| 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 (pqac-00000000, pqac-00000003, pqac-00000006). | 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 (pqac-00000008). | MYH7-specific. Loss-of-function/null variants lack sufficient evidence for pathogenicity (pqac-00000008). |
| 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 (pqac-00000010). | 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 (pqac-00000011, pqac-00000028). | 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 (pqac-00000001, pqac-00000002). | 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 (pqac-00000016, pqac-00000018). | 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 (pqac-00000023, pqac-00000024, pqac-00000026). | 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 (pqac-00000019, pqac-00000022). | 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 (pqac-00000012, pqac-00000013, pqac-00000014). | 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 (pqac-00000029, pqac-00000030, pqac-00000031). | 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.*