zeng, Longxian Cheng, Tobias Fehlmann, Philipp Ehlermann, Andreas Keller, Christoph Dieterich, Katrin Streckfuß-Bömeke, Yuhua Liao, Michael Gotthardt, Hugo A Katus, and Benjamin Meder. Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy. European Heart Journal, 38:3449–3460, Dec 2017. URL: https://doi.org/10.1093/eurheartj/ehx545, doi:10.1093/eurheartj/ehx545. This article has 280 citations and is from a highest quality peer-reviewed journal.

  5. (NCT06024759 chunk 1): Predictors of Risk in Left Ventricular Non-Compaction. London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's. 2023. ClinicalTrials.gov Identifier: NCT06024759

  6. (mazzarotto2021systematiclargescaleassessment pages 1-2): Francesco Mazzarotto, Megan H. Hawley, Matteo Beltrami, Leander Beekman, Antonio de Marvao, Kathryn A. McGurk, Ben Statton, Beatrice Boschi, Francesca Girolami, Angharad M. Roberts, Elisabeth M. Lodder, Mona Allouba, Soha Romeih, Yasmine Aguib, A. John Baksi, Antonis Pantazis, Sanjay K. Prasad, Elisabetta Cerbai, Magdi H. Yacoub, Declan P. O’Regan, Stuart A. Cook, James S. Ware, Birgit Funke, Iacopo Olivotto, Connie R. Bezzina, Paul J.R. Barton, and Roddy Walsh. Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies. Genetics in Medicine, 23:856-864, May 2021. URL: https://doi.org/10.1038/s41436-020-01049-x, doi:10.1038/s41436-020-01049-x. This article has 96 citations and is from a highest quality peer-reviewed journal.

  7. (kolokotronis2019biallelicmutationin pages 7-9): Konstantinos Kolokotronis, Jirko Kühnisch, Eva Klopocki, Josephine Dartsch, Simone Rost, Cathleen Huculak, Giulia Mearini, Stefan Störk, Lucie Carrier, Sabine Klaassen, and Brenda Gerull. Biallelic mutation in myh7 and mybpc3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype. Human Mutation, 40:1101-1114, Aug 2019. URL: https://doi.org/10.1002/humu.23757, doi:10.1002/humu.23757. This article has 46 citations and is from a domain leading peer-reviewed journal.

  8. (kolokotronis2019biallelicmutationin pages 1-2): Konstantinos Kolokotronis, Jirko Kühnisch, Eva Klopocki, Josephine Dartsch, Simone Rost, Cathleen Huculak, Giulia Mearini, Stefan Störk, Lucie Carrier, Sabine Klaassen, and Brenda Gerull. Biallelic mutation in myh7 and mybpc3 leads to severe cardiomyopathy with left ventricular noncompaction phenotype. Human Mutation, 40:1101-1114, Aug 2019. URL: https://doi.org/10.1002/humu.23757, doi:10.1002/humu.23757. This article has 46 citations and is from a domain leading peer-reviewed journal.

  9. (arbustini2014leftventricularnoncompaction pages 1-2): Eloisa Arbustini, Frank Weidemann, and Jennifer L. Hall. Left ventricular noncompaction: a distinct cardiomyopathy or a trait shared by different cardiac diseases? Journal of the American College of Cardiology, 64 17:1840-50, Oct 2014. URL: https://doi.org/10.1016/j.jacc.2014.08.030, doi:10.1016/j.jacc.2014.08.030. This article has 324 citations and is from a highest quality peer-reviewed journal.

  10. (fitzsimons2024electrophysiologicalphenotypingof pages 1-3): 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.

  11. (fitzsimons2024electrophysiologicalphenotypingof pages 8-10): 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.

  12. (mahendran2024emerginghallmarksof pages 6-10): Gowthami Mahendran and Margaret A. Schwarz. Emerging hallmarks of mitochondrial biochemistry in cardiac trabecular morphogenesis and left ventricular noncompaction (lvnc). New Insights on Cardiomyopathy, Feb 2024. URL: https://doi.org/10.5772/intechopen.109098, doi:10.5772/intechopen.109098. This article has 3 citations.

  13. (NCT02568072 chunk 1): Training-induced Increased Left Ventricular Trabeculation. St George's, University of London. 2015. ClinicalTrials.gov Identifier: NCT02568072

  14. (NCT06607471 chunk 23): Giovanni Peretto. Multimodal and Multidisciplinary Approach to Optimize Diagnostic, Prognostic, and Therapeutic Management of Patients with Non-ischemic Cardiomyopathies and Arrhythmogenic-inflammatory Phenotypes: a Multicenter, Observational, Retrospective and Prospective Registry Study.. Scientific Institute San Raffaele. 2018. ClinicalTrials.gov Identifier: NCT06607471

  15. (NCT01470014 chunk 1): Cardiac Computed Tomography: Characteristics of Isolated Left Ventricular Non-compaction. University of Zurich. 2011. ClinicalTrials.gov Identifier: NCT01470014

  16. (walsh2023thetroublewith pages 11-13): Roddy Walsh. The trouble with trabeculation: how genetics can help to unravel a complex and controversial phenotype. Journal of cardiovascular translational research, 16:1310-1324, Nov 2023. URL: https://doi.org/10.1007/s12265-023-10459-6, doi:10.1007/s12265-023-10459-6. This article has 11 citations and is from a peer-reviewed journal.

  17. (NCT02568072 chunk 2): Training-induced Increased Left Ventricular Trabeculation. St George's, University of London. 2015. ClinicalTrials.gov Identifier: NCT02568072

  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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