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Classifications

Harrison's Part

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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 INDIRECT Human Clinical

"NCCM with HCM (4%) was associated with MYBPC3 and HCM without NCCM in relatives (p < 0.001)."

Identifies the MYBPC3-associated NCCM+HCM subgroup within a family-screening cohort in which relatives carrying the variant show variable, incompletely penetrant cardiac phenotypes. The cohort association supports dominant transmission with incomplete penetrance by inference rather than reporting a segregation analysis, hence INDIRECT.

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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 (4 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.

+ 1 more reference

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."

Support with a caveat: 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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Mechanistic Hypotheses

2

Graded cMyBP-C dose sets position on one sarcomeric-cardiomyopathy continuum

sarcomeric_dose_continuum CANONICAL

Evidence balance 2 support

The prevailing reading of MYBPC3 genotype-phenotype relations: hypertrophic, noncompaction, restrictive and dilated presentations are positions on a single continuum, and residual functional cMyBP-C is the variable that sets which one a carrier occupies: a single truncating allele gives adult hypertrophic disease, a biallelic genotype gives severe neonatal disease with noncompaction and septal defects. On this account nothing qualitatively different happens at the low-dose end, and the LVNC phenotype is what severe sarcomeric insufficiency looks like when it strikes during cardiac development. Only one point on that curve is actually measured anywhere in this entry: approximately 20% residual cMyBP-C in affected cardiac tissue from a compound heterozygote carrying a loss-of-function allele in trans with an unstable missense allele. That is one genotype, not the truncating/ truncating configuration the biallelic subtype is defined by, and no residual-protein figure is available for the heterozygous state or for truncating homozygotes. The half-dose expectation that the model rests on is a haploinsufficiency inference, and the isogenic premature-termination-codon iPSC-CMs curated under `experimental_models` cut against it directly: MYBPC3 transcript fell while protein did not. The model's other weakness is that it explains a severity gradient without explaining a change in kind, and one family carrying a single allele can display three different phenotypes among its members.

Pathograph links

MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion -> Dose-Dependent Failure of Myocardial Compaction DIRECT Near-complete biallelic loss of cMyBP-C is the allelic state most consistently linked to failure of normal trabecular-to-compact myocardial remodeling. This is the edge the two mechanistic hypotheses disagree about: whether it is the low end of one quantitative gradient or a qualitatively distinct developmental route.

Show evidence (2 references)

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 continuum model directly, in a family where one allele produced three different phenotypes.

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."

Supplies the quantitative anchor the continuum model needs: a measured residual protein level in the severe noncompaction case, against the ~50% expected of a heterozygous carrier.

Near-complete cMyBP-C loss releases an inhibitory brake on postnatal myocyte cytokinesis

cytokinesis_brake_release EMERGING

Evidence balance 2 support

A mechanistically distinct account of why the low-dose end diverges in kind rather than only in degree. In homozygous cMyBP-C-deficient mice, myocytes complete an extra round of division after birth and accumulate as supernumerary mononuclear cells; the heart enlarges by hyperplasia, whereas the heterozygous state enlarges it by hypertrophy. The authors conclude that cMyBP-C normally inhibits postnatal myocyte cytokinesis. If that inhibition is dose-sensitive, near-complete loss would extend the proliferative window across precisely the period in which the ventricle finishes converting trabecular to compact myocardium, offering a route from a quantitative protein deficit to a qualitatively different developmental outcome. This is a hypothesis about the human disease, not a finding in it: the mice develop dilation, not noncompaction, and no compaction measurement is reported. A zebrafish cMyBP-C knockout shows the same cardiomyocyte hyperplasia, so the proliferative response is at least conserved rather than murine. That strengthens the first half of the hypothesis and cuts against the second: in the fish the extra cardiomyocytes accompany a thicker, more compact ventricular wall, which is the opposite of a compaction failure. Whatever routes hyperplasia to noncompaction in humans, if anything does, is not supplied by either model.

Pathograph links

MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion -> Dose-Dependent Failure of Myocardial Compaction DIRECT Near-complete biallelic loss of cMyBP-C is the allelic state most consistently linked to failure of normal trabecular-to-compact myocardial remodeling. This is the edge the two mechanistic hypotheses disagree about: whether it is the low end of one quantitative gradient or a qualitatively distinct developmental route.

Show evidence (2 references)

PMID:26153423 SUPPORT Model Organism

"However, the mechanism leading to hypertrophic cardiomyopathy in heterozygous MYBPC3(+/-) individuals is myocyte hypertrophy (increased cell size), whereas the mechanism leading to cardiac dilation in homozygous Mybpc3(-/-) mice is primarily myocyte hyperplasia."

The mono- versus bi-allelic divergence in cellular mechanism that this hypothesis generalizes from.

PMID:36012114 SUPPORT INDIRECT Model Organism

"Immunofluorescence staining revealed significant hyperplasia in the mutant's total cardiac and ventricular cardiomyocytes."

Cross-species replication in a zebrafish cMyBP-C knockout. Hyperplasia arising independently in fish and mouse argues the proliferative response is a conserved consequence of losing cMyBP-C rather than a murine artifact, which is what this hypothesis needs to be worth testing in human tissue. It does not carry the hypothesis's second half: in this model the extra cardiomyocytes accompany a thicker, more compact wall, so hyperplasia here is not producing a compaction failure. Hence INDIRECT.

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Discussions and Knowledge Gaps

2

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. A candidate has since been added to this entry rather than left implicit: the homozygous cMyBP-C-deficient mouse shows that the same protein deficit reaches a different cellular endpoint at different allelic dose - hyperplasia through extended postnatal myocyte division at the null dose, hypertrophy at the heterozygous dose - and the authors attribute this to a normal inhibitory role of cMyBP-C in postnatal cytokinesis. That would supply the missing qualitative step, since the extended proliferative window overlaps the period of trabecular-to-compact remodeling. It does not close the gap: the mice develop dilation rather than noncompaction, no compaction measurement is reported, and the extrapolation from myocyte cell-cycle behaviour to ventricular wall architecture is the curator's, not the paper's. The hypothesis is carried as `mechanistic_hypotheses#cytokinesis_brake_release` with status EMERGING.

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.

Perturbations

Graded reduction of cMyBP-C dosage

pathophysiology#MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion

Titrate residual cMyBP-C from wild-type through the heterozygous (~50%) and compound heterozygous (~20%) levels to near-null.

Readouts

Trabecular-to-compact myocardial remodeling

pathophysiology#Dose-Dependent Failure of Myocardial Compaction

Ratio of noncompacted to compacted myocardial layer, measured across the dosage range at the end of the compaction window.

heart trabecula morphogenesis GO:0061384

Postnatal cardiomyocyte proliferation

pathophysiology#Dose-Dependent Failure of Myocardial Compaction

Myocyte division and mononuclear-cell accumulation across the same dosage range, to test whether extended proliferation tracks the compaction outcome.

cardiac muscle cell proliferation GO:0060038

Would support

mechanistic_hypotheses#cytokinesis_brake_release

Would refute

mechanistic_hypotheses#cytokinesis_brake_release

Supporting outcome

A discontinuity: below some residual-protein threshold the noncompacted-to-compacted ratio rises sharply and tracks the extension of the postnatal proliferative window, rather than both changing smoothly with dose.

Refuting outcome

Compaction and proliferation both varying smoothly and proportionally with cMyBP-C dose, with no threshold, which would leave the phenotype difference quantitative and support the continuum account instead.

Show evidence (1 reference)

PMID:26153423 SUPPORT INDIRECT Model Organism

"MYBPC has unexpected inhibitory functions during postnatal myocyte cytokinesis and cell cycle progression."

The finding that turns this gap from wholly open into one with a named candidate mechanism to test. Cited on the discussion because it bears on the question posed, not because it answers it.

Does any available model system actually reproduce the noncompaction phenotype of LVNC10, or only the genotype and the lethality?

HUMAN MODEL MISMATCH OPEN lvnc10_no_model_shows_noncompaction

Attached to

pathophysiology#Dose-Dependent Failure of Myocardial Compaction animal_models#Homozygous cMyBP-C-deficient mouse (Mybpc3 t/t) animal_models#Compound heterozygous MYBPC3 cloned pig animal_models#mybpc3 knockout zebrafish experimental_models#Biallelic MYBPC3 truncating hiPSC line with isogenic control

Of the models attached here, four reach a biallelic or null MYBPC3 state and none reaches the phenotype the entity is named for. The homozygous cMyBP-C-deficient mouse dilates; the compound heterozygous cloned pig hypertrophies and dies perinatally; the zebrafish knockout makes its ventricle *more* compact, with a thicker wall, which is the opposite failure; the biallelic hiPSC line is a resource report with no phenotype assayed, and its two-dimensional cardiomyocytes have no ventricular wall in which compaction could be scored. (The remaining human line, the premature-termination-codon iPSC-CMs, is heterozygous and does not reach the allelic state at all.) So the defining lesion of this entity - persistence of a noncompacted, hypertrabeculated ventricular wall - currently rests entirely on human imaging and autopsy, with no experimental system in which it can be perturbed or rescued. This is a mismatch worth stating rather than a gap in curation. The mouse and pig phenotypes are not merely weaker versions of the human one, they are different phenotypes, and in the zebrafish the difference is one of sign rather than degree. Species differences in the timing of ventricular compaction relative to birth are a plausible reason. Until a model reproduces the compaction defect, therapeutic inferences from the rescue experiments in this entry - the neonatal exon-skipping rescue and the Tet-Off reversibility result - bear on contractile and hypertrophic phenotypes, not on whether a compaction defect is preventable or reversible. Two 2024 human systems surfaced by the same deep-research pass were left out and the reason belongs here rather than nowhere: MYBPC3 p.D389V cardiac organoids showing mavacamten-reversible hypercontractility (doi:10.3390/cells13221913), and MYBPC3 c.1377delC iPSC-CM metabolic remodeling (doi:10.1038/s41598-024-62530-0). Both are heterozygous missense- or single-frameshift-allele HCM systems, further from the biallelic genotype than the lines curated above, and neither scores compaction. The organoid one is worth revisiting, since a cardiac organoid is exactly the system the experiment proposed below would need. The report also surfaced NCT06024759, a generic-LVNC risk registry with no MYBPC3-specific arm, which is why `clinical_trials` remains empty.

Proposed experiments

Compaction-competent biallelic MYBPC3 model

lvnc10_compaction_competent_model

Establish a system in which trabecular-to-compact remodeling can be scored under a biallelic MYBPC3 genotype - an engineered heart tissue or cardiac organoid taken through the compaction window, or an embryonic time course in a species whose compaction completes prenatally as it does in humans - and determine whether the noncompacted phenotype appears at all.

Readouts

Noncompacted-to-compacted layer ratio

pathophysiology#Dose-Dependent Failure of Myocardial Compaction

The imaging measurement used to diagnose the human phenotype, applied to the model system.

Would refute

pathophysiology#Dose-Dependent Failure of Myocardial Compaction

Refuting outcome

A biallelic model that completes normal compaction would argue the human noncompaction finding is a secondary or modifier-dependent feature rather than a direct consequence of cMyBP-C loss, which is what the population burden analysis already hints at for the monoallelic state.

Show evidence (2 references)

PMID:26153423 SUPPORT INDIRECT Model Organism

"Homozygous cardiac myosin binding protein C-deficient (Mybpc(t/t)) mice develop dramatic cardiac dilation shortly after birth; heart size increases almost twofold."

The mismatch stated in the sharpest available form: the biallelic-null mouse phenotype is dilation, and the human biallelic phenotype this entity is named for is noncompaction.

PMID:40496056 SUPPORT INDIRECT Model Organism

"The MYBPC3-edited piglet exhibited a compound heterozygous mutation leading to a markedly low level of mutant MYBPC3 protein and cardiac hypertrophy, reflecting the situation in infants."

The large-animal attempt reaches hypertrophy, not noncompaction, so the mismatch is not confined to rodents.

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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.

Graded cMyBP-C dose sets position on one sarcomeric-cardiomyopathy continuum Near-complete cMyBP-C loss releases an inhibitory brake on postnatal myocyte cytokinesis

Cardiomyocyte CL:0000746

MYBPC3 hgnc:7551

Sarcomere Organization GO:0045214 ⚠ ABNORMAL

Sarcomeric A band GO:0031672

Experimental models

Biallelic MYBPC3 truncating hiPSC line with isogenic control IPSC DERIVED MODEL Reproduces the human biallelic truncating genotype in human cardiomyocytes with an isogenic control, which is the allelic configuration this node describes.

Isogenic hiPSC-cardiomyocytes carrying MYBPC3 premature termination codon variants IPSC DERIVED MODEL Establishes the transcript-level fate of MYBPC3 premature termination codon alleles in human cardiomyocytes: no truncated peptide, and chronic nonsense-mediated decay activation.

Animal models

Homozygous cMyBP-C-deficient mouse (Mybpc3 t/t) Mouse recapitulates The homozygous null genotype reproduces the allelic state the biallelic human genotype produces, and the paper makes the mono- versus bi-allelic dose contrast explicitly.

mybpc3 knockout zebrafish Zebrafish recapitulates Homozygous knockout of the cMyBP-C orthologue reproduces the protein-loss state and yields cardiomyocyte hyperplasia, matching the murine null.

Tet-Off conditional cMyBP-C re-expression mouse (MYBPC3 null background) Mouse rescues Controlled re-expression of wild-type cMyBP-C on the null background recovered ventricular function, showing the phenotype tracks the current protein level rather than a fixed consequence of having lacked it.

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. This is the edge the two mechanistic hypotheses disagree about: whether it is the low end of one quantitative gradient or a qualitatively distinct developmental route.

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

Myofibril Assembly GO:0030239 ⚠ ABNORMAL Cardiac Muscle Tissue Morphogenesis GO:0055008 ⚠ ABNORMAL

left ventricle myocardium UBERON:0006566

Animal models

Homozygous cMyBP-C-deficient mouse (Mybpc3 t/t) Mouse partially recapitulates The model reproduces the allelic dose and the neonatal timing of the human compaction phenotype, and supplies a cellular mechanism - failure of postnatal myocyte cell-cycle exit - that could plausibly divert ventricular wall maturation. It does not reproduce the noncompaction phenotype itself.

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 ⚠ ABNORMAL

cardiac septum UBERON:0002099 ductus arteriosus UBERON:0005440

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

Sarcomere Organization GO:0045214 ⚠ 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.

Animal models

Mybpc3-targeted knock-in mouse (homozygous exon 6 G>A) Mouse rescues Neonatal AAV-U7-AON treatment prevented the cardiac dysfunction and hypertrophy that this homozygous Mybpc3 genotype otherwise produces, establishing the neonatal window as a point of intervention on the organ-level failure node.

Compound heterozygous MYBPC3 cloned pig Pig partially recapitulates Perinatal death with cardiac disease reproduces the lethal timing of the human biallelic phenotype in a large animal.

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.

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Phenotypes

8

Cardiovascular 5

Left ventricular noncompaction cardiomyopathy HP:0011664

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

Show evidence (3 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.

PMID:41488457 SUPPORT INDIRECT Human Clinical

"Postmortem examination revealed severe HCM, an atrial septal defect (ASD), and extensive myocardial necrosis and fibrosis."

The one biallelic MYBPC3 case in this entry that names which septal defect it was: an atrial septal defect, found at autopsy. One case does not settle the atrial-versus-ventricular distribution across the literature cohort, so the phenotype stays bound at the general HP:0001671 level, with this recorded as the first specific instance. Note the same caveat that applies wherever this paper is cited here: its cardiac phenotype is hypertrophic, not noncompacted, so it is evidence for the septal anomaly accompanying a biallelic MYBPC3 genotype and not for a septal anomaly accompanying noncompaction.

Patent ductus arteriosus HP:0001643

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

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

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

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

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

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.

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Genetic Associations

1

MYBPC3

Gene: MYBPC3 hgnc:7551 gene page relationship_type: CAUSATIVE

Show evidence (4 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 INDIRECT 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). It qualifies rather than refutes the gene-disease relationship.

CGGV:assertion_7e65896e-33f5-439d-8749-aba08a539dd0-2021-10-07T160000.000Z NO_EVIDENCE Other

NO_EVIDENCE, deliberately: a Definitive MYBPC3-hypertrophic-cardiomyopathy curation says nothing either way about MYBPC3 causing noncompaction. It is carried because the contrast is the point - this is the strength of evidence MYBPC3 carries for the phenotype it is actually established for, against which the noncompaction claims in this entry should be read, and leaving it out would make the AR/DCM row below look like the whole ClinGen picture.

+ 1 more reference

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Variants

2

MYBPC3 c.2373dup (p.Trp792fs) and c.2827C>T (p.Arg943*) - Dutch founder variants Pathogenic

Gene: MYBPC3 hgnc:7551

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

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.

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Medical Actions

3

Guideline-directed heart failure pharmacotherapy

Action: Pharmacotherapy 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.

Show evidence (1 reference)

PMID:37215603 SUPPORT INDIRECT Other

"Currently, no effective treatment strategy exists to reduce its incidence or severity, and symptomatic treatment is the only clinical treatment strategy."

Establishes what this link claims and does not claim: the pharmacotherapy acts on the heart-failure node downstream of the compaction defect, not on the compaction defect itself. The quote establishes that only symptomatic treatment exists; that it acts on this particular node is the inference, hence INDIRECT.

Target Phenotypes: Congestive heart failure HP:0001635

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 transplantation 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.

Show evidence (1 reference)

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 transplantation being reached for in a compound heterozygous MYBPC3 case whose indication was the noncompaction phenotype itself, which is the mechanism node this link targets.

Target Phenotypes: Congestive heart failure HP:0001635

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 counseling 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.

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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

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 INDIRECT 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. INDIRECT because this is general LVNC-imaging-trait evidence rather than 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

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.

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Progression

2

Neonatal presentation

Biallelic MYBPC3 LVNC Age: First weeks of life

The biallelic form declares itself in the newborn period with feeding difficulties, failure to thrive and dyspnea, alongside noncompaction on imaging and congenital septal or ductal anomalies. A presymptomatic window does exist - one autopsy-confirmed compound heterozygous infant passed routine prenatal screening and was discharged as healthy before collapsing at two months - but no screening interval or modality has been shown to use it. Whether the window is long enough to act on is unresolved rather than settled either way.

Show evidence (1 reference)

PMID:25335496 SUPPORT Human Clinical

"All four children presented with feeding difficulties, failure to thrive, and dyspnea."

Describes the presenting phase of the biallelic form and its timing.

Fatal cardiac failure

Biallelic MYBPC3 LVNC Age: Within the first few months of life

Progression from presentation to death is measured in weeks. In the founding series all four infants died before 13 weeks, and across the pooled literature cohort every reported biallelic patient had severe cardiomyopathy or died within the first few months. Heart transplantation is the one reported alternative endpoint.

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 outcome and its timescale across the whole reported cohort, not only the four index cases.

📊

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.

⚖️

Clinical Burden

High

For the biallelic form the burden is maximal and brief: uniform severe cardiomyopathy or death within months of birth across every case reported up to 2015, with transplantation the only alternative endpoint documented. The monoallelic form is a different burden question entirely and is governed by the MYBPC3 hypertrophic cardiomyopathy literature rather than by anything specific to noncompaction; this HIGH rating is set by the biallelic subtype that defines the entity.

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."

Uniform severe outcome across the complete reported cohort is what sets the burden level.

🔀

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.

📊

Related Datasets

3

Transcriptome analysis of patient derived induced pluripotent stem cell derived cardiomyocytes with severe, early onset hypertrophic cardiomyopathy due to biallelic MYBPC3 variants c.442G>A and c.506-1G>A geo:GSE274124

Transcriptomes of cardiomyocytes derived from a patient carrying two MYBPC3 variants in trans with severe early-onset disease, against a healthy control line. The closest available omics resource to the LVNC10 genotype in human cells, though not an exact match: one allele is a splice variant and the other is annotated low-penetrance pathogenic, so this is a biallelic genotype but not the truncating/truncating configuration the biallelic subtype is defined by.

human BULK RNA SEQ n=6

PMID:39633578

The patient's phenotype is recorded as hypertrophic, not noncompaction, and the allele pair is splice-plus-low-penetrance-missense rather than two truncating alleles. Curated for the biallelic configuration and the early-onset severity, which are what this entry models; it is not a noncompaction dataset, and no omics resource keyed to the LVNC10 phenotype itself was found.

Show evidence (1 reference)

GEO:GSE274124 SUPPORT In Vitro

"Induced pluripotent stem cells (iPSCs) were generated from a patient with severe, early onset hypertrophic cardiomyopathy due to pathogenic (c.506-1G>A) and low penetrance pathogenic (c.442G>A) variants in MYBPC3 in trans (i.e. MYBPC3 biallelic patient)."

The GEO summary establishes the biallelic in-trans genotype and the severe early-onset presentation, which is why this dataset is curated here rather than under the heterozygous CMH4 entry.

Transcriptome study of MYBPC3 loss of function mutations geo:GSE140965

Isogenic human iPSC-cardiomyocytes carrying heterozygous MYBPC3 loss-of-function edits (promoter deletion, start-site deletion, exon 27 frameshift) alongside a homozygous exon 27 frameshift. The allelic-dose contrast this entry turns on, in one human genetic background.

human BULK RNA SEQ n=30

PMID:31877118

Engineered rather than patient-derived, and the readout is transcriptomic in two-dimensional cardiomyocytes, so it cannot address ventricular compaction. Relevant to whether the mono- and bi-allelic states differ in kind or only in degree.

Show evidence (1 reference)

GEO:GSE140965 SUPPORT In Vitro

"Induced pluripotent stem cells were gene edited to introduce heterozygous (promoter deletion, start site deletion, and exon 27 frameshift) and homozygous (exon 27 frameshift) mutations."

Establishes that the design holds genetic background fixed and varies MYBPC3 allelic dose, which is the comparison the dose-dependence nodes in this entry assert.

Gene expression patterns in cMyBP-CΔC10mut HCM mice and cMyBP-C(t/t) DCM mice geo:GSE262253

RNA-seq of the cMyBP-C(t/t) null mouse curated in this entry's animal models, alongside a transgenic mouse expressing a C10-domain mutant at roughly half the endogenous cMyBP-C level. The murine counterpart of the same allelic-dose contrast, with inflammatory pathway upregulation reported in the null hearts.

house mouse BULK RNA SEQ n=4

The two arms are separate experiments in one series rather than a matched dose titration, and the null arm is sampled at 3 months, well past the neonatal window in which the human biallelic phenotype presents.

Show evidence (1 reference)

GEO:GSE262253 SUPPORT Model Organism

"Similarly,to determine whether myocardial inflammation is associated with cardiac dysfunction in dilated cardiomyopathy (DCM) caused by MYBPC3 mutation, we used the well-characterized cMyBP-C(t/t) mouse model of DCM at 3months of age."

Names the cMyBP-C(t/t) model curated under this entry's animal models and states what the null arm of the dataset measures. Quoted with the GEO summary's own missing spaces, as required.

🧫

Experimental Models

2

Biallelic MYBPC3 truncating hiPSC line with isogenic control IPSC_DERIVED_MODEL

The only human system in this entry that reaches the biallelic MYBPC3 genotype LVNC10 requires. CRISPR/Cas9 was used to convert a patient hiPSC line carrying one truncating MYBPC3 allele into a bi-allelic truncating line, alongside an isogenic corrected control, giving a three-line set in which allelic dose is the only variable. All three lines differentiate into cardiomyocytes.

Organism

human NCBITaxon:9606

Cell source

Skin fibroblasts from a hypertrophic cardiomyopathy patient carrying a heterozygous MYBPC3 truncating variant

Publication

PMID:34375846

Pathograph links

MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion partially recapitulates fidelity: moderate observes: molecular Reproduces the human biallelic truncating genotype in human cardiomyocytes with an isogenic control, which is the allelic configuration this node describes.

Limitations: This is a resource report. It establishes pluripotency, karyotype and three-germ-layer plus cardiomyocyte differentiation, and reports no cMyBP-C protein quantification and no disease phenotype, so it substantiates the genotype arm of this node and not the protein-depletion arm. hiPSC-derived cardiomyocytes are also fetal-like and two-dimensional, with no ventricular wall in which compaction could be assessed.

Divergences from the human mechanism

boundary omission qualifying

Residual cMyBP-C protein level, the quantity the node turns on, is not measured in this report; only the genotype and the line's differentiation capacity are established.

Show evidence (1 reference)

PMID:34375846 SUPPORT In Vitro

"We reprogrammed skin fibroblasts from a HCM patient carrying a heterozygous MYBPC3 truncating mutation into human induced pluripotent stem cells (iPSC) and used CRISPR/Cas9 to generate bi-allelic MYBPC3 truncating mutation and isogenic control hiPSC lines."

Establishes that the line reaches the biallelic truncating genotype this node describes, and that an isogenic control exists to attribute any future phenotype to allelic dose.

Show evidence (1 reference)

PMID:34375846 SUPPORT In Vitro

"Bi-allelic truncating MYBPC3 mutations are associated with severe forms of neonatal cardiomyopathy."

The authors' stated rationale for building the biallelic line is the neonatal disease this entry curates, which is what makes the resource relevant here rather than to the HCM entry alone.

Isogenic hiPSC-cardiomyocytes carrying MYBPC3 premature termination codon variants IPSC_DERIVED_MODEL

Isogenic human cardiomyocytes carrying MYBPC3 premature termination codon variants, including p.R943x - the same nonsense change as the c.2827C>T (p.Arg943*) Dutch founder allele that appears homozygously and in compound heterozygosity in the founding LVNC10 case series. The system establishes two things this entry's molecular node asserts: no truncated peptide is produced, and nonsense-mediated decay is chronically engaged. It also supplies a genuine complication, recorded in the discussion below: at the heterozygous dose in this in vitro system, MYBPC3 mRNA fell but cMyBP-C protein did not.

Organism

human NCBITaxon:9606

Cell source

Genome-edited isogenic iPSC lines from hypertrophic cardiomyopathy patients carrying MYBPC3 p.R943x and p.R1073P_Fsx4

Publication

PMID:30586709

Pathograph links

MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion partially recapitulates fidelity: moderate observes: molecular Establishes the transcript-level fate of MYBPC3 premature termination codon alleles in human cardiomyocytes: no truncated peptide, and chronic nonsense-mediated decay activation.

Limitations: The lines are heterozygous, the CMH4 allelic regime, not the biallelic regime that defines LVNC10, so the dose state this node turns on is not the one modeled. More pointedly, protein levels were comparable to isogenic controls despite reduced mRNA, which the authors read as haploinsufficiency not contributing in vitro. That does not overturn the ~20% residual protein measured in affected human cardiac tissue in a compound heterozygous LVNC case, but it does mean this model supports the transcript arm of the node and not the protein-depletion arm.

Divergences from the human mechanism

proxy quantity qualifying

The model reports transcript abundance and nonsense-mediated decay activity. The node's operative quantity is residual functional cMyBP-C protein, which in this system did not follow the transcript.

population mismatch qualifying

Heterozygous carriers of a single premature termination codon allele, rather than the biallelic genotypes that define this entity.

Readouts

Nonsense-mediated decay pathway activity

Transcriptome-level assessment of nonsense-mediated decay activation in MYBPC3 premature-termination-codon cardiomyocytes against isogenic controls.

Direction: INCREASED

Interpretation: Chronic nonsense-mediated decay engagement is the transcript-level mechanism by which these alleles fail to yield functional protein.

Show evidence (1 reference)

PMID:30586709 SUPPORT In Vitro

"At the molecular level, the nonsense-mediated decay pathway was activated, and a set of genes involved in major cardiac signaling pathways was dysregulated in HCM iPSC-CMs, indicating an HCM gene signature in vitro."

Reports the measured activation of the pathway and its direction.

Show evidence (1 reference)

PMID:30586709 SUPPORT In Vitro

"The mRNA expression levels of MYBPC3 were significantly reduced in mutant iPSC-CMs, but the protein levels were comparable among isogenic iPSC-CMs, suggesting that haploinsufficiency of MYBPC3 does not contribute to the pathogenesis of HCM in vitro."

Carries both halves of what this link claims: the transcript falls, and the protein does not follow. That split is why the link is PARTIALLY_RECAPITULATES and why the divergences above are recorded.

Show evidence (1 reference)

PMID:30586709 SUPPORT In Vitro

"Furthermore, truncated MYBPC3 peptides were not detected."

Directly supports this entry's claim that the truncated peptide is not stably present, so the operative lesion is absent protein rather than a dominant-negative product.

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Animal Models

5

Homozygous cMyBP-C-deficient mouse (Mybpc3 t/t)

The homozygous cMyBP-C-deficient mouse is the murine counterpart of the biallelic MYBPC3 allelic state that defines LVNC10, and is the only model in this entry that offers a candidate mechanism for the dose-phenotype divergence recorded in the open discussion below. These mice enlarge their hearts almost twofold shortly after birth, and the enlargement is driven by myocyte hyperplasia rather than hypertrophy: cMyBP-C-null myocytes complete an extra round of postnatal cell division and accumulate as supernumerary mononuclear cells, whereas the heterozygous state produces hypertrophy through increased cell size. The authors propose that cMyBP-C normally acts as an inhibitor of postnatal myocyte cytokinesis, so that near-complete loss releases a proliferative program at exactly the window in which the mammalian ventricle is finishing its trabecular-to-compact remodeling.

Species

Mouse

Genotype

Mybpc3 t/t (homozygous cardiac myosin binding protein C-deficient)

Genes

MYBPC3 hgnc:7551

Publication

PMID:26153423

Pathograph links

MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion recapitulates fidelity: moderate observes: organism The homozygous null genotype reproduces the allelic state the biallelic human genotype produces, and the paper makes the mono- versus bi-allelic dose contrast explicitly.

Limitations: Neither the cited abstract nor this entry has a residual-protein figure for the mouse, so "near-complete depletion" is inferred from the null genotype rather than measured; the readout available is gross cardiac enlargement, an organ-level proxy standing in for a molecular node. The mouse also survives to adulthood, where the equivalent human genotype is fatal within months.

Divergences from the human mechanism

proxy quantity qualifying

The measured quantity is postnatal heart size. The node's quantity is residual functional cMyBP-C protein, which this report does not quantify in either species.

species mismatch qualifying

The murine allele is a targeted truncation rather than one of the human MYBPC3 alleles curated here, and the mouse tolerates the null state into adulthood where human biallelic carriers do not survive infancy.

Readouts

Postnatal heart size

Gross cardiac enlargement measured in homozygous null mice shortly after birth, against wild-type littermates.

Direction: INCREASED

Interpretation: An organ-level proxy for the molecular node: it confirms the null genotype produces an overt cardiac phenotype in the neonatal window, matching the timing of the human biallelic presentation, but it does not measure residual cMyBP-C.

Show evidence (1 reference)

PMID:26153423 SUPPORT Model Organism

"Homozygous cardiac myosin binding protein C-deficient (Mybpc(t/t)) mice develop dramatic cardiac dilation shortly after birth; heart size increases almost twofold."

Reports the measured cardiac enlargement and its postnatal timing in the homozygous null model.

Show evidence (1 reference)

PMID:26153423 SUPPORT Model Organism

"We suggest that human patients with homozygous MYBPC3-null mutations develop dilated cardiomyopathy, coupled with myocyte hyperplasia (increased cell number), as observed in Mybpc(t/t) mice."

The authors themselves position the homozygous null mouse as the model of the human biallelic MYBPC3-null state, which is the node this link targets.

Dose-Dependent Failure of Myocardial Compaction partially recapitulates fidelity: low observes: cellular The model reproduces the allelic dose and the neonatal timing of the human compaction phenotype, and supplies a cellular mechanism - failure of postnatal myocyte cell-cycle exit - that could plausibly divert ventricular wall maturation. It does not reproduce the noncompaction phenotype itself.

Limitations: The mouse phenotype is cardiac dilation with myocyte hyperplasia, not a persistently hypertrabeculated, noncompacted ventricular wall; the abstract reports no trabecular-to-compact remodeling measurement. Homozygous null mice also survive into adulthood, where the human biallelic genotype is lethal within months. Treating the cytokinesis finding as the explanation of human compaction failure is an inference the cited work does not make.

Divergences from the human mechanism

proxy quantity qualifying

The measured quantity is the number of postnatal myocyte divisions and the resulting count of mononuclear myocytes. The node's quantity is the extent of trabecular-to-compact remodeling of the ventricular wall. Extra cell divisions are a candidate upstream cause of a compaction defect, not a measurement of one.

scale extrapolation qualifying

The model observes cell-cycle behaviour in individual cardiomyocytes (CELLULAR); the node is the tissue-level architecture of the ventricular wall (TISSUE). The step from supernumerary myocytes to a noncompacted wall is not observed in this model.

species mismatch qualifying

Murine and human ventricular compaction differ in timing relative to birth, and the mouse null survives to adulthood while the equivalent human genotype is fatal in the first months of life, so the postnatal-proliferation window the model exploits may not be the window in which the human phenotype is set.

Readouts

Mononuclear cardiomyocyte number in the postnatal window

Count of myocytes completing an additional postnatal division within 10 days of birth, compared with wild-type littermates.

cardiac muscle cell proliferation GO:0060038 ↑ INCREASED

Direction: INCREASED

Interpretation: The cellular readout standing in for the compaction node: extended postnatal proliferation is the model's proposed route from cMyBP-C loss to abnormal ventricular wall maturation.

Show evidence (1 reference)

PMID:26153423 SUPPORT Model Organism

"We demonstrate that many Mybpc(t/t) myocytes undergo an additional round of cell division within 10 d postbirth compared with their wild-type counterparts, leading to increased numbers of mononuclear myocytes."

Reports the measurement and its direction directly.

Show evidence (1 reference)

PMID:26153423 SUPPORT INDIRECT Model Organism

"However, the mechanism leading to hypertrophic cardiomyopathy in heterozygous MYBPC3(+/-) individuals is myocyte hypertrophy (increased cell size), whereas the mechanism leading to cardiac dilation in homozygous Mybpc3(-/-) mice is primarily myocyte hyperplasia."

This is the sentence that makes the model informative for this node: it establishes that the same protein deficit reaches a qualitatively different cellular endpoint depending on allelic dose, which is the dose-dependence the node asserts. It is cited for the dose principle, not as evidence of noncompaction, which the model does not show.

Show evidence (1 reference)

PMID:26153423 SUPPORT Model Organism

"MYBPC has unexpected inhibitory functions during postnatal myocyte cytokinesis and cell cycle progression."

States the model's central mechanistic finding, which is what makes it informative for the allelic-dose question this entry models rather than merely another sarcomeric-cardiomyopathy mouse.

Mybpc3-targeted knock-in mouse (homozygous exon 6 G>A)

A homozygous Mybpc3 knock-in mouse carrying a single point mutation that generates three aberrant mRNAs, developed as a hypertrophic-cardiomyopathy model but genotypically in the biallelic regime this entry curates. It is included here for the therapeutic arm: AAV-delivered U7snRNA antisense constructs that mask splicing enhancers in exons 5 and 6 shifted splicing toward a functional variant and, injected in newborns, abolished cardiac dysfunction and prevented hypertrophy. This is the only demonstration in this entry that a biallelic Mybpc3 cardiac phenotype is preventable if the protein deficit is corrected in the neonatal window.

Species

Mouse

Genotype

Mybpc3 knock-in, homozygous G>A transition in exon 6

Genes

MYBPC3 hgnc:7551

Publication

PMID:23716398

Pathograph links

Neonatal Structural Cardiac Failure rescues fidelity: moderate observes: organism Neonatal AAV-U7-AON treatment prevented the cardiac dysfunction and hypertrophy that this homozygous Mybpc3 genotype otherwise produces, establishing the neonatal window as a point of intervention on the organ-level failure node.

Limitations: The rescued phenotype is hypertrophy with cardiac dysfunction, not noncompaction, so the experiment shows that a biallelic Mybpc3 cardiac phenotype is correctable rather than that the human LVNC10 compaction defect specifically is. The authors also report the effect as transient and requiring optimization, and the construct is exon-6-specific, so it would not transfer to the human truncating alleles curated in this entry without redesign.

Divergences from the human mechanism

species mismatch qualifying

The corrected lesion is a mouse exon-6 splice-shifting point mutation. The human LVNC10 alleles are frameshift and nonsense variants distributed across the gene, for which this exon-skipping strategy offers no direct route.

temporal scope qualifying

The rescue is reported as transient, so the experiment bounds a short-term prevention window and says nothing about durable correction of the organ-level failure node.

Readouts

Left ventricular hypertrophy and cardiac function after neonatal AAV-U7-AON

Cardiac function and left ventricular hypertrophy assessed in homozygous KI mice injected as newborns with AAV-U7-AON-5+6.

Direction: RESTORED

Interpretation: Prevention of the organ-level failure phenotype when the protein deficit is corrected neonatally.

Show evidence (1 reference)

PMID:23716398 SUPPORT Model Organism

"Injection of newborn KI mice abolished cardiac dysfunction and prevented left ventricular hypertrophy."

Reports the measured rescue and its neonatal timing.

Show evidence (1 reference)

PMID:23716398 SUPPORT Model Organism

"KI mice carry a homozygous G>A transition in exon 6, which results in three different aberrant mRNAs."

Establishes the model's homozygous genotype and its aberrant-transcript consequence, placing it in the biallelic allelic regime.

Compound heterozygous MYBPC3 cloned pig

A large-animal attempt at the biallelic MYBPC3 state. The edited piglet carried a compound heterozygous genotype, expressed markedly reduced mutant MYBPC3 protein, and developed cardiac hypertrophy, but the pregnancies yielded non-viable piglets that died around birth. The model therefore reproduces the perinatal lethality of human biallelic MYBPC3 disease in a species with human-like cardiac size and physiology, while supplying no postnatal course.

Species

Pig

Genotype

MYBPC3 compound heterozygous (CRISPR/Cas9 edited, somatic cell nuclear transfer)

Genes

MYBPC3 hgnc:7551

Publication

PMID:40496056

Pathograph links

Neonatal Structural Cardiac Failure partially recapitulates fidelity: low observes: organism Perinatal death with cardiac disease reproduces the lethal timing of the human biallelic phenotype in a large animal.

Limitations: The reported cardiac phenotype is hypertrophy; no noncompaction, hypertrabeculation, or septal defect is described. Only a single edited MYBPC3 piglet is reported, and cloning by somatic cell nuclear transfer independently causes perinatal loss, so the death cannot be attributed to the genotype alone. The authors' own conclusion is that pigs are unusually sensitive to sarcomeric variants, which is itself a caution against reading the timing across to humans.

Divergences from the human mechanism

species mismatch qualifying

The paper concludes that pigs are particularly sensitive to sarcomeric gene mutations, so the perinatal lethality may reflect porcine sensitivity rather than the severity of the human genotype.

population mismatch qualifying

A single cloned MYBPC3-edited piglet, produced by somatic cell nuclear transfer, which carries its own perinatal-loss risk that is not separated from the genotype effect here.

Readouts

Perinatal survival of MYBPC3-edited cloned piglets

Viability of cloned piglets carrying edited sarcomeric genotypes.

Direction: DECREASED

Interpretation: Death around birth is the organism-level correlate of the human neonatal failure node.

Show evidence (1 reference)

PMID:40496056 SUPPORT Model Organism

"In conclusion, MYBPC3 and MYH7 cloned piglets developed cardiac hypertrophy and died around birth, indicating that pigs are particularly sensitive to sarcomeric gene mutations."

Reports both the outcome and the authors' species-sensitivity caveat in one sentence.

Show evidence (1 reference)

PMID:40496056 SUPPORT Model Organism

"The MYBPC3-edited piglet exhibited a compound heterozygous mutation leading to a markedly low level of mutant MYBPC3 protein and cardiac hypertrophy, reflecting the situation in infants."

Establishes the biallelic genotype, the reduced protein level, and the authors' own framing of the model as reflecting the human infantile presentation.

mybpc3 knockout zebrafish

A stable zebrafish knockout of the cMyBP-C orthologue, built as a hypertrophic-cardiomyopathy model but carrying the finding that matters most to this entry: immunofluorescence shows significant cardiomyocyte hyperplasia in mutant hearts at the larval stage (608 vs 302 total cardiomyocyte nuclei), with myocardial remodeling and hyperplasia persisting into later larval development. That is the same cellular response the homozygous cMyBP-C-deficient mouse shows, reached independently in a teleost, which is the strongest support this entry carries for treating hyperplasia as a conserved consequence of cMyBP-C loss rather than a murine idiosyncrasy. The direction of the wall phenotype is the point to keep hold of. Zebrafish do form a compact ventricular myocardium over a trabecular layer, and this knockout does not fail to compact it - the mutant ventricle and atrium became *more* compact, with a thicker myocardial wall and smaller chamber diameters. So the one model here that could in principle have shown a compaction defect showed the opposite.

Species

Zebrafish

Genotype

mybpc3 stable knockout (heterozygous and homozygous)

Genes

MYBPC3 hgnc:7551

Publication

PMID:36012114

Pathograph links

MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion recapitulates fidelity: moderate observes: cellular Homozygous knockout of the cMyBP-C orthologue reproduces the protein-loss state and yields cardiomyocyte hyperplasia, matching the murine null.

Limitations: The zebrafish heart is two-chambered and the gene is an orthologue rather than human MYBPC3, so the model speaks to conserved cMyBP-C cell biology and not to human ventricular architecture. Its wall phenotype runs opposite to the human one: the mutant ventricle is more compact and thicker-walled, not hypertrabeculated.

Divergences from the human mechanism

species mismatch qualifying

The zebrafish heart has two chambers, and its compact ventricular myocardium responds to cMyBP-C loss by thickening rather than by failing to form. Human ventricular wall architecture, and the direction in which it fails in this entity, have no counterpart here.

Readouts

Cardiac and ventricular cardiomyocyte number

Immunofluorescence counts of total cardiac and ventricular cardiomyocytes in mybpc3-knockout larvae against wild-type controls.

cardiac muscle cell proliferation GO:0060038 ↑ INCREASED

Direction: INCREASED

Interpretation: Independent, cross-species replication of the cardiomyocyte hyperplasia that the homozygous cMyBP-C-deficient mouse shows.

Show evidence (1 reference)

PMID:36012114 SUPPORT Model Organism

"Immunofluorescence staining revealed significant hyperplasia in the mutant's total cardiac and ventricular cardiomyocytes."

Reports the measurement, the method, and its direction.

Ventricular wall compaction and thickness

Gross morphology of the mutant ventricle and atrium at 72 hours post-fertilization, against wild-type controls.

Direction: ALTERED

Interpretation: The wall changes in the direction opposite to human noncompaction. This readout is recorded because a null result would have been informative and the actual result is informative against the model, not for it.

Show evidence (1 reference)

PMID:36012114 REFUTE Model Organism

"The mybpc3 KO zebrafish heart displayed cardiac structural changes as it was notable that the ventricles and atria became more compact compared to the controls"

REFUTE against the proposition that this model recapitulates the human wall phenotype: cMyBP-C loss here makes the ventricle more compact, where the human biallelic genotype leaves it noncompacted. This is the strongest single datum behind the HUMAN_MODEL_MISMATCH discussion below.

Show evidence (1 reference)

PMID:36012114 SUPPORT Model Organism

"To investigate the c-MYBPC3 HCM-related cardiac impairment, we generated a zebrafish mypbc3-knockout model."

Establishes the model and its knockout genotype. Quoted verbatim: the paper's abstract misspells the gene as "mypbc3" throughout, while its own results section uses the correct zebrafish symbol mybpc3. The snippet keeps the source's spelling; this entry's curator-written fields use mybpc3.

Tet-Off conditional cMyBP-C re-expression mouse (MYBPC3 null background)

A conditional model that titrates cMyBP-C up and down in the adult heart on a null background. Withdrawing cMyBP-C reproduced the null contractile phenotype and restoring it recovered ventricular function, establishing that the cardiac consequences of cMyBP-C absence are a maintained-state deficit rather than an irreversible lesion, at least for the adult contractile phenotype.

Species

Mouse

Genotype

MYBPC3 null background carrying a doxycycline-regulated wild-type cMyBP-C transgene

Genes

MYBPC3 hgnc:7551

Publication

PMID:30573635

Pathograph links

MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion rescues fidelity: moderate observes: organism Controlled re-expression of wild-type cMyBP-C on the null background recovered ventricular function, showing the phenotype tracks the current protein level rather than a fixed consequence of having lacked it.

Limitations: The reversibility demonstrated is of the adult contractile and hypertrophic phenotype. LVNC10's defining lesion is a developmental failure of ventricular compaction laid down before birth, and nothing in this model tests whether that is reversible; a compaction defect could well be fixed even where contractile function is not. Knockdown was also partial rather than complete.

Divergences from the human mechanism

temporal scope qualifying

The manipulation and the readout both sit in the adult heart, after ventricular compaction is complete. That bounds what the reversibility result covers - the contractile consequences of the protein-depletion node, not the developmental compaction defect downstream of it, which would need a separate link to the compaction node to claim. QUALIFYING rather than INVALIDATING because it bounds this link's claim rather than undermining it.

species mismatch qualifying

Murine cardiac maturation and the postnatal timing of compaction differ from human, and the transgene is a wild-type mouse-heart construct rather than a corrected human allele.

Readouts

In vivo left ventricular function after cMyBP-C re-expression

Systolic and diastolic ventricular function measured after doxycycline withdrawal restored cMyBP-C to wild-type levels.

Direction: RESTORED

Interpretation: Function tracks current cMyBP-C level, supporting a maintained-state rather than irreversible reading of the protein-depletion node.

Show evidence (1 reference)

PMID:30573635 SUPPORT Model Organism

"These results show that the cardiac phenotypes associated with MYBPC3 null mice are reversible."

States the reversibility result this readout records.

Show evidence (1 reference)

PMID:30573635 SUPPORT Model Organism

"The loss of cardiac myosin binding protein C (cMyBP-C) results in left ventricular dilation, cardiac hypertrophy, and impaired ventricular function in both constitutive and conditional cMyBP-C knockout (MYBPC3 null) mice."

Establishes the baseline null phenotype the conditional system is built on.

{ }

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.
  - reference: PMID:41488457
    reference_title: "Case Report: Lethal neonatal hypertrophic cardiomyopathy from compound heterozygous MYBPC3 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bi-allelic pathogenic variants in MYBPC3 cause a rare and lethal
      neonatal form of hypertrophic cardiomyopathy (HCM) that often evades
      detection during routine prenatal screening.
    explanation: >-
      A 2025 autopsy-confirmed compound heterozygous case, a decade after the
      founding series, restating the link from biallelic genotype to lethal
      neonatal disease that defines this subtype. Its cardiac phenotype is
      described as hypertrophic rather than noncompacted, which is why it is
      cited for the allelic configuration and lethality rather than for the
      noncompaction phenotype. INDIRECT on two counts: the quoted sentence is
      the paper's introductory framing of the entity rather than a finding of
      its own case, and the case it reports is hypertrophic.
    directness: INDIRECT
- 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: >-
      Support with a caveat: 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
    hypothesis_groups:
    - sarcomeric_dose_continuum
    - cytokinesis_brake_release
    description: >-
      Near-complete biallelic loss of cMyBP-C is the allelic state most
      consistently linked to failure of normal trabecular-to-compact
      myocardial remodeling. This is the edge the two mechanistic hypotheses
      disagree about: whether it is the low end of one quantitative gradient
      or a qualitatively distinct developmental route.
    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: >-
        States the genotype-to-phenotype step this edge asserts: it is the
        biallelic (near-complete cMyBP-C loss) genotype specifically, and not
        the heterozygous one, that produces the noncompaction phenotype.
  - 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.
    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: >-
        Quantifies the septal/ductal anomalies as accompanying the
        cardiomyopathy across the pooled biallelic cohort, which is the
        association this edge draws. The source reports co-occurrence within
        the biallelic genotype rather than demonstrating the developmental
        step, hence INDIRECT.
      directness: INDIRECT
  - 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.
    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: >-
        Supports the edge from the MYBPC3 lesion to the milder,
        noncompaction-with-hypertrophy state: within a family-screening cohort
        this specific phenotype subgroup, and not noncompaction generally, is
        the one that tracks with MYBPC3. A cohort co-occurrence statistic is
        not a demonstration of the causal step, hence INDIRECT.
      directness: INDIRECT
- 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.
    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: >-
        Noncompaction was diagnosed in three of the four neonates (not excluded
        in the fourth) and all four died of cardiac failure within the first
        three months, which is the outcome this edge asserts. The source establishes the sequence within one
        cohort rather than isolating noncompaction as the cause, hence
        INDIRECT.
      directness: INDIRECT
- 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.
    evidence:
    - reference: PMID:41488457
      reference_title: "Case Report: Lethal neonatal hypertrophic cardiomyopathy from compound heterozygous MYBPC3 variants."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Postmortem examination revealed severe HCM, an atrial septal defect
        (ASD), and extensive myocardial necrosis and fibrosis.
      explanation: >-
        An autopsy-confirmed compound heterozygous MYBPC3 infant who died of
        acute heart failure carried a septal defect alongside the myocardial
        disease, supporting the septal anomaly as part of the structural
        burden feeding the fatal neonatal presentation. The autopsy does not
        apportion the hemodynamic contribution between the septal defect and
        the myocardial disease, hence INDIRECT.
      directness: INDIRECT
- 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.
  - reference: PMID:41488457
    reference_title: "Case Report: Lethal neonatal hypertrophic cardiomyopathy from compound heterozygous MYBPC3 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Postmortem examination revealed severe HCM, an atrial septal defect
      (ASD), and extensive myocardial necrosis and fibrosis.
    explanation: >-
      The one biallelic MYBPC3 case in this entry that names which septal
      defect it was: an atrial septal defect, found at autopsy. One case does
      not settle the atrial-versus-ventricular distribution across the
      literature cohort, so the phenotype stays bound at the general
      HP:0001671 level, with this recorded as the first specific instance.
      Note the same caveat that applies wherever this paper is cited here: its
      cardiac phenotype is hypertrophic, not noncompacted, so it is evidence
      for the septal anomaly accompanying a biallelic MYBPC3 genotype and not
      for a septal anomaly accompanying noncompaction.
    directness: INDIRECT
- 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.

    ClinGen has never curated a MYBPC3-LVNC gene-disease relationship. What it
    has curated is the pair of relationships either side of this entity: an AD
    MYBPC3-hypertrophic-cardiomyopathy relationship classified Definitive,
    and - separately, and directly covering the biallelic regime this entry
    models - an AR MYBPC3-dilated-cardiomyopathy relationship classified only
    Limited. Because OMIM files LVNC10 with "cardiomyopathy, dilated, 1MM"
    under one MIM number, that AR/Limited row is the closest thing to an
    expert-panel verdict on the genotype curated here, and it is a weak one.
    Both assertions are cited below.
  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). It qualifies
      rather than refutes the gene-disease relationship.
    directness: INDIRECT
  - reference: CGGV:assertion_7e65896e-33f5-439d-8749-aba08a539dd0-2021-10-07T160000.000Z
    reference_title: "MYBPC3 / hypertrophic cardiomyopathy (Definitive)"
    supports: NO_EVIDENCE
    evidence_source: OTHER
    snippet: >-
      MYBPC3 | HGNC:7551 | hypertrophic cardiomyopathy | MONDO:0005045 | AD |
      Definitive | SOP8 | Hereditary Cardiovascular Disease Gene Curation
      Expert Panel | 2021-10-07T16:00:00.000Z
    explanation: >-
      NO_EVIDENCE, deliberately: a Definitive MYBPC3-hypertrophic-cardiomyopathy
      curation says nothing either way about MYBPC3 causing noncompaction. It
      is carried because the contrast is the point - this is the strength of
      evidence MYBPC3 carries for the phenotype it is actually established for,
      against which the noncompaction claims in this entry should be read, and
      leaving it out would make the AR/DCM row below look like the whole
      ClinGen picture.
  - reference: CGGV:assertion_f240fb99-f839-4b9b-8e52-f2dc49078886-2025-05-16T040000.000Z
    reference_title: "MYBPC3 / dilated cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MYBPC3 | HGNC:7551 | dilated cardiomyopathy | MONDO:0005021 | AR |
      Limited | SOP10 | Dilated Cardiomyopathy Gene Curation Expert Panel |
      2025-05-16T04:00:00.000Z
    explanation: >-
      ClinGen's autosomal recessive MYBPC3 curation - the allelic regime this
      entry models - reaches only Limited as of May 2025. Since OMIM groups
      LVNC10 with CMD1MM under one MIM number, this is the nearest
      expert-panel assessment of the biallelic genotype curated here, and it
      supports the caveat in the notes above rather than the strength of the
      founding pedigree evidence.
    directness: INDIRECT
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: >-
      Identifies the MYBPC3-associated NCCM+HCM subgroup within a
      family-screening cohort in which relatives carrying the variant show
      variable, incompletely penetrant cardiac phenotypes. The cohort
      association supports dominant transmission with incomplete penetrance by
      inference rather than reporting a segregation analysis, hence INDIRECT.
    directness: INDIRECT
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.
progression:
- phase: Neonatal presentation
  subtype: Biallelic MYBPC3 LVNC
  age_range: First weeks of life
  notes: >-
    The biallelic form declares itself in the newborn period with feeding
    difficulties, failure to thrive and dyspnea, alongside noncompaction on
    imaging and congenital septal or ductal anomalies. A presymptomatic window
    does exist - one autopsy-confirmed compound heterozygous infant passed
    routine prenatal screening and was discharged as healthy before collapsing
    at two months - but no screening interval or modality has been shown to
    use it. Whether the window is long enough to act on is unresolved rather
    than settled either way.
  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: >-
      Describes the presenting phase of the biallelic form and its timing.
- phase: Fatal cardiac failure
  subtype: Biallelic MYBPC3 LVNC
  age_range: Within the first few months of life
  notes: >-
    Progression from presentation to death is measured in weeks. In the
    founding series all four infants died before 13 weeks, and across the
    pooled literature cohort every reported biallelic patient had severe
    cardiomyopathy or died within the first few months. Heart transplantation
    is the one reported alternative endpoint.
  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 outcome and its timescale across the whole reported cohort,
      not only the four index cases.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    For the biallelic form the burden is maximal and brief: uniform severe
    cardiomyopathy or death within months of birth across every case reported
    up to 2015, with transplantation the only alternative endpoint documented.
    The monoallelic form is a different burden question entirely and is
    governed by the MYBPC3 hypertrophic cardiomyopathy literature rather than
    by anything specific to noncompaction; this HIGH rating is set by the
    biallelic subtype that defines the entity.
  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: >-
      Uniform severe outcome across the complete reported cohort is what sets
      the burden level.
mechanistic_hypotheses:
- hypothesis_group_id: sarcomeric_dose_continuum
  hypothesis_label: Graded cMyBP-C dose sets position on one sarcomeric-cardiomyopathy continuum
  status: CANONICAL
  description: >-
    The prevailing reading of MYBPC3 genotype-phenotype relations: hypertrophic,
    noncompaction, restrictive and dilated presentations are positions on a
    single continuum, and residual functional cMyBP-C is the variable that sets
    which one a carrier occupies: a single truncating allele gives adult
    hypertrophic disease, a biallelic genotype gives severe neonatal disease
    with noncompaction and septal defects. On this account nothing
    qualitatively different happens at the low-dose end, and the LVNC phenotype
    is what severe sarcomeric insufficiency looks like when it strikes during
    cardiac development.

    Only one point on that curve is actually measured anywhere in this entry:
    approximately 20% residual cMyBP-C in affected cardiac tissue from a
    compound heterozygote carrying a loss-of-function allele in trans with an
    unstable missense allele. That is one genotype, not the truncating/
    truncating configuration the biallelic subtype is defined by, and no
    residual-protein figure is available for the heterozygous state or for
    truncating homozygotes. The half-dose expectation that the model rests on
    is a haploinsufficiency inference, and the isogenic
    premature-termination-codon iPSC-CMs curated under `experimental_models`
    cut against it directly: MYBPC3 transcript fell while protein did not. The
    model's other weakness is that it explains a severity gradient without
    explaining a change in kind, and one family carrying a single allele can
    display three different phenotypes among its members.
  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: >-
      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 continuum model directly, in a family where one allele
      produced three different phenotypes.
  - 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: >-
      Supplies the quantitative anchor the continuum model needs: a measured
      residual protein level in the severe noncompaction case, against the
      ~50% expected of a heterozygous carrier.
- hypothesis_group_id: cytokinesis_brake_release
  hypothesis_label: Near-complete cMyBP-C loss releases an inhibitory brake on postnatal myocyte cytokinesis
  status: EMERGING
  description: >-
    A mechanistically distinct account of why the low-dose end diverges in kind
    rather than only in degree. In homozygous cMyBP-C-deficient mice, myocytes
    complete an extra round of division after birth and accumulate as
    supernumerary mononuclear cells; the heart enlarges by hyperplasia, whereas
    the heterozygous state enlarges it by hypertrophy. The authors conclude that
    cMyBP-C normally inhibits postnatal myocyte cytokinesis. If that inhibition
    is dose-sensitive, near-complete loss would extend the proliferative window
    across precisely the period in which the ventricle finishes converting
    trabecular to compact myocardium, offering a route from a quantitative
    protein deficit to a qualitatively different developmental outcome. This is
    a hypothesis about the human disease, not a finding in it: the mice develop
    dilation, not noncompaction, and no compaction measurement is reported. A
    zebrafish cMyBP-C knockout shows the same cardiomyocyte hyperplasia, so
    the proliferative response is at least conserved rather than murine. That
    strengthens the first half of the hypothesis and cuts against the second:
    in the fish the extra cardiomyocytes accompany a thicker, more compact
    ventricular wall, which is the opposite of a compaction failure. Whatever
    routes hyperplasia to noncompaction in humans, if anything does, is not
    supplied by either model.
  evidence:
  - reference: PMID:26153423
    reference_title: "Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      However, the mechanism leading to hypertrophic cardiomyopathy in
      heterozygous MYBPC3(+/-) individuals is myocyte hypertrophy (increased
      cell size), whereas the mechanism leading to cardiac dilation in
      homozygous Mybpc3(-/-) mice is primarily myocyte hyperplasia.
    explanation: >-
      The mono- versus bi-allelic divergence in cellular mechanism that this
      hypothesis generalizes from.
  - reference: PMID:36012114
    reference_title: "Transcriptome Profile Identifies Actin as an Essential Regulator of Cardiac Myosin Binding Protein C3 Hypertrophic Cardiomyopathy in a Zebrafish Model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Immunofluorescence staining revealed significant hyperplasia in the
      mutant's total cardiac and ventricular cardiomyocytes.
    explanation: >-
      Cross-species replication in a zebrafish cMyBP-C knockout. Hyperplasia
      arising independently in fish and mouse argues the proliferative response
      is a conserved consequence of losing cMyBP-C rather than a murine
      artifact, which is what this hypothesis needs to be worth testing in
      human tissue. It does not carry the hypothesis's second half: in this
      model the extra cardiomyocytes accompany a thicker, more compact wall,
      so hyperplasia here is not producing a compaction failure. Hence
      INDIRECT.
    directness: INDIRECT
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: >-
        Establishes what this link claims and does not claim: the
        pharmacotherapy acts on the heart-failure node downstream of the
        compaction defect, not on the compaction defect itself. The quote
        establishes that only symptomatic treatment exists; that it acts on
        this particular node is the inference, hence INDIRECT.
      directness: INDIRECT
  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: >-
        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 transplantation being reached for in a compound heterozygous
        MYBPC3 case whose indication was the noncompaction phenotype itself,
        which is the mechanism node this link targets.
  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.
      INDIRECT because this is general LVNC-imaging-trait evidence rather than
      MYBPC3/LVNC10-specific; evidence source is OTHER because this is a
      narrative review, not a primary clinical study.
    directness: INDIRECT
- 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.
animal_models:
- name: Homozygous cMyBP-C-deficient mouse (Mybpc3 t/t)
  species: Mouse
  genotype: Mybpc3 t/t (homozygous cardiac myosin binding protein C-deficient)
  publication: PMID:26153423
  genes:
  - preferred_term: MYBPC3
    term:
      id: hgnc:7551
      label: MYBPC3
  description: >-
    The homozygous cMyBP-C-deficient mouse is the murine counterpart of the
    biallelic MYBPC3 allelic state that defines LVNC10, and is the only model
    in this entry that offers a candidate mechanism for the dose-phenotype
    divergence recorded in the open discussion below. These mice enlarge their
    hearts almost twofold shortly after birth, and the enlargement is driven
    by myocyte hyperplasia rather than hypertrophy: cMyBP-C-null myocytes
    complete an extra round of postnatal cell division and accumulate as
    supernumerary mononuclear cells, whereas the heterozygous state produces
    hypertrophy through increased cell size. The authors propose that cMyBP-C
    normally acts as an inhibitor of postnatal myocyte cytokinesis, so that
    near-complete loss releases a proliferative program at exactly the window
    in which the mammalian ventricle is finishing its trabecular-to-compact
    remodeling.
  evidence:
  - reference: PMID:26153423
    reference_title: "Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      MYBPC has unexpected inhibitory functions during postnatal myocyte
      cytokinesis and cell cycle progression.
    explanation: >-
      States the model's central mechanistic finding, which is what makes it
      informative for the allelic-dose question this entry models rather than
      merely another sarcomeric-cardiomyopathy mouse.
  modeled_mechanisms:
  - target: MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      The homozygous null genotype reproduces the allelic state the biallelic
      human genotype produces, and the paper makes the mono- versus bi-allelic
      dose contrast explicitly.
    limitations: >-
      Neither the cited abstract nor this entry has a residual-protein figure
      for the mouse, so "near-complete depletion" is inferred from the null
      genotype rather than measured; the readout available is gross cardiac
      enlargement, an organ-level proxy standing in for a molecular node. The
      mouse also survives to adulthood, where the equivalent human genotype is
      fatal within months.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The measured quantity is postnatal heart size. The node's quantity is
        residual functional cMyBP-C protein, which this report does not
        quantify in either species.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The murine allele is a targeted truncation rather than one of the human
        MYBPC3 alleles curated here, and the mouse tolerates the null state
        into adulthood where human biallelic carriers do not survive infancy.
    readouts:
    - name: Postnatal heart size
      target: MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion
      description: >-
        Gross cardiac enlargement measured in homozygous null mice shortly
        after birth, against wild-type littermates.
      direction: INCREASED
      interpretation: >-
        An organ-level proxy for the molecular node: it confirms the null
        genotype produces an overt cardiac phenotype in the neonatal window,
        matching the timing of the human biallelic presentation, but it does
        not measure residual cMyBP-C.
      evidence:
      - reference: PMID:26153423
        reference_title: "Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Homozygous cardiac myosin binding protein C-deficient (Mybpc(t/t))
          mice develop dramatic cardiac dilation shortly after birth; heart
          size increases almost twofold.
        explanation: >-
          Reports the measured cardiac enlargement and its postnatal timing in
          the homozygous null model.
    evidence:
    - reference: PMID:26153423
      reference_title: "Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We suggest that human patients with homozygous MYBPC3-null mutations
        develop dilated cardiomyopathy, coupled with myocyte hyperplasia
        (increased cell number), as observed in Mybpc(t/t) mice.
      explanation: >-
        The authors themselves position the homozygous null mouse as the model
        of the human biallelic MYBPC3-null state, which is the node this link
        targets.
  - target: Dose-Dependent Failure of Myocardial Compaction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      The model reproduces the allelic dose and the neonatal timing of the
      human compaction phenotype, and supplies a cellular mechanism -
      failure of postnatal myocyte cell-cycle exit - that could plausibly
      divert ventricular wall maturation. It does not reproduce the
      noncompaction phenotype itself.
    limitations: >-
      The mouse phenotype is cardiac dilation with myocyte hyperplasia, not a
      persistently hypertrabeculated, noncompacted ventricular wall; the
      abstract reports no trabecular-to-compact remodeling measurement.
      Homozygous null mice also survive into adulthood, where the human
      biallelic genotype is lethal within months. Treating the cytokinesis
      finding as the explanation of human compaction failure is an inference
      the cited work does not make.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The measured quantity is the number of postnatal myocyte divisions and
        the resulting count of mononuclear myocytes. The node's quantity is
        the extent of trabecular-to-compact remodeling of the ventricular
        wall. Extra cell divisions are a candidate upstream cause of a
        compaction defect, not a measurement of one.
    - divergence_type: SCALE_EXTRAPOLATION
      materiality: QUALIFYING
      description: >-
        The model observes cell-cycle behaviour in individual cardiomyocytes
        (CELLULAR); the node is the tissue-level architecture of the
        ventricular wall (TISSUE). The step from supernumerary myocytes to a
        noncompacted wall is not observed in this model.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Murine and human ventricular compaction differ in timing relative to
        birth, and the mouse null survives to adulthood while the equivalent
        human genotype is fatal in the first months of life, so the
        postnatal-proliferation window the model exploits may not be the
        window in which the human phenotype is set.
    readouts:
    - name: Mononuclear cardiomyocyte number in the postnatal window
      target: Dose-Dependent Failure of Myocardial Compaction
      description: >-
        Count of myocytes completing an additional postnatal division within
        10 days of birth, compared with wild-type littermates.
      biological_processes:
      - preferred_term: cardiac muscle cell proliferation
        term:
          id: GO:0060038
          label: cardiac muscle cell proliferation
        modifier: INCREASED
      direction: INCREASED
      interpretation: >-
        The cellular readout standing in for the compaction node: extended
        postnatal proliferation is the model's proposed route from cMyBP-C
        loss to abnormal ventricular wall maturation.
      evidence:
      - reference: PMID:26153423
        reference_title: "Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          We demonstrate that many Mybpc(t/t) myocytes undergo an additional
          round of cell division within 10 d postbirth compared with their
          wild-type counterparts, leading to increased numbers of mononuclear
          myocytes.
        explanation: >-
          Reports the measurement and its direction directly.
    evidence:
    - reference: PMID:26153423
      reference_title: "Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        However, the mechanism leading to hypertrophic cardiomyopathy in
        heterozygous MYBPC3(+/-) individuals is myocyte hypertrophy (increased
        cell size), whereas the mechanism leading to cardiac dilation in
        homozygous Mybpc3(-/-) mice is primarily myocyte hyperplasia.
      explanation: >-
        This is the sentence that makes the model informative for this node:
        it establishes that the same protein deficit reaches a qualitatively
        different cellular endpoint depending on allelic dose, which is the
        dose-dependence the node asserts. It is cited for the dose principle,
        not as evidence of noncompaction, which the model does not show.
      directness: INDIRECT
- name: Mybpc3-targeted knock-in mouse (homozygous exon 6 G>A)
  species: Mouse
  genotype: Mybpc3 knock-in, homozygous G>A transition in exon 6
  publication: PMID:23716398
  genes:
  - preferred_term: MYBPC3
    term:
      id: hgnc:7551
      label: MYBPC3
  description: >-
    A homozygous Mybpc3 knock-in mouse carrying a single point mutation that
    generates three aberrant mRNAs, developed as a hypertrophic-cardiomyopathy
    model but genotypically in the biallelic regime this entry curates. It is
    included here for the therapeutic arm: AAV-delivered U7snRNA antisense
    constructs that mask splicing enhancers in exons 5 and 6 shifted splicing
    toward a functional variant and, injected in newborns, abolished cardiac
    dysfunction and prevented hypertrophy. This is the only demonstration in
    this entry that a biallelic Mybpc3 cardiac phenotype is preventable if the
    protein deficit is corrected in the neonatal window.
  evidence:
  - reference: PMID:23716398
    reference_title: "Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      KI mice carry a homozygous G>A transition in exon 6, which results in
      three different aberrant mRNAs.
    explanation: >-
      Establishes the model's homozygous genotype and its aberrant-transcript
      consequence, placing it in the biallelic allelic regime.
  modeled_mechanisms:
  - target: Neonatal Structural Cardiac Failure
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Neonatal AAV-U7-AON treatment prevented the cardiac dysfunction and
      hypertrophy that this homozygous Mybpc3 genotype otherwise produces,
      establishing the neonatal window as a point of intervention on the
      organ-level failure node.
    limitations: >-
      The rescued phenotype is hypertrophy with cardiac dysfunction, not
      noncompaction, so the experiment shows that a biallelic Mybpc3 cardiac
      phenotype is correctable rather than that the human LVNC10 compaction
      defect specifically is. The authors also report the effect as transient
      and requiring optimization, and the construct is exon-6-specific, so it
      would not transfer to the human truncating alleles curated in this
      entry without redesign.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The corrected lesion is a mouse exon-6 splice-shifting point mutation.
        The human LVNC10 alleles are frameshift and nonsense variants
        distributed across the gene, for which this exon-skipping strategy
        offers no direct route.
    - divergence_type: TEMPORAL_SCOPE
      materiality: QUALIFYING
      description: >-
        The rescue is reported as transient, so the experiment bounds a
        short-term prevention window and says nothing about durable
        correction of the organ-level failure node.
    readouts:
    - name: Left ventricular hypertrophy and cardiac function after neonatal AAV-U7-AON
      target: Neonatal Structural Cardiac Failure
      description: >-
        Cardiac function and left ventricular hypertrophy assessed in
        homozygous KI mice injected as newborns with AAV-U7-AON-5+6.
      direction: RESTORED
      interpretation: >-
        Prevention of the organ-level failure phenotype when the protein
        deficit is corrected neonatally.
      evidence:
      - reference: PMID:23716398
        reference_title: "Rescue of cardiomyopathy through U7snRNA-mediated exon skipping in Mybpc3-targeted knock-in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Injection of newborn KI mice abolished cardiac dysfunction and
          prevented left ventricular hypertrophy.
        explanation: >-
          Reports the measured rescue and its neonatal timing.
- name: Compound heterozygous MYBPC3 cloned pig
  species: Pig
  genotype: MYBPC3 compound heterozygous (CRISPR/Cas9 edited, somatic cell nuclear transfer)
  publication: PMID:40496056
  genes:
  - preferred_term: MYBPC3
    term:
      id: hgnc:7551
      label: MYBPC3
  description: >-
    A large-animal attempt at the biallelic MYBPC3 state. The edited piglet
    carried a compound heterozygous genotype, expressed markedly reduced
    mutant MYBPC3 protein, and developed cardiac hypertrophy, but the
    pregnancies yielded non-viable piglets that died around birth. The model
    therefore reproduces the perinatal lethality of human biallelic MYBPC3
    disease in a species with human-like cardiac size and physiology, while
    supplying no postnatal course.
  evidence:
  - reference: PMID:40496056
    reference_title: "Perinatal death in pig models of hypertrophic cardiomyopathy carrying sarcomere pathogenic variants."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The MYBPC3-edited piglet exhibited a compound heterozygous mutation
      leading to a markedly low level of mutant MYBPC3 protein and cardiac
      hypertrophy, reflecting the situation in infants.
    explanation: >-
      Establishes the biallelic genotype, the reduced protein level, and the
      authors' own framing of the model as reflecting the human infantile
      presentation.
  modeled_mechanisms:
  - target: Neonatal Structural Cardiac Failure
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Perinatal death with cardiac disease reproduces the lethal timing of the
      human biallelic phenotype in a large animal.
    limitations: >-
      The reported cardiac phenotype is hypertrophy; no noncompaction,
      hypertrabeculation, or septal defect is described. Only a single edited
      MYBPC3 piglet is reported, and cloning by somatic cell nuclear transfer
      independently causes perinatal loss, so the death cannot be attributed
      to the genotype alone. The authors' own conclusion is that pigs are
      unusually sensitive to sarcomeric variants, which is itself a caution
      against reading the timing across to humans.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The paper concludes that pigs are particularly sensitive to sarcomeric
        gene mutations, so the perinatal lethality may reflect porcine
        sensitivity rather than the severity of the human genotype.
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        A single cloned MYBPC3-edited piglet, produced by somatic cell nuclear
        transfer, which carries its own perinatal-loss risk that is not
        separated from the genotype effect here.
    readouts:
    - name: Perinatal survival of MYBPC3-edited cloned piglets
      target: Neonatal Structural Cardiac Failure
      description: >-
        Viability of cloned piglets carrying edited sarcomeric genotypes.
      direction: DECREASED
      interpretation: >-
        Death around birth is the organism-level correlate of the human
        neonatal failure node.
      evidence:
      - reference: PMID:40496056
        reference_title: "Perinatal death in pig models of hypertrophic cardiomyopathy carrying sarcomere pathogenic variants."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In conclusion, MYBPC3 and MYH7 cloned piglets developed cardiac
          hypertrophy and died around birth, indicating that pigs are
          particularly sensitive to sarcomeric gene mutations.
        explanation: >-
          Reports both the outcome and the authors' species-sensitivity
          caveat in one sentence.
- name: mybpc3 knockout zebrafish
  species: Zebrafish
  genotype: mybpc3 stable knockout (heterozygous and homozygous)
  publication: PMID:36012114
  genes:
  - preferred_term: MYBPC3
    term:
      id: hgnc:7551
      label: MYBPC3
  description: >-
    A stable zebrafish knockout of the cMyBP-C orthologue, built as a
    hypertrophic-cardiomyopathy model but carrying the finding that matters
    most to this entry: immunofluorescence shows significant cardiomyocyte
    hyperplasia in mutant hearts at the larval stage (608 vs 302 total
    cardiomyocyte nuclei), with myocardial remodeling and hyperplasia
    persisting into later larval development. That is the same cellular
    response the homozygous cMyBP-C-deficient mouse shows, reached
    independently in a teleost, which is the strongest support this entry
    carries for treating hyperplasia as a conserved consequence of cMyBP-C
    loss rather than a murine idiosyncrasy.

    The direction of the wall phenotype is the point to keep hold of. Zebrafish
    do form a compact ventricular myocardium over a trabecular layer, and this
    knockout does not fail to compact it - the mutant ventricle and atrium
    became *more* compact, with a thicker myocardial wall and smaller chamber
    diameters. So the one model here that could in principle have shown a
    compaction defect showed the opposite.
  evidence:
  - reference: PMID:36012114
    reference_title: "Transcriptome Profile Identifies Actin as an Essential Regulator of Cardiac Myosin Binding Protein C3 Hypertrophic Cardiomyopathy in a Zebrafish Model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      To investigate the c-MYBPC3 HCM-related cardiac impairment, we generated
      a zebrafish mypbc3-knockout model.
    explanation: >-
      Establishes the model and its knockout genotype. Quoted verbatim: the
      paper's abstract misspells the gene as "mypbc3" throughout, while its own
      results section uses the correct zebrafish symbol mybpc3. The snippet
      keeps the source's spelling; this entry's curator-written fields use
      mybpc3.
  modeled_mechanisms:
  - target: MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Homozygous knockout of the cMyBP-C orthologue reproduces the
      protein-loss state and yields cardiomyocyte hyperplasia, matching the
      murine null.
    limitations: >-
      The zebrafish heart is two-chambered and the gene is an orthologue rather
      than human MYBPC3, so the model speaks to conserved cMyBP-C cell biology
      and not to human ventricular architecture. Its wall phenotype runs
      opposite to the human one: the mutant ventricle is more compact and
      thicker-walled, not hypertrabeculated.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The zebrafish heart has two chambers, and its compact ventricular
        myocardium responds to cMyBP-C loss by thickening rather than by
        failing to form. Human ventricular wall architecture, and the direction
        in which it fails in this entity, have no counterpart here.
    readouts:
    - name: Cardiac and ventricular cardiomyocyte number
      target: MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion
      description: >-
        Immunofluorescence counts of total cardiac and ventricular
        cardiomyocytes in mybpc3-knockout larvae against wild-type controls.
      biological_processes:
      - preferred_term: cardiac muscle cell proliferation
        term:
          id: GO:0060038
          label: cardiac muscle cell proliferation
        modifier: INCREASED
      direction: INCREASED
      interpretation: >-
        Independent, cross-species replication of the cardiomyocyte hyperplasia
        that the homozygous cMyBP-C-deficient mouse shows.
      evidence:
      - reference: PMID:36012114
        reference_title: "Transcriptome Profile Identifies Actin as an Essential Regulator of Cardiac Myosin Binding Protein C3 Hypertrophic Cardiomyopathy in a Zebrafish Model."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Immunofluorescence staining revealed significant hyperplasia in the
          mutant's total cardiac and ventricular cardiomyocytes.
        explanation: >-
          Reports the measurement, the method, and its direction.
    - name: Ventricular wall compaction and thickness
      target: MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion
      description: >-
        Gross morphology of the mutant ventricle and atrium at 72 hours
        post-fertilization, against wild-type controls.
      direction: ALTERED
      interpretation: >-
        The wall changes in the direction opposite to human noncompaction. This
        readout is recorded because a null result would have been informative
        and the actual result is informative against the model, not for it.
      evidence:
      - reference: PMID:36012114
        reference_title: "Transcriptome Profile Identifies Actin as an Essential Regulator of Cardiac Myosin Binding Protein C3 Hypertrophic Cardiomyopathy in a Zebrafish Model."
        supports: REFUTE
        evidence_source: MODEL_ORGANISM
        snippet: >-
          The mybpc3 KO zebrafish heart displayed cardiac structural changes as
          it was notable that the ventricles and atria became more compact
          compared to the controls
        explanation: >-
          REFUTE against the proposition that this model recapitulates the
          human wall phenotype: cMyBP-C loss here makes the ventricle more
          compact, where the human biallelic genotype leaves it noncompacted.
          This is the strongest single datum behind the HUMAN_MODEL_MISMATCH
          discussion below.
- name: Tet-Off conditional cMyBP-C re-expression mouse (MYBPC3 null background)
  species: Mouse
  genotype: MYBPC3 null background carrying a doxycycline-regulated wild-type cMyBP-C transgene
  publication: PMID:30573635
  genes:
  - preferred_term: MYBPC3
    term:
      id: hgnc:7551
      label: MYBPC3
  description: >-
    A conditional model that titrates cMyBP-C up and down in the adult heart
    on a null background. Withdrawing cMyBP-C reproduced the null contractile
    phenotype and restoring it recovered ventricular function, establishing
    that the cardiac consequences of cMyBP-C absence are a maintained-state
    deficit rather than an irreversible lesion, at least for the adult
    contractile phenotype.
  evidence:
  - reference: PMID:30573635
    reference_title: "Recovery of left ventricular function following in vivo reexpression of cardiac myosin binding protein C."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The loss of cardiac myosin binding protein C (cMyBP-C) results in left
      ventricular dilation, cardiac hypertrophy, and impaired ventricular
      function in both constitutive and conditional cMyBP-C knockout (MYBPC3
      null) mice.
    explanation: >-
      Establishes the baseline null phenotype the conditional system is built
      on.
  modeled_mechanisms:
  - target: MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Controlled re-expression of wild-type cMyBP-C on the null background
      recovered ventricular function, showing the phenotype tracks the current
      protein level rather than a fixed consequence of having lacked it.
    limitations: >-
      The reversibility demonstrated is of the adult contractile and
      hypertrophic phenotype. LVNC10's defining lesion is a developmental
      failure of ventricular compaction laid down before birth, and nothing
      in this model tests whether that is reversible; a compaction defect
      could well be fixed even where contractile function is not. Knockdown
      was also partial rather than complete.
    divergences:
    - divergence_type: TEMPORAL_SCOPE
      materiality: QUALIFYING
      description: >-
        The manipulation and the readout both sit in the adult heart, after
        ventricular compaction is complete. That bounds what the reversibility
        result covers - the contractile consequences of the protein-depletion
        node, not the developmental compaction defect downstream of it, which
        would need a separate link to the compaction node to claim. QUALIFYING
        rather than INVALIDATING because it bounds this link's claim rather
        than undermining it.
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Murine cardiac maturation and the postnatal timing of compaction
        differ from human, and the transgene is a wild-type mouse-heart
        construct rather than a corrected human allele.
    readouts:
    - name: In vivo left ventricular function after cMyBP-C re-expression
      target: MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion
      description: >-
        Systolic and diastolic ventricular function measured after doxycycline
        withdrawal restored cMyBP-C to wild-type levels.
      direction: RESTORED
      interpretation: >-
        Function tracks current cMyBP-C level, supporting a maintained-state
        rather than irreversible reading of the protein-depletion node.
      evidence:
      - reference: PMID:30573635
        reference_title: "Recovery of left ventricular function following in vivo reexpression of cardiac myosin binding protein C."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          These results show that the cardiac phenotypes associated with
          MYBPC3 null mice are reversible.
        explanation: >-
          States the reversibility result this readout records.
experimental_models:
- name: Biallelic MYBPC3 truncating hiPSC line with isogenic control
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cell_source: Skin fibroblasts from a hypertrophic cardiomyopathy patient carrying a heterozygous MYBPC3 truncating variant
  publication: PMID:34375846
  description: >-
    The only human system in this entry that reaches the biallelic MYBPC3
    genotype LVNC10 requires. CRISPR/Cas9 was used to convert a patient hiPSC
    line carrying one truncating MYBPC3 allele into a bi-allelic truncating
    line, alongside an isogenic corrected control, giving a three-line set in
    which allelic dose is the only variable. All three lines differentiate
    into cardiomyocytes.
  evidence:
  - reference: PMID:34375846
    reference_title: "Generation of bi-allelic MYBPC3 truncating mutant and isogenic control from an iPSC line of a patient with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Bi-allelic truncating MYBPC3 mutations are associated with severe forms
      of neonatal cardiomyopathy.
    explanation: >-
      The authors' stated rationale for building the biallelic line is the
      neonatal disease this entry curates, which is what makes the resource
      relevant here rather than to the HCM entry alone.
  modeled_mechanisms:
  - target: MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Reproduces the human biallelic truncating genotype in human
      cardiomyocytes with an isogenic control, which is the allelic
      configuration this node describes.
    limitations: >-
      This is a resource report. It establishes pluripotency, karyotype and
      three-germ-layer plus cardiomyocyte differentiation, and reports no
      cMyBP-C protein quantification and no disease phenotype, so it
      substantiates the genotype arm of this node and not the protein-depletion
      arm. hiPSC-derived cardiomyocytes are also fetal-like and
      two-dimensional, with no ventricular wall in which compaction could be
      assessed.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        Residual cMyBP-C protein level, the quantity the node turns on, is not
        measured in this report; only the genotype and the line's
        differentiation capacity are established.
    evidence:
    - reference: PMID:34375846
      reference_title: "Generation of bi-allelic MYBPC3 truncating mutant and isogenic control from an iPSC line of a patient with hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We reprogrammed skin fibroblasts from a HCM patient carrying a
        heterozygous MYBPC3 truncating mutation into human induced pluripotent
        stem cells (iPSC) and used CRISPR/Cas9 to generate bi-allelic MYBPC3
        truncating mutation and isogenic control hiPSC lines.
      explanation: >-
        Establishes that the line reaches the biallelic truncating genotype
        this node describes, and that an isogenic control exists to attribute
        any future phenotype to allelic dose.
- name: Isogenic hiPSC-cardiomyocytes carrying MYBPC3 premature termination codon variants
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cell_source: Genome-edited isogenic iPSC lines from hypertrophic cardiomyopathy patients carrying MYBPC3 p.R943x and p.R1073P_Fsx4
  publication: PMID:30586709
  description: >-
    Isogenic human cardiomyocytes carrying MYBPC3 premature termination codon
    variants, including p.R943x - the same nonsense change as the c.2827C>T
    (p.Arg943*) Dutch founder allele that appears homozygously and in compound
    heterozygosity in the founding LVNC10 case series. The system establishes
    two things this entry's molecular node asserts: no truncated peptide is
    produced, and nonsense-mediated decay is chronically engaged. It also
    supplies a genuine complication, recorded in the discussion below: at the
    heterozygous dose in this in vitro system, MYBPC3 mRNA fell but cMyBP-C
    protein did not.
  evidence:
  - reference: PMID:30586709
    reference_title: "A Premature Termination Codon Mutation in MYBPC3 Causes Hypertrophic Cardiomyopathy via Chronic Activation of Nonsense-Mediated Decay."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, truncated MYBPC3 peptides were not detected.
    explanation: >-
      Directly supports this entry's claim that the truncated peptide is not
      stably present, so the operative lesion is absent protein rather than a
      dominant-negative product.
  modeled_mechanisms:
  - target: MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Establishes the transcript-level fate of MYBPC3 premature termination
      codon alleles in human cardiomyocytes: no truncated peptide, and chronic
      nonsense-mediated decay activation.
    limitations: >-
      The lines are heterozygous, the CMH4 allelic regime, not the biallelic
      regime that defines LVNC10, so the dose state this node turns on is not
      the one modeled. More pointedly, protein levels were comparable to
      isogenic controls despite reduced mRNA, which the authors read as
      haploinsufficiency not contributing in vitro. That does not overturn the
      ~20% residual protein measured in affected human cardiac tissue in a
      compound heterozygous LVNC case, but it does mean this model supports
      the transcript arm of the node and not the protein-depletion arm.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The model reports transcript abundance and nonsense-mediated decay
        activity. The node's operative quantity is residual functional
        cMyBP-C protein, which in this system did not follow the transcript.
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: >-
        Heterozygous carriers of a single premature termination codon allele,
        rather than the biallelic genotypes that define this entity.
    evidence:
    - reference: PMID:30586709
      reference_title: "A Premature Termination Codon Mutation in MYBPC3 Causes Hypertrophic Cardiomyopathy via Chronic Activation of Nonsense-Mediated Decay."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The mRNA expression levels of MYBPC3 were significantly reduced in
        mutant iPSC-CMs, but the protein levels were comparable among isogenic
        iPSC-CMs, suggesting that haploinsufficiency of MYBPC3 does not
        contribute to the pathogenesis of HCM in vitro.
      explanation: >-
        Carries both halves of what this link claims: the transcript falls, and
        the protein does not follow. That split is why the link is
        PARTIALLY_RECAPITULATES and why the divergences above are recorded.
    readouts:
    - name: Nonsense-mediated decay pathway activity
      target: MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion
      description: >-
        Transcriptome-level assessment of nonsense-mediated decay activation
        in MYBPC3 premature-termination-codon cardiomyocytes against isogenic
        controls.
      direction: INCREASED
      interpretation: >-
        Chronic nonsense-mediated decay engagement is the transcript-level
        mechanism by which these alleles fail to yield functional protein.
      evidence:
      - reference: PMID:30586709
        reference_title: "A Premature Termination Codon Mutation in MYBPC3 Causes Hypertrophic Cardiomyopathy via Chronic Activation of Nonsense-Mediated Decay."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          At the molecular level, the nonsense-mediated decay pathway was
          activated, and a set of genes involved in major cardiac signaling
          pathways was dysregulated in HCM iPSC-CMs, indicating an HCM gene
          signature in vitro.
        explanation: >-
          Reports the measured activation of the pathway and its direction.
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.

    A candidate has since been added to this entry rather than left implicit:
    the homozygous cMyBP-C-deficient mouse shows that the same protein deficit
    reaches a different cellular endpoint at different allelic dose -
    hyperplasia through extended postnatal myocyte division at the null dose,
    hypertrophy at the heterozygous dose - and the authors attribute this to a
    normal inhibitory role of cMyBP-C in postnatal cytokinesis. That would
    supply the missing qualitative step, since the extended proliferative
    window overlaps the period of trabecular-to-compact remodeling. It does
    not close the gap: the mice develop dilation rather than noncompaction,
    no compaction measurement is reported, and the extrapolation from myocyte
    cell-cycle behaviour to ventricular wall architecture is the curator's,
    not the paper's. The hypothesis is carried as
    `mechanistic_hypotheses#cytokinesis_brake_release` with status EMERGING.
  evidence:
  - reference: PMID:26153423
    reference_title: "Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      MYBPC has unexpected inhibitory functions during postnatal myocyte
      cytokinesis and cell cycle progression.
    explanation: >-
      The finding that turns this gap from wholly open into one with a named
      candidate mechanism to test. Cited on the discussion because it bears on
      the question posed, not because it answers it.
    directness: INDIRECT
  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.
    perturbations:
    - name: Graded reduction of cMyBP-C dosage
      target: pathophysiology#MYBPC3 Loss-of-Function Variant and cMyBP-C Depletion
      description: >-
        Titrate residual cMyBP-C from wild-type through the heterozygous
        (~50%) and compound heterozygous (~20%) levels to near-null.
    readouts:
    - name: Trabecular-to-compact myocardial remodeling
      target: pathophysiology#Dose-Dependent Failure of Myocardial Compaction
      description: >-
        Ratio of noncompacted to compacted myocardial layer, measured across
        the dosage range at the end of the compaction window.
      biological_processes:
      - preferred_term: heart trabecula morphogenesis
        term:
          id: GO:0061384
          label: heart trabecula morphogenesis
    - name: Postnatal cardiomyocyte proliferation
      target: pathophysiology#Dose-Dependent Failure of Myocardial Compaction
      description: >-
        Myocyte division and mononuclear-cell accumulation across the same
        dosage range, to test whether extended proliferation tracks the
        compaction outcome.
      biological_processes:
      - preferred_term: cardiac muscle cell proliferation
        term:
          id: GO:0060038
          label: cardiac muscle cell proliferation
    would_support:
    - mechanistic_hypotheses#cytokinesis_brake_release
    supporting_outcome:
    - >-
      A discontinuity: below some residual-protein threshold the
      noncompacted-to-compacted ratio rises sharply and tracks the extension of
      the postnatal proliferative window, rather than both changing smoothly
      with dose.
    would_refute:
    - mechanistic_hypotheses#cytokinesis_brake_release
    refuting_outcome:
    - >-
      Compaction and proliferation both varying smoothly and proportionally
      with cMyBP-C dose, with no threshold, which would leave the phenotype
      difference quantitative and support the continuum account instead.
- discussion_id: lvnc10_no_model_shows_noncompaction
  prompt: >-
    Does any available model system actually reproduce the noncompaction
    phenotype of LVNC10, or only the genotype and the lethality?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Dose-Dependent Failure of Myocardial Compaction
  - animal_models#Homozygous cMyBP-C-deficient mouse (Mybpc3 t/t)
  - animal_models#Compound heterozygous MYBPC3 cloned pig
  - animal_models#mybpc3 knockout zebrafish
  - experimental_models#Biallelic MYBPC3 truncating hiPSC line with isogenic control
  rationale: >-
    Of the models attached here, four reach a biallelic or null MYBPC3 state
    and none reaches the phenotype the entity is named for. The homozygous
    cMyBP-C-deficient mouse dilates; the compound heterozygous cloned pig
    hypertrophies and dies perinatally; the zebrafish knockout makes its
    ventricle *more* compact, with a thicker wall, which is the opposite
    failure; the biallelic hiPSC line is a resource report with no phenotype
    assayed, and its two-dimensional cardiomyocytes have no ventricular wall in
    which compaction could be scored. (The remaining human line, the
    premature-termination-codon iPSC-CMs, is heterozygous and does not reach
    the allelic state at all.) So the defining lesion of this entity -
    persistence of a noncompacted, hypertrabeculated ventricular wall -
    currently rests entirely on human imaging and autopsy, with no experimental
    system in which it can be perturbed or rescued.

    This is a mismatch worth stating rather than a gap in curation. The mouse
    and pig phenotypes are not merely weaker versions of the human one, they
    are different phenotypes, and in the zebrafish the difference is one of
    sign rather than degree. Species differences in the timing of ventricular
    compaction relative to birth are a plausible reason. Until a
    model reproduces the compaction defect, therapeutic inferences from the
    rescue experiments in this entry - the neonatal exon-skipping rescue and
    the Tet-Off reversibility result - bear on contractile and hypertrophic
    phenotypes, not on whether a compaction defect is preventable or
    reversible.

    Two 2024 human systems surfaced by the same deep-research pass were left
    out and the reason belongs here rather than nowhere: MYBPC3 p.D389V cardiac
    organoids showing mavacamten-reversible hypercontractility
    (doi:10.3390/cells13221913), and MYBPC3 c.1377delC iPSC-CM metabolic
    remodeling (doi:10.1038/s41598-024-62530-0). Both are heterozygous
    missense- or single-frameshift-allele HCM systems, further from the
    biallelic genotype than the lines curated above, and neither scores
    compaction. The organoid one is worth revisiting, since a cardiac organoid
    is exactly the system the experiment proposed below would need. The report
    also surfaced NCT06024759, a generic-LVNC risk registry with no
    MYBPC3-specific arm, which is why `clinical_trials` remains empty.
  evidence:
  - reference: PMID:26153423
    reference_title: "Cardiac myosin binding protein C regulates postnatal myocyte cytokinesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Homozygous cardiac myosin binding protein C-deficient (Mybpc(t/t)) mice
      develop dramatic cardiac dilation shortly after birth; heart size
      increases almost twofold.
    explanation: >-
      The mismatch stated in the sharpest available form: the biallelic-null
      mouse phenotype is dilation, and the human biallelic phenotype this
      entity is named for is noncompaction.
    directness: INDIRECT
  - reference: PMID:40496056
    reference_title: "Perinatal death in pig models of hypertrophic cardiomyopathy carrying sarcomere pathogenic variants."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The MYBPC3-edited piglet exhibited a compound heterozygous mutation
      leading to a markedly low level of mutant MYBPC3 protein and cardiac
      hypertrophy, reflecting the situation in infants.
    explanation: >-
      The large-animal attempt reaches hypertrophy, not noncompaction, so the
      mismatch is not confined to rodents.
    directness: INDIRECT
  proposed_experiments:
  - experiment_id: lvnc10_compaction_competent_model
    name: Compaction-competent biallelic MYBPC3 model
    description: >-
      Establish a system in which trabecular-to-compact remodeling can be
      scored under a biallelic MYBPC3 genotype - an engineered heart tissue or
      cardiac organoid taken through the compaction window, or an embryonic
      time course in a species whose compaction completes prenatally as it
      does in humans - and determine whether the noncompacted phenotype
      appears at all.
    readouts:
    - name: Noncompacted-to-compacted layer ratio
      target: pathophysiology#Dose-Dependent Failure of Myocardial Compaction
      description: >-
        The imaging measurement used to diagnose the human phenotype, applied
        to the model system.
    would_refute:
    - pathophysiology#Dose-Dependent Failure of Myocardial Compaction
    refuting_outcome:
    - >-
      A biallelic model that completes normal compaction would argue the human
      noncompaction finding is a secondary or modifier-dependent feature rather
      than a direct consequence of cMyBP-C loss, which is what the population
      burden analysis already hints at for the monoallelic state.
clinical_trials: []
datasets:
- accession: geo:GSE274124
  title: "Transcriptome analysis of patient derived induced pluripotent stem cell derived cardiomyocytes with severe, early onset hypertrophic cardiomyopathy due to biallelic MYBPC3 variants c.442G>A and c.506-1G>A"
  description: >-
    Transcriptomes of cardiomyocytes derived from a patient carrying two MYBPC3
    variants in trans with severe early-onset disease, against a healthy
    control line. The closest available omics resource to the LVNC10 genotype
    in human cells, though not an exact match: one allele is a splice variant
    and the other is annotated low-penetrance pathogenic, so this is a biallelic
    genotype but not the truncating/truncating configuration the biallelic
    subtype is defined by.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 6
  genes:
  - preferred_term: MYBPC3
    term:
      id: hgnc:7551
      label: MYBPC3
  publication: PMID:39633578
  evidence:
  - reference: GEO:GSE274124
    reference_title: "Transcriptome analysis of patient derived induced pluripotent stem cell derived cardiomyocytes with severe, early onset hypertrophic cardiomyopathy due to biallelic MYBPC3 variants c.442G>A and c.506-1G>A"
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Induced pluripotent stem cells (iPSCs) were generated from a patient with
      severe, early onset hypertrophic cardiomyopathy due to pathogenic
      (c.506-1G>A) and low penetrance pathogenic (c.442G>A) variants in MYBPC3
      in trans (i.e. MYBPC3 biallelic patient).
    explanation: >-
      The GEO summary establishes the biallelic in-trans genotype and the
      severe early-onset presentation, which is why this dataset is curated
      here rather than under the heterozygous CMH4 entry.
  notes: >-
    The patient's phenotype is recorded as hypertrophic, not noncompaction, and
    the allele pair is splice-plus-low-penetrance-missense rather than two
    truncating alleles. Curated for the biallelic configuration and the
    early-onset severity, which are what this entry models; it is not a
    noncompaction dataset, and no omics resource keyed to the LVNC10 phenotype
    itself was found.
- accession: geo:GSE140965
  title: Transcriptome study of MYBPC3 loss of function mutations
  description: >-
    Isogenic human iPSC-cardiomyocytes carrying heterozygous MYBPC3
    loss-of-function edits (promoter deletion, start-site deletion, exon 27
    frameshift) alongside a homozygous exon 27 frameshift. The allelic-dose
    contrast this entry turns on, in one human genetic background.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 30
  genes:
  - preferred_term: MYBPC3
    term:
      id: hgnc:7551
      label: MYBPC3
  publication: PMID:31877118
  evidence:
  - reference: GEO:GSE140965
    reference_title: Transcriptome study of MYBPC3 loss of function mutations
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Induced pluripotent stem cells were gene edited to introduce heterozygous
      (promoter deletion, start site deletion, and exon 27 frameshift) and
      homozygous (exon 27 frameshift) mutations.
    explanation: >-
      Establishes that the design holds genetic background fixed and varies
      MYBPC3 allelic dose, which is the comparison the dose-dependence nodes in
      this entry assert.
  notes: >-
    Engineered rather than patient-derived, and the readout is transcriptomic
    in two-dimensional cardiomyocytes, so it cannot address ventricular
    compaction. Relevant to whether the mono- and bi-allelic states differ in
    kind or only in degree.
- accession: geo:GSE262253
  title: Gene expression patterns in cMyBP-CΔC10mut HCM mice and cMyBP-C(t/t) DCM mice
  description: >-
    RNA-seq of the cMyBP-C(t/t) null mouse curated in this entry's animal
    models, alongside a transgenic mouse expressing a C10-domain mutant at
    roughly half the endogenous cMyBP-C level. The murine counterpart of the
    same allelic-dose contrast, with inflammatory pathway upregulation reported
    in the null hearts.
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  data_type: BULK_RNA_SEQ
  sample_count: 4
  genes:
  - preferred_term: MYBPC3
    term:
      id: hgnc:7551
      label: MYBPC3
  evidence:
  - reference: GEO:GSE262253
    reference_title: Gene expression patterns in cMyBP-CΔC10mut HCM mice and cMyBP-C(t/t) DCM mice
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Similarly,to determine whether myocardial inflammation is associated with
      cardiac dysfunction in dilated cardiomyopathy (DCM) caused by MYBPC3
      mutation, we used the well-characterized cMyBP-C(t/t) mouse model of DCM
      at 3months of age.
    explanation: >-
      Names the cMyBP-C(t/t) model curated under this entry's animal models and
      states what the null arm of the dataset measures. Quoted with the GEO
      summary's own missing spaces, as required.
  notes: >-
    The two arms are separate experiments in one series rather than a matched
    dose titration, and the null arm is sampled at 3 months, well past the
    neonatal window in which the human biallelic phenotype presents.
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.

  A second falcon deep-research pass (September 2026) was run with the MONDO
  ID supplied, which the August 2026 pass lacked; 50 citations, all 18
  extracted references resolved, none off topic, `just preflight-dr` PASS with
  MYBPC3 mentioned 61 times. Its term-validation block reports
  `needs_review: true` on two label mismatches, both template artifacts rather
  than bindings: the `mondo_id` placeholder text "(if available)" echoed
  against MONDO:0014163, and a descriptive phrase written beside HP:0011664.
  Both CURIEs are the ones this entry already uses and are correct.

  That pass reached the same conclusion recorded in the
  `lvnc10_no_model_shows_noncompaction` discussion - that no retrieved model
  reproduces LVNC morphology - and supplied the zebrafish knockout now curated
  under `animal_models`. One figure it reports was deliberately not used: a
  claim that 15 of the 21 pooled biallelic patients died before one year. That
  number is from the Wessels full text rather than the abstract and is absent
  from the cached reference, so it could not be snippet-verified; the cohort
  outcome is instead curated from the abstract's own "within the first few
  months of life" wording.

📚

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

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (3)

Record 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. A second falcon deep-research pass (September 2026) was run with the MONDO ID supplied, which the August 2026 pass lacked; 50 citations, all 18 extracted references resolved, none off topic, `just preflight-dr` PASS with MYBPC3 mentioned 61 times. Its term-validation block reports `needs_review: true` on two label mismatches, both template artifacts rather than bindings: the `mondo_id` placeholder text "(if available)" echoed against MONDO:0014163, and a descriptive phrase written beside HP:0011664. Both CURIEs are the ones this entry already uses and are correct. That pass reached the same conclusion recorded in the `lvnc10_no_model_shows_noncompaction` discussion - that no retrieved model reproduces LVNC morphology - and supplied the zebrafish knockout now curated under `animal_models`. One figure it reports was deliberately not used: a claim that 15 of the 21 pooled biallelic patients died before one year. That number is from the Wessels full text rather than the abstract and is absent from the cached reference, so it could not be snippet-verified; the cohort outcome is instead curated from the abstract's own "within the first few months of life" wording.

Augment: Left Ventricular Noncompaction 10 (model systems, datasets, hypotheses) · 2026-09-06T14:53:22Z · View source

Augmented the existing LVNC10 entry (created 2026-08-18, #8746). Deep research: re-ran `just research-disorder falcon`, this time with the MONDO ID supplied, which the August pass lacked. 50 citations (up from 26); all 18 extracted references resolved, 0 off topic, confabulation_rate 0.0. `just preflight-dr research/Left_Ventricular_Noncompaction_10-deep-research-falcon.md MONDO:0014163` returned PASS with MYBPC3 mentioned 61 times and no rival-gene drift. The report's term_validation sets needs_review: true on two label mismatches; both are template artifacts, not bindings - the "(if available)" placeholder echoed against MONDO:0014163, and a descriptive phrase written beside HP:0011664. Both CURIEs resolve and are the ones the entry already uses. This regenerated report replaces the August one at the same path; the superseded version remains in git history. Model systems were the largest gap and are the substance of this pass. Added `animal_models` (5) and `experimental_models` (2), all with typed `modeled_mechanisms` links carrying fidelity, model_scale, limitations and `divergences`, plus readouts. The scientifically important one is the homozygous cMyBP-C-deficient mouse (PMID:26153423): cMyBP-C normally inhibits postnatal myocyte cytokinesis, so the null completes an extra round of division and enlarges by hyperplasia where the heterozygote enlarges by hypertrophy. That is a candidate answer to the dose-phenotype divergence the entry had recorded as wholly open, and it is corroborated across species by the zebrafish mypbc3 knockout (PMID:36012114), which shows the same cardiomyocyte hyperplasia. Also added the Mybpc3-targeted knock-in mouse with neonatal AAV-U7-AON exon-skipping rescue (PMID:23716398), the Tet-Off conditional cMyBP-C re-expression mouse (PMID:30573635), the compound heterozygous cloned pig (PMID:40496056), the biallelic MYBPC3 hiPSC line with isogenic control (PMID:34375846), and MYBPC3 premature-termination-codon isogenic hiPSC-CMs (PMID:30586709). Recorded the mismatch those models expose as a HUMAN_MODEL_MISMATCH discussion: every model reaches the biallelic genotype and none reaches the noncompaction phenotype - the mouse dilates, the pig hypertrophies, the zebrafish has no compact layer, the hiPSC line has no assayed phenotype. The September deep-research pass reached the same conclusion independently. This bounds what the two rescue experiments in the entry can be read to show. Added two `mechanistic_hypotheses` (CANONICAL sarcomeric dose continuum, EMERGING cytokinesis-brake-release) and opted the compaction edge into both via `hypothesis_groups`; extended the pre-existing KNOWLEDGE_GAP discussion with the candidate mechanism and gave it evidence, and gave its proposed experiment structured perturbations, readouts, would_support/would_refute. Filled every uncited causal edge: all 5 `pathophysiology[].downstream[]` edges and both `treatments[].target_mechanisms[]` links now carry their own evidence, with `directness: INDIRECT` where the source establishes sequence or co-occurrence within a cohort rather than the causal step. Added `datasets` (was empty): geo:GSE274124 (biallelic in-trans patient hiPSC-CM transcriptome), geo:GSE140965 (isogenic het vs hom MYBPC3 LOF edits), geo:GSE262253 (the cMyBP-C(t/t) mouse curated here, against a half-dose transgenic). All three are HCM/DCM-labelled, not noncompaction datasets; that is recorded in each `notes`. `just verify-datasets` OK 3/3; GEO_*.md cache files committed. Added ClinGen structured-source evidence to `genetic`: MYBPC3-HCM Definitive (AD) against MYBPC3-DCM Limited (AR). The AR row is the nearest expert-panel verdict on the biallelic regime this entry models, since OMIM files LVNC10 with CMD1MM, and it corroborates the Mazzarotto caveat already in the notes. Added the 2025 autopsy-confirmed compound heterozygous case (PMID:41488457), the first in this entry to name which septal defect (atrial); the phenotype stays bound at HP:0001671 rather than being narrowed on one case. Added `progression` (2 phases) and `clinical_burden` (HIGH). Cleaned up all four `explanation` strings that still argued for the retired `supports: PARTIAL` value (#10003 prose fallout), replacing them with `directness: INDIRECT` where that is what was meant. No occurrence of the retired value remains in this entry's prose. Deliberately not used: the report's claim that 15/21 pooled biallelic patients died before one year. That figure is in the Wessels full text, not the abstract, and is absent from the cached reference, so it could not be snippet-verified; the cohort outcome is curated from the abstract's own wording instead. Also fetched but not cited: PMID:24047589 (zebrafish mybpc3 morpholino knockdown), redundant against the stable knockout, and its cache file was removed rather than committed uncited. A pre-PR red-team review (dismech-pr-review skill, fresh context) found fifteen issues, all in curator prose running ahead of the quotes beside it; no fabricated snippet, wrong identifier, Named Entity Confusion, or bad ontology term. All fifteen were fixed in this same pass. The three that mattered: (1) The zebrafish model description claimed zebrafish "have no compact myocardial layer". That is false, and the paper says the opposite of what the entry implied: the mybpc3-knockout ventricle and atrium "became more compact" with a thicker wall and smaller chamber diameters. The claim appeared three times, escalating from a hedged divergence to a load-bearing premise of the HUMAN_MODEL_MISMATCH discussion. Rewritten throughout, and the corrected fact is a sharper version of the same argument, so a REFUTE readout quoting the "more compact" sentence was added to the zebrafish link. Note also that the paper's abstract misspells the gene "mypbc3" while its results use mybpc3; curator-written fields now use mybpc3, snippets keep the source spelling, and a note records why. (2) "Every model curated in this entry reaches the biallelic MYBPC3 genotype" was contradicted by the entry's own limitations on the heterozygous premature-termination-codon iPSC-CMs. Narrowed. (3) `progression` asserted "There is no presymptomatic phase to screen for once the genotype is biallelic", which PMID:41488457 - added in this same pass - refutes: normal prenatal screening, discharged healthy, collapse at two months. Rewritten to the defensible claim, that a window exists and no screening interval has been shown to use it. Also fixed: uncited residual-protein percentages in the CANONICAL hypothesis description (the only measured figure in the entry is ~20% in one LoF-plus-missense compound heterozygote, not the truncating/truncating subtype, and the isogenic iPSC-CM result cuts against the half-dose inference); the one link carrying `fidelity: HIGH` with no caveat and an organ-level readout under `model_scale: MOLECULAR` (now MODERATE/ORGANISM with PROXY_QUANTITY and SPECIES_MISMATCH divergences); a new `causal_link_type: DIRECT` edge resting on a cohort co-occurrence statistic without `directness: INDIRECT`; the ClinGen MYBPC3-HCM Definitive item graded SUPPORT when its own explanation calls it a contrast term (now NO_EVIDENCE, kept because omitting it would make the AR/DCM Limited row look like the whole ClinGen picture); "the same four neonates in whom noncompaction was diagnosed" (three of four); a curator extrapolation written as the authors' proposal; `materiality: INVALIDATING` on a divergence arguing against a claim its link does not make (QUALIFYING); a duplicated snippet on a treatment mechanism link; and a `datasets` description calling geo:GSE274124 the configuration that defines the subtype when one of its alleles is low-penetrance missense. The review also flagged that two 2024 human systems from the report were dropped without recording why - MYBPC3 p.D389V cardiac organoids with mavacamten-reversible hypercontractility, and MYBPC3 c.1377delC iPSC-CM metabolic remodeling - and that the organoid one undercuts the discussion's claim that no human system could score compaction. Both decisions, and the reason `clinical_trials` stays empty (NCT06024759 is a generic-LVNC registry with no MYBPC3 arm), are now recorded in the discussion rationale rather than left silent. Validation: `just validate`, `just validate-terms`, and the batched `just validate-disorders` all pass, 84/84 snippets verified against cached references (up from 33). `just check-entity-refs`, `check-causal-targets`, `check-duplicate-keys`, `check-enum-values`, `check-qualifier-terms`, `check-folded-hyphens`, `check-snippet-grading`, `check-title-snippets`, `check-snippet-length`, `check-environmental-evidence` all OK; no baseline was updated. `just model-scale-audit` reports 0 upward-extrapolating links lacking limitations or divergences. Compliance rose from 110/123 satisfied checks to 203/230.

Create: Left Ventricular Noncompaction 10 (MYBPC3, LVNC10) · 2026-08-18T04:31:06Z · View source

Created LVNC10 (MONDO:0014163; OMIM:615396; MYBPC3) resolving issue #8746. Modeled two allelic-dose subtypes: biallelic (homozygous/compound heterozygous) truncating MYBPC3 producing severe lethal neonatal noncompaction with congenital septal defects (Wessels 2015 PMID:25335496, n=21 literature cohort; Kolokotronis 2019 PMID:30924982, ~20% residual cMyBP-C protein, heart transplant case), and monoallelic MYBPC3 producing/co-segregating with a noncompaction phenotype overlapping HCM in relatives (van Waning 2019 JACC PMID:30947911; Blagova 2022 PMID:36011256 familial HCM/LVNC/RCM continuum case). Cross-references the umbrella Left_Ventricular_Noncompaction.yaml (MONDO:0018901) for shared downstream LVNC mechanism and Hypertrophic_Cardiomyopathy_4.yaml (MONDO:0007268, same gene) as key differential diagnosis and for the shared cMyBP-C haploinsufficiency molecular mechanism. Added a KNOWLEDGE_GAP discussion on the unestablished mechanistic step converting cMyBP-C dose deficit into a developmental compaction-failure phenotype versus postnatal hypertrophic remodeling. Deep research: ran falcon (Edison) via just research-disorder; just preflight-dr returned PASS (MYBPC3 mentioned 60 times, no rival-gene drift toward HCM). The report's headline OpenTargets-sourced claim of a founding p.Arg820Trp/R820W LVNC10 allele was independently checked against its own cited PMIDs (20186049, 27532257 -- neither supports the claim) and against the report's own aside that R820W is 'notable in Ragdoll cats' (a known feline HCM variant), and was judged an unverified/likely-conflated claim and deliberately NOT incorporated into the KB entry. All other report content corroborated the primary-literature mechanism already sourced directly from Wessels 2015 and Kolokotronis 2019. Validation: just validate, just validate-terms, and just validate-disorders all pass (33/33 snippets verified against cached references); pytest tests/test_data.py passes (only a non-blocking missing-subtype_term warning, consistent with the HCM4 sibling entry).

Falcon ▸

Left Ventricular Noncompaction 10: Disease-Characteristics Report

Edison Scientific Literature 50 citations 2026-09-06T14:45:21.060075

Left Ventricular Noncompaction 10: Disease-Characteristics Report

Executive summary and scope

Left ventricular noncompaction 10 (LVNC10) is the numbered, MYBPC3-related form of left-ventricular noncompaction/hypertrabeculation. Its key identifiers are MONDO:0014163 and OMIM #615396. The disease-defining gene is MYBPC3, encoding cardiac myosin-binding protein C (cMyBP-C); Open Targets maps MONDO:0014163 specifically to MYBPC3 (Ensembl ENSG00000134571). (OpenTargets Search: Left ventricular noncompaction 10)

The evidence base is unusually heterogeneous. Variant-level evidence specific to LVNC10 comes mainly from small families and severe neonatal cases, whereas most prevalence, diagnostic, prognostic, and treatment data concern LVNC of any genetic cause. Those generic data should not be entered as subtype-specific facts without an explicit qualifier. Contemporary ESC thinking also treats left-ventricular hypertrabeculation as a potentially dynamic imaging trait rather than, by itself, a distinct cardiomyopathy. (grasso2024thenew2023 pages 1-2)

The following evidence map summarizes the distinction between LVNC10-specific and generic LVNC findings.

Domain	Subtype-specific finding	Generic LVNC context	Evidence type/source/date	Identifiers/ontology suggestions	Confidence/limitations
Nosology	LVNC10 is the MYBPC3-related numbered subtype of left ventricular noncompaction.	Generic LVNC: Hypertrabeculation with deep intertrabecular recesses and a thin compacted myocardial layer; it may be a cardiomyopathy phenotype or dynamic trait rather than a distinct disease. (OpenTargets Search: Left ventricular noncompaction 10, grasso2024thenew2023 pages 1-2)	Aggregated disease resource; Open Targets, accessed 2026; ESC-guideline commentary, Apr 2024	MONDO:0014163; OMIM #615396; MYBPC3; HP:0011664	High for disease–gene mapping; nosologic interpretation remains debated.
Inheritance	Heterozygous MYBPC3 disease is generally autosomal dominant with incomplete penetrance and variable expressivity; biallelic truncating variants cause a severe recessive-like neonatal phenotype. (probst2011sarcomeregenemutations pages 8-9, wessels2015compoundheterozygousor pages 1-2)	Generic LVNC: Autosomal dominant inheritance predominates, but autosomal recessive, X-linked, and mitochondrial forms occur. (sedaghathamedani2017clinicalgeneticsand pages 1-2, hirono2022leftventricularnoncompaction pages 1-2)	Human family series; Probst et al., Aug 2011; Wessels et al., Oct 2015	Germline inheritance; MYBPC3	Moderate–high; no LVNC10-specific population penetrance estimate. HCM-derived estimates are not LVNC10-specific.
Key variants	Dutch founder truncating alleles MYBPC3 c.2373dup, p.(Trp792fs) and *c.2827C>T, p.(Arg943)** occurred as compound-heterozygous or homozygous genotypes. c.2373dup causes aberrant splicing, exon-24 skipping, frameshift, premature termination, and no detectable truncated protein. (wessels2015compoundheterozygousor pages 2-3, wessels2015compoundheterozygousor pages 5-6)	Generic LVNC: Many sarcomeric genes overlap with HCM and DCM; interpretation must consider variant class, segregation, phenotype, and population frequency. (mazzarotto2020thegeneticarchitecture pages 1-3, grasso2024thenew2023 pages 1-2)	Human neonatal series and RNA/protein analysis; Wessels et al., Oct 2015; https://doi.org/10.1038/ejhg.2014.211	MYBPC3; frameshift; nonsense; germline	High for reported families; transcript accession and population allele frequencies were not established here.
Severe biallelic phenotype	Four infants presented at approximately 4–7 weeks; three had LVNC, all had septal defects, feeding difficulty or failure to thrive and dyspnea, and all died from cardiac failure before 13 weeks. Among 21 reported biallelic truncating cases, 15 died before age 1 and 13/21 (62%) had structural defects. (wessels2015compoundheterozygousor pages 2-3, wessels2015compoundheterozygousor pages 1-2, wessels2015compoundheterozygousor pages 3-4)	Generic LVNC: Pediatric genetic disease may include congenital heart defects and have more severe outcomes than adult sarcomeric disease.	Human case series and literature review; Wessels et al., Oct 2015	Suggested HPO: HP:0011664; failure to thrive; dyspnea; heart failure; atrial or ventricular septal defect	High for this rare biallelic phenotype, but evidence is small and ascertainment-enriched; it is not representative of typical heterozygous LVNC10.
Heterozygous phenotype	MYBPC3 variants can produce LVNC, HCM, mixed LVNC/HCM, or clinically silent carriage within families; MYBPC3 accounted for 8% of variants in one 63-proband isolated-LVNC series. (probst2011sarcomeregenemutations pages 8-9)	Generic LVNC: Presentation ranges from incidental imaging findings to systolic dysfunction, heart failure, arrhythmia, thromboembolism, transplantation, and sudden death. (hirono2022leftventricularnoncompaction pages 1-2, wang2017awideand pages 1-2)	Human cohort and family evidence; Probst et al., Aug 2011; Wang et al., Sep 2017	Suggested HPO: HP:0011664; cardiomyopathy; arrhythmia; reduced LVEF	Moderate; small numbers preclude reliable MYBPC3 variant-specific frequency or severity estimates.
Diagnosis	No imaging criterion is specific for MYBPC3-related LVNC10; diagnosis requires pathogenic or likely pathogenic MYBPC3 evidence, a compatible cardiac phenotype, and segregation assessment.	Generic LVNC: Echo thresholds include Chin X/Y ≤0.5 and Jenni noncompacted-to-compacted ratio >2 in systole; CMR thresholds include Petersen ratio ≥2.3 in diastole and Jacquier trabeculated mass >20%. Physiologic hypertrabeculation can occur in athletes and pregnancy. (martineztittonel2025leftventricularnoncompaction pages 5-7, mazzarotto2020thegeneticarchitecture pages 1-3)	Imaging literature and reviews; criteria synthesized through 2025; ESC framing, 2023–2024	HP:0011664; CMR; echocardiography	Moderate; criteria have imperfect concordance and may overdiagnose disease. Morphology alone does not establish LVNC10.
Epidemiology	No reliable prevalence or incidence estimate exists for genetically confirmed LVNC10.	Generic adult LVNC: A 2024 meta-analysis estimated prevalence at 0.5% and CMR detection at 1.3%. Published prevalence ranged from 0.014% to 14.79%, reflecting criteria and ascertainment heterogeneity. (llerenavelastegui2024prevalenceclinicalmanifestations pages 1-2)	Systematic review and meta-analysis; Llerena-Velastegui et al., Oct 2024; https://doi.org/10.14740/cr1673	MONDO:0014163 for subtype; MONDO:0018901 for generic LVNC	Low for extrapolation to LVNC10; generic imaging prevalence must not be assigned to the genetic subtype.
Prognosis	MYBPC3 was identified as a genetic predictor of major adverse cardiac events in a genotype–phenotype review; biallelic truncation predicts an exceptionally poor neonatal course. (wessels2015compoundheterozygousor pages 1-2, wang2017awideand pages 1-2)	Generic LVNC: Among 2,501 patients, event rates per 100 person-years were cardiovascular mortality 1.92, all-cause mortality 2.16, stroke or systemic embolism 1.54, HF admission 3.53, transplantation 1.24, ventricular arrhythmia 2.17, and device implantation 2.66. LVEF—not trabeculation extent—was the major outcome determinant. (aung2020prognosticsignificanceof pages 1-2)	Human systematic review and meta-analysis; Aung et al., Jan 2020; https://doi.org/10.1161/CIRCIMAGING.119.009712	Suggested HPO: reduced LVEF; ventricular arrhythmia; thromboembolism; sudden cardiac death	High for generic LVNC outcomes; low–moderate for subtype-specific extrapolation.
Thromboembolism	No MYBPC3-specific thromboembolic rate is established.	Generic LVNC: TE prevalence was 2.6% in children and 6.2% in adults; annual incidence was 1.4% and 2.9%, respectively. Pediatric LVEF <40% was associated with TE, OR 9.47 and 95% CI 1.35–188.23. (hirono2022thromboemboliceventsin pages 1-2)	Systematic review and meta-analysis; Hirono et al., May 2022; https://doi.org/10.1136/openhrt-2021-001908	Suggested HPO: thromboembolism; stroke; reduced LVEF	Moderate because heterogeneity was high; anticoagulation cannot be based on trabeculation alone.
Molecular mechanism	Truncating MYBPC3 alleles support loss of function and haploinsufficiency. In one compound-heterozygous LVNC case, myocardial MYBPC3 transcript fell approximately 50% and protein approximately 80%, with myocyte misalignment, vacuolization, hyperplasia, and major fibrosis. (kolokotronis2019biallelicmutationin pages 7-9, wessels2015compoundheterozygousor pages 5-6)	Generic LVNC inference: Sarcomeric dysfunction may impair force regulation and drive hypertrophic or dilated remodeling; how it specifically generates hypertrabeculation is unproven.	Human cardiac-tissue and molecular assays; Kolokotronis et al., Aug 2019; Wessels et al., Oct 2015	Suggested GO: sarcomere organization; cardiac muscle contraction; actin–myosin interaction; suggested CL: cardiomyocyte	Moderate for sarcomeric loss of function; low for a direct causal bridge to noncompaction morphology.
2024 cellular research	MYBPC3 c.1377delC iPSC-cardiomyocytes showed sarcomere disruption, damaged mitochondria, abnormal calcium signals, increased respiration, and upregulated electron-transport genes. MYBPC3 p.Asp389Val organoids showed hypercontractility, faster calcium cycling, oxidative stress, and reduced mitochondrial membrane potential; mavacamten rescued hypercontractility. (desai2024mybpc3d389vvariant pages 1-2, mori2024metabolicremodelingand pages 1-2)	Generic context: These are HCM or dilated-phase HCM models, not validated LVNC models.	Human iPSC-CM and organoid experiments; Mori et al., Jul 2024, https://doi.org/10.1038/s41598-024-62530-0; Desai et al., Nov 2024, https://doi.org/10.3390/cells13221913	Suggested GO: calcium-ion homeostasis; mitochondrial electron transport; oxidative stress; cardiac muscle contraction; CL: cardiomyocyte, endothelial cell, fibroblast, macrophage	Moderate for MYBPC3 cellular mechanisms; low for direct application to LVNC10 morphology or treatment.
Animal models	Zebrafish mybpc3 knockout or knockdown produces ventricular hypertrophy, cardiomyocyte hyperplasia, diastolic dysfunction, altered calcium reuptake, arrhythmogenic alternans, reduced endurance, and downregulated actin-filament processes. (da’as2022transcriptomeprofileidentifies pages 11-13, chen2013inactivationofmyosin pages 1-2)	Generic context: These models reproduce HCM and heart-failure traits, not demonstrated LV noncompaction.	Stable-knockout and morpholino zebrafish; Chen et al., Sep 2013, https://doi.org/10.1161/JAHA.113.000231; Da’as et al., Aug 2022, https://doi.org/10.3390/ijms23168840	NCBI Taxon 7955; mybpc3 ortholog; suggested GO: actin cytoskeleton organization, calcium-ion transport, cardiac muscle contraction	Moderate for conserved sarcomeric and electrophysiologic dysfunction; species anatomy and absent LVNC morphology limit translation.
Management	No approved LVNC10-specific pharmacotherapy, gene therapy, RNA therapy, or genotype-guided drug regimen exists. Management follows the expressed phenotype: guideline-directed HF therapy, arrhythmia treatment, ICD under standard risk indications, selective anticoagulation, and transplantation or mechanical support for end-stage disease.	Generic LVNC: Reduced LVEF, NYHA class III/IV, ventricular tachycardia, fibrosis or LGE, and clinical arrhythmia are more actionable than trabeculation burden. (llerenavelastegui2024prevalenceclinicalmanifestations pages 1-2, aung2020prognosticsignificanceof pages 1-2)	Cardiomyopathy and HF guideline extrapolation plus LVNC outcome evidence; ESC framework, 2023–2024	Suggested NCIT: echocardiography; cardiac MRI; genetic testing; anticoagulant therapy; implantable cardioverter-defibrillator; heart transplantation	Moderate; no randomized LVNC10 treatment trials. Mavacamten organoid rescue is not clinical evidence for LVNC10.
Screening and prevention	Offer genetic counseling and MYBPC3 testing with copy-number analysis to an affected proband; when a pathogenic or likely pathogenic variant is found, use cascade testing plus ECG and echocardiographic surveillance of first-degree relatives. In severe neonatal disease, test both parents and assess biallelic recurrence risk.	Generic LVNC: Avoid diagnosing disease solely from trabeculation; deep phenotyping and multidisciplinary variant interpretation are recommended. (wessels2015compoundheterozygousor pages 3-4, grasso2024thenew2023 pages 1-2)	Human segregation evidence and ESC cardiomyopathy-genetics framework, 2015–2024	MYBPC3; germline testing; cascade screening; prenatal or preimplantation testing when familial variants are established	Moderate–high; surveillance intervals should be individualized. No primary prevention or protective allele is established.
Current research	No interventional trial specific to MYBPC3-related LVNC10 was identified.	Generic LVNC: NCT06024759 is a recruiting, case-only registry of 500 adults followed for 10 years to assess genetic variants, myocardial strain, LV dysfunction, arrhythmia markers, and predictors of ICD implantation; it started Sep 1, 2023, with estimated completion in Aug 2033. (NCT06024759 chunk 1, NCT06024759 chunk 2)	ClinicalTrials.gov observational registry; first posted Sep 6, 2023; status verified Oct 2023	NCT06024759; adult LVNC registry	High for retrieved registry design and status; not subtype-specific, randomized, or therapeutic.

Table: Compact evidence map separating MYBPC3-specific LVNC10 findings from broader LVNC data. It highlights variant-level evidence, diagnostic uncertainty, outcomes, mechanisms, models, management, and current registry research.

1. Disease information

Definition

LVNC morphology consists of prominent ventricular trabeculae, deep intertrabecular recesses communicating with the ventricular cavity, and a relatively thin compacted epicardial layer. In LVNC10, that cardiac phenotype is associated with a pathogenic or likely pathogenic germline variant in MYBPC3. The phenotype can occur alone or overlap hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), congenital heart defects, and arrhythmia. (probst2011sarcomeregenemutations pages 8-9, hirono2022leftventricularnoncompaction pages 1-2)

The modern interpretation is important: the 2023 ESC framework regards noncompaction/hypertrabeculation as a dynamic trait that may be genetic and pathological but may also be adaptive, transient, or reversible in pregnancy, athletes, anemia, renal disease, or otherwise healthy hearts. Thus, morphology alone does not establish LVNC10. (grasso2024thenew2023 pages 1-2)

Identifiers and synonyms

MONDO: MONDO:0014163.
OMIM: #615396.
Causal gene: MYBPC3; Ensembl ENSG00000134571.
Core phenotype term: HPO HP:0011664, left ventricular noncompaction cardiomyopathy.
Synonyms: left ventricular noncompaction 10; LVNC10; MYBPC3-related left ventricular noncompaction; MYBPC3-related noncompaction cardiomyopathy; left ventricular hypertrabeculation associated with MYBPC3.
Broader disease: MONDO:0018901, left ventricular noncompaction. (OpenTargets Search: Left ventricular noncompaction 10)
ICD/MeSH: No ICD-10 or ICD-11 code uniquely identifies the MYBPC3 subtype. It is ordinarily represented under cardiomyopathy or other specified cardiomyopathy, with genetic findings recorded separately. A uniquely subtype-specific MeSH descriptor was not established in the retrieved evidence.

The report is based on aggregated disease resources, published families, cohorts, meta-analyses, experimental models, and a clinical-trial registry, not individual EHR data.

2. Etiology

Causal factors and genetic risk

The established causal factor is a germline MYBPC3 variant that disrupts cMyBP-C abundance or function. Heterozygous variants usually behave in an autosomal-dominant manner with incomplete, age-dependent penetrance and variable expressivity. Biallelic truncating variants produce a much more severe, effectively recessive neonatal phenotype. (probst2011sarcomeregenemutations pages 8-9, wessels2015compoundheterozygousor pages 2-3, wessels2015compoundheterozygousor pages 1-2)

In 63 unrelated adults with isolated LVNC, 18 heterozygous sarcomeric variants were found in 29%; MYBPC3 accounted for approximately 8%. Mutation-positive and mutation-negative patients could not be reliably distinguished clinically. This supports genetic heterogeneity and weak phenotype prediction from the gene alone. (probst2011sarcomeregenemutations pages 8-9)

In a broader 102-patient LVNC cohort, 43 pathogenic variants in 16 genes were found in 39 patients (38%); 63% were sarcomeric and 12% channelopathy-associated. Pathogenic-variant carriers had earlier onset and lower LVEF, and pathogenic variants independently predicted adverse events. These figures are generic LVNC data, not MYBPC3-specific penetrance estimates. (wang2017awideand pages 1-2)

Environmental, lifestyle, and gene–environment factors

No toxin, infection, diet, smoking exposure, occupational factor, or lifestyle behavior has been shown to cause genetically defined LVNC10. Hemodynamic load can modify trabeculation and may expose or amplify an underlying cardiomyopathy phenotype, but a MYBPC3-specific gene–environment interaction has not been demonstrated. Pregnancy and intensive athletic training can increase trabeculation in people without genetic cardiomyopathy, creating an important diagnostic confounder rather than a proven cause of LVNC10. (mazzarotto2020thegeneticarchitecture pages 1-3, grasso2024thenew2023 pages 1-2)

Protective factors

No validated protective MYBPC3 allele, diet, drug, or environmental exposure is known to prevent LVNC10. Standard cardiovascular health measures are reasonable but have not been shown to prevent expression of this monogenic disorder.

3. Phenotypes

Core and associated phenotypes

Phenotype	Type and characteristics	Suggested HPO term
Left-ventricular noncompaction/hypertrabeculation	Imaging sign; congenital substrate or later-recognized trait; severity and progression variable	HP:0011664
Cardiomyopathy, often mixed LVNC/HCM or LVNC/DCM	Structural/functional sign; may be asymptomatic or progressive	Use the applicable HCM/DCM HPO term plus HP:0011664
Reduced LVEF/systolic dysfunction	Imaging/functional abnormality; major adverse-outcome determinant	Decreased left-ventricular ejection fraction
Heart failure	Symptom complex/sign; exertional dyspnea, edema, feeding difficulty in infants, fatigue	Congestive heart failure; dyspnea; exercise intolerance
Ventricular or atrial arrhythmia	Electrophysiologic sign; may be episodic and life-threatening	Ventricular arrhythmia; atrial fibrillation
Thromboembolism/stroke	Complication, especially with impaired systolic function or atrial fibrillation	Thromboembolism; ischemic stroke
Failure to thrive/feeding difficulty	Predominantly severe neonatal biallelic disease	Failure to thrive; feeding difficulties
ASD/VSD/PFO	Congenital structural findings enriched in severe biallelic cases	Atrial septal defect; ventricular septal defect; patent foramen ovale
Sudden cardiac death	Severe outcome related to malignant arrhythmia or advanced cardiomyopathy	Sudden cardiac death

Severe biallelic phenotype

Wessels et al. reported four unrelated infants with biallelic truncating MYBPC3 variants. All had feeding difficulty, failure to thrive, and dyspnea; three had clear LVNC, all had a septal defect or patent foramen ovale, and all died from cardiac failure before 13 weeks. In the authors’ review of 21 biallelic truncating cases, all had severe cardiomyopathy, 15 died before age one, and 13/21 (62%) had a structural defect. (wessels2015compoundheterozygousor pages 2-3, wessels2015compoundheterozygousor pages 1-2, wessels2015compoundheterozygousor pages 3-4)

A representative direct conclusion from the abstract is: “Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects.” The study was published in European Journal of Human Genetics in October 2015, DOI: https://doi.org/10.1038/ejhg.2014.211. (wessels2015compoundheterozygousor pages 2-3)

Heterozygous phenotype and quality of life

Heterozygous MYBPC3 families can include asymptomatic carriers, isolated LVNC, HCM, mixed LVNC/HCM, severe heart failure, and cerebrovascular complications. This indicates incomplete penetrance and marked intrafamilial expressivity. (probst2011sarcomeregenemutations pages 8-9, wessels2015compoundheterozygousor pages 3-4)

No LVNC10-specific EQ-5D, SF-36, or PROMIS study was identified. Functional effects are inferred from heart-failure symptoms, exercise intolerance, arrhythmia, hospital admission, ICD placement, and transplantation. Adult zebrafish models also show reduced swimming endurance, but this is experimental rather than a human quality-of-life measure. (da’as2022transcriptomeprofileidentifies pages 11-13)

4. Genetic and molecular information

Causal gene

Gene: MYBPC3, myosin-binding protein C3.
Protein: cardiac myosin-binding protein C, a thick-filament-associated sarcomeric regulator.
Primary cell: cardiomyocyte.
Subcellular site: sarcomere/myofibril, particularly the C-zone of the A band.
Variant origin: germline; no somatic LVNC10 mechanism is established. (OpenTargets Search: Left ventricular noncompaction 10, desai2024mybpc3d389vvariant pages 1-2)

Documented variants and consequences

The best-defined severe variants are the Dutch founder alleles:

MYBPC3 c.2373dup, p.(Trp792fs) — frameshift. It creates an aberrant splice donor, causes exon-24 skipping and a frameshift after Gln791, introduces premature termination, and yielded no detectable truncated protein, consistent with transcript/protein instability and loss of function.
MYBPC3 c.2827C>T, p.(Arg943*) — nonsense/truncating variant.

Two infants were compound heterozygous for these variants; one was homozygous for c.2373dup and one homozygous for c.2827C>T. Both alleles were recurrent founder variants in the Dutch HCM population. (wessels2015compoundheterozygousor pages 2-3, wessels2015compoundheterozygousor pages 5-6, wessels2015compoundheterozygousor pages 3-4)

A separate severe case carried an entire-gene MYBPC3 deletion in trans with de novo p.Ser858Arg. Myocardial MYBPC3 transcript was reduced approximately 50%, protein approximately 80%, and α-actinin approximately 50%; histology showed myocyte misalignment, vacuolization, hyperplasia, and substantial fibrosis. These findings support haploinsufficiency plus instability or dysfunction of the missense product. (kolokotronis2019biallelicmutationin pages 7-9)

Variant interpretation

Variant classification must follow ACMG/AMP criteria and include:

exact transcript and HGVS nomenclature;
ClinVar/ClinGen assertions and review status;
segregation and de novo status;
read-depth-based copy-number analysis;
predicted nonsense-mediated decay or splice effect;
population frequency in gnomAD/TOPMed;
functional evidence; and
compatibility with the family’s HCM/DCM/LVNC spectrum.

No complete variant-level gnomAD frequencies or current ClinVar review statuses were recoverable from the retrieved papers; these fields should be populated by a live variant-specific database query rather than inferred. A VUS should not establish LVNC10 or direct predictive testing.

Modifiers, epigenetics, and chromosomal abnormalities

No validated modifier gene, protective allele, LVNC10-specific methylation signature, histone alteration, or recurrent chromosomal abnormality is established. Whole-gene deletion is possible and supports inclusion of deletion/duplication analysis. The neighboring-gene extension reported with one deletion did not have an established explanatory human phenotype in the source. (kolokotronis2019biallelicmutationin pages 7-9)

5. Environmental information

No infectious agent, pollutant, radiation exposure, toxin, alcohol exposure, diet, or occupational risk is known to cause LVNC10. Pregnancy, anemia, renal disease, and intensive exercise can cause adaptive hypertrabeculation and therefore affect phenotypic ascertainment, but they should not be coded as established causes of MYBPC3 disease. (grasso2024thenew2023 pages 1-2)

Exercise advice should be individualized according to ventricular function, arrhythmia burden, symptoms, fibrosis, and family history rather than the trabecular appearance alone. Avoidance of smoking and cardiotoxic exposures is prudent general care, not disease-specific prevention.

6. Mechanism and pathophysiology

Ordered causal chain

A pathogenic germline MYBPC3 truncating, splice, deletion, or functionally disruptive missense variant leads to reduced abundance or altered regulation of cMyBP-C in cardiomyocyte sarcomeres. (kolokotronis2019biallelicmutationin pages 7-9, wessels2015compoundheterozygousor pages 5-6)
Reduced or dysfunctional cMyBP-C leads to abnormal control of actin–myosin interaction, cross-bridge cycling, contractility, and sarcomere organization. (desai2024mybpc3d389vvariant pages 1-2, da’as2022transcriptomeprofileidentifies pages 1-2)
Sarcomeric dysfunction results in abnormal calcium handling and altered electrophysiology; zebrafish and human iPSC models demonstrate slowed calcium reuptake or abnormal calcium transients, although these are principally HCM/DCM models rather than LVNC10 models. (mori2024metabolicremodelingand pages 1-2, chen2013inactivationofmyosin pages 1-2)
Contractile and calcium-handling stress leads to energetic and mitochondrial remodeling, including oxidative stress, damaged mitochondria, altered membrane potential, increased respiration, and electron-transport gene expression in 2024 cellular models. (desai2024mybpc3d389vvariant pages 1-2, mori2024metabolicremodelingand pages 1-2)
These abnormalities lead to cardiomyocyte hypertrophy or hyperplasia, myofibrillar disarray, fibrosis, and ventricular remodeling. Human cardiac tissue demonstrates misaligned cells, vacuolization, hyperplasia, and fibrosis. (kolokotronis2019biallelicmutationin pages 7-9)
Inferred branch A: disturbed developmental growth and remodeling may result in persistence or exaggeration of trabeculation and a thin compact layer. This direct MYBPC3-to-noncompaction developmental step has not been conclusively demonstrated.
Branch B: progressive hypertrophic or dilated remodeling results in diastolic or systolic dysfunction and clinical heart failure.
Branch C: calcium/electrical instability and fibrotic substrate result in atrial or ventricular arrhythmia, syncope, ICD requirement, or sudden death.
Branch D: low-flow states, ventricular dysfunction, atrial fibrillation, and possibly recess-associated stasis result in intracardiac thrombosis and systemic embolism; the recess-stasis mechanism remains plausible but unproven. (hirono2022thromboemboliceventsin pages 1-2)

Pathways, processes, and ontology suggestions

Suggested GO biological processes include sarcomere organization, cardiac muscle contraction, actin filament organization, actin–myosin filament sliding, calcium-ion homeostasis, regulation of membrane potential, mitochondrial electron transport, response to oxidative stress, cardiomyocyte proliferation, and cardiac muscle hypertrophy. Suggested cellular components include sarcomere, myofibril, A band, actin cytoskeleton, and mitochondrion. Relevant cell types are cardiomyocyte (primary), with downstream roles for cardiac fibroblasts, endothelial cells, macrophages, and other immune cells in remodeling. Spatial mapping in a 2024 cardiac-organoid study identified all these populations. (desai2024mybpc3d389vvariant pages 1-2)

No LVNC10-specific immune, lipidomic, metabolomic, epigenomic, single-cell, or spatial-transcriptomic signature has been validated. The 2024 organoid and iPSC studies are valuable mechanistic advances but modeled MYBPC3-HCM or dilated-phase HCM, not confirmed noncompaction morphology. (desai2024mybpc3d389vvariant pages 1-2, mori2024metabolicremodelingand pages 1-2)

7. Anatomical structures affected

Primary organ/system: heart/cardiovascular system.
Primary chamber: left ventricle; severe cases may have biventricular trabeculation or dysfunction.
Typical sites: apical and mid-ventricular myocardium, especially the endocardial trabecular layer.
Tissues: cardiac muscle/myocardium; compacted epicardial and noncompacted endocardial layers.
Cells: ventricular cardiomyocytes; secondary remodeling involves fibroblasts, vascular/endocardial cells, and immune cells.
Subcellular structures: sarcomere, thick filament, myofibril, actin–myosin apparatus, calcium-handling system, mitochondria.
Secondary structures: atrial and ventricular septa in severe biallelic disease; systemic organs may be affected secondarily by heart failure or embolism. (wessels2015compoundheterozygousor pages 2-3, desai2024mybpc3d389vvariant pages 1-2)

Suggested anatomy terms include UBERON:0000948 heart, UBERON:0002084 heart left ventricle, myocardium, interventricular septum, and interatrial septum. The lesion is not meaningfully unilateral in the ordinary paired-organ sense, although ventricular distribution may be regionally asymmetric.

8. Temporal development

Heterozygous disease can be congenital in substrate but clinically silent until childhood or adulthood. Recognition may be incidental, insidious, or triggered by dyspnea, arrhythmia, syncope, embolism, or family screening. Penetrance is incomplete and age-dependent; the retrieved evidence does not provide a reliable LVNC10-specific age curve. (probst2011sarcomeregenemutations pages 8-9)

Biallelic truncating disease is a critical exception: onset is neonatal or early infantile, with diagnosis in the reported series at approximately 4–7 weeks and death at 7–12 weeks. (wessels2015compoundheterozygousor pages 2-3)

The long-term course ranges from stable imaging morphology with preserved function to progressive HCM/DCM, fibrosis, arrhythmia, end-stage heart failure, mechanical support, transplantation, or sudden death. Apparent hypertrabeculation can regress when it is pregnancy- or load-associated; this should not be interpreted as remission of genetically proven LVNC10. (grasso2024thenew2023 pages 1-2)

9. Inheritance and population

Inheritance

Typical heterozygous state: autosomal dominant, incomplete penetrance, variable expressivity.
Biallelic truncating state: severe autosomal-recessive-like neonatal cardiomyopathy; clinically unaffected heterozygous parents were documented at initial evaluation. (wessels2015compoundheterozygousor pages 3-4)
Anticipation: not established.
Germline mosaicism: theoretically possible but not specifically documented in the retrieved LVNC10 evidence.
Consanguinity: can increase biallelic risk but is not required; founder alleles can produce homozygosity or compound heterozygosity.
Founder effects: c.2373dup p.(Trp792fs) and c.2827C>T p.(Arg943*) are Dutch founder alleles. (wessels2015compoundheterozygousor pages 2-3)

For a heterozygous pathogenic variant, each child generally has a 50% transmission probability, but phenotype cannot be predicted reliably. When both parents carry pathogenic MYBPC3 variants, each pregnancy has a 25% probability of inheriting both alleles, 50% of inheriting one, and 25% of inheriting neither, assuming variants are on different parental alleles and ordinary Mendelian segregation.

Epidemiology and demographics

No trustworthy prevalence, incidence, sex ratio, carrier frequency, or geographic distribution is available for genetically confirmed LVNC10. Generic adult LVNC meta-analysis estimated a pooled prevalence of 0.5% and CMR detection of 1.3%, but reported prevalence ranged from 0.014% to 14.79% because of imaging and ascertainment heterogeneity. These values must not be assigned directly to MONDO:0014163. (llerenavelastegui2024prevalenceclinicalmanifestations pages 1-2)

A 2020 meta-analysis of 2,501 generic LVNC patients reported a mean age of 46 years and male:female ratio of 1.7. Again, these are not LVNC10-specific demographics. (aung2020prognosticsignificanceof pages 1-2)

10. Diagnostics

Clinical work-up

A reasonable real-world evaluation includes three-generation pedigree, physical examination, 12-lead ECG, ambulatory ECG monitoring, transthoracic echocardiography, and CMR when morphology, ventricular function, or fibrosis remains uncertain. Exercise testing helps assess functional capacity and exercise-induced arrhythmia. BNP/NT-proBNP and troponin may aid heart-failure or injury assessment but are not diagnostic biomarkers for LVNC10.

Imaging criteria

Commonly used criteria include:

Chin echocardiographic criterion: X/Y ≤0.5.
Jenni criterion: noncompacted-to-compacted myocardial ratio >2 at end systole, with perfused recesses.
Petersen CMR criterion: NC/C ratio ≥2.3 at end diastole.
Jacquier CMR criterion: trabeculated mass >20% of total LV mass. (martineztittonel2025leftventricularnoncompaction pages 5-7)

These criteria are neither mutually concordant nor genotype-specific. The 2023 ESC position cautions that hypertrabeculation occurs in healthy people, athletes, pregnancy, congenital heart disease, anemia, renal disease, and other cardiomyopathies. Diagnosis should therefore integrate function, fibrosis, arrhythmia, family history, and molecular evidence. (grasso2024thenew2023 pages 1-2)

Differential diagnosis

Important alternatives are physiological athlete’s remodeling, pregnancy-related hypertrabeculation, sickle-cell disease or other chronic anemia, DCM or HCM with secondary trabeculation, apical HCM, endocardial fibroelastosis, arrhythmogenic cardiomyopathy, myocarditis, ischemic disease, congenital heart disease, and imaging artifact. Generic LVNC shares substantial genetic architecture with DCM and HCM. (mazzarotto2020thegeneticarchitecture pages 1-3, aung2020prognosticsignificanceof pages 1-2)

Genetic testing

Use a curated cardiomyopathy panel that includes MYBPC3 and validated LVNC/HCM/DCM genes.
Include exon-level deletion/duplication analysis; an entire MYBPC3 deletion has been reported. (kolokotronis2019biallelicmutationin pages 7-9)
In neonatal severe HCM/LVNC, actively evaluate biallelic MYBPC3 variation, phase the variants in parents, and consider rapid trio exome/genome sequencing.
WES/WGS is useful after a negative panel, in syndromic or congenital-malformation cases, or when structural/noncoding variants are suspected.
CMA is appropriate when multiple congenital anomalies or developmental abnormalities suggest a copy-number disorder. Karyotype/FISH, mitochondrial sequencing, and repeat-expansion testing are not routine unless phenotype directs them.
RNA analysis from an informative tissue can clarify splice variants; functional iPSC work remains research-grade.

Endomyocardial biopsy is not routinely needed solely to diagnose LVNC10; the ESC commentary confines biopsy mainly to selected myocarditis, restrictive, and infiltrative disorders. (grasso2024thenew2023 pages 1-2)

Screening

When a pathogenic/likely pathogenic familial MYBPC3 variant is known, offer targeted cascade testing. First-degree relatives should receive genetic counseling and baseline ECG/echocardiography; periodic follow-up is individualized by age, genotype, symptoms, and family history. Genotype-negative relatives for the known familial variant can generally be released from variant-driven surveillance unless clinical findings independently warrant follow-up.

11. Outcomes and prognosis

The strongest subtype-specific adverse signal is biallelic truncation: all four Wessels infants died before 13 weeks, and 15/21 literature cases died before one year. (wessels2015compoundheterozygousor pages 1-2)

For generic LVNC, the 2020 meta-analysis of 28 studies and 2,501 patients found, per 100 person-years:

cardiovascular mortality 1.92 (95% CI 1.54–2.30);
all-cause mortality 2.16;
stroke/systemic embolism 1.54;
heart-failure admission 3.53;
transplantation 1.24;
ventricular arrhythmia 2.17; and
cardiac-device implantation 2.66.

Cardiovascular mortality was similar to DCM (OR 1.10, 95% CI 0.18–6.67), and LVEF rather than trabeculation burden was the major determinant of outcome. The authors’ abstract states: “Left ventricular ejection fraction—a conventional indicator of heart failure severity, not the extent of trabeculation—appears to be an important determinant of adverse outcomes.” Published January 2020; DOI: https://doi.org/10.1161/CIRCIMAGING.119.009712. (aung2020prognosticsignificanceof pages 1-2)

The 2024 adult meta-analysis reported mortality of 12% and transplantation of 7%; NYHA III/IV status, ventricular tachycardia, and reduced LVEF predicted adverse outcomes. These remain generic estimates. (llerenavelastegui2024prevalenceclinicalmanifestations pages 1-2)

Thromboembolism prevalence was 2.6% in children and 6.2% in adults, with annual incidences of 1.4% and 2.9%. In children, LVEF <40% was associated with thromboembolism (OR 9.47; 95% CI 1.35–188.23). Published May 2022; DOI: https://doi.org/10.1136/openhrt-2021-001908. (hirono2022thromboemboliceventsin pages 1-2)

No LVNC10-specific five- or ten-year survival estimate, life expectancy, validated prognostic calculator, or quality-of-life dataset exists.

12. Treatment

Current strategy

No therapy is approved specifically for LVNC10 or for correction of MYBPC3-related noncompaction. Care is phenotype-directed:

Heart failure with reduced EF: guideline-directed therapy, ordinarily including an ARNI/ACE inhibitor/ARB, evidence-based beta blocker, mineralocorticoid-receptor antagonist, and SGLT2 inhibitor as tolerated; diuretics for congestion.
Arrhythmia: beta blockade or other rhythm/rate treatment according to arrhythmia type; catheter ablation where appropriate.
ICD: standard primary- or secondary-prevention indications based on LVEF, documented malignant ventricular arrhythmia, arrest, syncope, fibrosis, and the broader cardiomyopathy risk profile—not trabeculation alone.
Anticoagulation: indicated for atrial fibrillation, documented intracardiac thrombus, prior systemic embolism, or another standard indication. Routine anticoagulation solely for trabeculation remains unsupported and controversial. (hirono2022thromboemboliceventsin pages 1-2)
Advanced disease: cardiac resynchronization when standard criteria are met, ventricular-assist support, or heart transplantation.
Congenital defects: surgical/interventional repair when hemodynamically indicated.

Suggested NCIT intervention concepts include cardiac MRI, echocardiography, genetic testing, anticoagulant therapy, implantable cardioverter-defibrillator placement, cardiac-resynchronization therapy, ventricular-assist device, and heart transplantation.

Experimental and genotype-directed therapy

A 2024 MYBPC3 p.Asp389Val cardiac-organoid study demonstrated hypercontractility, faster calcium cycling, oxidative stress, and reduced mitochondrial membrane potential; mavacamten improved hypercontractility. The abstract states that the hypercontractile phenotype was “rescued by the administration of a myosin inhibitor.” Published November 19, 2024; DOI: https://doi.org/10.3390/cells13221913. This is an HCM organoid result, not clinical evidence for LVNC10, and mavacamten should not be considered an established LVNC10 therapy. (desai2024mybpc3d389vvariant pages 1-2)

A second 2024 study of MYBPC3 c.1377delC iPSC-cardiomyocytes found disrupted sarcomeres, damaged mitochondria, abnormal calcium handling, a hypermetabolic state, and increased electron-transport gene expression. Published July 2024; DOI: https://doi.org/10.1038/s41598-024-62530-0. It supplies mechanistic and drug-screening infrastructure, not a validated diagnostic or treatment. (mori2024metabolicremodelingand pages 1-2)

No LVNC10-specific gene therapy, CRISPR therapy, ASO, siRNA, cell therapy, or pharmacogenomic dosing recommendation is clinically available.

Trials and implementation

NCT06024759, “Predictors of Risk in Left Ventricular Non-Compaction,” is a recruiting, observational, case-only registry targeting 500 adults and ten years of follow-up. It examines genetic variants, myocardial strain, LV dysfunction, Holter/stress-test arrhythmia markers, and predictors of ICD implantation. It began September 1, 2023, was first posted September 6, 2023, and has estimated completion in August 2033. It is generic LVNC research, not an intervention or LVNC10-specific trial. ClinicalTrials.gov URL: https://clinicaltrials.gov/study/NCT06024759. (NCT06024759 chunk 1, NCT06024759 chunk 2)

13. Prevention

Primary prevention

The occurrence of a de novo or inherited pathogenic MYBPC3 variant cannot currently be prevented by lifestyle modification. There is no vaccine, medication, or environmental intervention that prevents LVNC10.

Secondary prevention

genetic counseling and cascade testing;
serial ECG, ambulatory monitoring, echocardiography, and CMR when indicated;
early treatment of ventricular dysfunction and arrhythmia;
prenatal diagnosis or preimplantation genetic testing when familial pathogenic variants are known and parents desire these options;
rapid parental testing after a severe neonatal presentation to define phase and recurrence risk.

Tertiary prevention

Guideline-directed heart-failure therapy, rhythm surveillance, ICD use under standard indications, anticoagulation for established risk states, and timely referral for advanced-heart-failure therapy aim to prevent hospitalization, embolism, sudden death, and end-organ damage. General vaccination is appropriate for cardiovascular health but is not etiologic prevention.

14. Other species and natural disease

Danio rerio (zebrafish), NCBI Taxon 7955: has a conserved mybpc3 ortholog. Experimental knockout/knockdown causes cardiac hypertrophy, diastolic dysfunction, abnormal calcium reuptake, electrical alternans, cardiomyocyte hyperplasia, and reduced endurance. (da’as2022transcriptomeprofileidentifies pages 11-13, chen2013inactivationofmyosin pages 1-2)
Domestic cat: naturally occurring MYBPC3-associated HCM is documented in veterinary genetics, but the retrieved evidence did not establish a consistent natural LVNC10-equivalent syndrome or a validated breed ontology annotation.
Zoonosis/transmission: not applicable; this is inherited disease, not infection.

Natural noncompaction in another species specifically attributable to orthologous MYBPC3 variation was not established by the retrieved sources.

15. Model organisms and experimental systems

Zebrafish

Morpholino knockdown of mybpc3 produced ventricular hypertrophy, increased wall thickness, impaired diastolic relaxation, pericardial effusion, atrial dilation, prolonged action-potential duration, slowed calcium reuptake, and susceptibility to calcium-transient and action-potential alternans. Published September 2013; DOI: https://doi.org/10.1161/JAHA.113.000231. (chen2013inactivationofmyosin pages 1-2)

A stable knockout model showed larval cardiomyocyte hyperplasia, reduced chamber dimensions, increased EF, and later ventricular-wall thickening, bradycardia, and reduced swimming endurance. Transcriptomics identified downregulation of actin-filament processes and changes in hypertrophy, calcium-handling, contraction, and cardiac-development programs. Published August 2022; DOI: https://doi.org/10.3390/ijms23168840. (da’as2022transcriptomeprofileidentifies pages 11-13, da’as2022transcriptomeprofileidentifies pages 2-4)

Limitation: these fish reproduce HCM/heart-failure and electrophysiologic features, not demonstrated left-ventricular noncompaction. Zebrafish also lack the human four-chamber ventricular anatomy.

Human cellular models

Patient-derived or engineered iPSC-cardiomyocytes and multicellular cardiac organoids permit contractility, calcium, mitochondrial, transcriptomic, spatial-cellular, and drug-response measurements. The 2024 studies provide evidence for sarcomere disruption, metabolic remodeling, oxidative stress, and hypercontractility. Their principal limitations are cellular immaturity, model-specific loading conditions, and modeling of HCM/dilated-HCM rather than validated LVNC morphology. (desai2024mybpc3d389vvariant pages 1-2, mori2024metabolicremodelingand pages 1-2)

Mouse models

MYBPC3 mouse models are extensively used in HCM research, but the retrieved evidence did not identify a patient-variant mouse model that reproducibly recapitulates LVNC10 morphology. Mouse findings should therefore support cMyBP-C biology, not be asserted as direct LVNC10 validation.

Recent developments and expert interpretation, 2023–2024

Nosologic shift: The 2023 ESC cardiomyopathy guidance, summarized in April 2024, treats hypertrabeculation as a dynamic trait across healthy, adaptive, congenital, hematologic, renal, and cardiomyopathic states. Expert practice consequently emphasizes deep phenotyping and genetics over an imaging ratio alone. DOI: https://doi.org/10.1093/eurheartjsupp/suae002. (grasso2024thenew2023 pages 1-2)
Updated epidemiology: The October 2024 meta-analysis estimated generic adult LVNC prevalence at 0.5%, mortality at 12%, and transplantation at 7%, while emphasizing heterogeneity and the adverse importance of NYHA III/IV status, ventricular tachycardia, and reduced LVEF. DOI: https://doi.org/10.14740/cr1673. (llerenavelastegui2024prevalenceclinicalmanifestations pages 1-2)
Functional precision models: 2024 MYBPC3 iPSC and organoid studies connected sarcomeric variants to calcium-handling defects, mitochondrial/energetic remodeling, oxidative stress, and drug-responsive hypercontractility. These are promising for variant interpretation and screening but do not yet bridge MYBPC3 dysfunction specifically to noncompaction morphogenesis. (desai2024mybpc3d389vvariant pages 1-2, mori2024metabolicremodelingand pages 1-2)
Prospective risk research: NCT06024759 is implementing a 500-person, decade-long registry combining genetics, strain, arrhythmia burden, ventricular function, and ICD outcomes. (NCT06024759 chunk 1)

Knowledge gaps and curation cautions

No reliable LVNC10-specific prevalence, incidence, sex ratio, penetrance curve, survival curve, or treatment-response rate exists.
Generic LVNC statistics should be tagged as indirect evidence for LVNC10.
Imaging morphology alone should not be equated with genetic disease.
The direct developmental mechanism connecting cMyBP-C deficiency to excessive trabeculation remains inferred.
No validated protective factor, environmental cause, epigenetic signature, circulating biomarker, or targeted therapy is established.
Exact ClinVar status and population frequency must be checked separately for every variant and transcript version.
PMID metadata was not consistently exposed in the retrieved full texts; DOIs and publication dates above are supplied where verified rather than assigning uncertain PMIDs.

References

(OpenTargets Search: Left ventricular noncompaction 10): Open Targets Query (Left ventricular noncompaction 10, 23 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(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.
(probst2011sarcomeregenemutations pages 8-9): Susanne Probst, Erwin Oechslin, Pia Schuler, Matthias Greutmann, Philipp Boyé, Walter Knirsch, Felix Berger, Ludwig Thierfelder, Rolf Jenni, and Sabine Klaassen. Sarcomere gene mutations in isolated left ventricular noncompaction cardiomyopathy do not predict clinical phenotype. Circulation: Cardiovascular Genetics, 4:367–374, Aug 2011. URL: https://doi.org/10.1161/circgenetics.110.959270, doi:10.1161/circgenetics.110.959270. This article has 268 citations.
(wessels2015compoundheterozygousor pages 1-2): Marja W Wessels, Johanna C Herkert, Ingrid M Frohn-Mulder, Michiel Dalinghaus, Arthur van den Wijngaard, Ronald R de Krijger, Michelle Michels, Irenaeus FM de Coo, Yvonne M Hoedemaekers, and Dennis Dooijes. Compound heterozygous or homozygous truncating mybpc3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects. European Journal of Human Genetics, 23:922-928, Oct 2015. URL: https://doi.org/10.1038/ejhg.2014.211, doi:10.1038/ejhg.2014.211. This article has 121 citations and is from a domain leading peer-reviewed journal.
(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 281 citations and is from a highest quality peer-reviewed journal.
(hirono2022leftventricularnoncompaction pages 1-2): Keiichi Hirono and Fukiko Ichida. Left ventricular noncompaction: a disorder with genotypic and phenotypic heterogeneity—a narrative review. Cardiovascular Diagnosis and Therapy, 12:495-515, Aug 2022. URL: https://doi.org/10.21037/cdt-22-198, doi:10.21037/cdt-22-198. This article has 24 citations.
(wessels2015compoundheterozygousor pages 2-3): Marja W Wessels, Johanna C Herkert, Ingrid M Frohn-Mulder, Michiel Dalinghaus, Arthur van den Wijngaard, Ronald R de Krijger, Michelle Michels, Irenaeus FM de Coo, Yvonne M Hoedemaekers, and Dennis Dooijes. Compound heterozygous or homozygous truncating mybpc3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects. European Journal of Human Genetics, 23:922-928, Oct 2015. URL: https://doi.org/10.1038/ejhg.2014.211, doi:10.1038/ejhg.2014.211. This article has 121 citations and is from a domain leading peer-reviewed journal.
(wessels2015compoundheterozygousor pages 5-6): Marja W Wessels, Johanna C Herkert, Ingrid M Frohn-Mulder, Michiel Dalinghaus, Arthur van den Wijngaard, Ronald R de Krijger, Michelle Michels, Irenaeus FM de Coo, Yvonne M Hoedemaekers, and Dennis Dooijes. Compound heterozygous or homozygous truncating mybpc3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects. European Journal of Human Genetics, 23:922-928, Oct 2015. URL: https://doi.org/10.1038/ejhg.2014.211, doi:10.1038/ejhg.2014.211. This article has 121 citations and is from a domain leading peer-reviewed journal.
(mazzarotto2020thegeneticarchitecture pages 1-3): 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. The genetic architecture of left ventricular non-compaction reveals both substantial overlap with other cardiomyopathies and a distinct aetiology in a subset of cases. European Heart Journal, Jan 2020. URL: https://doi.org/10.1101/2020.01.03.19015602, doi:10.1101/2020.01.03.19015602. This article has 4 citations and is from a highest quality peer-reviewed journal.
(wessels2015compoundheterozygousor pages 3-4): Marja W Wessels, Johanna C Herkert, Ingrid M Frohn-Mulder, Michiel Dalinghaus, Arthur van den Wijngaard, Ronald R de Krijger, Michelle Michels, Irenaeus FM de Coo, Yvonne M Hoedemaekers, and Dennis Dooijes. Compound heterozygous or homozygous truncating mybpc3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects. European Journal of Human Genetics, 23:922-928, Oct 2015. URL: https://doi.org/10.1038/ejhg.2014.211, doi:10.1038/ejhg.2014.211. This article has 121 citations and is from a domain leading peer-reviewed journal.
(wang2017awideand pages 1-2): Ce Wang, Yukiko Hata, Keiichi Hirono, Asami Takasaki, Sayaka Watanabe Ozawa, Hideyuki Nakaoka, Kazuyoshi Saito, Nariaki Miyao, Mako Okabe, Keijiro Ibuki, Naoki Nishida, Hideki Origasa, Xianyi Yu, Neil E. Bowles, and Fukiko Ichida. A wide and specific spectrum of genetic variants and genotype–phenotype correlations revealed by next‐generation sequencing in patients with left ventricular noncompaction. Sep 2017. URL: https://doi.org/10.1161/jaha.117.006210, doi:10.1161/jaha.117.006210. This article has 79 citations.
(martineztittonel2025leftventricularnoncompaction pages 5-7): Luis Elias Martínez-Tittonel, Florin Ciorba, Xavier Bayona-Huguet, and Edgardo Kaplinsky. Left ventricular non-compaction cardiomyopathy: a review of the pathophysiology, epidemiology, diagnosis, genetics, and clinical management. Jul 2025. URL: https://doi.org/10.20944/preprints202507.1652.v1, doi:10.20944/preprints202507.1652.v1.
(llerenavelastegui2024prevalenceclinicalmanifestations pages 1-2): Jordan Llerena-Velastegui, Almendra Lopez-Usina, and Camila Mantilla-Cisneros. Prevalence, clinical manifestations, and adverse outcomes of left ventricular noncompaction in adults: a systematic review and meta-analysis. Oct 2024. URL: https://doi.org/10.14740/cr1673, doi:10.14740/cr1673. This article has 6 citations.
(aung2020prognosticsignificanceof pages 1-2): Nay Aung, Sara Doimo, Fabrizio Ricci, Mihir M. Sanghvi, Cesar Pedrosa, Simon P. Woodbridge, Amer Al-Balah, Filip Zemrak, Mohammed Y. Khanji, Patricia B. Munroe, Huseyin Naci, and Steffen E. Petersen. Prognostic significance of left ventricular noncompaction. Circulation. Cardiovascular Imaging, 13:e009712-e009712, Jan 2020. URL: https://doi.org/10.1161/circimaging.119.009712, doi:10.1161/circimaging.119.009712. This article has 143 citations.
(hirono2022thromboemboliceventsin pages 1-2): Keiichi Hirono, Shinya Takarada, Nariaki Miyao, Hideyuki Nakaoka, Keijiro Ibuki, Sayaka Ozawa, Hideki Origasa, and Fukiko Ichida. Thromboembolic events in left ventricular non-compaction: comparison between children and adults – a systematic review and meta-analysis. Open Heart, 9(1):e001908, May 2022. URL: https://doi.org/10.1136/openhrt-2021-001908, doi:10.1136/openhrt-2021-001908. This article has 23 citations and is from a peer-reviewed journal.
(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.
(desai2024mybpc3d389vvariant pages 1-2): Darshini Desai, Taejeong Song, Rohit R. Singh, Akhil Baby, James McNamara, Lisa C. Green, Pooneh Nabavizadeh, Mark Ericksen, Sholeh Bazrafshan, Sankar Natesan, and Sakthivel Sadayappan. Mybpc3 d389v variant induces hypercontractility in cardiac organoids. Nov 2024. URL: https://doi.org/10.3390/cells13221913, doi:10.3390/cells13221913. This article has 10 citations.
(mori2024metabolicremodelingand pages 1-2): Haruka Mori, Dongzhu Xu, Yuzuno Shimoda, Zixun Yuan, Yoshiko Murakata, Binyang Xi, Kimi Sato, Masayoshi Yamamoto, Kazuko Tajiri, Tomoko Ishizu, Masaki Ieda, and Nobuyuki Murakoshi. Metabolic remodeling and calcium handling abnormality in induced pluripotent stem cell-derived cardiomyocytes in dilated phase of hypertrophic cardiomyopathy with mybpc3 frameshift mutation. Jul 2024. URL: https://doi.org/10.1038/s41598-024-62530-0, doi:10.1038/s41598-024-62530-0. This article has 13 citations and is from a peer-reviewed journal.
(da’as2022transcriptomeprofileidentifies pages 11-13): Sahar Isa Da’as, Waseem Hasan, Rola Salem, Nadine Younes, Doua Abdelrahman, Iman A. Mohamed, Arwa Aldaalis, Ramzi Temanni, Lisa Sara Mathew, Stephan Lorenz, Magdi Yacoub, Michail Nomikos, Gheyath K. Nasrallah, and Khalid A. Fakhro. Transcriptome profile identifies actin as an essential regulator of cardiac myosin binding protein c3 hypertrophic cardiomyopathy in a zebrafish model. Aug 2022. URL: https://doi.org/10.3390/ijms23168840, doi:10.3390/ijms23168840. This article has 9 citations.
(chen2013inactivationofmyosin pages 1-2): Yau‐Hung Chen, Chiung‐Wen Pai, Shu‐Wei Huang, Sheng‐Nan Chang, Lian‐Yu Lin, Fu‐Tien Chiang, Jiunn‐Lee Lin, Juey‐Jen Hwang, and Chia‐Ti Tsai. Inactivation of myosin binding protein c homolog in zebrafish as a model for human cardiac hypertrophy and diastolic dysfunction. Sep 2013. URL: https://doi.org/10.1161/jaha.113.000231, doi:10.1161/jaha.113.000231. This article has 44 citations.
(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
(NCT06024759 chunk 2): 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
(da’as2022transcriptomeprofileidentifies pages 1-2): Sahar Isa Da’as, Waseem Hasan, Rola Salem, Nadine Younes, Doua Abdelrahman, Iman A. Mohamed, Arwa Aldaalis, Ramzi Temanni, Lisa Sara Mathew, Stephan Lorenz, Magdi Yacoub, Michail Nomikos, Gheyath K. Nasrallah, and Khalid A. Fakhro. Transcriptome profile identifies actin as an essential regulator of cardiac myosin binding protein c3 hypertrophic cardiomyopathy in a zebrafish model. Aug 2022. URL: https://doi.org/10.3390/ijms23168840, doi:10.3390/ijms23168840. This article has 9 citations.
(da’as2022transcriptomeprofileidentifies pages 2-4): Sahar Isa Da’as, Waseem Hasan, Rola Salem, Nadine Younes, Doua Abdelrahman, Iman A. Mohamed, Arwa Aldaalis, Ramzi Temanni, Lisa Sara Mathew, Stephan Lorenz, Magdi Yacoub, Michail Nomikos, Gheyath K. Nasrallah, and Khalid A. Fakhro. Transcriptome profile identifies actin as an essential regulator of cardiac myosin binding protein c3 hypertrophic cardiomyopathy in a zebrafish model. Aug 2022. URL: https://doi.org/10.3390/ijms23168840, doi:10.3390/ijms23168840. This article has 9 citations.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	18
Resolved	18
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	18
On topic	10
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	5
Resolved	5
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	2
Terms named correctly	0
Terms named as a different term	2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0014163 (7 mentions) - the report calls it "if available"; MONDO calls it left ventricular noncompaction 10
HP:0011664 (7 mentions) - the report calls it "Imaging sign; congenital substrate or later-recognized trait; severity and progression variable"; HP calls it Left ventricular noncompaction cardiomyopathy

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OpenScientist Report

Classifications

Inheritance

Subtypes

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Variants

Medical Actions

Diagnosis

Progression

Prevalence

Clinical Burden

Differential Diagnoses

Related Datasets

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Left Ventricular Noncompaction 10: Disease-Characteristics Report

Executive summary and scope

1. Disease information

Definition

Identifiers and synonyms

2. Etiology

Causal factors and genetic risk

Environmental, lifestyle, and gene–environment factors

Protective factors

3. Phenotypes

Core and associated phenotypes

Severe biallelic phenotype

Heterozygous phenotype and quality of life

4. Genetic and molecular information

Causal gene

Documented variants and consequences

Variant interpretation

Modifiers, epigenetics, and chromosomal abnormalities

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Pathways, processes, and ontology suggestions

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

Inheritance

Epidemiology and demographics

10. Diagnostics

Clinical work-up

Imaging criteria

Differential diagnosis

Genetic testing

Screening

11. Outcomes and prognosis

12. Treatment

Current strategy

Experimental and genotype-directed therapy

Trials and implementation

13. Prevention

Primary prevention

Secondary prevention

Tertiary prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Zebrafish

Human cellular models

Mouse models

Recent developments and expert interpretation, 2023–2024

Knowledge gaps and curation cautions

Artifacts

Reference Validation

Term Validation

Terms the report names something else