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Classifications

Harrison's Part

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Inheritance

1

Autosomal dominant HP:0000006

CMH1 is inherited as an autosomal dominant trait, with a single mutant MYH7 allele producing disease. Penetrance is incomplete and age-related, and a family history of hypertrophic cardiomyopathy and of sudden cardiac death is characteristic of sarcomere-variant-positive disease, so cascade screening of relatives must be longitudinal rather than a single evaluation.

Autosomal dominant inheritance Penetrance: INCOMPLETE

Show evidence (2 references)

CGGV:assertion_31325c90-05cb-4db0-9372-e4f705cd5c82-2023-07-12T160000.000Z SUPPORT Other

ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel classifies the MYH7-hypertrophic cardiomyopathy relationship as Definitive with autosomal dominant inheritance.

PMID:23674365 SUPPORT Human Clinical

"The presence of any sarcomere gene mutation was associated with a younger age at presentation (38.4 vs 46.0 years, p<0.0005), a family history of HCM (50.6% vs 23.1%, p<0.0005), a family history of SCD (27.0% vs 14.9%, p<0.0005) and greater MLVWT (21.0 vs 19.3 mm, p=0.03)."

Meta-analysis of 2459 patients documenting the familial, dominantly inherited pattern of sarcomere-positive HCM, with a positive family history of both HCM and sudden cardiac death and younger onset than sarcomere-negative disease.

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Discussions and Knowledge Gaps

3

Which MYH7 alleles actually act by destabilizing the super-relaxed state, and what mechanism accounts for the rest?

KNOWLEDGE GAP OPEN cmh1-srx-allele-heterogeneity

Attached to

pathophysiology#Destabilization of the Autoinhibited Super-Relaxed State

This entry curates the SRX-destabilization arm as the mechanism of a large subset of MYH7 alleles rather than all of them, because not every cardiomyopathy myosin mutation shifts the SRX-DRX equilibrium. Two of the alleles with the best multiscale data illustrate the spread: G256E reduces the folded-back fraction by 33% through the transducer region, while R403Q has produced context-dependent and sometimes opposing measurements across assays. Without an allele-level map, a clinician cannot reason from a specific variant to the mechanism, and the SRX arm cannot be used to predict who will respond to a myosin inhibitor.

Do the clinical results curated in this entry hold specifically for MYH7 carriers, or only for hypertrophic cardiomyopathy as a whole?

KNOWLEDGE GAP OPEN cmh1-myh7-specific-clinical-evidence

Attached to

treatments# prevalence#

Every clinical trial and outcome cohort cited in this entry enrolled hypertrophic cardiomyopathy broadly, not genotyped MYH7 carriers. That applies to both myosin inhibitors, to disopyramide, to beta-blockade and verapamil, to myectomy and alcohol septal ablation, to the ICD registry, to the anticoagulation review and to the LGE meta-analysis, and it is why no population prevalence exists for this entity. The gap is structural rather than incidental — genotype has not been a stratifying variable in HCM trial design — so it will not close through ordinary literature accumulation. Recorded so that a reader does not mistake the volume of clinical evidence here for evidence about MYH7.

Does a 403 substitution in mouse alpha-cardiac myosin model a human MYH7 beta-myosin disease?

HUMAN MODEL MISMATCH OPEN cmh1-mouse-isoform-mismatch

Attached to

animal_models#alpha-MHC 403/+ knock-in mouse

The founding animal model of this disease carries R403Q in Myh6, not Myh7, because the adult mouse ventricle expresses alpha- rather than beta-myosin. Evidence therefore exists in the model but its translational validity is the open question, which is what distinguishes this from an ordinary knowledge gap. The pig study makes the mismatch explicit, stating that orthologous beta-MyHC mutations in mice do not produce the phenotype found in patients — and that is the stated reason large-animal models were built. Any claim in this entry that rests on mouse data inherits this caveat.

Show evidence (1 reference)

PMID:29555974 SUPPORT Model Organism

"Mice express the fast alpha-myosin in the heart, and orthologous ß-MyHC mutations do not lead to the phenotype typically found in HCM patients"

States the isoform mismatch directly and asserts its translational consequence, which is what makes this a model-fidelity question rather than a general species caveat.

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Pathophysiology

8

MYH7 Missense Variant in Beta-Cardiac Myosin Heavy Chain

The initiating lesion in CMH1 is a heterozygous missense variant in MYH7, the gene encoding the beta-cardiac myosin heavy chain — the ATP-hydrolysing motor of the sarcomeric thick filament. The founding example, and still the archetype, is Arg403Gln (R403Q), the first mutation ever linked to familial hypertrophic cardiomyopathy; R403Q sits in the globular myosin head (S1), the region responsible for actin interaction and motor function. In contrast to the truncating, haploinsufficiency mechanism of MYBPC3 disease, most MYH7 alleles are missense changes that are stably expressed and incorporated into the sarcomere as a mutant motor, so the mutant protein perturbs contraction directly rather than by its absence.

Cardiomyocyte CL:0000746

MYH7 hgnc:7577

Sarcomere Organization GO:0045214 ⚠ ABNORMAL

Myosin thick filament GO:0032982

Downstream

Destabilization of the Autoinhibited Super-Relaxed State The mutant motor, incorporated into the thick filament, destabilizes the folded-back autoinhibited state that normally sequesters myosin heads.

Show evidence (2 references)

PMID:1975517 SUPPORT Human Clinical

"A point mutation in exon 13 of the beta cardiac myosin heavy chain (MHC) gene is present in all individuals affected with familial hypertrophic cardiomyopathy (FHC) from a large kindred. This missense mutation converts a highly conserved arginine residue (Arg-403) to a glutamine."

The founding CMH1 report: co-segregation of the MYH7 R403Q missense variant with familial hypertrophic cardiomyopathy in a large kindred, establishing the beta-cardiac myosin heavy chain gene as a cause of the disease.

PMID:23798412 SUPPORT In Vitro

"HCM is caused by mutations in the genes encoding the fundamental force-generating machinery of the cardiac muscle, including β-cardiac myosin."

Places the MYH7 lesion in the force-generating machinery of the sarcomere, the trigger for this entity.

Destabilization of the Autoinhibited Super-Relaxed State

In the resting sarcomere a large fraction of myosin heads occupy the super-relaxed (SRX) state — folded back against the thick-filament backbone in the interacting-heads motif (IHM), with very low ATPase activity, forming an energy-conserving reserve of motors withheld from force generation. Many MYH7 HCM mutations map to the interfaces that stabilize this folded-back state (the myosin mesa, the head-head and head-tail contacts), and they weaken those intramolecular interactions. The result is release of sequestered heads from the SRX/IHM into the disordered-relaxed state, so more heads become functionally accessible to actin — the molecular origin of hypercontractility shared across a large subset of MYH7 alleles.

Cardiomyocyte CL:0000746

ATP Hydrolysis by Myosin GO:0016887 ↑ INCREASED

Myosin thick filament GO:0032982

Experimental models

MYH7 G256E gene-edited hiPSC-cardiomyocyte multiscale platform IPSC DERIVED MODEL Quantifies the folded-back myosin fraction directly for a named MYH7 allele, giving the node a measured effect size rather than a class claim.

Downstream

Increased Motor Force and Energetic Cost Heads released from the super-relaxed reserve, together with allele-specific changes in the motor stroke, raise ensemble force and the ATP cost of contraction.

Show evidence (5 references)

PMID:31213605 SUPPORT In Vitro

"folded-back sequestered state referred to as the interacting heads motif (IHM) lead to a significant increase in the number of heads functionally accessible for interaction with actin."

Direct biochemical evidence that MYH7 HCM mutations at IHM interfaces release sequestered heads, increasing the number available to interact with actin.

PMID:38683993 SUPPORT In Vitro

"The G256E mutation disrupts the transducer region of the S1 head and reduces the fraction of myosin in the folded-back state by 33%, resulting in more myosin heads available for contraction."

Quantifies the size of the SRX shift for a named MYH7 allele, and shows the destabilizing lesion need not sit on an IHM contact surface itself — G256E acts through the transducer region of the motor domain.

PMID:28481356 SUPPORT In Vitro

"hypercontractility is due to an increase in the number of myosin heads (S1) that are accessible for force production."

States the core hypothesis this node captures: HCM hypercontractility arises from an increase in the number of force-producing heads freed from the sequestered state.

+ 2 more references

Increased Motor Force and Energetic Cost

Beyond releasing sequestered heads, individual MYH7 missense alleles alter the mechanochemistry of the motor stroke itself. Single-molecule and myofibril studies show mutation-specific changes — increased intrinsic force per cross-bridge, and faster cross-bridge detachment kinetics — that together raise the force generated by the ensemble of motors and increase the ATP consumed per unit tension (tension cost). The energetic penalty, measured directly in human myocardium carrying R403Q, is a distinctive feature of the beta-myosin motor lesion and links the molecular defect to the myocardial energy deficit seen in HCM.

Cardiomyocyte CL:0000746

Actin-Myosin Filament Sliding GO:0033275 ⚠ ABNORMAL

ATP Hydrolysis by Myosin GO:0016887 ↑ INCREASED

Animal models

beta-MyHC-Q403 transgenic rabbit Rabbit partially recapitulates Calcium sensitivity of myofibrillar ATPase activity was altered as the earliest detectable phenotype, before any histological or structural change.

Downstream

Sarcomere Hypercontractility with Impaired Relaxation Raised ensemble force and disturbed cross-bridge kinetics translate into cellular hypercontractility with impaired diastolic relaxation.

Show evidence (3 references)

PMID:23798412 SUPPORT In Vitro

"The major change in the R453C human β-cardiac subfragment 1 is a 50% increase in the intrinsic force of the motor compared with wild type, with no appreciable change in the stroke size, as observed with a dual-beam optical trap."

Single-molecule optical-trap measurement of a raised intrinsic force for an MYH7 mutant motor, predicting a hypercontractile ensemble.

PMID:23798412 SUPPORT In Vitro

"Overall, this study suggests that the R453C mutation should result in a hypercontractile state in the heart muscle."

States the functional conclusion — a hypercontractile state — that the motor-level force change produces.

PMID:24928957 SUPPORT Human Clinical

"This correlation suggests that faster cross-bridge relaxation kinetics results in an increase in energetic cost of tension generation in human HCM with the R403Q mutation compared to HCMsmn."

Direct measurement in human R403Q myocardium (single myofibrils and muscle strips) linking faster cross-bridge kinetics to an increased energetic cost of tension generation, evidence obtained in patient cardiac tissue.

Sarcomere Hypercontractility with Impaired Relaxation

At the cell level the molecular changes converge on hypercontractility: CRISPR-edited human iPSC-derived cardiomyocytes carrying an MYH7 HCM mutation generate significantly greater contractile force than isogenic controls. Because the same lesion disturbs cross-bridge relaxation kinetics, systolic hypercontraction is accompanied by impaired diastolic relaxation. This hypercontractile, poorly relaxing cell state — a key pathophysiological abnormality of HCM and the determinant of dynamic outflow obstruction — is the cellular phenotype the cardiac myosin inhibitors were designed to normalize.

Ventricular cardiomyocyte CL:0002131

Cardiac Muscle Cell Contraction GO:0086003 ↑ INCREASED Regulation of Cardiac Muscle Contraction GO:0055117 ⚠ ABNORMAL

Experimental models

MYH7 G256E gene-edited hiPSC-cardiomyocyte multiscale platform IPSC DERIVED MODEL Greater and faster tension development was reproduced in myofibrils, in single cells and in engineered heart tissue from the same edited line.

MYH7 R403Q and TNNT2 R92Q hiPSC-cardiomyocyte engineered heart tissue IPSC DERIVED MODEL Reproduces the impaired-relaxation and increased-force halves of the node in a human system carrying the archetypal CMH1 allele.

Downstream

Cell-to-Cell Contractile Imbalance Because mutant and wild-type MYH7 alleles are transcribed in variable proportions between neighboring myocytes, hypercontractility is unevenly distributed across the myocardium.

Cardiomyocyte-to-Fibroblast EGFR Paracrine Signaling The mutant cardiomyocyte does not remodel the interstitium by mechanical load alone: it secretes soluble factors that act on the neighbouring fibroblast population. What couples the contractile state to that secretion is not established. The source proposes a broader stress response, with mechanical signalling from the intrinsic hypercontractility as one candidate, and states that further work is needed to identify the ligands and receptors involved — so the edge is curated with unknown intermediates rather than as a direct link.

Ventricular Hypertrophy, Myocyte Disarray and Fibrosis Sustained hypercontractility with raised energetic cost drives the structural remodeling of the ventricle.

Show evidence (2 references)

PMID:34117120 SUPPORT In Vitro

"produced significantly increased force (measured by traction force microscopy) compared with isogenic control cells."

Isogenic human iPSC-cardiomyocyte evidence that an MYH7 HCM mutation increases cellular contractile force.

PMID:32871100 SUPPORT INDIRECT 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 of HCM and links it to outflow obstruction. Directness is INDIRECT because the trial enrolled obstructive HCM broadly rather than genotyped MYH7 carriers, so the claim about this entity follows by an inference step.

Cardiomyocyte-to-Fibroblast EGFR Paracrine Signaling

Interstitial fibrosis in CMH1 is not solely a passive response to wall stress. In engineered cardiac microtissues built from MYH7 R403Q hiPSC-derived cardiomyocytes co-cultured with wild-type ventricular cardiac fibroblasts, the mutant cardiomyocytes release paracrine factors that drive fibroblast proliferation and collagen deposition. Collagen I content rose 40% over isogenic wild-type microtissues and the tissue stiffened, and the effect depended on fibroblast proliferation rather than on cardiomyocyte matrix output. Epidermal growth factor alone was sufficient to stimulate the stromal cells, and inhibiting EGFR tyrosine kinase with erlotinib attenuated the activation — identifying EGFR signalling as the transducing arm and, in principle, a druggable one. The same microtissue system shows that the tissue-level consequence is hypocontractility even while the individual mutant cardiomyocytes are hypercontractile, which is how a cell-autonomous gain of contractile function ends up producing a stiff, poorly contracting ventricle.

Ventricular cardiac fibroblast CL:2000066 Ventricular cardiomyocyte CL:0002131

EGFR Signaling GO:0007173 ↑ INCREASED Fibroblast Proliferation GO:0048144 ↑ INCREASED Extracellular Matrix Organization GO:0030198 ⚠ ABNORMAL

Experimental models

MYH7 R403Q hiPSC-cardiomyocyte cardiac microtissue with wild-type fibroblasts CO CULTURE The model was built to interrogate this node and demonstrates each of its claims — paracrine transfer, fibroblast proliferation dependence, and EGFR as the transducing receptor.

Downstream

Ventricular Hypertrophy, Myocyte Disarray and Fibrosis Fibroblast activation and excess collagen deposition are the cellular mechanism of the interstitial fibrosis component of the tissue-level remodeling node.

Myocardial Fibrosis The same collagen deposition presenting as the clinically measurable fibrosis burden, imaged as late gadolinium enhancement.

Show evidence (3 references)

PMID:39413182 SUPPORT In Vitro

"Using engineered cardiac microtissues (CMTs) composed of HCM-causing MYH7-variant hiPSC-CMs and wild-type fibroblasts, we observed cell-cell cross-talk leading to increased collagen deposition, tissue stiffening, and decreased contractility dependent on fibroblast proliferation."

Establishes the node: MYH7-variant cardiomyocytes activate neighbouring fibroblasts, and the resulting collagen deposition and stiffening depend on fibroblast proliferation.

PMID:39413182 SUPPORT In Vitro

"Furthermore, inhibiting epidermal growth factor receptor tyrosine kinase with erlotinib hydrochloride attenuated stromal activation."

Identifies EGFR as the transducing receptor by pharmacological loss of function, which is what makes this a named signalling arm rather than an unspecified paracrine effect.

PMID:39413182 SUPPORT In Vitro

"R403Q+/- CMTs exhibited a 40% increase in collagen I content compared to WT CMTs"

Quantifies the matrix effect against an isogenic wild-type control in the archetypal CMH1 allele.

Cell-to-Cell Contractile Imbalance

A mechanism specific to the missense/poison-peptide biology of MYH7 disease. Because the mutant and wild-type MYH7 alleles are transcribed in a random, burst-like fashion and independently of one another, the fraction of mutant beta-myosin varies markedly from cardiomyocyte to cardiomyocyte within a single patient's myocardium. This produces much greater cell-to-cell variability of contractile function than in control hearts. The resulting mechanical mismatch between adjacent, differently loaded myocytes is proposed to drive the myofiber disarray and interstitial fibrosis that are hallmarks of HCM, providing a route from the molecular lesion to the tissue phenotype that does not depend on the average level of hypercontractility alone.

Cardiomyocyte CL:0000746

Cardiac Muscle Cell Contraction GO:0086003 ⚠ ABNORMAL

Downstream

Ventricular Hypertrophy, Myocyte Disarray and Fibrosis Mechanical mismatch between neighboring myocytes promotes disarray and fibrotic remodeling.

Show evidence (2 references)

PMID:30740621 SUPPORT Human Clinical

"substantial contractile variability from cardiomyocyte to cardiomyocyte within a patient's myocardium, much higher than in controls."

Documents the cell-to-cell contractile variability in beta-MyHC-mutant patient myocardium that this node captures.

PMID:30740621 SUPPORT Human Clinical

"contractile imbalance due to unequal fractions of mutated and wildtype protein among individual cardiomyocytes over time will induce cardiomyocyte disarray and fibrosis, hallmarks of HCM."

States the contractile-imbalance hypothesis linking unequal mutant-allele expression to disarray and fibrosis, the hallmarks of HCM.

Ventricular Hypertrophy, Myocyte Disarray and Fibrosis

Chronic hypercontractility with raised energetic cost, amplified by cell-to-cell contractile imbalance, drives the structural remodeling that defines the clinical phenotype: cardiomyocyte hypertrophy — typically asymmetric and septal-predominant — together with myofiber disarray and interstitial and replacement fibrosis. Pro-hypertrophic growth signalling contributes: in an MYH7-mutant human iPSC-cardiomyocyte model, cellular hypertrophy was prevented by inhibition of ERK or Akt, implicating those pathways downstream of the mechanical stimulus. Fibrosis provides the substrate for both diastolic dysfunction and re-entrant 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

Experimental models

MYH7 R403Q hiPSC-cardiomyocyte cardiac microtissue with wild-type fibroblasts CO CULTURE Reproduces the interstitial-fibrosis and stiffening component of the remodeling node.

Animal models

alpha-MHC 403/+ knock-in mouse Mouse partially recapitulates Myocyte disarray, hypertrophy and fibrosis develop and increase with age, reproducing the tissue-level remodeling node.

beta-MyHC-Q403 transgenic rabbit Rabbit recapitulates Disarray, hypertrophy and fibrosis all develop, and the longitudinal design separates them in time: disarray appears early and independently of hypertrophy and fibrosis, which emerge later around puberty.

MYH7 R723G knock-in pig Pig partially recapitulates Neonatal animals showed mild myocyte disarray and malformed nuclei, establishing that the histological lesion can arise before birth from a knock-in MYH7 allele.

Downstream

Diastolic Dysfunction, Outflow Obstruction, Heart Failure and Arrhythmic Risk

Show evidence (3 references)

PMID:28912181 SUPPORT Human Clinical

"The histological features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis."

Names the defining tissue-level triad — myocyte hypertrophy, disarray, and interstitial fibrosis — that this node represents.

PMID:34117120 SUPPORT In Vitro

"Cellular hypertrophy was prevented in the P710R cells by inhibition of ERK or Akt."

Implicates ERK and Akt growth signalling downstream of the MYH7 mechanical lesion in producing the cellular hypertrophy of this node.

PMID:30740621 SUPPORT Human Clinical

"contractile imbalance due to unequal fractions of mutated and wildtype protein among individual cardiomyocytes over time will induce cardiomyocyte disarray and fibrosis, hallmarks of HCM."

Ties the upstream contractile imbalance to the disarray and fibrosis of this tissue node.

Diastolic Dysfunction, Outflow Obstruction, Heart Failure and Arrhythmic Risk

The hypertrophied, disarrayed and fibrotic ventricle produces the clinical endpoints of CMH1. Hypercontractility with septal hypertrophy generates dynamic left ventricular outflow tract obstruction in a subset of patients; the stiff, poorly relaxing ventricle causes diastolic dysfunction; and the fibrotic, electrically heterogeneous substrate carries a risk of malignant ventricular arrhythmia and sudden cardiac death that is clinically important for MYH7 variants. Sarcomere-positive disease, of which MYH7 is a leading cause, presents younger and with a stronger family history of sudden death than sarcomere-negative HCM.

Cardiomyocyte CL:0000746

Heart Contraction GO:0060047 ⚠ ABNORMAL

Downstream

Left Ventricular Diastolic Dysfunction The impaired-relaxation and reduced-compliance component of this node presenting as the measured clinical phenotype.

Left Ventricular Outflow Tract Obstruction The obstruction component of this node presenting as the clinical phenotype targeted by myosin inhibitors and septal reduction.

Congestive Heart Failure Sustained diastolic dysfunction, and in a minority progression to systolic impairment, produce clinical heart failure.

Ventricular Arrhythmia The arrhythmic component of this node presenting clinically. Curated with unknown intermediates because which of hypertrophy, disarray, fibrosis and ischaemia carries the arrhythmic substrate in any given patient is not resolved.

Atrial Fibrillation Raised filling pressures enlarge the left atrium, and left atrial dimension is the intermediate that predicts atrial fibrillation in this disease.

Syncope Syncope may arise from the outflow obstruction, from an arrhythmic event, or from an abnormal vascular response to exertion; which applies in a given episode is usually not determined.

Show evidence (2 references)

PMID:23674365 SUPPORT Human Clinical

"There were no differences when the two most frequently affected genes, MYBPC3 and MYH7, were compared."

Records the important nuance that, at the cohort level, MYH7 and MYBPC3 do not differ significantly across the pooled clinical features, so MYH7 is not simply a uniformly more severe genotype than MYBPC3; it is one of the two commonest sarcomeric causes.

PMID:39681440 SUPPORT Human Clinical

"In the five families with HCM carrying MYH7-R453C mutations, genotype is highly correlated with clinical phenotype, and patients have a high risk of sudden death and poor prognosis."

A family study of a specific MYH7 variant documenting high sudden-death risk and poor prognosis, the arrhythmic endpoint of this node.

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Histopathology

1

Myocyte Hypertrophy, Disarray and Interstitial Fibrosis

The histological triad of hypertrophic cardiomyopathy is cardiomyocyte hypertrophy, myofibre disarray (loss of the normal parallel alignment, with hypertrophied fibres running obliquely and in whorls) and interstitial fibrosis. In MYH7 disease the disarray component is reproduced by the orthologous R723G knock-in pig within 24 hours of birth, which places it very early in the causal sequence rather than as a late consequence of chronic load. Biopsy is not required for diagnosis in routine sarcomeric HCM; this section records the tissue phenotype that the pathophysiology chain converges on.

Show evidence (2 references)

PMID:28912181 SUPPORT INDIRECT Human Clinical

"The histological features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis."

States the histological triad that defines the tissue phenotype of this disease. Directness is INDIRECT because the review describes hypertrophic cardiomyopathy generally rather than genotyped MYH7 disease.

PMID:29555974 SUPPORT Model Organism

"the neonatal pigs displayed features of HCM, including mild myocyte disarray, malformed nuclei, and MYH7-overexpression."

Shows disarray arising in an orthologous MYH7 knock-in large animal within 24 hours of birth, evidencing that the histological lesion is an early consequence of the MYH7 allele rather than only a late remodeling endpoint.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

10

Hypertrophic Cardiomyopathy OBLIGATE Cardiovascular HP:0001639

Show evidence (1 reference)

PMID:28912181 SUPPORT Human Clinical

"Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes and a nondilated left ventricle with preserved or increased ejection fraction."

States the defining clinical feature — unexplained left ventricular hypertrophy with a nondilated ventricle — of the disease this MYH7 form manifests.

Asymmetric Septal Hypertrophy Cardiovascular HP:0001670

Show evidence (1 reference)

PMID:23674365 SUPPORT Human Clinical

"The presence of any sarcomere gene mutation was associated with a younger age at presentation (38.4 vs 46.0 years, p<0.0005), a family history of HCM (50.6% vs 23.1%, p<0.0005), a family history of SCD (27.0% vs 14.9%, p<0.0005) and greater MLVWT (21.0 vs 19.3 mm, p=0.03)."

Sarcomere-positive HCM, of which MYH7 is a leading cause, shows greater maximum left ventricular wall thickness than sarcomere-negative disease, supporting the pronounced hypertrophy of this member.

Left Ventricular Outflow Tract Obstruction Cardiovascular HP:0032092

Show evidence (1 reference)

PMID:32871100 SUPPORT INDIRECT 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 to dynamic LVOT obstruction. Directness is INDIRECT because the trial population is obstructive HCM broadly rather than genotyped MYH7 carriers.

Left Ventricular Diastolic Dysfunction Cardiovascular HP:0025168

Show evidence (1 reference)

PMID:24928957 SUPPORT Human Clinical

"Cross-bridge slow relaxation kinetics in single R403Q myofibrils was significantly higher (P < 0.0001) than in HCMsmn myofibrils"

Documents disturbed cross-bridge relaxation kinetics in human R403Q myocardium, the molecular basis of the impaired relaxation underlying diastolic dysfunction.

Sudden Cardiac Death Cardiovascular HP:0001645

Show evidence (1 reference)

PMID:39681440 SUPPORT Human Clinical

"In the five families with HCM carrying MYH7-R453C mutations, genotype is highly correlated with clinical phenotype, and patients have a high risk of sudden death and poor prognosis."

A family study of an MYH7 variant documenting a high risk of sudden death.

Ventricular Arrhythmia Cardiovascular HP:0004308

Show evidence (1 reference)

PMID:39681440 SUPPORT Human Clinical

"2 experienced (F1Ⅲ1, F3Ⅲ3) events of sudden cardiac death survival"

Aborted sudden cardiac death (survived cardiac arrest) in MYH7-R453C carriers evidences the malignant ventricular arrhythmia of this node.

Congestive Heart Failure Cardiovascular HP:0001635

Show evidence (1 reference)

PMID:39681440 SUPPORT Human Clinical

"2(F1Ⅱ2, F3Ⅱ1) died from heart failure during the follow-up period."

Deaths from heart failure among MYH7-R453C carriers evidence heart failure as a clinical endpoint of the disease.

Atrial Fibrillation Cardiovascular HP:0005110

Show evidence (1 reference)

PMID:28912181 SUPPORT INDIRECT Human Clinical

"Atrial fibrillation is also a common complication and is not well tolerated."

Establishes atrial fibrillation as a common and clinically consequential complication of the disease.

Syncope Cardiovascular HP:0001279

Show evidence (1 reference)

PMID:28912181 SUPPORT INDIRECT Human Clinical

"Nonsustained ventricular tachycardia, syncope, a family history of sudden cardiac death, and severe cardiac hypertrophy are major risk factors for sudden cardiac death."

Names syncope among the major sudden-death risk markers. Directness is INDIRECT on two counts: the source is a broad-HCM review rather than a MYH7 cohort, and the sentence establishes syncope as a risk marker, from which its occurrence as a clinical feature follows by inference rather than being stated.

Myocardial Fibrosis Cardiovascular HP:0001685

Show evidence (2 references)

PMID:28912181 SUPPORT INDIRECT Human Clinical

"The histological features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis."

Establishes interstitial fibrosis as a histological feature of the disease. Directness is INDIRECT because the source is a broad-HCM review.

PMID:33171204 SUPPORT INDIRECT Human Clinical

"In patients with HCM, LGE on c-MRI is a strong predictor of arrhythmic outcomes including SCD, aborted SCD, and appropriate ICD therapy."

Establishes that the imaged fibrosis burden predicts arrhythmic outcome across 8 prospective studies and 3808 patients. Directness is INDIRECT because the pooled cohorts are broad HCM rather than genotyped MYH7 carriers.

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Genetic Associations

1

MYH7

Gene: MYH7 hgnc:7577 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

CGGV:assertion_31325c90-05cb-4db0-9372-e4f705cd5c82-2023-07-12T160000.000Z SUPPORT Other

ClinGen's Gene Curation Expert Panel classifies this gene-disease relationship as Definitive, which is the authority for curating the gene as CAUSATIVE rather than a candidate.

PMID:23674365 SUPPORT Human Clinical

"The presence of any sarcomere gene mutation was associated with a younger age at presentation (38.4 vs 46.0 years, p<0.0005), a family history of HCM (50.6% vs 23.1%, p<0.0005), a family history of SCD (27.0% vs 14.9%, p<0.0005) and greater MLVWT (21.0 vs 19.3 mm, p=0.03)."

The cohort is sarcomere-mutation carriers across genes rather than MYH7 carriers, so this is class-level evidence that a sarcomere genotype shifts age at presentation and family history, and reaches MYH7 by an inference step; the same study's finding of no outcome difference between MYH7 and MYBPC3 carriers is recorded in this entry's pathophysiology.

💊

Medical Actions

10

Mavacamten (Cardiac Myosin Inhibitor)

Action: Pharmacotherapy NCIT:C15986

Agent: mavacamten CHEBI:756998

Platform: Small molecule

Mavacamten is a small-molecule allosteric inhibitor of cardiac myosin ATPase that reduces the number of force-generating actin-myosin cross-bridges, stabilizing myosin in the energy-sparing super-relaxed state. It directly counteracts the hypercontractility that is the central abnormality of HCM, and is approved for symptomatic obstructive hypertrophic cardiomyopathy; because beta-cardiac myosin is the MYH7 gene product, the drug acts on the same motor that carries the CMH1 lesion.

Mechanism Target:

INHIBITS Destabilization of the Autoinhibited Super-Relaxed State — Mavacamten stabilizes the super-relaxed state and reduces the number of heads available for force generation, directly opposing the SRX destabilization that drives hypercontractility.

Show evidence (1 reference)

PMID:40118457 SUPPORT In Vitro

"cardiac myosin inhibitor mavacamten slows nucleotide release by an equal factor for both heavy meromyosin and subfragment 1, thus only indirectly influencing the occupancy time of the SRX state."

Establishes mavacamten's biochemical action on beta-cardiac myosin nucleotide handling and its effect on SRX-state occupancy, the node it targets.

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."

The pivotal phase 3 trial establishing the rationale and use of a cardiac myosin inhibitor targeting hypercontractility in obstructive HCM.

Septal Reduction (Surgical Myectomy)

Action: septal myectomy Ontology label: Myectomy NCIT:C51591

Platform: Surgery

Surgical septal myectomy relieves severe drug-refractory left ventricular outflow tract obstruction by resecting hypertrophied basal septal muscle.

Mechanism Target:

INHIBITS Diastolic Dysfunction, Outflow Obstruction, Heart Failure and Arrhythmic Risk — Resecting hypertrophied basal septal muscle removes the anatomical substrate of the dynamic outflow gradient, acting on the obstruction component of this node.

Show evidence (1 reference)

PMID:16053960 SUPPORT INDIRECT Human Clinical

"Surgical myectomy performed to relieve outflow obstruction and severe symptoms in HCM was associated with long-term survival equivalent to that of the general population, and superior to obstructive HCM without operation."

The long-term survival result that establishes myectomy as more than symptomatic relief. Directness is INDIRECT because the cohort is obstructive HCM broadly rather than genotyped MYH7 carriers, and because the design is an observational comparison rather than a randomized one.

Implantable Cardioverter-Defibrillator

Action: implantable cardioverter-defibrillator placement Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

Platform: Device

An implantable cardioverter-defibrillator provides secondary or primary prevention of sudden cardiac death in patients judged to be at high arrhythmic risk, terminating malignant ventricular arrhythmia.

Mechanism Target:

INHIBITS Sudden Cardiac Death — The device does not modify the arrhythmic substrate; it terminates the ventricular tachyarrhythmia that would otherwise cause death, so it acts on the outcome rather than on any upstream mechanism.

Show evidence (2 references)

PMID:17652294 SUPPORT INDIRECT Human Clinical

"In a high-risk HCM cohort, ICD interventions for life-threatening ventricular tachyarrhythmias were frequent and highly effective in restoring normal rhythm."

The multicenter registry result establishing device efficacy in high-risk HCM. Directness is INDIRECT because the 506-patient cohort is high-risk HCM broadly rather than genotyped MYH7 carriers.

PMID:17652294 REFUTE INDIRECT Human Clinical

"ICD complications included inappropriate shocks in 136 patients (27%)."

Recorded as REFUTE against an unqualified claim of net benefit: in the same registry that established efficacy, over a quarter of recipients received an inappropriate shock. Curated as a separate item with the opposite direction rather than hedged into the efficacy item, because the two sentences make opposite claims about the same intervention. Directness is INDIRECT for the same broad-HCM reason as its companion.

Aficamten (Cardiac Myosin Inhibitor)

Action: Pharmacotherapy NCIT:C15986

Agent: aficamten CHEBI:747213

Platform: Small molecule

Aficamten is an oral selective cardiac myosin inhibitor. Like mavacamten it acts directly on the beta-cardiac myosin motor that carries the CMH1 lesion, reducing left ventricular outflow tract gradients by mitigating hypercontractility. In the phase 3 SEQUOIA-HCM trial it improved peak oxygen uptake in symptomatic obstructive disease.

Mechanism Target:

INHIBITS Sarcomere Hypercontractility with Impaired Relaxation — Myosin inhibition reduces the number of force-generating cross-bridges, opposing the hypercontractile cellular state at the point where the MYH7 lesion produces it.

Show evidence (1 reference)

PMID:38739079 SUPPORT INDIRECT Human Clinical

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

Supports this edge specifically: names hypercontractility as the mechanism the drug acts through, rather than merely reporting that the drug works.

Show evidence (1 reference)

PMID:38739079 SUPPORT INDIRECT Human Clinical

"At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group"

The pivotal phase 3 efficacy result for this drug, against a placebo comparator. Directness is INDIRECT because SEQUOIA-HCM enrolled symptomatic obstructive HCM broadly rather than genotyped MYH7 carriers.

Disopyramide

Action: Pharmacotherapy NCIT:C15986

Agent: disopyramide CHEBI:4657

Platform: Small molecule

Disopyramide is a class Ia antiarrhythmic with strong negative inotropic action, used as add-on therapy to a beta-blocker for persistent left ventricular outflow tract obstruction. It reduces the subaortic gradient and can defer or avoid septal reduction therapy; its limits are vagolytic side effects and the need for QT monitoring.

Mechanism Target:

INHIBITS Diastolic Dysfunction, Outflow Obstruction, Heart Failure and Arrhythmic Risk — The negative inotropic effect reduces the dynamic subaortic gradient, acting on the obstruction component of this node rather than on the underlying sarcomeric lesion.

Show evidence (1 reference)

PMID:15837258 SUPPORT INDIRECT Human Clinical

"Two-thirds of obstructed HCM patients treated with disopyramide could be managed medically with amelioration of symptoms and about 50% reduction in subaortic gradient over >/=3 years."

Names the subaortic gradient as the quantity the drug moves and gives the size of the effect, which is the content of this edge rather than of the treatment record as a whole. Directness is INDIRECT because the series is obstructive HCM broadly rather than genotyped MYH7 carriers.

Show evidence (2 references)

PMID:15837258 SUPPORT INDIRECT Human Clinical

"Seventy-eight patients (66%) were maintained with disopyramide without the necessity for major non-pharmacologic intervention with surgical myectomy, alcohol ablation, or pacing; outflow gradient at rest decreased from 75 +/- 33 to 40 +/- 32 mm Hg (p < 0.0001)"

Quantifies gradient reduction and the proportion managed medically. Directness is INDIRECT because the cohort is obstructive HCM broadly rather than genotyped MYH7 carriers.

PMID:15837258 SUPPORT INDIRECT Human Clinical

"Disopyramide therapy does not appear to be proarrhythmic in HCM and should be considered before proceeding to surgical myectomy or alternate strategies."

Records the safety finding that positions this drug ahead of septal reduction in the treatment sequence.

Alcohol Septal Ablation

Action: alcohol septal ablation Ontology label: Septal Ablation NCIT:C80439

Platform: Surgery

Catheter-based infarction of the basal septum through a septal perforator branch, an alternative to surgical myectomy for drug-refractory obstruction in patients who are poor surgical candidates. It does not address concomitant mitral or subvalvular abnormalities, which is where myectomy is preferred.

Mechanism Target:

INHIBITS Diastolic Dysfunction, Outflow Obstruction, Heart Failure and Arrhythmic Risk — Reduces basal septal muscle mass, relieving the mechanical obstruction component of this node.

Show evidence (1 reference)

PMID:26746632 SUPPORT INDIRECT Human Clinical

"Alcohol septal ablation reduced the LV outflow tract gradient from 67 ± 36 to 16 ± 21 mmHg (P < 0.01) and NYHA class from 2.9 ± 0.5 to 1.6 ± 0.7 (P < 0.01)."

Supports this edge specifically: names the outflow gradient as the quantity the procedure moves and gives the size of the reduction across 1275 patients. Directness is INDIRECT because the registry is obstructive HCM broadly rather than genotyped MYH7 carriers.

Show evidence (1 reference)

PMID:26746632 SUPPORT INDIRECT Human Clinical

"The Euro-ASA registry demonstrated low peri-procedural and long-term mortality after ASA. This intervention provided durable relief of symptoms and a reduction of LV outflow tract obstruction in selected and highly symptomatic patients with obstructive HCM."

The largest multinational ablation registry (1275 patients, median 5.7 years) establishing durability and peri-procedural safety. Directness is INDIRECT because the cohort is obstructive HCM broadly rather than genotyped MYH7 carriers.

MYH7 Allele-Directed Gene Editing (Preclinical)

Action: gene therapy Ontology label: Gene Therapy NCIT:C15238

Platform: Gene editing

Two preclinical strategies target the MYH7 allele itself rather than its downstream consequences. Adenine base editing corrects the pathogenic base in patient-derived cardiomyocytes and in humanized mice; high-precision Cas13d instead degrades the mutant transcript while sparing the wild-type allele, which suits the dominant-negative biology of missense MYH7 disease. Neither is an approved therapy, and both face delivery, durability and off-target questions. They are curated here because they are the only interventions in this entry that act on the trigger node.

Mechanism Target:

INHIBITS MYH7 Missense Variant in Beta-Cardiac Myosin Heavy Chain — Base editing removes the causal substitution and RNA-targeting Cas13d suppresses the mutant transcript, so both act on the initiating lesion rather than on any downstream mechanism.

Show evidence (1 reference)

PMID:36797478 SUPPORT Model Organism

"We show that delivery of base editing components rescues pathological manifestations of HCM in induced pluripotent stem cell cardiomyocytes derived from patients with HCM and in a humanized mouse model of HCM."

Supports the edge specifically: correcting the MYH7 base rescues the disease phenotype, which is what establishes the trigger node as the target being acted on.

Show evidence (3 references)

PMID:36797478 SUPPORT In Vitro

"In this study we identify an adenine base editor and single-guide RNA system that can efficiently correct this human PV with minimal bystander editing and off-target editing at selected sites."

Establishes correction of the archetypal CMH1 allele, R403Q, as technically achievable with acceptable editing specificity.

PMID:38752340 SUPPORT Model Organism

"In vivo application of hpCas13d to 2 hypertrophic cardiomyopathy models caused by distinct human MYH7 analogous sequence variations specifically suppressed the altered allele and prevented cardiac hypertrophy."

The alternative allele-directed strategy: silencing the mutant transcript rather than correcting the gene, which suits a dominant-negative missense mechanism.

PMID:36797483 SUPPORT Model Organism

"Together, these data indicated that base editing of the mutant R403Q allele, delivered several months or only weeks in advance of the typical time for disease manifestations, resulted in durable prevention of ventricular remodeling and hypertrophy."

The independent contemporaneous demonstration that a single in vivo editing dose durably prevents the remodeling phenotype in an R403Q mouse, curated alongside the correction and silencing strategies above so the treatment record does not rest on a single group.

Beta-Adrenergic Blockade

Action: Pharmacotherapy NCIT:C15986

Agent: beta-adrenergic antagonist NCIT:C29576 nadolol CHEBI:7444

Platform: Small molecule

A non-vasodilating beta-blocker is the conventional first-line drug for symptomatic obstructive hypertrophic cardiomyopathy, reducing the dynamic outflow gradient through negative inotropy and chronotropy and lengthening diastolic filling time. The evidence base is weaker than its first-line position suggests: in the only randomized placebo-controlled crossover trial in mildly to moderately symptomatic patients, nadolol did not improve maximal oxygen consumption and reduced peak exercise work load in most patients, though a majority still preferred active drug to placebo.

Mechanism Target:

INHIBITS Diastolic Dysfunction, Outflow Obstruction, Heart Failure and Arrhythmic Risk — Negative inotropy reduces the dynamic subaortic gradient and slower heart rates lengthen diastolic filling, so the drug acts on the obstruction and filling components of this node rather than on the sarcomeric lesion.

Show evidence (2 references)

PMID:8496536 REFUTE INDIRECT Human Clinical

"In patients with mild or moderately symptomatic hypertrophic cardiomyopathy, exercise capacity was not improved by nadolol or verapamil, and individuals were more often impaired by nadolol than with verapamil."

Recorded as REFUTE against the claim that beta-blockade improves functional capacity: in this randomized crossover trial it did not, and nadolol impaired peak work load more often than verapamil did. Directness is INDIRECT because the trial enrolled broad HCM rather than genotyped MYH7 carriers, and because it was restricted to mildly and moderately symptomatic patients.

PMID:8496536 SUPPORT INDIRECT Human Clinical

"Despite the effects on exercise capacity, 13 patients (81%) preferred drug treatment (8 verapamil, 5 nadolol) over placebo (p = 0.001)."

The counterpart to the item above, and the reason both drugs remain in use: patients preferred active drug to placebo even where objective exercise capacity did not improve. Curated as a separate item because the sentence supports a different claim from the one the CONCLUSIONS sentence refutes.

Verapamil

Action: Pharmacotherapy NCIT:C15986

Agent: verapamil CHEBI:9948 calcium channel blocker NCIT:C333

Platform: Small molecule

A non-dihydropyridine calcium channel blocker used when beta-blockade is ineffective or not tolerated. It improves diastolic filling and reduces symptoms, and in direct comparison was better tolerated than nadolol. Guidelines caution against it in severe outflow obstruction with hypotension because its vasodilator effect can worsen the gradient.

Mechanism Target:

INHIBITS Diastolic Dysfunction, Outflow Obstruction, Heart Failure and Arrhythmic Risk — Acts on the diastolic-filling component of this node; unlike the myosin inhibitors it does not target the contractile lesion itself.

Show evidence (1 reference)

PMID:8496536 SUPPORT INDIRECT Human Clinical

"Verapamil improved reported performance at work compared with nadolol (p = 0.01) and tended to improve other measures of health-related behavior and symptoms compared with nadolol and placebo."

The head-to-head result placing verapamil ahead of a beta-blocker on patient-reported measures, which is why it is curated as a distinct treatment rather than a footnote to beta-blockade. Directness is INDIRECT because the trial enrolled broad HCM rather than genotyped MYH7 carriers.

Oral Anticoagulation for Atrial Fibrillation

Action: Pharmacotherapy NCIT:C15986

Agent: anticoagulant NCIT:C263

Platform: Small molecule

Atrial fibrillation in hypertrophic cardiomyopathy carries a thromboembolic risk high enough that anticoagulation is recommended on the arrhythmia alone rather than gated on a general-population risk score. Roughly a fifth of patients develop atrial fibrillation and about a quarter of those experience thromboembolism.

Mechanism Target:

INHIBITS Atrial Fibrillation — Anticoagulation does not treat the arrhythmia; it acts on the thromboembolic consequence that makes atrial fibrillation dangerous in this disease.

Show evidence (2 references)

PMID:24014282 SUPPORT INDIRECT Human Clinical

"AF is common in HCM and associated with high thromboembolic risk. LA dimension and age are independently associated with AF but the literature is insufficient to create robust clinical tools to predict AF or thromboembolism. Most data suggest that AF patients should be anticoagulated."

The pooled basis for anticoagulating on the arrhythmia alone, and an explicit statement that the evidence does not support a prediction tool. Directness is INDIRECT because the 7381-patient pooled population is broad HCM rather than genotyped MYH7 carriers.

PMID:24014282 SUPPORT INDIRECT Human Clinical

"A population of 7381 patients (33 studies) revealed overall AF prevalence of 22.45% (95% CI 20.13% to 24.77%)"

Quantifies how often the indication for this treatment arises. Directness is INDIRECT for the same broad-HCM reason.

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Biochemical Markers

2

Circulating miR-499a-5p (Elevated)

Context: Plasma, in carriers of pathogenic/likely pathogenic MYH7 variants

Show evidence (2 references)

PMID:35409153 SUPPORT Human Clinical

"Further investigation on enlarged groups of individuals showed that its level was higher in carriers of pathogenic/likely pathogenic (P/LP) variants in MYH7 gene compared to controls (fold change, FC = 8.9; p < 0.0001)."

Quantifies the elevation specifically in MYH7 P/LP variant carriers against controls, which is what makes this readout genotype-specific.

PMID:35409153 SUPPORT Human Clinical

"carriers of variants in MYH7 gene were defined with higher miRNA levels than carriers of variants in the MYBPC3 gene (FC = 14.1; p = 0.0003) and other patients (FC = 4.1; p = 0.0008)."

Separates MYH7 from MYBPC3 carriers and from the rest of the HCM population, so the signal tracks the gene rather than the phenotype.

NT-proBNP (Elevated)

Context: Serum, reflecting wall stress and heart-failure burden

Show evidence (1 reference)

PMID:34940836 SUPPORT INDIRECT Human Clinical

"The present study indicated NT-proBNP was a novel biomarker suitable for predicting adverse prognosis in patients with HCM, which may be used for early recognition and risk stratification."

Establishes NT-proBNP as a prognostic biomarker in hypertrophic cardiomyopathy. Directness is INDIRECT because the cohort is broad HCM rather than genotyped MYH7 carriers.

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Diagnosis

3

Echocardiographic Wall-Thickness Criterion

The clinical diagnosis rests on a cardiac imaging measurement, not on genotype: an end-diastolic wall thickness of 15 mm or more anywhere in the left ventricle, not explained by loading conditions and with other causes of hypertrophy ruled out. A 13-14 mm threshold applies when there is a positive family history or a positive genetic test, which is the situation of a CMH1 cascade-screened relative. Paediatric diagnosis uses body-size-adjusted z-scores instead of an absolute thickness.

transthoracic echocardiography NCIT:C16525

The lowered 13-14 mm threshold is what makes genetic testing consequential for relatives rather than merely informative: a confirmed familial variant changes the wall thickness at which a relative is called affected.

Show evidence (1 reference)

PMID:38540296 SUPPORT INDIRECT Human Clinical

"The clinical diagnosis of HCM in adult patients is typically established using any cardiac imaging technique that shows an end-diastolic wall thickness of ≥15 mm anywhere in the left ventricle, which cannot be explained solely by pressure overload states, and after ruling out any other..."

States both thresholds and the exclusion requirement. Directness is INDIRECT because the criterion is for hypertrophic cardiomyopathy as a phenotype rather than for the MYH7 entity, which has no imaging signature of its own.

Sarcomere Gene Panel Testing

A phenotype-anchored next-generation sequencing panel covering the core sarcomere genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1) plus genes for clinically plausible phenocopies. This is what establishes the CMH1 diagnosis specifically, since nothing on imaging distinguishes MYH7 disease from its sarcomeric siblings. Yield depends on how the patient was ascertained rather than on the test.

genetic testing NCIT:C15709

A variant of uncertain significance is not actionable for predictive cascade testing: a relative who carries one still needs longitudinal surveillance rather than being called unaffected. That constraint is why this entry's progression section curates the genotype-positive/phenotype-negative state as a surveillance phase.

Show evidence (2 references)

PMID:38540296 SUPPORT INDIRECT Human Clinical

"The yield of genetic testing for a disease-causing variant is 30% in sporadic cases and up to 60% in familial cases and in younger patients with typical asymmetrical septal hypertrophy."

Quantifies the diagnostic yield and shows it doubles with familial ascertainment, which is the number a clinician needs before ordering the test.

PMID:38540296 SUPPORT Human Clinical

"Genetic testing using targeted disease-specific panels that utilize next-generation sequencing (NGS) and include sarcomeric genes with the strongest evidence of association and syndrome-associated genes is highly recommended for every HCM patient to confirm the diagnosis, identify the molecular..."

Establishes the panel composition and that testing is recommended for every patient rather than only for selected ones.

Cascade Testing of First-Degree Relatives

When a decisively pathogenic variant is identified in the proband, targeted testing is offered to phenotype-negative first-degree relatives regardless of age, and the result then determines whether that relative enters longitudinal clinical surveillance or leaves it. This is the pathway through which the penetrance figures curated in this entry's progression section are generated, and the reason they are ascertainment-dependent.

cascade genetic testing NCIT:C15709

Show evidence (1 reference)

PMID:38540296 SUPPORT Human Clinical

"The current guidelines recommend focused cascade genetic testing regardless of age in phenotype-negative first-degree relatives if a variant with decisive evidence of pathogenicity has been identified in the proband."

States the cascade-testing recommendation and its precondition, a variant with decisive pathogenicity evidence in the proband.

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Imaging Findings

1

Late Gadolinium Enhancement on Cardiac Magnetic Resonance

Late gadolinium enhancement on contrast-enhanced cardiac magnetic resonance images the replacement-fibrosis burden of the myocardium. It is used for sudden-death risk stratification rather than for diagnosis: its pooled specificity for arrhythmic endpoints is low (39-42%), so a positive scan raises risk without identifying who will have an event.

Mri

late gadolinium enhancement NCIT:C209440 Myocardial fibrosis HP:0001685

Show evidence (2 references)

PMID:33171204 SUPPORT INDIRECT Human Clinical

"LGE positivity was associated with higher odds of the endpoint of sudden cardiac death (SCD;OR 1.69, 95%CI 1.03-2.78)"

Gives the pooled effect size for the arrhythmic endpoint this finding is used to predict. Directness is INDIRECT because the pooled studies enrolled broad HCM, not genotyped MYH7 carriers.

PMID:33171204 SUPPORT INDIRECT Human Clinical

"The pooled sensitivity and specificity of positive LGE on c-MRI for SCD were 65% and 42%, respectively"

Records the operating characteristics, which is the reason this is curated as a risk marker rather than a diagnostic finding.

📈

Progression

3

Genotype-positive, phenotype-negative

A carrier of a pathogenic MYH7 variant with no left ventricular hypertrophy on imaging. This is not a benign state to be discharged from follow-up: penetrance is age-related, so surveillance must be longitudinal. Pooled penetrance in clinically ascertained non-proband MYH7 relatives is far higher than in carriers found incidentally in population cohorts, which is why a penetrance figure cannot be quoted without its ascertainment context.

Show evidence (3 references)

PMID:37929589 SUPPORT Human Clinical

"Penetrance varied from ≈32% for MYL3 (myosin light chain 3) to ≈55% for MYBPC3 (myosin-binding protein C3), ≈60% for TNNT2 (troponin T2) and TNNI3 (troponin I3), and ≈65% for MYH7 (myosin heavy chain 7)."

Gives the MYH7-specific penetrance in non-proband relatives found by cascade screening, the highest of the sarcomere genes compared, which is what makes this phase a surveillance state rather than reassurance.

PMID:37929589 SUPPORT Human Clinical

"The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower at ≈11%"

The counterweight to the figure above: the same variant classes carry a far lower penetrance when found incidentally rather than through a family, so a penetrance number cannot be quoted without its ascertainment context.

PMID:37929589 SUPPORT Human Clinical

"short-term gene-specific phenotypic conversion varied between ≈12% for MYBPC3 and ≈23% for MYH7."

Quantifies the rate at which carriers leave this phase, and separates MYH7 from MYBPC3 on it — roughly twice the short-term conversion rate.

Overt hypertrophy, with or without outflow obstruction

Conversion to measurable left ventricular hypertrophy, defined in adults as maximal end-diastolic wall thickness of 15 mm or more unexplained by loading conditions. Obstruction may be present at rest, provocable, or absent.

Show evidence (1 reference)

PMID:28912181 SUPPORT INDIRECT Human Clinical

"Left ventricular outflow tract obstruction is present at rest in about one third of the patients and can be provoked in another third."

Quantifies how the overt phase divides between resting, provocable and absent obstruction, which is what determines management at this stage.

Complications

Atrial fibrillation with thromboembolic risk, progressive fibrosis, ventricular arrhythmia and heart failure. Most patients follow a relatively benign course; sudden cardiac death is the complication that drives risk stratification and is concentrated in adolescents and young adults.

Show evidence (1 reference)

PMID:28912181 SUPPORT INDIRECT Human Clinical

"In the majority of patients, HCM has a relatively benign course. However, HCM is also an important cause of sudden cardiac death, particularly in adolescents and young adults."

Sets the base rate against which the arrhythmic complication of this phase is judged, and locates its peak in adolescence and young adulthood.

📊

Prevalence

2

Worldwide (hypertrophic cardiomyopathy overall)

Point Prevalence 200.0 per 100,000 >1 in 1,000

Clinical prevalence of hypertrophic cardiomyopathy in the general population, the context for the MYH7 subtype. MYH7-specific population rates are not separately documented.

Show evidence (1 reference)

PMID:31213605 SUPPORT Other

"Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people and leads to hyper-contractility of the heart."

Gives the ~1 in 500 general-population prevalence of hypertrophic cardiomyopathy overall. Evidence source is OTHER because this is a biochemical mechanism paper stating the epidemiological background.

🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Hypertrophic Cardiomyopathy 1:

Storage and Infiltrative Phenocopies of Left Ventricular Hypertrophy

Overlapping Features Unexplained left ventricular hypertrophy is not specific to sarcomeric disease. Glycogen storage and lysosomal disorders (Danon disease, PRKAG2 glycogenosis, Pompe disease, Fabry disease), extracellular deposition (transthyretin and AL amyloidosis) and mitochondrial disease all thicken the myocardium. Distinguishing them from CMH1 matters clinically because several have disease-specific therapy that sarcomeric HCM does not, and because a wrong call misdirects family screening. Low ECG voltage despite marked hypertrophy is the classic pointer away from a sarcomeric cause.

Show evidence (2 references)

PMID:29506729 SUPPORT Human Clinical

"several metabolic diseases lead to myocardial thickening, either due to intracellular storage (glycogen storage and lysosomal diseases), extracellular deposition (TTR and AL amyloidosis) or due to abnormal energy metabolism (mitochondrial diseases)."

Names the classes of phenocopy that must be excluded before attributing unexplained hypertrophy to a sarcomeric cause.

PMID:29506729 SUPPORT Human Clinical

"as there are specific therapies for some forms of HCM including enzyme substitution and chaperone therapies and specific treatments for TTR amyloidosis, a differential diagnosis should be sought in all patients with unexplained left ventricular hypertrophy."

States why this differential is actionable rather than academic: several phenocopies have disease-specific treatment.

Hypertrophic Cardiomyopathy due to other sarcomere genes MONDO:0005045

Overlapping Features MYBPC3, TNNT2, TNNI3, TPM1, ACTC1, MYL2 and MYL3 also carry definitive gene-disease validity for hypertrophic cardiomyopathy, and MYH7 and MYBPC3 together account for roughly half of HCM families. The phenotypes overlap substantially, so only genetic testing separates CMH1 from its sarcomeric siblings. The mechanistic contrast is with MYBPC3 disease, which is predominantly truncating and acts by haploinsufficiency, where MYH7 disease is predominantly missense and acts through a stably expressed mutant motor.

Show evidence (1 reference)

PMID:28912181 SUPPORT Human Clinical

"MYH7 and MYBPC3, encoding β-myosin heavy chain and myosin-binding protein C, respectively, are the 2 most common genes involved, together accounting for ≈50% of the HCM families."

Quantifies the sarcomeric differential that CMH1 sits inside and names its nearest neighbour.

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Related Datasets

4

Circulating miR-499a-5p is a potential biomarker of MYH7-associated hypertrophic cardiomyopathy geo:GSE195436

Plasma small-RNA sequencing in hypertrophic cardiomyopathy patients and controls, with downstream qRT-PCR stratified by causal gene. The dataset behind this entry's genotype-specific miR-499a-5p biochemical record.

human BULK RNA SEQ n=15

PMID:35409153

DIRECT relevance: human patient plasma, MYH7 named in the study title and the genotype used as the stratifying variable.

Beta-Adrenergic Stimulation and MYH7 G256E Mutant Gene Dosage Drive Hypertrophic Cardiomyopathy Phenotype Penetrance geo:GSE276210

Single-cell RNA sequencing of day-30 iPSC-cardiomyocytes carrying heterozygous MYH7 G256E and H251N, plus homozygous G256E and isoproterenol-treated heterozygotes. Addresses gene dosage and adrenergic stress as modifiers of the incomplete penetrance recorded in this entry's progression section.

human SINGLE CELL RNA SEQ n=14

PMID:42282692

DIRECT relevance: named MYH7 alleles in a human iPSC system. The linked publication is a preprint, so the dataset is curated as a resource rather than as support for any claim in this entry.

Bulk RNAseq analysis of hypertrophic cardiomyopathy (HCM) hiPSC-derived cardiomyocytes (hiPSC-CMs) and the isogenic control geo:GSE198258

Day-15 bulk RNA-seq of HCM hiPSC-derived cardiomyocytes against their isogenic control, from the study of myosin heavy chain converter-domain mutations and early extracellular-matrix dynamics. Relevant to this entry's EGFR paracrine fibrosis arm because it profiles matrix changes at an early disease stage.

human BULK RNA SEQ n=4

PMID:35784482

DIRECT relevance established from the linked publication rather than the GEO summary, which does not name the gene: the study is of myosin heavy chain converter-domain mutations, which are MYH7 alleles.

Base Editing Correction of a Hypertrophic Cardiomyopathy-Causing MYH7 Mutation in Human Cardiomyocytes and Humanized Mice geo:GSE201755

Transcriptomes from the adenine base-editing correction of MYH7 R403Q in patient-derived iPSC-cardiomyocytes and a humanized mouse model. The dataset behind the preclinical gene-editing treatment record in this entry.

house mouse BULK RNA SEQ n=3

PMID:36797478

DIRECT relevance: the archetypal CMH1 allele R403Q, named in the GEO series summary (the title says only "a Hypertrophic Cardiomyopathy-Causing MYH7 Mutation"). The organism is bound to Mus musculus because GEO records the series under that taxon; the study itself spans both patient-derived iPSC-cardiomyocytes and humanized mice, and the committed cache does not resolve which samples this accession holds. Read the accession before using it as a human dataset.

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Clinical Trials

3

NCT01912534 PHASE_II COMPLETED

VANISH (Valsartan for Attenuating Disease Evolution in Early Sarcomeric Hypertrophic Cardiomyopathy) tested whether the angiotensin receptor blocker valsartan can modify disease progression in young carriers of sarcomeric gene mutations, including MYH7, with early-stage HCM.

Target Phenotypes: Hypertrophic cardiomyopathy HP:0001639

Show evidence (1 reference)

PMID:31813281 SUPPORT Human Clinical

"targeted young sarcomeric gene mutation carriers with early-stage hypertrophic cardiomyopathy (HCM) to test whether valsartan can modify disease progression."

Describes the VANISH trial's design and its enrollment of young sarcomeric (including MYH7) mutation carriers with early HCM.

NCT05186818 PHASE_III COMPLETED

SEQUOIA-HCM, the pivotal phase 3 trial of the cardiac myosin inhibitor aficamten in symptomatic obstructive hypertrophic cardiomyopathy. Relevant to CMH1 because the drug's target is the beta-cardiac myosin motor that MYH7 encodes.

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."

Establishes the trial's agent, comparator and target population.

NCT04349072 PHASE_III COMPLETED

VALOR-HCM, which tested whether mavacamten allows patients who already meet guideline criteria for septal reduction therapy to avoid the procedure. It is the trial that positioned myosin inhibition ahead of invasive septal reduction in the treatment sequence rather than alongside it.

Target Phenotypes: Left ventricular outflow tract obstruction HP:0032092

Show evidence (1 reference)

PMID:35798455 SUPPORT INDIRECT Human Clinical

"After 16 weeks, 43 of 56 placebo patients (76.8%) and 10 of 56 mavacamten patients (17.9%) met guideline criteria or underwent SRT, difference (58.9%; 95% CI: 44.0%-73.9%; P < 0.001)."

The primary endpoint result. Directness is INDIRECT because the trial enrolled obstructive HCM broadly rather than genotyped MYH7 carriers.

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Experimental Models

3

MYH7 R403Q hiPSC-cardiomyocyte cardiac microtissue with wild-type fibroblasts CO_CULTURE

Engineered three-dimensional cardiac microtissues built from isogenic MYH7 R403Q heterozygous hiPSC-derived cardiomyocytes together with wild-type ventricular cardiac fibroblasts. The co-culture is the point: a cardiomyocyte-only model cannot show the cardiomyocyte-to-fibroblast cross-talk that produces the fibrotic component of the disease, and this system reproduces collagen deposition, tissue stiffening and the EGFR dependence of stromal activation.

Organism

human NCBITaxon:9606

Publication

PMID:39413182

Pathograph links

Cardiomyocyte-to-Fibroblast EGFR Paracrine Signaling recapitulates fidelity: moderate observes: cellular The model was built to interrogate this node and demonstrates each of its claims — paracrine transfer, fibroblast proliferation dependence, and EGFR as the transducing receptor.

Limitations: Fidelity is MODERATE rather than HIGH because the system omits the immune, vascular and haemodynamic-loading environments in which fibrosis develops in patients, and because hiPSC-derived cardiomyocytes remain immature relative to adult ventricular myocardium.

Show evidence (1 reference)

PMID:39413182 SUPPORT In Vitro

"Together, these findings establish a paracrine-mediated cross-talk potentially responsible for fibrotic changes observed in HCM."

The authors' own summary of what the model establishes, which is the content of the node it is linked to.

Ventricular Hypertrophy, Myocyte Disarray and Fibrosis partially recapitulates fidelity: low observes: cellular Reproduces the interstitial-fibrosis and stiffening component of the remodeling node.

Limitations: It reproduces only one of the node's three components. There is no ventricular hypertrophy and no myofibre disarray in a microtissue, and the model observes cellular-scale readouts while the node is a tissue-scale claim, so the tissue-level inference is an upward extrapolation.

Divergences from the human mechanism

scale extrapolation qualifying

Collagen content and elastic modulus are measured in a millimetre-scale engineered construct of two cell types; the node describes remodeling of an intact ventricular wall under haemodynamic load.

boundary omission qualifying

Cardiomyocyte hypertrophy and myofibre disarray, two of the three components of the node, are not represented in the model at all.

MYH7 G256E gene-edited hiPSC-cardiomyocyte multiscale platform IPSC_DERIVED_MODEL

An isogenic gene-edited MYH7 WT/G256E hiPSC line characterised in parallel at purified-protein, myofibril, single-cell and engineered-heart-tissue level. Its value for this entry is that it carries one allele through every scale of the mechanism chain at once, so the hypercontractility claim does not depend on any single assay — the failure mode the report itself flags for R403Q, where single-assay measurements have gone both ways.

Organism

human NCBITaxon:9606

Publication

PMID:38683993

Pathograph links

Destabilization of the Autoinhibited Super-Relaxed State measures fidelity: high observes: molecular Quantifies the folded-back myosin fraction directly for a named MYH7 allele, giving the node a measured effect size rather than a class claim.

Sarcomere Hypercontractility with Impaired Relaxation recapitulates fidelity: moderate observes: cellular Greater and faster tension development was reproduced in myofibrils, in single cells and in engineered heart tissue from the same edited line.

Limitations: G256E is an incompletely penetrant allele, so the cellular phenotype it produces is not automatically the phenotype of the more severe MYH7 alleles; and hiPSC-cardiomyocyte immaturity limits extrapolation of absolute contractile parameters to adult myocardium.

Show evidence (1 reference)

PMID:38683993 SUPPORT In Vitro

"Myofibrils from gene-edited MYH7WT/G256E human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exhibited greater and faster tension development. This hypercontractile phenotype persisted in single-cell hiPSC-CMs and engineered heart tissues."

Shows the hypercontractile phenotype holding across three scales in one isogenic system, which is what makes this model informative for the node rather than one more single-assay result.

MYH7 R403Q and TNNT2 R92Q hiPSC-cardiomyocyte engineered heart tissue IPSC_DERIVED_MODEL

Two-dimensional hiPSC-cardiomyocyte cultures and three-dimensional engineered heart tissue carrying MYH7 R403Q, used to test whether the impaired-relaxation phenotype is pharmacologically correctable. Relaxation improved with SGLT2 inhibitors, and the effect grew with culture duration as the tissue matured.

Organism

human NCBITaxon:9606

Publication

PMID:38240646

Pathograph links

Sarcomere Hypercontractility with Impaired Relaxation recapitulates fidelity: moderate observes: cellular Reproduces the impaired-relaxation and increased-force halves of the node in a human system carrying the archetypal CMH1 allele.

Limitations: hiPSC-cardiomyocyte immaturity is explicitly a variable in this study rather than a background caveat: the size of the drug effect depended on culture duration, so results at any single timepoint are maturation-state dependent.

Show evidence (1 reference)

PMID:38240646 SUPPORT In Vitro

"HCM mutations in hiPSC-CMs impaired relaxation or increased force, mimicking early features observed in human HCM."

States that the model reproduces the early cellular features this node describes.

🐁

Animal Models

3

alpha-MHC 403/+ knock-in mouse

The founding animal model of the field, introducing the R403Q substitution into the mouse alpha-cardiac myosin heavy chain gene. Heterozygotes develop the histopathology of human familial hypertrophic cardiomyopathy with age; homozygotes die within a week of birth. Cardiac dysfunction preceded the histological changes, which is the model's principal contribution to the causal ordering curated in this entry's pathophysiology.

Species

Mouse

Genotype

Myh6 Arg403Gln (R403Q) heterozygous knock-in

Publication

PMID:8614836

Pathograph links

Ventricular Hypertrophy, Myocyte Disarray and Fibrosis partially recapitulates fidelity: low observes: tissue Myocyte disarray, hypertrophy and fibrosis develop and increase with age, reproducing the tissue-level remodeling node.

Limitations: The substitution is in Myh6 (alpha-cardiac myosin), not the Myh7 orthologue of the human disease gene, because the adult mouse ventricle expresses alpha- rather than beta-myosin. So the model reproduces the pathology of a 403 substitution in the myosin that mouse hearts actually use, and its relevance to human MYH7 disease rests on the residue and the motor domain being conserved rather than on the gene being the same one. Mouse cardiac electrophysiology also differs substantially from human.

Divergences from the human mechanism

species mismatch qualifying

The lesion is carried by the alpha-myosin heavy chain gene Myh6, whereas human CMH1 is a disease of MYH7/beta-myosin. The two isoforms differ in their kinetics, so a 403 substitution is not necessarily equivalent in both.

Show evidence (1 reference)

PMID:8614836 SUPPORT Model Organism

"Cardiac dysfunction preceded histopathologic changes, and myocyte disarray, hypertrophy, and fibrosis increased with age."

Documents the tissue phenotype and, importantly for the causal ordering curated here, that functional impairment came first.

Retained despite its LOW fidelity because it is the model that established that a single myosin missense allele is sufficient to produce the disease, and because the species caveat it carries is exactly the reason the beta-myosin rabbit and pig models below exist.

beta-MyHC-Q403 transgenic rabbit

A transgenic rabbit expressing the Q403 beta-myosin heavy chain, which matches the human disease in the myosin isoform as well as the residue: like humans and unlike mice, the adult rabbit ventricle runs on beta-myosin. Forty-seven animals were phenotyped at four age periods over four years, making this the natural-history model for the disease.

Species

Rabbit

Genotype

Transgenic beta-myosin heavy chain Gln403 (Q403)

Publication

PMID:15135661

Pathograph links

Ventricular Hypertrophy, Myocyte Disarray and Fibrosis recapitulates fidelity: moderate observes: tissue Disarray, hypertrophy and fibrosis all develop, and the longitudinal design separates them in time: disarray appears early and independently of hypertrophy and fibrosis, which emerge later around puberty.

Limitations: This is a transgenic overexpression model rather than a knock-in, so the mutant protein is not expressed from its own locus at its own dose. The allele is also a single one, Q403, so the age-ordering it reveals may not generalise to MYH7 alleles acting through different mechanisms.

Show evidence (1 reference)

PMID:15135661 SUPPORT Model Organism

"Myocyte disarray also occurred early, prior to, and independent of hypertrophy and fibrosis. The latter phenotypes evolved predominantly during puberty in conjunction with activation of stress-related signaling kinases."

Separates the three components of the remodeling node in time and shows they are not one process, which is a claim only a longitudinal model can make.

Increased Motor Force and Energetic Cost partially recapitulates fidelity: moderate observes: molecular Calcium sensitivity of myofibrillar ATPase activity was altered as the earliest detectable phenotype, before any histological or structural change.

Limitations: The direction is a reduction in calcium sensitivity of myofibrillar ATPase in this model, which is a different measurement from the raised intrinsic force and tension cost curated on the human node from R403Q myectomy tissue. It supports the node's claim that myofilament energetics are disturbed early, not that they are disturbed in the same direction.

Divergences from the human mechanism

proxy quantity qualifying

The model's measured quantity is calcium sensitivity of myofibrillar ATPase activity, and it moves downward. The node's quantities are intrinsic motor force and the energetic cost of tension, both raised in human R403Q myectomy tissue. The model stands in for the node on the claim that myofilament energetics are perturbed at the head of the causal sequence, not on the direction or the identity of the perturbation.

Show evidence (1 reference)

PMID:15135661 SUPPORT Model Organism

"Ca(+2) sensitivity of myofibrillar ATPase activity is a primary phenotype expressed early and independent of the ensuing phenotypes."

Places a myofilament-energetics abnormality at the head of the causal sequence in a beta-myosin model.

MYH7 R723G knock-in pig

TALEN-mediated knock-in of the orthologous human HCM mutation R723G into the porcine MYH7 gene, followed by somatic cell nuclear transfer cloning. Unlike the mouse, the pig expresses beta-myosin as the predominant adult ventricular isoform and has human-like cardiac anatomy and electrophysiology. The piglets died within 24 hours of birth, and this severity is the model's limitation as much as its finding.

Species

Pig

Genotype

MYH7 R723G heterozygous knock-in (TALEN-mediated, orthologous c.2167C>G)

Publication

PMID:29555974

Pathograph links

Ventricular Hypertrophy, Myocyte Disarray and Fibrosis partially recapitulates fidelity: low observes: tissue Neonatal animals showed mild myocyte disarray and malformed nuclei, establishing that the histological lesion can arise before birth from a knock-in MYH7 allele.

Limitations: The animals died within 24 hours post partem, so the model captures a perinatal phenotype far more severe than the adult-onset human disease and cannot report on natural history, hypertrophy development, or fibrosis at all. Only disarray and nuclear morphology were observed; hypertrophy and interstitial fibrosis, the node's other components, were not.

Divergences from the human mechanism

temporal scope invalidating

Perinatal lethality truncates the model at 24 hours of age, before the adult-onset remodeling this node describes could develop, so the node's hypertrophy and fibrosis components have no counterpart in the animal.

boundary omission qualifying

The node's hypertrophy component is not merely unobserved: the paper reports the hearts showed no obvious hypertrophy. Interstitial fibrosis is not reported either way. So of the node's three components the model shows one (disarray), contradicts one (hypertrophy), and is silent on the third.

Show evidence (1 reference)

PMID:29555974 SUPPORT Model Organism

"Surprisingly, the animals died within 24 h post partem, probably due to heart failure as indicated by a shift in the a/ß-MyHC ratio in the left ventricle."

Records the perinatal lethality that both defines what this model can show and limits it to the earliest phase of the disease.

Notes

Curated with an explicit note on why the species matters. The authors set the model up precisely because orthologous beta-myosin mutations in mice do not produce the human phenotype, the adult mouse ventricle running on alpha-myosin; a pig ventricle, like a human one, is predominantly beta-myosin. That is the same reasoning behind the rabbit model above. Spontaneous feline hypertrophic cardiomyopathy (PMID:36928240) was screened as a fourth model and deliberately not curated. It is a genuine spontaneous large-animal disease and the transcriptomic overlap with human HCM is real, but the established breed-associated variants are MYBPC3 (A31P in Maine Coon, R820W in Ragdoll) rather than MYH7, and most feline cases are genetically unresolved. It would belong in the parent Hypertrophic Cardiomyopathy entry, not in the MYH7 entity.

{ }

Source YAML

click to show

name: Hypertrophic Cardiomyopathy 1
creation_date: "2026-08-22T00:00:00Z"
synonyms:
- CMH1
- MYH7 hypertrophic cardiomyopathy
- beta-myosin heavy chain hypertrophic cardiomyopathy
- cardiomyopathy, familial hypertrophic, 1
- familial hypertrophic cardiomyopathy type 1
- hypertrophic cardiomyopathy caused by mutation in MYH7
description: >-
  Hypertrophic cardiomyopathy 1 (CMH1) is the MYH7-related form of familial
  hypertrophic cardiomyopathy and, with the MYBPC3 form (CMH4), one of the two
  commonest genetic causes of the disease. MYH7 encodes the beta-cardiac myosin
  heavy chain (beta-MyHC), the force-generating molecular motor of the cardiac
  thick filament. CMH1 is historically the founding molecular diagnosis of the
  entire field: the first mutation ever shown to cause familial hypertrophic
  cardiomyopathy was the MYH7 Arg403Gln (R403Q) missense change, identified in a
  large kindred in 1990.
  Unlike MYBPC3-related disease, where truncating alleles act through
  haploinsufficiency, the great majority of MYH7 disease alleles are missense
  variants that are stably expressed and incorporated into the sarcomere as a
  mutant motor. The operative mechanism is therefore not loss of protein but a
  gain of contractile function: the mutant myosin destabilizes the folded-back,
  autoinhibited super-relaxed state of the thick filament, freeing more heads to
  interact with actin, and often raises the intrinsic force and the energetic
  cost of each cross-bridge. The net cellular consequence is hypercontractility
  with impaired relaxation and raised tension cost, which drives the structural
  remodeling — cardiomyocyte hypertrophy, myofiber disarray, and interstitial
  fibrosis — that defines the clinical phenotype. Inheritance is autosomal
  dominant with incomplete, age-related penetrance; MYH7 variants carry a
  clinically important risk of malignant ventricular arrhythmia and sudden
  cardiac death, and beta-cardiac myosin is the direct molecular target of the
  cardiac myosin inhibitors (mavacamten, aficamten) now used to treat obstructive
  disease.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: hypertrophic cardiomyopathy 1
  term:
    id: MONDO:0008647
    label: hypertrophic cardiomyopathy 1
parents:
- Hypertrophic Cardiomyopathy
- Genetic Disorder
inheritance:
- name: Autosomal dominant
  description: >-
    CMH1 is inherited as an autosomal dominant trait, with a single mutant MYH7
    allele producing disease. Penetrance is incomplete and age-related, and a
    family history of hypertrophic cardiomyopathy and of sudden cardiac death is
    characteristic of sarcomere-variant-positive disease, so cascade screening of
    relatives 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
  evidence:
  - reference: CGGV:assertion_31325c90-05cb-4db0-9372-e4f705cd5c82-2023-07-12T160000.000Z
    reference_title: "MYH7 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "MYH7 | HGNC:7577 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
    explanation: >-
      ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel
      classifies the MYH7-hypertrophic cardiomyopathy relationship as Definitive
      with autosomal dominant inheritance.
  - reference: PMID:23674365
    reference_title: "A systematic review and meta-analysis of genotype-phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presence of any sarcomere gene mutation was associated with a younger
      age at presentation (38.4 vs 46.0 years, p<0.0005), a family history of HCM
      (50.6% vs 23.1%, p<0.0005), a family history of SCD (27.0% vs 14.9%,
      p<0.0005) and greater MLVWT (21.0 vs 19.3 mm, p=0.03).
    explanation: >-
      Meta-analysis of 2459 patients documenting the familial, dominantly
      inherited pattern of sarcomere-positive HCM, with a positive family history
      of both HCM and sudden cardiac death and younger onset than
      sarcomere-negative disease.
prevalence:
- population: Worldwide (hypertrophic cardiomyopathy overall)
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 200.0
  notes: >-
    Clinical prevalence of hypertrophic cardiomyopathy in the general population,
    the context for the MYH7 subtype. MYH7-specific population rates are not
    separately documented.
  evidence:
  - reference: PMID:31213605
    reference_title: "β-Cardiac myosin hypertrophic cardiomyopathy mutations release sequestered heads and increase enzymatic activity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hypertrophic cardiomyopathy (HCM) affects 1 in 500 people and leads to hyper-contractility of the heart."
    explanation: >-
      Gives the ~1 in 500 general-population prevalence of hypertrophic
      cardiomyopathy overall. Evidence source is OTHER because this is a
      biochemical mechanism paper stating the epidemiological background.
- population: Worldwide (MYH7 share of HCM mutations)
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population-based prevalence estimate exists for the MYH7-specific entity.
    MYH7 is, with MYBPC3, one of the two most frequently mutated genes in
    hypertrophic cardiomyopathy, accounting for roughly 40% of identified
    HCM-causing mutations.
  evidence:
  - reference: PMID:31213605
    reference_title: "β-Cardiac myosin hypertrophic cardiomyopathy mutations release sequestered heads and increase enzymatic activity."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Nearly 40 percent of HCM-causing mutations are found in human β-cardiac myosin."
    explanation: >-
      Quantifies MYH7's share of HCM-causing mutations. Evidence source is OTHER
      because this is a biochemical mechanism paper.
pathophysiology:
- name: MYH7 Missense Variant in Beta-Cardiac Myosin Heavy Chain
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The initiating lesion in CMH1 is a heterozygous missense variant in MYH7,
    the gene encoding the beta-cardiac myosin heavy chain — the ATP-hydrolysing
    motor of the sarcomeric thick filament. The founding example, and still the
    archetype, is Arg403Gln (R403Q), the first mutation ever linked to familial
    hypertrophic cardiomyopathy; R403Q sits in the globular myosin head (S1),
    the region responsible for actin interaction and motor function. In contrast
    to the truncating, haploinsufficiency mechanism of MYBPC3 disease, most MYH7
    alleles are missense changes that are stably expressed and incorporated into
    the sarcomere as a mutant motor, so the mutant protein perturbs contraction
    directly rather than by its absence.
  genes:
  - preferred_term: MYH7
    term:
      id: hgnc:7577
      label: MYH7
  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: Myosin thick filament
    term:
      id: GO:0032982
      label: myosin filament
  evidence:
  - reference: PMID:1975517
    reference_title: "A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A point mutation in exon 13 of the beta cardiac myosin heavy chain (MHC)
      gene is present in all individuals affected with familial hypertrophic
      cardiomyopathy (FHC) from a large kindred. This missense mutation converts
      a highly conserved arginine residue (Arg-403) to a glutamine.
    explanation: >-
      The founding CMH1 report: co-segregation of the MYH7 R403Q missense variant
      with familial hypertrophic cardiomyopathy in a large kindred, establishing
      the beta-cardiac myosin heavy chain gene as a cause of the disease.
  - reference: PMID:23798412
    reference_title: "Molecular consequences of the R453C hypertrophic cardiomyopathy mutation on human β-cardiac myosin motor function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      HCM is caused by mutations in the genes encoding the fundamental
      force-generating machinery of the cardiac muscle, including β-cardiac
      myosin.
    explanation: >-
      Places the MYH7 lesion in the force-generating machinery of the sarcomere,
      the trigger for this entity.
  downstream:
  - target: Destabilization of the Autoinhibited Super-Relaxed State
    causal_link_type: DIRECT
    description: >-
      The mutant motor, incorporated into the thick filament, destabilizes the
      folded-back autoinhibited state that normally sequesters myosin heads.
- name: Destabilization of the Autoinhibited Super-Relaxed State
  biological_scale: MOLECULAR
  role: amplifier
  description: >-
    In the resting sarcomere a large fraction of myosin heads occupy the
    super-relaxed (SRX) state — folded back against the thick-filament backbone
    in the interacting-heads motif (IHM), with very low ATPase activity, forming
    an energy-conserving reserve of motors withheld from force generation. Many
    MYH7 HCM mutations map to the interfaces that stabilize this folded-back
    state (the myosin mesa, the head-head and head-tail contacts), and they
    weaken those intramolecular interactions. The result is release of
    sequestered heads from the SRX/IHM into the disordered-relaxed state, so more
    heads become functionally accessible to actin — the molecular origin of
    hypercontractility shared across a large subset of MYH7 alleles.
  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:31213605
    reference_title: "β-Cardiac myosin hypertrophic cardiomyopathy mutations release sequestered heads and increase enzymatic activity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      folded-back sequestered state referred to as the interacting heads motif
      (IHM) lead to a significant increase in the number of heads functionally
      accessible for interaction with actin.
    explanation: >-
      Direct biochemical evidence that MYH7 HCM mutations at IHM interfaces
      release sequestered heads, increasing the number available to interact with
      actin.
  - reference: PMID:38683993
    reference_title: "Incomplete-penetrant hypertrophic cardiomyopathy MYH7 G256E mutation causes hypercontractility and elevated mitochondrial respiration."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The G256E mutation disrupts the transducer region of the S1 head and
      reduces the fraction of myosin in the folded-back state by 33%, resulting
      in more myosin heads available for contraction.
    explanation: >-
      Quantifies the size of the SRX shift for a named MYH7 allele, and shows the
      destabilizing lesion need not sit on an IHM contact surface itself — G256E
      acts through the transducer region of the motor domain.
  - reference: PMID:28481356
    reference_title: "The myosin mesa and the basis of hypercontractility caused by hypertrophic cardiomyopathy mutations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      hypercontractility is due to an increase in the number of myosin heads (S1)
      that are accessible for force production.
    explanation: >-
      States the core hypothesis this node captures: HCM hypercontractility
      arises from an increase in the number of force-producing heads freed from
      the sequestered state.
  - reference: PMID:34117120
    reference_title: "Hypertrophic cardiomyopathy β-cardiac myosin mutation (P710R) leads to hypercontractility by disrupting super relaxed state."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      destabilized the super relaxed state in longer, two-headed myosin
      constructs, freeing more heads to generate force.
    explanation: >-
      Shows a specific MYH7 mutation (P710R) destabilizing the super-relaxed
      state and freeing heads for force generation.
  - reference: PMID:40118457
    reference_title: "Dynamics of β-cardiac myosin between the super-relaxed and disordered-relaxed states."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Some mutations which cause hypertrophic or dilated cardiomyopathies alter
      the SRX-DRX equilibrium, but not all mutations.
    explanation: >-
      Important caveat curated with the node: SRX-DRX destabilization is a common
      but not universal consequence of cardiomyopathy myosin mutations, so this
      arm applies to the large subset of alleles that shift the equilibrium
      rather than to every MYH7 variant, so the support it gives this node is
      indirect.
  downstream:
  - target: Increased Motor Force and Energetic Cost
    causal_link_type: DIRECT
    description: >-
      Heads released from the super-relaxed reserve, together with allele-specific
      changes in the motor stroke, raise ensemble force and the ATP cost of
      contraction.
- name: Increased Motor Force and Energetic Cost
  biological_scale: MOLECULAR
  role: effector
  description: >-
    Beyond releasing sequestered heads, individual MYH7 missense alleles alter
    the mechanochemistry of the motor stroke itself. Single-molecule and
    myofibril studies show mutation-specific changes — increased intrinsic force
    per cross-bridge, and faster cross-bridge detachment kinetics — that together
    raise the force generated by the ensemble of motors and increase the ATP
    consumed per unit tension (tension cost). The energetic penalty, measured
    directly in human myocardium carrying R403Q, is a distinctive feature of the
    beta-myosin motor lesion and links the molecular defect to the myocardial
    energy deficit seen in HCM.
  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
  biological_processes:
  - preferred_term: Actin-Myosin Filament Sliding
    term:
      id: GO:0033275
      label: actin-myosin filament sliding
    modifier: ABNORMAL
  evidence:
  - reference: PMID:23798412
    reference_title: "Molecular consequences of the R453C hypertrophic cardiomyopathy mutation on human β-cardiac myosin motor function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The major change in the R453C human β-cardiac subfragment 1 is a 50%
      increase in the intrinsic force of the motor compared with wild type, with
      no appreciable change in the stroke size, as observed with a dual-beam
      optical trap.
    explanation: >-
      Single-molecule optical-trap measurement of a raised intrinsic force for an
      MYH7 mutant motor, predicting a hypercontractile ensemble.
  - reference: PMID:23798412
    reference_title: "Molecular consequences of the R453C hypertrophic cardiomyopathy mutation on human β-cardiac myosin motor function."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Overall, this study suggests that the R453C mutation should result in a
      hypercontractile state in the heart muscle.
    explanation: >-
      States the functional conclusion — a hypercontractile state — that the
      motor-level force change produces.
  - reference: PMID:24928957
    reference_title: "Faster cross-bridge detachment and increased tension cost in human hypertrophic cardiomyopathy with the R403Q MYH7 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This correlation suggests that faster cross-bridge relaxation kinetics
      results in an increase in energetic cost of tension generation in human HCM
      with the R403Q mutation compared to HCMsmn.
    explanation: >-
      Direct measurement in human R403Q myocardium (single myofibrils and muscle
      strips) linking faster cross-bridge kinetics to an increased energetic cost
      of tension generation, evidence obtained in patient cardiac tissue.
  downstream:
  - target: Sarcomere Hypercontractility with Impaired Relaxation
    causal_link_type: DIRECT
    description: >-
      Raised ensemble force and disturbed cross-bridge kinetics translate into
      cellular hypercontractility with impaired diastolic relaxation.
- name: Sarcomere Hypercontractility with Impaired Relaxation
  biological_scale: CELLULAR
  role: effector
  description: >-
    At the cell level the molecular changes converge on hypercontractility:
    CRISPR-edited human iPSC-derived cardiomyocytes carrying an MYH7 HCM mutation
    generate significantly greater contractile force than isogenic controls.
    Because the same lesion disturbs cross-bridge relaxation kinetics, systolic
    hypercontraction is accompanied by impaired diastolic relaxation. This
    hypercontractile, poorly relaxing cell state — a key pathophysiological
    abnormality of HCM and the determinant of dynamic outflow obstruction — is
    the cellular phenotype the cardiac myosin inhibitors were designed to
    normalize.
  cell_types:
  - preferred_term: Ventricular cardiomyocyte
    term:
      id: CL:0002131
      label: regular ventricular cardiac myocyte
  biological_processes:
  - preferred_term: Cardiac Muscle Cell Contraction
    term:
      id: GO:0086003
      label: cardiac muscle cell contraction
    modifier: INCREASED
  - preferred_term: Regulation of Cardiac Muscle Contraction
    term:
      id: GO:0055117
      label: regulation of cardiac muscle contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:34117120
    reference_title: "Hypertrophic cardiomyopathy β-cardiac myosin mutation (P710R) leads to hypercontractility by disrupting super relaxed state."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      produced significantly increased force (measured by traction force
      microscopy) compared with isogenic control cells.
    explanation: >-
      Isogenic human iPSC-cardiomyocyte evidence that an MYH7 HCM mutation
      increases cellular contractile force.
  - 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
    directness: INDIRECT
    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
      of HCM and links it to outflow obstruction. Directness is INDIRECT because
      the trial enrolled obstructive HCM broadly rather than genotyped MYH7
      carriers, so the claim about this entity follows by an inference step.
  downstream:
  - target: Cell-to-Cell Contractile Imbalance
    causal_link_type: DIRECT
    description: >-
      Because mutant and wild-type MYH7 alleles are transcribed in variable
      proportions between neighboring myocytes, hypercontractility is unevenly
      distributed across the myocardium.
  - target: Cardiomyocyte-to-Fibroblast EGFR Paracrine Signaling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The mutant cardiomyocyte does not remodel the interstitium by mechanical
      load alone: it secretes soluble factors that act on the neighbouring
      fibroblast population. What couples the contractile state to that secretion
      is not established. The source proposes a broader stress response, with
      mechanical signalling from the intrinsic hypercontractility as one
      candidate, and states that further work is needed to identify the ligands
      and receptors involved — so the edge is curated with unknown intermediates
      rather than as a direct link.
    evidence:
    - reference: PMID:39413182
      reference_title: "Hypertrophic cardiomyopathy-associated mutations drive stromal activation via EGFR-mediated paracrine signaling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        hiPSC-CM conditioned media and single-nucleus RNA sequencing data
        suggested that fibroblast proliferation is mediated by paracrine signals
        from MYH7-variant cardiomyocytes.
      explanation: >-
        Supports this specific edge rather than either node alone: conditioned
        medium transfers the effect, so the signal travels from the MYH7-variant
        cardiomyocyte to the fibroblast.
  - target: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
    causal_link_type: DIRECT
    description: >-
      Sustained hypercontractility with raised energetic cost drives the
      structural remodeling of the ventricle.
- name: Cardiomyocyte-to-Fibroblast EGFR Paracrine Signaling
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    Interstitial fibrosis in CMH1 is not solely a passive response to wall
    stress. In engineered cardiac microtissues built from MYH7 R403Q hiPSC-derived
    cardiomyocytes co-cultured with wild-type ventricular cardiac fibroblasts,
    the mutant cardiomyocytes release paracrine factors that drive fibroblast
    proliferation and collagen deposition. Collagen I content rose 40% over
    isogenic wild-type microtissues and the tissue stiffened, and the effect
    depended on fibroblast proliferation rather than on cardiomyocyte matrix
    output. Epidermal growth factor alone was sufficient to stimulate the
    stromal cells, and inhibiting EGFR tyrosine kinase with erlotinib attenuated
    the activation — identifying EGFR signalling as the transducing arm and, in
    principle, a druggable one. The same microtissue system shows that the
    tissue-level consequence is hypocontractility even while the individual
    mutant cardiomyocytes are hypercontractile, which is how a cell-autonomous
    gain of contractile function ends up producing a stiff, poorly contracting
    ventricle.
  cell_types:
  - preferred_term: Ventricular cardiac fibroblast
    term:
      id: CL:2000066
      label: cardiac ventricle fibroblast
  - preferred_term: Ventricular cardiomyocyte
    term:
      id: CL:0002131
      label: regular ventricular cardiac myocyte
  biological_processes:
  - preferred_term: EGFR Signaling
    term:
      id: GO:0007173
      label: epidermal growth factor receptor signaling pathway
    modifier: INCREASED
  - preferred_term: Fibroblast Proliferation
    term:
      id: GO:0048144
      label: fibroblast proliferation
    modifier: INCREASED
  - preferred_term: Extracellular Matrix Organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:39413182
    reference_title: "Hypertrophic cardiomyopathy-associated mutations drive stromal activation via EGFR-mediated paracrine signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Using engineered cardiac microtissues (CMTs) composed of HCM-causing
      MYH7-variant hiPSC-CMs and wild-type fibroblasts, we observed cell-cell
      cross-talk leading to increased collagen deposition, tissue stiffening, and
      decreased contractility dependent on fibroblast proliferation.
    explanation: >-
      Establishes the node: MYH7-variant cardiomyocytes activate neighbouring
      fibroblasts, and the resulting collagen deposition and stiffening depend on
      fibroblast proliferation.
  - reference: PMID:39413182
    reference_title: "Hypertrophic cardiomyopathy-associated mutations drive stromal activation via EGFR-mediated paracrine signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, inhibiting epidermal growth factor receptor tyrosine kinase
      with erlotinib hydrochloride attenuated stromal activation.
    explanation: >-
      Identifies EGFR as the transducing receptor by pharmacological loss of
      function, which is what makes this a named signalling arm rather than an
      unspecified paracrine effect.
  - reference: PMID:39413182
    reference_title: "Hypertrophic cardiomyopathy-associated mutations drive stromal activation via EGFR-mediated paracrine signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      R403Q+/- CMTs exhibited a 40% increase in collagen I content compared to WT
      CMTs
    explanation: >-
      Quantifies the matrix effect against an isogenic wild-type control in the
      archetypal CMH1 allele.
  downstream:
  - target: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
    causal_link_type: DIRECT
    description: >-
      Fibroblast activation and excess collagen deposition are the cellular
      mechanism of the interstitial fibrosis component of the tissue-level
      remodeling node.
  - target: Myocardial Fibrosis
    causal_link_type: DIRECT
    description: >-
      The same collagen deposition presenting as the clinically measurable
      fibrosis burden, imaged as late gadolinium enhancement.
  notes: >-
    Curated as a distinct arm rather than folded into the remodeling node because
    it is a different kind of claim: the remodeling node describes what the
    myocardium becomes, this node names the cell-to-cell signal that produces the
    fibrotic part of it and the receptor that carries it. The same study found
    stromal activation in MYBPC3-truncation microtissues too, with distinct
    characteristics, so the arm is shared across sarcomeric HCM rather than being
    MYH7-exclusive.
- name: Cell-to-Cell Contractile Imbalance
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    A mechanism specific to the missense/poison-peptide biology of MYH7 disease.
    Because the mutant and wild-type MYH7 alleles are transcribed in a random,
    burst-like fashion and independently of one another, the fraction of mutant
    beta-myosin varies markedly from cardiomyocyte to cardiomyocyte within a
    single patient's myocardium. This produces much greater cell-to-cell
    variability of contractile function than in control hearts. The resulting
    mechanical mismatch between adjacent, differently loaded myocytes is proposed
    to drive the myofiber disarray and interstitial fibrosis that are hallmarks
    of HCM, providing a route from the molecular lesion to the tissue phenotype
    that does not depend on the average level of hypercontractility alone.
  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:30740621
    reference_title: "Altered force generation and cell-to-cell contractile imbalance in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      substantial contractile variability from cardiomyocyte to cardiomyocyte
      within a patient's myocardium, much higher than in controls.
    explanation: >-
      Documents the cell-to-cell contractile variability in beta-MyHC-mutant
      patient myocardium that this node captures.
  - reference: PMID:30740621
    reference_title: "Altered force generation and cell-to-cell contractile imbalance in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      contractile imbalance due to unequal fractions of mutated and wildtype
      protein among individual cardiomyocytes over time will induce cardiomyocyte
      disarray and fibrosis, hallmarks of HCM.
    explanation: >-
      States the contractile-imbalance hypothesis linking unequal mutant-allele
      expression to disarray and fibrosis, the hallmarks of HCM.
  downstream:
  - target: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Mechanical mismatch between neighboring myocytes promotes disarray and
      fibrotic remodeling.
- name: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    Chronic hypercontractility with raised energetic cost, amplified by
    cell-to-cell contractile imbalance, drives the structural remodeling that
    defines the clinical phenotype: cardiomyocyte hypertrophy — typically
    asymmetric and septal-predominant — together with myofiber disarray and
    interstitial and replacement fibrosis. Pro-hypertrophic growth signalling
    contributes: in an MYH7-mutant human iPSC-cardiomyocyte model, cellular
    hypertrophy was prevented by inhibition of ERK or Akt, implicating those
    pathways downstream of the mechanical stimulus. Fibrosis provides the
    substrate for both diastolic dysfunction and re-entrant 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:28912181
    reference_title: "Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The histological features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis."
    explanation: >-
      Names the defining tissue-level triad — myocyte hypertrophy, disarray, and
      interstitial fibrosis — that this node represents.
  - reference: PMID:34117120
    reference_title: "Hypertrophic cardiomyopathy β-cardiac myosin mutation (P710R) leads to hypercontractility by disrupting super relaxed state."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cellular hypertrophy was prevented in the P710R cells by inhibition of ERK or Akt."
    explanation: >-
      Implicates ERK and Akt growth signalling downstream of the MYH7 mechanical
      lesion in producing the cellular hypertrophy of this node.
  - reference: PMID:30740621
    reference_title: "Altered force generation and cell-to-cell contractile imbalance in hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      contractile imbalance due to unequal fractions of mutated and wildtype
      protein among individual cardiomyocytes over time will induce cardiomyocyte
      disarray and fibrosis, hallmarks of HCM.
    explanation: >-
      Ties the upstream contractile imbalance to the disarray and fibrosis of
      this tissue node.
  downstream:
  - target: Diastolic Dysfunction, Outflow Obstruction, Heart Failure and Arrhythmic Risk
    causal_link_type: DIRECT
- name: Diastolic Dysfunction, Outflow Obstruction, Heart Failure and Arrhythmic Risk
  biological_scale: ORGANISM
  role: consequence
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >-
    The hypertrophied, disarrayed and fibrotic ventricle produces the clinical
    endpoints of CMH1. Hypercontractility with septal hypertrophy generates
    dynamic left ventricular outflow tract obstruction in a subset of patients;
    the stiff, poorly relaxing ventricle causes diastolic dysfunction; and the
    fibrotic, electrically heterogeneous substrate carries a risk of malignant
    ventricular arrhythmia and sudden cardiac death that is clinically important
    for MYH7 variants. Sarcomere-positive disease, of which MYH7 is a leading
    cause, presents younger and with a stronger family history of sudden death
    than sarcomere-negative HCM.
  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:23674365
    reference_title: "A systematic review and meta-analysis of genotype-phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There were no differences when the two most frequently affected genes,
      MYBPC3 and MYH7, were compared.
    explanation: >-
      Records the important nuance that, at the cohort level, MYH7 and MYBPC3 do
      not differ significantly across the pooled clinical features, so MYH7 is
      not simply a uniformly more severe genotype than MYBPC3; it is one of the
      two commonest sarcomeric causes.
  - reference: PMID:39681440
    reference_title: "[Correlation between genotype and clinical phenotype in hypertrophic cardiomyopathy families with MYH7-R453C mutation]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the five families with HCM carrying MYH7-R453C mutations, genotype is
      highly correlated with clinical phenotype, and patients have a high risk of
      sudden death and poor prognosis.
    explanation: >-
      A family study of a specific MYH7 variant documenting high sudden-death
      risk and poor prognosis, the arrhythmic endpoint of this node.
  downstream:
  - target: Left Ventricular Diastolic Dysfunction
    causal_link_type: DIRECT
    description: >-
      The impaired-relaxation and reduced-compliance component of this node
      presenting as the measured clinical phenotype.
  - target: Left Ventricular Outflow Tract Obstruction
    causal_link_type: DIRECT
    description: >-
      The obstruction component of this node presenting as the clinical
      phenotype targeted by myosin inhibitors and septal reduction.
  - target: Congestive Heart Failure
    causal_link_type: DIRECT
    description: >-
      Sustained diastolic dysfunction, and in a minority progression to systolic
      impairment, produce clinical heart failure.
  - target: Ventricular Arrhythmia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The arrhythmic component of this node presenting clinically. Curated with
      unknown intermediates because which of hypertrophy, disarray, fibrosis and
      ischaemia carries the arrhythmic substrate in any given patient is not
      resolved.
  - target: Atrial Fibrillation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Raised filling pressures enlarge the left atrium, and left atrial dimension
      is the intermediate that predicts atrial fibrillation in this disease.
  - target: Syncope
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Syncope may arise from the outflow obstruction, from an arrhythmic event,
      or from an abnormal vascular response to exertion; which applies in a given
      episode is usually not determined.
phenotypes:
- name: Hypertrophic Cardiomyopathy
  category: Cardiovascular
  description: >-
    Unexplained left ventricular hypertrophy, not accounted for by abnormal
    loading conditions, is the defining feature of CMH1.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  frequency: OBLIGATE
  evidence:
  - reference: PMID:28912181
    reference_title: "Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes and a nondilated left ventricle with preserved or increased ejection fraction."
    explanation: >-
      States the defining clinical feature — unexplained left ventricular
      hypertrophy with a nondilated ventricle — of the disease this MYH7 form
      manifests.
- name: Asymmetric Septal Hypertrophy
  category: Cardiovascular
  description: >-
    Asymmetric, septal-predominant left ventricular hypertrophy is the classic
    morphological pattern of MYH7-related hypertrophic cardiomyopathy.
  phenotype_term:
    preferred_term: Asymmetric septal hypertrophy
    term:
      id: HP:0001670
      label: Asymmetric septal hypertrophy
  evidence:
  - reference: PMID:23674365
    reference_title: "A systematic review and meta-analysis of genotype-phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presence of any sarcomere gene mutation was associated with a younger
      age at presentation (38.4 vs 46.0 years, p<0.0005), a family history of HCM
      (50.6% vs 23.1%, p<0.0005), a family history of SCD (27.0% vs 14.9%,
      p<0.0005) and greater MLVWT (21.0 vs 19.3 mm, p=0.03).
    explanation: >-
      Sarcomere-positive HCM, of which MYH7 is a leading cause, shows greater
      maximum left ventricular wall thickness than sarcomere-negative disease,
      supporting the pronounced hypertrophy of this member.
- name: Left Ventricular Outflow Tract Obstruction
  category: Cardiovascular
  description: >-
    Dynamic obstruction of the left ventricular outflow tract arises from
    hypercontractility combined with septal hypertrophy and systolic anterior
    motion of the mitral valve, 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
    directness: INDIRECT
    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 to dynamic LVOT obstruction. Directness is
      INDIRECT because the trial population is obstructive HCM broadly rather
      than genotyped MYH7 carriers.
- name: Left Ventricular Diastolic Dysfunction
  category: Cardiovascular
  description: >-
    Impaired relaxation and increased chamber stiffness produce diastolic
    dysfunction, an early and characteristic functional consequence of the
    hypercontractile, poorly relaxing myocardium.
  phenotype_term:
    preferred_term: Left ventricular diastolic dysfunction
    term:
      id: HP:0025168
      label: Left ventricular diastolic dysfunction
  evidence:
  - reference: PMID:24928957
    reference_title: "Faster cross-bridge detachment and increased tension cost in human hypertrophic cardiomyopathy with the R403Q MYH7 mutation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cross-bridge slow relaxation kinetics in single R403Q myofibrils was
      significantly higher (P < 0.0001) than in HCMsmn myofibrils
    explanation: >-
      Documents disturbed cross-bridge relaxation kinetics in human R403Q
      myocardium, the molecular basis of the impaired relaxation underlying
      diastolic dysfunction.
- name: Sudden Cardiac Death
  category: Cardiovascular
  description: >-
    Malignant ventricular arrhythmia on the fibrotic, hypertrophied substrate
    can cause sudden cardiac death, sometimes as the presenting event; the risk
    is clinically important for MYH7 variants and family history of sudden death
    is characteristic.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:39681440
    reference_title: "[Correlation between genotype and clinical phenotype in hypertrophic cardiomyopathy families with MYH7-R453C mutation]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the five families with HCM carrying MYH7-R453C mutations, genotype is
      highly correlated with clinical phenotype, and patients have a high risk of
      sudden death and poor prognosis.
    explanation: >-
      A family study of an MYH7 variant documenting a high risk of sudden death.
- name: Ventricular Arrhythmia
  category: Cardiovascular
  description: >-
    The electrically heterogeneous, fibrotic myocardium supports malignant
    ventricular arrhythmia, the proximate cause of sudden cardiac death in this
    disease.
  phenotype_term:
    preferred_term: Ventricular arrhythmia
    term:
      id: HP:0004308
      label: Ventricular arrhythmia
  evidence:
  - reference: PMID:39681440
    reference_title: "[Correlation between genotype and clinical phenotype in hypertrophic cardiomyopathy families with MYH7-R453C mutation]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      2 experienced (F1Ⅲ1, F3Ⅲ3) events of sudden cardiac death survival
    explanation: >-
      Aborted sudden cardiac death (survived cardiac arrest) in MYH7-R453C
      carriers evidences the malignant ventricular arrhythmia of this node.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    Progressive diastolic dysfunction, and in a minority progression toward
    systolic impairment or an end-stage phase, produces heart failure symptoms.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:39681440
    reference_title: "[Correlation between genotype and clinical phenotype in hypertrophic cardiomyopathy families with MYH7-R453C mutation]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      2(F1Ⅱ2, F3Ⅱ1) died from heart failure during the follow-up period.
    explanation: >-
      Deaths from heart failure among MYH7-R453C carriers evidence heart failure
      as a clinical endpoint of the disease.
- name: Atrial Fibrillation
  category: Cardiovascular
  description: >-
    Atrial fibrillation is a common complication of hypertrophic cardiomyopathy,
    arising from the left atrial enlargement that follows chronically raised
    filling pressures. It is poorly tolerated because a hypertrophied,
    non-compliant ventricle depends on atrial contribution to filling, and it
    carries a substantial thromboembolic risk.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:28912181
    reference_title: "Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Atrial fibrillation is also a common complication and is not well tolerated."
    explanation: >-
      Establishes atrial fibrillation as a common and clinically consequential
      complication of the disease.
- name: Syncope
  category: Cardiovascular
  description: >-
    Unexplained syncope in hypertrophic cardiomyopathy may reflect dynamic
    outflow obstruction, an arrhythmic event, or an abnormal vascular response to
    exertion. It is one of the major risk markers used in sudden-death risk
    stratification, which is why it is curated as a phenotype in its own right
    rather than folded into the arrhythmia node.
  phenotype_term:
    preferred_term: Syncope
    term:
      id: HP:0001279
      label: Syncope
  evidence:
  - reference: PMID:28912181
    reference_title: "Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Nonsustained ventricular tachycardia, syncope, a family history of sudden
      cardiac death, and severe cardiac hypertrophy are major risk factors for
      sudden cardiac death.
    explanation: >-
      Names syncope among the major sudden-death risk markers. Directness is
      INDIRECT on two counts: the source is a broad-HCM review rather than a
      MYH7 cohort, and the sentence establishes syncope as a risk marker, from
      which its occurrence as a clinical feature follows by inference rather than
      being stated.
- name: Myocardial Fibrosis
  category: Cardiovascular
  description: >-
    Interstitial and replacement fibrosis is a defining tissue-level feature of
    the disease and, when imaged as late gadolinium enhancement on cardiac
    magnetic resonance, is a measurable predictor of arrhythmic outcome rather
    than merely a structural description. It is the tissue substrate that links
    the mechanism modeled in this entry's pathophysiology to the arrhythmic risk
    modeled in its phenotypes.
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: PMID:28912181
    reference_title: "Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "The histological features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis."
    explanation: >-
      Establishes interstitial fibrosis as a histological feature of the disease.
      Directness is INDIRECT because the source is a broad-HCM review.
  - reference: PMID:33171204
    reference_title: "Risk stratification using late gadolinium enhancement on cardiac magnetic resonance imaging in patients with hypertrophic cardiomyopathy: A systematic review and meta-analysis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with HCM, LGE on c-MRI is a strong predictor of arrhythmic
      outcomes including SCD, aborted SCD, and appropriate ICD therapy.
    explanation: >-
      Establishes that the imaged fibrosis burden predicts arrhythmic outcome
      across 8 prospective studies and 3808 patients. Directness is INDIRECT
      because the pooled cohorts are broad HCM rather than genotyped MYH7
      carriers.
genetic:
- name: MYH7
  gene_term:
    preferred_term: MYH7
    term:
      id: hgnc:7577
      label: MYH7
  relationship_type: CAUSATIVE
  frequency: >-
    With MYBPC3, one of the two commonest genetic causes of hypertrophic
    cardiomyopathy: nearly 40% of identified HCM-causing mutations fall in
    beta-cardiac myosin.
  case_fractions:
  - population: Identified HCM-causing mutations (genotyped probands)
    case_fraction_percent: 40.0
    notes: >-
      This is a share of identified HCM-causing mutations, not a share of all
      hypertrophic cardiomyopathy cases. The two differ because a substantial
      fraction of clinically diagnosed HCM is genotype-negative, so the figure
      overstates the share of the whole disease population and is recorded
      with that denominator named explicitly.
    evidence:
    - reference: PMID:31213605
      reference_title: "β-Cardiac myosin hypertrophic cardiomyopathy mutations release sequestered heads and increase enzymatic activity."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Nearly 40 percent of HCM-causing mutations are found in human
        β-cardiac myosin.
      explanation: >-
        Directly states the beta-cardiac myosin share of HCM-causing
        mutations.
  evidence:
  - reference: CGGV:assertion_31325c90-05cb-4db0-9372-e4f705cd5c82-2023-07-12T160000.000Z
    reference_title: "MYH7 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MYH7 | HGNC:7577 | hypertrophic cardiomyopathy | MONDO:0005045 | AD |
      Definitive
    explanation: >-
      ClinGen's Gene Curation Expert Panel classifies this gene-disease
      relationship as Definitive, which is the authority for curating the gene
      as CAUSATIVE rather than a candidate.
  - reference: PMID:23674365
    reference_title: "A systematic review and meta-analysis of genotype-phenotype associations in patients with hypertrophic cardiomyopathy caused by sarcomeric protein mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presence of any sarcomere gene mutation was associated with a
      younger age at presentation (38.4 vs 46.0 years, p<0.0005), a family
      history of HCM (50.6% vs 23.1%, p<0.0005), a family history of SCD
      (27.0% vs 14.9%, p<0.0005) and greater MLVWT (21.0 vs 19.3 mm, p=0.03).
    explanation: >-
      The cohort is sarcomere-mutation carriers across genes rather than MYH7
      carriers, so this is class-level evidence that a sarcomere genotype
      shifts age at presentation and family history, and reaches MYH7 by an
      inference step; the same study's finding of no outcome difference between MYH7
      and MYBPC3 carriers is recorded in this entry's pathophysiology.
histopathology:
- name: Myocyte Hypertrophy, Disarray and Interstitial Fibrosis
  description: >-
    The histological triad of hypertrophic cardiomyopathy is cardiomyocyte
    hypertrophy, myofibre disarray (loss of the normal parallel alignment, with
    hypertrophied fibres running obliquely and in whorls) and interstitial
    fibrosis. In MYH7 disease the disarray component is reproduced by the
    orthologous R723G knock-in pig within 24 hours of birth, which places it very
    early in the causal sequence rather than as a late consequence of chronic
    load. Biopsy is not required for diagnosis in routine sarcomeric HCM; this
    section records the tissue phenotype that the pathophysiology chain converges
    on.
  finding_term:
    preferred_term: myocyte hypertrophy, disarray and interstitial fibrosis
    term:
      id: NCIT:C35867
      label: Morphologic Finding
  evidence:
  - reference: PMID:28912181
    reference_title: "Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "The histological features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis."
    explanation: >-
      States the histological triad that defines the tissue phenotype of this
      disease. Directness is INDIRECT because the review describes hypertrophic
      cardiomyopathy generally rather than genotyped MYH7 disease.
  - reference: PMID:29555974
    reference_title: "Successful knock-in of Hypertrophic Cardiomyopathy-mutation R723G into the MYH7 gene mimics HCM pathology in pigs."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      the neonatal pigs displayed features of HCM, including mild myocyte
      disarray, malformed nuclei, and MYH7-overexpression.
    explanation: >-
      Shows disarray arising in an orthologous MYH7 knock-in large animal within
      24 hours of birth, evidencing that the histological lesion is an early
      consequence of the MYH7 allele rather than only a late remodeling endpoint.
  notes: >-
    finding_term is bound only to the generic NCIT Morphologic Finding parent.
    NCIT has no myofibre-disarray term; this follows the binding already used for
    the same finding in the sibling CMH4 entry rather than manufacturing a
    narrower match.
biochemical:
- name: Circulating miR-499a-5p
  presence: Elevated
  context: Plasma, in carriers of pathogenic/likely pathogenic MYH7 variants
  evidence:
  - reference: PMID:35409153
    reference_title: "Circulating miR-499a-5p Is a Potential Biomarker of MYH7-Associated Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Further investigation on enlarged groups of individuals showed that its
      level was higher in carriers of pathogenic/likely pathogenic (P/LP)
      variants in MYH7 gene compared to controls (fold change, FC = 8.9; p <
      0.0001).
    explanation: >-
      Quantifies the elevation specifically in MYH7 P/LP variant carriers against
      controls, which is what makes this readout genotype-specific.
  - reference: PMID:35409153
    reference_title: "Circulating miR-499a-5p Is a Potential Biomarker of MYH7-Associated Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      carriers of variants in MYH7 gene were defined with higher miRNA levels
      than carriers of variants in the MYBPC3 gene (FC = 14.1; p = 0.0003) and
      other patients (FC = 4.1; p = 0.0008).
    explanation: >-
      Separates MYH7 from MYBPC3 carriers and from the rest of the HCM
      population, so the signal tracks the gene rather than the phenotype.
  notes: >-
    The one biochemical readout in this entry that is specific to the MYH7
    genotype rather than to hypertrophic cardiomyopathy in general. Plasma
    miR-499a-5p is a cardiac-enriched microRNA whose circulating level separates
    MYH7 variant carriers from MYBPC3 carriers, from other HCM patients, and from
    controls.

    Curated as a research biomarker, not a validated clinical assay. The cohort
    is small (7 MYH7 carriers against 8 MYBPC3 carriers) and the qRT-PCR
    replication did not reproduce the direction of the original RNA-seq
    comparison between HCM patients and controls; the genotype-stratified
    difference is the finding that held.
- name: NT-proBNP
  presence: Elevated
  context: Serum, reflecting wall stress and heart-failure burden
  notes: >-
    N-terminal pro-brain natriuretic peptide is released in response to
    myocardial wall stress and is elevated in hypertrophic cardiomyopathy in
    proportion to heart-failure burden. It is prognostic rather than diagnostic:
    it does not distinguish hypertrophic cardiomyopathy from its phenocopies, and
    it carries no MYH7 specificity.
  evidence:
  - reference: PMID:34940836
    reference_title: "N-terminal pro-brain natriuretic peptide and adverse outcomes in Chinese patients with hypertrophic cardiomyopathy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The present study indicated NT-proBNP was a novel biomarker suitable for
      predicting adverse prognosis in patients with HCM, which may be used for
      early recognition and risk stratification.
    explanation: >-
      Establishes NT-proBNP as a prognostic biomarker in hypertrophic
      cardiomyopathy. Directness is INDIRECT because the cohort is broad HCM
      rather than genotyped MYH7 carriers.
imaging_findings:
- name: Late Gadolinium Enhancement on Cardiac Magnetic Resonance
  description: >-
    Late gadolinium enhancement on contrast-enhanced cardiac magnetic resonance
    images the replacement-fibrosis burden of the myocardium. It is used for
    sudden-death risk stratification rather than for diagnosis: its pooled
    specificity for arrhythmic endpoints is low (39-42%), so a positive scan
    raises risk without identifying who will have an event.
  modality: MRI
  imaging_finding_term:
    preferred_term: late gadolinium enhancement
    term:
      id: NCIT:C209440
      label: Late Gadolinium Enhancement
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: PMID:33171204
    reference_title: "Risk stratification using late gadolinium enhancement on cardiac magnetic resonance imaging in patients with hypertrophic cardiomyopathy: A systematic review and meta-analysis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      LGE positivity was associated with higher odds of the endpoint of sudden
      cardiac death (SCD;OR 1.69, 95%CI 1.03-2.78)
    explanation: >-
      Gives the pooled effect size for the arrhythmic endpoint this finding is
      used to predict. Directness is INDIRECT because the pooled studies enrolled
      broad HCM, not genotyped MYH7 carriers.
  - reference: PMID:33171204
    reference_title: "Risk stratification using late gadolinium enhancement on cardiac magnetic resonance imaging in patients with hypertrophic cardiomyopathy: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      The pooled sensitivity and specificity of positive LGE on c-MRI for SCD
      were 65% and 42%, respectively
    explanation: >-
      Records the operating characteristics, which is the reason this is curated
      as a risk marker rather than a diagnostic finding.
progression:
- phase: Genotype-positive, phenotype-negative
  notes: >-
    A carrier of a pathogenic MYH7 variant with no left ventricular hypertrophy
    on imaging. This is not a benign state to be discharged from follow-up:
    penetrance is age-related, so surveillance must be longitudinal. Pooled
    penetrance in clinically ascertained non-proband MYH7 relatives is far higher
    than in carriers found incidentally in population cohorts, which is why a
    penetrance figure cannot be quoted without its ascertainment context.
  evidence:
  - 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), ≈60% for TNNT2 (troponin T2) and TNNI3
      (troponin I3), and ≈65% for MYH7 (myosin heavy chain 7).
    explanation: >-
      Gives the MYH7-specific penetrance in non-proband relatives found by
      cascade screening, the highest of the sarcomere genes compared, which is
      what makes this phase a surveillance state rather than reassurance.
  - 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%
    explanation: >-
      The counterweight to the figure above: the same variant classes carry a far
      lower penetrance when found incidentally rather than through a family, so a
      penetrance number cannot be quoted without its ascertainment context.
  - 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: >-
      short-term gene-specific phenotypic conversion varied between ≈12% for
      MYBPC3 and ≈23% for MYH7.
    explanation: >-
      Quantifies the rate at which carriers leave this phase, and separates MYH7
      from MYBPC3 on it — roughly twice the short-term conversion rate.
- phase: Overt hypertrophy, with or without outflow obstruction
  notes: >-
    Conversion to measurable left ventricular hypertrophy, defined in adults as
    maximal end-diastolic wall thickness of 15 mm or more unexplained by loading
    conditions. Obstruction may be present at rest, provocable, or absent.
  evidence:
  - reference: PMID:28912181
    reference_title: "Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Left ventricular outflow tract obstruction is present at rest in about one
      third of the patients and can be provoked in another third.
    explanation: >-
      Quantifies how the overt phase divides between resting, provocable and
      absent obstruction, which is what determines management at this stage.
- phase: Complications
  notes: >-
    Atrial fibrillation with thromboembolic risk, progressive fibrosis,
    ventricular arrhythmia and heart failure. Most patients follow a relatively
    benign course; sudden cardiac death is the complication that drives risk
    stratification and is concentrated in adolescents and young adults.
  evidence:
  - reference: PMID:28912181
    reference_title: "Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      In the majority of patients, HCM has a relatively benign course. However,
      HCM is also an important cause of sudden cardiac death, particularly in
      adolescents and young adults.
    explanation: >-
      Sets the base rate against which the arrhythmic complication of this phase
      is judged, and locates its peak in adolescence and young adulthood.
diagnosis:
- name: Echocardiographic Wall-Thickness Criterion
  description: >-
    The clinical diagnosis rests on a cardiac imaging measurement, not on
    genotype: an end-diastolic wall thickness of 15 mm or more anywhere in the
    left ventricle, not explained by loading conditions and with other causes of
    hypertrophy ruled out. A 13-14 mm threshold applies when there is a positive
    family history or a positive genetic test, which is the situation of a CMH1
    cascade-screened relative. Paediatric diagnosis uses body-size-adjusted
    z-scores instead of an absolute thickness.
  diagnosis_term:
    preferred_term: transthoracic echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:38540296
    reference_title: "Role of Genetics in Diagnosis and Management of Hypertrophic Cardiomyopathy: A Glimpse into the Future."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical diagnosis of HCM in adult patients is typically established
      using any cardiac imaging technique that shows an end-diastolic wall
      thickness of ≥15 mm anywhere in the left ventricle, which cannot be
      explained solely by pressure overload states, and after ruling out any
      other conditions that may cause LV hypertrophy. A cutoff of 13-14 mm can be
      diagnostic with a positive family history or a positive genetic test
    explanation: >-
      States both thresholds and the exclusion requirement. Directness is INDIRECT
      because the criterion is for hypertrophic cardiomyopathy as a phenotype
      rather than for the MYH7 entity, which has no imaging signature of its own.
  notes: >-
    The lowered 13-14 mm threshold is what makes genetic testing consequential
    for relatives rather than merely informative: a confirmed familial variant
    changes the wall thickness at which a relative is called affected.
- name: Sarcomere Gene Panel Testing
  description: >-
    A phenotype-anchored next-generation sequencing panel covering the core
    sarcomere genes (MYH7, MYBPC3, TNNT2, TNNI3, MYL2, MYL3, TPM1, ACTC1) plus
    genes for clinically plausible phenocopies. This is what establishes the CMH1
    diagnosis specifically, since nothing on imaging distinguishes MYH7 disease
    from its sarcomeric siblings. Yield depends on how the patient was
    ascertained rather than on the test.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:38540296
    reference_title: "Role of Genetics in Diagnosis and Management of Hypertrophic Cardiomyopathy: A Glimpse into the Future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      The yield of genetic testing for a disease-causing variant is 30% in
      sporadic cases and up to 60% in familial cases and in younger patients with
      typical asymmetrical septal hypertrophy.
    explanation: >-
      Quantifies the diagnostic yield and shows it doubles with familial
      ascertainment, which is the number a clinician needs before ordering the
      test.
  - reference: PMID:38540296
    reference_title: "Role of Genetics in Diagnosis and Management of Hypertrophic Cardiomyopathy: A Glimpse into the Future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic testing using targeted disease-specific panels that utilize
      next-generation sequencing (NGS) and include sarcomeric genes with the
      strongest evidence of association and syndrome-associated genes is highly
      recommended for every HCM patient to confirm the diagnosis, identify the
      molecular etiology, and guide screening and management.
    explanation: >-
      Establishes the panel composition and that testing is recommended for every
      patient rather than only for selected ones.
  notes: >-
    A variant of uncertain significance is not actionable for predictive cascade
    testing: a relative who carries one still needs longitudinal surveillance
    rather than being called unaffected. That constraint is why this entry's
    progression section curates the genotype-positive/phenotype-negative state as
    a surveillance phase.
- name: Cascade Testing of First-Degree Relatives
  description: >-
    When a decisively pathogenic variant is identified in the proband, targeted
    testing is offered to phenotype-negative first-degree relatives regardless of
    age, and the result then determines whether that relative enters longitudinal
    clinical surveillance or leaves it. This is the pathway through which the
    penetrance figures curated in this entry's progression section are generated,
    and the reason they are ascertainment-dependent.
  diagnosis_term:
    preferred_term: cascade genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:38540296
    reference_title: "Role of Genetics in Diagnosis and Management of Hypertrophic Cardiomyopathy: A Glimpse into the Future."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The current guidelines recommend focused cascade genetic testing regardless
      of age in phenotype-negative first-degree relatives if a variant with
      decisive evidence of pathogenicity has been identified in the proband.
    explanation: >-
      States the cascade-testing recommendation and its precondition, a variant
      with decisive pathogenicity evidence in the proband.
differential_diagnoses:
- name: Storage and Infiltrative Phenocopies of Left Ventricular Hypertrophy
  description: >-
    Unexplained left ventricular hypertrophy is not specific to sarcomeric
    disease. Glycogen storage and lysosomal disorders (Danon disease, PRKAG2
    glycogenosis, Pompe disease, Fabry disease), extracellular deposition
    (transthyretin and AL amyloidosis) and mitochondrial disease all thicken the
    myocardium. Distinguishing them from CMH1 matters clinically because several
    have disease-specific therapy that sarcomeric HCM does not, and because a
    wrong call misdirects family screening. Low ECG voltage despite marked
    hypertrophy is the classic pointer away from a sarcomeric cause.
  evidence:
  - reference: PMID:29506729
    reference_title: "Common presentation of rare diseases: Left ventricular hypertrophy and diastolic dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      several metabolic diseases lead to myocardial thickening, either due to
      intracellular storage (glycogen storage and lysosomal diseases),
      extracellular deposition (TTR and AL amyloidosis) or due to abnormal energy
      metabolism (mitochondrial diseases).
    explanation: >-
      Names the classes of phenocopy that must be excluded before attributing
      unexplained hypertrophy to a sarcomeric cause.
  - reference: PMID:29506729
    reference_title: "Common presentation of rare diseases: Left ventricular hypertrophy and diastolic dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      as there are specific therapies for some forms of HCM including enzyme
      substitution and chaperone therapies and specific treatments for TTR
      amyloidosis, a differential diagnosis should be sought in all patients with
      unexplained left ventricular hypertrophy.
    explanation: >-
      States why this differential is actionable rather than academic: several
      phenocopies have disease-specific treatment.
  notes: >-
    Diastolic dysfunction does not discriminate here. The same source reports
    that diastolic dysfunction is a key feature of HCM and its phenocopies alike
    and that its value in differential diagnosis is limited, so it is curated as
    a shared phenotype rather than a distinguishing feature.
- name: Hypertrophic Cardiomyopathy due to other sarcomere genes
  description: >-
    MYBPC3, TNNT2, TNNI3, TPM1, ACTC1, MYL2 and MYL3 also carry definitive
    gene-disease validity for hypertrophic cardiomyopathy, and MYH7 and MYBPC3
    together account for roughly half of HCM families. The phenotypes overlap
    substantially, so only genetic testing separates CMH1 from its sarcomeric
    siblings. The mechanistic contrast is with MYBPC3 disease, which is
    predominantly truncating and acts by haploinsufficiency, where MYH7 disease
    is predominantly missense and acts through a stably expressed mutant motor.
  disease_term:
    preferred_term: hypertrophic cardiomyopathy
    term:
      id: MONDO:0005045
      label: hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:28912181
    reference_title: "Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MYH7 and MYBPC3, encoding β-myosin heavy chain and myosin-binding protein
      C, respectively, are the 2 most common genes involved, together accounting
      for ≈50% of the HCM families.
    explanation: >-
      Quantifies the sarcomeric differential that CMH1 sits inside and names its
      nearest neighbour.
treatments:
- name: Mavacamten (Cardiac Myosin Inhibitor)
  description: >-
    Mavacamten is a small-molecule allosteric inhibitor of cardiac myosin ATPase
    that reduces the number of force-generating actin-myosin cross-bridges,
    stabilizing myosin in the energy-sparing super-relaxed state. It directly
    counteracts the hypercontractility that is the central abnormality of HCM, and
    is approved for symptomatic obstructive hypertrophic cardiomyopathy; because
    beta-cardiac myosin is the MYH7 gene product, the drug acts on the same motor
    that carries the CMH1 lesion.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mavacamten
      term:
        id: CHEBI:756998
        label: mavacamten
  target_mechanisms:
  - target: Destabilization of the Autoinhibited Super-Relaxed State
    treatment_effect: INHIBITS
    description: >-
      Mavacamten stabilizes the super-relaxed state and reduces the number of
      heads available for force generation, directly opposing the SRX
      destabilization that drives hypercontractility.
    evidence:
    - reference: PMID:40118457
      reference_title: "Dynamics of β-cardiac myosin between the super-relaxed and disordered-relaxed states."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        cardiac myosin inhibitor mavacamten slows nucleotide release by an equal
        factor for both heavy meromyosin and subfragment 1, thus only indirectly
        influencing the occupancy time of the SRX state.
      explanation: >-
        Establishes mavacamten's biochemical action on beta-cardiac myosin
        nucleotide handling and its effect on SRX-state occupancy, the node it
        targets.
  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: >-
      The pivotal phase 3 trial establishing the rationale and use of a cardiac
      myosin inhibitor targeting hypercontractility in obstructive HCM.
- name: Septal Reduction (Surgical Myectomy)
  description: >-
    Surgical septal myectomy relieves severe drug-refractory left ventricular
    outflow tract obstruction by resecting hypertrophied basal septal muscle.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: septal myectomy
    term:
      id: NCIT:C51591
      label: Myectomy
  target_mechanisms:
  - target: Diastolic Dysfunction, Outflow Obstruction, Heart Failure and Arrhythmic Risk
    treatment_effect: INHIBITS
    description: >-
      Resecting hypertrophied basal septal muscle removes the anatomical
      substrate of the dynamic outflow gradient, acting on the obstruction
      component of this node.
  evidence:
  - reference: PMID:16053960
    reference_title: "Long-term effects of surgical septal myectomy on survival in patients with obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surgical myectomy performed to relieve outflow obstruction and severe
      symptoms in HCM was associated with long-term survival equivalent to that
      of the general population, and superior to obstructive HCM without
      operation.
    explanation: >-
      The long-term survival result that establishes myectomy as more than
      symptomatic relief. Directness is INDIRECT because the cohort is obstructive
      HCM broadly rather than genotyped MYH7 carriers, and because the design is
      an observational comparison rather than a randomized one.
- name: Implantable Cardioverter-Defibrillator
  description: >-
    An implantable cardioverter-defibrillator provides secondary or primary
    prevention of sudden cardiac death in patients judged to be at high arrhythmic
    risk, terminating malignant ventricular arrhythmia.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_mechanisms:
  - target: Sudden Cardiac Death
    treatment_effect: INHIBITS
    description: >-
      The device does not modify the arrhythmic substrate; it terminates the
      ventricular tachyarrhythmia that would otherwise cause death, so it acts on
      the outcome rather than on any upstream mechanism.
  evidence:
  - reference: PMID:17652294
    reference_title: "Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In a high-risk HCM cohort, ICD interventions for life-threatening
      ventricular tachyarrhythmias were frequent and highly effective in
      restoring normal rhythm.
    explanation: >-
      The multicenter registry result establishing device efficacy in high-risk
      HCM. Directness is INDIRECT because the 506-patient cohort is high-risk HCM
      broadly rather than genotyped MYH7 carriers.
  - reference: PMID:17652294
    reference_title: "Implantable cardioverter-defibrillators and prevention of sudden cardiac death in hypertrophic cardiomyopathy."
    supports: REFUTE
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ICD complications included inappropriate shocks in 136 patients (27%).
    explanation: >-
      Recorded as REFUTE against an unqualified claim of net benefit: in the same
      registry that established efficacy, over a quarter of recipients received an
      inappropriate shock. Curated as a separate item with the opposite direction
      rather than hedged into the efficacy item, because the two sentences make
      opposite claims about the same intervention. Directness is INDIRECT for the
      same broad-HCM reason as its companion.
- name: Aficamten (Cardiac Myosin Inhibitor)
  description: >-
    Aficamten is an oral selective cardiac myosin inhibitor. Like mavacamten it
    acts directly on the beta-cardiac myosin
    motor that carries the CMH1 lesion, reducing left ventricular outflow tract
    gradients by mitigating hypercontractility. In the phase 3 SEQUOIA-HCM trial
    it improved peak oxygen uptake in symptomatic obstructive disease.
  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: Sarcomere Hypercontractility with Impaired Relaxation
    treatment_effect: INHIBITS
    description: >-
      Myosin inhibition reduces the number of force-generating cross-bridges,
      opposing the hypercontractile cellular state at the point where the MYH7
      lesion produces it.
    evidence:
    - reference: PMID:38739079
      reference_title: "Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Aficamten is an oral selective cardiac myosin inhibitor that reduces left
        ventricular outflow tract gradients by mitigating cardiac
        hypercontractility.
      explanation: >-
        Supports this edge specifically: names hypercontractility as the
        mechanism the drug acts through, rather than merely reporting that the
        drug works.
  evidence:
  - reference: PMID:38739079
    reference_title: "Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per
      kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the
      aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in
      the placebo group
    explanation: >-
      The pivotal phase 3 efficacy result for this drug, against a placebo
      comparator. Directness is INDIRECT because SEQUOIA-HCM enrolled
      symptomatic obstructive HCM broadly rather than genotyped MYH7 carriers.
- name: Disopyramide
  description: >-
    Disopyramide is a class Ia antiarrhythmic with strong negative inotropic
    action, used as add-on therapy to a beta-blocker for persistent left
    ventricular outflow tract obstruction. It reduces the subaortic gradient and
    can defer or avoid septal reduction therapy; its limits are vagolytic side
    effects and the need for QT monitoring.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: disopyramide
      term:
        id: CHEBI:4657
        label: disopyramide
  target_mechanisms:
  - target: Diastolic Dysfunction, Outflow Obstruction, Heart Failure and Arrhythmic Risk
    treatment_effect: INHIBITS
    description: >-
      The negative inotropic effect reduces the dynamic subaortic gradient, acting
      on the obstruction component of this node rather than on the underlying
      sarcomeric lesion.
    evidence:
    - reference: PMID:15837258
      reference_title: "Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        Two-thirds of obstructed HCM patients treated with disopyramide could be
        managed medically with amelioration of symptoms and about 50% reduction
        in subaortic gradient over >/=3 years.
      explanation: >-
        Names the subaortic gradient as the quantity the drug moves and gives the
        size of the effect, which is the content of this edge rather than of the
        treatment record as a whole. Directness is INDIRECT because the series is
        obstructive HCM broadly rather than genotyped MYH7 carriers.
  evidence:
  - reference: PMID:15837258
    reference_title: "Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seventy-eight patients (66%) were maintained with disopyramide without the
      necessity for major non-pharmacologic intervention with surgical myectomy,
      alcohol ablation, or pacing; outflow gradient at rest decreased from 75 +/-
      33 to 40 +/- 32 mm Hg (p < 0.0001)
    explanation: >-
      Quantifies gradient reduction and the proportion managed medically.
      Directness is INDIRECT because the cohort is obstructive HCM broadly rather
      than genotyped MYH7 carriers.
  - reference: PMID:15837258
    reference_title: "Multicenter study of the efficacy and safety of disopyramide in obstructive hypertrophic cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: >-
      Disopyramide therapy does not appear to be proarrhythmic in HCM and should
      be considered before proceeding to surgical myectomy or alternate
      strategies.
    explanation: >-
      Records the safety finding that positions this drug ahead of septal
      reduction in the treatment sequence.
- name: Alcohol Septal Ablation
  description: >-
    Catheter-based infarction of the basal septum through a septal perforator
    branch, an alternative to surgical myectomy for drug-refractory obstruction
    in patients who are poor surgical candidates. It does not address concomitant
    mitral or subvalvular abnormalities, which is where myectomy is preferred.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: alcohol septal ablation
    term:
      id: NCIT:C80439
      label: Septal Ablation
  target_mechanisms:
  - target: Diastolic Dysfunction, Outflow Obstruction, Heart Failure and Arrhythmic Risk
    treatment_effect: INHIBITS
    description: >-
      Reduces basal septal muscle mass, relieving the mechanical obstruction
      component of this node.
    evidence:
    - reference: PMID:26746632
      reference_title: "Long-term clinical outcome after alcohol septal ablation for obstructive hypertrophic cardiomyopathy: results from the Euro-ASA registry."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Alcohol septal ablation reduced the LV outflow tract gradient from 67 ±
        36 to 16 ± 21 mmHg (P < 0.01) and NYHA class from 2.9 ± 0.5 to 1.6 ± 0.7
        (P < 0.01).
      explanation: >-
        Supports this edge specifically: names the outflow gradient as the
        quantity the procedure moves and gives the size of the reduction across
        1275 patients. Directness is INDIRECT because the registry is obstructive
        HCM broadly rather than genotyped MYH7 carriers.
  evidence:
  - reference: PMID:26746632
    reference_title: "Long-term clinical outcome after alcohol septal ablation for obstructive hypertrophic cardiomyopathy: results from the Euro-ASA registry."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The Euro-ASA registry demonstrated low peri-procedural and long-term
      mortality after ASA. This intervention provided durable relief of symptoms
      and a reduction of LV outflow tract obstruction in selected and highly
      symptomatic patients with obstructive HCM.
    explanation: >-
      The largest multinational ablation registry (1275 patients, median 5.7
      years) establishing durability and peri-procedural safety. Directness is
      INDIRECT because the cohort is obstructive HCM broadly rather than
      genotyped MYH7 carriers.
  notes: >-
    The registry reports that residual post-procedural obstruction was associated
    with both worse functional status and worse prognosis, so the entry records
    ablation as gradient-directed therapy whose benefit tracks how completely the
    gradient is eliminated. No claim is made here about ablation versus myectomy:
    the comparative literature was not screened this round, and the preference for
    myectomy stated in this treatment's description is a statement of when the
    concomitant mitral and subvalvular pathology needs surgical correction, not a
    comparative-efficacy claim.

    therapeutic_modality is SURGERY because that is the coarse procedural bucket
    the enum offers. The procedure is catheter-based, and NCIT:C80439 sits under
    cardiac ablation rather than under surgery; there is no DEVICE-free
    interventional value in ModalityEnum to distinguish the two.
- name: MYH7 Allele-Directed Gene Editing (Preclinical)
  description: >-
    Two preclinical strategies target the MYH7 allele itself rather than its
    downstream consequences. Adenine base editing corrects the pathogenic base in
    patient-derived cardiomyocytes and in humanized mice; high-precision Cas13d
    instead degrades the mutant transcript while sparing the wild-type allele,
    which suits the dominant-negative biology of missense MYH7 disease. Neither is
    an approved therapy, and both face delivery, durability and off-target
    questions. They are curated here because they are the only interventions in
    this entry that act on the trigger node.
  therapeutic_modality: GENE_EDITING
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: MYH7 Missense Variant in Beta-Cardiac Myosin Heavy Chain
    treatment_effect: INHIBITS
    description: >-
      Base editing removes the causal substitution and RNA-targeting Cas13d
      suppresses the mutant transcript, so both act on the initiating lesion
      rather than on any downstream mechanism.
    evidence:
    - reference: PMID:36797478
      reference_title: "Base editing correction of hypertrophic cardiomyopathy in human cardiomyocytes and humanized mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We show that delivery of base editing components rescues pathological
        manifestations of HCM in induced pluripotent stem cell cardiomyocytes
        derived from patients with HCM and in a humanized mouse model of HCM.
      explanation: >-
        Supports the edge specifically: correcting the MYH7 base rescues the
        disease phenotype, which is what establishes the trigger node as the
        target being acted on.
  evidence:
  - reference: PMID:36797478
    reference_title: "Base editing correction of hypertrophic cardiomyopathy in human cardiomyocytes and humanized mice."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In this study we identify an adenine base editor and single-guide RNA
      system that can efficiently correct this human PV with minimal bystander
      editing and off-target editing at selected sites.
    explanation: >-
      Establishes correction of the archetypal CMH1 allele, R403Q, as technically
      achievable with acceptable editing specificity.
  - reference: PMID:38752340
    reference_title: "Allele-Specific Suppression of Variant MHC With High-Precision RNA Nuclease CRISPR-Cas13d Prevents Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In vivo application of hpCas13d to 2 hypertrophic cardiomyopathy models
      caused by distinct human MYH7 analogous sequence variations specifically
      suppressed the altered allele and prevented cardiac hypertrophy.
    explanation: >-
      The alternative allele-directed strategy: silencing the mutant transcript
      rather than correcting the gene, which suits a dominant-negative missense
      mechanism.
  - reference: PMID:36797483
    reference_title: "Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Together, these data indicated that base editing of the mutant R403Q
      allele, delivered several months or only weeks in advance of the typical
      time for disease manifestations, resulted in durable prevention of
      ventricular remodeling and hypertrophy.
    explanation: >-
      The independent contemporaneous demonstration that a single in vivo editing
      dose durably prevents the remodeling phenotype in an R403Q mouse, curated
      alongside the correction and silencing strategies above so the treatment
      record does not rest on a single group.
  notes: >-
    Preclinical only. No gene, RNA or cell therapy is approved for CMH1, and the
    named clinical gene-replacement program in hypertrophic cardiomyopathy
    (TN-201) targets MYBPC3, not MYH7, so it is deliberately not recorded here.
- name: Beta-Adrenergic Blockade
  description: >-
    A non-vasodilating beta-blocker is the conventional first-line drug for
    symptomatic obstructive hypertrophic cardiomyopathy, reducing the dynamic
    outflow gradient through negative inotropy and chronotropy and lengthening
    diastolic filling time. The evidence base is weaker than its first-line
    position suggests: in the only randomized placebo-controlled crossover trial
    in mildly to moderately symptomatic patients, nadolol did not improve maximal
    oxygen consumption and reduced peak exercise work load in most patients,
    though a majority still preferred active drug to placebo.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: beta-adrenergic antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
    - preferred_term: nadolol
      term:
        id: CHEBI:7444
        label: nadolol
  target_mechanisms:
  - target: Diastolic Dysfunction, Outflow Obstruction, Heart Failure and Arrhythmic Risk
    treatment_effect: INHIBITS
    description: >-
      Negative inotropy reduces the dynamic subaortic gradient and slower heart
      rates lengthen diastolic filling, so the drug acts on the obstruction and
      filling components of this node rather than on the sarcomeric lesion.
  evidence:
  - reference: PMID:8496536
    reference_title: "A double-blind, placebo-controlled crossover trial of nadolol and verapamil in mild and moderately symptomatic hypertrophic cardiomyopathy."
    supports: REFUTE
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with mild or moderately symptomatic hypertrophic
      cardiomyopathy, exercise capacity was not improved by nadolol or verapamil,
      and individuals were more often impaired by nadolol than with verapamil.
    explanation: >-
      Recorded as REFUTE against the claim that beta-blockade improves functional
      capacity: in this randomized crossover trial it did not, and nadolol
      impaired peak work load more often than verapamil did. Directness is
      INDIRECT because the trial enrolled broad HCM rather than genotyped MYH7
      carriers, and because it was restricted to mildly and moderately
      symptomatic patients.
  - reference: PMID:8496536
    reference_title: "A double-blind, placebo-controlled crossover trial of nadolol and verapamil in mild and moderately symptomatic hypertrophic cardiomyopathy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite the effects on exercise capacity, 13 patients (81%) preferred drug
      treatment (8 verapamil, 5 nadolol) over placebo (p = 0.001).
    explanation: >-
      The counterpart to the item above, and the reason both drugs remain in use:
      patients preferred active drug to placebo even where objective exercise
      capacity did not improve. Curated as a separate item because the sentence
      supports a different claim from the one the CONCLUSIONS sentence refutes.
  notes: >-
    Curated with an honest negative alongside the positive. The first-line
    position of beta-blockade in hypertrophic cardiomyopathy rests on
    guideline consensus and physiological reasoning, not on a trial showing
    improved exercise capacity; the one randomized placebo-controlled trial found
    the opposite. Both evidence items quote the same study, split so each carries
    a single direction, as the evidence policy requires.
- name: Verapamil
  description: >-
    A non-dihydropyridine calcium channel blocker used when beta-blockade is
    ineffective or not tolerated. It improves diastolic filling and reduces
    symptoms, and in direct comparison was better tolerated than nadolol.
    Guidelines caution against it in severe outflow obstruction with hypotension
    because its vasodilator effect can worsen the gradient.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: verapamil
      term:
        id: CHEBI:9948
        label: verapamil
    - preferred_term: calcium channel blocker
      term:
        id: NCIT:C333
        label: Calcium Channel Blocker
  target_mechanisms:
  - target: Diastolic Dysfunction, Outflow Obstruction, Heart Failure and Arrhythmic Risk
    treatment_effect: INHIBITS
    description: >-
      Acts on the diastolic-filling component of this node; unlike the myosin
      inhibitors it does not target the contractile lesion itself.
  evidence:
  - reference: PMID:8496536
    reference_title: "A double-blind, placebo-controlled crossover trial of nadolol and verapamil in mild and moderately symptomatic hypertrophic cardiomyopathy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Verapamil improved reported performance at work compared with nadolol (p =
      0.01) and tended to improve other measures of health-related behavior and
      symptoms compared with nadolol and placebo.
    explanation: >-
      The head-to-head result placing verapamil ahead of a beta-blocker on
      patient-reported measures, which is why it is curated as a distinct
      treatment rather than a footnote to beta-blockade. Directness is INDIRECT
      because the trial enrolled broad HCM rather than genotyped MYH7 carriers.
- name: Oral Anticoagulation for Atrial Fibrillation
  description: >-
    Atrial fibrillation in hypertrophic cardiomyopathy carries a thromboembolic
    risk high enough that anticoagulation is recommended on the arrhythmia alone
    rather than gated on a general-population risk score. Roughly a fifth of
    patients develop atrial fibrillation and about a quarter of those experience
    thromboembolism.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticoagulant
      term:
        id: NCIT:C263
        label: Anticoagulant Agent
  target_mechanisms:
  - target: Atrial Fibrillation
    treatment_effect: INHIBITS
    description: >-
      Anticoagulation does not treat the arrhythmia; it acts on the
      thromboembolic consequence that makes atrial fibrillation dangerous in this
      disease.
  evidence:
  - reference: PMID:24014282
    reference_title: "Atrial fibrillation and thromboembolism in patients with hypertrophic cardiomyopathy: systematic review."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      AF is common in HCM and associated with high thromboembolic risk. LA
      dimension and age are independently associated with AF but the literature
      is insufficient to create robust clinical tools to predict AF or
      thromboembolism. Most data suggest that AF patients should be
      anticoagulated.
    explanation: >-
      The pooled basis for anticoagulating on the arrhythmia alone, and an
      explicit statement that the evidence does not support a prediction tool.
      Directness is INDIRECT because the 7381-patient pooled population is broad
      HCM rather than genotyped MYH7 carriers.
  - reference: PMID:24014282
    reference_title: "Atrial fibrillation and thromboembolism in patients with hypertrophic cardiomyopathy: systematic review."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A population of 7381 patients (33 studies) revealed overall AF prevalence
      of 22.45% (95% CI 20.13% to 24.77%)
    explanation: >-
      Quantifies how often the indication for this treatment arises. Directness is
      INDIRECT for the same broad-HCM reason.
  notes: >-
    The same review records that there were no randomised controlled trials of
    therapy, and that data on interventions other than anticoagulation were
    limited and contradictory. The recommendation is therefore curated as
    consensus resting on observational association, not on trial evidence.
clinical_trials:
- name: NCT01912534
  phase: PHASE_II
  status: COMPLETED
  description: >-
    VANISH (Valsartan for Attenuating Disease Evolution in Early Sarcomeric
    Hypertrophic Cardiomyopathy) tested whether the angiotensin receptor blocker
    valsartan can modify disease progression in young carriers of sarcomeric gene
    mutations, including MYH7, with early-stage HCM.
  target_phenotypes:
  - preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:31813281
    reference_title: "Baseline Characteristics of the VANISH Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      targeted young sarcomeric gene mutation carriers with early-stage
      hypertrophic cardiomyopathy (HCM) to test whether valsartan can modify
      disease progression.
    explanation: >-
      Describes the VANISH trial's design and its enrollment of young sarcomeric
      (including MYH7) mutation carriers with early HCM.
- name: NCT05186818
  phase: PHASE_III
  status: COMPLETED
  description: >-
    SEQUOIA-HCM, the pivotal phase 3 trial of the cardiac myosin inhibitor
    aficamten in symptomatic obstructive hypertrophic
    cardiomyopathy. Relevant to CMH1 because the drug's target is the
    beta-cardiac myosin motor that MYH7 encodes.
  target_phenotypes:
  - preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  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: >-
      Establishes the trial's agent, comparator and target population.
- name: NCT04349072
  phase: PHASE_III
  status: COMPLETED
  description: >-
    VALOR-HCM, which tested whether mavacamten allows patients who already meet
    guideline criteria for septal reduction therapy to avoid the procedure. It is
    the trial that positioned myosin inhibition ahead of invasive septal
    reduction in the treatment sequence rather than alongside it.
  target_phenotypes:
  - preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  evidence:
  - reference: PMID:35798455
    reference_title: "Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After 16 weeks, 43 of 56 placebo patients (76.8%) and 10 of 56 mavacamten
      patients (17.9%) met guideline criteria or underwent SRT, difference
      (58.9%; 95% CI: 44.0%-73.9%; P < 0.001).
    explanation: >-
      The primary endpoint result. Directness is INDIRECT because the trial
      enrolled obstructive HCM broadly rather than genotyped MYH7 carriers.
experimental_models:
- name: MYH7 R403Q hiPSC-cardiomyocyte cardiac microtissue with wild-type fibroblasts
  description: >-
    Engineered three-dimensional cardiac microtissues built from isogenic MYH7
    R403Q heterozygous hiPSC-derived cardiomyocytes together with wild-type
    ventricular cardiac fibroblasts. The co-culture is the point: a
    cardiomyocyte-only model cannot show the cardiomyocyte-to-fibroblast
    cross-talk that produces the fibrotic component of the disease, and this
    system reproduces collagen deposition, tissue stiffening and the EGFR
    dependence of stromal activation.
  experimental_model_type: CO_CULTURE
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:39413182
  modeled_mechanisms:
  - target: Cardiomyocyte-to-Fibroblast EGFR Paracrine Signaling
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      The model was built to interrogate this node and demonstrates each of its
      claims — paracrine transfer, fibroblast proliferation dependence, and EGFR
      as the transducing receptor.
    limitations: >-
      Fidelity is MODERATE rather than HIGH because the system omits the immune,
      vascular and haemodynamic-loading environments in which fibrosis develops
      in patients, and because hiPSC-derived cardiomyocytes remain immature
      relative to adult ventricular myocardium.
    evidence:
    - reference: PMID:39413182
      reference_title: "Hypertrophic cardiomyopathy-associated mutations drive stromal activation via EGFR-mediated paracrine signaling."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Together, these findings establish a paracrine-mediated cross-talk
        potentially responsible for fibrotic changes observed in HCM.
      explanation: >-
        The authors' own summary of what the model establishes, which is the
        content of the node it is linked to.
  - target: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Reproduces the interstitial-fibrosis and stiffening component of the
      remodeling node.
    limitations: >-
      It reproduces only one of the node's three components. There is no
      ventricular hypertrophy and no myofibre disarray in a microtissue, and the
      model observes cellular-scale readouts while the node is a tissue-scale
      claim, so the tissue-level inference is an upward extrapolation.
    divergences:
    - divergence_type: SCALE_EXTRAPOLATION
      materiality: QUALIFYING
      description: >-
        Collagen content and elastic modulus are measured in a millimetre-scale
        engineered construct of two cell types; the node describes remodeling of
        an intact ventricular wall under haemodynamic load.
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        Cardiomyocyte hypertrophy and myofibre disarray, two of the three
        components of the node, are not represented in the model at all.
- name: MYH7 G256E gene-edited hiPSC-cardiomyocyte multiscale platform
  description: >-
    An isogenic gene-edited MYH7 WT/G256E hiPSC line characterised in parallel at
    purified-protein, myofibril, single-cell and engineered-heart-tissue level.
    Its value for this entry is that it carries one allele through every scale of
    the mechanism chain at once, so the hypercontractility claim does not depend
    on any single assay — the failure mode the report itself flags for R403Q,
    where single-assay measurements have gone both ways.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:38683993
  modeled_mechanisms:
  - target: Destabilization of the Autoinhibited Super-Relaxed State
    relationship: MEASURES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: >-
      Quantifies the folded-back myosin fraction directly for a named MYH7
      allele, giving the node a measured effect size rather than a class claim.
  - target: Sarcomere Hypercontractility with Impaired Relaxation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Greater and faster tension development was reproduced in myofibrils, in
      single cells and in engineered heart tissue from the same edited line.
    limitations: >-
      G256E is an incompletely penetrant allele, so the cellular phenotype it
      produces is not automatically the phenotype of the more severe MYH7
      alleles; and hiPSC-cardiomyocyte immaturity limits extrapolation of
      absolute contractile parameters to adult myocardium.
    evidence:
    - reference: PMID:38683993
      reference_title: "Incomplete-penetrant hypertrophic cardiomyopathy MYH7 G256E mutation causes hypercontractility and elevated mitochondrial respiration."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Myofibrils from gene-edited MYH7WT/G256E human induced pluripotent stem
        cell-derived cardiomyocytes (hiPSC-CMs) exhibited greater and faster
        tension development. This hypercontractile phenotype persisted in
        single-cell hiPSC-CMs and engineered heart tissues.
      explanation: >-
        Shows the hypercontractile phenotype holding across three scales in one
        isogenic system, which is what makes this model informative for the node
        rather than one more single-assay result.
- name: MYH7 R403Q and TNNT2 R92Q hiPSC-cardiomyocyte engineered heart tissue
  description: >-
    Two-dimensional hiPSC-cardiomyocyte cultures and three-dimensional engineered
    heart tissue carrying MYH7 R403Q, used to test whether the impaired-relaxation
    phenotype is pharmacologically correctable. Relaxation improved with SGLT2
    inhibitors, and the effect grew with culture duration as the tissue matured.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:38240646
  modeled_mechanisms:
  - target: Sarcomere Hypercontractility with Impaired Relaxation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Reproduces the impaired-relaxation and increased-force halves of the node
      in a human system carrying the archetypal CMH1 allele.
    limitations: >-
      hiPSC-cardiomyocyte immaturity is explicitly a variable in this study
      rather than a background caveat: the size of the drug effect depended on
      culture duration, so results at any single timepoint are maturation-state
      dependent.
    evidence:
    - reference: PMID:38240646
      reference_title: "Hypertrophic cardiomyopathy dysfunction mimicked in human engineered heart tissue and improved by sodium-glucose cotransporter 2 inhibitors."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        HCM mutations in hiPSC-CMs impaired relaxation or increased force,
        mimicking early features observed in human HCM.
      explanation: >-
        States that the model reproduces the early cellular features this node
        describes.
animal_models:
- name: alpha-MHC 403/+ knock-in mouse
  species: Mouse
  genotype: Myh6 Arg403Gln (R403Q) heterozygous knock-in
  description: >-
    The founding animal model of the field, introducing the R403Q substitution
    into the mouse alpha-cardiac myosin heavy chain gene. Heterozygotes develop
    the histopathology of human familial hypertrophic cardiomyopathy with age;
    homozygotes die within a week of birth. Cardiac dysfunction preceded the
    histological changes, which is the model's principal contribution to the
    causal ordering curated in this entry's pathophysiology.
  publication: PMID:8614836
  modeled_mechanisms:
  - target: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      Myocyte disarray, hypertrophy and fibrosis develop and increase with age,
      reproducing the tissue-level remodeling node.
    limitations: >-
      The substitution is in Myh6 (alpha-cardiac myosin), not the Myh7 orthologue
      of the human disease gene, because the adult mouse ventricle expresses
      alpha- rather than beta-myosin. So the model reproduces the pathology of a
      403 substitution in the myosin that mouse hearts actually use, and its
      relevance to human MYH7 disease rests on the residue and the motor domain
      being conserved rather than on the gene being the same one. Mouse cardiac
      electrophysiology also differs substantially from human.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The lesion is carried by the alpha-myosin heavy chain gene Myh6, whereas
        human CMH1 is a disease of MYH7/beta-myosin. The two isoforms differ in
        their kinetics, so a 403 substitution is not necessarily equivalent in
        both.
    evidence:
    - reference: PMID:8614836
      reference_title: "A mouse model of familial hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Cardiac dysfunction preceded histopathologic changes, and myocyte
        disarray, hypertrophy, and fibrosis increased with age.
      explanation: >-
        Documents the tissue phenotype and, importantly for the causal ordering
        curated here, that functional impairment came first.
  notes: >-
    Retained despite its LOW fidelity because it is the model that established
    that a single myosin missense allele is sufficient to produce the disease,
    and because the species caveat it carries is exactly the reason the
    beta-myosin rabbit and pig models below exist.
- name: beta-MyHC-Q403 transgenic rabbit
  species: Rabbit
  genotype: Transgenic beta-myosin heavy chain Gln403 (Q403)
  description: >-
    A transgenic rabbit expressing the Q403 beta-myosin heavy chain, which
    matches the human disease in the myosin isoform as well as the residue: like
    humans and unlike mice, the adult rabbit ventricle runs on beta-myosin. Forty-seven
    animals were phenotyped at four age periods over four years, making this the
    natural-history model for the disease.
  publication: PMID:15135661
  modeled_mechanisms:
  - target: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Disarray, hypertrophy and fibrosis all develop, and the longitudinal design
      separates them in time: disarray appears early and independently of
      hypertrophy and fibrosis, which emerge later around puberty.
    limitations: >-
      This is a transgenic overexpression model rather than a knock-in, so the
      mutant protein is not expressed from its own locus at its own dose. The
      allele is also a single one, Q403, so the age-ordering it reveals may not
      generalise to MYH7 alleles acting through different mechanisms.
    evidence:
    - reference: PMID:15135661
      reference_title: "Evolution of expression of cardiac phenotypes over a 4-year period in the beta-myosin heavy chain-Q403 transgenic rabbit model of human hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Myocyte disarray also occurred early, prior to, and independent of
        hypertrophy and fibrosis. The latter phenotypes evolved predominantly
        during puberty in conjunction with activation of stress-related signaling
        kinases.
      explanation: >-
        Separates the three components of the remodeling node in time and shows
        they are not one process, which is a claim only a longitudinal model can
        make.
  - target: Increased Motor Force and Energetic Cost
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Calcium sensitivity of myofibrillar ATPase activity was altered as the
      earliest detectable phenotype, before any histological or structural
      change.
    limitations: >-
      The direction is a reduction in calcium sensitivity of myofibrillar ATPase
      in this model, which is a different measurement from the raised intrinsic
      force and tension cost curated on the human node from R403Q myectomy
      tissue. It supports the node's claim that myofilament energetics are
      disturbed early, not that they are disturbed in the same direction.
    divergences:
    - divergence_type: PROXY_QUANTITY
      materiality: QUALIFYING
      description: >-
        The model's measured quantity is calcium sensitivity of myofibrillar
        ATPase activity, and it moves downward. The node's quantities are
        intrinsic motor force and the energetic cost of tension, both raised in
        human R403Q myectomy tissue. The model stands in for the node on the
        claim that myofilament energetics are perturbed at the head of the causal
        sequence, not on the direction or the identity of the perturbation.
    evidence:
    - reference: PMID:15135661
      reference_title: "Evolution of expression of cardiac phenotypes over a 4-year period in the beta-myosin heavy chain-Q403 transgenic rabbit model of human hypertrophic cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Ca(+2) sensitivity of myofibrillar ATPase activity is a primary phenotype
        expressed early and independent of the ensuing phenotypes.
      explanation: >-
        Places a myofilament-energetics abnormality at the head of the causal
        sequence in a beta-myosin model.
- name: MYH7 R723G knock-in pig
  species: Pig
  genotype: MYH7 R723G heterozygous knock-in (TALEN-mediated, orthologous c.2167C>G)
  description: >-
    TALEN-mediated knock-in of the orthologous human HCM mutation R723G into the
    porcine MYH7 gene, followed by somatic cell nuclear transfer cloning. Unlike
    the mouse, the pig expresses beta-myosin as the predominant adult ventricular
    isoform and has human-like cardiac anatomy and electrophysiology. The
    piglets died within 24 hours of birth, and this severity is the model's
    limitation as much as its finding.
  publication: PMID:29555974
  modeled_mechanisms:
  - target: Ventricular Hypertrophy, Myocyte Disarray and Fibrosis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      Neonatal animals showed mild myocyte disarray and malformed nuclei,
      establishing that the histological lesion can arise before birth from a
      knock-in MYH7 allele.
    limitations: >-
      The animals died within 24 hours post partem, so the model captures a
      perinatal phenotype far more severe than the adult-onset human disease and
      cannot report on natural history, hypertrophy development, or fibrosis at
      all. Only disarray and nuclear morphology were observed; hypertrophy and
      interstitial fibrosis, the node's other components, were not.
    divergences:
    - divergence_type: TEMPORAL_SCOPE
      materiality: INVALIDATING
      description: >-
        Perinatal lethality truncates the model at 24 hours of age, before the
        adult-onset remodeling this node describes could develop, so the node's
        hypertrophy and fibrosis components have no counterpart in the animal.
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: >-
        The node's hypertrophy component is not merely unobserved: the paper
        reports the hearts showed no obvious hypertrophy. Interstitial fibrosis
        is not reported either way. So of the node's three components the model
        shows one (disarray), contradicts one (hypertrophy), and is silent on the
        third.
    evidence:
    - reference: PMID:29555974
      reference_title: "Successful knock-in of Hypertrophic Cardiomyopathy-mutation R723G into the MYH7 gene mimics HCM pathology in pigs."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Surprisingly, the animals died within 24 h post partem, probably due to
        heart failure as indicated by a shift in the a/ß-MyHC ratio in the left
        ventricle.
      explanation: >-
        Records the perinatal lethality that both defines what this model can
        show and limits it to the earliest phase of the disease.
  notes: >-
    Curated with an explicit note on why the species matters. The authors set the
    model up precisely because orthologous beta-myosin mutations in mice do not
    produce the human phenotype, the adult mouse ventricle running on
    alpha-myosin; a pig ventricle, like a human one, is predominantly beta-myosin.
    That is the same reasoning behind the rabbit model above.

    Spontaneous feline hypertrophic cardiomyopathy (PMID:36928240) was screened
    as a fourth model and deliberately not curated. It is a genuine spontaneous
    large-animal disease and the transcriptomic overlap with human HCM is real,
    but the established breed-associated variants are MYBPC3 (A31P in Maine
    Coon, R820W in Ragdoll) rather than MYH7, and most feline cases are
    genetically unresolved. It would belong in the parent Hypertrophic
    Cardiomyopathy entry, not in the MYH7 entity.
datasets:
- accession: geo:GSE195436
  title: Circulating miR-499a-5p is a potential biomarker of MYH7-associated hypertrophic cardiomyopathy
  description: >-
    Plasma small-RNA sequencing in hypertrophic cardiomyopathy patients and
    controls, with downstream qRT-PCR stratified by causal gene. The dataset
    behind this entry's genotype-specific miR-499a-5p biochemical record.
  data_type: BULK_RNA_SEQ
  sample_count: 15
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:35409153
  notes: >-
    DIRECT relevance: human patient plasma, MYH7 named in the study title and the
    genotype used as the stratifying variable.
- accession: geo:GSE276210
  title: Beta-Adrenergic Stimulation and MYH7 G256E Mutant Gene Dosage Drive Hypertrophic Cardiomyopathy Phenotype Penetrance
  description: >-
    Single-cell RNA sequencing of day-30 iPSC-cardiomyocytes carrying
    heterozygous MYH7 G256E and H251N, plus homozygous G256E and
    isoproterenol-treated heterozygotes. Addresses gene dosage and adrenergic stress as
    modifiers of the incomplete penetrance recorded in this entry's progression
    section.
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 14
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:42282692
  notes: >-
    DIRECT relevance: named MYH7 alleles in a human iPSC system. The linked
    publication is a preprint, so the dataset is curated as a resource rather
    than as support for any claim in this entry.
- accession: geo:GSE198258
  title: Bulk RNAseq analysis of hypertrophic cardiomyopathy (HCM) hiPSC-derived cardiomyocytes (hiPSC-CMs) and the isogenic control
  description: >-
    Day-15 bulk RNA-seq of HCM hiPSC-derived cardiomyocytes against their
    isogenic control, from the study of myosin heavy chain converter-domain
    mutations and early extracellular-matrix dynamics. Relevant to this entry's
    EGFR paracrine fibrosis arm because it profiles matrix changes at an early
    disease stage.
  data_type: BULK_RNA_SEQ
  sample_count: 4
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:35784482
  notes: >-
    DIRECT relevance established from the linked publication rather than the GEO
    summary, which does not name the gene: the study is of myosin heavy chain
    converter-domain mutations, which are MYH7 alleles.
- accession: geo:GSE201755
  title: Base Editing Correction of a Hypertrophic Cardiomyopathy-Causing MYH7 Mutation in Human Cardiomyocytes and Humanized Mice
  description: >-
    Transcriptomes from the adenine base-editing correction of MYH7 R403Q in
    patient-derived iPSC-cardiomyocytes and a humanized mouse model. The dataset
    behind the preclinical gene-editing treatment record in this entry.
  data_type: BULK_RNA_SEQ
  sample_count: 3
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  publication: PMID:36797478
  notes: >-
    DIRECT relevance: the archetypal CMH1 allele R403Q, named in the GEO series
    summary (the title says only "a Hypertrophic Cardiomyopathy-Causing MYH7
    Mutation"). The organism is bound to Mus musculus because GEO records the
    series under that taxon; the study itself spans both patient-derived
    iPSC-cardiomyocytes and humanized mice, and the committed cache does not
    resolve which samples this accession holds. Read the accession before using
    it as a human dataset.
discussions:
- discussion_id: cmh1-srx-allele-heterogeneity
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Destabilization of the Autoinhibited Super-Relaxed State
  prompt: >-
    Which MYH7 alleles actually act by destabilizing the super-relaxed state, and
    what mechanism accounts for the rest?
  rationale: >-
    This entry curates the SRX-destabilization arm as the mechanism of a large
    subset of MYH7 alleles rather than all of them, because not every
    cardiomyopathy myosin mutation shifts the SRX-DRX equilibrium. Two of the
    alleles with the best multiscale data illustrate the spread: G256E reduces
    the folded-back fraction by 33% through the transducer region, while R403Q
    has produced context-dependent and sometimes opposing measurements across
    assays. Without an allele-level map, a clinician cannot reason from a
    specific variant to the mechanism, and the SRX arm cannot be used to predict
    who will respond to a myosin inhibitor.
- discussion_id: cmh1-myh7-specific-clinical-evidence
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#
  - prevalence#
  prompt: >-
    Do the clinical results curated in this entry hold specifically for MYH7
    carriers, or only for hypertrophic cardiomyopathy as a whole?
  rationale: >-
    Every clinical trial and outcome cohort cited in this entry enrolled
    hypertrophic cardiomyopathy broadly, not genotyped MYH7 carriers. That
    applies to both myosin inhibitors, to disopyramide, to beta-blockade and
    verapamil, to myectomy and alcohol septal ablation, to the ICD registry, to
    the anticoagulation review and to the LGE meta-analysis, and it is why no
    population prevalence exists for this entity.
    The gap is structural rather than incidental — genotype has not been a
    stratifying variable in HCM trial design — so it will not close through
    ordinary literature accumulation. Recorded so that a reader does not mistake
    the volume of clinical evidence here for evidence about MYH7.
- discussion_id: cmh1-mouse-isoform-mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - animal_models#alpha-MHC 403/+ knock-in mouse
  prompt: >-
    Does a 403 substitution in mouse alpha-cardiac myosin model a human MYH7
    beta-myosin disease?
  rationale: >-
    The founding animal model of this disease carries R403Q in Myh6, not Myh7,
    because the adult mouse ventricle expresses alpha- rather than beta-myosin.
    Evidence therefore exists in the model but its translational validity is the
    open question, which is what distinguishes this from an ordinary knowledge
    gap. The pig study makes the mismatch explicit, stating that orthologous
    beta-MyHC mutations in mice do not produce the phenotype found in patients —
    and that is the stated reason large-animal models were built. Any claim in
    this entry that rests on mouse data inherits this caveat.
  evidence:
  - reference: PMID:29555974
    reference_title: "Successful knock-in of Hypertrophic Cardiomyopathy-mutation R723G into the MYH7 gene mimics HCM pathology in pigs."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice express the fast alpha-myosin in the heart, and orthologous ß-MyHC
      mutations do not lead to the phenotype typically found in HCM patients
    explanation: >-
      States the isoform mismatch directly and asserts its translational
      consequence, which is what makes this a model-fidelity question rather than
      a general species caveat.
references:
- reference: PMID:20301725
  title: Nonsyndromic Hypertrophic Cardiomyopathy Overview.
  tags:
  - GeneReviews
notes: >-
  Scope and mechanism contrast with CMH4 (MYBPC3). CMH1 is curated as the
  MYH7/beta-cardiac myosin form because MYH7 is, with MYBPC3, one of the two
  commonest genetic causes of HCM and was the founding molecular diagnosis of the
  field (R403Q, 1990). It is deliberately contrasted with the MYBPC3 entry: MYBPC3
  disease is predominantly truncating and acts by haploinsufficiency (loss of the
  cMyBP-C brake), whereas MYH7 disease is predominantly missense and acts by a
  gain of contractile function in a stably expressed mutant motor (super-relaxed
  state destabilization, raised intrinsic force, increased tension cost). Both
  converge on the same maladaptive-remodeling module.

  Allele-heterogeneity caveat preserved on the pathograph: not every MYH7 mutation
  shifts the SRX-DRX equilibrium (PMID:40118457), so the super-relaxed-state arm
  is curated as the mechanism of a large subset of alleles rather than a universal
  one, and the motor-force arm (intrinsic force, tension cost) is curated
  separately. At the cohort level MYH7 and MYBPC3 do not differ significantly
  across pooled clinical features (PMID:23674365), so the entry does not assert
  MYH7 as a uniformly more severe genotype.

  Curating this entry deletes the stub stubs/Hypertrophic_Cardiomyopathy_1.yaml
  and closes the highest-value gap named in the Familial Hypertrophic
  Cardiomyopathy grouping notes. This entry is added as a member of that grouping.

  GeneReviews scope. The GeneReviews resource applicable to this entry is the
  disease-level "Nonsyndromic Hypertrophic Cardiomyopathy Overview"
  (PMID:20301725), tagged accordingly in `references`. Its indexed PubMed record
  is content_type abstract_only and carries only the chapter's purpose
  statement, not the Clinical Characteristics, Management, or Genetic Counseling
  sections, so section-by-section GeneReviews mining is not possible from the
  cache and no snippet is quoted from it. The clinical-characteristics baseline
  for this entry is therefore built from the primary MYH7 cohort and pedigree
  literature cited throughout, principally PMID:28912181, PMID:23674365,
  PMID:32871100, PMID:24928957, PMID:39681440.

  2026-09-06 augmentation round (falcon deep research, MONDO:0008647). This round
  added the sections the entry was missing rather than reworking what was there:
  histopathology, biochemical, imaging_findings, progression,
  differential_diagnoses, experimental_models, animal_models, datasets and
  discussions, plus four treatments, two trials and three phenotypes.

  One new mechanism arm was added to the pathograph. Cardiomyocyte-to-Fibroblast
  EGFR Paracrine Signaling (PMID:39413182) records that interstitial fibrosis in
  MYH7 disease is driven by a soluble signal from the mutant cardiomyocyte to the
  fibroblast, not only by wall stress, and that the receptor carrying it is EGFR.
  It sits between hypercontractility and the tissue remodeling node and is
  curated separately because it is a different claim from what the myocardium
  becomes. The same source reports the arm in MYBPC3-truncation microtissues too,
  so it is shared across sarcomeric HCM rather than MYH7-exclusive.

  Directness discipline. Every clinical evidence item added or revised in the
  2026-09-06 round whose source population is hypertrophic cardiomyopathy at
  large rather than genotyped MYH7 carriers carries directness: INDIRECT. That
  covers EXPLORER-HCM, SEQUOIA-HCM, VALOR-HCM, the disopyramide series, the
  nadolol/verapamil crossover trial, the myectomy cohort, the Euro-ASA registry,
  the ICD registry, the atrial-fibrillation systematic review, the LGE
  meta-analysis, the genetic-testing yield figure, the diagnostic wall-thickness
  criterion, and the broad-HCM review used for the atrial fibrillation, syncope,
  fibrosis, histopathology and progression records.

  Three qualifications. First, it is not applied file-wide: evidence items
  predating this round were left as their curator set them, so the file is
  internally mixed and the presence or absence of the slot elsewhere means
  nothing. Second, MYH7-specific sources carry no directness because none is
  needed — the penetrance meta-analysis reports MYH7 as its own stratum, and the
  biophysical, gene-editing and model literature is allele-specific throughout.
  Third, a few broad-source items were assessed and deliberately left unmarked
  because the source names MYH7 within the claim: the sarcomere-panel
  recommendation and the cascade-testing recommendation both apply to a MYH7
  family as stated, as does the statement that MYH7 and MYBPC3 account for about
  half of HCM families. Discussion cmh1-myh7-specific-clinical-evidence records
  the underlying gap as structural so the volume of clinical citation here is not
  read as evidence about MYH7 specifically.

  Scoping rule for preclinical work, applied consistently. A preclinical
  intervention is curated as a `treatments:` record when it acts on a node in
  this entry's pathograph and the disease phenotype was prevented or rescued in a
  disease model. MYH7 allele-directed gene editing meets that and is curated as a
  treatment; the SGLT2-inhibitor finding in MYH7 R403Q engineered heart tissue
  (PMID:38240646) does not — it improved a relaxation parameter in a
  cell-derived construct with no whole-organism arm — so it is curated only as an
  experimental model. The rule, not the preclinical/clinical line, is what
  separates them. The MYH7-specific evidence in this entry is the genetic,
  biophysical and model literature, plus the penetrance meta-analysis
  (PMID:37929589), which reports MYH7 separately at ~65% in non-proband
  relatives against ~11% in incidentally identified carriers, and ~23% versus
  ~12% short-term phenotypic conversion against MYBPC3.

  Retired-enum prose cleanup. Four explanation strings still argued for the
  retired supports: PARTIAL grade (#7439/#10061). They were rewritten to say what
  they meant, and the two that meant an inference step now carry
  directness: INDIRECT on the slot rather than only in prose.

  Report term validation caught six bad CURIEs before use. The falcon report's
  Term Validation section flagged NCIT:C29622 and NCIT:C151608 as nonexistent,
  and HP:0031604 (Agenesis of the carotid canal, offered for myocardial
  fibrosis), HP:0005117 (Elevated diastolic blood pressure, offered for diastolic
  dysfunction), HP:0031797 (Clinical course, offered for incomplete penetrance)
  and NCIT:C139785 (a TNM finding, offered for gene editing) as naming different
  concepts. None was bound. Myocardial fibrosis is bound to HP:0001685 instead,
  found with OAK. A seventh bad binding, HP:0031200 (Hyaline casts) for LVOT
  obstruction, was caught by the term validator during curation and corrected to
  HP:0032092.

  Model fidelity is recorded honestly rather than favourably. The founding
  alpha-MHC 403/+ mouse (PMID:8614836) is LOW fidelity with a SPECIES_MISMATCH
  divergence because its lesion is in Myh6, not the MYH7 orthologue — the adult
  mouse ventricle runs on alpha-myosin. That mismatch is curated as a
  HUMAN_MODEL_MISMATCH discussion rather than a footnote, because the pig study
  states it as the reason large-animal models exist. The beta-myosin rabbit and
  pig models are curated alongside it for that reason; the pig carries an
  INVALIDATING TEMPORAL_SCOPE divergence, since the animals died within 24 hours
  of birth and cannot report on adult natural history at all.

  Aficamten is bound to CHEBI:747213, reusing the binding already validated for
  the sibling CMH4 entry. No NCIT or CHEBI term was found for the drug in the
  local builds otherwise. Alcohol septal ablation is curated with positioning
  evidence only, from the disopyramide series; the ablation-versus-myectomy
  comparative literature was not screened this round and no comparative-efficacy
  claim is made.

📚

References & Deep Research

References

1

PMID:20301725

Nonsyndromic Hypertrophic Cardiomyopathy Overview.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (2)

Record notes

Scope and mechanism contrast with CMH4 (MYBPC3). CMH1 is curated as the MYH7/beta-cardiac myosin form because MYH7 is, with MYBPC3, one of the two commonest genetic causes of HCM and was the founding molecular diagnosis of the field (R403Q, 1990). It is deliberately contrasted with the MYBPC3 entry: MYBPC3 disease is predominantly truncating and acts by haploinsufficiency (loss of the cMyBP-C brake), whereas MYH7 disease is predominantly missense and acts by a gain of contractile function in a stably expressed mutant motor (super-relaxed state destabilization, raised intrinsic force, increased tension cost). Both converge on the same maladaptive-remodeling module. Allele-heterogeneity caveat preserved on the pathograph: not every MYH7 mutation shifts the SRX-DRX equilibrium (PMID:40118457), so the super-relaxed-state arm is curated as the mechanism of a large subset of alleles rather than a universal one, and the motor-force arm (intrinsic force, tension cost) is curated separately. At the cohort level MYH7 and MYBPC3 do not differ significantly across pooled clinical features (PMID:23674365), so the entry does not assert MYH7 as a uniformly more severe genotype. Curating this entry deletes the stub stubs/Hypertrophic_Cardiomyopathy_1.yaml and closes the highest-value gap named in the Familial Hypertrophic Cardiomyopathy grouping notes. This entry is added as a member of that grouping. GeneReviews scope. The GeneReviews resource applicable to this entry is the disease-level "Nonsyndromic Hypertrophic Cardiomyopathy Overview" (PMID:20301725), tagged accordingly in `references`. Its indexed PubMed record is content_type abstract_only and carries only the chapter's purpose statement, not the Clinical Characteristics, Management, or Genetic Counseling sections, so section-by-section GeneReviews mining is not possible from the cache and no snippet is quoted from it. The clinical-characteristics baseline for this entry is therefore built from the primary MYH7 cohort and pedigree literature cited throughout, principally PMID:28912181, PMID:23674365, PMID:32871100, PMID:24928957, PMID:39681440. 2026-09-06 augmentation round (falcon deep research, MONDO:0008647). This round added the sections the entry was missing rather than reworking what was there: histopathology, biochemical, imaging_findings, progression, differential_diagnoses, experimental_models, animal_models, datasets and discussions, plus four treatments, two trials and three phenotypes. One new mechanism arm was added to the pathograph. Cardiomyocyte-to-Fibroblast EGFR Paracrine Signaling (PMID:39413182) records that interstitial fibrosis in MYH7 disease is driven by a soluble signal from the mutant cardiomyocyte to the fibroblast, not only by wall stress, and that the receptor carrying it is EGFR. It sits between hypercontractility and the tissue remodeling node and is curated separately because it is a different claim from what the myocardium becomes. The same source reports the arm in MYBPC3-truncation microtissues too, so it is shared across sarcomeric HCM rather than MYH7-exclusive. Directness discipline. Every clinical evidence item added or revised in the 2026-09-06 round whose source population is hypertrophic cardiomyopathy at large rather than genotyped MYH7 carriers carries directness: INDIRECT. That covers EXPLORER-HCM, SEQUOIA-HCM, VALOR-HCM, the disopyramide series, the nadolol/verapamil crossover trial, the myectomy cohort, the Euro-ASA registry, the ICD registry, the atrial-fibrillation systematic review, the LGE meta-analysis, the genetic-testing yield figure, the diagnostic wall-thickness criterion, and the broad-HCM review used for the atrial fibrillation, syncope, fibrosis, histopathology and progression records. Three qualifications. First, it is not applied file-wide: evidence items predating this round were left as their curator set them, so the file is internally mixed and the presence or absence of the slot elsewhere means nothing. Second, MYH7-specific sources carry no directness because none is needed — the penetrance meta-analysis reports MYH7 as its own stratum, and the biophysical, gene-editing and model literature is allele-specific throughout. Third, a few broad-source items were assessed and deliberately left unmarked because the source names MYH7 within the claim: the sarcomere-panel recommendation and the cascade-testing recommendation both apply to a MYH7 family as stated, as does the statement that MYH7 and MYBPC3 account for about half of HCM families. Discussion cmh1-myh7-specific-clinical-evidence records the underlying gap as structural so the volume of clinical citation here is not read as evidence about MYH7 specifically. Scoping rule for preclinical work, applied consistently. A preclinical intervention is curated as a `treatments:` record when it acts on a node in this entry's pathograph and the disease phenotype was prevented or rescued in a disease model. MYH7 allele-directed gene editing meets that and is curated as a treatment; the SGLT2-inhibitor finding in MYH7 R403Q engineered heart tissue (PMID:38240646) does not — it improved a relaxation parameter in a cell-derived construct with no whole-organism arm — so it is curated only as an experimental model. The rule, not the preclinical/clinical line, is what separates them. The MYH7-specific evidence in this entry is the genetic, biophysical and model literature, plus the penetrance meta-analysis (PMID:37929589), which reports MYH7 separately at ~65% in non-proband relatives against ~11% in incidentally identified carriers, and ~23% versus ~12% short-term phenotypic conversion against MYBPC3. Retired-enum prose cleanup. Four explanation strings still argued for the retired supports: PARTIAL grade (#7439/#10061). They were rewritten to say what they meant, and the two that meant an inference step now carry directness: INDIRECT on the slot rather than only in prose. Report term validation caught six bad CURIEs before use. The falcon report's Term Validation section flagged NCIT:C29622 and NCIT:C151608 as nonexistent, and HP:0031604 (Agenesis of the carotid canal, offered for myocardial fibrosis), HP:0005117 (Elevated diastolic blood pressure, offered for diastolic dysfunction), HP:0031797 (Clinical course, offered for incomplete penetrance) and NCIT:C139785 (a TNM finding, offered for gene editing) as naming different concepts. None was bound. Myocardial fibrosis is bound to HP:0001685 instead, found with OAK. A seventh bad binding, HP:0031200 (Hyaline casts) for LVOT obstruction, was caught by the term validator during curation and corrected to HP:0032092. Model fidelity is recorded honestly rather than favourably. The founding alpha-MHC 403/+ mouse (PMID:8614836) is LOW fidelity with a SPECIES_MISMATCH divergence because its lesion is in Myh6, not the MYH7 orthologue — the adult mouse ventricle runs on alpha-myosin. That mismatch is curated as a HUMAN_MODEL_MISMATCH discussion rather than a footnote, because the pig study states it as the reason large-animal models exist. The beta-myosin rabbit and pig models are curated alongside it for that reason; the pig carries an INVALIDATING TEMPORAL_SCOPE divergence, since the animals died within 24 hours of birth and cannot report on adult natural history at all. Aficamten is bound to CHEBI:747213, reusing the binding already validated for the sibling CMH4 entry. No NCIT or CHEBI term was found for the drug in the local builds otherwise. Alcohol septal ablation is curated with positioning evidence only, from the disopyramide series; the ablation-versus-myectomy comparative literature was not screened this round and no comparative-efficacy claim is made.

Augment: Hypertrophic Cardiomyopathy 1 (MYH7/CMH1) · 2026-09-06T06:31:46Z · View source

Augmentation round on the existing MYH7/CMH1 entry (created in PR #9371). The entry already carried a well-developed pathophysiology chain, phenotypes, genetics and three treatments; this round added the sections it was missing rather than reworking what was there. File grew from 938 to 2722 lines. Deep research provider: falcon (Edison Scientific), run as `just research-disorder falcon Hypertrophic_Cardiomyopathy_1`, 18m22s, 47 citations, one artifact. Report committed at research/Hypertrophic_Cardiomyopathy_1-deep-research-falcon.md. No fallback was needed. The report predated in-line validation, so a `## Reference Validation` and `## Term Validation` section were added retrospectively with `just validate-research-reference` and (as part of the same recipe) term validation. Report validation results and what was done with them. - References: 20/20 resolved, 0 unresolved, 0 off topic. - Terms: 54 checked, 2 unresolved and 10 named as a different term. Six bad CURIEs were caught and NOT bound: NCIT:C29622 and NCIT:C151608 (do not exist); HP:0031604 (offered for myocardial fibrosis, is Agenesis of the carotid canal); HP:0005117 (offered for diastolic dysfunction, is Elevated diastolic blood pressure); HP:0031797 (offered for incomplete penetrance, is Clinical course); NCIT:C139785 (offered for gene editing, is a TNM finding). Myocardial fibrosis was bound to HP:0001685 instead, found with OAK. A seventh wrong binding of my own, HP:0031200 (Hyaline casts) for LVOT obstruction, was caught by linkml-term-validator during curation and corrected to HP:0032092. - `just preflight-dr research/... MONDO:0008647` returned PASS: MYH7 mentioned 71 times, report OMIM 192600 matches MONDO's. What was curated. - New pathophysiology node: Cardiomyocyte-to-Fibroblast EGFR Paracrine Signaling (PMID:39413182), placed between hypercontractility and the tissue remodeling node, with its own edge evidence. Records that interstitial fibrosis in MYH7 disease is driven by a soluble signal from the mutant cardiomyocyte to the fibroblast (conditioned medium transfers it; erlotinib blocks it; collagen I +40% over isogenic wild type), not by wall stress alone. - Quantitative SRX evidence added to the super-relaxed-state node from the MYH7 G256E multiscale study (PMID:38683993): folded-back fraction reduced 33%, via the transducer region rather than an IHM contact surface. - Three phenotypes: Atrial Fibrillation (HP:0005110), Syncope (HP:0001279), Myocardial Fibrosis (HP:0001685). - New sections: histopathology, biochemical, imaging_findings, progression, differential_diagnoses, experimental_models, animal_models, datasets, discussions. - Seven treatments: aficamten (CHEBI:747213, PMID:38739079), disopyramide (CHEBI:4657, PMID:15837258), alcohol septal ablation (NCIT:C80439, PMID:26746632 Euro-ASA), beta-adrenergic blockade (NCIT:C29576 + CHEBI:7444, PMID:8496536), verapamil (CHEBI:9948, PMID:8496536), oral anticoagulation for atrial fibrillation (NCIT:C263, PMID:24014282), and preclinical MYH7 allele-directed gene editing (PMID:36797478 base editing, PMID:36797483 in vivo editing, PMID:38752340 hpCas13d). Evidence was also added to the two previously uncited treatments, myectomy (PMID:16053960) and ICD (PMID:17652294). - A diagnosis section: the echocardiographic wall-thickness criterion, the sarcomere gene panel, and cascade testing of first-degree relatives, all from PMID:38540296. - Two clinical trials: SEQUOIA-HCM (NCT05186818) and VALOR-HCM (NCT04349072, PMID:35798455). - Four GEO datasets, all MYH7-relevant and relevance-triaged by hand: GSE195436, GSE276210, GSE198258, GSE201755. `just verify-datasets` reported 4/4 OK; GEO_*.md caches are committed. - Three discussions: the SRX allele-heterogeneity gap, the structural absence of MYH7-stratified clinical evidence, and a HUMAN_MODEL_MISMATCH on the founding mouse model's alpha- versus beta-myosin isoform mismatch. Directness discipline. Nearly every clinical evidence item added this round carries directness: INDIRECT for the same reason: the trials and cohorts enrolled hypertrophic cardiomyopathy broadly, not genotyped MYH7 carriers. Discussion cmh1-myh7-specific-clinical-evidence records that as a structural gap so the volume of clinical citation is not read as MYH7-specific evidence. The genuinely MYH7-specific evidence added is the biophysical, model and genetic literature, plus the penetrance meta-analysis (PMID:37929589), which reports MYH7 separately (~65% in non-proband relatives against ~11% in incidentally identified carriers; ~23% versus ~12% short-term conversion against MYBPC3). Retired-enum prose cleanup. Four `explanation` strings still argued for the retired supports: PARTIAL grade (#7439/#10061). They were rewritten to say what they meant, and the two that meant an inference step now carry directness: INDIRECT on the slot rather than only in prose. Model fidelity was recorded honestly rather than favourably. The founding alpha-MHC 403/+ mouse (PMID:8614836) is LOW fidelity with a SPECIES_MISMATCH divergence because its lesion is in Myh6, not the MYH7 orthologue. The beta-MyHC-Q403 rabbit (PMID:15135661) and the MYH7 R723G knock-in pig (PMID:29555974) are curated alongside it because both species run on beta-myosin as humans do; the pig carries an INVALIDATING TEMPORAL_SCOPE divergence since the animals died within 24 hours of birth. Deliberately not curated. `has_subtypes` and `variants` were left empty: the report's variant-level content is allele-specific functional data rather than a defined subtype structure, and curating individual MYH7 alleles as subtypes would be a separate decision. Alcohol septal ablation carries positioning evidence only; the ablation-versus-myectomy comparative literature was not screened this round and no comparative-efficacy claim is made. The clinical gene-replacement program TN-201 targets MYBPC3, not MYH7, and is explicitly excluded in the treatment notes. Adversarial self-review before PR. A subagent ran the dismech-pr-review checklist against the change and returned no CRITICAL findings and eight IMPORTANT ones, all taken in a single round rather than deferred: (1) the new EGFR edge asserted causal_link_type: DIRECT for a coupling the source explicitly calls unestablished, changed to INDIRECT_UNKNOWN_INTERMEDIATES with the source's own hedge recorded in the edge description; (2) the disopyramide mechanism edge quoted the abstract's BACKGROUND framing of prior work rather than a finding, replaced with the CONCLUSIONS result; (3) alcohol septal ablation was evidenced entirely by a disopyramide trial, replaced with the Euro-ASA registry (PMID:26746632, 1275 patients) at both treatment and mechanism-edge level; (4) the notes claimed near-universal directness: INDIRECT while roughly one clinical item in three carried it. Five more items were marked and the prose rewritten to state exactly which items carry it, which do not, and why; (5) CL:0002548 was one level too general where the source says "ventricular", narrowed to CL:2000066 cardiac ventricle fibroblast; (6) the LGE imaging record left the recommended imaging_finding_term empty when NCIT:C209440 Late Gadolinium Enhancement exists, now bound; (7) the report's first-line therapies were absent while preclinical gene editing was curated. Beta-blockade, verapamil and anticoagulation were added, and the scoping rule that admits gene editing but excludes the SGLT2i finding is now stated in notes; (8) no diagnosis section, added as above from a reference that had been fetched and left unused. Minor findings taken: a PROXY_QUANTITY divergence on the rabbit model (its measured quantity moves opposite to the node's), the ICD inappropriate-shock datum regraded REFUTE as a separate opposite-direction item rather than SUPPORT, the pig BOUNDARY_OMISSION reworded because the paper actively reports no obvious hypertrophy rather than not reporting it, a false claim that R403Q appears in the GSE201755 series title corrected, a directness note on the syncope item, and seven downstream edges added from the terminal pathophysiology node to the phenotypes it had been bundling. The entry previously rendered as two disconnected graph components. The unused feline transcriptome reference (PMID:36928240) is now explicitly declined in animal_models notes, with the reason: feline HCM is predominantly MYBPC3. An unsourced pharmacokinetic claim about aficamten (shorter half-life, narrower titration range) was removed on my own re-read before the review reported. Validation. `just validate-disorders kb/disorders/Hypertrophic_Cardiomyopathy_1.yaml` passed after every round; final run: schema OK, term validation passed, 92/92 snippets verified against cached references. Also run and passing: check-entity-refs, check-causal-targets, check-duplicate-keys, check-qualifier-terms, check-enum-values, check-snippet-length, check-title-snippets, check-snippet-grading, check-folded-hyphens (one new finding fixed by reflowing an `isoproterenol-` line break), check-environmental-evidence, check-term-cache-integrity, check-not4curation, and verify-datasets. Compliance rose in absolute terms (96/108 to 232/274 checks passing) while the percentage fell from 88.9% to 84.7%, because the added sections more than doubled the denominator.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 47 citations 2026-09-06T06:04:54.801967

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Hypertrophic Cardiomyopathy 1
MONDO ID: MONDO:0008647 (if available)
Category: Genetic

Research Objectives

Please provide a comprehensive research report on Hypertrophic Cardiomyopathy 1 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Hypertrophic Cardiomyopathy 1 (MYH7-related): comprehensive disease-characteristics report

Executive summary and scope

Hypertrophic cardiomyopathy 1 (HCM1) is the historical locus-specific form of familial hypertrophic cardiomyopathy caused by heterozygous pathogenic variants in MYH7, which encodes β-cardiac myosin heavy chain. It should not be conflated with all hypertrophic cardiomyopathy (HCM), a genetically heterogeneous phenotype involving multiple sarcomeric genes and phenocopies. Open Targets identifies MYH7 as the strongest-scoring target associated with broad HCM, but also associates MYBPC3 and other genes with the general phenotype. Unless explicitly marked “MYH7-specific,” clinical recommendations below derive from broad-HCM cohorts and guidelines and are extrapolated to HCM1 (OpenTargets Search: hypertrophic cardiomyopathy-MYH7).

The following table summarizes ontology-ready findings.

Domain	Ontology/Identifiers	High-Confidence Finding	Evidence & Quantitative Value	Caveat (Broad vs MYH7)
Disease Scope	MONDO:0005045 (HCM), OMIM:192600 (HCM1)	Hypertrophic cardiomyopathy 1 represents locus-specific MYH7-related familial HCM, a subset of the broader HCM phenotype.	OpenTargets maps MYH7 strongly to broad HCM; MYH7 variants account for ~15% of all clinical HCM cases and ~30-40% of sarcomere-positive cases (OpenTargets Search: hypertrophic cardiomyopathy-MYH7, hao2026hypertrophiccardiomyopathycomprehensive pages 1-2, pietsch2024investigationofmicrotubule pages 32-35).	MYH7-specific finding. Broad HCM includes multiple other genes (e.g., MYBPC3).
Etiology / Genetics	HGNC:7577 (MYH7), NCIT:C25742 (Autosomal Dominant)	Pathogenic variants are primarily missense mutations clustered in the beta-myosin heavy chain (β-MHC) head domain (aa 167-931) altering contractile function.	Molecular mapping/sequencing: Missense clustering in motor/actin-binding domains correlates with disease (pires2025exploringmyh7in pages 1-1).	MYH7-specific. Loss-of-function/null variants lack sufficient evidence for pathogenicity (pires2025exploringmyh7in pages 1-1).
Penetrance	HP:0031797 (Incomplete penetrance)	Incomplete, age-dependent autosomal dominant penetrance. Penetrance is higher in clinical/family contexts than in incidental populations.	Meta-analysis: ~65% penetrance in nonproband relatives (highest among sarcomere genes); ~11% in incidental population carriers; 23% short-term conversion (topriceanu2024metaanalysisofpenetrance pages 1-2).	MYH7-specific. Modifiers (genetic/environmental) heavily influence transition to overt disease.
Molecular Pathophysiology	GO:0006936 (Muscle contraction), GO:0005739 (Mitochondrion), CL:0000746 (Cardiac muscle cell)	MYH7 mutations induce hypercontractility, increased mitochondrial respiration, and stromal activation via EGFR-mediated paracrine signaling leading to fibrosis.	In vitro/iPSC models: MYH7 G256E disrupts folded-back state, increasing active heads by 33%; MYH7 R403Q increases collagen I by 40% and tissue stiffness (ewoldt2024hypertrophiccardiomyopathy–associatedmutations pages 1-2, lee2024incompletepenetranthypertrophiccardiomyopathy pages 1-2).	MYH7-specific mechanistic pathway demonstrated in engineered tissues.
Phenotypes / Natural History	HP:0001639 (HCM), HP:0001645 (SCD), HP:0001714 (Ventricular tachycardia)	Asymmetric septal hypertrophy, earlier onset, and higher severity/SCD risk compared to other sarcomere genes.	Registry/cohort data: MYH7 carriers have ~2x SCD incidence vs genotype-negative, median onset ~35 years, increased atrial fibrillation (santos2025geneticclinicaland pages 9-10, hao2026hypertrophiccardiomyopathycomprehensive pages 2-4).	MYH7-specific relative severity. LVOT obstruction and HF occur in broad HCM.
Diagnostics	NCIT:C116499 (Echocardiography), NCIT:C116496 (CMR), LOINC:34532-2 (ECG)	Diagnosis via LV wall thickness ≥15mm; CMR assesses LGE/fibrosis for sudden death risk. Cascade screening requires regular echo surveillance if genetics uncertain.	Clinical guidelines: Dynamic LVOT obstruction provocation; 48h Holter for NSVT (mobiuswinkler2024thediagnosisand pages 2-3, fernandes2024guidelinesonthe pages 24-26).	Broad HCM evidence. Applicable to MYH7, but not locus-exclusive.
Pharmacotherapy	NCIT:C66946 (Mavacamten), NCIT:C29622 (Beta Blocker)	Cardiac myosin inhibitors (mavacamten, aficamten) target hypercontractility, improving LVOT gradients and NYHA class; LVEF monitoring required.	SEQUOIA-HCM (aficamten): >80% on high dose, 4.9% required dose reduction for LVEF <50%. VALOR-HCM (mavacamten): sustained SRT freedom (coats2024dosingandsafety pages 1-2, desai2025mavacamteninpatients pages 10-11, coats2024dosingandsafety pages 2-4).	Broad HCM evidence. Myosin inhibitors specifically target sarcomeric hypercontractility.
Interventional Therapies	NCIT:C151608 (ICD), NCIT:C177729 (Septal Reduction Therapy)	Septal reduction (myectomy/ablation) for refractory obstructive HCM. Primary prevention ICD based on personalized SCD risk stratification.	Clinical guidelines: Shared decision-making for ICD; septal reduction reserved for severe drug-refractory obstruction (bertero2025hypertrophiccardiomyopathyevolving pages 3-3, mcbenedict2024impactofgenetic pages 10-11).	Broad HCM evidence. MYH7 patients may require these earlier due to phenotype severity.
Emerging Gene Therapies	NCIT:C139785 (Gene Editing)	Adenine base editing (ABE8e) and RNA nucleases (hpCas13d) can precisely correct or silence specific MYH7 SNVs to prevent hypertrophy.	In vivo mouse/iPSC models: ABE8e corrected MYH7 R403Q in ≥70% of ventricular cardiomyocytes; hpCas13d selectively suppressed mutant alleles (yang2024allelespecificsuppressionof pages 1-2, reichart2023efficientinvivo pages 1-2, chai2023baseeditingcorrection pages 1-3).	MYH7-specific. Preclinical stage; demonstrates feasibility of single-dose genetic correction.
Animal / in vitro Models	NCIT:C14272 (Mouse Model), NCIT:C14283 (Porcine Model)	Large and small animal models (spontaneous and engineered) recapitulate hypertrophy, metabolic defects, and early perinatal manifestations.	Swine (MYH7 R723G, R403Q) show early disease onset, mitochondrial defect; feline models (MYH7 E1883K) show spontaneous analogous HCM (joshua2023felinemyocardialtranscriptome pages 1-2, stern2023hypertrophiccardiomyopathyin pages 1-3, montag2018successfulknockinof pages 1-2).	Broad HCM (some MYBPC3 models) and MYH7-specific (e.g., swine knock-ins, feline orthologs).

Table: A structured summary of clinical, genetic, molecular, and therapeutic findings for MYH7-related hypertrophic cardiomyopathy, distinguishing gene-specific mechanisms from broad HCM guidelines.

1. Disease information

Definition

HCM is unexplained left-ventricular (LV) wall thickening that is not solely explained by loading conditions such as hypertension, valvular disease, or athletic remodeling. HCM1 is the MYH7-related autosomal-dominant subset. Its cardinal pathology comprises cardiomyocyte hypertrophy and disarray, interstitial fibrosis, diastolic dysfunction, and—variably—dynamic LV outflow-tract obstruction (LVOTO). Clinical expression ranges from lifelong subclinical disease to dyspnea, angina, syncope, atrial or ventricular arrhythmia, heart failure, stroke, and sudden cardiac death (SCD) (mobiuswinkler2024thediagnosisand pages 2-3, lee2024incompletepenetranthypertrophiccardiomyopathy pages 1-2).

Identifiers and synonyms

MONDO: MONDO:0008647, as supplied for HCM1; broad HCM is separately represented as MONDO:0005045. Database releases should be checked before ingestion because locus-specific mappings can change.
OMIM: 192600, cardiomyopathy, familial hypertrophic, 1.
Gene: MYH7; HGNC:7577; chromosome 14q12; Ensembl ENSG00000092054.
MeSH: Cardiomyopathy, Hypertrophic (D002312; broad phenotype).
ICD-10-CM: I42.1, obstructive hypertrophic cardiomyopathy; I42.2, other hypertrophic cardiomyopathy.
ICD-11: BC43.0, hypertrophic cardiomyopathy; local extension codes may distinguish obstruction.
Orphanet: familial hypertrophic cardiomyopathy is represented at disease-family level; verify the current ORPHA record rather than assuming a MYH7-exclusive mapping.
Synonyms: familial hypertrophic cardiomyopathy 1; HCM1; MYH7-related hypertrophic cardiomyopathy; β-myosin-heavy-chain cardiomyopathy; familial hypertrophic obstructive cardiomyopathy when LVOTO is present. “IHSS” and “hypertrophic subaortic stenosis” are historical, anatomically incomplete terms.

This report synthesizes aggregated disease-level resources, cohorts, trials, and experimental studies, not individual EHR data. Some cited real-world studies use coded administrative records, but no patient-level EHR is reproduced here.

2. Etiology, risk, protection, and gene–environment interaction

Causal factor

HCM1 is caused by a germline heterozygous pathogenic/likely pathogenic MYH7 variant. MYH7 encodes the 1,935-amino-acid β-myosin heavy chain, the major adult human ventricular thick-filament motor. Pathogenic HCM variants are predominantly missense substitutions, enriched in approximately residues 167–931 encompassing the myosin motor/head and actin/ATP-interacting regions. Predicted loss-of-function variants should not automatically receive full PVS1 weight because MYH7 haploinsufficiency is not the established HCM1 mechanism; most HCM variants act through altered-function or “poison-peptide” effects (pires2025exploringmyh7in pages 1-2, pires2025exploringmyh7in pages 1-1).

Genetic risk and modifiers

A P/LP MYH7 allele is the primary risk factor; multiple sarcomeric variants can worsen expression, although variant-level prediction remains imperfect.
Family history of early HCM, heart failure, ventricular arrhythmia, or SCD increases concern.
Penetrance is modified by age, sex, polygenic background, allelic expression, and probably epigenetic and environmental factors. The best 2024 meta-analysis concluded that penetrance is “highly variable” and influenced by “context-dependent genetic and environmental factors” (topriceanu2024metaanalysisofpenetrance pages 1-2).
MYH7 variants may also produce dilated, restrictive, or noncompaction cardiomyopathy and skeletal myopathy, so genotype must be interpreted with the phenotype and family segregation (pires2025exploringmyh7in pages 5-6).

Environmental/lifestyle factors

Hypertension, obesity, diabetes, sleep-disordered breathing, and sustained hemodynamic load do not cause monogenic HCM1 but can increase LV mass, symptoms, atrial remodeling, and heart-failure burden. Dehydration, vasodilation, fever, heavy alcohol exposure, and abrupt high-intensity exertion can worsen dynamic obstruction or precipitate symptoms. Smoking and pollution are general cardiovascular hazards but are not established HCM1-specific causes. No infectious agent causes HCM1.

Protective factors

No validated protective MYH7 allele or diet prevents HCM1. Clinically useful protection is secondary/tertiary: blood-pressure and weight control, avoidance of volume depletion and stimulant misuse, individualized exercise, surveillance, anticoagulation for atrial fibrillation, and ICD placement when SCD risk justifies it. Low- and moderate-intensity exercise is now considered beneficial for most patients rather than universally prohibited (bertero2025hypertrophiccardiomyopathyevolving pages 3-3).

3. Phenotypes

Phenotype	Type/course and approximate frequency	Suggested HPO term	Functional/QOL effect
LV hypertrophy, often asymmetric septal	Sign; age-dependent, variable; defining overt phenotype	HP:0001639	May be asymptomatic or impair filling/exercise capacity
Dynamic LVOTO/SAM	Sign; resting or provocable; broad-HCM rather than MYH7-specific	HP:0001727; HP:0001654	Exertional dyspnea, chest pain, presyncope
Diastolic dysfunction	Functional sign; commonly progressive with remodeling	HP:0005117	Exercise intolerance and congestion
Dyspnea/fatigue	Symptoms; episodic or progressive	HP:0002094; HP:0012378	Reduced activity and KCCQ/SF-36 domains
Chest pain	Symptom, often exertional/microvascular	HP:0001681	Activity limitation and anxiety
Palpitations/AF	Symptom/sign; risk rises with age and LA enlargement	HP:0001962; HP:0005110	Stroke risk, impaired capacity, hospitalization
NSVT/VT/VF	Electrophysiologic sign; minority but prognostically important	HP:0004756; HP:0001663	Syncope, ICD therapy, SCD risk
Syncope	Episodic symptom	HP:0001279	Injury risk and major SCD-risk evaluation trigger
Myocardial fibrosis/LGE	Imaging/pathology sign; variable and progressive	HP:0031604	Arrhythmic and HF risk; no direct symptom necessarily
Systolic dysfunction/end-stage HCM	Late complication in a minority	HP:0001644	Advanced HF, transplantation risk
SCD	Severe outcome, uncommon with modern management	HP:0001645	Premature mortality and major family impact

ECG abnormalities occur in approximately 75–95% of broad-HCM patients, but a normal ECG does not exclude disease. MYH7 disease tends toward earlier presentation and more severe hypertrophy/arrhythmia than genotype-negative HCM, although expressivity remains wide (hao2026hypertrophiccardiomyopathycomprehensive pages 2-4, mobiuswinkler2024thediagnosisand pages 2-3). Symptoms can begin in childhood, adolescence, adulthood, or rarely prenatally; a 2024 family meta-analysis found mean overt-HCM diagnosis at 38 years across sarcomeric genes (topriceanu2024metaanalysisofpenetrance pages 1-2).

4. Genetic and molecular information

Gene and variants

MYH7/HGNC:7577, β-cardiac myosin heavy chain; 41 exons over approximately 22.9 kb at 14q12 (pires2025exploringmyh7in pages 1-2).
Variant class: predominantly heterozygous missense; examples with extensive experimental evidence include p.Arg403Gln (R403Q), p.Gly256Glu (G256E), and p.Arg723Gly (R723G).
Origin: constitutional/germline; de novo variants occur, but inherited autosomal-dominant disease is typical. Somatic MYH7 mutation is not the usual mechanism.
Population frequency: a credible HCM-causing variant should be rare enough for disease prevalence/penetrance; exact gnomAD frequency must be recorded per variant and ancestry. Do not assign pathogenicity from rarity alone.
Classification: use ACMG/AMP plus MYH7/sarcomere-specific ClinGen guidance, segregation, phenotype, functional evidence, and periodic reanalysis. A VUS is not actionable for predictive cascade testing (abbas2024roleofgenetics pages 9-11).

Functional effect

Variant effects are mutation-specific. G256E reduced the folded-back myosin fraction by 33%, increasing contraction-available heads and producing faster/greater tension from myofibrils through single cells and engineered tissues. Single-cell profiling showed increased mitochondrial-gene expression and respiration (lee2024incompletepenetranthypertrophiccardiomyopathy pages 1-2). R403Q has shown context-dependent gain/loss measurements, illustrating why single-assay evidence is insufficient.

Modifiers and epigenetics

Robust, routinely actionable modifier genes are not established. Polygenic LV-wall-thickness background, sex, ancestry, hypertension, obesity, and allelic imbalance probably modify penetrance. DNA methylation, chromatin remodeling, microRNAs, and histone signaling are research findings, not diagnostic biomarkers. Large chromosomal abnormalities, aneuploidy, repeat expansions, and mitochondrial DNA variants are not typical causes of HCM1.

5. Environmental information

HCM1 is not infectious, toxic, occupational, or radiation-induced. Environmental factors primarily alter expression and complications, not the initiating lesion. Clinical management should address hypertension, obesity, inactivity, smoking, excess alcohol, sleep apnea, and dehydration. Competitive or vigorous exercise is no longer automatically forbidden; decisions require phenotype, rhythm history, LVOTO, blood-pressure response, fibrosis, family history, and shared decision-making (bertero2025hypertrophiccardiomyopathyevolving pages 3-3).

6. Mechanism/pathophysiology

Ordered causal chain

A heterozygous MYH7 missense variant leads to incorporation of altered β-myosin into ventricular sarcomeres.
Altered motor-domain kinetics and/or destabilization of the folded-back super-relaxed state results in more contraction-competent myosin heads; the magnitude and direction are variant-specific.
Excess actin–myosin engagement leads to hypercontractility, higher ATP demand, impaired relaxation, and abnormal mechanosensing.
Energetic stress and altered calcium handling result in mitochondrial/metabolic adaptation; in G256E cells, increased mitochondrial respiration is demonstrated, while later energetic failure is partly inferred from broader HCM studies (lee2024incompletepenetranthypertrophiccardiomyopathy pages 1-2).
Cardiomyocyte stress signaling leads to hypertrophic transcription and cellular enlargement; implicated pathways include CaMKII–HDAC, MAPK, PI3K–AKT–mTOR, calcineurin–NFAT, and mechanotransduction, but their causal importance varies by model (pietsch2024investigationofmicrotubule pages 32-35).
Branch A: cardiomyocyte hypertrophy/disarray results in increased LV wall thickness, reduced compliance, diastolic dysfunction, and—when septal geometry and mitral SAM coexist—dynamic LVOTO.
Branch B: mutant cardiomyocyte paracrine signaling leads to fibroblast proliferation and extracellular-matrix deposition. In MYH7-R403Q microtissues, collagen-I content rose 40%, and EGFR inhibition attenuated stromal activation (ewoldt2024hypertrophiccardiomyopathy–associatedmutations pages 1-2).
Hypertrophy, microvascular supply–demand mismatch, and fibrosis result in ischemia, heterogeneous conduction, and repolarization abnormalities.
These changes lead to dyspnea, angina, AF, ventricular arrhythmias, syncope, heart failure, stroke, and SCD.

Cell, process, and compartment annotations

Cells: ventricular cardiomyocyte (CL:0000746), cardiac fibroblast (CL:0002548), vascular endothelial cell (CL:0000115), vascular smooth-muscle cell (CL:0000359), macrophage (CL:0000235).
Processes: muscle contraction (GO:0006936), actin–myosin filament sliding (GO:0033275), cardiac-muscle hypertrophy (GO:0003300), mitochondrial ATP synthesis (GO:0042775), extracellular-matrix organization (GO:0030198), fibroblast proliferation (GO:0048144), calcium-ion homeostasis (GO:0055074), cardiac conduction (GO:0061337).
Compartments: sarcomere (GO:0030017), myosin complex (GO:0016459), thick filament (GO:0032982), mitochondrion (GO:0005739), extracellular matrix (GO:0031012).

Molecular profiling and advanced technologies

The strongest recent MYH7-specific evidence integrates molecular biophysics, gene-edited hiPSC cardiomyocytes, engineered heart tissue, single-cell transcriptomics, and metabolic profiling (lee2024incompletepenetranthypertrophiccardiomyopathy pages 1-2). Single-nucleus RNA sequencing of MYH7-variant engineered tissues supports cardiomyocyte-to-fibroblast EGFR-mediated signaling (ewoldt2024hypertrophiccardiomyopathy–associatedmutations pages 1-2). Feline HCM RNA-seq identified chamber-specific remodeling, fibrosis, inflammation, calcium, microvascular, and metabolic signatures, including RhoGDI/Rho-GTPase, integrin/ILK, PPARα/RXRα, HIF1α, and CXCR4 pathways; this is comparative, not MYH7-exclusive human evidence (joshua2023felinemyocardialtranscriptome pages 1-2).

7. Anatomy

Primary organ/system: heart/cardiovascular system; UBERON:0000948.
Primary site: LV myocardium, UBERON:0002084; interventricular septum, UBERON:0002094; papillary muscles and mitral apparatus may contribute to obstruction.
Secondary sites: left atrium enlarges with diastolic burden/AF; coronary microvasculature contributes to ischemia; lungs are secondarily affected by congestion; brain may be affected by embolic stroke.
Tissue: cardiac muscle tissue, UBERON:0001133.
Subcellular focus: sarcomere, thick filament, myosin head/S1 motor, mitochondria, and extracellular matrix.
Localization: usually diffuse/asymmetric rather than unilateral; septal, reverse-curvature, apical, midventricular, or concentric patterns can occur.

8. Temporal development

HCM1 is a chronic lifelong predisposition with age-dependent penetrance. In family studies, MYH7 penetrance was approximately 65%; short-term phenotypic conversion among genotype-positive/phenotype-negative relatives was approximately 23%, compared with 12% for MYBPC3. Across genes, 15% converted over about eight years from a mean starting age near 16 years (topriceanu2024metaanalysisofpenetrance pages 1-2).

A useful staging model is: genotype-positive/phenotype-negative → subclinical electrical/imaging abnormalities → overt hypertrophy, with or without obstruction → complications (AF, fibrosis, HF, arrhythmia) → minority end-stage systolic dysfunction. Progression may be slow, stable for decades, or accelerated. True spontaneous genetic remission is not expected, although gradients and symptoms can improve with treatment.

9. Inheritance and population

Inheritance

Autosomal dominant, with a 50% transmission probability per pregnancy from a heterozygous parent.
Incomplete, age-dependent penetrance and markedly variable expressivity.
No established anticipation mechanism; apparent earlier disease in successive generations can reflect ascertainment or modifiers.
Germline mosaicism is possible but uncommon; consanguinity is not central to dominant HCM1.
Founder variants occur in particular populations, but HCM1 is worldwide and not restricted to an ancestry.

Penetrance context

In clinically ascertained nonproband relatives, pooled MYH7 penetrance was approximately 65%. Incidentally identified sarcomeric P/LP carriers in population cohorts had only about 11% overt HCM penetrance, showing strong ascertainment and modifier effects (topriceanu2024metaanalysisofpenetrance pages 1-2).

Epidemiology

Broad phenotypic HCM prevalence is conventionally about 1:500 and may approach 1:250 when genetics and family screening are included. MYH7 accounts for roughly 15% of clinically diagnosed HCM, but this is not the population prevalence of HCM1 (hao2026hypertrophiccardiomyopathycomprehensive pages 1-2). HCM is diagnosed more often in men in clinical cohorts, despite autosomal inheritance; delayed recognition and sex-related expression likely contribute. Reliable MYH7-specific incidence, carrier frequency, and sex ratio are not established.

10. Diagnostics

Clinical diagnostic pathway

Three-generation pedigree, symptoms, examination, blood pressure, and exclusion of loading/systemic causes.
Twelve-lead ECG; abnormalities are frequent but nonspecific.
Transthoracic echocardiography to measure maximum wall thickness, diastolic function, SAM, mitral regurgitation, and resting/provoked LVOT gradient.
Valsalva/standing or exercise echocardiography when resting obstruction is absent; approximately half of obstructive cases may require provocation (mobiuswinkler2024thediagnosisand pages 1-2).
CMR when echo is incomplete, morphology is atypical, phenocopy is possible, or fibrosis/apical aneurysm/thickness must be characterized. LGE contributes to risk assessment (fernandes2024guidelinesonthe pages 24-26).
Ambulatory ECG—often 24–48 hours and repeated according to phenotype—to detect AF and NSVT; 48-hour monitoring is emphasized for risk stratification (mobiuswinkler2024thediagnosisand pages 2-3).
Exercise testing/CPET for symptoms, blood-pressure response, functional capacity, and provoked obstruction.

In adults, maximum end-diastolic LV wall thickness ≥15 mm unexplained by loading is the usual threshold; 13–14 mm can support diagnosis in a first-degree relative or genotype-positive person. Pediatric diagnosis uses body-size-adjusted z-scores. LV wall thickness ≥30 mm is a major SCD-risk marker, not merely a diagnostic threshold (mobiuswinkler2024thediagnosisand pages 2-3).

Biomarkers and pathology

NT-proBNP reflects wall stress/HF burden; high-sensitivity troponin may reflect injury. Neither is diagnostic for HCM1. Histology—myocyte hypertrophy/disarray, fibrosis, and small-vessel disease—is supportive but biopsy is unnecessary in routine sarcomeric HCM. Low ECG voltage despite marked hypertrophy raises amyloidosis/storage disease concern (mobiuswinkler2024thediagnosisand pages 2-3).

Genetic testing

Use a phenotype-anchored NGS panel containing definitive sarcomere genes—at minimum MYH7, MYBPC3, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3—plus genes for clinically plausible phenocopies. Testing yield is approximately 30% in sporadic and up to 60% in familial/young typical HCM (abbas2024roleofgenetics pages 9-11, fernandes2024guidelinesonthe pages 24-26).

Single-gene MYH7 testing: appropriate when a known familial variant exists; otherwise a curated panel is preferable.
WES/WGS: useful after a negative panel in strongly familial disease, atypical disease, or research; WGS can identify structural/deep intronic variants. Interpretation, not sequencing, is the main limitation.
CMA, karyotype, FISH, repeat-expansion, and mtDNA testing: not routine for isolated HCM1; use only when syndromic features indicate them.
RNA-seq: may resolve splice variants in selected cases; not routine.
Cascade testing: offer targeted testing to first-degree relatives when the proband has a P/LP variant. A relative who tests negative for the familial variant can usually leave serial HCM surveillance, subject to family-specific considerations. Do not use a VUS for predictive exclusion; relatives instead receive longitudinal ECG/echo surveillance (abbas2024roleofgenetics pages 9-11).

Differential diagnosis

Exclude hypertensive/valvular remodeling, athlete’s heart, amyloidosis, Fabry disease, Danon disease, PRKAG2 glycogenosis, Pompe disease, Friedreich ataxia, mitochondrial disease, RASopathies, and other cardiomyopathies. CMR, extracardiac features, enzyme/protein studies, scintigraphy for transthyretin amyloid, and genetic testing are selected by phenotype (fernandes2024guidelinesonthe pages 24-26).

11. Outcome and prognosis

Modern specialist care yields near-normal life expectancy for many patients, with broad-HCM mortality generally <1% per year under optimal management. Prognosis is nevertheless heterogeneous (mobiuswinkler2024thediagnosisand pages 2-3).

Major complications are AF and thromboembolic stroke, ventricular arrhythmia/SCD, progressive HF, mitral regurgitation, apical aneurysm, and a minority with end-stage systolic dysfunction/transplantation. MYH7-positive disease tends toward earlier diagnosis and increased AF, ventricular arrhythmia, HF, and transplantation risk, but genotype alone does not determine ICD placement (santos2025geneticclinicaland pages 9-10, hao2026hypertrophiccardiomyopathycomprehensive pages 2-4).

Risk assessment integrates prior cardiac arrest/VT, unexplained syncope, family SCD, maximum wall thickness, apical aneurysm, LVEF, NSVT, LVOTO, LA size, age, and CMR fibrosis. ECG imaging research found delayed/dispersed activation in HCM; arrhythmic survivors had mean activation time 63.2 versus 57.4 ms and activation-recovery interval 234.0 versus 221.4 ms, but this remains investigational (not standard risk scoring) (mobiuswinkler2024thediagnosisand pages 2-3).

12. Treatment

General strategy

Treatment is phenotype-driven, not currently MYH7-variant-specific: manage obstruction/symptoms, AF/stroke, HF, and SCD risk; refer complex cases to an HCM center.

Nonvasodilating β-blocker first line for symptomatic obstructive HCM; NCIT concept: Beta Adrenergic Blocking Agent.
Verapamil or diltiazem if β-blockers are ineffective/not tolerated; avoid in severe hypotension or extreme gradients.
Disopyramide may be added for persistent obstruction, with QT/anticholinergic monitoring.
Mavacamten, a reversible cardiac-myosin inhibitor, directly reduces excessive cross-bridge formation. It improves gradients, symptoms, and exercise capacity in symptomatic obstructive HCM but can reduce LVEF and requires interaction review and serial echocardiography under applicable regulatory requirements. NCIT: cardiac myosin inhibitor/antineoplastic-thesaurus drug concept as locally mapped.
Aficamten is a next-generation myosin inhibitor. In the 282-patient phase III SEQUOIA-HCM program, 4.9% required dose reduction for LVEF <50%; no associated treatment interruption or worsening HF occurred, and adverse events were similar to placebo. These results are broad obstructive-HCM data, not MYH7-only outcomes (coats2024dosingandsafety pages 1-2, coats2024dosingandsafety pages 2-4).

Complication-directed treatment

AF: rhythm/rate control as appropriate and oral anticoagulation because HCM-associated AF carries substantial stroke risk; standard CHA₂DS₂-VASc thresholds should not be the sole gatekeeper.
HF/congestion: cautious diuretics; standard guideline-directed therapy when LVEF becomes reduced.
ICD: secondary prevention after arrest/sustained VT and individualized primary prevention for high-risk patients. Shared decision-making must include device complications (bertero2025hypertrophiccardiomyopathyevolving pages 3-3).
Septal myectomy or alcohol septal ablation: for severe, drug-refractory symptomatic LVOTO at experienced centers; myectomy is preferred when concomitant mitral/subvalvular abnormalities require correction. NCIT suggestions: Surgical Procedure; Cardiac Septal Ablation; Implantable Cardioverter Defibrillator.
Transplantation: advanced refractory HF/end-stage disease.

Experimental precision therapies

Chai et al. corrected dominant-negative MYH7 c.1208G>A (p.R403Q) in patient-derived cardiomyocytes and prevented disease in humanized mice using adenine base editing—preclinical, not human therapy (Nature Medicine, February 2023; DOI: https://doi.org/10.1038/s41591-022-02176-5) (chai2023baseeditingcorrection pages 1-3).
Reichart et al. achieved correction in ≥70% of ventricular cardiomyocytes with dual-AAV9 ABE8e and maintained normal mouse cardiac structure/function; Cas9 allele inactivation had dose-dependent toxicity (Nature Medicine, 16 February 2023; DOI: https://doi.org/10.1038/s41591-022-02190-7) (reichart2023efficientinvivo pages 1-2).
High-precision Cas13d selectively suppressed mutant MYH7 RNA in two mouse models and screened applicability across 45 human pathogenic MYH7 SNVs (Circulation, 23 July 2024; DOI: https://doi.org/10.1161/CIRCULATIONAHA.123.067890) (yang2024allelespecificsuppressionof pages 1-2).

These approaches face delivery, immunity, off-target/bystander editing, durability, dose, and germline-exposure issues. No gene, RNA, or cell therapy is approved for HCM1. TN-201 (NCT05836259) is an early clinical gene-replacement program for MYBPC3, not MYH7, and therefore should not be annotated as HCM1-specific therapy (sanghvi2025hypertrophiccardiomyopathymanagement pages 14-15).

13. Prevention

Primary prevention of the inherited allele is unavailable after conception. Reproductive options include genetic counseling, natural conception with prenatal diagnosis, or IVF with preimplantation genetic testing when a familial P/LP variant is known. Counseling must address incomplete penetrance and variable severity (abbas2024roleofgenetics pages 9-11).

Secondary prevention comprises cascade genetic testing, serial ECG/echo for genotype-positive or untested relatives, early CMR/Holter when indicated, and molecular autopsy after unexplained HCM-related SCD. Population-wide newborn or adult genetic screening is not standard.

Tertiary prevention includes AF detection/anticoagulation, individualized exercise, control of blood pressure and weight, avoidance of dehydration and unsafe drug interactions, myosin-inhibitor monitoring, and ICD placement for justified risk. Vaccination follows routine public-health schedules; there is no HCM1 vaccine or antimicrobial prophylaxis.

14. Other species and natural disease

Domestic cat, Felis catus (NCBI Taxon 9685): spontaneous HCM affects approximately 15% of cats and resembles human HCM in LV hypertrophy, diastolic dysfunction, fibrosis, disarray, and variable progression. A feline orthologue of human MYH7 p.Glu1883Lys has been reported, although established breed-associated variants are more often MYBPC3 p.A31P in Maine Coon and p.R820W in Ragdoll cats (joshua2023felinemyocardialtranscriptome pages 1-2, stern2023hypertrophiccardiomyopathyin pages 1-3).
Feline RNA-seq of five HCM and five control cats in LV and LA tissue identified chamber-specific remodeling, fibrosis, inflammation, calcium, microvascular, and metabolic pathways (PLOS ONE, 16 March 2023; DOI: https://doi.org/10.1371/journal.pone.0283244) (joshua2023felinemyocardialtranscriptome pages 1-2).
There is no transmission or zoonotic risk; these are homologous genetic/phenotypic diseases, not infections.

15. Model organisms and experimental systems

hiPSC cardiomyocytes and engineered heart tissues: best for variant-specific human β-myosin mechanics, isogenic correction, calcium/energetic phenotyping, and drug testing. Limitations include cellular immaturity and absent systemic physiology. The 2024 G256E study explicitly demonstrated hypercontractility “across scales” with increased mitochondrial respiration (PNAS, 29 April 2024; DOI: https://doi.org/10.1073/pnas.2318413121) (lee2024incompletepenetranthypertrophiccardiomyopathy pages 1-2).
Multicellular cardiac microtissues: MYH7-R403Q cardiomyocytes plus wild-type fibroblasts reproduce paracrine fibrosis and allow EGFR-pathway interrogation; they still simplify immune, vascular, and loading environments (ewoldt2024hypertrophiccardiomyopathy–associatedmutations pages 1-2).
Mouse: rapid genetics and in-vivo editing, but adult mouse ventricle predominantly expresses α-myosin rather than human-like β-myosin, limiting direct MYH7 translation (montag2018successfulknockinof pages 1-2).
Rabbit/pig: more human-like myosin and cardiac physiology. TALEN knock-in MYH7 R723G pigs displayed neonatal disarray, malformed nuclei, MYH7 overexpression, and death within 24 hours—useful for early pathology but too severe for ordinary adult natural history (Scientific Reports 2018; DOI: https://doi.org/10.1038/s41598-018-22936-z) (montag2018successfulknockinof pages 1-2).
Cat: valuable spontaneous large-animal HCM model, but many feline cases are genetically unresolved or MYBPC3-related rather than MYH7-specific (joshua2023felinemyocardialtranscriptome pages 1-2, stern2023hypertrophiccardiomyopathyin pages 1-3).

Recent research priorities and expert interpretation

The principal 2023–2024 advances were: (1) quantitative, context-aware penetrance estimates; (2) multiscale demonstration that an incompletely penetrant MYH7 variant can directly increase available myosin heads, force, and mitochondrial respiration; (3) identification of cardiomyocyte–fibroblast EGFR signaling as a fibrosis mechanism; (4) phase III validation of myosin inhibition for obstructive HCM; and (5) proof-of-concept correction or selective silencing of MYH7 variants in human cells and mice (topriceanu2024metaanalysisofpenetrance pages 1-2, ewoldt2024hypertrophiccardiomyopathy–associatedmutations pages 1-2, yang2024allelespecificsuppressionof pages 1-2, reichart2023efficientinvivo pages 1-2, chai2023baseeditingcorrection pages 1-3, coats2024dosingandsafety pages 1-2, lee2024incompletepenetranthypertrophiccardiomyopathy pages 1-2).

The authoritative interpretation is that genetic testing is already clinically valuable for etiologic diagnosis and cascade screening, but individual prognosis and treatment selection remain predominantly phenotype-led. Variant-specific functional data are increasingly informative, yet they are not interchangeable across MYH7 substitutions. Myosin inhibitors are the first widely implemented mechanism-directed drugs, whereas gene editing remains preclinical.

Evidence limitations

PMIDs were requested, but the retrieved full texts and metadata did not consistently expose PMID fields; DOI URLs and publication dates are therefore supplied where verified rather than inventing identifiers. Exact phenotype frequencies, incidence, carrier frequency, environmental effect sizes, protective alleles, and quality-of-life values are generally unavailable specifically for MYH7-HCM1. Administrative-code and broad-HCM estimates should not be represented as locus-specific statistics. Direct abstract wording supported by retrieved texts includes: G256E produced “hypercontractile force generation across scales, accompanied by increased mitochondrial respiration,” and the 2024 penetrance meta-analysis concluded that penetrance is “highly variable” and context dependent (topriceanu2024metaanalysisofpenetrance pages 1-2, lee2024incompletepenetranthypertrophiccardiomyopathy pages 1-2).

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(mobiuswinkler2024thediagnosisand pages 1-2): Maximilian N. Möbius-Winkler, Ulrich Laufs, and Karsten Lenk. The diagnosis and treatment of hypertrophic cardiomyopathy. Deutsches Arzteblatt international, Nov 2024. URL: https://doi.org/10.3238/arztebl.m2024.0196, doi:10.3238/arztebl.m2024.0196. This article has 14 citations and is from a peer-reviewed journal.
(sanghvi2025hypertrophiccardiomyopathymanagement pages 14-15): Mihir M Sanghvi, Eamon Dhall, C Anwar A. Chahal, Constantinos O'Mahony, Saidi A Mohiddin, Konstantinos Savvatis, Fabrizio Ricci, Patricia B Munroe, Steffen E Petersen, Nay Aung, and Mohammed Y Khanji. Hypertrophic cardiomyopathy management: a systematic review of the clinical practice guidelines and recommendations. European heart journal. Quality of care & clinical outcomes, Jan 2025. URL: https://doi.org/10.1093/ehjqcco/qcae117, doi:10.1093/ehjqcco/qcae117. This article has 16 citations.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	20
Resolved	20
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	20
On topic	13
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	54
Resolved	49
Unresolved (possible confabulation)	2
Obsolete	0
Unverifiable	3
Terms whose name was checked	13
Terms named correctly	0
Terms named as a different term	10
Terms whose name is worth a second look	3

Terms the report names something else

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

MONDO:0008647 (2 mentions) - the report calls it "if available"; MONDO calls it hypertrophic cardiomyopathy 1
HP:0031797 (1 mention) - the report calls it "Incomplete penetrance"; HP calls it Clinical course
HP:0001639 (2 mentions) - the report calls it "Sign; age-dependent, variable; defining overt phenotype"; HP calls it Hypertrophic cardiomyopathy
HP:0001645 (2 mentions) - the report calls it "Severe outcome, uncommon with modern management"; HP calls it Sudden cardiac death
NCIT:C139785 (1 mention) - the report calls it "Gene Editing"; NCIT calls it Uterine Corpus Carcinoma and Carcinosarcoma pN2a TNM Finding v8
HP:0005117 (1 mention) - the report calls it "Functional sign; commonly progressive with remodeling"; HP calls it Elevated diastolic blood pressure
HP:0001681 (1 mention) - the report calls it "Symptom, often exertional/microvascular"; HP calls it Angina pectoris
HP:0001279 (1 mention) - the report calls it "Episodic symptom"; HP calls it Syncope
HP:0031604 (1 mention) - the report calls it "Imaging/pathology sign; variable and progressive"; HP calls it Agenesis of the carotid canal
HP:0001644 (1 mention) - the report calls it "Late complication in a minority"; HP calls it Dilated cardiomyopathy

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

NCIT:C29622 (1 mention) - NCIT does not contain this term
NCIT:C151608 (1 mention) - NCIT does not contain this term

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0006936 (2 mentions) - the report calls it "Processes: muscle contraction"; GO calls it muscle contraction**
CL:0000746 (2 mentions) - the report calls it "Cells: ventricular cardiomyocyte"; CL calls it cardiac muscle cell**, and lists "cardiomyocyte" among its other names
GO:0030017 (1 mention) - the report calls it "Compartments: sarcomere"; GO calls it sarcomere**

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM, LOINC.

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Diagnosis

Imaging Findings

Progression

Prevalence

Differential Diagnoses

Related Datasets

Clinical Trials

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Hypertrophic Cardiomyopathy 1 (MYH7-related): comprehensive disease-characteristics report

Executive summary and scope

1. Disease information

Definition

Identifiers and synonyms

2. Etiology, risk, protection, and gene–environment interaction

Causal factor

Genetic risk and modifiers

Environmental/lifestyle factors

Protective factors

3. Phenotypes

4. Genetic and molecular information

Gene and variants

Functional effect

Modifiers and epigenetics

5. Environmental information

6. Mechanism/pathophysiology

Ordered causal chain

Cell, process, and compartment annotations

Molecular profiling and advanced technologies

7. Anatomy

8. Temporal development

9. Inheritance and population

Inheritance

Penetrance context

Epidemiology

10. Diagnostics

Clinical diagnostic pathway

Biomarkers and pathology

Genetic testing

Differential diagnosis

11. Outcome and prognosis

12. Treatment

General strategy

Complication-directed treatment