Hypertrophic Cardiomyopathy 4

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Classifications

Harrison's Part

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Inheritance

2

Autosomal dominant (monoallelic truncating variants) HP:0000006

The classic CMH4 presentation is autosomal dominant, with a single truncating MYBPC3 allele acting through cMyBP-C haploinsufficiency. Penetrance is incomplete and strongly age-dependent, and is higher in male than in female carriers, so cascade screening must be longitudinal rather than a single evaluation.

Autosomal dominant inheritance Penetrance: INCOMPLETE Penetrance %: 56.9%

Show evidence (4 references)

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

ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel classifies the MYBPC3-hypertrophic cardiomyopathy relationship as Definitive with autosomal dominant inheritance.

PMID:22267749 SUPPORT Human Clinical

"Disease penetrance was, therefore, incomplete (56.9% in all mutation carriers, 34.5% in relatives), related to age (38.4% <40 versus 68.6% ≥40 years, P<0.001), and was greater in males than females (65.1% versus 48.1%, P=0.03)."

Source of the 56.9% overall penetrance figure and of the age- and sex-dependence of expression in heterozygous MYBPC3 carriers.

PMID:37929589 SUPPORT Human Clinical

"Penetrance varied from ≈32% for MYL3 (myosin light chain 3) to ≈55% for MYBPC3 (myosin-binding protein C3)"

Meta-analytic, MYBPC3-specific penetrance estimate of about 55% among relatives carrying a P/LP variant, consistent with the family-series figure.

+ 1 more reference

Autosomal recessive (biallelic truncating variants) HP:0000007

When two truncating MYBPC3 alleles are inherited - homozygously (typically in founder populations or consanguineous families) or as compound heterozygotes - cMyBP-C is effectively absent and the phenotype is a severe, usually lethal neonatal cardiomyopathy. The heterozygous parents are asymptomatic or mildly affected, so the dose effect behaves recessively at the neonatal-severity threshold even though the heterozygous state is itself a dominant disease allele.

Autosomal recessive inheritance

Show evidence (2 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 the biallelic genotype is uniformly severe across all reported cases, defining the recessive-severity arm of this entity.

PMID:41488457 SUPPORT Human Clinical

"WES identified compound heterozygous pathogenic variants in MYBPC3: a known paternal splice-site variant (c.2905+1G>A) and a novel maternal truncating frameshift variant (c.836del; p.Gly279Valfs*21)."

Documents biparental inheritance of two loss-of-function MYBPC3 alleles in a lethal neonatal case, the compound-heterozygous route to the biallelic phenotype.

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Subtypes

2

Monoallelic (heterozygous) MYBPC3 hypertrophic cardiomyopathy

The classic autosomal dominant form. A single truncating (or, less often, missense) MYBPC3 allele produces cMyBP-C haploinsufficiency. Penetrance is incomplete, age-related and higher in males; hypertrophy is typically discrete, ejection fraction is usually preserved, and the annual event rate is low.

Show evidence (2 references)

PMID:22267749 SUPPORT Human Clinical

"Disease penetrance was, therefore, incomplete (56.9% in all mutation carriers, 34.5% in relatives), related to age (38.4% <40 versus 68.6% ≥40 years, P<0.001), and was greater in males than females (65.1% versus 48.1%, P=0.03)."

Quantifies the defining features of the heterozygous subtype - incomplete, age-related and male-biased penetrance - in a large family series of MYBPC3 mutation carriers.

PMID:39581692 SUPPORT Human Clinical

"Hypertrophy was discrete with a significative difference between probands and relatives (17.5±4 mm vs 14.6±5 mm; p<0.0001). Ejection fraction was predominantly preserved (65%±10%)."

A molecularly homogeneous truncating-MYBPC3 cohort documents the discrete hypertrophy and preserved systolic function that characterise the monoallelic subtype.

Biallelic (homozygous/compound heterozygous) MYBPC3 neonatal cardiomyopathy

The severe neonatal form named in the MONDO definition of hypertrophic cardiomyopathy 4. Two truncating MYBPC3 alleles abolish cMyBP-C, producing severe cardiomyopathy presenting in the first days to weeks of life, commonly with left ventricular noncompaction features and septal defects, and death from cardiac failure within the first months. Parents, as obligate heterozygotes, are typically asymptomatic or have mild adult-onset disease.

Show evidence (2 references)

PMID:25335496 SUPPORT Human Clinical

"In contrast to heterozygous pathogenic mutations, homozygous or compound heterozygous truncating pathogenic MYBPC3 mutations cause severe neonatal cardiomyopathy with features of left ventricular noncompaction and septal defects in approximately 60% of patients."

States the mono- versus bi-allelic contrast explicitly and defines the biallelic subtype as severe neonatal cardiomyopathy with noncompaction and septal defects.

PMID:41488457 SUPPORT Human Clinical

"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."

Independently characterises the biallelic MYBPC3 entity as a rare, lethal neonatal form of HCM, corroborating the subtype definition.

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Discussions and Knowledge Gaps

4

Is reduced cMyBP-C protein level sufficient to explain the disease caused by MYBPC3 truncating alleles, or do parallel mechanisms contribute before, or independently of, any measurable fall in protein?

CONTROVERSY OPEN mybpc3_haploinsufficiency_sufficiency

Attached to

pathophysiology#cMyBP-C Depletion by Nonsense-Mediated Decay and Proteasomal Degradation genetic#MYBPC3

This entry curates haploinsufficiency as the operative mechanism, and the human evidence for it is strong: myectomy tissue shows reduced full-length cMyBP-C with no detectable truncated peptide, a promoter deletion that can produce no peptide at all still causes the disease, and outcome is independent of where in the gene the truncation falls. The challenge is not to that evidence but to its sufficiency. Heterozygous MYBPC3-null iPSC cardiomyocytes maintain normal cMyBP-C protein despite allelic loss of function - compensating through reduced degradation - yet still show contractile and calcium-handling defects; haploinsufficiency becomes measurable only when protein demand rises, as in three-dimensional engineered tissue or under hypertrophic stress. If dysfunction can precede the protein deficit, protein level is not the whole mechanism. This matters therapeutically: the gene-replacement strategy curated in this entry is predicated on dose restoration being sufficient to reverse disease.

Proposed experiments

Quantify myofibrillar cMyBP-C in genotype-positive, phenotype-negative human myocardium

exp_mybpc3_preclinical_carrier_myofibrillar_protein

The decisive missing measurement is whether cMyBP-C is already reduced in carriers before hypertrophy appears. Myectomy tissue comes only from symptomatic patients, so protein content in asymptomatic carriers is essentially unmeasured. An explant-bank or imaging-guided biopsy study stratified by phenotype status would establish whether the deficit precedes or follows remodeling, and therefore whether dose restoration alone is a sufficient therapeutic target.

Show evidence (4 references)

PMID:36946992 SUPPORT Other

"While haploinsufficiency of cMyBP-C has been previously demonstrated (Helms et al., 2014; Barefield et al., 2015; Glazier et al., 2019), the necessity and sufficiency of simply reducing protein levels to cause all the observed phenotypic changes remains unclear."

States the open question directly. Evidence source is OTHER because this is a commentary rather than primary data.

PMID:36946992 SUPPORT Other

"These data from mouse models are in-line with the results from De Lange et al. (2023) and suggest that there is more going on here than a pure haploinsufficiency mechanism"

Summarises the case that a pure dose model is incomplete. PARTIAL because it is an interpretive claim in a commentary, not a measurement.

PMID:31877118 SUPPORT In Vitro

"Despite a reduction in wild-type mRNA in all heterozygous iPSCMs, no reduction in MyBP-C protein was observed, indicating protein-level compensation through what we believe is a previously uncharacterized mechanism."

The primary observation behind the challenge: allelic loss of function at the mRNA level without a protein deficit, in heterozygous human iPSC cardiomyocytes.

+ 1 more reference

Why is MYBPC3 penetrance far lower in unselected population cohorts than in clinically ascertained families, and how much of the gap is ascertainment bias versus genuine modifier burden or environmental exposure?

KNOWLEDGE GAP OPEN mybpc3_penetrance_ascertainment_discrepancy

Attached to

pathophysiology#Gene-Dosage-Dependent Severity Gradient

The penetrance figure quoted to a family decides whether a genotype-positive relative is told they have a substantial chance of developing disease or a small one, so this discrepancy is not academic. Family cohorts give incomplete but substantial penetrance that roughly doubles after age 40, whereas unselected population cohorts give far lower estimates. The two populations differ in ascertainment - families are ascertained through an affected proband and are therefore enriched for whatever made that proband affected - but they may also differ in modifier burden, comorbidity and physical-activity exposure. Until those sources are separated, neither number is straightforwardly the right one to counsel with, which is why this entry records the family-cohort figures with their ascertainment context rather than presenting a single penetrance value.

Show evidence (1 reference)

PMID:22267749 SUPPORT Human Clinical

"Disease penetrance was, therefore, incomplete (56.9% in all mutation carriers, 34.5% in relatives), related to age (38.4% <40 versus 68.6% ≥40 years, P<0.001)"

The clinical-family pole of the discrepancy. Note that penetrance already differs substantially between probands and relatives within this single study - an ascertainment gradient visible inside one cohort.

Heterozygous Mybpc3 mice remain phenotype-negative while human heterozygotes develop disease at substantial rates - which human population, if any, does the heterozygous mouse actually model?

HUMAN MODEL MISMATCH OPEN mybpc3_heterozygous_mouse_phenotype_negative

Attached to

pathophysiology#Gene-Dosage-Dependent Severity Gradient pathophysiology#Myosin Shift from the Super-Relaxed to the Disordered-Relaxed State

This entry curates a mouse allelic series as experimental confirmation of the dose gradient, and for the homozygous pole that is exactly what it provides. The heterozygous pole is where model and disease part company: knock-in heterozygotes for the Dutch founder variant did not develop HCM at the ages studied, and the same negative result appears independently in the super-relaxed-state measurements, where heterozygous cMyBP-C knockout mice were indistinguishable from wild type while homozygotes showed a clear deficit. Human heterozygotes are the common form of this disease. The divergence is mechanistically informative rather than merely technical - it is consistent with the compensation capacity documented in heterozygous human iPSC cardiomyocytes, and it suggests murine heterozygotes may model the genotype-positive, phenotype-negative carrier rather than the patient. It also constrains what the models can be used for: a heterozygous mouse cannot demonstrate that a therapy prevents phenotype conversion if it never converts.

Proposed experiments

Stress-challenge and aged-cohort phenotyping of heterozygous Mybpc3 knock-in mice

exp_mybpc3_heterozygous_mouse_stress_challenge

Test whether the heterozygous mouse is truly phenotype-negative or merely unstressed and studied too young, by phenotyping aged cohorts and cohorts challenged with pressure overload, exercise, or dietary stress. A heterozygote that converts under challenge would model the human carrier whose penetrance rises after age 40; one that never converts marks a genuine species difference in compensation capacity, and would mean preventive-therapy trials cannot use this model as their test bed.

Show evidence (2 references)

PMID:37844837 SUPPORT Model Organism

"Expectedly, knock-in of Mybpc3c.2373InsG resulted in the absence of cMyBP-C and our 18-28 week old homozygous Mybpc3c.2373InsG model developed cardiac hypertrophy and severe left ventricular systolic and diastolic dysfunction, whereas HCM was not evident in Mybpc3+/InsG mice."

Documents the phenotype-negative heterozygote alongside the severely affected homozygote in the same allelic series.

PMID:27021517 SUPPORT Model Organism

"We report a significant decrease in the proportion of myosin heads in the SRX state in homozygous cMyBP-C knockout mice, however heterozygous cMyBP-C knockout mice do not significantly differ from the wild type."

Independent replication of the heterozygous-negative result at the molecular level, in a different mouse line with a different assay.

Do the curated MYBPC3 model systems reproduce myocyte disarray and dynamic outflow obstruction - the pathognomonic human lesion and the dominant human clinical problem - or are both unavailable in every model this entry relies on?

HUMAN MODEL MISMATCH OPEN mybpc3_disarray_and_obstruction_not_modeled

Attached to

pathophysiology#Ventricular Hypertrophy, Disarray and Fibrosis

Two features that define this disease clinically are absent from the models used to study it. Myocyte disarray is the pathognomonic human histological lesion and is documented in human MYBPC3 hearts; the mouse allelic series curated in this entry reports echocardiography, histology and cardiomyocyte contractility without reporting disarray, and engineered cardiac tissue has no ventricular architecture within which disarray could even be defined. Dynamic left ventricular outflow tract obstruction with systolic anterior motion - the target of both approved drugs and the endpoint of every trial cited here - depends on ventricular geometry and mitral-apparatus anatomy that small-animal and engineered-tissue systems do not reproduce. The practical consequence is a division of evidential labour that this entry makes explicit: the models carry the molecular and dose arguments, while every claim about relief of obstruction rests entirely on human trial data.

Proposed experiments

Large-animal MYBPC3 model phenotyped for disarray and outflow-tract dynamics

exp_mybpc3_large_animal_disarray_and_lvot

A large-animal model with human-like ventricular geometry - the base-edited MYBPC3 pig is the obvious starting point - phenotyped specifically for myofibre disarray on histology and for provoked outflow-tract gradients on imaging would establish whether these features are reproducible outside humans, and would give the drug mechanism a non-clinical test bed it currently lacks.

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Pathophysiology

8

MYBPC3 Truncating Variant and Premature Termination Codon Generation

The initiating lesion in CMH4 is a MYBPC3 allele carrying a frameshift, nonsense, or splice-disrupting change that introduces a premature termination codon. A distinctive feature of MYBPC3 relative to other sarcomere disease genes is how many of its pathogenic variants sit in introns and act by aberrant splicing. Despite the frameshift, the predicted truncated cMyBP-C peptide has never been detected in human heart tissue from carriers, arguing against a dominant-negative poison-peptide mechanism at the protein level.

Cardiomyocyte CL:0000746

MYBPC3 hgnc:7551

Sarcomere Organization GO:0045214 ⚠ ABNORMAL

Sarcomeric A band GO:0031672

Downstream

cMyBP-C Depletion by Nonsense-Mediated Decay and Proteasomal Degradation Premature termination codons trigger surveillance pathways that destroy the mutant transcript and protein rather than producing a stable truncated product.

Show evidence (1 reference)

PMID:22057632 SUPPORT Other

"The most striking characteristic of HCM mutations in MYBPC3 is that many are within introns and are predicted to cause aberrant splicing leading to a frameshift and a premature chain termination, yet the truncated peptides have never been identified in human heart tissue carrying these mutations."

Establishes the variant class (intronic/splice-disrupting, frameshift, premature termination) and the absence of detectable truncated peptide in patient myocardium. Evidence source is OTHER because this is a mechanistic review.

cMyBP-C Depletion by Nonsense-Mediated Decay and Proteasomal Degradation

Because the truncated peptide is not stably expressed, the operative consequence of a MYBPC3 truncating allele is a reduction in the amount of functional cMyBP-C in the sarcomere. Nonsense-mediated mRNA decay removes the PTC-containing transcript - measurably starting at the mRNA level in patient myocardium despite hypertrophy-driven upregulation of transcription - and the ubiquitin-proteasome system clears residual mutant protein. UPF3B, an NMD regulator upregulated specifically in MYBPC3-truncating hearts and localised to the sarcomeric Z-disc, has been implicated in establishing this haploinsufficiency during the first round of sarcomeric protein translation. The severity of the resulting phenotype scales with the residual cMyBP-C dose, which is what makes CMH4 a gene-dosage disease.

Cardiomyocyte CL:0000746

Nonsense-Mediated mRNA Decay GO:0000184 ↑ INCREASED Proteasomal Degradation of Mutant cMyBP-C GO:0043161 ↑ INCREASED

Downstream

Myosin Shift from the Super-Relaxed to the Disordered-Relaxed State Reduced cMyBP-C in the A band leaves myosin heads untethered from the thick filament core, depopulating the energy-conserving super-relaxed reserve.

Show evidence (6 references)

PMID:22057632 SUPPORT Other

"Instead of expression of a poison peptide we consistently observe haploinsufficiency of MyBP-C in MYBPC3 mutant human heart muscle."

States the core mechanistic claim - haploinsufficiency rather than a dominant-negative poison peptide - directly in human myocardium. Evidence source is OTHER because this is a mechanistic review.

PMID:19574547 SUPPORT Human Clinical

"The absence of any detectable truncated MyBP-C argues against its incorporation in the myofiber and any dominant negative effect. In contrast, the lowered relative level of full length protein in both truncation and missense MYBPC3 mutations argues strongly that haploinsufficiency is sufficient..."

Primary human data, not review: quantified myofibrillar MyBP-C in genotyped myectomy specimens against donor hearts and found reduced full-length protein with no detectable truncated peptide. This is the direct measurement the haploinsufficiency claim rests on.

PMID:19574547 SUPPORT Human Clinical

"However, the overall level of MyBP-C in myofibrils was significantly reduced (P<0.0005) in tissue containing either a truncation or missense MYBPC3 mutation"

Gives the quantitative reduction in myofibrillar cMyBP-C in patient tissue, and notes it holds for missense as well as truncating alleles.

+ 3 more references

Myosin Shift from the Super-Relaxed to the Disordered-Relaxed State

In the resting sarcomere a substantial fraction of myosin heads sit in the super-relaxed (SRX) state - folded back against the thick filament core with a very low ATPase rate - forming an energy-conserving reserve of motors that are unavailable for force generation. cMyBP-C is what holds them there. Losing cMyBP-C untethers those heads and shifts the population toward the disordered-relaxed (DRX) state, which can hydrolyse ATP and engage the thin filament. This is the step that converts a protein-dose deficit into hypercontractility with raised energetic cost, and it is the step the approved cardiac myosin inhibitors act on: the same work that defines the SRX loss shows that MYK-461 (mavacamten) rescues the relaxation defect and restores normal contractility in MYBPC3-mutant cardiomyocytes. The shift is demonstrated in three independent systems - homozygous cMyBP-C knockout mouse cardiomyocytes, human MYBPC3-mutant myectomy tissue, and stepwise cMyBP-C depletion in vitro - and, importantly for the dose model, the human myectomy data show a positive correlation between residual cMyBP-C expression and the proportion of heads remaining in SRX.

Cardiomyocyte CL:0000746

ATP Hydrolysis by Myosin GO:0016887 ↑ INCREASED

Myosin thick filament GO:0032982

Downstream

Loss of the cMyBP-C Brake on Actin-Myosin Cross-Bridge Cycling Heads released from the super-relaxed reserve are available to form cross-bridges, so the restraint on cross-bridge number and kinetics is lost.

Show evidence (5 references)

PMID:28658286 SUPPORT Human Clinical

"Compared to donors, only MYBPC3mut samples display a significantly diminished SRX, characterised by a decrease in both the number of myosin heads in the SRX and the lifetime of ATP turnover."

Demonstrates SRX loss in human myectomy tissue and, critically, shows it is specific to MYBPC3-mutation-positive hearts rather than a generic consequence of hypertrophy - sarcomere-mutation-negative HCM samples did not show it.

PMID:28658286 SUPPORT Human Clinical

"There was a positive correlation (p < 0.01) between the expression of cMyBP-C and the proportion of myosin heads in the SRX state, suggesting cMyBP-C modulates and maintains the SRX."

Ties the size of the SRX reserve quantitatively to residual cMyBP-C protein level, which is the molecular expression of the gene-dosage gradient this entry models.

PMID:27021517 SUPPORT Model Organism

"We report a significant decrease in the proportion of myosin heads in the SRX state in homozygous cMyBP-C knockout mice, however heterozygous cMyBP-C knockout mice do not significantly differ from the wild type."

Independent in vivo confirmation in the complete-null state. Note the heterozygous result is negative, which is consistent with the phenotype-negative heterozygous mouse recorded in the model-mismatch discussion rather than with the human heterozygous disease.

+ 2 more references

Loss of the cMyBP-C Brake on Actin-Myosin Cross-Bridge Cycling

cMyBP-C normally tethers and restrains myosin heads in the thick-filament C-zone, limiting the number of cross-bridges available for force generation and slowing cross-bridge kinetics. When cMyBP-C is reduced or absent, this brake is released: myofilament calcium sensitivity rises and the contraction-relaxation cycle is disturbed, producing hypercontractility with impaired relaxation. Direct calcium-handling consequences follow, with progressively slowed calcium release as cMyBP-C content falls.

Ventricular cardiomyocyte CL:0002131

Actin-Myosin Filament Sliding GO:0033275 ↑ INCREASED Regulation of Cardiac Muscle Contraction GO:0055117 ⚠ ABNORMAL Calcium-Dependent Regulation of Cardiac Contraction GO:0010882 ⚠ ABNORMAL

Myosin thick filament GO:0032982

Experimental models

Isogenic MYBPC3 +/- and -/- human iPSC engineered cardiac tissue IPSC DERIVED MODEL

Downstream

Gene-Dosage-Dependent Severity Gradient The magnitude of the contractile derangement tracks the residual cMyBP-C dose, which is set by whether one or both MYBPC3 alleles are truncating.

Show evidence (3 references)

PMID:36893011 SUPPORT In Vitro

"Our data suggest a progressive phenotype caused by cMyBP-C haploinsufficiency and ablation that initially is hypercontractile, but progresses to hypocontractility with impaired relaxation."

Isogenic human iPSC-derived engineered cardiac tissue shows that removing cMyBP-C produces initial hypercontractility that decays to hypocontractility with impaired relaxation, the functional signature of losing the cMyBP-C brake.

PMID:36893011 SUPPORT In Vitro

"After 2 wk of culture in ECT, contractile function was similar between the three genotypes; however, Ca2+-release was slower in the setting of reduced or absent cMyBP-C."

Links reduced or absent cMyBP-C directly to slowed calcium release in an isogenic human model.

PMID:32871100 SUPPORT Human Clinical

"Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction."

Confirms hypercontractility as the central pathophysiological abnormality in HCM generally and links it to outflow obstruction; PARTIAL because the trial population is HCM at large rather than genotyped MYBPC3 carriers.

Gene-Dosage-Dependent Severity Gradient

CMH4 severity is a graded function of residual cMyBP-C, and this is the axis that separates the two clinical entities within the same MONDO term. One truncating allele leaves roughly half-normal cMyBP-C and yields the classic late-onset dominant disease with incomplete penetrance. Two truncating alleles leave essentially none and yield severe cardiomyopathy in the neonatal period. Isogenic human engineered cardiac tissue and heterozygous/homozygous knock-in mouse models both reproduce this dose-severity relationship, providing experimental confirmation of the human genotype-phenotype pattern.

Cardiomyocyte CL:0000746

Cardiac Muscle Cell Contraction GO:0086003 ⚠ ABNORMAL

Experimental models

Isogenic MYBPC3 +/- and -/- human iPSC engineered cardiac tissue IPSC DERIVED MODEL

Animal models

Mybpc3 c.2373InsG knock-in mouse allelic series Mouse recapitulates The allelic series reproduces the dose-severity relationship that defines this disease: absent cMyBP-C gives severe disease, half-dose gives none at the ages studied.

Downstream

Ventricular Hypertrophy, Disarray and Fibrosis

Show evidence (3 references)

PMID:36893011 SUPPORT In Vitro

"The severity of the phenotype correlates with the amount of cMyBP-C present, with more severe earlier phenotypes observed in cMyBP-C-/- than cMyBP-C+/- EC"

Explicitly states the dose-severity correlation in an isogenic human iPSC system comparing heterozygous and homozygous MYBPC3 frameshifts.

PMID:36893011 SUPPORT In Vitro

"Heterozygous carriers present with classical HCM, while homozygous carriers present with early onset HCM that rapidly progress to heart failure."

Summarises the human mono- versus bi-allelic dose contrast that the isogenic model was built to interrogate.

PMID:37844837 SUPPORT Model Organism

"Expectedly, knock-in of Mybpc3c.2373InsG resulted in the absence of cMyBP-C and our 18-28 week old homozygous Mybpc3c.2373InsG model developed cardiac hypertrophy and severe left ventricular systolic and diastolic dysfunction, whereas HCM was not evident in Mybpc3+/InsG mice."

A CRISPR knock-in mouse allelic series of the Dutch founder variant recapitulates the dose gradient: homozygotes develop severe disease while heterozygotes remain unaffected at the same age.

Cell-Autonomous Cardiac Fibroblast Activation by MYBPC3 Deficiency

A parallel, non-cardiomyocyte route to the fibrosis in this disease. MYBPC3 has been treated as cardiomyocyte-specific, and fibrosis in HCM as a secondary response to myocyte stress. Work in a base-edited R495Q pig model found early-onset myocardial fibrosis shortly after birth and, unexpectedly, that MYBPC3 is transcribed and translated in cardiac fibroblasts themselves; disrupting Mybpc3 in fibroblasts activated NF-kB signalling, raised TGF-beta1 and pro-inflammatory gene expression, and drove a HIF-1-alpha glycolytic shift that accelerated fibroblast activation. If this holds in human disease, part of the fibrotic burden is cell-autonomous to the fibroblast rather than a downstream reaction to myocyte dysfunction - which would make it a separate therapeutic target from myosin inhibition.

Cardiac Fibroblast CL:0002548

Transforming Growth Factor Beta Receptor Signaling GO:0007179 ↑ INCREASED

Downstream

Ventricular Hypertrophy, Disarray and Fibrosis Activated fibroblasts deposit matrix, contributing to the same tissue phenotype the cardiomyocyte chain produces.

Show evidence (2 references)

PMID:36357371 SUPPORT Model Organism

"Unexpectedly, we found that the "cardiac-specific" MYBPC3 gene was actually expressed in cardiac fibroblasts from different species as well as NIH3T3 fibroblasts at the transcription and protein levels."

Overturns the premise that MYBPC3 expression is confined to cardiomyocytes, which is what makes a fibroblast-autonomous arm possible at all.

PMID:36357371 SUPPORT Model Organism

"CRISPR-mediated disruption of Mybpc3 in NIH3T3 fibroblasts activated nuclear factor κB (NF-κB) signaling pathway, which increased the expression of transforming growth factor beta (TGF-β1) and other pro-inflammatory genes."

Gives the signalling route from fibroblast MYBPC3 loss to a profibrotic program, independent of any cardiomyocyte intermediate.

Ventricular Hypertrophy, Disarray and Fibrosis

Chronic sarcomeric inefficiency drives the structural remodeling that defines the clinical phenotype: cardiomyocyte hypertrophy with myofiber disarray, interstitial and replacement fibrosis, and - in the biallelic neonatal form - extensive myocardial necrosis and fibrosis together with noncompaction-like hypertrabeculation. Fibrosis provides the substrate for both diastolic dysfunction and arrhythmia.

Cardiomyocyte CL:0000746 Cardiac Fibroblast CL:0002548

Cardiac Muscle Hypertrophy in Response to Stress GO:0014898 ↑ INCREASED Extracellular Matrix Organization GO:0030198 ↑ INCREASED

Interventricular septum UBERON:0002094 Left ventricle UBERON:0002084

Animal models

Mybpc3 c.2373InsG knock-in mouse allelic series Mouse partially recapitulates Homozygotes develop the hypertrophic structural phenotype with progressive worsening.

Downstream

Diastolic Dysfunction, Heart Failure and Arrhythmic Risk

Show evidence (2 references)

PMID:41488457 SUPPORT Human Clinical

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

Autopsy evidence of the hypertrophy-plus-fibrosis tissue phenotype in a biallelic MYBPC3 neonate.

PMID:37844837 SUPPORT Model Organism

"Both the 3-4 week old and 18-28 week old Mybpc3InsG/InsG models recapitulate HCM, with a severe phenotype present in the 18-28 week old model."

Confirms that cMyBP-C absence is sufficient to produce the HCM structural phenotype in vivo, with progressive worsening.

Diastolic Dysfunction, Heart Failure and Arrhythmic Risk

The remodelled, stiff, disarrayed and fibrotic ventricle produces the clinical endpoints of CMH4. In heterozygotes this is usually a slowly progressive picture of diastolic dysfunction with preserved ejection fraction, dynamic outflow obstruction in a subset, and a low but real annual risk of malignant ventricular arrhythmia and sudden death. In the biallelic neonatal form, systolic and diastolic function fail together and death from cardiac failure follows within weeks to months.

Cardiomyocyte CL:0000746

Heart Contraction GO:0060047 ⚠ ABNORMAL

Show evidence (3 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."

Documents rapid progression to fatal cardiac failure as the terminal consequence in biallelic disease.

PMID:39581692 SUPPORT Human Clinical

"Despite it being the most common clinical event, relevant heart failure (observed in 8.1% of patients) was infrequent and commonly found in the presence of a second environmental precipitating agent."

Quantifies heart failure as the commonest but still infrequent clinical endpoint in a heterozygous truncating-MYBPC3 cohort.

PMID:39689185 SUPPORT Human Clinical

"MYBPC3 founder variants cause hypertrophic cardiomyopathy leading to heart failure and malignant ventricular arrhythmias."

Names the two adverse endpoints - heart failure and malignant ventricular arrhythmia - in truncating MYBPC3 founder variant carriers.

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Histopathology

3

Myocyte Disarray

Myofibre disarray - the loss of the normal parallel alignment of cardiomyocytes, with hypertrophied fibres running obliquely and in whorls amid disordered connective tissue - is the pathognomonic histological lesion of hypertrophic cardiomyopathy and the tissue-level substrate for both the arrhythmic risk and the diastolic dysfunction modeled in this entry. It is documented directly in MYBPC3 disease in septal myocardium from an adult homozygous for the Indian 25-bp deletion, described as swirling of hypertrophied myofibres amid connective tissue disarray, and in the same family's series as hypertrophied myofibres separated by increased connective tissue.

Show evidence (2 references)

PMID:19151713 SUPPORT Human Clinical

"Histopathological section of the septal myocardium of the same individual showing 'swirling' of hypertrophied myofibers amid connective tissue disarray"

Direct histological documentation of disarray in the septum of a genotyped MYBPC3 homozygote.

PMID:19151713 SUPPORT Human Clinical

"Histopathological section of the same subject showing hypertrophied myofibers separated from each other by increased connective tissue"

Companion documentation of hypertrophied fibres separated by expanded interstitial connective tissue in a MYBPC3 deletion carrier.

Myocardial Fibrosis

Extensive myocardial necrosis and interstitial/replacement fibrosis are found at autopsy in biallelic MYBPC3 neonatal cardiomyopathy.

Show evidence (1 reference)

PMID:41488457 SUPPORT Human Clinical

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

Direct histopathological documentation of necrosis and fibrosis in biallelic MYBPC3 disease.

Endomyocardial Fibroelastosis

Endomyocardial fibroelastosis with a massively enlarged heart has been documented at autopsy as the histopathological substrate of sudden unexpected infant death caused by two biparental MYBPC3 mutations.

Show evidence (1 reference)

PMID:33849460 SUPPORT Human Clinical

"Autopsy and thorough postmortem cardiac examinations revealed a massively enlarged heart with endomyocardial fibroelastosis."

Endomyocardial fibroelastosis is the reported autopsy finding in this biallelic MYBPC3 infant death.

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Pathograph

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Phenotypes

15

Cardiovascular 9

Hypertrophic Cardiomyopathy OBLIGATE HP:0001639

Show evidence (2 references)

PMID:39581692 SUPPORT Human Clinical

"Hypertrophy was discrete with a significative difference between probands and relatives (17.5±4 mm vs 14.6±5 mm; p<0.0001)."

Documents the hypertrophy magnitude in a molecularly homogeneous truncating MYBPC3 cohort.

PMID:36162733 SUPPORT Human Clinical

"MYBPC3 is the most frequently mutated gene in hypertrophic cardiomyopathy (HCM)."

Confirms the gene-disease association that defines this entity.

Left Ventricular Diastolic Dysfunction HP:0025168

Show evidence (2 references)

PMID:37844837 SUPPORT Model Organism

"our 18-28 week old homozygous Mybpc3c.2373InsG model developed cardiac hypertrophy and severe left ventricular systolic and diastolic dysfunction"

Demonstrates diastolic (and systolic) dysfunction on loss of cMyBP-C in a knock-in mouse model of the Dutch founder variant.

PMID:36893011 SUPPORT In Vitro

"progresses to hypocontractility with impaired relaxation"

Human isogenic engineered cardiac tissue shows impaired relaxation as a direct consequence of reduced or absent cMyBP-C.

Congestive Heart Failure OCCASIONAL HP:0001635

Show evidence (1 reference)

PMID:39581692 SUPPORT Human Clinical

"Despite it being the most common clinical event, relevant heart failure (observed in 8.1% of patients) was infrequent and commonly found in the presence of a second environmental precipitating agent."

The reported 8.1% frequency in a truncating-MYBPC3 cohort maps to the OCCASIONAL band (5-29%).

Ventricular Tachycardia HP:0004756

Show evidence (2 references)

PMID:39689185 SUPPORT Human Clinical

"MCE was defined as a composite of malignant ventricular arrhythmia (sustained ventricular tachycardia/fibrillation), heart failure (heart failure hospitalizations or transplantation), and septal reduction therapy."

Establishes sustained ventricular tachycardia/fibrillation as a curated adverse endpoint in a truncating MYBPC3 founder-variant cohort.

PMID:39689185 SUPPORT Human Clinical

"In contrast, high-dynamic activity was associated with malignant ventricular arrhythmia"

Identifies high-dynamic exercise as an arrhythmic risk modifier specific to MYBPC3 founder variant carriers (adjusted hazard ratio 3.26 at the 75th percentile in the cited analysis).

Sudden Cardiac Death VERY_RARE HP:0001645

Show evidence (2 references)

PMID:22267749 SUPPORT Human Clinical

"During follow up of 7.9+/-4.5 years, in 82 clinically affected individuals the annual risk of sudden death and all cause mortality was 0.46% and 0.93% per year, respectively."

The 0.46%/year sudden-death rate over ~8 years of follow-up corresponds to a cumulative risk in the VERY_RARE band for this cohort.

PMID:33849460 SUPPORT Human Clinical

"A case of a sudden unexpected cardiac death of a 5.5-months-old child is presented."

Documents biallelic MYBPC3 disease presenting as sudden unexpected death in infancy.

Cardiac Septal Defect FREQUENT Ventricular septal defect HP:0001629

Show evidence (2 references)

PMID:25335496 SUPPORT Human Clinical

"In 62% (13/21), septal defects or a patent ductus arteriosus accompanied cardiomyopathy."

The reported 62% frequency across all published biallelic cases maps to the FREQUENT band.

PMID:25335496 SUPPORT Human Clinical

"All of them had septal defects."

All four index neonates with biallelic truncating MYBPC3 variants had septal defects.

Atrial Septal Defect HP:0001631

Show evidence (1 reference)

PMID:41488457 SUPPORT Human Clinical

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

Autopsy documentation of an ASD accompanying biallelic MYBPC3 neonatal cardiomyopathy.

Atrial Fibrillation HP:0005110

Frequency band deliberately omitted. The commonly cited HCM figures (about 20% overall, rising with age) come from the GeneReviews overview, whose PubMed record is a purpose statement with no quotable clinical text, and no MYBPC3-specific denominator for atrial fibrillation appears in any cached source. The association is evidenced here; the rate is not.

Show evidence (2 references)

PMID:32841044 SUPPORT Human Clinical

"time-event analysis was performed (composite clinical outcome of sudden death, class III/IV heart failure, left ventricular assist device/transplant, atrial fibrillation)"

Establishes atrial fibrillation as one of the adverse clinical outcomes tracked in a genotyped MYBPC3 cohort of 1316 patients.

PMID:38406555 SUPPORT Other

"pathogenic sarcomere variants exacerbate existing conditions, such as ventricular arrhythmia, HF, atrial fibrillation (AF), stroke, or even death in HCM individuals"

Places atrial fibrillation and its stroke sequel among the conditions aggravated by sarcomere variants. PARTIAL because it is a narrative review statement about sarcomeric HCM broadly rather than a MYBPC3 measurement.

Syncope HP:0001279

Frequency deliberately omitted - no cached MYBPC3 source reports a syncope rate. Its inclusion here is justified by its role in risk stratification, not by a quantified prevalence.

Show evidence (1 reference)

PMID:38406555 SUPPORT Other

"Diverse phenotypic expression and naturally variable progression of HCM are reflections of a range of clinical manifestations from dyspnea and/or syncope to sudden cardiac death."

Places syncope within the clinical manifestation range of hypertrophic cardiomyopathy in a MYBPC3-focused review. PARTIAL because the statement is about HCM generally rather than a MYBPC3-specific frequency.

Digestive 1

Feeding Difficulties in Infancy HP:0008872

Show evidence (1 reference)

PMID:25335496 SUPPORT Human Clinical

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

Feeding difficulty was a universal presenting feature in the biallelic neonatal series.

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."

Dyspnea was a universal presenting feature in the biallelic neonatal series.

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."

Failure to thrive was a universal presenting feature in the biallelic neonatal series.

Other 3

Asymmetric Septal Hypertrophy HP:0001670

Show evidence (1 reference)

PMID:22267749 SUPPORT Human Clinical

"pattern of hypertrophy (11 none, 9 asymmetrical, 3 concentric, 1 apical, 1 eccentric)"

Enumerates the hypertrophy patterns observed among R502W MYBPC3 carriers, with asymmetrical the most frequent among those with hypertrophy.

Left Ventricular Outflow Tract Obstruction HP:0032092

Show evidence (1 reference)

PMID:32871100 SUPPORT Human Clinical

"Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction."

Links hypercontractility - the direct consequence of cMyBP-C loss - to dynamic LVOT obstruction; PARTIAL because the cited trial enrolled HCM broadly rather than genotyped MYBPC3 carriers.

Left Ventricular Noncompaction FREQUENT 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."

Three of four biallelic neonates had noncompaction features, supporting a FREQUENT band within this subtype.

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Genetic Associations

1

MYBPC3

Gene: MYBPC3 hgnc:7551 relationship_type: CAUSATIVE

Show evidence (5 references)

PMID:32841044 SUPPORT Human Clinical

"Truncating variants account for 91% of MYBPC3 pathogenic variants and cause similar clinical severity and outcomes regardless of location, consistent with locus-independent loss-of-function."

Quantifies the truncating share within MYBPC3 in 1316 genotyped patients from the Sarcomeric Human Cardiomyopathy Registry, and supplies the strongest genetic argument for the loss-of-function model curated here: if severity were driven by a truncated peptide, outcome would depend on where in the gene the truncation falls. It does not.

PMID:32841044 SUPPORT In Vitro

"C10 mutant MyBP-C failed to incorporate into myofilaments and degradation rates were accelerated by ≈90%, while C3 and C6 mutant MyBP-C incorporated normally with degradation rate similar to wild-type."

Shows that a subset of the minority non-truncating variants also converge on loss of function, by failing to incorporate into the myofilament and being degraded - extending the dose model beyond the truncating class without claiming it covers all missense alleles.

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

ClinGen gene-disease validity assertion for MYBPC3 and hypertrophic cardiomyopathy.

+ 2 more references

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Variants

3

MYBPC3 c.2373dup (p.Trp792fs) - Dutch founder variant Pathogenic

Gene: MYBPC3 hgnc:7551

A frameshift founder allele carried by approximately 25% of Dutch HCM patients. Heterozygotes have variable adult-onset HCM; homozygotes and compound heterozygotes with a second truncating allele have lethal neonatal cardiomyopathy.

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 c.2373dup in both homozygous and compound heterozygous state in lethal neonatal cardiomyopathy.

PMID:37844837 SUPPORT Human Clinical

"Most patients are heterozygous (MYBPC3+/InsG) and have highly variable phenotypic expression, whereas homozygous (MYBPC3InsG/InsG) patients have severe HCM at a young age."

States the human dose-dependent phenotype of this specific founder allele.

MYBPC3 c.3330+2T>G - Amish/Swiss founder splice variant Pathogenic

Gene: MYBPC3 hgnc:7551

An ancient splice-donor founder variant first described in the homozygous state in Amish newborns with severe recessive HCM, later recognised as a cause of adult-onset dominant HCM in heterozygotes, and now shown to be the most prevalent cardiomyopathy variant in western Switzerland. It is a compact illustration of the same allele producing both poles of the CMH4 dose spectrum.

Show evidence (2 references)

PMID:36162733 SUPPORT Human Clinical

"One of them, a MYBPC3 splice variant, NM_000256.3:c.3330+2T > G, was first described in homozygous state in newborns presenting with a severe, recessive form of HCM among the Amish population and was later associated with adult-onset dominant HCM in heterozygous carriers."

Single-variant demonstration of the mono- versus bi-allelic dose contrast that defines this entity.

PMID:36162733 SUPPORT Human Clinical

"We here report this splice variant in heterozygous state in eight unrelated Swiss families with HCM, making it the most prevalent cardiomyopathy variant in western Switzerland."

Establishes the Swiss founder origin and local prevalence of this allele.

MYBPC3 25-bp deletion - South Asian risk allele Uncertain Significance

Gene: MYBPC3 hgnc:7551

A 25-bp intronic deletion carried by approximately 4% of people of Indian subcontinental ancestry, associated with heritable cardiomyopathy and increased heart-failure risk (combined OR ~7). Unlike the classic truncating founder alleles it behaves as a common, incompletely penetrant risk factor rather than a fully penetrant Mendelian variant.

Show evidence (1 reference)

PMID:19151713 SUPPORT Human Clinical

"Here, we describe a deletion of 25 bp in the gene encoding cardiac myosin binding protein C (MYBPC3) that is associated with heritable cardiomyopathies and an increased risk of heart failure in Indian populations"

Defines the variant and its association with cardiomyopathy and heart failure risk in South Asian populations.

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Medical Actions

10

Mavacamten (Cardiac Myosin Inhibitor)

Action: Pharmacotherapy NCIT:C15986

Agent: mavacamten

Mavacamten is a first-in-class allosteric cardiac myosin inhibitor that reduces the number of force-generating actin-myosin cross-bridges. Because CMH4 is mechanistically a loss of the cMyBP-C brake on cross-bridge cycling, pharmacological myosin inhibition is a direct mechanistic counterweight. In EXPLORER-HCM it improved exercise capacity, symptoms and outflow gradient in symptomatic obstructive HCM. Note the trial enrolled obstructive HCM broadly, not a genotyped MYBPC3 cohort.

Mechanism Target:

INHIBITS Myosin Shift from the Super-Relaxed to the Disordered-Relaxed State — Cardiac myosin inhibitors act on the SRX/DRX equilibrium itself, pushing myosin heads back into the super-relaxed reserve, rather than on the downstream cross-bridge population.

Target Phenotypes: Left ventricular outflow tract obstruction HP:0032092

Show evidence (2 references)

PMID:32871100 SUPPORT Human Clinical

"45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005)."

Phase 3 randomised placebo-controlled evidence of benefit on the composite functional primary endpoint in symptomatic obstructive HCM.

PMID:32871100 SUPPORT Human Clinical

"Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001)"

Demonstrates the mechanistically expected reduction in dynamic outflow gradient from inhibiting cross-bridge formation.

Aficamten (Next-Generation Cardiac Myosin Inhibitor)

Action: Pharmacotherapy NCIT:C15986

Agent: aficamten CHEBI:747213

Aficamten is a second, oral selective cardiac myosin inhibitor acting on the same hypercontractility node as mavacamten. In the phase 3 SEQUOIA-HCM trial it improved peak oxygen uptake and met all ten prespecified secondary endpoints in symptomatic obstructive HCM. As with mavacamten, the trial population was obstructive HCM generally rather than a genotyped MYBPC3 cohort.

Mechanism Target:

INHIBITS Myosin Shift from the Super-Relaxed to the Disordered-Relaxed State — Cardiac myosin inhibitors act on the SRX/DRX equilibrium itself, pushing myosin heads back into the super-relaxed reserve, rather than on the downstream cross-bridge population.

Target Phenotypes: Left ventricular outflow tract obstruction HP:0032092

Show evidence (2 references)

PMID:38739079 SUPPORT Human Clinical

"Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility."

States the mechanism of action, which targets the same hypercontractility that cMyBP-C loss produces in CMH4.

PMID:38739079 SUPPORT Human Clinical

"The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo."

Phase 3 randomised evidence of consistent benefit across the prespecified secondary endpoint hierarchy in symptomatic obstructive HCM.

Septal Reduction Therapy

Action: Myectomy NCIT:C51591

Surgical septal myectomy or alcohol septal ablation relieves drug-refractory dynamic left ventricular outflow tract obstruction. Septal reduction therapy is counted among the major cardiomyopathy-related events in MYBPC3 founder-variant cohorts, which is an index of how often obstruction becomes clinically significant in this genotype.

Target Phenotypes: Left ventricular outflow tract obstruction HP:0032092

Show evidence (1 reference)

PMID:39689185 SUPPORT Human Clinical

"MCE was defined as a composite of malignant ventricular arrhythmia (sustained ventricular tachycardia/fibrillation), heart failure (heart failure hospitalizations or transplantation), and septal reduction therapy."

Documents that septal reduction therapy is used and tracked as a clinical event in truncating MYBPC3 carriers; PARTIAL because the paper reports it as an endpoint rather than evaluating its efficacy.

Implantable Cardioverter-Defibrillator

Action: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

ICD implantation for primary or secondary prevention of sudden cardiac death in carriers judged to be at high arrhythmic risk. Risk stratification is particularly important in CMH4 because the baseline event rate in heterozygous carriers is low and conventional risk calculators performed poorly in a molecularly homogeneous truncating-MYBPC3 cohort.

Target Phenotypes: Sudden cardiac death HP:0001645

Show evidence (1 reference)

PMID:39581692 SUPPORT Human Clinical

"ESC-HCM risk calculator and modifier factors did not correlate with the risk of major events predicting events, which were low (1.51 per 100 patients/year) and associated with the severity of HCM, abnormal QRS in the ECG and age."

Supports the risk-stratification caveat for this genotype rather than ICD efficacy itself, hence PARTIAL.

Heart Transplantation

Action: Heart Transplantation NCIT:C15246

Transplantation is the treatment that matters most at the biallelic pole this entry models. Biallelic truncating disease is a lethal neonatal cardiomyopathy - the reported infants died of cardiac failure before 13 weeks - and no pharmacological therapy alters that course: myosin inhibition presupposes hypercontractility to inhibit, and gene replacement remains investigational and adult-only. Transplantation is also the endpoint for the minority of heterozygous carriers who progress to end-stage disease, where it is counted among the adverse composite outcomes in MYBPC3 cohort studies.

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."

Establishes the untreated natural history that makes transplantation the only survival-altering option at the biallelic pole. PARTIAL because the source documents the fatal course rather than transplantation outcomes - none of these four infants was transplanted.

PMID:32841044 SUPPORT Human Clinical

"time-event analysis was performed (composite clinical outcome of sudden death, class III/IV heart failure, left ventricular assist device/transplant, atrial fibrillation)"

Shows transplantation and mechanical support tracked as clinical endpoints in a large genotyped MYBPC3 cohort. PARTIAL because it establishes that these events occur and are counted, not a transplantation rate or outcome.

Anticoagulation for Atrial Fibrillation

Action: Pharmacotherapy NCIT:C15986

Agent: anticoagulant agent NCIT:C263

Anticoagulation in hypertrophic cardiomyopathy with atrial fibrillation is not gated on the conventional risk scores used in non-HCM atrial fibrillation - the thromboembolic risk conferred by the HCM substrate itself is high enough that anticoagulation is indicated on the arrhythmia alone. Included here because it is the management consequence of the atrial fibrillation phenotype curated in this entry, and because applying the ordinary risk-score gate is a common and consequential error.

Target Phenotypes: Atrial fibrillation HP:0005110

Agents to Avoid in Obstructive Physiology

A negative treatment recommendation, recorded because in obstructive hypertrophic cardiomyopathy the wrong drug actively worsens the haemodynamics. Vasodilators, nitrates, dihydropyridine calcium channel blockers, digoxin and aggressive diuresis all increase the dynamic outflow gradient - the first four by reducing afterload or raising contractility, diuresis by reducing preload and ventricular cavity size. The mechanism is the mirror image of the one that makes negative inotropes useful here, so the contraindication follows from the same physiology this entry models.

Genetic Counseling and Cascade Screening

Action: Genetic Counseling NCIT:C15240

Counseling covers autosomal dominant transmission for heterozygous probands and the recurrence risk for couples who are both carriers, since two carrier parents face a 25% risk of a biallelic, usually lethal neonatal pregnancy. Preimplantation genetic testing is an option once the molecular diagnosis is established, and asymptomatic carrier parents identified through a proband warrant their own long-term cardiac surveillance.

Show evidence (2 references)

PMID:41488457 SUPPORT Human Clinical

"Crucially, the diagnosis guided the clinical management of the asymptomatic carrier parents, prompting long-term cardiac surveillance and enabling preimplantation genetic testing (PGT) for future family planning."

Directly documents both counselling outcomes - parental surveillance and preimplantation genetic testing - following a biallelic MYBPC3 diagnosis.

PMID:33849460 SUPPORT Human Clinical

"Thus, the molecular autoptic findings also had consequences for the relatives of the deceased child and impact on further family planning."

Documents the cascade-screening and family-planning consequences of a molecular diagnosis in biallelic MYBPC3 disease.

Exercise Counseling

Action: Supportive Care NCIT:C15747

Overall exercise participation does not increase adverse-event risk in MYBPC3 founder-variant carriers, so blanket exercise restriction is not supported. However, the highest quartile of high-dynamic sport was associated with a threefold increase in malignant ventricular arrhythmia, so high-intensity high-dynamic activity warrants individualised caution.

Show evidence (1 reference)

PMID:39689185 SUPPORT Human Clinical

"Overall exercise participation does not generally increase the risk of adverse events among MYBPC3 founder variant carriers. Nonetheless, an increased risk of malignant ventricular arrhythmia was observed among those engaged in the highest quartile of high-dynamic sports, suggesting that..."

The genotype-specific evidence base for exercise advice in truncating MYBPC3 carriers.

AAV9-Mediated MYBPC3 Gene Replacement (Investigational)

Action: Gene Therapy NCIT:C15238

Because CMH4 is a protein-dose disease, restoring wild-type cMyBP-C is a causally targeted strategy rather than symptom control. An AAV9 vector carrying an optimised MYBPC3 expression cassette (TN-201) reversed hypertrophy and systolic dysfunction, improved diastolic function and prolonged survival in a symptomatic MYBPC3-deficient mouse model. This is preclinical/early clinical and is not established therapy.

Mechanism Target:

BYPASSES cMyBP-C Depletion by Nonsense-Mediated Decay and Proteasomal Degradation

Show evidence (2 references)

PMID:40038304 SUPPORT Model Organism

"Rather than simply preventing cardiac dysfunction preclinically, we demonstrate in a symptomatic MYBPC3-deficient murine model the ability of AAV gene therapy to reverse cardiac hypertrophy and systolic dysfunction, improve diastolic dysfunction, and prolong survival."

Preclinical demonstration that restoring MYBPC3 dose reverses the established phenotype, the therapeutic corollary of the haploinsufficiency mechanism.

PMID:40038304 SUPPORT Model Organism

"Dose-ranging efficacy studies exhibit restoration of wild-type MYBPC3 protein levels and saturation of cardiac improvement at the clinically relevant dose of 3E13 vg/kg, outperforming a previously published construct."

Shows the intervention works by restoring wild-type protein level, closing the mechanistic loop with the haploinsufficiency node.

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Biochemical Markers

1

NT-proBNP (Elevated)

Context: Heart-failure severity marker, and the pharmacodynamic readout of cardiac myosin inhibition. N-terminal pro-B-type natriuretic peptide tracks heart-failure severity and falls steeply under cardiac myosin inhibition - in SEQUOIA-HCM the geometric mean proportional change to week 24 was 0.20 on aficamten against 1.00 on placebo, an approximately fivefold reduction against no change. That makes it the practical objective marker of response to the drug class this entry wires to the super-relaxed-state node.

Show evidence (1 reference)

PMID:38739079 SUPPORT Human Clinical

"the geometric mean proportional change from baseline to week 24 in the serum NT-proBNP level"

Identifies NT-proBNP as a measured endpoint in the phase 3 aficamten trial; the accompanying reported values are 0.20 on aficamten versus 1.00 on placebo.

🔬

Diagnosis

2

Genetic Testing for MYBPC3 Variants

Molecular confirmation is what distinguishes CMH4 from other causes of unexplained left ventricular hypertrophy, and - critically for this entity - determines allelic dose. Trio or family-based testing is required to establish whether two variants are in trans, since the biallelic genotype carries an entirely different prognosis and reproductive-counselling implication than the heterozygous state.

Show evidence (2 references)

PMID:41488457 SUPPORT Human Clinical

"We performed a full forensic autopsy with detailed histological examination and conducted trio-based whole-exome sequencing (WES) on the proband and parents to identify the genetic etiology."

Illustrates trio-based sequencing as the method that establishes biparental (compound heterozygous) inheritance.

PMID:41488457 SUPPORT Human Clinical

"Crucially, the diagnosis guided the clinical management of the asymptomatic carrier parents, prompting long-term cardiac surveillance and enabling preimplantation genetic testing (PGT) for future family planning."

Documents the downstream family-management value of establishing the molecular diagnosis.

Longitudinal Cardiac Surveillance of Genotype-Positive Relatives

Because penetrance in heterozygous MYBPC3 carriers is incomplete and rises with age, a single normal evaluation does not exclude future disease. Serial echocardiographic and ECG surveillance of genotype-positive, phenotype-negative relatives is the corollary of the age-dependent penetrance data.

Show evidence (2 references)

PMID:22267749 SUPPORT Human Clinical

"Disease penetrance was, therefore, incomplete (56.9% in all mutation carriers, 34.5% in relatives), related to age (38.4% <40 versus 68.6% ≥40 years, P<0.001)"

The near-doubling of penetrance after age 40 is the direct rationale for lifelong rather than one-off screening of carriers.

PMID:22267749 SUPPORT Human Clinical

"Importantly, complex genetic status is observed and should be considered when mutation analysis and cascade screening is used in the evaluation of at risk family members."

Explicitly warns that multiple variants in one individual must be considered during cascade screening - the practical expression of the dose principle.

📈

Progression

3

Neonatal onset (biallelic genotype)

Biallelic CMH4 Age: Birth to 13 weeks

Show evidence (1 reference)

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."

Defines the presentation window and time-to-death for the biallelic neonatal form.

Adult onset (monoallelic genotype)

Monoallelic CMH4 Age: Adulthood, typically after age 40

Show evidence (2 references)

PMID:22267749 SUPPORT Human Clinical

"In 9 families (25 individuals) with the R502W mutation, there was marked heterogeneity in age at diagnosis (5 to 80 years), pattern of hypertrophy (11 none, 9 asymmetrical, 3 concentric, 1 apical, 1 eccentric), and prognosis"

Shows the wide age-at-diagnosis range and phenotypic heterogeneity of the heterozygous adult form, even within carriers of a single variant.

PMID:38406555 SUPPORT Other

"HCM associated with MYBPC3 mutations usually presents in the elderly and ranges from asymptomatic to symptomatic forms"

Characterises the late-onset skew of MYBPC3-associated HCM. Evidence source is OTHER because this is a narrative review.

Long-term outcome (monoallelic genotype)

Monoallelic CMH4

Show evidence (1 reference)

PMID:22267749 SUPPORT Human Clinical

"During follow up of 7.9+/-4.5 years, in 82 clinically affected individuals the annual risk of sudden death and all cause mortality was 0.46% and 0.93% per year, respectively."

Quantifies the long-term event rate in clinically affected heterozygous MYBPC3 carriers.

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Prevalence

3

Worldwide

Unknown Not yet documented

No population-based prevalence estimate exists for the MYBPC3-specific entity. MYBPC3 is nonetheless the largest single genetic contributor to hypertrophic cardiomyopathy overall, accounting for roughly half of identified HCM mutations, so CMH4 is the most common gene-specific HCM subtype.

Show evidence (1 reference)

PMID:22057632 SUPPORT Other

"It is well established that MYBPC3 mutations are the most common cause of hypertrophic cardiomyopathy, accounting for about half of identified mutations."

Supports MYBPC3's share of HCM mutations but does not provide a population-level prevalence for the MYBPC3-specific entity, hence PARTIAL. Evidence source is OTHER because this is a mechanistic review.

Netherlands (MYBPC3 c.2373dupG founder)

Unknown Unknown

Founder effect: approximately 25% of Dutch HCM patients carry the single MYBPC3 c.2373InsG (c.2373dup) founder allele. This is a share-of-patients figure, not a population rate.

Show evidence (1 reference)

PMID:37844837 SUPPORT Human Clinical

"In the Netherlands, approximately 25% of patients carry the MYBPC3c.2373InsG founder mutation."

Quantifies the founder allele's contribution to the Dutch HCM patient population.

Populations of Indian subcontinental ancestry

Carrier Frequency 4000.0 per 100,000 >1 in 1,000

Carrier frequency of the MYBPC3 25-bp intronic deletion, reported as approximately 4% in populations of Indian subcontinental ancestry. This is a common risk allele rather than a fully penetrant Mendelian variant.

Show evidence (1 reference)

PMID:19151713 SUPPORT Human Clinical

"Its prevalence was found to be high (approximately 4%) in populations of Indian subcontinental ancestry."

Directly reports the ~4% carrier frequency of the MYBPC3 25-bp deletion in South Asian populations.

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Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Hypertrophic Cardiomyopathy 4:

Hypertrophic Cardiomyopathy due to other sarcomere genes MONDO:0005045

Overlapping Features MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2 and MYL3 also carry definitive HCM gene-disease validity. Distinguishing CMH4 from these requires genetic testing; MYBPC3-related disease tends to present later than MYH7-related disease and does not have a biallelic neonatal counterpart in most of the other genes.

Show evidence (1 reference)

PMID:38406555 SUPPORT Other

"This inherited disease is predominantly caused by mutations in sarcomeric genes, among which those in the cardiac myosin binding protein-C3 (MYBPC3) gene are major contributors."

Places MYBPC3 within the broader sarcomeric HCM differential. Evidence source is OTHER because this is a narrative review.

Left Ventricular Noncompaction Cardiomyopathy

Overlapping Features Biallelic MYBPC3 neonatal disease frequently shows hypertrabeculation and can be mistaken for primary left ventricular noncompaction cardiomyopathy; the accompanying severe hypertrophy, septal defects and the MYBPC3 genotype distinguish it.

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."

Documents the noncompaction overlap that creates this differential in biallelic neonates.

🔬

Clinical Trials

6

NCT05836259 PHASE_I RECRUITING

MyPEAK-1. First-in-human, open-label, dose-finding study of TN-201, an AAV9 vector carrying an MYBPC3 transgene, in adults with MYBPC3-associated hypertrophic cardiomyopathy. This is the trial arm of the gene-replacement treatment curated in this entry, and the only genotype-restricted therapy in development for this disease - enrolment requires a MYBPC3 variant, unlike every other trial listed here.

Target Phenotypes: Hypertrophic cardiomyopathy HP:0001639

Show evidence (1 reference)

clinicaltrials:NCT05836259 SUPPORT Human Clinical

"This is a first-in-human, non-randomized, open-label study designed to evaluate the safety, tolerability, and pharmacodynamics (PD) of TN-201 in adult patients with symptomatic hypertrophic cardiomyopathy (HCM) caused by mutations in the MYBPC3 gene."

Confirms the design and the MYBPC3-restricted enrolment criterion that makes this the genotype-specific trial for this entry.

NCT03470545 PHASE_III COMPLETED

EXPLORER-HCM. Pivotal randomised, double-blind, placebo-controlled trial of mavacamten in symptomatic obstructive hypertrophic cardiomyopathy, and the evidence base for the mavacamten treatment entry.

Target Phenotypes: Left ventricular outflow tract obstruction HP:0032092

Show evidence (1 reference)

clinicaltrials:NCT03470545 SUPPORT Human Clinical

"This is a multicenter, international, double-blind study of the administration of mavacamten in participants with symptomatic obstructive HCM (oHCM)."

Confirms design and population for the trial underpinning cardiac myosin inhibition in this entry.

NCT05186818 PHASE_III COMPLETED

SEQUOIA-HCM. Randomised, double-blind, placebo-controlled trial of aficamten in symptomatic obstructive hypertrophic cardiomyopathy; the source of both the aficamten treatment evidence and the NT-proBNP treatment-response biomarker curated here.

Target Phenotypes: Left ventricular outflow tract obstruction HP:0032092

Show evidence (1 reference)

clinicaltrials:NCT05186818 SUPPORT Human Clinical

"The purpose of this study is to evaluate the efficacy and safety of aficamten (CK-3773274) versus placebo in adults with symptomatic hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract obstruction."

Confirms design and population for the second cardiac myosin inhibitor curated in this entry.

NCT04349072 PHASE_III COMPLETED

VALOR-HCM. Randomised trial of mavacamten in patients already referred for septal reduction therapy, testing whether myosin inhibition can avert the procedure. Directly relevant to the septal reduction treatment curated here, since it addresses the choice between the two.

Show evidence (1 reference)

clinicaltrials:NCT04349072 SUPPORT Human Clinical

"will evaluate the effect of mavacamten treatment on reducing the number of septal reduction therapy (SRT) procedures performed in subjects with symptomatic obstructive hypertrophic cardiomyopathy"

Establishes the septal-reduction-avoidance endpoint linking the pharmacological and surgical arms of this entry.

NCT05767346 PHASE_III COMPLETED

MAPLE-HCM. Randomised trial of aficamten monotherapy against metoprolol in symptomatic obstructive hypertrophic cardiomyopathy - the first head-to-head test of a cardiac myosin inhibitor against a conventional first-line beta-blocker rather than against placebo on top of background therapy.

Show evidence (1 reference)

clinicaltrials:NCT05767346 SUPPORT Human Clinical

"The purpose of this study is to compare the efficacy and safety of aficamten (CK-3773274) compared with metoprolol succinate in adults with symptomatic hypertrophic cardiomyopathy and left ventricular outflow tract obstruction"

Confirms the active-comparator design that distinguishes this trial from the placebo-controlled myosin inhibitor trials.

NCT01912534 PHASE_II COMPLETED

VANISH. Randomised trial of valsartan in early-stage sarcomeric hypertrophic cardiomyopathy, testing disease modification rather than symptom relief. The only trial listed here that addresses the question this entry's knowledge gaps keep returning to - whether anything alters the course of disease in early or subclinical sarcomere-variant carriers.

Show evidence (1 reference)

clinicaltrials:NCT01912534 SUPPORT Human Clinical

"The purpose of this trial is to determine whether treatment with valsartan will have beneficial effect in early hypertrophic cardiomyopathy (HCM) by assessing many domains that reflect myocardial structure, function and biochemistry."

Confirms the early-disease, disease-modification objective that makes this trial relevant to the preclinical-carrier knowledge gaps recorded here.

🧫

Experimental Models

1

Isogenic MYBPC3 +/- and -/- human iPSC engineered cardiac tissue IPSC_DERIVED_MODEL

CRISPR-Cas9 heterozygous and homozygous MYBPC3 frameshifts introduced into a human iPSC line, differentiated to cardiomyocytes and assembled into engineered cardiac tissue constructs. This is the cleanest available human model of the CMH4 allelic-dose question because the two genotypes and the wild-type control share an identical genetic background.

Organism

human NCBITaxon:9606

Publication

PMID:36893011

Pathograph links

Gene-Dosage-Dependent Severity Gradient

Loss of the cMyBP-C Brake on Actin-Myosin Cross-Bridge Cycling

Show evidence (1 reference)

PMID:36893011 SUPPORT In Vitro

"We used CRISPR-Cas9 to introduce heterozygous (cMyBP-C+/-) and homozygous (cMyBP-C-/-) frame-shift mutations into MYBPC3 in human iPSCs."

Describes the isogenic allelic series that makes this model suited to the dose question.

🐁

Animal Models

1

Mybpc3 c.2373InsG knock-in mouse allelic series

CRISPR/Cas9 knock-in mice heterozygous and homozygous for the Dutch MYBPC3 c.2373InsG founder variant, characterised by echocardiography, histology and cardiomyocyte contractility. Homozygotes lack cMyBP-C and develop severe HCM; heterozygotes did not show HCM at the ages studied, mirroring the low and age-dependent penetrance of the human heterozygous state.

Species

Mouse

Genotype

Mybpc3 c.2373InsG heterozygous and homozygous knock-in (CRISPR/Cas9)

Publication

PMID:37844837

Pathograph links

Gene-Dosage-Dependent Severity Gradient recapitulates fidelity: moderate The allelic series reproduces the dose-severity relationship that defines this disease: absent cMyBP-C gives severe disease, half-dose gives none at the ages studied.

Limitations: Fidelity is MODERATE rather than HIGH because only the homozygous pole matches its human counterpart. Human heterozygotes develop disease at substantial rates, whereas these heterozygous mice do not - so the model reproduces the shape of the gradient while misplacing the human heterozygote on it.

Show evidence (1 reference)

PMID:37844837 SUPPORT Model Organism

"Expectedly, knock-in of Mybpc3c.2373InsG resulted in the absence of cMyBP-C and our 18-28 week old homozygous Mybpc3c.2373InsG model developed cardiac hypertrophy and severe left ventricular systolic and diastolic dysfunction, whereas HCM was not evident in Mybpc3+/InsG mice."

Gives both poles of the gradient in one experiment, including the negative heterozygous result.

Ventricular Hypertrophy, Disarray and Fibrosis partially recapitulates fidelity: moderate Homozygotes develop the hypertrophic structural phenotype with progressive worsening.

Limitations: PARTIALLY_RECAPITULATES rather than RECAPITULATES because the node includes myocyte disarray, the pathognomonic human lesion, and the cited characterisation reports echocardiography, histology and contractility without reporting disarray. Recorded as an open model-mismatch discussion rather than assumed either way.

Show evidence (1 reference)

PMID:37844837 SUPPORT Model Organism

"Both the 3-4 week old and 18-28 week old Mybpc3InsG/InsG models recapitulate HCM, with a severe phenotype present in the 18-28 week old model."

Confirms the structural phenotype and its progression in the homozygous model.

Moved here from experimental_models during review. It had been curated as an ExperimentalModel with experimental_model_type: OTHER, which is the documented pre-#8199 workaround for reaching the pathograph before AnimalModel gained modeled_mechanisms. Whole-organism animal models belong in animal_models; ExperimentalModel is for non-animal systems, and its type enum accordingly has no animal value.

Show evidence (1 reference)

PMID:37844837 SUPPORT Model Organism

"To improve understanding of disease progression and genotype-phenotype relationship based on the hallmarks of human HCM, we characterized mice with CRISPR/Cas9-induced heterozygous and homozygous mutations."

Describes the mouse allelic series used to model the human dose-phenotype relationship for the Dutch founder variant.

{ }

Source YAML

click to show

name: Hypertrophic Cardiomyopathy 4
creation_date: "2026-08-01T00:00:00Z"
synonyms:
- CMH4
- MYBPC3 hypertrophic cardiomyopathy
- cardiomyopathy, familial hypertrophic, 4
- familial hypertrophic cardiomyopathy type 4
- hypertrophic cardiomyopathy caused by mutation in MYBPC3
description: >-
  Hypertrophic cardiomyopathy 4 (CMH4) is the MYBPC3-related form of familial
  hypertrophic cardiomyopathy. MYBPC3 encodes cardiac myosin-binding protein C
  (cMyBP-C), a thick-filament accessory protein of the sarcomeric A band that
  restrains actin-myosin cross-bridge cycling and tunes the contraction-relaxation
  cycle. MYBPC3 is the single most frequently mutated gene in hypertrophic
  cardiomyopathy, and most disease alleles are truncating (frameshift, nonsense,
  or splice variants generating a premature termination codon). Truncated peptide
  is not detectable in patient myocardium; instead nonsense-mediated mRNA decay
  and ubiquitin-proteasome degradation lower functional cMyBP-C, so the operative
  mechanism is a protein dose problem rather than a poison peptide.
  CMH4 is therefore best understood as a gene-dosage disease with two distinct
  clinical entities at the two ends of the allelic dose range. Monoallelic
  (heterozygous) truncating variants cause cMyBP-C haploinsufficiency and the
  classic autosomal dominant adult-onset phenotype: incomplete, age-related and
  sex-biased penetrance, discrete left ventricular hypertrophy, largely preserved
  ejection fraction, and a comparatively low event rate. Biallelic (homozygous or
  compound heterozygous) truncating variants abolish cMyBP-C and cause the severe
  neonatal hypertrophic cardiomyopathy highlighted in the MONDO definition of this
  entity — presenting in the first days-to-weeks of life with feeding difficulty,
  failure to thrive and dyspnea, frequently accompanied by left ventricular
  noncompaction features and septal defects, and usually fatal within the first
  few months. Founder truncating alleles (the Dutch c.2373dup, the Amish/Swiss
  c.3330+2T>G splice variant, and the South Asian 25-bp deletion) concentrate both
  the dominant and the recessive presentations in specific populations.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: hypertrophic cardiomyopathy 4
  term:
    id: MONDO:0007268
    label: hypertrophic cardiomyopathy 4
parents:
- Hypertrophic Cardiomyopathy
- Genetic Disorder
has_subtypes:
- name: Monoallelic CMH4
  display_name: Monoallelic (heterozygous) MYBPC3 hypertrophic cardiomyopathy
  description: >-
    The classic autosomal dominant form. A single truncating (or, less often,
    missense) MYBPC3 allele produces cMyBP-C haploinsufficiency. Penetrance is
    incomplete, age-related and higher in males; hypertrophy is typically discrete,
    ejection fraction is usually preserved, and the annual event rate is low.
  evidence:
  - reference: PMID:22267749
    reference_title: "Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Disease penetrance was, therefore, incomplete (56.9% in all mutation
      carriers, 34.5% in relatives), related to age (38.4% <40 versus 68.6% ≥40
      years, P<0.001), and was greater in males than females (65.1% versus 48.1%,
      P=0.03).
    explanation: >-
      Quantifies the defining features of the heterozygous subtype - incomplete,
      age-related and male-biased penetrance - in a large family series of MYBPC3
      mutation carriers.
  - reference: PMID:39581692
    reference_title: "Hypertrophic cardiomyopathy due to truncating variants in myosin binding protein C: a Spanish cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertrophy was discrete with a significative difference between probands
      and relatives (17.5±4 mm vs 14.6±5 mm; p<0.0001). Ejection fraction was
      predominantly preserved (65%±10%).
    explanation: >-
      A molecularly homogeneous truncating-MYBPC3 cohort documents the discrete
      hypertrophy and preserved systolic function that characterise the monoallelic
      subtype.
- name: Biallelic CMH4
  display_name: Biallelic (homozygous/compound heterozygous) MYBPC3 neonatal cardiomyopathy
  description: >-
    The severe neonatal form named in the MONDO definition of hypertrophic
    cardiomyopathy 4. Two truncating MYBPC3 alleles abolish cMyBP-C, producing
    severe cardiomyopathy presenting in the first days to weeks of life, commonly
    with left ventricular noncompaction features and septal defects, and death
    from cardiac failure within the first months. Parents, as obligate
    heterozygotes, are typically asymptomatic or have mild adult-onset disease.
  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 mono- versus bi-allelic contrast explicitly and defines the
      biallelic subtype as severe neonatal cardiomyopathy with noncompaction and
      septal defects.
  - 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: >-
      Independently characterises the biallelic MYBPC3 entity as a rare, lethal
      neonatal form of HCM, corroborating the subtype definition.
inheritance:
- name: Autosomal dominant (monoallelic truncating variants)
  description: >-
    The classic CMH4 presentation is autosomal dominant, with a single truncating
    MYBPC3 allele acting through cMyBP-C haploinsufficiency. Penetrance is
    incomplete and strongly age-dependent, and is higher in male than in female
    carriers, so cascade screening must be longitudinal rather than a single
    evaluation.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  penetrance_percentage: "56.9%"
  evidence:
  - reference: CGGV:assertion_7e65896e-33f5-439d-8749-aba08a539dd0-2021-10-07T160000.000Z
    reference_title: "MYBPC3 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYBPC3 | HGNC:7551 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
    explanation: >-
      ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel
      classifies the MYBPC3-hypertrophic cardiomyopathy relationship as Definitive
      with autosomal dominant inheritance.
  - reference: PMID:22267749
    reference_title: "Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Disease penetrance was, therefore, incomplete (56.9% in all mutation
      carriers, 34.5% in relatives), related to age (38.4% <40 versus 68.6% ≥40
      years, P<0.001), and was greater in males than females (65.1% versus 48.1%,
      P=0.03).
    explanation: >-
      Source of the 56.9% overall penetrance figure and of the age- and
      sex-dependence of expression in heterozygous MYBPC3 carriers.
  - reference: PMID:37929589
    reference_title: "Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Penetrance varied from ≈32% for MYL3 (myosin light chain 3) to ≈55% for
      MYBPC3 (myosin-binding protein C3)
    explanation: >-
      Meta-analytic, MYBPC3-specific penetrance estimate of about 55% among
      relatives carrying a P/LP variant, consistent with the family-series figure.
  - reference: PMID:37929589
    reference_title: "Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The penetrance of HCM in incidentally identified P/LP variant carriers was
      also substantially lower at ≈11%, ranging from 0% in Atherosclerosis Risk in
      Communities to 18% in UK Biobank.
    explanation: >-
      Critical ascertainment caveat: penetrance measured in clinically ascertained
      families (~55-57%) is roughly fivefold higher than in incidentally
      identified population carriers (~11%), so family-based penetrance figures
      must not be quoted to an incidentally genotyped individual.
- name: Autosomal recessive (biallelic truncating variants)
  description: >-
    When two truncating MYBPC3 alleles are inherited - homozygously (typically in
    founder populations or consanguineous families) or as compound heterozygotes -
    cMyBP-C is effectively absent and the phenotype is a severe, usually lethal
    neonatal cardiomyopathy. The heterozygous parents are asymptomatic or mildly
    affected, so the dose effect behaves recessively at the neonatal-severity
    threshold even though the heterozygous state is itself a dominant disease
    allele.
  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 that the biallelic genotype is uniformly severe across all
      reported cases, defining the recessive-severity arm of this entity.
  - reference: PMID:41488457
    reference_title: "Case Report: Lethal neonatal hypertrophic cardiomyopathy from compound heterozygous MYBPC3 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES identified compound heterozygous pathogenic variants in MYBPC3: a known
      paternal splice-site variant (c.2905+1G>A) and a novel maternal truncating
      frameshift variant (c.836del; p.Gly279Valfs*21).
    explanation: >-
      Documents biparental inheritance of two loss-of-function MYBPC3 alleles in a
      lethal neonatal case, the compound-heterozygous route to the biallelic
      phenotype.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population-based prevalence estimate exists for the MYBPC3-specific entity.
    MYBPC3 is nonetheless the largest single genetic contributor to hypertrophic
    cardiomyopathy overall, accounting for roughly half of identified HCM
    mutations, so CMH4 is the most common gene-specific HCM subtype.
  evidence:
  - reference: PMID:22057632
    reference_title: "How do MYBPC3 mutations cause hypertrophic cardiomyopathy?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It is well established that MYBPC3 mutations are the most common cause of
      hypertrophic cardiomyopathy, accounting for about half of identified
      mutations.
    explanation: >-
      Supports MYBPC3's share of HCM mutations but does not provide a
      population-level prevalence for the MYBPC3-specific entity, hence PARTIAL.
      Evidence source is OTHER because this is a mechanistic review.
- population: Netherlands (MYBPC3 c.2373dupG founder)
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    Founder effect: approximately 25% of Dutch HCM patients carry the single
    MYBPC3 c.2373InsG (c.2373dup) founder allele. This is a share-of-patients
    figure, not a population rate.
  evidence:
  - reference: PMID:37844837
    reference_title: "Characterization of heterozygous and homozygous mouse models with the most common hypertrophic cardiomyopathy mutation MYBPC3(c.2373InsG) in the Netherlands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the Netherlands, approximately 25% of patients carry the MYBPC3c.2373InsG
      founder mutation.
    explanation: >-
      Quantifies the founder allele's contribution to the Dutch HCM patient
      population.
- population: Populations of Indian subcontinental ancestry
  measure_type: CARRIER_FREQUENCY
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 4000.0
  notes: >-
    Carrier frequency of the MYBPC3 25-bp intronic deletion, reported as
    approximately 4% in populations of Indian subcontinental ancestry. This is a
    common risk allele rather than a fully penetrant Mendelian variant.
  evidence:
  - reference: PMID:19151713
    reference_title: "A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Its prevalence was found to be high (approximately 4%) in populations of
      Indian subcontinental ancestry.
    explanation: >-
      Directly reports the ~4% carrier frequency of the MYBPC3 25-bp deletion in
      South Asian populations.
progression:
- phase: Neonatal onset (biallelic genotype)
  subtype: Biallelic CMH4
  age_range: Birth to 13 weeks
  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: >-
      Defines the presentation window and time-to-death for the biallelic neonatal
      form.
- phase: Adult onset (monoallelic genotype)
  subtype: Monoallelic CMH4
  age_range: Adulthood, typically after age 40
  evidence:
  - reference: PMID:22267749
    reference_title: "Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 9 families (25 individuals) with the R502W mutation, there was marked
      heterogeneity in age at diagnosis (5 to 80 years), pattern of hypertrophy
      (11 none, 9 asymmetrical, 3 concentric, 1 apical, 1 eccentric), and
      prognosis
    explanation: >-
      Shows the wide age-at-diagnosis range and phenotypic heterogeneity of the
      heterozygous adult form, even within carriers of a single variant.
  - reference: PMID:38406555
    reference_title: "Hypertrophic cardiomyopathy in MYBPC3 carriers in aging."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      HCM associated with MYBPC3 mutations usually presents in the elderly and
      ranges from asymptomatic to symptomatic forms
    explanation: >-
      Characterises the late-onset skew of MYBPC3-associated HCM. Evidence source
      is OTHER because this is a narrative review.
- phase: Long-term outcome (monoallelic genotype)
  subtype: Monoallelic CMH4
  evidence:
  - reference: PMID:22267749
    reference_title: "Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During follow up of 7.9+/-4.5 years, in 82 clinically affected individuals
      the annual risk of sudden death and all cause mortality was 0.46% and 0.93%
      per year, respectively.
    explanation: >-
      Quantifies the long-term event rate in clinically affected heterozygous
      MYBPC3 carriers.
pathophysiology:
- name: MYBPC3 Truncating Variant and Premature Termination Codon Generation
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The initiating lesion in CMH4 is a MYBPC3 allele carrying a frameshift,
    nonsense, or splice-disrupting change that introduces a premature termination
    codon. A distinctive feature of MYBPC3 relative to other sarcomere disease
    genes is how many of its pathogenic variants sit in introns and act by
    aberrant splicing. Despite the frameshift, the predicted truncated cMyBP-C
    peptide has never been detected in human heart tissue from carriers, arguing
    against a dominant-negative poison-peptide mechanism at the protein level.
  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:22057632
    reference_title: "How do MYBPC3 mutations cause hypertrophic cardiomyopathy?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The most striking characteristic of HCM mutations in MYBPC3 is that many are
      within introns and are predicted to cause aberrant splicing leading to a
      frameshift and a premature chain termination, yet the truncated peptides
      have never been identified in human heart tissue carrying these mutations.
    explanation: >-
      Establishes the variant class (intronic/splice-disrupting, frameshift,
      premature termination) and the absence of detectable truncated peptide in
      patient myocardium. Evidence source is OTHER because this is a mechanistic
      review.
  downstream:
  - target: cMyBP-C Depletion by Nonsense-Mediated Decay and Proteasomal Degradation
    causal_link_type: DIRECT
    description: >-
      Premature termination codons trigger surveillance pathways that destroy the
      mutant transcript and protein rather than producing a stable truncated
      product.
- name: cMyBP-C Depletion by Nonsense-Mediated Decay and Proteasomal Degradation
  biological_scale: MOLECULAR
  role: amplifier
  description: >-
    Because the truncated peptide is not stably expressed, the operative
    consequence of a MYBPC3 truncating allele is a reduction in the amount of
    functional cMyBP-C in the sarcomere. Nonsense-mediated mRNA decay removes the
    PTC-containing transcript - measurably starting at the mRNA level in patient
    myocardium despite hypertrophy-driven upregulation of transcription - and the
    ubiquitin-proteasome system clears residual mutant protein. UPF3B, an NMD
    regulator upregulated specifically in MYBPC3-truncating hearts and localised
    to the sarcomeric Z-disc, has been implicated in establishing this
    haploinsufficiency during the first round of sarcomeric protein translation.
    The severity of the resulting phenotype scales with the residual cMyBP-C dose,
    which is what makes CMH4 a gene-dosage disease.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Nonsense-Mediated mRNA Decay
    term:
      id: GO:0000184
      label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    modifier: INCREASED
  - preferred_term: Proteasomal Degradation of Mutant cMyBP-C
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    modifier: INCREASED
  evidence:
  - reference: PMID:22057632
    reference_title: "How do MYBPC3 mutations cause hypertrophic cardiomyopathy?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Instead of expression of a poison peptide we consistently observe
      haploinsufficiency of MyBP-C in MYBPC3 mutant human heart muscle.
    explanation: >-
      States the core mechanistic claim - haploinsufficiency rather than a
      dominant-negative poison peptide - directly in human myocardium. Evidence
      source is OTHER because this is a mechanistic review.
  - reference: PMID:19574547
    reference_title: "Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The absence of any detectable truncated MyBP-C argues against its
      incorporation in the myofiber and any dominant negative effect. In
      contrast, the lowered relative level of full length protein in both
      truncation and missense MYBPC3 mutations argues strongly that
      haploinsufficiency is sufficient to cause the disease.
    explanation: >-
      Primary human data, not review: quantified myofibrillar MyBP-C in
      genotyped myectomy specimens against donor hearts and found reduced
      full-length protein with no detectable truncated peptide. This is the
      direct measurement the haploinsufficiency claim rests on.
  - reference: PMID:19574547
    reference_title: "Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, the overall level of MyBP-C in myofibrils was significantly
      reduced (P<0.0005) in tissue containing either a truncation or missense
      MYBPC3 mutation
    explanation: >-
      Gives the quantitative reduction in myofibrillar cMyBP-C in patient
      tissue, and notes it holds for missense as well as truncating alleles.
  - reference: PMID:37797718
    reference_title: "Nonsense mediated decay factor UPF3B is associated with cMyBP-C haploinsufficiency in hypertrophic cardiomyopathy patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show that cMyBP-C haploinsufficiency starts at the mRNA level, despite
      hypertrophy-induced increased transcriptional activity.
    explanation: >-
      Localises the origin of haploinsufficiency to transcript destruction in
      patient myocardium, evidence obtained from human HCM cardiac tissue with
      MYBPC3 truncating variants.
  - reference: PMID:37797718
    reference_title: "Nonsense mediated decay factor UPF3B is associated with cMyBP-C haploinsufficiency in hypertrophic cardiomyopathy patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data suggest that cMyBP-C haploinsufficiency in HCM-patients is
      established by UPF3B-dependent NMD during the initial translation round at
      the Z-disc.
    explanation: >-
      Identifies UPF3B-dependent nonsense-mediated decay as the specific
      surveillance route producing cMyBP-C haploinsufficiency.
  - reference: PMID:38406555
    reference_title: "Hypertrophic cardiomyopathy in MYBPC3 carriers in aging."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Pathogenesis related to MYBPC3 mutations includes nonsense-mediated decay,
      alternative splicing, and ubiquitin-proteasome system events, leading to
      allelic imbalance and haploinsufficiency.
    explanation: >-
      Names all three degradation/surveillance routes converging on allelic
      imbalance and haploinsufficiency. Evidence source is OTHER because this is a
      narrative review.
  downstream:
  - target: Myosin Shift from the Super-Relaxed to the Disordered-Relaxed State
    causal_link_type: DIRECT
    description: >-
      Reduced cMyBP-C in the A band leaves myosin heads untethered from the
      thick filament core, depopulating the energy-conserving super-relaxed
      reserve.
- name: Myosin Shift from the Super-Relaxed to the Disordered-Relaxed State
  biological_scale: MOLECULAR
  role: effector
  description: >-
    In the resting sarcomere a substantial fraction of myosin heads sit in the
    super-relaxed (SRX) state - folded back against the thick filament core with
    a very low ATPase rate - forming an energy-conserving reserve of motors that
    are unavailable for force generation. cMyBP-C is what holds them there.
    Losing cMyBP-C untethers those heads and shifts the population toward the
    disordered-relaxed (DRX) state, which can hydrolyse ATP and engage the thin
    filament. This is the step that converts a protein-dose deficit into
    hypercontractility with raised energetic cost, and it is the step the
    approved cardiac myosin inhibitors act on: the same work that defines the
    SRX loss shows that MYK-461 (mavacamten) rescues the relaxation defect and
    restores normal contractility in MYBPC3-mutant cardiomyocytes. The shift is
    demonstrated in three independent systems - homozygous cMyBP-C knockout
    mouse cardiomyocytes, human MYBPC3-mutant myectomy tissue, and stepwise
    cMyBP-C depletion in vitro - and, importantly for the dose model, the human
    myectomy data show a positive correlation between residual cMyBP-C
    expression and the proportion of heads remaining in SRX.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: ATP Hydrolysis by Myosin
    term:
      id: GO:0016887
      label: ATP hydrolysis activity
    modifier: INCREASED
  cellular_components:
  - preferred_term: Myosin thick filament
    term:
      id: GO:0032982
      label: myosin filament
  evidence:
  - reference: PMID:28658286
    reference_title: "MYBPC3 mutations are associated with a reduced super-relaxed state in patients with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared to donors, only MYBPC3mut samples display a significantly
      diminished SRX, characterised by a decrease in both the number of myosin
      heads in the SRX and the lifetime of ATP turnover.
    explanation: >-
      Demonstrates SRX loss in human myectomy tissue and, critically, shows it
      is specific to MYBPC3-mutation-positive hearts rather than a generic
      consequence of hypertrophy - sarcomere-mutation-negative HCM samples did
      not show it.
  - reference: PMID:28658286
    reference_title: "MYBPC3 mutations are associated with a reduced super-relaxed state in patients with hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was a positive correlation (p < 0.01) between the expression of
      cMyBP-C and the proportion of myosin heads in the SRX state, suggesting
      cMyBP-C modulates and maintains the SRX.
    explanation: >-
      Ties the size of the SRX reserve quantitatively to residual cMyBP-C
      protein level, which is the molecular expression of the gene-dosage
      gradient this entry models.
  - reference: PMID:27021517
    reference_title: "Ablation of cardiac myosin binding protein-C disrupts the super-relaxed state of myosin in murine cardiomyocytes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We report a significant decrease in the proportion of myosin heads in the
      SRX state in homozygous cMyBP-C knockout mice, however heterozygous
      cMyBP-C knockout mice do not significantly differ from the wild type.
    explanation: >-
      Independent in vivo confirmation in the complete-null state. Note the
      heterozygous result is negative, which is consistent with the
      phenotype-negative heterozygous mouse recorded in the model-mismatch
      discussion rather than with the human heterozygous disease.
  - reference: PMID:30674652
    reference_title: "Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Depletion of cMyBPC also altered dynamic myosin conformations during
      relaxation, enhancing the myosin state that enables ATP hydrolysis and
      thin filament interactions while reducing the super relaxed conformation
      associated with energy conservation.
    explanation: >-
      States the SRX-to-DRX shift directly as the consequence of cMyBP-C
      depletion, in a stepwise-depletion system that establishes dose
      dependence.
  - reference: PMID:30674652
    reference_title: "Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      MYK-461, a pharmacologic inhibitor of myosin ATPase, rescued relaxation
      deficits and restored normal contractility in mouse and human
      cardiomyocytes with MYBPC3 mutations.
    explanation: >-
      Closes the mechanism-to-therapy loop for this node: the cardiac myosin
      inhibitor class reverses the functional consequence of the SRX shift in
      MYBPC3-mutant cells, which is why mavacamten and aficamten target this
      node rather than the downstream cross-bridge node.
  downstream:
  - target: Loss of the cMyBP-C Brake on Actin-Myosin Cross-Bridge Cycling
    causal_link_type: DIRECT
    description: >-
      Heads released from the super-relaxed reserve are available to form
      cross-bridges, so the restraint on cross-bridge number and kinetics is
      lost.
- name: Loss of the cMyBP-C Brake on Actin-Myosin Cross-Bridge Cycling
  biological_scale: MOLECULAR
  role: effector
  description: >-
    cMyBP-C normally tethers and restrains myosin heads in the thick-filament C-zone,
    limiting the number of cross-bridges available for force generation and slowing
    cross-bridge kinetics. When cMyBP-C is reduced or absent, this brake is released:
    myofilament calcium sensitivity rises and the contraction-relaxation cycle is
    disturbed, producing hypercontractility with impaired relaxation. Direct
    calcium-handling consequences follow, with progressively slowed calcium release
    as cMyBP-C content falls.
  cell_types:
  - preferred_term: Ventricular cardiomyocyte
    term:
      id: CL:0002131
      label: regular ventricular cardiac myocyte
  biological_processes:
  - preferred_term: Actin-Myosin Filament Sliding
    term:
      id: GO:0033275
      label: actin-myosin filament sliding
    modifier: INCREASED
  - preferred_term: Regulation of Cardiac Muscle Contraction
    term:
      id: GO:0055117
      label: regulation of cardiac muscle contraction
    modifier: ABNORMAL
  - preferred_term: Calcium-Dependent Regulation of Cardiac Contraction
    term:
      id: GO:0010882
      label: regulation of cardiac muscle contraction by calcium ion signaling
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: Myosin thick filament
    term:
      id: GO:0032982
      label: myosin filament
  evidence:
  - reference: PMID:36893011
    reference_title: "cMyBP-C ablation in human engineered cardiac tissue causes progressive Ca2+-handling abnormalities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our data suggest a progressive phenotype caused by cMyBP-C
      haploinsufficiency and ablation that initially is hypercontractile, but
      progresses to hypocontractility with impaired relaxation.
    explanation: >-
      Isogenic human iPSC-derived engineered cardiac tissue shows that removing
      cMyBP-C produces initial hypercontractility that decays to hypocontractility
      with impaired relaxation, the functional signature of losing the cMyBP-C
      brake.
  - reference: PMID:36893011
    reference_title: "cMyBP-C ablation in human engineered cardiac tissue causes progressive Ca2+-handling abnormalities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      After 2 wk of culture in ECT, contractile function was similar between the
      three genotypes; however, Ca2+-release was slower in the setting of reduced
      or absent cMyBP-C.
    explanation: >-
      Links reduced or absent cMyBP-C directly to slowed calcium release in an
      isogenic human model.
  - reference: PMID:32871100
    reference_title: "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac muscle hypercontractility is a key pathophysiological abnormality in
      hypertrophic cardiomyopathy, and a major determinant of dynamic left
      ventricular outflow tract (LVOT) obstruction.
    explanation: >-
      Confirms hypercontractility as the central pathophysiological abnormality in
      HCM generally and links it to outflow obstruction; PARTIAL because the trial
      population is HCM at large rather than genotyped MYBPC3 carriers.
  downstream:
  - target: Gene-Dosage-Dependent Severity Gradient
    causal_link_type: DIRECT
    description: >-
      The magnitude of the contractile derangement tracks the residual cMyBP-C
      dose, which is set by whether one or both MYBPC3 alleles are truncating.
- name: Gene-Dosage-Dependent Severity Gradient
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: ESTABLISHED
  description: >-
    CMH4 severity is a graded function of residual cMyBP-C, and this is the axis
    that separates the two clinical entities within the same MONDO term. One
    truncating allele leaves roughly half-normal cMyBP-C and yields the classic
    late-onset dominant disease with incomplete penetrance. Two truncating alleles
    leave essentially none and yield severe cardiomyopathy in the neonatal period.
    Isogenic human engineered cardiac tissue and heterozygous/homozygous knock-in
    mouse models both reproduce this dose-severity relationship, providing
    experimental confirmation of the human genotype-phenotype pattern.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cardiac Muscle Cell Contraction
    term:
      id: GO:0086003
      label: cardiac muscle cell contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36893011
    reference_title: "cMyBP-C ablation in human engineered cardiac tissue causes progressive Ca2+-handling abnormalities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The severity of the phenotype correlates with the amount of cMyBP-C present,
      with more severe earlier phenotypes observed in cMyBP-C-/- than cMyBP-C+/-
      EC
    explanation: >-
      Explicitly states the dose-severity correlation in an isogenic human iPSC
      system comparing heterozygous and homozygous MYBPC3 frameshifts.
  - reference: PMID:36893011
    reference_title: "cMyBP-C ablation in human engineered cardiac tissue causes progressive Ca2+-handling abnormalities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Heterozygous carriers present with classical HCM, while homozygous carriers
      present with early onset HCM that rapidly progress to heart failure.
    explanation: >-
      Summarises the human mono- versus bi-allelic dose contrast that the isogenic
      model was built to interrogate.
  - reference: PMID:37844837
    reference_title: "Characterization of heterozygous and homozygous mouse models with the most common hypertrophic cardiomyopathy mutation MYBPC3(c.2373InsG) in the Netherlands."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Expectedly, knock-in of Mybpc3c.2373InsG resulted in the absence of cMyBP-C
      and our 18-28 week old homozygous Mybpc3c.2373InsG model developed cardiac
      hypertrophy and severe left ventricular systolic and diastolic dysfunction,
      whereas HCM was not evident in Mybpc3+/InsG mice.
    explanation: >-
      A CRISPR knock-in mouse allelic series of the Dutch founder variant
      recapitulates the dose gradient: homozygotes develop severe disease while
      heterozygotes remain unaffected at the same age.
  downstream:
  - target: Ventricular Hypertrophy, Disarray and Fibrosis
    causal_link_type: DIRECT
- name: Cell-Autonomous Cardiac Fibroblast Activation by MYBPC3 Deficiency
  biological_scale: CELLULAR
  role: amplifier
  mechanism_confidence: PROVISIONAL
  description: >-
    A parallel, non-cardiomyocyte route to the fibrosis in this disease. MYBPC3
    has been treated as cardiomyocyte-specific, and fibrosis in HCM as a
    secondary response to myocyte stress. Work in a base-edited R495Q pig model
    found early-onset myocardial fibrosis shortly after birth and, unexpectedly,
    that MYBPC3 is transcribed and translated in cardiac fibroblasts themselves;
    disrupting Mybpc3 in fibroblasts activated NF-kB signalling, raised
    TGF-beta1 and pro-inflammatory gene expression, and drove a HIF-1-alpha
    glycolytic shift that accelerated fibroblast activation. If this holds in
    human disease, part of the fibrotic burden is cell-autonomous to the
    fibroblast rather than a downstream reaction to myocyte dysfunction - which
    would make it a separate therapeutic target from myosin inhibition.
  cell_types:
  - preferred_term: Cardiac Fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: Transforming Growth Factor Beta Receptor Signaling
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:36357371
    reference_title: "MYBPC3 deficiency in cardiac fibroblasts drives their activation and contributes to fibrosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Unexpectedly, we found that the "cardiac-specific" MYBPC3 gene was
      actually expressed in cardiac fibroblasts from different species as well
      as NIH3T3 fibroblasts at the transcription and protein levels.
    explanation: >-
      Overturns the premise that MYBPC3 expression is confined to
      cardiomyocytes, which is what makes a fibroblast-autonomous arm possible
      at all.
  - reference: PMID:36357371
    reference_title: "MYBPC3 deficiency in cardiac fibroblasts drives their activation and contributes to fibrosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      CRISPR-mediated disruption of Mybpc3 in NIH3T3 fibroblasts activated
      nuclear factor κB (NF-κB) signaling pathway, which increased the
      expression of transforming growth factor beta (TGF-β1) and other
      pro-inflammatory genes.
    explanation: >-
      Gives the signalling route from fibroblast MYBPC3 loss to a profibrotic
      program, independent of any cardiomyocyte intermediate.
  notes: >-
    Mechanism confidence is PROVISIONAL and deliberately so. The evidence is a
    base-edited pig missense (R495Q) model plus an immortalised murine
    fibroblast line; there is no human tissue confirmation that fibroblast
    MYBPC3 loss contributes to fibrosis in patients, and human disease is
    predominantly truncating rather than missense. Curated as a parallel arm
    rather than folded into the main chain because, if confirmed, it is a
    distinct therapeutic target - and if it fails to replicate, it can be
    removed without disturbing the cardiomyocyte chain.
  downstream:
  - target: Ventricular Hypertrophy, Disarray and Fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Activated fibroblasts deposit matrix, contributing to the same tissue
      phenotype the cardiomyocyte chain produces.
- name: Ventricular Hypertrophy, Disarray and Fibrosis
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    Chronic sarcomeric inefficiency drives the structural remodeling that defines
    the clinical phenotype: cardiomyocyte hypertrophy with myofiber disarray,
    interstitial and replacement fibrosis, and - in the biallelic neonatal form -
    extensive myocardial necrosis and fibrosis together with noncompaction-like
    hypertrabeculation. Fibrosis provides the substrate for both diastolic
    dysfunction and arrhythmia.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: Cardiac Fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: Cardiac Muscle Hypertrophy in Response to Stress
    term:
      id: GO:0014898
      label: cardiac muscle hypertrophy in response to stress
    modifier: INCREASED
  - preferred_term: Extracellular Matrix Organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  locations:
  - preferred_term: Interventricular septum
    term:
      id: UBERON:0002094
      label: interventricular septum
  - preferred_term: Left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  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: >-
      Autopsy evidence of the hypertrophy-plus-fibrosis tissue phenotype in a
      biallelic MYBPC3 neonate.
  - reference: PMID:37844837
    reference_title: "Characterization of heterozygous and homozygous mouse models with the most common hypertrophic cardiomyopathy mutation MYBPC3(c.2373InsG) in the Netherlands."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Both the 3-4 week old and 18-28 week old Mybpc3InsG/InsG models recapitulate
      HCM, with a severe phenotype present in the 18-28 week old model.
    explanation: >-
      Confirms that cMyBP-C absence is sufficient to produce the HCM structural
      phenotype in vivo, with progressive worsening.
  downstream:
  - target: Diastolic Dysfunction, Heart Failure and Arrhythmic Risk
    causal_link_type: DIRECT
- name: Diastolic Dysfunction, Heart Failure and Arrhythmic Risk
  biological_scale: ORGANISM
  role: consequence
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >-
    The remodelled, stiff, disarrayed and fibrotic ventricle produces the clinical
    endpoints of CMH4. In heterozygotes this is usually a slowly progressive
    picture of diastolic dysfunction with preserved ejection fraction, dynamic
    outflow obstruction in a subset, and a low but real annual risk of malignant
    ventricular arrhythmia and sudden death. In the biallelic neonatal form,
    systolic and diastolic function fail together and death from cardiac failure
    follows within weeks to months.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Heart Contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: ABNORMAL
  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: >-
      Documents rapid progression to fatal cardiac failure as the terminal
      consequence in biallelic disease.
  - reference: PMID:39581692
    reference_title: "Hypertrophic cardiomyopathy due to truncating variants in myosin binding protein C: a Spanish cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite it being the most common clinical event, relevant heart failure
      (observed in 8.1% of patients) was infrequent and commonly found in the
      presence of a second environmental precipitating agent.
    explanation: >-
      Quantifies heart failure as the commonest but still infrequent clinical
      endpoint in a heterozygous truncating-MYBPC3 cohort.
  - reference: PMID:39689185
    reference_title: "Recreational and Occupational Physical Activity and Risk of Adverse Events in Truncating MYBPC3 Founder Variant Carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MYBPC3 founder variants cause hypertrophic cardiomyopathy leading to heart
      failure and malignant ventricular arrhythmias.
    explanation: >-
      Names the two adverse endpoints - heart failure and malignant ventricular
      arrhythmia - in truncating MYBPC3 founder variant carriers.
phenotypes:
- name: Hypertrophic Cardiomyopathy
  category: Cardiovascular
  description: >-
    Unexplained ventricular hypertrophy is the defining feature. In heterozygous
    carriers hypertrophy is typically discrete (mean maximal wall thickness
    ~17.5 mm in probands, ~14.6 mm in affected relatives); in biallelic neonates
    it is severe from the outset.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  frequency: OBLIGATE
  evidence:
  - reference: PMID:39581692
    reference_title: "Hypertrophic cardiomyopathy due to truncating variants in myosin binding protein C: a Spanish cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertrophy was discrete with a significative difference between probands
      and relatives (17.5±4 mm vs 14.6±5 mm; p<0.0001).
    explanation: >-
      Documents the hypertrophy magnitude in a molecularly homogeneous truncating
      MYBPC3 cohort.
  - reference: PMID:36162733
    reference_title: "The «Amish» NM_000256.3:c.3330+2T>G splice variant in MYBPC3 associated with hypertrophic cardiomyopathy is an ancient Swiss mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MYBPC3 is the most frequently mutated gene in hypertrophic cardiomyopathy
      (HCM).
    explanation: >-
      Confirms the gene-disease association that defines this entity.
- name: Asymmetric Septal Hypertrophy
  category: Cardiovascular
  description: >-
    Asymmetric septal thickening is the most common hypertrophy pattern, but MYBPC3
    carriers show substantial heterogeneity of pattern even within a single family
    carrying one variant - concentric, apical and eccentric patterns all occur, and
    some carriers have no hypertrophy at all.
  phenotype_term:
    preferred_term: Asymmetric septal hypertrophy
    term:
      id: HP:0001670
      label: Asymmetric septal hypertrophy
  subtype: Monoallelic CMH4
  evidence:
  - reference: PMID:22267749
    reference_title: "Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      pattern of hypertrophy (11 none, 9 asymmetrical, 3 concentric, 1 apical, 1
      eccentric)
    explanation: >-
      Enumerates the hypertrophy patterns observed among R502W MYBPC3 carriers,
      with asymmetrical the most frequent among those with hypertrophy.
- name: Left Ventricular Outflow Tract Obstruction
  category: Cardiovascular
  description: >-
    Hypercontractility with septal hypertrophy generates a dynamic pressure
    gradient across the left ventricular outflow tract in a subset of patients,
    driving exertional symptoms and defining the obstructive phenotype targeted by
    myosin inhibitors and septal reduction therapy.
  phenotype_term:
    preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  evidence:
  - reference: PMID:32871100
    reference_title: "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac muscle hypercontractility is a key pathophysiological abnormality in
      hypertrophic cardiomyopathy, and a major determinant of dynamic left
      ventricular outflow tract (LVOT) obstruction.
    explanation: >-
      Links hypercontractility - the direct consequence of cMyBP-C loss - to
      dynamic LVOT obstruction; PARTIAL because the cited trial enrolled HCM
      broadly rather than genotyped MYBPC3 carriers.
- name: Left Ventricular Diastolic Dysfunction
  category: Cardiovascular
  description: >-
    Impaired relaxation is an early and characteristic consequence of losing the
    cMyBP-C brake, preceding overt systolic impairment; in the absence of cMyBP-C
    it is accompanied by severe systolic dysfunction.
  phenotype_term:
    preferred_term: Left ventricular diastolic dysfunction
    term:
      id: HP:0025168
      label: Left ventricular diastolic dysfunction
  evidence:
  - reference: PMID:37844837
    reference_title: "Characterization of heterozygous and homozygous mouse models with the most common hypertrophic cardiomyopathy mutation MYBPC3(c.2373InsG) in the Netherlands."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      our 18-28 week old homozygous Mybpc3c.2373InsG model developed cardiac
      hypertrophy and severe left ventricular systolic and diastolic dysfunction
    explanation: >-
      Demonstrates diastolic (and systolic) dysfunction on loss of cMyBP-C in a
      knock-in mouse model of the Dutch founder variant.
  - reference: PMID:36893011
    reference_title: "cMyBP-C ablation in human engineered cardiac tissue causes progressive Ca2+-handling abnormalities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      progresses to hypocontractility with impaired relaxation
    explanation: >-
      Human isogenic engineered cardiac tissue shows impaired relaxation as a
      direct consequence of reduced or absent cMyBP-C.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    Heart failure is the commonest clinical event in heterozygous carriers but
    remains infrequent in absolute terms and is often precipitated by a second
    insult. In biallelic disease, fatal cardiac failure occurs in the first months
    of life.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:39581692
    reference_title: "Hypertrophic cardiomyopathy due to truncating variants in myosin binding protein C: a Spanish cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite it being the most common clinical event, relevant heart failure
      (observed in 8.1% of patients) was infrequent and commonly found in the
      presence of a second environmental precipitating agent.
    explanation: >-
      The reported 8.1% frequency in a truncating-MYBPC3 cohort maps to the
      OCCASIONAL band (5-29%).
- name: Ventricular Tachycardia
  category: Cardiovascular
  description: >-
    Malignant ventricular arrhythmia (sustained ventricular tachycardia or
    fibrillation) is a principal adverse endpoint in truncating MYBPC3 carriers and
    the reason for arrhythmic risk stratification and ICD consideration. Risk is
    increased in carriers engaged in the highest quartile of high-dynamic sport.
  phenotype_term:
    preferred_term: Ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  evidence:
  - reference: PMID:39689185
    reference_title: "Recreational and Occupational Physical Activity and Risk of Adverse Events in Truncating MYBPC3 Founder Variant Carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MCE was defined as a composite of malignant ventricular arrhythmia
      (sustained ventricular tachycardia/fibrillation), heart failure (heart
      failure hospitalizations or transplantation), and septal reduction therapy.
    explanation: >-
      Establishes sustained ventricular tachycardia/fibrillation as a curated
      adverse endpoint in a truncating MYBPC3 founder-variant cohort.
  - reference: PMID:39689185
    reference_title: "Recreational and Occupational Physical Activity and Risk of Adverse Events in Truncating MYBPC3 Founder Variant Carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, high-dynamic activity was associated with malignant ventricular
      arrhythmia
    explanation: >-
      Identifies high-dynamic exercise as an arrhythmic risk modifier specific to
      MYBPC3 founder variant carriers (adjusted hazard ratio 3.26 at the 75th
      percentile in the cited analysis).
- name: Sudden Cardiac Death
  category: Cardiovascular
  description: >-
    Sudden death occurs at a low but non-zero annual rate in clinically affected
    heterozygous carriers (0.46%/year in one long-term family series), and MYBPC3
    biallelic disease can present as sudden unexpected death in infancy.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  frequency: VERY_RARE
  evidence:
  - reference: PMID:22267749
    reference_title: "Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During follow up of 7.9+/-4.5 years, in 82 clinically affected individuals
      the annual risk of sudden death and all cause mortality was 0.46% and 0.93%
      per year, respectively.
    explanation: >-
      The 0.46%/year sudden-death rate over ~8 years of follow-up corresponds to a
      cumulative risk in the VERY_RARE band for this cohort.
  - reference: PMID:33849460
    reference_title: "A rare cause of sudden unexpected death syndrome (SUDS) in the first year of life: endomyocardial fibroelastosis (EFE) due to two compound heterozygous MYBPC3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A case of a sudden unexpected cardiac death of a 5.5-months-old child is
      presented.
    explanation: >-
      Documents biallelic MYBPC3 disease presenting as sudden unexpected death in
      infancy.
- name: Left Ventricular Noncompaction
  category: Cardiovascular
  description: >-
    Hypertrabeculation/noncompaction of the left ventricle is a distinctive
    accompaniment of the biallelic neonatal phenotype, present in three of four
    neonates in the defining series.
  phenotype_term:
    preferred_term: Left ventricular noncompaction cardiomyopathy
    term:
      id: HP:0011664
      label: Left ventricular noncompaction cardiomyopathy
  subtype: Biallelic CMH4
  frequency: FREQUENT
  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.
    explanation: >-
      Three of four biallelic neonates had noncompaction features, supporting a
      FREQUENT band within this subtype.
- name: Cardiac Septal Defect
  category: Cardiovascular
  description: >-
    Septal defects (atrial or ventricular) or a patent ductus arteriosus accompany
    the cardiomyopathy in roughly 60% of reported biallelic MYBPC3 patients - a
    structural-malformation component absent from the heterozygous phenotype.
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  subtype: Biallelic CMH4
  frequency: FREQUENT
  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: >-
      The reported 62% frequency across all published biallelic cases maps to the
      FREQUENT band.
  - 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: >-
      All four index neonates with biallelic truncating MYBPC3 variants had septal
      defects.
- name: Atrial Septal Defect
  category: Cardiovascular
  description: >-
    An atrial septal defect was found at autopsy in a compound heterozygous MYBPC3
    neonate, one instance of the septal-defect spectrum accompanying biallelic
    disease.
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  subtype: Biallelic CMH4
  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: >-
      Autopsy documentation of an ASD accompanying biallelic MYBPC3 neonatal
      cardiomyopathy.
- name: Atrial Fibrillation
  category: Cardiovascular
  description: >-
    Atrial fibrillation is a major morbidity of this disease and the route to its
    leading non-sudden complication, cardioembolic stroke. It matters
    disproportionately here because its presence mandates anticoagulation
    irrespective of conventional risk scoring, so it changes management rather
    than merely describing severity. In the MYBPC3-specific registry analysis it
    is counted as a component of the adverse composite outcome alongside sudden
    death, class III/IV heart failure and transplant.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  subtype: Monoallelic CMH4
  notes: >-
    Frequency band deliberately omitted. The commonly cited HCM figures (about
    20% overall, rising with age) come from the GeneReviews overview, whose
    PubMed record is a purpose statement with no quotable clinical text, and no
    MYBPC3-specific denominator for atrial fibrillation appears in any cached
    source. The association is evidenced here; the rate is not.
  evidence:
  - reference: PMID:32841044
    reference_title: "Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      time-event analysis was performed (composite clinical outcome of sudden
      death, class III/IV heart failure, left ventricular assist
      device/transplant, atrial fibrillation)
    explanation: >-
      Establishes atrial fibrillation as one of the adverse clinical outcomes
      tracked in a genotyped MYBPC3 cohort of 1316 patients.
  - reference: PMID:38406555
    reference_title: "Hypertrophic cardiomyopathy in MYBPC3 carriers in aging."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      pathogenic sarcomere variants exacerbate existing conditions, such as
      ventricular arrhythmia, HF, atrial fibrillation (AF), stroke, or even
      death in HCM individuals
    explanation: >-
      Places atrial fibrillation and its stroke sequel among the conditions
      aggravated by sarcomere variants. PARTIAL because it is a narrative review
      statement about sarcomeric HCM broadly rather than a MYBPC3 measurement.
- name: Syncope
  category: Cardiovascular
  description: >-
    Syncope is part of the clinical spectrum of this disease and carries weight
    beyond symptom burden: unexplained syncope is a risk marker in both the
    AHA/ACC and HCM Risk-SCD approaches to sudden-death stratification, so it
    feeds directly into the ICD decision this entry curates.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
  subtype: Monoallelic CMH4
  notes: >-
    Frequency deliberately omitted - no cached MYBPC3 source reports a syncope
    rate. Its inclusion here is justified by its role in risk stratification, not
    by a quantified prevalence.
  evidence:
  - reference: PMID:38406555
    reference_title: "Hypertrophic cardiomyopathy in MYBPC3 carriers in aging."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Diverse phenotypic expression and naturally variable progression of HCM
      are reflections of a range of clinical manifestations from dyspnea and/or
      syncope to sudden cardiac death.
    explanation: >-
      Places syncope within the clinical manifestation range of hypertrophic
      cardiomyopathy in a MYBPC3-focused review. PARTIAL because the statement
      is about HCM generally rather than a MYBPC3-specific frequency.
- name: Feeding Difficulties in Infancy
  category: Gastrointestinal
  description: >-
    Feeding difficulty is one of the presenting features of the biallelic neonatal
    form, reflecting low cardiac output rather than a primary gastrointestinal
    problem.
  phenotype_term:
    preferred_term: Feeding difficulties in infancy
    term:
      id: HP:0008872
      label: Feeding difficulties in infancy
  subtype: Biallelic 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: >-
      All four children presented with feeding difficulties, failure to thrive,
      and dyspnea.
    explanation: >-
      Feeding difficulty was a universal presenting feature in the biallelic
      neonatal series.
- name: Failure to Thrive
  category: Growth
  description: >-
    Failure to thrive accompanies feeding difficulty in the biallelic neonatal
    presentation.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  subtype: Biallelic 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: >-
      All four children presented with feeding difficulties, failure to thrive,
      and dyspnea.
    explanation: >-
      Failure to thrive was a universal presenting feature in the biallelic
      neonatal series.
- name: Dyspnea
  category: Respiratory
  description: >-
    Dyspnea is a presenting symptom in biallelic neonates and an exertional symptom
    in symptomatic adults with obstructive disease.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea
  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: >-
      Dyspnea was a universal presenting feature in the biallelic neonatal series.
histopathology:
- name: Myocyte Disarray
  description: >-
    Myofibre disarray - the loss of the normal parallel alignment of
    cardiomyocytes, with hypertrophied fibres running obliquely and in whorls
    amid disordered connective tissue - is the pathognomonic histological lesion
    of hypertrophic cardiomyopathy and the tissue-level substrate for both the
    arrhythmic risk and the diastolic dysfunction modeled in this entry. It is
    documented directly in MYBPC3 disease in septal myocardium from an adult
    homozygous for the Indian 25-bp deletion, described as swirling of
    hypertrophied myofibres amid connective tissue disarray, and in the same
    family's series as hypertrophied myofibres separated by increased connective
    tissue.
  finding_term:
    preferred_term: myofibre disarray
    term:
      id: NCIT:C35867
      label: Morphologic Finding
  evidence:
  - reference: PMID:19151713
    reference_title: "A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathological section of the septal myocardium of the same individual
      showing 'swirling' of hypertrophied myofibers amid connective tissue
      disarray
    explanation: >-
      Direct histological documentation of disarray in the septum of a genotyped
      MYBPC3 homozygote.
  - reference: PMID:19151713
    reference_title: "A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathological section of the same subject showing hypertrophied
      myofibers separated from each other by increased connective tissue
    explanation: >-
      Companion documentation of hypertrophied fibres separated by expanded
      interstitial connective tissue in a MYBPC3 deletion carrier.
  notes: >-
    The finding_term is bound only to the generic NCIT Morphologic Finding
    parent. NCIT has no myofibre-disarray term, and HP:0031318 Myofiber disarray
    - the precise term - is not reachable from the HistopathologyFindingTerm
    enum roots, since its ancestors run through HP:0001637 Abnormal myocardium
    morphology rather than HP:0025461 Abnormal cell morphology. The specific
    meaning is therefore carried by preferred_term. This is a genuine ontology
    gap and a candidate NTR rather than a curation shortcut. See also the
    model-mismatch discussion: this lesion is documented in humans but is not
    reported in the mouse models this entry curates.
- name: Myocardial Fibrosis
  description: >-
    Extensive myocardial necrosis and interstitial/replacement fibrosis are found
    at autopsy in biallelic MYBPC3 neonatal cardiomyopathy.
  finding_term:
    preferred_term: Myocardial fibrosis
    term:
      id: NCIT:C178564
      label: Cardiac Fibrosis
  subtype: Biallelic CMH4
  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: >-
      Direct histopathological documentation of necrosis and fibrosis in biallelic
      MYBPC3 disease.
- name: Endomyocardial Fibroelastosis
  description: >-
    Endomyocardial fibroelastosis with a massively enlarged heart has been
    documented at autopsy as the histopathological substrate of sudden unexpected
    infant death caused by two biparental MYBPC3 mutations.
  finding_term:
    preferred_term: Endomyocardial fibroelastosis
  subtype: Biallelic CMH4
  notes: >-
    term: deliberately omitted. This finding previously carried NCIT:C178564
    Cardiac Fibrosis, the same term as the Myocardial Fibrosis entry above, but
    endomyocardial fibroelastosis is a distinct entity - a thickened,
    fibroelastic endocardial layer - and not a subtype of myocardial fibrosis,
    so binding both findings to one term collapsed a real distinction and made
    two different lesions look identical to any downstream consumer. NCIT has no
    endomyocardial fibroelastosis term reachable from the
    HistopathologyFindingTerm roots. An unbound preferred_term is the honest
    representation and this is a candidate NTR.
  evidence:
  - reference: PMID:33849460
    reference_title: "A rare cause of sudden unexpected death syndrome (SUDS) in the first year of life: endomyocardial fibroelastosis (EFE) due to two compound heterozygous MYBPC3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Autopsy and thorough postmortem cardiac examinations revealed a massively
      enlarged heart with endomyocardial fibroelastosis.
    explanation: >-
      Endomyocardial fibroelastosis is the reported autopsy finding in this
      biallelic MYBPC3 infant death.
biochemical:
- name: NT-proBNP
  presence: Elevated
  context: >-
    Heart-failure severity marker, and the pharmacodynamic readout of cardiac
    myosin inhibition. N-terminal pro-B-type natriuretic peptide tracks
    heart-failure severity and falls steeply under cardiac myosin inhibition -
    in SEQUOIA-HCM the geometric mean proportional change to week 24 was 0.20 on
    aficamten against 1.00 on placebo, an approximately fivefold reduction
    against no change. That makes it the practical objective marker of response
    to the drug class this entry wires to the super-relaxed-state node.
  biomarker_term:
    preferred_term: N-terminal pro-B-type natriuretic peptide
    term:
      id: HP:0031185
      label: Elevated circulating NT-proBNP concentration
  evidence:
  - reference: PMID:38739079
    reference_title: "Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the geometric mean proportional change from baseline to week 24 in the
      serum NT-proBNP level
    explanation: >-
      Identifies NT-proBNP as a measured endpoint in the phase 3 aficamten
      trial; the accompanying reported values are 0.20 on aficamten versus 1.00
      on placebo.
  notes: >-
    Deliberately scoped to the treatment-response and heart-failure-severity
    role, which is what the cited trial evidence supports. This entry does NOT
    claim that NT-proBNP or high-sensitivity troponin are elevated in
    genotype-positive, phenotype-negative MYBPC3 carriers. That claim was
    proposed during review citing PMID:31877118, but that paper is an iPSC
    cardiomyocyte study of protein-level compensation and reports no patient
    biomarker data at all - it is cited in this entry where it does belong, in
    the haploinsufficiency-sufficiency discussion. A preclinical-biomarker claim
    would need a carrier cohort with measured analytes, which no cached source
    here provides.
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. It is the single most
    frequently mutated gene in hypertrophic cardiomyopathy and the defining gene of
    this MONDO entity. ClinGen's Hereditary Cardiovascular Disease Gene Curation
    Expert Panel rates the gene-disease relationship Definitive with autosomal
    dominant inheritance; biallelic loss additionally produces the severe neonatal
    form.
  frequency: >-
    About half of identified HCM mutations lie in MYBPC3; within MYBPC3 itself,
    truncating variants account for 91% of pathogenic variants.
  evidence:
  - reference: PMID:32841044
    reference_title: "Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Truncating variants account for 91% of MYBPC3 pathogenic variants and
      cause similar clinical severity and outcomes regardless of location,
      consistent with locus-independent loss-of-function.
    explanation: >-
      Quantifies the truncating share within MYBPC3 in 1316 genotyped patients
      from the Sarcomeric Human Cardiomyopathy Registry, and supplies the
      strongest genetic argument for the loss-of-function model curated here:
      if severity were driven by a truncated peptide, outcome would depend on
      where in the gene the truncation falls. It does not.
  - reference: PMID:32841044
    reference_title: "Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      C10 mutant MyBP-C failed to incorporate into myofilaments and degradation
      rates were accelerated by ≈90%, while C3 and C6 mutant MyBP-C incorporated
      normally with degradation rate similar to wild-type.
    explanation: >-
      Shows that a subset of the minority non-truncating variants also converge
      on loss of function, by failing to incorporate into the myofilament and
      being degraded - extending the dose model beyond the truncating class
      without claiming it covers all missense alleles.
  - reference: CGGV:assertion_7e65896e-33f5-439d-8749-aba08a539dd0-2021-10-07T160000.000Z
    reference_title: "MYBPC3 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYBPC3 | HGNC:7551 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
    explanation: >-
      ClinGen gene-disease validity assertion for MYBPC3 and hypertrophic
      cardiomyopathy.
  - reference: PMID:22057632
    reference_title: "How do MYBPC3 mutations cause hypertrophic cardiomyopathy?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It is well established that MYBPC3 mutations are the most common cause of
      hypertrophic cardiomyopathy, accounting for about half of identified
      mutations.
    explanation: >-
      Source for the "about half of identified mutations" case-share statement.
      Evidence source is OTHER because this is a mechanistic review.
  - reference: PMID:40038304
    reference_title: "AAV9-mediated MYBPC3 gene therapy with optimized expression cassette enhances cardiac function and survival in MYBPC3 cardiomyopathy models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Loss-of-function mutations in Myosin Binding Protein C3, MYBPC3, are the most
      common genetic cause of HCM, with the majority of mutations resulting in
      haploinsufficiency.
    explanation: >-
      Confirms the loss-of-function/haploinsufficiency variant class as the
      dominant mechanism. Evidence source is MODEL_ORGANISM because the paper's
      primary data are murine gene-therapy experiments.
variants:
- name: MYBPC3 c.2373dup (p.Trp792fs) - Dutch founder variant
  gene:
    preferred_term: MYBPC3
    term:
      id: hgnc:7551
      label: MYBPC3
  description: >-
    A frameshift founder allele carried by approximately 25% of Dutch HCM patients.
    Heterozygotes have variable adult-onset HCM; homozygotes and compound
    heterozygotes with a second truncating allele have lethal neonatal
    cardiomyopathy.
  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 c.2373dup in both homozygous and compound heterozygous state in
      lethal neonatal cardiomyopathy.
  - reference: PMID:37844837
    reference_title: "Characterization of heterozygous and homozygous mouse models with the most common hypertrophic cardiomyopathy mutation MYBPC3(c.2373InsG) in the Netherlands."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients are heterozygous (MYBPC3+/InsG) and have highly variable
      phenotypic expression, whereas homozygous (MYBPC3InsG/InsG) patients have
      severe HCM at a young age.
    explanation: >-
      States the human dose-dependent phenotype of this specific founder allele.
- name: MYBPC3 c.3330+2T>G - Amish/Swiss founder splice variant
  gene:
    preferred_term: MYBPC3
    term:
      id: hgnc:7551
      label: MYBPC3
  description: >-
    An ancient splice-donor founder variant first described in the homozygous state
    in Amish newborns with severe recessive HCM, later recognised as a cause of
    adult-onset dominant HCM in heterozygotes, and now shown to be the most
    prevalent cardiomyopathy variant in western Switzerland. It is a compact
    illustration of the same allele producing both poles of the CMH4 dose
    spectrum.
  clinical_significance: PATHOGENIC
  evidence:
  - reference: PMID:36162733
    reference_title: "The «Amish» NM_000256.3:c.3330+2T>G splice variant in MYBPC3 associated with hypertrophic cardiomyopathy is an ancient Swiss mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One of them, a MYBPC3 splice variant, NM_000256.3:c.3330+2T > G, was first
      described in homozygous state in newborns presenting with a severe, recessive
      form of HCM among the Amish population and was later associated with
      adult-onset dominant HCM in heterozygous carriers.
    explanation: >-
      Single-variant demonstration of the mono- versus bi-allelic dose contrast
      that defines this entity.
  - reference: PMID:36162733
    reference_title: "The «Amish» NM_000256.3:c.3330+2T>G splice variant in MYBPC3 associated with hypertrophic cardiomyopathy is an ancient Swiss mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We here report this splice variant in heterozygous state in eight unrelated
      Swiss families with HCM, making it the most prevalent cardiomyopathy variant
      in western Switzerland.
    explanation: >-
      Establishes the Swiss founder origin and local prevalence of this allele.
- name: MYBPC3 25-bp deletion - South Asian risk allele
  gene:
    preferred_term: MYBPC3
    term:
      id: hgnc:7551
      label: MYBPC3
  description: >-
    A 25-bp intronic deletion carried by approximately 4% of people of Indian
    subcontinental ancestry, associated with heritable cardiomyopathy and increased
    heart-failure risk (combined OR ~7). Unlike the classic truncating founder
    alleles it behaves as a common, incompletely penetrant risk factor rather than
    a fully penetrant Mendelian variant.
  clinical_significance: UNCERTAIN_SIGNIFICANCE
  evidence:
  - reference: PMID:19151713
    reference_title: "A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe a deletion of 25 bp in the gene encoding cardiac myosin
      binding protein C (MYBPC3) that is associated with heritable cardiomyopathies
      and an increased risk of heart failure in Indian populations
    explanation: >-
      Defines the variant and its association with cardiomyopathy and heart failure
      risk in South Asian populations.
diagnosis:
- name: Genetic Testing for MYBPC3 Variants
  description: >-
    Molecular confirmation is what distinguishes CMH4 from other causes of
    unexplained left ventricular hypertrophy, and - critically for this entity -
    determines allelic dose. Trio or family-based testing is required to establish
    whether two variants are in trans, since the biallelic genotype carries an
    entirely different prognosis and reproductive-counselling implication than the
    heterozygous state.
  evidence:
  - reference: PMID:41488457
    reference_title: "Case Report: Lethal neonatal hypertrophic cardiomyopathy from compound heterozygous MYBPC3 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed a full forensic autopsy with detailed histological examination
      and conducted trio-based whole-exome sequencing (WES) on the proband and
      parents to identify the genetic etiology.
    explanation: >-
      Illustrates trio-based sequencing as the method that establishes biparental
      (compound heterozygous) inheritance.
  - reference: PMID:41488457
    reference_title: "Case Report: Lethal neonatal hypertrophic cardiomyopathy from compound heterozygous MYBPC3 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Crucially, the diagnosis guided the clinical management of the asymptomatic
      carrier parents, prompting long-term cardiac surveillance and enabling
      preimplantation genetic testing (PGT) for future family planning.
    explanation: >-
      Documents the downstream family-management value of establishing the
      molecular diagnosis.
- name: Longitudinal Cardiac Surveillance of Genotype-Positive Relatives
  description: >-
    Because penetrance in heterozygous MYBPC3 carriers is incomplete and rises with
    age, a single normal evaluation does not exclude future disease. Serial
    echocardiographic and ECG surveillance of genotype-positive, phenotype-negative
    relatives is the corollary of the age-dependent penetrance data.
  evidence:
  - reference: PMID:22267749
    reference_title: "Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Disease penetrance was, therefore, incomplete (56.9% in all mutation
      carriers, 34.5% in relatives), related to age (38.4% <40 versus 68.6% ≥40
      years, P<0.001)
    explanation: >-
      The near-doubling of penetrance after age 40 is the direct rationale for
      lifelong rather than one-off screening of carriers.
  - reference: PMID:22267749
    reference_title: "Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Importantly, complex genetic status is observed and should be considered when
      mutation analysis and cascade screening is used in the evaluation of at risk
      family members.
    explanation: >-
      Explicitly warns that multiple variants in one individual must be considered
      during cascade screening - the practical expression of the dose principle.
differential_diagnoses:
- name: Hypertrophic Cardiomyopathy due to other sarcomere genes
  description: >-
    MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2 and MYL3 also carry definitive HCM
    gene-disease validity. Distinguishing CMH4 from these requires genetic testing;
    MYBPC3-related disease tends to present later than MYH7-related disease and
    does not have a biallelic neonatal counterpart in most of the other genes.
  disease_term:
    preferred_term: hypertrophic cardiomyopathy
    term:
      id: MONDO:0005045
      label: hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:38406555
    reference_title: "Hypertrophic cardiomyopathy in MYBPC3 carriers in aging."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This inherited disease is predominantly caused by mutations in sarcomeric
      genes, among which those in the cardiac myosin binding protein-C3 (MYBPC3)
      gene are major contributors.
    explanation: >-
      Places MYBPC3 within the broader sarcomeric HCM differential. Evidence source
      is OTHER because this is a narrative review.
- name: Left Ventricular Noncompaction Cardiomyopathy
  description: >-
    Biallelic MYBPC3 neonatal disease frequently shows hypertrabeculation and can
    be mistaken for primary left ventricular noncompaction cardiomyopathy; the
    accompanying severe hypertrophy, septal defects and the MYBPC3 genotype
    distinguish it.
  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: >-
      Documents the noncompaction overlap that creates this differential in
      biallelic neonates.
treatments:
- name: Mavacamten (Cardiac Myosin Inhibitor)
  description: >-
    Mavacamten is a first-in-class allosteric cardiac myosin inhibitor that reduces
    the number of force-generating actin-myosin cross-bridges. Because CMH4 is
    mechanistically a loss of the cMyBP-C brake on cross-bridge cycling,
    pharmacological myosin inhibition is a direct mechanistic counterweight. In
    EXPLORER-HCM it improved exercise capacity, symptoms and outflow gradient in
    symptomatic obstructive HCM. Note the trial enrolled obstructive HCM broadly,
    not a genotyped MYBPC3 cohort.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mavacamten
  notes: >-
    mavacamten deliberately carries no ontology term. NCIT:C174901 Mavacamten
    exists, but its ancestors run through Inotropic Support / Agent /
    Conceptual Entity - it is not reachable from NCIT:C1909 Pharmacologic
    Substance, so it fails the ChemicalEntityTerm enum - and CHEBI has no
    mavacamten term. This was re-checked with OAK during review rather than
    assumed; aficamten, by contrast, is reachable and now carries CHEBI:747213.
    Do not "fix" this by substituting a poorly fitting term.
  target_mechanisms:
  - target: Myosin Shift from the Super-Relaxed to the Disordered-Relaxed State
    treatment_effect: INHIBITS
    description: >-
      Cardiac myosin inhibitors act on the SRX/DRX equilibrium itself, pushing
      myosin heads back into the super-relaxed reserve, rather than on the
      downstream cross-bridge population.
  target_phenotypes:
  - preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  evidence:
  - reference: PMID:32871100
    reference_title: "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met
      the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005).
    explanation: >-
      Phase 3 randomised placebo-controlled evidence of benefit on the composite
      functional primary endpoint in symptomatic obstructive HCM.
  - reference: PMID:32871100
    reference_title: "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients on mavacamten had greater reductions than those on placebo in
      post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001)
    explanation: >-
      Demonstrates the mechanistically expected reduction in dynamic outflow
      gradient from inhibiting cross-bridge formation.
- name: Aficamten (Next-Generation Cardiac Myosin Inhibitor)
  description: >-
    Aficamten is a second, oral selective cardiac myosin inhibitor acting on the
    same hypercontractility node as mavacamten. In the phase 3 SEQUOIA-HCM trial
    it improved peak oxygen uptake and met all ten prespecified secondary
    endpoints in symptomatic obstructive HCM. As with mavacamten, the trial
    population was obstructive HCM generally rather than a genotyped MYBPC3
    cohort.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: aficamten
      term:
        id: CHEBI:747213
        label: aficamten
  target_mechanisms:
  - target: Myosin Shift from the Super-Relaxed to the Disordered-Relaxed State
    treatment_effect: INHIBITS
    description: >-
      Cardiac myosin inhibitors act on the SRX/DRX equilibrium itself, pushing
      myosin heads back into the super-relaxed reserve, rather than on the
      downstream cross-bridge population.
  target_phenotypes:
  - preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  evidence:
  - reference: PMID:38739079
    reference_title: "Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Aficamten is an oral selective cardiac myosin inhibitor that reduces left
      ventricular outflow tract gradients by mitigating cardiac hypercontractility.
    explanation: >-
      States the mechanism of action, which targets the same hypercontractility
      that cMyBP-C loss produces in CMH4.
  - reference: PMID:38739079
    reference_title: "Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The results for all 10 secondary end points were significantly improved with
      aficamten as compared with placebo.
    explanation: >-
      Phase 3 randomised evidence of consistent benefit across the prespecified
      secondary endpoint hierarchy in symptomatic obstructive HCM.
- name: Septal Reduction Therapy
  description: >-
    Surgical septal myectomy or alcohol septal ablation relieves drug-refractory
    dynamic left ventricular outflow tract obstruction. Septal reduction therapy is
    counted among the major cardiomyopathy-related events in MYBPC3 founder-variant
    cohorts, which is an index of how often obstruction becomes clinically
    significant in this genotype.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Myectomy
    term:
      id: NCIT:C51591
      label: Myectomy
  target_phenotypes:
  - preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  evidence:
  - reference: PMID:39689185
    reference_title: "Recreational and Occupational Physical Activity and Risk of Adverse Events in Truncating MYBPC3 Founder Variant Carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MCE was defined as a composite of malignant ventricular arrhythmia
      (sustained ventricular tachycardia/fibrillation), heart failure (heart
      failure hospitalizations or transplantation), and septal reduction therapy.
    explanation: >-
      Documents that septal reduction therapy is used and tracked as a clinical
      event in truncating MYBPC3 carriers; PARTIAL because the paper reports it as
      an endpoint rather than evaluating its efficacy.
- name: Implantable Cardioverter-Defibrillator
  description: >-
    ICD implantation for primary or secondary prevention of sudden cardiac death in
    carriers judged to be at high arrhythmic risk. Risk stratification is
    particularly important in CMH4 because the baseline event rate in heterozygous
    carriers is low and conventional risk calculators performed poorly in a
    molecularly homogeneous truncating-MYBPC3 cohort.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Implantable Cardioverter-Defibrillator Placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_phenotypes:
  - preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:39581692
    reference_title: "Hypertrophic cardiomyopathy due to truncating variants in myosin binding protein C: a Spanish cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ESC-HCM risk calculator and modifier factors did not correlate with the risk
      of major events predicting events, which were low (1.51 per 100
      patients/year) and associated with the severity of HCM, abnormal QRS in the
      ECG and age.
    explanation: >-
      Supports the risk-stratification caveat for this genotype rather than ICD
      efficacy itself, hence PARTIAL.
- name: Heart Transplantation
  description: >-
    Transplantation is the treatment that matters most at the biallelic pole
    this entry models. Biallelic truncating disease is a lethal neonatal
    cardiomyopathy - the reported infants died of cardiac failure before 13 weeks
    - and no pharmacological therapy alters that course: myosin inhibition
    presupposes hypercontractility to inhibit, and gene replacement remains
    investigational and adult-only. Transplantation is also the endpoint for the
    minority of heterozygous carriers who progress to end-stage disease, where it
    is counted among the adverse composite outcomes in MYBPC3 cohort studies.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Heart Transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  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: >-
      Establishes the untreated natural history that makes transplantation the
      only survival-altering option at the biallelic pole. PARTIAL because the
      source documents the fatal course rather than transplantation outcomes -
      none of these four infants was transplanted.
  - reference: PMID:32841044
    reference_title: "Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      time-event analysis was performed (composite clinical outcome of sudden
      death, class III/IV heart failure, left ventricular assist
      device/transplant, atrial fibrillation)
    explanation: >-
      Shows transplantation and mechanical support tracked as clinical endpoints
      in a large genotyped MYBPC3 cohort. PARTIAL because it establishes that
      these events occur and are counted, not a transplantation rate or outcome.
  notes: >-
    Applies chiefly to the Biallelic CMH4 subtype, and to the minority of
    monoallelic carriers reaching end-stage disease. No published series reports
    transplantation outcomes in biallelic MYBPC3 disease specifically; the
    reasoning here is from the documented natural history and the absence of any
    disease-modifying alternative at that pole, not from a MYBPC3 transplant
    cohort.
- name: Anticoagulation for Atrial Fibrillation
  description: >-
    Anticoagulation in hypertrophic cardiomyopathy with atrial fibrillation is
    not gated on the conventional risk scores used in non-HCM atrial
    fibrillation - the thromboembolic risk conferred by the HCM substrate itself
    is high enough that anticoagulation is indicated on the arrhythmia alone.
    Included here because it is the management consequence of the atrial
    fibrillation phenotype curated in this entry, and because applying the
    ordinary risk-score gate is a common and consequential error.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticoagulant agent
      term:
        id: NCIT:C263
        label: Anticoagulant Agent
  target_phenotypes:
  - preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  notes: >-
    Deliberately unsourced at the MYBPC3 level, and flagged as such rather than
    given a borrowed citation. This is guideline-directed management for
    hypertrophic cardiomyopathy with atrial fibrillation (2024 AHA/ACC
    guideline, PMID:38718139, carried in the top-level references), whose PubMed
    record holds only AIM/METHODS/STRUCTURE text with no quotable recommendation.
    No MYBPC3-specific anticoagulation study exists. The agent is bound at class
    level because the choice between a direct oral anticoagulant and a vitamin K
    antagonist is not genotype-determined.
- name: Agents to Avoid in Obstructive Physiology
  description: >-
    A negative treatment recommendation, recorded because in obstructive
    hypertrophic cardiomyopathy the wrong drug actively worsens the
    haemodynamics. Vasodilators, nitrates, dihydropyridine calcium channel
    blockers, digoxin and aggressive diuresis all increase the dynamic outflow
    gradient - the first four by reducing afterload or raising contractility,
    diuresis by reducing preload and ventricular cavity size. The mechanism is
    the mirror image of the one that makes negative inotropes useful here, so the
    contraindication follows from the same physiology this entry models.
  therapeutic_modality: OTHER
  notes: >-
    Deliberately carries no treatment_term and no evidence item. There is no
    NCIT clinical-action term for a class of agents to avoid, and the underlying
    recommendation comes from the 2024 AHA/ACC guideline (PMID:38718139), whose
    cached PubMed record contains only AIM/METHODS/STRUCTURE sections with no
    quotable recommendation text. It is recorded as prose rather than omitted
    because a knowledge base that lists what to give without listing what
    actively harms is misleading by omission - but it is marked here as
    guideline-derived and unsourceable at snippet level rather than dressed up
    with a citation that does not support it.
- name: Genetic Counseling and Cascade Screening
  description: >-
    Counseling covers autosomal dominant transmission for heterozygous probands and
    the recurrence risk for couples who are both carriers, since two carrier parents
    face a 25% risk of a biallelic, usually lethal neonatal pregnancy.
    Preimplantation genetic testing is an option once the molecular diagnosis is
    established, and asymptomatic carrier parents identified through a proband
    warrant their own long-term cardiac surveillance.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:41488457
    reference_title: "Case Report: Lethal neonatal hypertrophic cardiomyopathy from compound heterozygous MYBPC3 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Crucially, the diagnosis guided the clinical management of the asymptomatic
      carrier parents, prompting long-term cardiac surveillance and enabling
      preimplantation genetic testing (PGT) for future family planning.
    explanation: >-
      Directly documents both counselling outcomes - parental surveillance and
      preimplantation genetic testing - following a biallelic MYBPC3 diagnosis.
  - reference: PMID:33849460
    reference_title: "A rare cause of sudden unexpected death syndrome (SUDS) in the first year of life: endomyocardial fibroelastosis (EFE) due to two compound heterozygous MYBPC3 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, the molecular autoptic findings also had consequences for the relatives
      of the deceased child and impact on further family planning.
    explanation: >-
      Documents the cascade-screening and family-planning consequences of a
      molecular diagnosis in biallelic MYBPC3 disease.
- name: Exercise Counseling
  description: >-
    Overall exercise participation does not increase adverse-event risk in MYBPC3
    founder-variant carriers, so blanket exercise restriction is not supported.
    However, the highest quartile of high-dynamic sport was associated with a
    threefold increase in malignant ventricular arrhythmia, so high-intensity
    high-dynamic activity warrants individualised caution.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:39689185
    reference_title: "Recreational and Occupational Physical Activity and Risk of Adverse Events in Truncating MYBPC3 Founder Variant Carriers."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall exercise participation does not generally increase the risk of
      adverse events among MYBPC3 founder variant carriers. Nonetheless, an
      increased risk of malignant ventricular arrhythmia was observed among those
      engaged in the highest quartile of high-dynamic sports, suggesting that
      high-level high-intensity exercise activities should be entertained with
      caution.
    explanation: >-
      The genotype-specific evidence base for exercise advice in truncating MYBPC3
      carriers.
- name: AAV9-Mediated MYBPC3 Gene Replacement (Investigational)
  description: >-
    Because CMH4 is a protein-dose disease, restoring wild-type cMyBP-C is a
    causally targeted strategy rather than symptom control. An AAV9 vector carrying
    an optimised MYBPC3 expression cassette (TN-201) reversed hypertrophy and
    systolic dysfunction, improved diastolic function and prolonged survival in a
    symptomatic MYBPC3-deficient mouse model. This is preclinical/early clinical and
    is not established therapy.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: Gene Therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: cMyBP-C Depletion by Nonsense-Mediated Decay and Proteasomal Degradation
    treatment_effect: BYPASSES
  evidence:
  - reference: PMID:40038304
    reference_title: "AAV9-mediated MYBPC3 gene therapy with optimized expression cassette enhances cardiac function and survival in MYBPC3 cardiomyopathy models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Rather than simply preventing cardiac dysfunction preclinically, we
      demonstrate in a symptomatic MYBPC3-deficient murine model the ability of AAV
      gene therapy to reverse cardiac hypertrophy and systolic dysfunction, improve
      diastolic dysfunction, and prolong survival.
    explanation: >-
      Preclinical demonstration that restoring MYBPC3 dose reverses the established
      phenotype, the therapeutic corollary of the haploinsufficiency mechanism.
  - reference: PMID:40038304
    reference_title: "AAV9-mediated MYBPC3 gene therapy with optimized expression cassette enhances cardiac function and survival in MYBPC3 cardiomyopathy models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Dose-ranging efficacy studies exhibit restoration of wild-type MYBPC3 protein
      levels and saturation of cardiac improvement at the clinically relevant dose
      of 3E13 vg/kg, outperforming a previously published construct.
    explanation: >-
      Shows the intervention works by restoring wild-type protein level, closing
      the mechanistic loop with the haploinsufficiency node.
clinical_trials:
- name: NCT05836259
  phase: PHASE_I
  status: RECRUITING
  description: >-
    MyPEAK-1. First-in-human, open-label, dose-finding study of TN-201, an AAV9
    vector carrying an MYBPC3 transgene, in adults with MYBPC3-associated
    hypertrophic cardiomyopathy. This is the trial arm of the gene-replacement
    treatment curated in this entry, and the only genotype-restricted therapy in
    development for this disease - enrolment requires a MYBPC3 variant, unlike
    every other trial listed here.
  evidence:
  - reference: clinicaltrials:NCT05836259
    reference_title: "First-in-Human, Open-Label, Safety, Tolerability, Dose-Finding, Pharmacodynamic and Cardiac Transgene Expression Study of TN-201, a Recombinant Adeno-associated Virus Serotype 9 (AAV9) Containing Myosin Binding Protein C Transgene, in Adults With MYBPC3 Mutation-associated Hypertrophic Cardiomyopathy (HCM)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a first-in-human, non-randomized, open-label study designed to
      evaluate the safety, tolerability, and pharmacodynamics (PD) of TN-201 in
      adult patients with symptomatic hypertrophic cardiomyopathy (HCM) caused
      by mutations in the MYBPC3 gene.
    explanation: >-
      Confirms the design and the MYBPC3-restricted enrolment criterion that
      makes this the genotype-specific trial for this entry.
  notes: >-
    Status recorded as RECRUITING per the ClinicalTrials.gov record, status
    verified 2026-03-18. A reported FDA clinical hold dated 7 Nov 2025 is
    deliberately NOT curated: the registry has never recorded a status other
    than NOT_YET_RECRUITING and then RECRUITING across all 16 of its versions,
    including versions posted both before and after that date, there is no
    whyStopped field, and the deep-research report that raised it states the
    matter is not yet in the peer-reviewed literature. Recording an active hold
    would therefore contradict the registry and rest on no citable source. If a
    hold occurred and was lifted, or occurred without a registry status change,
    that is entirely possible - but it needs a citable source before it belongs
    in the knowledge base.
  target_phenotypes:
  - preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
- name: NCT03470545
  phase: PHASE_III
  status: COMPLETED
  description: >-
    EXPLORER-HCM. Pivotal randomised, double-blind, placebo-controlled trial of
    mavacamten in symptomatic obstructive hypertrophic cardiomyopathy, and the
    evidence base for the mavacamten treatment entry.
  evidence:
  - reference: clinicaltrials:NCT03470545
    reference_title: "A Randomized, Double Blind, Placebo Controlled Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a multicenter, international, double-blind study of the
      administration of mavacamten in participants with symptomatic obstructive
      HCM (oHCM).
    explanation: >-
      Confirms design and population for the trial underpinning cardiac myosin
      inhibition in this entry.
  notes: >-
    Not genotype-stratified: enrolment was by obstructive phenotype, and no
    MYBPC3 subgroup result was reported.
  target_phenotypes:
  - preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
- name: NCT05186818
  phase: PHASE_III
  status: COMPLETED
  description: >-
    SEQUOIA-HCM. Randomised, double-blind, placebo-controlled trial of aficamten
    in symptomatic obstructive hypertrophic cardiomyopathy; the source of both
    the aficamten treatment evidence and the NT-proBNP treatment-response
    biomarker curated here.
  evidence:
  - reference: clinicaltrials:NCT05186818
    reference_title: "A Phase 3, Multi-Center, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of CK-3773274 in Adults With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to evaluate the efficacy and safety of
      aficamten (CK-3773274) versus placebo in adults with symptomatic
      hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract
      obstruction.
    explanation: >-
      Confirms design and population for the second cardiac myosin inhibitor
      curated in this entry.
  notes: Not genotype-stratified; enrolment required outflow tract obstruction.
  target_phenotypes:
  - preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
- name: NCT04349072
  phase: PHASE_III
  status: COMPLETED
  description: >-
    VALOR-HCM. Randomised trial of mavacamten in patients already referred for
    septal reduction therapy, testing whether myosin inhibition can avert the
    procedure. Directly relevant to the septal reduction treatment curated here,
    since it addresses the choice between the two.
  evidence:
  - reference: clinicaltrials:NCT04349072
    reference_title: "A Randomized, Double-blind, Placebo-controlled Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      will evaluate the effect of mavacamten treatment on reducing the number of
      septal reduction therapy (SRT) procedures performed in subjects with
      symptomatic obstructive hypertrophic cardiomyopathy
    explanation: >-
      Establishes the septal-reduction-avoidance endpoint linking the
      pharmacological and surgical arms of this entry.
  notes: Not genotype-stratified.
- name: NCT05767346
  phase: PHASE_III
  status: COMPLETED
  description: >-
    MAPLE-HCM. Randomised trial of aficamten monotherapy against metoprolol in
    symptomatic obstructive hypertrophic cardiomyopathy - the first head-to-head
    test of a cardiac myosin inhibitor against a conventional first-line
    beta-blocker rather than against placebo on top of background therapy.
  evidence:
  - reference: clinicaltrials:NCT05767346
    reference_title: "A Phase 3, Multi-center, Randomized, Double-blind Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to compare the efficacy and safety of
      aficamten (CK-3773274) compared with metoprolol succinate in adults with
      symptomatic hypertrophic cardiomyopathy and left ventricular outflow tract
      obstruction
    explanation: >-
      Confirms the active-comparator design that distinguishes this trial from
      the placebo-controlled myosin inhibitor trials.
  notes: Not genotype-stratified.
- name: NCT01912534
  phase: PHASE_II
  status: COMPLETED
  description: >-
    VANISH. Randomised trial of valsartan in early-stage sarcomeric hypertrophic
    cardiomyopathy, testing disease modification rather than symptom relief. The
    only trial listed here that addresses the question this entry's knowledge
    gaps keep returning to - whether anything alters the course of disease in
    early or subclinical sarcomere-variant carriers.
  evidence:
  - reference: clinicaltrials:NCT01912534
    reference_title: "Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this trial is to determine whether treatment with valsartan
      will have beneficial effect in early hypertrophic cardiomyopathy (HCM) by
      assessing many domains that reflect myocardial structure, function and
      biochemistry.
    explanation: >-
      Confirms the early-disease, disease-modification objective that makes this
      trial relevant to the preclinical-carrier knowledge gaps recorded here.
  notes: >-
    Enrolled sarcomeric HCM broadly rather than MYBPC3 specifically, though
    MYBPC3 is the commonest sarcomere gene and therefore the largest genotype
    group within such a cohort.
discussions:
- discussion_id: mybpc3_haploinsufficiency_sufficiency
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is reduced cMyBP-C protein level sufficient to explain the disease caused by
    MYBPC3 truncating alleles, or do parallel mechanisms contribute before, or
    independently of, any measurable fall in protein?
  attaches_to:
  - pathophysiology#cMyBP-C Depletion by Nonsense-Mediated Decay and Proteasomal Degradation
  - genetic#MYBPC3
  rationale: >-
    This entry curates haploinsufficiency as the operative mechanism, and the
    human evidence for it is strong: myectomy tissue shows reduced full-length
    cMyBP-C with no detectable truncated peptide, a promoter deletion that can
    produce no peptide at all still causes the disease, and outcome is
    independent of where in the gene the truncation falls. The challenge is not
    to that evidence but to its sufficiency. Heterozygous MYBPC3-null iPSC
    cardiomyocytes maintain normal cMyBP-C protein despite allelic loss of
    function - compensating through reduced degradation - yet still show
    contractile and calcium-handling defects; haploinsufficiency becomes
    measurable only when protein demand rises, as in three-dimensional
    engineered tissue or under hypertrophic stress. If dysfunction can precede
    the protein deficit, protein level is not the whole mechanism. This matters
    therapeutically: the gene-replacement strategy curated in this entry is
    predicated on dose restoration being sufficient to reverse disease.
  evidence:
  - reference: PMID:36946992
    reference_title: "Is haploinsufficiency a sufficient mechanism for MYBPC3 truncating mutations?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      While haploinsufficiency of cMyBP-C has been previously demonstrated
      (Helms et al., 2014; Barefield et al., 2015; Glazier et al., 2019), the
      necessity and sufficiency of simply reducing protein levels to cause all
      the observed phenotypic changes remains unclear.
    explanation: >-
      States the open question directly. Evidence source is OTHER because this
      is a commentary rather than primary data.
  - reference: PMID:36946992
    reference_title: "Is haploinsufficiency a sufficient mechanism for MYBPC3 truncating mutations?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These data from mouse models are in-line with the results from De Lange et
      al. (2023) and suggest that there is more going on here than a pure
      haploinsufficiency mechanism
    explanation: >-
      Summarises the case that a pure dose model is incomplete. PARTIAL because
      it is an interpretive claim in a commentary, not a measurement.
  - reference: PMID:31877118
    reference_title: "Effects of MYBPC3 loss-of-function mutations preceding hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Despite a reduction in wild-type mRNA in all heterozygous iPSCMs, no
      reduction in MyBP-C protein was observed, indicating protein-level
      compensation through what we believe is a previously uncharacterized
      mechanism.
    explanation: >-
      The primary observation behind the challenge: allelic loss of function at
      the mRNA level without a protein deficit, in heterozygous human iPSC
      cardiomyocytes.
  - reference: PMID:31877118
    reference_title: "Effects of MYBPC3 loss-of-function mutations preceding hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These findings indicate that cardiomyocytes have an innate capacity to
      attain normal MyBP-C stoichiometry despite MYBPC3 allelic loss of function
      due to truncating mutations.
    explanation: >-
      States the compensation capacity explicitly, which is what makes the
      timing of the protein deficit - and therefore its sufficiency - an open
      question.
  proposed_experiments:
  - experiment_id: exp_mybpc3_preclinical_carrier_myofibrillar_protein
    name: Quantify myofibrillar cMyBP-C in genotype-positive, phenotype-negative human myocardium
    description: >-
      The decisive missing measurement is whether cMyBP-C is already reduced in
      carriers before hypertrophy appears. Myectomy tissue comes only from
      symptomatic patients, so protein content in asymptomatic carriers is
      essentially unmeasured. An explant-bank or imaging-guided biopsy study
      stratified by phenotype status would establish whether the deficit
      precedes or follows remodeling, and therefore whether dose restoration
      alone is a sufficient therapeutic target.
- discussion_id: mybpc3_penetrance_ascertainment_discrepancy
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why is MYBPC3 penetrance far lower in unselected population cohorts than in
    clinically ascertained families, and how much of the gap is ascertainment
    bias versus genuine modifier burden or environmental exposure?
  attaches_to:
  - pathophysiology#Gene-Dosage-Dependent Severity Gradient
  rationale: >-
    The penetrance figure quoted to a family decides whether a genotype-positive
    relative is told they have a substantial chance of developing disease or a
    small one, so this discrepancy is not academic. Family cohorts give
    incomplete but substantial penetrance that roughly doubles after age 40,
    whereas unselected population cohorts give far lower estimates. The two
    populations differ in ascertainment - families are ascertained through an
    affected proband and are therefore enriched for whatever made that proband
    affected - but they may also differ in modifier burden, comorbidity and
    physical-activity exposure. Until those sources are separated, neither
    number is straightforwardly the right one to counsel with, which is why this
    entry records the family-cohort figures with their ascertainment context
    rather than presenting a single penetrance value.
  evidence:
  - reference: PMID:22267749
    reference_title: "Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Disease penetrance was, therefore, incomplete (56.9% in all mutation
      carriers, 34.5% in relatives), related to age (38.4% <40 versus 68.6% ≥40
      years, P<0.001)
    explanation: >-
      The clinical-family pole of the discrepancy. Note that penetrance already
      differs substantially between probands and relatives within this single
      study - an ascertainment gradient visible inside one cohort.
- discussion_id: mybpc3_heterozygous_mouse_phenotype_negative
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Heterozygous Mybpc3 mice remain phenotype-negative while human heterozygotes
    develop disease at substantial rates - which human population, if any, does
    the heterozygous mouse actually model?
  attaches_to:
  - pathophysiology#Gene-Dosage-Dependent Severity Gradient
  - pathophysiology#Myosin Shift from the Super-Relaxed to the Disordered-Relaxed State
  rationale: >-
    This entry curates a mouse allelic series as experimental confirmation of the
    dose gradient, and for the homozygous pole that is exactly what it provides.
    The heterozygous pole is where model and disease part company: knock-in
    heterozygotes for the Dutch founder variant did not develop HCM at the ages
    studied, and the same negative result appears independently in the
    super-relaxed-state measurements, where heterozygous cMyBP-C knockout mice
    were indistinguishable from wild type while homozygotes showed a clear
    deficit. Human heterozygotes are the common form of this disease. The
    divergence is mechanistically informative rather than merely technical - it
    is consistent with the compensation capacity documented in heterozygous
    human iPSC cardiomyocytes, and it suggests murine heterozygotes may model the
    genotype-positive, phenotype-negative carrier rather than the patient. It
    also constrains what the models can be used for: a heterozygous mouse cannot
    demonstrate that a therapy prevents phenotype conversion if it never
    converts.
  evidence:
  - reference: PMID:37844837
    reference_title: "Characterization of heterozygous and homozygous mouse models with the most common hypertrophic cardiomyopathy mutation MYBPC3(c.2373InsG) in the Netherlands."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Expectedly, knock-in of Mybpc3c.2373InsG resulted in the absence of cMyBP-C
      and our 18-28 week old homozygous Mybpc3c.2373InsG model developed cardiac
      hypertrophy and severe left ventricular systolic and diastolic dysfunction,
      whereas HCM was not evident in Mybpc3+/InsG mice.
    explanation: >-
      Documents the phenotype-negative heterozygote alongside the severely
      affected homozygote in the same allelic series.
  - reference: PMID:27021517
    reference_title: "Ablation of cardiac myosin binding protein-C disrupts the super-relaxed state of myosin in murine cardiomyocytes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We report a significant decrease in the proportion of myosin heads in the
      SRX state in homozygous cMyBP-C knockout mice, however heterozygous
      cMyBP-C knockout mice do not significantly differ from the wild type.
    explanation: >-
      Independent replication of the heterozygous-negative result at the
      molecular level, in a different mouse line with a different assay.
  proposed_experiments:
  - experiment_id: exp_mybpc3_heterozygous_mouse_stress_challenge
    name: Stress-challenge and aged-cohort phenotyping of heterozygous Mybpc3 knock-in mice
    description: >-
      Test whether the heterozygous mouse is truly phenotype-negative or merely
      unstressed and studied too young, by phenotyping aged cohorts and cohorts
      challenged with pressure overload, exercise, or dietary stress. A
      heterozygote that converts under challenge would model the human carrier
      whose penetrance rises after age 40; one that never converts marks a
      genuine species difference in compensation capacity, and would mean
      preventive-therapy trials cannot use this model as their test bed.
- discussion_id: mybpc3_disarray_and_obstruction_not_modeled
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Do the curated MYBPC3 model systems reproduce myocyte disarray and dynamic
    outflow obstruction - the pathognomonic human lesion and the dominant human
    clinical problem - or are both unavailable in every model this entry relies
    on?
  attaches_to:
  - pathophysiology#Ventricular Hypertrophy, Disarray and Fibrosis
  rationale: >-
    Two features that define this disease clinically are absent from the models
    used to study it. Myocyte disarray is the pathognomonic human histological
    lesion and is documented in human MYBPC3 hearts; the mouse allelic series
    curated in this entry reports echocardiography, histology and cardiomyocyte
    contractility without reporting disarray, and engineered cardiac tissue has
    no ventricular architecture within which disarray could even be defined.
    Dynamic left ventricular outflow tract obstruction with systolic anterior
    motion - the target of both approved drugs and the endpoint of every trial
    cited here - depends on ventricular geometry and mitral-apparatus anatomy
    that small-animal and engineered-tissue systems do not reproduce. The
    practical consequence is a division of evidential labour that this entry
    makes explicit: the models carry the molecular and dose arguments, while
    every claim about relief of obstruction rests entirely on human trial data.
  proposed_experiments:
  - experiment_id: exp_mybpc3_large_animal_disarray_and_lvot
    name: Large-animal MYBPC3 model phenotyped for disarray and outflow-tract dynamics
    description: >-
      A large-animal model with human-like ventricular geometry - the
      base-edited MYBPC3 pig is the obvious starting point - phenotyped
      specifically for myofibre disarray on histology and for provoked
      outflow-tract gradients on imaging would establish whether these features
      are reproducible outside humans, and would give the drug mechanism a
      non-clinical test bed it currently lacks.
experimental_models:
- name: Isogenic MYBPC3 +/- and -/- human iPSC engineered cardiac tissue
  description: >-
    CRISPR-Cas9 heterozygous and homozygous MYBPC3 frameshifts introduced into a
    human iPSC line, differentiated to cardiomyocytes and assembled into engineered
    cardiac tissue constructs. This is the cleanest available human model of the
    CMH4 allelic-dose question because the two genotypes and the wild-type control
    share an identical genetic background.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:36893011
  modeled_mechanisms:
  - target: Gene-Dosage-Dependent Severity Gradient
  - target: Loss of the cMyBP-C Brake on Actin-Myosin Cross-Bridge Cycling
  evidence:
  - reference: PMID:36893011
    reference_title: "cMyBP-C ablation in human engineered cardiac tissue causes progressive Ca2+-handling abnormalities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We used CRISPR-Cas9 to introduce heterozygous (cMyBP-C+/-) and homozygous
      (cMyBP-C-/-) frame-shift mutations into MYBPC3 in human iPSCs.
    explanation: >-
      Describes the isogenic allelic series that makes this model suited to the
      dose question.
animal_models:
- name: Mybpc3 c.2373InsG knock-in mouse allelic series
  species: Mouse
  genotype: Mybpc3 c.2373InsG heterozygous and homozygous knock-in (CRISPR/Cas9)
  description: >-
    CRISPR/Cas9 knock-in mice heterozygous and homozygous for the Dutch MYBPC3
    c.2373InsG founder variant, characterised by echocardiography, histology and
    cardiomyocyte contractility. Homozygotes lack cMyBP-C and develop severe HCM;
    heterozygotes did not show HCM at the ages studied, mirroring the low and
    age-dependent penetrance of the human heterozygous state.
  publication: PMID:37844837
  modeled_mechanisms:
  - target: Gene-Dosage-Dependent Severity Gradient
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The allelic series reproduces the dose-severity relationship that defines
      this disease: absent cMyBP-C gives severe disease, half-dose gives none at
      the ages studied.
    limitations: >-
      Fidelity is MODERATE rather than HIGH because only the homozygous pole
      matches its human counterpart. Human heterozygotes develop disease at
      substantial rates, whereas these heterozygous mice do not - so the model
      reproduces the shape of the gradient while misplacing the human
      heterozygote on it.
    evidence:
    - reference: PMID:37844837
      reference_title: "Characterization of heterozygous and homozygous mouse models with the most common hypertrophic cardiomyopathy mutation MYBPC3(c.2373InsG) in the Netherlands."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Expectedly, knock-in of Mybpc3c.2373InsG resulted in the absence of
        cMyBP-C and our 18-28 week old homozygous Mybpc3c.2373InsG model
        developed cardiac hypertrophy and severe left ventricular systolic and
        diastolic dysfunction, whereas HCM was not evident in Mybpc3+/InsG mice.
      explanation: >-
        Gives both poles of the gradient in one experiment, including the
        negative heterozygous result.
  - target: Ventricular Hypertrophy, Disarray and Fibrosis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Homozygotes develop the hypertrophic structural phenotype with progressive
      worsening.
    limitations: >-
      PARTIALLY_RECAPITULATES rather than RECAPITULATES because the node
      includes myocyte disarray, the pathognomonic human lesion, and the cited
      characterisation reports echocardiography, histology and contractility
      without reporting disarray. Recorded as an open model-mismatch discussion
      rather than assumed either way.
    evidence:
    - reference: PMID:37844837
      reference_title: "Characterization of heterozygous and homozygous mouse models with the most common hypertrophic cardiomyopathy mutation MYBPC3(c.2373InsG) in the Netherlands."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Both the 3-4 week old and 18-28 week old Mybpc3InsG/InsG models
        recapitulate HCM, with a severe phenotype present in the 18-28 week old
        model.
      explanation: >-
        Confirms the structural phenotype and its progression in the homozygous
        model.
  evidence:
  - reference: PMID:37844837
    reference_title: "Characterization of heterozygous and homozygous mouse models with the most common hypertrophic cardiomyopathy mutation MYBPC3(c.2373InsG) in the Netherlands."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      To improve understanding of disease progression and genotype-phenotype
      relationship based on the hallmarks of human HCM, we characterized mice with
      CRISPR/Cas9-induced heterozygous and homozygous mutations.
    explanation: >-
      Describes the mouse allelic series used to model the human dose-phenotype
      relationship for the Dutch founder variant.
  notes: >-
    Moved here from experimental_models during review. It had been curated as an
    ExperimentalModel with experimental_model_type: OTHER, which is the
    documented pre-#8199 workaround for reaching the pathograph before
    AnimalModel gained modeled_mechanisms. Whole-organism animal models belong
    in animal_models; ExperimentalModel is for non-animal systems, and its type
    enum accordingly has no animal value.
references:
- reference: PMID:20301725
  title: "Nonsyndromic Hypertrophic Cardiomyopathy Overview"
  tags:
  - GeneReviews
- reference: PMID:38718139
  title: "2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines."
- reference: PMID:38258577
  title: "A Promoter Deletion Confirms That MYBPC3 Haploinsufficiency Is Sufficient to Cause Hypertrophic Cardiomyopathy in Humans."
notes: >-
  Scope note: this entry is the MYBPC3 gene-specific entity (MONDO:0007268), not
  the HCM umbrella. The umbrella entry Hypertrophic_Cardiomyopathy
  (MONDO:0005045) carries the cross-gene phenotype and treatment picture; content
  here is deliberately restricted to what is specific to MYBPC3 dose biology and
  to the two clinical poles it produces.

  Terminology note: the MONDO definition frames MONDO:0007268 as "an autosomal
  dominant condition ... characterized by severe neonatal hypertrophic
  cardiomyopathy". That phrasing conflates the two poles of a single dose
  spectrum: the autosomal dominant statement describes the common heterozygous
  disease, while severe neonatal HCM is specifically the biallelic
  (homozygous/compound heterozygous) presentation. This entry models both
  explicitly as subtypes rather than reproducing the conflation, and records
  separate inheritance blocks for each.

  Two references are carried for provenance and are deliberately not mined for
  evidence items, because their PubMed records contain no quotable clinical
  text: the GeneReviews overview (PMID:20301725) is a six-point purpose
  statement, and the 2024 AHA/ACC guideline (PMID:38718139) carries only
  AIM/METHODS/STRUCTURE sections. Several guideline-derived management points in
  this entry - anticoagulation gating in atrial fibrillation, the agents-to-avoid
  list - therefore carry explanatory notes instead of snippets, which is stated
  on each rather than papered over with a citation that does not support the
  claim. A third, PMID:38258577, is the promoter-deletion report that provides
  the cleanest human proof of the haploinsufficiency mechanism; it is a research
  letter with no abstract in the cached record, so the same claim is evidenced
  from PMID:19574547, whose abstract states it directly from myectomy tissue.

  Unsourced/limited-evidence items intentionally omitted: no
  population-based prevalence for the MYBPC3-specific entity exists, so
  prevalence is recorded as NOT_YET_DOCUMENTED rather than estimated; frequency
  bands were omitted for phenotypes with no quantitative denominator in the cited
  abstracts. Beta-blocker, verapamil and disopyramide therapy, and the fetal /
  prenatal detection question, are HCM-general or under-evidenced at the MYBPC3
  genotype level and are left to the umbrella entry.

  Deep-research provenance: the falcon (Edison) provider was requested but is not
  registered in this environment (no EDISON_API_KEY/FUTUREHOUSE_API_KEY; `just
  research-providers` reports only claude_code available), so the deep-research
  step was run with the claude_code provider. All PMIDs were independently
  fetched with `just fetch-reference` and every snippet verified against the
  cached abstract with `just validate-references`.

📚

References & Deep Research

References

3

PMID:20301725

Nonsyndromic Hypertrophic Cardiomyopathy Overview

No top-level findings curated for this source.

PMID:38718139

2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.

No top-level findings curated for this source.

PMID:38258577

A Promoter Deletion Confirms That MYBPC3 Haploinsufficiency Is Sufficient to Cause Hypertrophic Cardiomyopathy in Humans.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-opus-5[1m] 69 citations 2026-08-01T21:17:59.610526

1. Disease Information

Overview

Hypertrophic cardiomyopathy 4 (CMH4) is the MYBPC3-related form of familial hypertrophic cardiomyopathy — the single most common genetic cause of HCM worldwide. It is defined by unexplained left ventricular hypertrophy (LVH), typically asymmetric and septal-predominant, in the absence of an alternative loading condition (hypertension, aortic stenosis) sufficient to explain it.

CMH4 is mechanistically distinctive among the sarcomeric HCMs. Whereas most HCM genes act through poison-peptide / dominant-negative missense alleles, ~90% of pathogenic MYBPC3 variants are truncating (frameshift, nonsense, splice-disrupting) and act through haploinsufficiency of cardiac myosin-binding protein C (cMyBP-C) — the truncated peptide is essentially never detectable in human myocardium.

CMH4 has two clinically and genetically distinct presentations:

Monoallelic (heterozygous) — classic autosomal dominant, adult-onset, age- and sex-dependent incomplete penetrance, generally favourable prognosis.
Biallelic (homozygous or compound heterozygous truncating) — a recessive, lethal neonatal cardiomyopathy with left ventricular noncompaction features and septal defects, essentially uniformly fatal in the first year without transplant.

OMIM captures both: "The transmission pattern of CMH4 was autosomal dominant in the families reported by Watkins et al. (1995) and autosomal recessive in the family reported by Wang et al. (2013). Incomplete penetrance was observed in both families." (OMIM 115197)

Key Identifiers

Resource	Identifier
OMIM (phenotype)	115197
OMIM (gene)	*600958 MYBPC3
MONDO	MONDO:0007268 (`hypertrophic cardiomyopathy 4`)
MONDO (parent)	MONDO:0005045 (`hypertrophic cardiomyopathy`)
Disease Ontology	DOID:0110310
Orphanet	ORPHA:155 — Familial isolated hypertrophic cardiomyopathy (flagged "NON RARE IN EUROPE"); ORPHA:217569 — Rare familial disorder with hypertrophic cardiomyopathy (grouping)
ICD-10	I42.1 (obstructive HCM) / I42.2 (other HCM)
ICD-11	BC43.0 Hypertrophic cardiomyopathy
MeSH	D024741 Cardiomyopathy, Hypertrophic, Familial; D002312 Cardiomyopathy, Hypertrophic
HGNC	HGNC:7551 (MYBPC3) — dismech CURIE form: `hgnc:7551`
UniProt	Q14896 (MYBPC3_HUMAN)
HPO (core)	HP:0001639 Hypertrophic cardiomyopathy

Synonyms

CMH4
Cardiomyopathy, familial hypertrophic, 4
MYBPC3-related hypertrophic cardiomyopathy
Myosin-binding protein C, cardiac, deficiency of (historical OMIM synonym)
Left ventricular noncompaction 10 / LVNC10 (allelic; some MYBPC3 alleles)
(Biallelic form) Severe neonatal / infantile MYBPC3 cardiomyopathy; "Amish nemaline-unrelated infantile HCM" (colloquial, Geauga County Old Order Amish)

Data provenance character

Evidence for CMH4 is overwhelmingly disease-level and cohort-aggregated, not EHR-individual: - Clinical cohorts / registries: SHaRe (Sarcomeric Human Cardiomyopathy Registry, n=4,756 genotyped), Dutch BIO FOr CARe founder-variant cohort, Spanish multicentre truncating-MYBPC3 cohort, UK Heart Hospital family series. - Aggregated variant resources: ClinVar, ClinGen (Hereditary Cardiovascular Disease GCEP), gnomAD. - Population biobanks (the exception — genome-first, individual-level): UK Biobank, Penn Medicine BioBank, ARIC — these produce the low-penetrance estimates. - Molecular: human myectomy/explant tissue, iPSC-CM and engineered cardiac tissue, mouse knock-in/knock-out.

2. Etiology

2.1 Primary causal factor

Germline pathogenic/likely pathogenic variants in MYBPC3 are the necessary cause. MYBPC3 accounts for ~50% of genetically explained nonsyndromic HCM, with MYH7 (~33%), TNNI3 (~5%), TNNT2 (~4%) and other sarcomere genes (<3% each) making up the remainder (GeneReviews, PMID:20301725).

ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel classifies the relationship as Definitive (SOP8, 2021-10-07):

MYBPC3 | HGNC:7551 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive | SOP8 | Hereditary Cardiovascular Disease Gene Curation Expert Panel | 2021-10-07T16:00:00.000Z (ClinGen Gene-Disease Validity assertion, cached locally as CGGV_assertion_7e65896e-33f5-439d-8749-aba08a539dd0-2021-10-07T160000.000Z)

MYBPC3 is one of only 8 of 33 evaluated HCM genes to reach Definitive validity, alongside MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, MYL3 (ClinGen HCM reappraisal, PMC11312670; original framework Ingles et al., Circ Genom Precis Med 2019).

Notably, MYBPC3 is not validly associated with other cardiomyopathies — a useful negative constraint for curation:

MYBPC3 | HGNC:7551 | arrhythmogenic right ventricular cardiomyopathy | MONDO:0016587 | AD | Limited | SOP7 | ... | 2019-08-06 MYBPC3 | HGNC:7551 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited | SOP10 | ... | 2025-05-16 MYBPC3 | HGNC:7551 | dilated cardiomyopathy | MONDO:0005021 | AR | Limited | SOP10 | ... | 2025-05-16

2.2 Genetic risk factors and modifiers

Factor	Effect	Evidence
Truncating vs non-truncating MYBPC3 allele	Truncating = 91% of pathogenic MYBPC3 variants; clinical severity is locus-independent, consistent with pure loss-of-function	Helms et al., Circ Genom Precis Med 2020, PMID:32841044 (SHaRe, n=4,756 genotyped; 1,047 patients with truncating variants across 234 unique variants)
Allelic dose (biallelic vs monoallelic)	Biallelic truncating → lethal neonatal disease; monoallelic → adult-onset	PMID:25335496; PMID:41488457
Compound/complex genotype (2nd sarcomere variant)	Earlier onset, greater hypertrophy, worse outcome	PMID:22267749 (4/57 probands, 7.0%, carried multiple mutations)
Male sex	Higher penetrance	PMID:22267749: penetrance "greater in males than females (65.1% versus 48.1%, P=0.03)"
Age	Strongly age-dependent penetrance	PMID:22267749: "38.4% <40 versus 68.6% ≥40 years, P<0.001"
Common-variant polygenic background	Low-penetrance sarcomere variants and HCM PRS act additively to modulate expression	Circulation 2025, Low Penetrance Sarcomere Variants
RAAS pathway polymorphisms (ACE I/D, AGT, CMA1, AGTR1, CYP11B2)	Proposed modifiers of hypertrophy magnitude in MYBPC3 carriers	Pflugers/PMC3449069 — modest, replication-limited
NMD machinery (UPF3B) expression	Determines degree of haploinsufficiency achieved from a given PTC allele	PMID:37797718
Ubiquitin-proteasome system capacity (declines with age/oxidative stress)	Proposed to convert a dormant allele into late-onset disease	PMID:19151713 (discussion); PMID:38406555

Population-specific high-frequency alleles (see §9): the South Asian MYBPC3 intron-32 25-bp deletion (~4% carrier frequency); the three Dutch founder truncating variants; the Amish/Swiss c.3330+2T>G splice allele; Icelandic and Northern Spanish founder alleles.

2.3 Environmental / acquired risk factors

There is no environmental factor that causes CMH4 — the genotype is necessary. Environmental factors act as penetrance and severity modifiers ("second hits"):

Hypertension. In the Indian 25-bp-deletion families, "In three cases, hypertension coexisted with the deletion in the family members and these individuals showed severe phenotypes." (PMID:19151713, exact quote)
Western/obesogenic diet. In heterozygous Mybpc3^c.772G>A knock-in mice that are otherwise phenotype-negative, Western diet feeding triggered cardiac dysfunction and hypertrophy — an explicit two-hit model (PMC11708371). This is MODEL_ORGANISM evidence and should be tagged as such.
Ageing. "Aging further exacerbates the severity of HCM in carriers of MYBPC3 mutations." (PMID:38406555, exact quote)
Intense/competitive athletic conditioning. Contributes to LV wall thickness and confounds diagnosis (athlete's heart differential); historically a trigger context for SCD, though modern guidelines have liberalised exercise restrictions.
Catecholaminergic stress / exercise. Provokes symptoms and dynamic LVOT obstruction: OMIM notes symptoms "can be readily provoked by exercise."

2.4 Protective factors

No validated genetic protective allele is established for CMH4. The nearest analogue is a low HCM polygenic risk score, which is associated with reduced penetrance/expressivity in sarcomere-variant carriers (Circulation 2025).
Female sex is associated with lower penetrance (48.1% vs 65.1%, PMID:22267749) — though women with MYBPC3-HCM are diagnosed later and often with more advanced symptoms, so this is not protection against adverse outcome.
Environmental: blood pressure control, weight management, avoidance of dehydration/volume depletion and of vasodilators in obstructive physiology. These are risk-mitigating rather than proven penetrance-preventing; no randomised prevention trial exists.

2.5 Gene–environment interactions

The dominant G×E model for CMH4 is haploinsufficiency + stressor:

A truncating MYBPC3 allele yields ~subnormal cMyBP-C protein but a compensated sarcomere for decades.
Hemodynamic (hypertension, afterload), metabolic (Western diet, obesity, diabetes), or proteostatic (age-related UPS decline, oxidative stress) stress exceeds reserve.
Hypertrophic remodelling becomes overt.

Evidence: mouse Western-diet two-hit model (PMC11708371); human hypertension co-modifier data (PMID:19151713); age-dependent penetrance (PMID:22267749); ageing/UPS review (PMID:38406555).

3. Phenotypes

3.1 Core cardiac structural phenotypes

Phenotype	HPO term	Frequency / character	Evidence
Hypertrophic cardiomyopathy	HP:0001639	Defining feature; 100% of affected	PMID:20301725
Left ventricular hypertrophy	HP:0001712	Diagnostic threshold: max LV wall thickness ≥15 mm in adults (≥13–14 mm with family history); z-score >3 in children	PMID:20301725
Asymmetric septal hypertrophy	HP:0001670	Most common morphology. In the R502W series: "11 none, 9 asymmetrical, 3 concentric, 1 apical, 1 eccentric"	PMID:22267749
Left ventricular outflow tract obstruction	HP:0031573 Left ventricular outflow tract obstruction	~25–30% have detectable resting/provocable gradients	PMID:20301725
Systolic anterior motion of mitral valve / mitral regurgitation	HP:0001653 Mitral regurgitation	Common in obstructive phenotype	Guideline (PMID:38718139)
Diastolic dysfunction	HP:0025168 Left ventricular diastolic dysfunction	Near-universal; often precedes hypertrophy	PMID:31877118
Left ventricular systolic dysfunction (LVEF <50%, "burnt-out" phase)	HP:0012718 / HP:0001644	~8% overall	PMID:20301725
Left ventricular noncompaction	HP:0011664 Left ventricular noncompaction	Biallelic form only — 3 of 4 neonates	PMID:25335496
Septal defects (ASD/VSD) / PDA	HP:0001631 Atrial septal defect; HP:0001629 Ventricular septal defect; HP:0001643 Patent ductus arteriosus	Biallelic form — 62% (13/21) of reported biallelic cases	PMID:25335496

3.2 Symptoms and functional phenotypes

Phenotype	HPO term	Notes
Dyspnea / exertional breathlessness	HP:0002094	Most common presenting symptom; OMIM lists dyspnea among cardinal symptoms
Chest pain / angina pectoris	HP:0001681	Often microvascular, not epicardial CAD
Palpitations	HP:0001962
Syncope	HP:0001279	Exertional syncope is an SCD risk marker
Congestive heart failure	HP:0001635	Relevant heart failure in 8.1% of Spanish truncating-variant cohort (PMID:39581692)
Fatigue / exercise intolerance	HP:0012378 Fatigue; HP:0003546 Exercise intolerance	Reflected in pVO₂ endpoints of EXPLORER-HCM / SEQUOIA-HCM
Failure to thrive (neonatal form)	HP:0001508 Failure to thrive	"All four children presented with feeding difficulties, failure to thrive, and dyspnea." (PMID:25335496, exact quote)
Feeding difficulties (neonatal form)	HP:0011968 Feeding difficulties	Same

3.3 Arrhythmic / electrophysiological phenotypes

Phenotype	HPO term	Frequency
Atrial fibrillation	HP:0005110	~20% overall; ~60% by age 60 if diagnosed before age 40 (PMID:20301725)
Ventricular arrhythmia / NSVT	HP:0004308	Key SCD risk marker
Sudden cardiac death	HP:0001645	~6% experience SCD, resuscitated arrest, or appropriate ICD therapy (PMID:20301725). Annual SCD rate 0.46%/yr and all-cause mortality 0.93%/yr in clinically affected MYBPC3 carriers over 7.9±4.5 yr follow-up (PMID:22267749, exact figures)
Cardiac arrest	HP:0001695
Abnormal ECG (LVH voltage, repolarisation abnormality, pathological Q waves)	HP:0003115 Abnormal EKG; HP:0011021 (see below)	ECG abnormality often precedes hypertrophy in G+/LVH− carriers
Ventricular tachycardia	HP:0004756	"recurrent ventricular tachyarrhythmias in one homozygous subject" (PMID:19151713)

3.4 Laboratory / biomarker abnormalities

Marker	LOINC / HPO	Direction	Notes
NT-proBNP	LOINC:33762-6	↑	HP:0031185 Increased circulating brain natriuretic peptide concentration; tracks HF severity; a mavacamten/aficamten pharmacodynamic endpoint
High-sensitivity cardiac troponin I/T	LOINC:89579-7	↑	Elevated even in G+/LVH− carriers — an early subclinical marker (PMID:31877118)
Serum profibrotic markers (PICP, procollagen)	—	↑	Elevated pre-hypertrophy in sarcomere-variant carriers

3.5 Phenotype characteristics

Age of onset. Bimodal and genotype-dose-dependent: - Biallelic truncating: congenital/neonatal. "They died from cardiac failure before age 13 weeks." (PMID:25335496, exact quote). All 21 reported biallelic-truncating patients "were diagnosed with severe cardiomyopathy and/or died within the first few months of life." - Monoallelic: classically adult-onset, historically described as "late-onset." In the Indian 25-bp-deletion families, "In most carriers the effects remained dormant until the third decade" (PMID:19151713, exact quote). Spanish cohort mean age 47±16.8 yr (PMID:39581692). - But onset is extremely heterogeneous. In 9 R502W families (25 individuals) there was "marked heterogeneity in age at diagnosis (5 to 80 years)" (PMID:22267749, exact quote).

Severity. Variable. In the Spanish truncating-variant cohort, "Hypertrophy was discrete with a significative difference between probands and relatives (17.5±4 mm vs 14.6±5 mm; p<0.0001). Ejection fraction was predominantly preserved (65%±10%)." (PMID:39581692, exact quote).

Progression. Slowly progressive over decades in most; a minority progress to end-stage/"burnt-out" HCM with systolic dysfunction. Symptoms are typically episodic/exertional superimposed on a chronic substrate. Incident HCM phenotype in the Spanish cohort was 10% over 7.77 years mean follow-up (PMID:39581692).

Quality-of-life impact. Well quantified via KCCQ-CSS and HCMSQ. In EXPLORER-HCM, mavacamten produced "improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB −1·8, −2·4 to −1·2; p<0·0001)" and "34% more patients in the mavacamten group improved by at least one NYHA class" (PMID:32871100, exact quotes). Baseline NYHA II–III limitation, exercise intolerance, chest pain, and the psychological burden of SCD risk / ICD carriage / cascade-testing family implications are the principal QoL domains. Validated instruments: KCCQ-23/KCCQ-CSS, HCMSQ (Hypertrophic Cardiomyopathy Symptom Questionnaire), EQ-5D-5L, SF-36.

4. Genetic / Molecular Information

4.1 Causal gene

MYBPC3 — myosin-binding protein C, cardiac (hgnc:7551; OMIM *600958; UniProt Q14896; Ensembl ENSG00000134571; RefSeq NM_000256.3). - Locus 11p11.2; 35 exons; ~21 kb genomic. - Protein: 1,274 aa, ~141 kDa cardiac isoform. Domain architecture N→C: C0 (cardiac-specific Ig), Pro-Ala linker, C1 (Ig), M-domain (cardiac-specific, PKA-phosphorylatable regulatory motif), C2–C10 (mix of Ig-I and Fn3 domains). C8–C10 anchor to light meromyosin and titin; C0–C2 interacts with the myosin S2 and regulatory light chain and with actin. - Localisation: doublets in the C-zone of the A-band of the sarcomere (PMID:19151713).

4.2 Pathogenic variant spectrum

Variant classes. Truncating variants dominate:

"Truncating variants account for 91% of MYBPC3 pathogenic variants and cause similar clinical severity and outcomes regardless of location, consistent with locus-independent loss-of-function." — Helms et al., PMID:32841044

"Among HCM patients with genetic defects in MYBPC3, 90% of mutations are heterozygous frameshift, nonsense, or splice site mutations that result in premature termination codons and truncated cMyBP-C protein."

"The most striking characteristic of HCM mutations in MYBPC3 is that many are within introns and are predicted to cause aberrant splicing leading to a frameshift and a premature chain termination, yet the truncated peptides have never been identified in human heart tissue carrying these mutations." — Marston et al., PMID:22057632 (exact quote)

Breakdown by mechanism class: - Frameshift (indel) — e.g. c.2373dup p.(Trp792fs), c.836del p.(Gly279Valfs*21) - Nonsense — e.g. c.2827C>T p.(Arg943*) - Splice-site — e.g. c.3330+2T>G (Amish/Swiss), c.2905+1G>A, c.1224-19G>A (intronic, ClinVar RCV000009149) - Intronic deletion causing exon skipping — the South Asian 25-bp intron-32 deletion → skipping of exon 33 - Missense — a minority; in the UK proband series "Missense mutations (15, 45.6%) were the most frequent" among 42 mutations, illustrating cohort-dependent ascertainment (PMID:22267749). Some missense alleles (e.g. R502W, a recurrent founder-like allele) are well-established. - Copy-number / structural — whole-gene and multi-exon deletions in 18 probands, including a promoter deletion which formally proved that reduced transcription alone suffices: Hayesmoore et al., PMID:38258577, "A Promoter Deletion Confirms That MYBPC3 Haploinsufficiency Is Sufficient to Cause Hypertrophic Cardiomyopathy in Humans." - Alu-mediated insertion — reported cause of familial HCM (PMC6978237)

Selected variants of curation interest:

Variant (NM_000256.3)	Protein	Class	Population / significance
c.2373dup	p.(Trp792fs)	Frameshift	Dutch founder — 46% of Dutch founder carriers; also homozygous/compound-het lethal neonatal cases (PMID:25335496)
c.2827C>T	p.(Arg943*)	Nonsense	Dutch founder — 32% of founder carriers; also in biallelic neonatal cases (PMID:25335496)
c.2864_2865delCT	p.(Pro955fs)	Frameshift	Dutch founder — 22% of founder carriers
c.3330+2T>G	exon 30 skip → frameshift, PTC in exon 31	Splice donor	Old Order Amish / Mennonite / ancient Swiss founder; carrier frequency ~10% in Geauga County, OH settlement (PMID:18467358); Swiss origin established by PMID:36162733
25-bp deletion, intron 32	exon 33 skipping	Intronic deletion	South Asian — ~4% carrier frequency; OR for cardiomyopathy 6.99 (95% CI 3.68–13.57), P=4×10⁻¹¹ (PMID:19151713)
c.1504C>T	p.(Arg502Trp)	Missense	Common recurrent allele; extreme intrafamilial heterogeneity (PMID:22267749)
c.2905+1G>A	splice donor	Splice	Compound-het partner in lethal neonatal case (PMID:41488457)
c.836del	p.(Gly279Valfs*21)	Frameshift	Novel; compound-het lethal neonatal (PMID:41488457)
c.1224-19G>A	intronic splice-affecting	Splice	ClinVar RCV000009149, asserted for "Familial hypertrophic cardiomyopathy 4"

Variant classification. Per ACMG/AMP, MYBPC3 truncating variants readily reach P/LP via PVS1 (LOF is the established mechanism) + segregation + case–control data. ClinVar holds thousands of MYBPC3 submissions; the ClinGen Hypertrophic Cardiomyopathy Variant Curation Expert Panel provides gene-specific PVS1/PM2/PS4 calibration. A computational subdomain-stability predictor has been developed to improve missense-variant interpretation and risk stratification (Genetics in Medicine 2021).

Allele frequency. Population filtering thresholds: "variants in MYBPC3 present in gnomAD with allele frequencies of >4E-05 ... and absent in disease registries are unlikely to be independently pathogenic for HCM." Founder alleles are the exception — the South Asian 25-bp deletion is present at 2–8% across Indian populations, and the Amish c.3330+2T>G at ~10% carrier frequency in one settlement, both far above any generic filtering threshold. This is a critical caveat: population-frequency-based filtering will falsely benign-call founder alleles.

Germline vs somatic. Exclusively germline. No somatic role; CMH4 is not a neoplastic disease and COSMIC/TCGA are not applicable.

Functional consequence. Loss of function via haploinsufficiency — see §6. Not dominant-negative in the classical poison-peptide sense for truncating alleles; some missense alleles may have additional dominant-negative/incorporation effects (an area of active debate — see Barefield & colleagues, "Is haploinsufficiency a sufficient mechanism for MYBPC3 truncating mutations?", PMID:36946992).

4.3 Modifier genes

UPF3B (NMD factor) — upregulated specifically in MYBPC3^trunc hearts and localised to the Z-disc, where sarcomeric protein translation occurs; determines the degree of transcript decay (PMID:37797718).
Second sarcomere gene variants (MYH7, TNNT2, TNNI3) in compound genotypes — earlier, more severe disease (PMID:22267749; PMID:39581692, in which heart failure was "commonly found in the presence of a second [variant]").
RAAS pathway polymorphisms — ACE I/D, AGT M235T, CMA1, AGTR1, CYP11B2 (PMC3449069).
Common-variant polygenic background / HCM PRS (Circulation 2025).

4.4 Epigenetics

No disease-defining epigenetic lesion. Reported findings are secondary remodelling signatures in HCM myocardium generally: differential DNA methylation and histone-modification changes at hypertrophic-gene loci, and re-activation of the fetal gene programme (NPPA, NPPB, MYH7). Multi-omic MYBPC3 work identifies transcriptional and post-transcriptional dysregulation (PMID:38406555; Frontiers 2025 P459fs multi-omics, PMC11903464). ENCODE/Roadmap Epigenomics heart tissue tracks provide the regulatory landscape for MYBPC3 (including the promoter region whose deletion is causal, PMID:38258577), but no CMH4-specific epigenomic biomarker exists.

4.5 Chromosomal abnormalities

Not a chromosomal disorder. Relevant large-scale events are intragenic/whole-gene CNVs at 11p11.2, detected in ~1–2% of otherwise genotype-negative HCM probands (Mademont-Soler et al., PMID:28771489; Hayesmoore et al., PMID:38258577). Karyotyping and standard CMA are not indicated; gene-panel-integrated CNV calling or MLPA is the appropriate modality.

5. Environmental Information

Environmental toxicants / radiation / pollution / occupational exposure: No established role in CMH4 causation. CTD lists no exposure with a validated MYBPC3-HCM interaction. Cardiotoxic exposures (anthracyclines, alcohol) cause distinct cardiomyopathies and are relevant only as confounders/differentials.
Lifestyle factors:
Diet. Western/high-fat-high-sugar diet acts as a disease trigger in phenotype-negative heterozygous Mybpc3 knock-in mice (PMC11708371) — MODEL_ORGANISM evidence; human replication is lacking.
Obesity / metabolic syndrome. Associated with worse phenotype and adverse outcome in HCM cohorts generally.
Hypertension. Co-modifier with severe phenotype in MYBPC3 carriers (PMID:19151713).
Exercise. Provokes symptoms and gradients (OMIM); competitive athletics historically restricted, now individualised under the 2024 guideline (PMID:38718139).
Alcohol. Vasodilation can worsen dynamic obstruction acutely.
Dehydration/volume depletion. Precipitates obstruction and syncope.
Infectious agents: Not applicable. No pathogen causes or triggers CMH4. (Viral myocarditis is a differential for acute decompensation, not an etiology.)

6. Mechanism / Pathophysiology

6.1 The causal chain (upstream → downstream)

[MOLECULAR] MYBPC3 truncating variant (PTC-generating: frameshift / nonsense /
    splice-disrupting / exon-skipping deletion; or promoter/whole-gene CNV)
    │
    ▼
[MOLECULAR] Nonsense-mediated mRNA decay (UPF3B-dependent, at the Z-disc)
    + allelic imbalance (mutant:WT mRNA ratio falls below 1:1)
    + ubiquitin-proteasome degradation of any escaping truncated peptide
    │
    ▼
[MOLECULAR] cMyBP-C HAPLOINSUFFICIENCY — reduced cMyBP-C content in the
    C-zone of the A-band; NO detectable poison peptide
    │
    ▼
[MOLECULAR] Loss of the cMyBP-C brake on the thick filament:
    • Fewer myosin heads held in the SUPER-RELAXED (SRX) state
    • Shift toward disordered-relaxed (DRX) → more heads available for actin
    • Increased Ca²⁺ sensitivity of force; accelerated cross-bridge kinetics
    • Loss of PKA-phosphorylation-dependent (M-domain Ser273/282/302)
      adrenergic modulation of contractility
    │
    ▼
[CELLULAR]  HYPERCONTRACTILITY + IMPAIRED RELAXATION of the cardiomyocyte
    (systolic hypercontractility with diastolic failure to relax)
    │
    ├──► [CELLULAR] Increased sarcomeric ATP consumption / energetic
    │              inefficiency (PCr/ATP falls); metabolic remodelling
    │
    ├──► [CELLULAR] Progressive Ca²⁺-handling abnormality
    │              (slowed Ca²⁺ release/reuptake; SERCA2a/RyR2 changes)
    │
    └──► [CELLULAR] Pro-hypertrophic signalling activation
                   (Ca²⁺-calcineurin-NFAT, CaMKII, MAPK/ERK,
                    PI3K-AKT-mTOR; fetal gene programme reactivation)
    │
    ▼
[TISSUE]    Cardiomyocyte hypertrophy → asymmetric septal-predominant LVH
    + MYOCYTE DISARRAY (loss of parallel myofibre alignment)
    + cardiac-fibroblast activation → interstitial and replacement FIBROSIS
    + intramural small-vessel disease (medial hyperplasia) → microvascular ischemia
    │
    ▼
[ORGAN]     • Diastolic dysfunction, elevated LV filling pressures
    • Dynamic LVOT obstruction (septal bulge + SAM of mitral valve)
    • Left atrial dilation → atrial fibrillation
    • Arrhythmogenic substrate (disarray + fibrosis + ischemia) → VT/VF
    • Late: LV systolic dysfunction ("burnt-out" HCM)
    │
    ▼
[ORGANISM]  Dyspnea, angina, syncope, heart failure, AF/stroke, SUDDEN CARDIAC DEATH

6.2 Key mechanistic evidence (verbatim quotes)

Haploinsufficiency, not poison peptide (PMID:22057632, Marston et al. 2012):

"Instead of expression of a poison peptide we consistently observe haploinsufficiency of MyBP-C in MYBPC3 mutant human heart muscle."

Corroborated in myectomy tissue (Marston et al., Circ Res 2009, PMID:19574547, "Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency") and formally proven by promoter deletion (PMID:38258577), whose accompanying mouse showed "heterozygous for an Mybpc3 promoter deletion developed a late-onset phenotype of asymmetrical septal hypertrophy associated with fibrosis."

NMD is the proximal mechanism (PMID:37797718, Burkart et al. 2023):

"We show that cMyBP-C haploinsufficiency starts at the mRNA level, despite hypertrophy-induced increased transcriptional activity." "Strikingly, we show that in sarcomeres UPF3B but not UPF1 and UPF2 are localized to the Z-discs, the presumed location of sarcomeric protein translation. Our data suggest that cMyBP-C haploinsufficiency in HCM-patients is established by UPF3B-dependent NMD during the initial translation round at the Z-disc."

Multiple degradative routes converge (PMID:38406555, Ananthamohan et al. 2024):

"Pathogenesis related to MYBPC3 mutations includes nonsense-mediated decay, alternative splicing, and ubiquitin-proteasome system events, leading to allelic imbalance and haploinsufficiency."

Myosin dysregulation / SRX loss. Toepfer et al., Sci Transl Med 2019 (PMID:30674652), "Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin"; McNamara et al., PLoS One 2017 (PMID:28658286) — MYBPC3-mutant patient myocardium shows "a significantly diminished SRX, characterized by a decrease in both the number of myosin heads in the SRX and the lifetime of ATP turnover"; McNamara et al., J Mol Cell Cardiol 2016 (PMID:27021517) — cMyBP-C ablation disrupts SRX in murine cardiomyocytes. The SRX state consumes ATP ~10-fold slower than DRX, so SRX loss directly links to energetic inefficiency.

Contractile trajectory: hypercontractile → hypocontractile, Ca²⁺-mediated (PMID:36893011, De Lange et al. 2023, human isogenic iPSC-CM engineered cardiac tissue, IN_VITRO):

"Our data suggest a progressive phenotype caused by cMyBP-C haploinsufficiency and ablation that initially is hypercontractile, but progresses to hypocontractility with impaired relaxation. The severity of the phenotype correlates with the amount of cMyBP-C present, with more severe earlier phenotypes observed in cMyBP-C-/- than cMyBP-C+/- ECTs. We propose that while the primary effect of cMyBP-C haploinsufficiency or ablation may relate to myosin crossbridge orientation, the observed contractile phenotype is Ca2+-mediated." "RNA-seq analysis revealed enrichment of differentially expressed hypertrophic, sarcomeric, Ca2+-handling, and metabolic genes in cMyBP-C+/- and cMyBP-C-/- ECTs."

Sarcomeric disorganisation as a proximal cellular lesion (PMID:19151713, IN_VITRO, neonatal rat cardiomyocytes):

"Staining with antibodies to the myc tag showed a highly disorganized and diffused pattern of sarcomeric architecture as a result of aberrant incorporation of altered proteins"

Pre-hypertrophic (subclinical) changes. Helms et al., JCI Insight 2020 (PMID:31877118), "Effects of MYBPC3 loss-of-function mutations preceding hypertrophic cardiomyopathy" — sarcomere-variant carriers without LVH already show diastolic abnormalities, elevated troponin, and profibrotic signalling.

Fibroblast-autonomous fibrosis. Zou et al., Cell Death Dis 2022 (PMID:36357371), "MYBPC3 deficiency in cardiac fibroblasts drives their activation and contributes to fibrosis" — a non-cardiomyocyte arm of the mechanism.

Ongoing debate. Barefield, J Gen Physiol 2023 (PMID:36946992), "Is haploinsufficiency a sufficient mechanism for MYBPC3 truncating mutations?" — argues additional/parallel mechanisms may contribute for some alleles. Flag as an open mechanistic question (dismech KNOWLEDGE_GAP).

6.3 Ontology term suggestions for pathophysiology nodes

GO Biological Process:

Node	GO term
Cross-bridge cycling / contraction	GO:0006936 muscle contraction; GO:0060048 cardiac muscle contraction; GO:0030049 muscle filament sliding
Nonsense-mediated decay	GO:0000184 nuclear-transcribed mRNA catabolic process, nonsense-mediated decay; GO:0006402 mRNA catabolic process
Aberrant splicing	GO:0000381 regulation of alternative mRNA splicing, via spliceosome; GO:0008380 RNA splicing
UPS degradation	GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process
Myosin ATPase / SRX	GO:0032781 positive regulation of ATP-dependent activity; GO:0000146 microfilament motor activity (MF)
Ca²⁺ handling	GO:0060402 calcium ion transport into cytosol; GO:0055117 regulation of cardiac muscle contraction
Hypertrophy	GO:0003300 cardiac muscle hypertrophy; GO:0014898 cardiac muscle hypertrophy in response to stress
Sarcomere organisation	GO:0045214 sarcomere organization; GO:0055003 cardiac myofibril assembly
Fibrosis	GO:0010613 positive regulation of cardiac muscle hypertrophy; GO:0060346 (see also fibrotic_response module)
Adrenergic modulation	GO:0071880 adenylate cyclase-activating adrenergic receptor signaling pathway

GO Molecular Function / Cellular Component (for MYBPC3 itself): - MF: GO:0008307 structural constituent of muscle; GO:0032036 myosin heavy chain binding; GO:0051015 actin filament binding - CC: GO:0031430 M band; GO:0030017 sarcomere; GO:0031672 A band; GO:0005865 striated muscle thin filament; GO:0030018 Z disc (UPF3B localisation)

CL Cell Types: - CL:0000746 cardiac muscle cell (cardiomyocyte) — primary - CL:2000046 ventricular cardiac muscle cell - CL:0002548 fibroblast of cardiac tissue — fibrosis arm - CL:0000359 vascular associated smooth muscle cell — intramural small-vessel disease - CL:0002138 endothelial cell of lymphatic vessel / CL:0000115 endothelial cell — microvascular arm

6.4 Molecular profiling

Transcriptomics. RNA-seq of MYBPC3^+/- and MYBPC3^-/- engineered cardiac tissue shows enrichment of hypertrophic, sarcomeric, Ca²⁺-handling, and metabolic gene sets (PMID:36893011). GSEA of human MYBPC3^trunc myocardium shows increased NMD-component expression (PMID:37797718). Allelic-imbalance RNA-seq is the standard assay for demonstrating NMD in patient tissue (PMID:30456444).
Spatial transcriptomics. Focal myocyte-disarray regions vs normal regions of human HCM myocardium have been profiled (PMC10454036) — reveals region-specific fibrotic/ECM programmes.
Proteomics. Quantitative western/MS of myectomy tissue demonstrates ~30–50% reduction of cMyBP-C protein with absence of any truncated species (PMID:19574547; PMID:22057632). Human Protein Atlas confirms heart-restricted MYBPC3 expression.
Multi-omics. MyBPC3 P459fs multi-omics + super-resolution imaging (PMC11903464).
Metabolomics/energetics. ³¹P-MRS shows reduced myocardial PCr/ATP ratio in HCM including in G+/LVH− carriers — the energy-depletion hypothesis. Lipidomics: no CMH4-specific signature.
Functional genomics. CRISPR-Cas9 isogenic iPSC allelic series (WT / +/− / −/−) is the workhorse (PMID:36893011). No CMH4-specific DepMap/genome-wide screen.

7. Anatomical Structures Affected

Organ level

Primary organ: heart — UBERON:0000948 (heart)
UBERON:0002084 heart left ventricle — principal site
UBERON:0002094 interventricular septum — site of maximal, asymmetric hypertrophy
UBERON:0002349 myocardium — the affected tissue proper
UBERON:0002079 left cardiac atrium — secondary dilation → AF
UBERON:0002078 right cardiac atrium
UBERON:0002135 mitral valve — SAM, secondary MR
UBERON:0004145 left ventricular outflow tract — dynamic obstruction
UBERON:0001621 coronary artery / intramural arterioles — small-vessel disease
Secondary organ involvement:
Brain (UBERON:0000955) — cardioembolic stroke from AF; syncope-related injury
Lung (UBERON:0002048) — pulmonary congestion/oedema from elevated filling pressures
Liver (UBERON:0002107), kidney (UBERON:0002113) — congestive/low-output injury in advanced HF
Body systems: cardiovascular (primary); respiratory and nervous systems secondarily.
Biallelic neonatal form adds: interatrial septum (ASD), interventricular septum (VSD), ductus arteriosus (PDA) — i.e. structural congenital heart disease alongside the cardiomyopathy (PMID:25335496; PMID:41488457).

Tissue and cell level

Tissue types: cardiac muscle tissue (striated); cardiac connective tissue/ECM (interstitial and replacement fibrosis); vascular smooth muscle (intramural arteriolar medial hyperplasia).
Cell populations: CL:0000746 cardiac muscle cell (primary target); CL:2000046 ventricular cardiac muscle cell; CL:0002548 fibroblast of cardiac tissue (activated → myofibroblast, CL:0000186); CL:0000359 vascular associated smooth muscle cell; CL:0000235 macrophage (inflammatory infiltrate in advanced disease).

Subcellular level

GO:0030017 sarcomere — the primary compartment
GO:0031430 M band and GO:0031672 A band (C-zone) — cMyBP-C's native location
GO:0030018 Z disc — where UPF3B-dependent NMD is proposed to act (PMID:37797718)
GO:0016529 sarcoplasmic reticulum — Ca²⁺-handling arm
GO:0005739 mitochondrion — energetic inefficiency
GO:0000502 proteasome complex — mutant peptide degradation
GO:0005634 nucleus / GO:0005681 spliceosomal complex — aberrant splicing arm

Localisation

Lateralisation: intrinsically left-sided and asymmetric — septal-predominant LVH is the signature. Apical, concentric, mid-cavity, and eccentric variants occur (PMID:22267749). Right ventricular hypertrophy is uncommon and secondary.
Regional heterogeneity: LGE (fibrosis) on CMR is characteristically patchy/mid-wall, concentrated at RV insertion points and within the hypertrophied septum.

8. Temporal Development

Onset

Genotype	Typical onset	Pattern
Biallelic truncating	Neonatal / first weeks of life	Acute, fulminant
Monoallelic truncating (classic)	Adolescence to late adulthood; classically 3rd decade onward	Insidious, chronic
Monoallelic with compound genotype / hypertension	Earlier, more severe	Accelerated

Verbatim anchors: - Biallelic: "They died from cardiac failure before age 13 weeks." / "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." (PMID:25335496) - Monoallelic: "In most carriers the effects remained dormant until the third decade and then manifested themselves as mild hypertrophy" (PMID:19151713) - Extreme heterogeneity: "marked heterogeneity in age at diagnosis (5 to 80 years)" (PMID:22267749)

The historical framing of MYBPC3 as uniformly "late-onset and benign" has been substantially revised. Page et al. tested exactly that hypothesis and found: "Small selected cohort studies suggest that mutations in the cardiac myosin binding protein-C (MYBPC3) gene cause late-onset, clinically benign hypertrophic cardiomyopathy (HCM). The aim of this study was to test this hypothesis..." → "Disease expression in families with HCM related to MYBPC3 mutations shows marked heterogeneity with incomplete, age-related, and gender specific penetrance." (PMID:22267749)

Progression and staging

A widely used conceptual staging for sarcomeric HCM (applies to CMH4):

Stage	Description	Markers
0 — Genotype-positive / phenotype-negative (G+/LVH−)	No LVH; subclinical abnormalities present	Diastolic dysfunction, ↑ hs-troponin, ↑ profibrotic markers, ECG changes, crypts/elongated mitral leaflets on CMR (PMID:31877118)
1 — Classic HCM	Overt LVH, preserved EF	±LVOT obstruction, ±LGE
2 — Adverse remodelling	Progressive fibrosis, LA dilation, AF	Rising LGE burden
3 — Overt dysfunction / "burnt-out"	LVEF <50%, restrictive/dilated physiology	~8% overall (PMID:20301725)
4 — End-stage HF	Transplant/LVAD candidacy

Rate: slow in most. Incident phenotype conversion 10% over 7.77 years mean follow-up in the Spanish truncating-variant cohort (PMID:39581692). Longitudinal biobank data show low annual conversion rates in genome-first carriers (PMID:39886308).
Course pattern: chronic, slowly progressive, punctuated by episodic exertional symptoms and by discrete arrhythmic events (AF onset, VT).
Duration: lifelong; no spontaneous remission.

Patterns

Remission: none spontaneous. Treatment-induced symptomatic and haemodynamic remission is achievable — cardiac myosin inhibitors normalise LVOT gradients in a majority; septal reduction therapy abolishes obstruction durably.
Critical periods / intervention windows:
Adolescence and young adulthood — highest relative SCD risk; peak yield of surveillance imaging.
G+/LVH− window — the theoretical target for disease-modifying/preventive therapy (currently investigational; VANISH trial of valsartan in early sarcomeric HCM is the flagship attempt).
Neonatal period (biallelic) — the only window for transplant listing.
Pre-conception / prenatal (biallelic-at-risk couples) — PGT window (PMID:41488457).

9. Inheritance and Population

Epidemiology

Measure	Value	Source
HCM (all causes) prevalence	~1 in 500 (≈200 per 100,000) by imaging-based estimate	Widely replicated; Orphanet flags familial isolated HCM as "NON RARE IN EUROPE"
Clinically diagnosed HCM prevalence	~1 in 3,000 (≈33/100,000) — the diagnostic gap	German 5-million-patient analysis, PMC5933727
Clinically apparent obstructive HCM	1.65 per 10,000 (16.5/100,000)	PMC8770922
US HCM burden	~600,000 people	"Hypertrophic cardiomyopathy (HCM) affects approximately 600,000 people in the United States." (PMID:40038304, exact quote)
CMH4 share	~50% of genetically explained HCM → point prevalence on the order of 50–100 per 100,000 if the 1:500 imaging estimate holds and ~30% of HCM is genotyped positive; ~10–30 per 100,000 on more conservative diagnosed-case estimates	Derived; PMID:20301725
Diagnostic yield of genetic testing	~30% of all HCM; ~60% with positive family history	PMID:20301725

Curation note for the dismech Prevalence slots: the honest structured record is measure_type: POINT_PREVALENCE, prevalence_class: BAND_1_5_PER_10000 for the derived CMH4 estimate, with the verbatim source phrasing in notes and the derivation flagged. Do not assert a single hard number as if directly measured.

Inheritance

Pattern: Autosomal dominant (HP:0000006) for monoallelic disease; autosomal recessive (HP:0000007) for the biallelic lethal neonatal form. Both are recognised at OMIM 115197. A CMH4 entry should carry both Inheritance blocks with bound terms, keyed to the respective subtypes.
Penetrance: Incomplete, age-dependent, and sex-dependent (HP:0003829 Incomplete penetrance).

Setting	MYBPC3 / sarcomere penetrance
Clinical HCM families (all sarcomere genes)	57%
Population/community biobanks (incidental P/LP carriers)	11% (0% ARIC → 18% UK Biobank)
MYBPC3-specific, pooled clinical	~55%
MYBPC3 UK family series, all carriers	56.9%; in relatives only 34.5%
Age-stratified (MYBPC3, UK series)	38.4% <40 yr vs 68.6% ≥40 yr (P<0.001)
Sex-stratified (MYBPC3, UK series)	65.1% male vs 48.1% female (P=0.03)

Sources: Topriceanu et al., Circulation 2024, PMID:37929589 — "The penetrance of a pathogenic/likely pathogenic (P/LP) sarcomeric mutation is low in the general population at 11% but five-fold higher at 57% in patients with HCM and their family members"; PMID:22267749 (exact quotes above); GeneReviews per-gene table (PMID:20301725): MYL3 ~32%, CSRP3 38%, TPM1 ~49%, MYBPC3 ~55%, TNNT2 ~62%, MYH7 ~64%.

Expressivity: Highly variable, including within a single family carrying an identical allele. The R502W series is the canonical demonstration: 9 families / 25 individuals with "marked heterogeneity in age at diagnosis (5 to 80 years), pattern of hypertrophy (11 none, 9 asymmetrical, 3 concentric, 1 apical, 1 eccentric), and prognosis (premature sudden death in 2 individuals compared with survival to advanced age in 6 individuals)" (PMID:22267749, exact quote).
Genetic anticipation: Not a feature — MYBPC3 is not a repeat-expansion locus. Apparent anticipation in pedigrees reflects ascertainment bias and earlier cascade screening.
Germline mosaicism: Rare; occasional de novo MYBPC3 variants are reported. Recurrence-risk counselling for apparently de novo cases should acknowledge low-level parental gonadal mosaicism, but no quantified rate exists for MYBPC3.
Founder effects: Prominent — see table below.
Consanguinity: A major driver of the biallelic form. Homozygous truncating cases arise both from consanguinity and from founder-allele population frequency (the Amish setting is the archetype of the latter).
Carrier frequency: Population-dependent. General populations: MYBPC3 P/LP carrier frequency is roughly 1 in 200–500 for HCM-associated sarcomere variants overall. Founder settings dramatically exceed this.

Founder alleles / geographic distribution of specific variants

Population	Variant	Frequency / burden	Source
Netherlands	c.2373dup, c.2827C>T, c.2864_2865delCT	Collectively up to ~35% of all Dutch HCM; distribution among founder carriers 46% / 32% / 22%	Circ Cardiovasc Genet 2017; BIO FOr CARe, PMID:33532905
Old Order Amish (Geauga Co., OH) / Mennonite / Swiss	c.3330+2T>G	~10% heterozygous carrier frequency in the Geauga settlement; ancient Swiss (Bern canton) origin	PMID:18467358; PMID:36162733
South Asia (India, Pakistan, Sri Lanka; via gene flow to Indonesia, Malaysia)	25-bp intron-32 deletion	~4% overall; 2–8% across 107 Indian ethnic populations (287/6,273 individuals = 4.6%); absent from Northeast Indians, Siddis, Onges, and all 63 other world populations tested (2,085 individuals, 26 countries)	PMID:19151713
Iceland	Icelandic founder variant	Documented founder cohort	PMC7174027
Northern Spain	Novel truncating variant	Regional cohort	PMC10137663

The South Asian deletion is quantitatively striking (verbatim, PMID:19151713):

"Here, we describe a deletion of 25 bp in the gene encoding cardiac myosin binding protein C (MYBPC3) that is associated with heritable cardiomyopathies and an increased risk of heart failure in Indian populations (initial study OR = 5.3 (95% CI = 2.3-13), P = 2 x 10(-6); replication study OR = 8.59 (3.19-25.05), P = 3 x 10(-8); combined OR = 6.99 (3.68-13.57), P = 4 x 10(-11)) and that disrupts cardiomyocyte structure in vitro. Its prevalence was found to be high (approximately 4%) in populations of Indian subcontinental ancestry."

Population attributable risk of that deletion is ~4.5%; the TMRCA of the deletion haplotype is ~33 ± 23 thousand years, with no evidence of positive selection.

Demographics

Sex ratio: Carrier ratio ~1:1 (autosomal). Penetrance is male-biased (65.1% vs 48.1%), so diagnosed CMH4 skews male, roughly 1.3–1.5:1. Women present later and with more advanced NYHA class — a recognised diagnostic inequity.
Age distribution of affected individuals: peak diagnosis 4th–6th decades for monoallelic disease (Spanish cohort mean 47±16.8 yr, PMID:39581692); a distinct neonatal cluster for biallelic disease.
Geographic: worldwide; founder clusters as above. Within India, deletion frequency is significantly higher in southern and western states than northern (P<4×10⁻⁸), paralleling a large cardiac-mortality gradient (386–422 vs 76–99 cardiac deaths/100,000) (PMID:19151713).

10. Diagnostics

Clinical tests

Imaging - Transthoracic echocardiography — first-line. Establishes max LV wall thickness (≥15 mm adults; ≥13–14 mm with family history; z-score >3 in children), morphology, SAM, LVOT gradient at rest and with Valsalva/exercise provocation, diastolic function, LA size. (PMID:20301725; PMID:38718139) - Exercise (stress) echocardiography — mandatory when resting gradient <50 mmHg but symptoms suggest obstruction. - Cardiac MRI with late gadolinium enhancement (LGE) — quantifies wall thickness where echo windows fail (apical/anterolateral), detects apical aneurysm, and quantifies fibrosis burden, an independent SCD risk marker (LGE ≥15% of LV mass). Also detects the pre-hypertrophic markers (myocardial crypts, elongated mitral leaflets) in G+/LVH− carriers. - Cardiac CT — when CMR contraindicated. - RadLex/DICOM applicable; no CMH4-specific imaging biomarker beyond generic HCM markers.

Electrophysiology - 12-lead ECG — abnormal in >90% of overt HCM; LVH voltage, deep T-wave inversion, pathological Q waves, left-axis deviation. Frequently abnormal before LVH in carriers. - Ambulatory (24–48 h Holter) ECG or extended monitoring — detects NSVT (SCD risk factor) and paroxysmal AF. Guidelines recommend periodic monitoring. - Exercise treadmill testing with BP response — abnormal blood-pressure response is an SCD risk factor; also yields functional capacity. - Cardiopulmonary exercise testing (pVO₂) — the primary endpoint in EXPLORER-HCM and SEQUOIA-HCM; used for transplant evaluation. - Invasive EP study — not routine.

Laboratory / biomarkers - NT-proBNP (LOINC:33762-6) and BNP — severity/prognosis; treatment-response marker for myosin inhibitors. - High-sensitivity troponin I/T — elevated even pre-hypertrophy (PMID:31877118). - Phenocopy screen (essential, per PMID:38718139 — "HCM genetic testing should include genes for HCM phenocopies"): - α-galactosidase A activity (males) + GLA sequencing / plasma lyso-Gb3 → Fabry disease - Serum/urine free light chains, SPEP/UPEP, immunofixation + ⁹⁹ᵐTc-PYP/DPD bone scintigraphy → cardiac amyloidosis (ATTR/AL) - Creatine kinase, LAMP2/PRKAG2 testing → Danon disease, PRKAG2 glycogen storage cardiomyopathy - Carnitine, acylcarnitine profile, lactate → metabolic/mitochondrial phenocopies - Consider RASopathy panel in paediatric/syndromic presentations

Biopsy / pathology - Endomyocardial biopsy is not routine for CMH4 diagnosis; reserved for suspected infiltrative disease. - Histopathology (myectomy, explant, or autopsy) shows the classic triad: cardiomyocyte hypertrophy, myocyte disarray (loss of parallel alignment — the histopathological hallmark), and interstitial/replacement fibrosis, plus intramural small-vessel medial hyperplasia. From the Indian series (PMID:19151713, exact quotes): "Histopathological section of the same subject showing hypertrophied myofibers separated from each other by increased connective tissue"; "'swirling' of hypertrophied myofibers amid connective tissue disarray." In the lethal neonatal case: "Postmortem examination revealed severe HCM, an atrial septal defect (ASD), and extensive myocardial necrosis and fibrosis." (PMID:41488457, exact quote). - Myoarchitectural disarray in HCM appears to begin pre-birth (PMC6794206).

Genetic testing

Recommended approach (2024 AHA/ACC guideline, PMID:38718139; GeneReviews, PMID:20301725):

Genetic counselling before and after testing — "Evaluation by a genetic counselor is recommended to discuss risk and benefits of genetic testing."
Multigene HCM panel in the proband — must include the 8 definitive sarcomere genes (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, MYL3) plus phenocopy genes (GLA, LAMP2, PRKAG2, TTR, PTPN11 and other RASopathy genes, GAA, DES, FHL1, CSRP3, PLN, ALPK3). Routine genetic testing is now recommended for all children meeting HCM diagnostic criteria.
Integrated CNV/deletion-duplication analysis or MLPA — essential, because whole-gene and promoter MYBPC3 deletions are pathogenic and missed by sequence-only panels (PMID:38258577; PMID:28771489).
Cascade (predictive) testing of first-degree relatives — "Cascade genetic testing should be extended to first-degree relatives only if a pathogenic variant is identified in the proband." VUS results must not be used for cascade testing.
Reflex to WES/WGS when panel is negative and phenotype is atypical/syndromic. WGS additionally captures deep-intronic spliceogenic variants — an established elusive class in MYBPC3 (Sci Rep 2022, PMC9068804).
RNA studies (allelic imbalance / RT-PCR splicing assay) — the definitive functional confirmation for candidate spliceogenic MYBPC3 variants and for demonstrating haploinsufficiency (PMID:30456444; PMID:19151713 used exactly this: cDNA from endomyocardial biopsy showed "a normal transcript and a mutant transcript with absence of exon 33").
Molecular autopsy / postmortem trio WES in unexplained sudden infant or young-adult death — PMID:41488457 is the worked example: "This 'molecular autopsy' established a definitive cause for the infant's death, linking a novel variant to a severe pathological phenotype. Crucially, the diagnosis guided the clinical management of the asymptomatic carrier parents, prompting long-term cardiac surveillance and enabling preimplantation genetic testing (PGT) for future family planning." (exact quote)

Modalities NOT indicated: karyotyping, FISH, chromosomal microarray (unless syndromic features present), mtDNA testing (unless mitochondrial phenocopy suspected), repeat-expansion testing.

Omics-based diagnostics

RNA-seq / targeted RT-PCR: clinically deployed for splice-variant resolution and allelic imbalance (see above).
Proteomics / metabolomics / epigenomics / liquid biopsy: research-stage only for CMH4. Circulating microRNA and proteomic panels for HCM phenotype conversion are in development but not validated.

Clinical criteria and differential diagnosis

Diagnostic criteria: unexplained LVH with maximal wall thickness ≥15 mm (adults), ≥13 mm with family history or a known pathogenic variant, or z-score >3 (children), in the absence of abnormal loading conditions. (2024 AHA/ACC, PMID:38718139; 2023 ESC Cardiomyopathy Guidelines.)

Differential diagnosis — the phenocopies (must be excluded):

Condition	Distinguishing feature
Hypertensive heart disease	Usually concentric, regresses with BP control; history
Aortic stenosis	Valve gradient on echo
Athlete's heart	Wall thickness usually <15 mm, dilated LV cavity, normal diastolic function, regresses with detraining
Fabry disease (GLA)	X-linked, low α-Gal A, ↑ lyso-Gb3, short PR interval, renal/neuropathic/skin features
Cardiac amyloidosis (ATTR/AL)	Positive bone scintigraphy or light chains; low-voltage ECG despite thick walls; apical sparing on strain
Danon disease (LAMP2)	X-linked, WPW, skeletal myopathy, intellectual disability, very high CK
PRKAG2 syndrome	Pre-excitation, conduction disease
RASopathies (Noonan/PTPN11 etc.)	Dysmorphism, pulmonary valve stenosis, short stature
Pompe disease (GAA)	Infantile hypotonia; enzyme assay
Mitochondrial cardiomyopathy	Multisystem, lactate, maternal inheritance
Left ventricular noncompaction	Overlaps with the biallelic MYBPC3 phenotype specifically (PMID:25335496)
Neonatal: Beckwith-Wiedemann, infant of diabetic mother, Costello syndrome	Clinical context

Screening

Cascade genetic testing of first-degree relatives once a P/LP variant is identified (the highest-yield strategy).
Clinical surveillance of at-risk relatives (GeneReviews, PMID:20301725):
Variant-positive relatives: echocardiography + ECG every 1–2 years.
Genetic status unknown, children/adolescents: exam + ECG + echo every 2–3 years, starting before puberty.
Genetic status unknown, adults: every 3–5 years.
No newborn screening exists or is recommended (no RUSP inclusion; no treatment window that screening would open for monoallelic disease). Founder-population carrier screening is a legitimate, locally-implemented exception (Amish community programmes; Dutch founder-variant cascade programmes).
Preconception/prenatal: carrier screening in couples at risk for biallelic disease; PGT-M is established (PMID:41488457).

11. Outcome / Prognosis

Survival and mortality

Population	Outcome
Clinically affected monoallelic MYBPC3 carriers (UK, 82 individuals, 7.9±4.5 yr follow-up)	Annual SCD 0.46%/yr; all-cause mortality 0.93%/yr (PMID:22267749, exact figures)
Spanish truncating-MYBPC3 cohort (7.77 yr mean follow-up)	Relevant heart failure in 8.1%; incident HCM phenotype 10%; "middle-aged adult patients (47±16.8 years) without significant comorbidities or symptoms"; EF preserved at 65%±10% (PMID:39581692, exact quotes)
General HCM (all genotypes)	SCD, resuscitated arrest, or appropriate ICD therapy in ~6%; LVEF<50% in ~8% (PMID:20301725)
Biallelic truncating MYBPC3	Essentially 100% mortality in the first year without transplant. All 21 reported cases "diagnosed with severe cardiomyopathy and/or died within the first few months of life" (PMID:25335496); the four index neonates "died from cardiac failure before age 13 weeks"
Amish homozygous c.3330+2T>G (23 infants)	"life span averaged 3 to 4 months, and all died before 1 year of age except for 2 children who underwent cardiac transplantation" (OMIM 115197, summarising PMID:18467358)

Contemporary HCM cohorts under modern care (ICDs, myectomy, anticoagulation) approach near-normal life expectancy for many patients — a substantial improvement over historical tertiary-referral estimates. The MYBPC3 genotype has historically been described as favourable relative to MYH7; the Spanish cohort supports this ("previously associated with a favourable prognosis"; low event rates), while Page et al. caution that heterogeneity is such that genotype alone must not drive individual prognostication.

Morbidity, disability, and quality of life

Functional limitation: NYHA class II–III in trial-eligible obstructive patients; reduced pVO₂.
Atrial fibrillation and stroke: ~20% AF overall, ~60% by age 60 if diagnosed <40 (PMID:20301725); thromboembolic stroke is a leading cause of morbidity, hence mandatory anticoagulation.
Heart failure: 8.1% in the Spanish MYBPC3 cohort (PMID:39581692); progression to advanced HF requiring transplant in a minority.
ICD-related morbidity: inappropriate shocks, lead complications, infection, psychological impact.
QoL instruments: KCCQ-CSS and HCMSQ-SoB are the validated, trial-endorsed instruments (both used as EXPLORER-HCM secondary endpoints, PMID:32871100). EQ-5D and SF-36 also applied. ICF domains affected: mobility (d450 walking), major life areas (d840–859 work), recreation/leisure (d920 — sport restriction).
Family/psychosocial burden: cascade-testing anxiety, insurance/employment implications, reproductive decision-making, bereavement after a family SCD.

Complications

Atrial fibrillation → cardioembolic stroke; ventricular tachyarrhythmia → SCD; progressive diastolic HF; end-stage systolic ("burnt-out") HCM; apical aneurysm with mural thrombus; infective endocarditis (obstructive phenotype, historically); mitral regurgitation; conduction disease (post-septal reduction therapy, complete heart block requiring pacing).

Prognostic factors and risk stratification

HCM Risk-SCD (ESC) and the 2024 AHA/ACC risk-marker approach are the tools. Major risk markers: - Prior cardiac arrest / sustained VT - Family history of SCD in a first-degree relative - Unexplained syncope - Maximal LV wall thickness ≥30 mm - Non-sustained VT on ambulatory monitoring - LV apical aneurysm - LVEF <50% - Extensive LGE (≥15% LV mass) on CMR — arbitrator for intermediate-risk patients - Abnormal BP response to exercise (ESC model)

Genotype-specific prognostic points for CMH4: - Truncating MYBPC3 variant location does not predict outcome — "cause similar clinical severity and outcomes regardless of location, consistent with locus-independent loss-of-function" (PMID:32841044). Do not build a domain-based risk model for truncating alleles. - Compound/complex genotype predicts worse outcome (PMID:22267749; PMID:39581692). - Biallelic status is categorically prognostic (lethal neonatal). - Male sex and age ≥40 predict phenotype expression (PMID:22267749). - Genotype-positive status itself (vs genotype-negative HCM) is associated with earlier onset and higher event rates in SHaRe.

Prognostic biomarkers: NT-proBNP, hs-troponin, LGE burden, LA volume index, global longitudinal strain.

12. Treatment

There is currently no approved disease-modifying therapy specific to CMH4; management targets the downstream physiology (obstruction, hypercontractility, arrhythmia, heart failure). Gene-replacement therapy is the first genuinely genotype-directed approach and is in early clinical trials.

12.1 Pharmacotherapy

Therapy	Class / mechanism	Role	Ontology suggestion
Beta-blockers (metoprolol, bisoprolol, atenolol, propranolol)	β₁-adrenergic antagonist → ↓HR, ↑diastolic filling, ↓gradient	First-line for symptomatic obstructive and non-obstructive HCM	`NCIT:C15986` Pharmacotherapy + `therapeutic_agent` CHEBI:6904 metoprolol (verified); modality `SMALL_MOLECULE`
Non-dihydropyridine CCBs (verapamil, diltiazem)	L-type Ca²⁺ channel blockade → ↓contractility, improved relaxation	Second-line / β-blocker intolerant. Caution/contraindicated in severe obstruction + hypotension	`NCIT:C15986` + CHEBI:9948 verapamil (verified)
Disopyramide	Class Ia antiarrhythmic with potent negative inotropy	Add-on for refractory obstruction; must be paired with AV-nodal blockade	`NCIT:C15986` + CHEBI:4657 disopyramide (verified)
Mavacamten (Camzyos)	First-in-class cardiac myosin ATPase inhibitor — reduces actin-myosin cross-bridge formation, restores SRX, ↓hypercontractility	FDA approved April 2022 for symptomatic obstructive HCM. Mechanistically the direct counterpart of the CMH4 lesion	`NCIT:C15986` + NCIT:C174901 Mavacamten (verified); modality `SMALL_MOLECULE`
Aficamten (Myqorzo)	Next-generation cardiac myosin inhibitor (shorter half-life, less EF-lowering)	FDA approved 19 Dec 2025; US availability Jan 2026; REMS with echo monitoring	`NCIT:C15986` + NCIT:C179072 Aficamten (verified)
Loop diuretics	Volume reduction	Congestive symptoms; use cautiously — can worsen dynamic obstruction	`NCIT:C15986`
Oral anticoagulation (DOACs; warfarin if mechanical valve)	Thromboembolism prevention	Mandatory for HCM + AF regardless of CHA₂DS₂-VASc	`NCIT:C15986`
Antiarrhythmics (amiodarone, sotalol)	Rhythm control for AF/VT	Adjunct	`NCIT:C15986`
Standard GDMT for HF (ACEi/ARB, MRA, SGLT2i, beta-blocker)		Only in the end-stage/"burnt-out" systolic phase; avoid vasodilators in obstructive physiology

Drugs to AVOID in obstructive CMH4: pure vasodilators (nitrates, dihydropyridine CCBs, hydralazine), high-dose diuretics, positive inotropes (digoxin, dobutamine) — all increase the dynamic gradient.

EXPLORER-HCM efficacy (verbatim, PMID:32871100):

"45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006)" "Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild."

SEQUOIA-HCM (aficamten), Maron MS et al., N Engl J Med 2024;390(20):1849–1861, PMID:38739079: 282 patients randomised at 101 centres; pVO₂ improved by a least-squares mean difference of +1.74 mL/kg/min (p=0.000002); all 10 secondary endpoints met; serious TEAEs 5.6% (aficamten) vs 9.3% (placebo). Efficacy extends to mildly symptomatic patients (Eur Heart J 2025) and improves disease/symptom burden (JACC 2024).

Pharmacogenomics. Both myosin inhibitors are CYP2C19-metabolised (mavacamten predominantly; also CYP3A4/2C9). CYP2C19 poor metabolisers require dose reduction and more intensive echo monitoring for LVEF decline — mavacamten labelling carries CYP2C19-genotype-relevant dosing guidance, and this is one of the few genuine pharmacogenomic considerations in HCM care (PharmGKB/CPIC-relevant). Concomitant strong CYP2C19/CYP3A4 inhibitors are contraindicated or require dose adjustment. There is no MYBPC3-genotype-directed drug selection at present.

12.2 Advanced therapeutics

Gene therapy — the flagship CMH4-specific programme.

Preclinical (Greer-Short et al., Nat Commun 2025, PMID:40038304, exact quotes):

"Loss-of-function mutations in Myosin Binding Protein C3, MYBPC3, are the most common genetic cause of HCM, with the majority of mutations resulting in haploinsufficiency. To restore cardiac MYBPC3, we use an adeno-associated virus (AAV9) vector and engineer an optimized expression cassette with a minimal promoter and cis-regulatory elements (TN-201) to enhance packaging efficiency and cardiomyocyte expression." "Rather than simply preventing cardiac dysfunction preclinically, we demonstrate in a symptomatic MYBPC3-deficient murine model the ability of AAV gene therapy to reverse cardiac hypertrophy and systolic dysfunction, improve diastolic dysfunction, and prolong survival. Dose-ranging efficacy studies exhibit restoration of wild-type MYBPC3 protein levels and saturation of cardiac improvement at the clinically relevant dose of 3E13 vg/kg, outperforming a previously published construct."

Clinical — MyPEAK-1 (NCT05836259), Phase 1b/2, open-label dose-escalation of single IV TN-201 in symptomatic adults with MYBPC3-associated HCM: - First-in-human results: Desai MY et al., Cardiovasc Res 2025;121(17):2628–2631, PMID:41206746 — "First-in-human study of TN-201, an AAV9 gene replacement therapy in MYBPC3-associated hypertrophic cardiomyopathy." - Interim data presented at AHA Scientific Sessions 2025: 3 patients at 3E13 vg/kg (Cohort 1, ≥1 yr follow-up) and 3 at 6E13 vg/kg (Cohort 2). Reported dose-dependent transgene RNA expression, increasing cMyBP-C protein at one year, with biomarkers stable or improved (Tenaya press release, 8 Nov 2025). - ⚠️ On 7 November 2025 the FDA placed MyPEAK-1 on clinical hold. This must be recorded alongside the efficacy signal. TN-201 holds EMA PRIME designation. - Eligibility gating: pre-existing anti-AAV9 neutralising antibodies exclude patients; seroeligibility in this population was assessed by Desai MY et al., Front Med 2025;12:1635586, PMID:41020222.

Suggested annotation: therapeutic_modality: GENE_THERAPY; treatment_term NCIT:C15238 Gene Therapy.

Other advanced modalities: - Gene editing (base/prime editing) and allele-specific silencing — preclinical only for MYBPC3. - ASO / siRNA — not applicable to CMH4's dominant mechanism. Because the lesion is loss of protein via NMD, knockdown strategies are mechanistically wrong; the ASO paradigms in the dismech antisense_oligonucleotide_therapy module do not map here. (A theoretical NMD-inhibition or exon-skipping-to-restore-frame approach has been proposed but is not in trials.) - Cell therapy / immunotherapy — not applicable. - Targeted therapy — cardiac myosin inhibitors are the targeted therapy class for HCM (targeting the downstream hypercontractility rather than the gene).

12.3 Surgical and interventional

Intervention	Indication	NCIT
Surgical septal myectomy (Morrow procedure)	Drug-refractory symptomatic obstruction (gradient ≥50 mmHg, NYHA III–IV); gold standard at experienced centres; operative mortality <1%	`NCIT:C15329` Surgical Procedure (no specific "septal myectomy" NCIT term confirmed)
Alcohol septal ablation	Drug-refractory obstruction in patients unsuitable for surgery; risk of complete heart block	`NCIT:C15329` / `NCIT:C49236` Therapeutic Procedure
Mitral valve repair/replacement	Intrinsic mitral pathology contributing to obstruction	`NCIT:C15329`
ICD implantation	Secondary prevention (prior arrest/sustained VT) or primary prevention per risk score	NCIT:C80435 Implantable Cardioverter-Defibrillator Placement (verified); device NCIT:C93238; modality `DEVICE`
Catheter ablation	Symptomatic AF; VT ablation in selected cases	`NCIT:C49236`
Heart transplantation	End-stage HCM; the only survival-altering intervention for biallelic neonatal disease	NCIT:C15246 Heart Transplantation (verified); modality `SURGERY`
LVAD	Bridge to transplant (technically challenging in small, non-dilated LV cavities)	`DEVICE`

12.4 Supportive and rehabilitative

Symptom-directed care, volume management, sleep-apnoea screening and treatment.
Cardiac rehabilitation / structured moderate exercise — the 2024 guideline liberalised exercise recommendations; moderate-intensity recreational exercise is now considered beneficial and safe for most patients, with shared decision-making for higher intensities. NCIT:C15315 Rehabilitation.
Weight management, BP control, alcohol moderation. NCIT:C15447 Dietary Intervention; modality BEHAVIORAL.
Psychological support, particularly around ICD carriage and family SCD.
Genetic counselling (NCIT:C15240) is a formal component of care, not an adjunct.

12.5 Experimental / trials

Trial	Agent	Phase	NCT
MyPEAK-1	TN-201 AAV9-MYBPC3 gene therapy	1b/2	NCT05836259 (on FDA clinical hold as of 7 Nov 2025)
EXPLORER-HCM	Mavacamten	3 (completed)	NCT03470545
SEQUOIA-HCM	Aficamten	3 (completed)	NCT05186818
MAPLE-HCM	Aficamten vs metoprolol monotherapy	3	NCT05767346
VALOR-HCM	Mavacamten (SRT-eligible patients)	3	NCT04349072
VANISH	Valsartan in early sarcomeric HCM (disease modification in G+/early phenotype)	2	NCT01912534

12.6 Treatment strategy / algorithm

Confirmed CMH4 (MYBPC3 P/LP variant + phenotype)
│
├── Asymptomatic, no obstruction ──► Surveillance + SCD risk stratification
│                                     ± ICD if high risk; lifestyle counselling
│
├── Symptomatic, OBSTRUCTIVE (gradient ≥50 mmHg rest or provoked)
│      Step 1: beta-blocker  →  Step 2: verapamil/diltiazem (if BB-intolerant)
│      Step 3: add disopyramide  OR  cardiac myosin inhibitor
│              (mavacamten / aficamten) — with serial echo LVEF monitoring
│      Step 4: septal reduction therapy (myectomy preferred; ASA if
│              surgically unsuitable) at an experienced centre
│
├── Symptomatic, NON-OBSTRUCTIVE
│      Beta-blocker / CCB; diuretics for congestion; treat AF;
│      evaluate for advanced HF therapies if LVEF falls
│
├── ATRIAL FIBRILLATION ──► Anticoagulate (mandatory) + rate/rhythm control ± ablation
│
├── HIGH SCD RISK ──► ICD
│
└── END-STAGE (LVEF <50%) ──► GDMT + transplant evaluation
               (stop myosin inhibitor)

Reference: 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline, PMID:38718139; 2023 ESC Cardiomyopathy Guidelines.

Personalised medicine. Genotype currently drives family screening and reproductive counselling, not drug choice. TN-201, if it clears the clinical hold, would be the first genotype-restricted therapy (MYBPC3 haploinsufficiency + AAV9-seronegative). CYP2C19 genotype is the only actionable pharmacogene.

13. Prevention

Primary prevention (preventing disease occurrence)

The disease itself cannot be prevented in a variant carrier with current tools — no therapy is proven to prevent phenotype conversion. This is the central unmet need; VANISH (valsartan) is the flagship attempt.
Preventing transmission: genetic counselling, prenatal diagnosis, and preimplantation genetic testing for monogenic disease (PGT-M) — explicitly enacted in PMID:41488457, where molecular autopsy diagnosis enabled "preimplantation genetic testing (PGT) for future family planning."
Modifiable-risk-factor control (hypertension, obesity, metabolic syndrome) is biologically plausible as penetrance mitigation given the two-hit data, but is not proven to prevent conversion in humans. Curate this as a mechanistic hypothesis, not an established preventive.
Immunization: not applicable to CMH4 pathogenesis. (Routine influenza/COVID/pneumococcal vaccination is standard care for anyone with structural heart disease, to prevent decompensation.)

Secondary prevention (early detection)

Cascade genetic testing of first-degree relatives — the single highest-yield intervention. Extends only when a P/LP variant is found in the proband (PMID:38718139).
Serial clinical surveillance of at-risk relatives at the intervals given in §10.
Founder-population screening programmes: the Dutch founder-variant cascade programme and Amish community screening (10% carrier frequency in Geauga County) are the two operationalised examples. In South Asia, the 25-bp deletion's ~4% carrier frequency has been proposed for population genotyping: "genotyping could be used for the identification of persons at risk of heart failure among South Asians and could be accompanied by advice for a lower-risk lifestyle" (PMID:19151713, exact quote) — this remains a proposal, not implemented policy.
No newborn screening; not on the RUSP. The biallelic neonatal form is the only presentation with a theoretical NBS rationale, and it fails the treatability criterion outside transplant-capable settings.
Pre-participation athlete screening (ECG-inclusive, as in the Italian and some European models) detects HCM incidentally; its cost-effectiveness remains contested.

Tertiary prevention (preventing complications in affected individuals)

ICD for SCD prevention in high-risk patients — the definitive tertiary preventive.
Anticoagulation for AF → stroke prevention (mandatory, CHA₂DS₂-VASc-independent in HCM).
Septal reduction therapy to prevent progressive HF from chronic obstruction.
Avoidance of dehydration, vasodilators, and inotropes in obstructive physiology.
AF screening with periodic ambulatory monitoring.
Blood-pressure and weight control to limit remodelling.

Risk stratification

HCM Risk-SCD (ESC) and the 2024 AHA/ACC marker-based approach (see §11), with CMR-LGE as the arbitrator for intermediate-risk patients.

Counselling

Formal genetic counselling before and after testing (guideline Class I).
Reproductive counselling covering AD 50% transmission risk, and — crucially for CMH4 — the recessive biallelic risk when both partners carry truncating MYBPC3 variants, which is a real scenario in founder populations and consanguineous families. This is the single most consequential CMH4-specific counselling point.
Counselling must convey incomplete, age- and sex-dependent penetrance: a positive predictive test does not mean certain disease (population penetrance 11–18%; family-based ~55%).

Public health / environmental

Community AED placement and CPR training in schools and sports venues.
Founder-population health education (Amish, Dutch, South Asian diaspora).
No environmental intervention applies.

14. Other Species / Natural Disease

Taxonomy and natural disease

Domestic cat — Felis catus, NCBITaxon:9685 is the outstanding natural model. Feline HCM is the most common feline heart disease and is genuinely MYBPC3-driven, making it a true comparative-pathology counterpart rather than an induced model.

OMIA entry	Phenotype
OMIA:000515-9685	Cardiomyopathy, hypertrophic, in Felis catus
OMIA:002951-9685	Cardiomyopathy, hypertrophic, MYBPC3-related, autosomal dominant
OMIA:002952-9685	Cardiomyopathy, hypertrophic, MYBPC3-related, autosomal recessive

Breeds (VBO-relevant): - Maine Coon — MYBPC3 p.A31P (c.91G>C, exon 3; Ala→Pro, predicted conformational change). Restricted to Maine Coons. - Ragdoll — MYBPC3 p.R820W (C>T; Arg→Trp). Restricted to Ragdolls. - A third variant, A74T, is a widely distributed polymorphism of uncertain significance.

Genotype–phenotype in cats (directly parallel to the human allelic-dose relationship):

"HCM was most prevalent in Maine Coon homozygotes for the A31P mutation and the penetrance increased with age. The penetrance of the heterozygote genotype was lower (0.08) compared to the P/P genotype (0.58) in Maine Coon."

Transmission is autosomal dominant with incomplete penetrance — "the mutation does not appear to behave as a simple dominant trait, but rather as a dominant trait with incomplete penetrance." Age-dependent penetrance and homozygote-severity gradient are exactly the human pattern.

Sources: Longeri et al., J Vet Intern Med 2013; OMIA:002951; OMIA:002952; Maine Coon p.A31P clinical significance, PMC3044103; Feline HCM advances 2025, PMC11946439.

Veterinary importance: Feline HCM causes congestive heart failure, aortic thromboembolism ("saddle thrombus") — a feline-specific complication with no direct human counterpart in HCM — and sudden death. Genotype testing (UC Davis VGL, LabGenVet) is used in breeding programmes to reduce allele frequency. This is a live example of population-level allele management.

Orthologous genes

Species	NCBITaxon	Gene	NCBI Gene ID
Human	9606	MYBPC3	4607
Mouse	10090	Mybpc3	17868
Rat	10116	Mybpc3	116717
Cat	9685	MYBPC3	100135684
Zebrafish	7955	mybpc3	559147

Comparative biology

Conservation: the C0–C10 domain architecture, the cardiac-specific C0 domain and PKA-phosphorylatable M-domain, and the C-zone A-band localisation are conserved across mammals. The thick-filament SRX regulatory mechanism is deeply conserved.
Comparative pathology: cat and human share asymmetric septal hypertrophy, myocyte disarray, interstitial fibrosis, LVOT obstruction with SAM, diastolic dysfunction, atrial enlargement/thrombosis, arrhythmia, and sudden death. Differences: cats develop aortic thromboembolism far more readily; feline HCM is more often diagnosed by auscultation of a dynamic murmur; the human LVNC/septal-defect biallelic phenotype has no clear feline analogue.
Mouse divergence: heterozygous Mybpc3 mice are largely phenotype-negative without a second hit, unlike humans — a genuine HUMAN_MODEL_MISMATCH for the dismech schema.

Transmission

Not zoonotic. No cross-species transmission. CMH4 is a germline Mendelian disorder; the feline disease is an independent, convergent MYBPC3 disorder, not transmitted between species.

15. Model Organisms

15.1 Mouse (Mus musculus, NCBITaxon:10090) — the primary in vivo model

Model	Type	Phenotype	Notes / source
Mybpc3^InsG/InsG (homozygous knock-in of the Dutch c.2373insG)	Knock-in, homozygous	"cardiac and cellular hypertrophy, and severe contractile dysfunction"; cardiac hypertrophy with severe LV systolic and diastolic dysfunction; contractile dysfunction already present at 3–4 weeks	The canonical Carrier-lab model; J Mol Cell Cardiol 2023
Mybpc3^+/InsG (heterozygous)	Knock-in, heterozygous	No cardiac phenotype at 18–28 weeks vs WT — recapitulates human non-penetrance	Same
Mybpc3^c.772G>A heterozygous + Western diet	Knock-in + dietary challenge	Western diet triggered cardiac dysfunction and hypertrophy in otherwise phenotype-negative hets — two-hit model	PMC11708371
Mybpc3 knockout (cMyBP-C null)	Constitutive KO	Cardiac hypertrophy; structural mitral valve abnormalities; disrupted myosin SRX	PMC4725593; SRX: PMID:27021517
Mybpc3 promoter-deletion heterozygote	Regulatory KO	"developed a late-onset phenotype of asymmetrical septal hypertrophy associated with fibrosis" — the best mouse recapitulation of adult human CMH4	PMID:38258577
Symptomatic MYBPC3-deficient murine model (TN-201 studies)	Gene-therapy testbed	AAV9-MYBPC3 "reverse[d] cardiac hypertrophy and systolic dysfunction, improve[d] diastolic dysfunction, and prolong[ed] survival"	PMID:40038304

15.2 Human iPSC and engineered tissue — the leading in vitro system

CRISPR-Cas9 isogenic MYBPC3 allelic series in human iPSCs (WT / cMyBP-C^+/- / cMyBP-C^-/-), differentiated to cardiomyocytes and assembled into cardiac micropatterns and engineered cardiac tissues (ECTs) — PMID:36893011. This is the highest-fidelity human system currently available and reproduces the allelic-dose severity gradient, the haploinsufficiency-in-3D phenomenon ("While heterozygous frame shifts did not alter cMyBP-C protein levels in 2-D cardiomyocytes, cMyBP-C+/- ECTs were haploinsufficient" — exact quote), and the hypercontractile→hypocontractile trajectory.
Patient-derived iPSC lines from Dutch founder-variant families with variable HCM severity — enables isogenic-vs-background comparison of modifiers (Stem Cell Res 2025).
Neonatal rat ventricular cardiomyocytes with adenoviral WT vs mutant cMyBP-C — the classic sarcomere-disorganisation readout (PMID:19151713).
Human myectomy / explant tissue — the gold standard for demonstrating haploinsufficiency, allelic imbalance, and absent truncated protein (PMID:19574547; PMID:22057632; PMID:37797718; PMID:30456444).
Cardiac fibroblast cultures — for the fibroblast-autonomous fibrosis arm (PMID:36357371).

15.3 Other systems

Zebrafish (Danio rerio, NCBITaxon:7955) — mybpc3 morphant/mutant work exists for cardiac development; less used for HCM modelling than mouse or iPSC.
Drosophila — a Human Disease Model report for CMH4 exists (FlyBase FBhh0000414), but Drosophila lacks a true cMyBP-C ortholog with cardiac-specific C0/M-domain regulation; utility is limited to generic sarcomere biology.
C. elegans, yeast — not applicable.

15.4 Phenotype recapitulation and limitations

Recapitulated well: - Allelic-dose severity gradient (het mild/absent → homozygous severe) — mouse, iPSC-ECT, cat - Haploinsufficiency without poison peptide — human tissue, mouse, iPSC-ECT - Late-onset asymmetric septal hypertrophy with fibrosis — promoter-deletion mouse - Contractile hypercontractility → hypocontractility trajectory — iPSC-ECT - Ca²⁺-handling deterioration — iPSC-ECT - SRX disruption — mouse KO, human tissue - Rescue by MYBPC3 restoration — mouse gene therapy

Not recapitulated (HUMAN_MODEL_MISMATCH candidates for the dismech entry): 1. Heterozygous mice are phenotype-negative without a second hit, whereas ~55% of human heterozygotes develop HCM in family-based studies. The mouse underestimates dominant penetrance. (Conversely, this is arguably a faithful model of the 11–18% population penetrance — the mismatch is really about which human population is the referent, which is itself a curatable question.) 2. Myocyte disarray — the human histopathological hallmark — is poorly reproduced in mice. 3. Dynamic LVOT obstruction with SAM, the dominant clinical problem, does not occur in mice (small, differently shaped LV; different mitral apparatus). 4. Atrial fibrillation and thromboembolic stroke are not modelled in mice. 5. Sudden cardiac death from VT/VF in a structurally HCM heart is not reliably reproduced. 6. iPSC-CMs are immature — fetal-like sarcomeres, negative force-frequency relationship, low mitochondrial density. Time-in-culture (2 wk vs 6 wk in PMID:36893011) is itself a variable, which is why that study's progressive phenotype is interpretable but not directly age-mappable to human decades. 7. The biallelic neonatal LVNC + septal-defect phenotype — septal defects have not been convincingly modelled. 8. Species differences in cMyBP-C phosphorylation stoichiometry and in the alpha/beta myosin heavy-chain ratio (mouse ventricle is α-MHC-dominant, human is β-MHC-dominant) limit direct translation of contractile measurements.

15.5 Research applications

Mechanism of haploinsufficiency and NMD; SRX/thick-filament regulation; Ca²⁺-handling; energetics; fibrosis; preclinical gene-therapy dose-finding and efficacy (the direct enabler of TN-201, PMID:40038304); myosin-inhibitor pharmacology; G×E (diet, exercise, hypertension) second-hit modelling.

15.6 Model resources

MGI (mouse; Mybpc3 MGI:1338871), IMPC, IMSR, JAX, MMRRC, EMMA (mouse strains); RGD (rat); ZFIN (zebrafish); Cellosaurus/hPSCreg (iPSC lines); OMIA (feline natural disease); Alliance of Genome Resources (cross-species integration).

Appendix A — Consolidated Ontology Term Suggestions

Disease: MONDO:0007268 hypertrophic cardiomyopathy 4 (parent MONDO:0005045)

Gene: hgnc:7551 MYBPC3 (lowercase prefix per dismech convention)

HPO (all verified against sqlite:obo:hp): HP:0001639 Hypertrophic cardiomyopathy · HP:0001712 Left ventricular hypertrophy · HP:0001670 Asymmetric septal hypertrophy · HP:0002094 Dyspnea · HP:0001681 Angina pectoris · HP:0001962 Palpitations · HP:0001279 Syncope · HP:0001635 Congestive heart failure · HP:0005110 Atrial fibrillation · HP:0004308 Ventricular arrhythmia · HP:0001695 Cardiac arrest · HP:0001645 Sudden cardiac death · HP:0011675 Arrhythmia (Additional terms to verify before use: HP:0031573, HP:0025168, HP:0011664, HP:0001631, HP:0001629, HP:0001643, HP:0001508, HP:0011968, HP:0001653, HP:0003115, HP:0031185, HP:0003829, HP:0000006, HP:0000007)

GO BP (verified): GO:0006936 muscle contraction · GO:0060048 cardiac muscle contraction · GO:0030049 muscle filament sliding · GO:0000381 regulation of alternative mRNA splicing, via spliceosome · GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process · GO:0006402 mRNA catabolic process · GO:0032781 positive regulation of ATP-dependent activity (To verify: GO:0000184 NMD, GO:0003300 cardiac muscle hypertrophy, GO:0045214 sarcomere organization, GO:0031430 M band, GO:0030017 sarcomere, GO:0030018 Z disc)

CL (verified): CL:0000746 cardiac muscle cell · CL:0002548 fibroblast of cardiac tissue · CL:0000057 fibroblast

UBERON (verified): UBERON:0000948 heart · UBERON:0002084 heart left ventricle · UBERON:0002094 interventricular septum · UBERON:0002349 myocardium · UBERON:0002078 right cardiac atrium

CHEBI (verified): CHEBI:6904 metoprolol · CHEBI:9948 verapamil · CHEBI:4657 disopyramide (Mavacamten and aficamten are absent from the local CHEBI adapter — use NCIT.)

NCIT (verified): NCIT:C174901 Mavacamten · NCIT:C179072 Aficamten · NCIT:C80435 Implantable Cardioverter-Defibrillator Placement · NCIT:C93238 Implantable Cardioverter-Defibrillator · NCIT:C15246 Heart Transplantation (To verify: NCIT:C15986 Pharmacotherapy, NCIT:C15238 Gene Therapy, NCIT:C15329 Surgical Procedure, NCIT:C15240 Genetic Counseling, NCIT:C15315 Rehabilitation, NCIT:C49236 Therapeutic Procedure)

Candidate dismech conforms_to module targets: - cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling — the structural/contractile cardiomyopathy final common pathway - fibrotic_response#Mesenchymal Cell Activation — the cardiac-fibroblast arm (PMID:36357371) - thrombogenesis#Coagulation Cascade Activation and Thrombin-Driven Fibrin Formation — the AF→cardioembolic-stroke arm (indirect; consider whether it belongs on this entry or on a comorbidity entry) - Note: cardiac_ion_channel_repolarization is not appropriate — CMH4 is a structural/contractile cardiomyopathy in a structurally abnormal heart, not an inherited channelopathy in a structurally normal heart. The arrhythmic substrate here is disarray + fibrosis + ischemia, not a repolarization defect. - antisense_oligonucleotide_therapy is not applicable (see §12.2).

Appendix B — Evidence Register

Verified locally (abstract/full text present in `references_cache/`; snippets above are exact substrings)

PMID	Citation	Evidence source
19151713	Dhandapany PS et al. A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia. Nat Genet 2009;41(2):187-91. doi:10.1038/ng.309	HUMAN_CLINICAL (+ IN_VITRO for the cardiomyocyte arm)
20301725	Cirino AL, Channaoui N, Ho C. Nonsyndromic Hypertrophic Cardiomyopathy Overview. GeneReviews, 2008 Aug 5 [updated 2025 Mar 6]	HUMAN_CLINICAL (review)
22057632	Marston S et al. How do MYBPC3 mutations cause hypertrophic cardiomyopathy? J Muscle Res Cell Motil 2012;33(1):75-80	HUMAN_CLINICAL (review of human tissue data)
22267749	Page SP et al. Cardiac myosin binding protein-C mutations in families with hypertrophic cardiomyopathy: disease expression in relation to age, gender, and long term outcome. Circ Cardiovasc Genet 2012;5(2):156-66	HUMAN_CLINICAL
25335496	Wessels MW et al. Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects. Eur J Hum Genet 2015;23(7):922-8	HUMAN_CLINICAL
32871100	Olivotto I et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM). Lancet 2020;396(10253):759-769	HUMAN_CLINICAL (RCT)
36893011	De Lange WJ et al. cMyBP-C ablation in human engineered cardiac tissue causes progressive Ca2+-handling abnormalities. J Gen Physiol 2023;155(4):e202213204	IN_VITRO
37797718	Burkart V et al. Nonsense mediated decay factor UPF3B is associated with cMyBP-C haploinsufficiency in hypertrophic cardiomyopathy patients. J Mol Cell Cardiol 2023;185:26-37	HUMAN_CLINICAL (patient myocardium)
38406555	Ananthamohan K, Stelzer JE, Sadayappan S. Hypertrophic cardiomyopathy in MYBPC3 carriers in aging. J Cardiovasc Aging 2024;4:9	HUMAN_CLINICAL (review)
39581692	Melendo-Viu M et al. Hypertrophic cardiomyopathy due to truncating variants in myosin binding protein C: a Spanish cohort. Open Heart 2024;11(2):e002891	HUMAN_CLINICAL
40038304	Greer-Short A et al. AAV9-mediated MYBPC3 gene therapy with optimized expression cassette enhances cardiac function and survival in MYBPC3 cardiomyopathy models. Nat Commun 2025;16(1):2196	MODEL_ORGANISM
41488457	Wang J et al. Case Report: Lethal neonatal hypertrophic cardiomyopathy from compound heterozygous MYBPC3 variants. Front Cardiovasc Med 2025;12:1726463	HUMAN_CLINICAL
CGGV assertions (4)	ClinGen MYBPC3 gene-disease validity: HCM Definitive AD (2021-10-07); ARVC Limited (2019-08-06); DCM Limited AD and AR (2025-05-16)	OTHER

Identified and bibliographically verified via NCBI eutils; abstracts NOT locally cached — fetch with `just fetch-reference PMID:xxxxx` and re-verify any snippet before committing to the KB

PMID	Citation
18467358	Homozygous mutation of MYBPC3 associated with severe infantile hypertrophic cardiomyopathy at high frequency among the Amish. Heart 2008
19574547	Marston S et al. Evidence from human myectomy samples that MYBPC3 mutations cause hypertrophic cardiomyopathy through haploinsufficiency. Circ Res 2009
27021517	McNamara JW et al. Ablation of cardiac myosin binding protein-C disrupts the super-relaxed state of myosin in murine cardiomyocytes. J Mol Cell Cardiol 2016
28658286	McNamara JW et al. MYBPC3 mutations are associated with a reduced super-relaxed state in patients with hypertrophic cardiomyopathy. PLoS One 2017
28771489	Mademont-Soler I et al. Additional value of screening for minor genes and copy number variants in hypertrophic cardiomyopathy. PLoS One 2017
30456444	Allelic imbalance and haploinsufficiency in MYBPC3-linked hypertrophic cardiomyopathy. Pflügers Arch 2019
30674652	Toepfer CN et al. Hypertrophic cardiomyopathy mutations in MYBPC3 dysregulate myosin. Sci Transl Med 2019
31877118	Helms AS et al. Effects of MYBPC3 loss-of-function mutations preceding hypertrophic cardiomyopathy. JCI Insight 2020
32841044	Helms AS et al. Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients With Hypertrophic Cardiomyopathy. Circ Genom Precis Med 2020
33532905	BIO FOr CARe: biomarkers of hypertrophic cardiomyopathy development and progression in carriers of Dutch founder truncating MYBPC3 variants. Neth Heart J 2021
36162733	The «Amish» NM_000256.3:c.3330+2T>G splice variant in MYBPC3 associated with hypertrophic cardiomyopathy is an ancient Swiss mutation. Eur J Med Genet 2022
36357371	Zou X et al. MYBPC3 deficiency in cardiac fibroblasts drives their activation and contributes to fibrosis. Cell Death Dis 2022
36946992	Barefield DY. Is haploinsufficiency a sufficient mechanism for MYBPC3 truncating mutations? J Gen Physiol 2023
37929589	Topriceanu C et al. Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy. Circulation 2024;149:107-123
38258577	Hayesmoore JBG et al. A Promoter Deletion Confirms That MYBPC3 Haploinsufficiency Is Sufficient to Cause Hypertrophic Cardiomyopathy in Humans. Circ Genom Precis Med 2024
38718139	Ommen SR, Ho CY et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy. Circulation 2024
38739079	Maron MS et al. Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy. N Engl J Med 2024;390(20):1849-1861
39886308	Longitudinal Evaluation of Genetic Hypertrophic Cardiomyopathy Penetrance and Transition to Disease in an Academic Biobank. JACC Adv 2025
41020222	Desai MY et al. High rate of seroeligibility among MYBPC3-associated hypertrophic cardiomyopathy patients for TN-201. Front Med 2025;12:1635586
41134850	Zhang Y et al. A novel variant in MYBPC3 causes hypertrophic cardiomyopathy by haploinsufficiency. PLoS One 2025
41206746	Desai MY et al. First-in-human study of TN-201, an AAV9 gene replacement therapy in MYBPC3-associated hypertrophic cardiomyopathy. Cardiovasc Res 2025;121(17):2628-2631

Non-PMID / structured and grey sources

OMIM 115197, OMIM *600958 · ClinGen HCM GCEP reappraisal (PMC11312670) · ClinVar RCV000009149, RCV000009152 · Orphanet ORPHA:155, ORPHA:217569 · OMIA:000515-9685, OMIA:002951-9685, OMIA:002952-9685 · ClinicalTrials.gov NCT05836259, NCT03470545, NCT05186818, NCT05767346, NCT04349072, NCT01912534 · Tenaya Therapeutics investor releases (AHA 2025 interim data; 7 Nov 2025 FDA clinical hold) · Cytokinetics investor releases (Myqorzo/aficamten FDA approval 19 Dec 2025).

Appendix C — Notable Gaps and Open Questions (candidate dismech `discussions`)

Kind	Question
`KNOWLEDGE_GAP`	Is haploinsufficiency sufficient for all MYBPC3 truncating alleles, or do some contribute a parallel dominant-negative/proteotoxic effect? (PMID:36946992 vs PMID:22057632/38258577)
`KNOWLEDGE_GAP`	Why is penetrance 11–18% in population biobanks but ~55% in clinical families? How much is ascertainment vs genuine modifier burden vs environment? (PMID:37929589)
`KNOWLEDGE_GAP`	No therapy prevents phenotype conversion in G+/LVH− carriers. What is the intervention window and the right endpoint?
`HUMAN_MODEL_MISMATCH`	Heterozygous Mybpc3 mice are phenotype-negative without a second hit; human heterozygotes reach ~55% penetrance in families. Which human referent population does the mouse actually model?
`HUMAN_MODEL_MISMATCH`	Myocyte disarray, the human histopathological hallmark, is poorly reproduced in mouse models.
`HUMAN_MODEL_MISMATCH`	Dynamic LVOT obstruction with SAM — the dominant clinical problem and the target of both approved drugs — cannot be modelled in mice; drug efficacy claims for that mechanism rest entirely on human trial data.
`KNOWLEDGE_GAP`	Does the Western-diet two-hit effect (mouse, PMC11708371) operate in human MYBPC3 carriers? No human interventional or prospective dietary data exist.
`KNOWLEDGE_GAP`	Reason for the FDA clinical hold on MyPEAK-1 (7 Nov 2025) and its implications for AAV9 cardiac gene therapy dosing — not yet in the peer-reviewed literature.

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Classifications

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Variants

Medical Actions

Biochemical Markers

Diagnosis

Progression

Prevalence

Differential Diagnoses

Clinical Trials

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

Overview

Key Identifiers

Synonyms

Data provenance character

2. Etiology

2.1 Primary causal factor

2.2 Genetic risk factors and modifiers

2.3 Environmental / acquired risk factors

2.4 Protective factors

2.5 Gene–environment interactions

3. Phenotypes

3.1 Core cardiac structural phenotypes

3.2 Symptoms and functional phenotypes

3.3 Arrhythmic / electrophysiological phenotypes

3.4 Laboratory / biomarker abnormalities

3.5 Phenotype characteristics

4. Genetic / Molecular Information

4.1 Causal gene

4.2 Pathogenic variant spectrum

4.3 Modifier genes

4.4 Epigenetics

4.5 Chromosomal abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 The causal chain (upstream → downstream)

6.2 Key mechanistic evidence (verbatim quotes)

6.3 Ontology term suggestions for pathophysiology nodes

6.4 Molecular profiling

7. Anatomical Structures Affected

Organ level

Tissue and cell level

Subcellular level

Localisation

8. Temporal Development

Onset

Progression and staging

Patterns

9. Inheritance and Population

Epidemiology

Inheritance

Founder alleles / geographic distribution of specific variants

Demographics

10. Diagnostics

Clinical tests

Genetic testing

Omics-based diagnostics

Clinical criteria and differential diagnosis

Screening

11. Outcome / Prognosis

Survival and mortality

Morbidity, disability, and quality of life

Complications

Prognostic factors and risk stratification

12. Treatment

Verified locally (abstract/full text present in `references_cache/`; snippets above are exact substrings)

Identified and bibliographically verified via NCBI eutils; abstracts NOT locally cached — fetch with `just fetch-reference PMID:xxxxx` and re-verify any snippet before committing to the KB

Appendix C — Notable Gaps and Open Questions (candidate dismech `discussions`)