Hypertrophic Cardiomyopathy 14

1. Disease Information

Overview

Hypertrophic cardiomyopathy 14 (CMH14) is the MYH6-attributed member of the numbered OMIM hypertrophic cardiomyopathy series. It denotes hypertrophic cardiomyopathy — unexplained left ventricular hypertrophy, classically asymmetric and septal, not explained by loading conditions — in a person carrying a heterozygous missense variant in MYH6, encoding the α (alpha) heavy chain of cardiac myosin. It is not a clinically distinguishable entity: no CMH14-specific phenotype, imaging finding, natural history, or treatment exists. Its only definitional feature is the genotype, and that genotype–phenotype link is the disputed one.

The concept traces to exactly two publications:

• Niimura et al., Circulation 2002 (PMID:11815426) — one MYH6 missense variant (R795Q) among 31 patients with elderly-onset HCM.
• Carniel et al., Circulation 2005 (PMID:15998695) — one MYH6 missense variant (Q1065H) in 1 of 21 HCM probands.

ClinGen's tally: "It has been associated with HCM in 3 probands in 2 publications. Four unique heterozygous missense variants have been reported in humans with limited evidence to support their pathogenicity."

Key identifiers

Synonyms

CMH14; cardiomyopathy, familial hypertrophic, 14; hypertrophic cardiomyopathy caused by mutation in MYH6; MYH6-related hypertrophic cardiomyopathy; α-myosin heavy chain hypertrophic cardiomyopathy. (The existing YAML synonym list is correct.)

Provenance of the underlying information

Aggregated disease-level resources plus a very small number of individual case reports. There is no EHR cohort, registry, or biobank study of CMH14 as such — the total human evidence base is 3 probands. The most informative sources are meta-level: the ClinGen curation record, the Walsh et al. case-vs-control burden analysis (PMID:27532257), and gnomAD population frequencies.

2. Etiology

Disease causal factors

Asserted: heterozygous missense variation in MYH6 (14q11.2), autosomal dominant, acting on the α-cardiac myosin heavy chain motor.

Actual evidentiary status: the causal claim does not survive contemporary gene-level burden analysis. Walsh et al. (PMID:27532257) compared variant burden in cardiomyopathy cases against ExAC and reported for MYH6 an excess-variant odds ratio of 1.06 (95% CI 0.34–3.34) with an etiological fraction of 0.06 (0.00–0.70) — i.e. indistinguishable from background. The paper names MYH6 explicitly as one of the offenders:

"For example, MYBPC3, MYH6, and SCN5A have all been reported to be major contributors to DCM but show little or no excess burden despite adequate numbers and power; instead, we see that these are in fact genes that have the highest background variation." — Walsh et al., Genet Med 2017 (PMID:27532257)

This is the mechanistic crux: MYH6 carries an unusually high rate of rare missense variation in unselected populations (gnomAD v4 pLI = 0, LOEUF ≈ 0.63; it is not LoF-constrained), so a rare MYH6 missense allele found in an HCM proband is a weak observation. The A1004S variant, reported in DCM, sits at ~1.1% in the general population (Anfinson et al. 2022, PMID:35621855) — far commoner than the disease.

ClinGen also discounted the Carniel proband on exactly this ground: "Additional missense variants have been reported in humans, but were not scored because probands have variants in another HCM gene (Rubattu et al. 2016… Liu et al. 2021… Suzuki et al. 2022), or high frequency in the population (Carniel et al. 2005)."

Genetic risk factors

Candidate causal variants (the entire reported set for HCM):

Rubattu et al. (PMID:27483260) found MYH6 variants in 3/41 (7.5%) of identified variants in a 70-patient Italian NGS cohort, and noted a distribution signal worth recording:

"The distribution of the identified gene mutations was similar between the two groups with the exceptions of MYH6 and TNNT2. In fact, mutations in MYH6 were identified in the LO group only, whereas mutations in TNNT2 were identified in the EO group only." — Rubattu et al. 2016 (PMID:27483260), late-onset (≥65 y) vs early-onset (≤25 y)

This converges with Niimura's original elderly-onset finding and is the only replicated phenotypic association in the literature: to whatever extent MYH6 variants associate with HCM at all, they do so in late-onset, family-history-negative disease — the phenotype for which the causal prior is weakest and phenocopy risk highest.

Susceptibility / modifier loci: none established for CMH14. The general HCM modifier landscape (common-variant polygenic scores, hypertension, sarcomere-negative status) applies non-specifically and is not MYH6-informed.

Related MYH6 gene–disease relationships (ClinGen, HGNC:7576) — these are the important nosological neighbours and should be recorded in the entry, because they show the gene is real even where the HCM link is not:

MYH6 also carries a well-replicated arrhythmia association outside ClinGen's HCM curation — see §3.

Environmental risk factors

None specific to CMH14. Generic HCM modifiers of phenotype expression: age, systemic hypertension (HP:0000822), athletic conditioning (a diagnostic confounder rather than a cause), obesity, and male sex. None have been studied in MYH6 carriers.

Protective factors

Not established. No protective MYH6 allele is described. Guideline-era HCM care (ICD for primary prevention, septal reduction, myosin inhibitors) modifies outcome but is disease-level, not genotype-level.

Gene–environment interactions

Not applicable / not studied for CMH14. No GxE literature exists for MYH6 in HCM. Note one genuinely interesting environmental observation for the gene: Gorza et al. (PMID:6234108) showed that chronic haemodynamic overload shifts human atrial MHC composition toward β, i.e. the α-MHC content of the tissue where MYH6 actually dominates is itself load-dependent. That is a mechanism-relevant load–isoform interaction, but it has never been tested against MYH6 genotype.

3. Phenotypes

There is no CMH14-specific phenotype. The phenotype list below is the OMIM 613251 clinical synopsis and the HCM phenotype in general. Frequencies are HCM-level, not MYH6-level, and must be curated with that qualifier — the 3-proband evidence base cannot support any frequency claim.

Core cardiac phenotypes (all category: Cardiovascular)

OMIM 613251 clinical synopsis phenotype set, per the entry: ventricular hypertrophy (often asymmetric, involving the interventricular septum); dyspnea; syncope; collapse; palpitations; chest pain — exercise-triggered. Age of onset third to eighth decade. Variability within and between families, "ranging from benign to malignant forms with a high risk of cardiac failure and sudden cardiac death."

The MYH6-specific phenotype signals that are real (and are not HCM)

These belong in the entry as differential/context, not as CMH14 phenotypes:

Sick sinus syndrome (HP:0011704) — the single best-supported MYH6 human phenotype association:

"A missense variant in this gene, c.2161C>T, results in the conceptual amino acid substitution p.Arg721Trp, has an allelic frequency of 0.38% in Icelanders and associates with sick sinus syndrome with an odds ratio = 12.53 and P = 1.5 × 10⁻²⁹. We show that the lifetime risk of being diagnosed with sick sinus syndrome is around 6% for non-carriers of c.2161C>T but is approximately 50% for carriers." — Holm et al., Nat Genet 2011 (PMID:21378987)

Also HP:0001688 Sinus bradycardia, HP:0012722 Heart block.

Atrial septal defect (HP:0001631) — the ClinGen Definitive MYH6 relationship:

"The underlying mutation is a missense substitution, I820N, in alpha-myosin heavy chain (MYH6), a structural protein expressed at high levels in the developing atria, which affects the binding of the heavy chain to its regulatory light chain." — Ching et al., Nat Genet 2005 (PMID:15735645)

Hypoplastic left heart syndrome with reduced RV EF — recessive/compound-heterozygous MYH6:

"Secondary family-based filtering for de novo and recessive variants revealed rare inherited missense mutations on both paternal and maternal alleles of MYH6… in 2 patients who developed right ventricular dysfunction 3 to 11 years postoperatively. Parents and siblings who were heterozygous carriers had normal echocardiograms." — Theis et al., Circ Cardiovasc Genet 2015 (PMID:26085007)

Dilated cardiomyopathy (HP:0001644) — Carniel's same paper that supplied the HCM proband found three DCM probands (P830L, A1004S, E1457K), and framed MYH6 as a pleiotropic locus:

"This study suggests that mutations in MYH6 may cause a spectrum of phenotypes ranging from DCM to HCM." — Carniel et al. 2005 (PMID:15998695)

That pleiotropy claim, read alongside the burden data, is better explained as non-specific rare variation than as a genuine allelic series.

Quality-of-life impact

No CMH14-specific QoL data. HCM-level: the disease-specific instrument is the Kansas City Cardiomyopathy Questionnaire (KCCQ-23/KCCQ-CSS), used as a primary or key secondary endpoint in EXPLORER-HCM and SEQUOIA-HCM; generic instruments are SF-36 and EQ-5D. Dominant QoL drivers in HCM are exertional limitation, ICD-related anxiety and shock burden, activity restriction, and reproductive/family-screening distress. Not available for CMH14 specifically — do not curate a per-phenotype QoL claim.

4. Genetic / Molecular Information

Causal gene

MYH6 (myosin heavy chain 6, cardiac muscle, alpha), hgnc:7576, OMIM 160710, 14q11.2, transcript NM_002471.4, protein NP_002462.2 / UniProt P13533 (1939 aa). It lies head-to-head with MYH7 (β-MHC) in a tandem gene cluster; the two proteins are ~93% identical, which is exactly why the MYH7 mechanistic literature has been borrowed to explain MYH6 and exactly why that borrowing is unsafe.

Weiss et al. sequenced the whole family and drew the relevant conclusion about how these isoforms differ:

"Results indicate that functional diversity among MyHCs is likely to be accomplished by having small pockets of sequence diversity in an otherwise highly conserved molecule." — Weiss et al., J Mol Biol 1999 (PMID:10388558) — cited by ClinGen as part of the (limited) experimental support

Pathogenic variants

Covered in §2. Key point for the KB: not one MYH6 variant is currently classified Pathogenic or Likely Pathogenic for HCM by any ClinVar submitter applying ACMG/AMP criteria. The two OMIM allelic variants are VUS (R795Q) and conflicting-VUS/likely-benign (Q1065H). Curate functional_impact_category as absent or UNKNOWN, not GAIN_OF_FUNCTION — the schema's FunctionalImpactEnum should not be used to assert a consequence nobody has demonstrated.

• Variant type/class: missense throughout (one reported frameshift, p.Lys364fs, in a proband also carrying an MYH7 variant).
• Somatic vs germline: germline only. No somatic role; MYH6 is not a COSMIC/cancer gene in this context.
• Population frequency: see table in §2. The population-genetic signature is the diagnostic problem — MYH6 is not LoF-constrained (gnomAD v4 pLI 0, LOEUF ≈ 0.63) and carries high background missense variation.
• Functional consequences: unknown for the HCM-reported alleles. The functional work that exists is on other MYH6 alleles from other phenotypes (see §6).

Modifier genes

None established. What the literature actually shows is oligogenic confounding rather than modification: two of the four HCM-reported MYH6 probands also carried a variant in a definitive HCM gene (TNNT2, MYH7). Suzuki et al. argued the double hit drives severity —

"Family members with the double variants demonstrated severe phenotypes, such as sudden cardiac-related death and heart failure. These double variants were well segregated and might be responsible for the severity of cardiovascular events in affected family members." — Suzuki et al., J Cardiol Cases 2022 (PMID:35911064)

— but ClinGen declined to score these, and the parsimonious reading is that the definitive-gene allele is causal and MYH6 is a passenger. If dismech curates this, relationship_type: MODIFIER on the MYH6 genetic: entry with an explicit notes: stating the alternative interpretation would be honest; asserting modification would not.

Epigenetic information

Not available for CMH14. No methylation, histone, or chromatin study addresses MYH6 variant carriers. The MYH6/MYH7 locus is under well-characterised developmental and hormonal (thyroid hormone) transcriptional control and is regulated by the Mir-208a intronic miRNA within Myh6, plus antisense/lncRNA regulation of the MYH7/MYH6 switch — but this is isoform-switch biology, not CMH14 epigenetics. Do not curate as disease mechanism.

Chromosomal abnormalities

Not applicable. No CNV, translocation, or aneuploidy mechanism; ClinGen records no dosage-sensitivity curation for MYH6 (0 classifications), so haploinsufficiency and triplosensitivity are both unassessed.

5. Environmental Information

• Environmental factors: none identified. No toxicological, radiation, occupational, or pollutant association with CMH14 (CTD has no MYH6–HCM environmental interaction of note).
• Lifestyle factors: high-intensity competitive athletics is relevant to HCM management (risk stratification, shared decision-making on participation per the 2024 AHA/ACC guideline) and to differential diagnosis (athlete's heart), but is not an aetiological factor. Hypertension and obesity influence LVH phenotype non-specifically.
• Infectious agents: not applicable.

For the dismech environmental: block: I would leave it empty rather than manufacture entries. If the check-environmental-evidence gate ever needs an answer here, the waiver sentence form ("Left deliberately uncited." + ≥20 words of recorded search) is the right instrument.

6. Mechanism / Pathophysiology

Ordered causal chain

Read this whole section as inference. ClinGen's verdict — "The mechanism for disease remains unknown" — is the primary finding. Every arrow below is either (a) demonstrated for a different MYH6 allele in a different phenotype, or (b) demonstrated for MYH7 and transposed. I mark each step accordingly.

Branch A — the asserted (MYH7-analogy) chain, entirely INFERRED for MYH6:

1. A heterozygous MYH6 missense allele results in a single amino acid substitution in α-cardiac myosin heavy chain. [Demonstrated — this is just the variant.]
2. The substituted residue is predicted to perturb motor-domain, converter, lever-arm, or coiled-coil tail structure. [Computational only. Carniel: "All MYH6 mutations were distributed in highly conserved residues, were predicted to change the structure or chemical bonds of alphaMyHC." Note "predicted" — no biophysical assay was done on Q1065H or R795Q. The human α-MHC structure has never been solved; all structural inference is by homology to β-MHC (Anfinson 2022, PMID:35621855).]
3. Altered actomyosin cross-bridge kinetics lead to hypercontractility with impaired relaxation and inefficient ATP utilisation. [Transposed from MYH7. Never measured for any HCM-reported MYH6 allele.]
4. Sarcomeric energetic stress and altered Ca²⁺ handling lead to activation of hypertrophic signalling in ventricular cardiomyocytes (CL:0002131 regular ventricular cardiac myocyte). [Inferred.]
5. Hypertrophic signalling results in cardiomyocyte hypertrophy and myofibrillar disarray (GO:0014898 cardiac muscle hypertrophy in response to stress). [Inferred.]
6. Sustained hypertrophy plus microvascular ischaemia result in interstitial and replacement fibrosis via cardiac fibroblast (CL:0000057 fibroblast) activation → HP:0001685 Myocardial fibrosis. [Inferred; established for HCM generally.]
7. Asymmetric septal thickening (UBERON:0002094 interventricular septum) results in dynamic LVOT obstruction with systolic anterior motion of the mitral valve → HP:0001653 Mitral regurgitation and HP:0002875 Exertional dyspnea. [Established for HCM; not MYH6-attributed.]
8. Diastolic stiffening results in elevated filling pressures → HP:0031295 Left atrial enlargement → HP:0005110 Atrial fibrillation.
9. Fibrosis and disarray create a re-entrant substrate → HP:0004756 Ventricular tachycardia → HP:0001645 Sudden cardiac death.

Branch B — the alternative and arguably better-supported chain, "MYH6 is an atrial gene":

1. α-MHC is the atrial-predominant isoform in the adult human heart, a minor ventricular component. [Demonstrated.]

"Myosin heavy chain alpha was found to be a major component of atrial myosin and a minor component of ventricular myosin, while heavy chain beta was found to be a major component of ventricular myosin and a minor component of atrial myosin." — Gorza et al., Circ Res 1984 (PMID:6234108) — the expression evidence ClinGen scored

1. A MYH6 missense allele therefore acts principally on atrial cardiomyocytes (CL:0002129 regular atrial cardiac myocyte) and the developing atrium, not the adult LV. Anfinson et al. found exactly this pattern in patient tissue: "atrial sarcomeres were disrupted with the R443P, K849del, and E1503V variants, while the ventricular sarcomere structure remained intact… consistent with α-MHC being the predominant atrial MHC isoform postnatally." (PMID:35621855)
2. Atrial sarcomere disorganisation and contractile impairment lead to the phenotypes MYH6 is definitively or strongly associated with — atrial septal defect, sick sinus syndrome, HLHS — and do not straightforwardly lead to ventricular hypertrophy.
3. Where ventricular pathology is seen in MYH6 carriers, it may be secondary to atrial dysfunction: "Given the predominance of β-MHC in the postnatal ventricles, it is possible that ventricular fibrosis is, at the cellular level, a downstream response to atrial cardiomyocyte dysfunction caused by MYH6 variants in the patients studied." (PMID:35621855)

Branch B is the single most useful thing in this report for dismech. It explains why the MYH6–HCM link is weak on first principles — the gene's product is barely present in the tissue that hypertrophies — and it converts an "absence of evidence" curation into a positive mechanistic statement. It also has an elegant model-organism proof of the atrial→ventricular direction:

"We find that the zebrafish locus weak atrium encodes an atrium-specific myosin heavy chain that is required for atrial myofibrillar organization and contraction… However, the weak atrium mutant ventricle becomes unusually compact, exhibiting a thickened myocardial wall, a narrow lumen and changes in myocardial gene expression. As weak atrium/atrial myosin heavy chain is expressed only in the atrium, the ventricular phenotypes in weak atrium mutants represent a secondary response to atrial dysfunction." — Berdougo et al., Development 2003 (PMID:14573521)

A thickened ventricular myocardial wall arising secondarily to an atrium-restricted myosin defect is the closest thing in the whole literature to a mechanism by which MYH6 could produce ventricular hypertrophy — and it is a zebrafish nonsense allele, not a human HCM missense allele. Curate it as evidence_source: MODEL_ORGANISM, directness: INDIRECT, and say plainly in explanation what the inference step is.

Molecular pathways

• Actomyosin cross-bridge cycling / thick-filament regulation. Reactome R-HSA-390522 (Striated Muscle Contraction); KEGG hsa04260 (Cardiac muscle contraction) and hsa05410 (Hypertrophic cardiomyopathy).
• Downstream hypertrophic signalling implicated in HCM generally (calcineurin–NFAT, MAPK, PI3K–AKT–mTOR, TGF-β to fibroblasts) — none demonstrated for MYH6.

Cellular processes (GO — all CURIEs below verified against cache/go/terms.csv)

For a CMH14 node, GO:0000146 / GO:0016887 / GO:0051015 with modifier: UNKNOWN-equivalent (i.e. omit modifier) is more honest than tagging GAIN_OF_FUNCTION. Per the repo's GOF/LOF guidance, "the pathway is very active" would be INCREASED; here nobody has measured whether it is.

Protein dysfunction

α-MHC is an ATP-driven actin-based motor; ClinGen scored biochemical function evidence for "MHC-α interactions with ATP, actin and the light chains (Weiss et al. 1999)." The functional studies that exist target non-HCM alleles:

• I820N (ASD): decreases α-MHC affinity for the regulatory light chain (Ching 2005, PMID:15735645).
• E933del (SSS): enhances MyBP-C binding; slows electrical propagation in HL-1 atrial cardiomyocytes; disrupts sarcomere structure with perinuclear α-MHC aggregation in NRVCMs.
• R721W (SSS): disrupted sarcomere structure and perinuclear aggregation in NRVCMs.
• A230P, A1366D, E526K, R1822_E1823dup, R443P: decreased sarcomere organisation in cultured cardiomyocytes; H252Q increased myofibril striations; V700M no effect despite being predicted damaging.
• A1004S (DCM): slower and reduced shortening in NRVCMs; P830L (DCM): no difference from WT — the opposite of what the structural prediction implied.

All from Anfinson et al. 2022 (PMID:35621855). The pattern is important: in vitro effect does not track with in silico prediction, and no HCM-reported allele has been assayed at all. Anfinson also notes: "At present, no such 'mutational hotspots' have been identified in MYH6" — unlike MYH7, where clustering informs ACMG/AMP classification.

Metabolic changes

Liu et al. (PMID:34087240) reported metabolomic disturbance in a pedigree carrying MYH6-rs372446459 together with TNNT2-rs397516484:

"They also showed disturbances of carbohydrate metabolism, including the citrate cycle (TCA cycle), glycolysis/gluconeogenesis, fructose and mannose metabolism, pentose and glucuronate interconversions and amino sugar and nucleotide sugar metabolism."

Do not attribute this to MYH6. The proband carried two sarcomere variants; the metabolomic signal cannot be assigned. If curated, it needs directness: INDIRECT and an explanation naming the confound.

Immune system involvement

Not applicable. No autoimmune or immunodeficiency component.

Tissue damage mechanisms

Myocardial fibrosis (HP:0001685), microvascular dysfunction/ischaemia, and myocyte disarray are the canonical HCM tissue lesions — established for HCM, unstudied in MYH6 carriers. Anfinson notes other groups have reported fibrosis in MYH6 carriers' conduction system, ventricular walls, and ventricular septum.

Biochemical abnormalities / epigenetic changes / molecular profiling

• Transcriptomics: GTEx confirms MYH6 atrial-appendage-predominant expression. No CMH14 case–control transcriptomic dataset exists. One relevant in-vitro finding: MYH6-R443P iPSC-CMs showed "sarcomere disorganization and the upregulation of MYH7" — an isoform-compensation signal (PMID:35621855).
• Proteomics, metabolomics, lipidomics, spatial transcriptomics, single-cell, multi-omics, CRISPR/RNAi screens: no CMH14-specific data. Do not populate a datasets: block by relaxing the search to "MYH6" or to "hypertrophic cardiomyopathy" — that is precisely the Named Entity Confusion trap the repo's dataset guidance warns about (searching a causal gene surfaces whatever disease the gene is famous for; here that would return ASD/HLHS/SSS datasets, and relaxing to the parent term collapses CMH14 into generic HCM). If datasets: is populated at all, every accession needs just verify-datasets plus manual relevance triage, and I would expect the honest answer to be an empty block.

7. Anatomical Structures Affected

Organ level

• Primary: heart (UBERON:0000948); specifically the left ventricle (UBERON:0002084 heart left ventricle), left ventricular myocardium (UBERON:0006566), interventricular septum (UBERON:0002094), myocardium (UBERON:0002349).
• On the Branch-B mechanism, the primary site is instead the cardiac atrium — right cardiac atrium (UBERON:0002078) and the atrial septum / cardiac septum (UBERON:0002099) — plus the sinoatrial node region.
• Secondary: pulmonary circulation (post-capillary pulmonary hypertension from elevated filling pressures); systemic circulation and brain (cardioembolic stroke from AF).
• Body system: cardiovascular, exclusively. CMH14 is a non-syndromic, heart-restricted phenotype — no skeletal, neurological, renal, or dermatological involvement, which is a useful negative for differential diagnosis against syndromic LVH mimics.

Tissue and cell level

Tissue types: striated cardiac muscle; cardiac connective tissue/interstitium.

Subcellular level

Sarcomere (GO:0030017), thick/myosin filament (GO:0032982), A-band and M-band, contractile fibre. Mitochondrial energetic involvement is inferred from MYH7 biology, not shown for MYH6.

Localization and lateralization

Bilateral in the sense of being a whole-organ genetic disease, but the hypertrophy is characteristically asymmetric — septal-predominant, with the basal anteroseptum the classic site (HP:0001670). Apical, mid-cavity, and concentric variants occur. On Branch B the relevant asymmetry is chamber-level (atrial > ventricular), not wall-level.

8. Temporal Development

Onset

• OMIM 613251: "variable age of onset from the third to eighth decade of life."
• The replicated signal is late onset. Niimura's cohort: "Initial symptoms occurred at 59.3 (+/-12.3) years, and diagnosis was made at 62.8 (+/-10.8) years. None had family histories of cardiomyopathy." Carniel's HCM proband was diagnosed at 27 and died of congestive heart failure at 45 — the exception. Rubattu found MYH6 variants only in the late-onset (≥65 y) group.
• Onset pattern: insidious and chronic. Hypertrophy develops subclinically; presentation is usually with exertional symptoms, an incidental murmur/ECG abnormality, or a family/screening echo.
• HPO onset: Adult onset / Middle age onset / Late onset are the defensible categories. Do not curate childhood onset for CMH14.

Note the epistemic trap here. Elderly-onset, family-history-negative HCM is exactly the setting where a rare missense variant is least likely to be causal and a phenocopy (hypertensive LVH, cardiac amyloidosis, age-related sigmoid septum) is most likely — and it is the only setting where MYH6 variants have been replicated. Niimura's own framing acknowledged the distributional oddity: "The distribution of mutations in elderly-onset disease is strikingly different (P<0.00001) from that of familial, early onset hypertrophic cardiomyopathy."

Progression

• Stages: the HCM natural-history stages apply — (i) subclinical/G+P− genotype-positive phenotype-negative; (ii) classic hypertrophic phase with or without obstruction; (iii) adverse remodelling; (iv) end-stage/"burnt-out" HCM with systolic dysfunction (EF <50%), affecting ~3–5% of HCM patients.
• Rate: slow and variable over decades.
• Course: chronic, progressive, lifelong; punctuated by episodic arrhythmic events.
• The one CMH14-specific progression claim in the literature is Carniel's, and it is derived from a single proband: "the HCM phenotype was characterized by progression toward dilation, left ventricular dysfunction, and refractory heart failure." If curated as a progression: phase, it needs an explicit n=1 caveat in notes — a single patient cannot establish a phenotype's natural history.

Patterns

• Remission: none spontaneous. Obstruction is relieved by septal reduction therapy or myosin inhibition, and symptoms remit; the myopathy does not.
• Critical periods: adolescence/early adulthood is the window of maximal hypertrophy development in sarcomeric HCM and drives the paediatric screening schedule — but is likely irrelevant to a late-onset MYH6 phenotype. For the definitive MYH6 congenital phenotypes, the critical period is cardiac septation in embryogenesis.

9. Inheritance and Population

Epidemiology

• HCM overall: phenotypic prevalence classically ~1 in 500 (0.2%; 200 per 100,000). The JACC reappraisal opens with exactly this figure: "Hypertrophic cardiomyopathy (HCM) is an inherited cardiac condition affecting ∼1 in 500 and exhibits marked genetic heterogeneity." (PMID:39971408). Genotypic prevalence including non-penetrant carriers may approach 1 in 200.
• CMH14 specifically: no prevalence estimate exists and none can be constructed. With 3 probands worldwide and a disputed gene–disease relationship, the correct dismech prevalence record is measure_type: CASES_IN_LITERATURE with prevalence_class: NOT_YET_DOCUMENTED (or UNKNOWN) and notes recording the 3-proband count. Do not compute a rate_per_100000.
• Incidence: not available.

For genetic etiology

• Inheritance pattern: autosomal dominant as asserted (ClinGen MOI: AD). HPO HP:0000006 Autosomal dominant inheritance.
• Penetrance: unknown and, on the burden data, likely very low or zero for the reported alleles. Note the instructive contrast: for the sick sinus syndrome association, penetrance is quantified and high (lifetime risk ~50% for R721W carriers vs ~6% non-carriers, Holm 2011). Nothing comparable exists for HCM.
• Expressivity: OMIM describes "variability within and between families, ranging from benign to malignant forms." With n=3, this is HCM-general language, not a CMH14 observation.
• Genetic anticipation: not applicable (not a repeat-expansion disorder).
• Germline mosaicism: not reported.
• Founder effects: none for HCM alleles. There is a MYH6 founder-like signal for a different phenotype — R721W at 0.38% allele frequency in Icelanders (Holm 2011) — worth recording as context but not as CMH14 epidemiology.
• Consanguinity: not relevant to the dominant HCM claim. It is relevant to the recessive MYH6–HLHS mechanism (compound heterozygosity; Theis 2015).
• Carrier frequency: not applicable to a dominant condition. The relevant population figure is the allele frequency of the reported variants (§2) — and their commonness relative to the disease is the argument against pathogenicity.

Population demographics

• Affected populations: no ethnic enrichment for CMH14. Q1065H is notably commoner in East Asian ancestry (~0.1% in ExAC), which further undercuts pathogenicity rather than indicating a founder disease population.
• Geographic distribution: reported probands are from US (Niimura), US/Italy (Carniel), Italy (Rubattu), China (Liu; Wang iPSC line), and Japan (Suzuki). This is publication geography, not disease geography.
• Sex ratio: not established for CMH14. HCM overall is diagnosed more often in men (roughly 3:2), though this partly reflects ascertainment; women present later and with worse outcomes. Niimura's late-onset cohort was 18 women / 13 men.
• Age distribution: skewed late — see §8.

10. Diagnostics

CMH14 is diagnosed as HCM plus a genotype. There is no CMH14-specific test.

Clinical tests

Note that no biomarker distinguishes CMH14 from any other HCM, and none is MYH6-informed.

Genetic testing

• Recommended approach: a targeted HCM gene panel on the proband, per the 2024 AHA/ACC guideline. The panel should be narrow. This is the operational consequence of the ClinGen work, and it is stated bluntly in the reappraisal: "Nine (29%) genes were downgraded to disputed, further discouraging clinical reporting of variants in these genes." (PMID:39971408). MYH6 is one of those nine.
• Practical implication: a MYH6 variant found on a legacy broad panel should not be reported as causative of HCM, and should not be used for cascade testing. A laboratory still returning MYH6 for HCM is using a stale gene list. Rubattu reached the same conclusion empirically in 2016: "Our findings support the choice of a limited, well-selected panel of HCM genes as the best tool for diagnostic purposes."
• The genes that should be on the panel (ClinGen Definitive/Strong/Moderate, per PMID:39971408 — 29 genes): the sarcomere core MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, MYL3 plus TNNC1 (newly upgraded, "a 9th sarcomere gene with definitive HCM association"); sarcomere-associated ACTN2, CSRP3, FHOD3, FLNC (missense), PLN, DES, ALPK3, TRIM63 (AR), PRKAG2; syndromic/phenocopy GLA, LAMP2, TTR, FHL1, CACNA1C, PTPN11, RAF1, RIT1; and MT-TI, KLHL24 (moderate).
• WES / WGS: reasonable when the phenotype is syndromic or panel-negative with strong family history. WGS was the discovery modality for the recessive MYH6–HLHS finding (Theis 2015).
• Single-gene testing: appropriate only for cascade testing of a known familial variant. Not applicable to MYH6/HCM, since no MYH6 variant meets the P/LP bar.
• CMA, karyotyping, FISH, mtDNA testing, repeat-expansion testing: not indicated for CMH14. CMA has a role in syndromic congenital heart disease, and mtDNA testing is relevant for the MT-TI phenocopy — neither is a CMH14 test.

Clinical criteria

Diagnosis (2024 AHA/ACC, PMID:38718139; 2023 ESC cardiomyopathy guideline, PMID:37622657): LV wall thickness ≥15 mm in any segment by any imaging modality, not solely explained by abnormal loading conditions; ≥13 mm in first-degree relatives of an affected proband or in genotype-positive individuals. Paediatric criteria use z-scores (≥2 SD, or ≥2.5 SD in relatives).

Differential diagnosis — and this is where CMH14's late-onset skew matters most:

Screening

• Cascade clinical screening of first-degree relatives — ECG + echo, repeating every 1–2 years in adolescence and every 3–5 years in adults — is the guideline standard and remains appropriate for CMH14 families, because the phenotype is real even where the genotype attribution is not.
• Cascade genetic testing is not appropriate for a MYH6 variant, since no such variant is P/LP. This distinction (clinical screening yes, genetic screening no) is the key practical point for the entry.
• Newborn screening: not applicable.
• Preparticipation athletic screening: ECG-based programmes detect HCM but are population-level and not CMH14-specific.

11. Outcome / Prognosis

All figures below are HCM-level. There is no CMH14 survival, mortality, or morbidity dataset.

• Survival / mortality: contemporary HCM cohorts show near-normal life expectancy with modern management; HCM-related mortality ~0.5%/yr, down from historical tertiary-referral estimates of 2–4%/yr. Sudden cardiac death, heart failure, and stroke are the three modes.
• Life expectancy: approaching that of the general population in guideline-managed cohorts; substantially reduced in the minority progressing to end-stage disease.
• Morbidity / disability: exertional limitation, AF-related stroke, ICD-related complications, restriction from competitive sport. Disease-specific instrument: KCCQ. No ICF-coded disability data for CMH14.
• Complications: LVOT obstruction; atrial fibrillation with thromboembolism; ventricular arrhythmia and SCD; progressive heart failure; infective endocarditis (rare); end-stage systolic dysfunction requiring transplant.
• Recovery potential: none — the myopathy is not reversible. Symptomatic and haemodynamic improvement with obstruction relief is excellent.
• Prognostic factors (HCM SCD risk, per 2024 AHA/ACC / HCM Risk-SCD): prior cardiac arrest or sustained VT; family history of SCD; unexplained syncope; maximal LV wall thickness ≥30 mm; NSVT; LV apical aneurysm; LV systolic dysfunction (EF <50%); extensive LGE on CMR.
• Genotype as a prognostic factor: sarcomere-positive HCM is associated with earlier onset and worse outcomes than sarcomere-negative HCM in general. This does not transfer to MYH6. A MYH6 VUS should not be entered into risk stratification, and I would flag any clinical use of it as an error.
• Prognostic biomarkers: NT-proBNP and hs-troponin correlate with adverse outcome in HCM; LGE burden is the strongest imaging prognosticator. None MYH6-specific.

12. Treatment

There is no MYH6-directed therapy, and no evidence that MYH6 genotype should alter management. Management is standard HCM care. NCIT bindings below are verified against cache/ncit/terms.csv where marked ✓.

Pharmacotherapy

The mechanistic irony worth curating. Mavacamten and aficamten are allosteric inhibitors of cardiac β-myosin (MYH7) ATPase, reducing the number of force-generating cross-bridges. They target the ventricular isoform. If CMH14 were genuinely an α-MHC (MYH6) disease, the pharmacological rationale for these agents in it would be indirect at best. Anfinson et al. raise the corresponding therapeutic question for MYH6 carriers and note it cuts both ways:

"However, choosing to use a cardiac MHC-specific activator vs. inhibitor requires the understanding of whether a specific variant will cause systolic or diastolic dysfunction." — Anfinson et al. 2022 (PMID:35621855)

Their evidence_source for that passage is a review, and the drug-approval detail in it is dated (mavacamten approval was pending at writing; it has since been approved) — quote it for the mechanistic point, not the regulatory status.

Pivotal trials (for a clinical_trials: block): - EXPLORER-HCM, NCT03470545, PHASE_III, COMPLETED — mavacamten in symptomatic obstructive HCM (Olivotto et al., Lancet 2020, PMID:32871100). - SEQUOIA-HCM, NCT05186818, PHASE_III, COMPLETED — aficamten in obstructive HCM (Maron et al., NEJM 2024, PMID:38739079).

Use the enum values PHASE_III / COMPLETED, not the prose spellings.

Pharmacogenomics

No CPIC or PharmGKB guideline is keyed to MYH6. Mavacamten dosing is pharmacogenomically guided — by CYP2C19 metabolizer status (poor metabolizers require reduced starting dose and altered titration; this is in the US label and in the 2024 guideline). That is a drug-metabolism interaction, not a MYH6 interaction, and should be curated on the treatment, not the gene.

Advanced therapeutics

• Gene therapy / gene editing: none for CMH14. AAV-based approaches (e.g. MYBPC3 replacement, allele-specific editing for MYH7) are in early development for other HCM genotypes. Nothing MYH6-directed.
• RNA-based therapy (ASO/siRNA): none for CMH14. Leave aso_details absent.
• Cell therapy, immunotherapy: not applicable.

Surgical and interventional

Per the repo's device rule: bind the clinical action (NCIT:C15329) and carry the device in a qualifiers predicate–value pair with NCIT:C16830 as the predicate. Do not put a device term in the treatment_term.term slot.

Supportive, rehabilitative, and counselling

• Supportive care NCIT:C15747 ✓ — heart-failure management, volume optimisation, avoidance of dehydration and high-dose vasodilators/diuretics in obstructive physiology.
• Exercise counselling — the 2024 guideline liberalised recommendations toward shared decision-making on vigorous and competitive activity; therapeutic_modality: BEHAVIORAL.
• Cardiac rehabilitation NCIT:C15302 Physical Therapy ✓ / NCIT:C15315 Rehabilitation — moderate-intensity exercise is now considered beneficial.
• Genetic counselling NCIT:C15240 ✓ — and this is the one place where CMH14's disputed status changes clinical practice directly. The counselling content is: this MYH6 variant does not explain the HCM, cascade genetic testing on it is not indicated, and relatives need clinical (ECG/echo) screening regardless. therapeutic_modality: BEHAVIORAL.

Treatment strategy

Guideline algorithms (2024 AHA/ACC PMID:38718139; 2023 ESC PMID:37622657) branch on obstructive vs non-obstructive physiology and on SCD risk — not on genotype. Beta blocker → add/switch verapamil or disopyramide → myosin inhibitor → septal reduction therapy for refractory obstruction; parallel SCD risk assessment for ICD; parallel AF management. Personalised-medicine approaches in HCM are genotype-informed for family screening and for phenocopy-specific therapy (e.g. agalsidase for Fabry, tafamidis for ATTR) — neither pathway is available for MYH6.

13. Prevention

• Primary prevention (preventing the disease): not possible — a germline dominant condition. Reproductive options (PGT-M, prenatal diagnosis) exist in principle for definitively pathogenic HCM variants; they are not offered for a VUS, which is what every MYH6 HCM allele currently is.
• Secondary prevention (early detection):
• Cascade clinical screening of first-degree relatives — ECG and echo, every 1–2 years in adolescence, every 3–5 years in adults. Appropriate and recommended.
• Cascade genetic screening — not indicated for MYH6, as above.
• Preparticipation athletic screening — population-level, not CMH14-specific.
• Tertiary prevention (preventing complications in affected people): this is where nearly all real preventive value sits.
• ICD for primary SCD prevention in high-risk patients (the largest single mortality intervention in HCM).
• Anticoagulation for any documented AF, to prevent cardioembolic stroke.
• Relief of LVOT obstruction to prevent progressive symptoms and remodelling.
• Blood-pressure control, weight management, sleep-apnoea treatment, endocarditis awareness.
• Immunization: not applicable as disease prevention; influenza/COVID/pneumococcal vaccination is standard for patients with structural heart disease.
• Risk stratification: HCM Risk-SCD (ESC) and the 2024 AHA/ACC major-risk-marker approach. Note both are validated on HCM cohorts and neither incorporates MYH6 genotype.
• Genetic counselling: see §12. The counselling message is dominated by the disputed-gene finding.
• Public health / environmental interventions: not applicable. No environmental exposure to modify.

14. Other Species / Natural Disease

• Taxonomy: Homo sapiens, NCBITaxon:9606. Species used experimentally: Mus musculus NCBITaxon:10090; Danio rerio NCBITaxon:7955; Rattus norvegicus NCBITaxon:10116; Gallus gallus NCBITaxon:9031 (Ching's chick morpholino).
• Orthologous genes: mouse Myh6 (MGI:97255, NCBI Gene 17888); rat Myh6 (NCBI Gene 29556); zebrafish myh6 / amhc (ZFIN ZDB-GENE-031112-1); chick MYH6. The α/β MHC pair is deeply conserved across gnathostomes.

The single most important comparative fact — and it is a trap for anyone extrapolating from mouse: the α/β ventricular isoform ratio is inverted between human and rodent. Adult human ventricle is β-MHC (MYH7)-dominant with α-MHC a minor component; adult mouse and rat ventricle is α-MHC (Myh6)-dominant. A mouse Myh6 ventricular phenotype therefore has no straightforward human counterpart. ClinGen made this exact call when refusing to score the classic mouse HCM models:

"Additional studies on mice models of HCM using pre-engineered heterozygous, pathogenic MYH7 variant orthologous to the human p.R403Q allele into the mouse MYH6 were reviewed, but not scored because these mice models are not analogous to human MYH6." — ClinGen CGGV:assertion_ee5380a4…

This should be curated in dismech as a discussions: entry with kind: HUMAN_MODEL_MISMATCH, not KNOWLEDGE_GAP — evidence exists in the model, and it is the translational validity that is the open question. That is precisely the distinction the repo's guidance draws.

• Natural disease in other species: hypertrophic cardiomyopathy is the commonest feline heart disease (~15% of cats; higher in Maine Coon and Ragdoll breeds), and it is a genuine spontaneous animal model. But it is not MYH6. The identified feline causal variants are in MYBPC3 — Maine Coon p.A31P and Ragdoll p.R820W (OMIA 000515-9685). No MYH6 variant causes naturally occurring HCM in any species. Curate this as a negative comparative finding; it is informative, and the VBO breed terms (Maine Coon, Ragdoll) belong on the feline MYBPC3 concept, not here.
• Comparative pathology: myocyte hypertrophy, disarray, and interstitial fibrosis are conserved lesions across human and feline HCM.
• Evolutionary conservation of mechanism: the sarcomere and the α/β MHC duplication are ancient and conserved; the chamber-specific deployment of the two isoforms differs by species, which is exactly what breaks the translational chain here.
• Zoonotic potential / cross-species transmission: not applicable.

15. Model Organisms

No model organism carries a human CMH14-associated MYH6 allele. This is the experimental gap, and it is stark: of the four MYH6 variants reported in HCM probands, zero have been functionally assayed in any system.

Available models and what they actually show

Model types not available

Rat, Drosophila, C. elegans, yeast, organ-chip, and engineered heart tissue models of MYH6-HCM: none exist. No humanized MYH6 mouse, no conditional MYH6 knock-in of a human HCM allele, no CRISPR-corrected isogenic iPSC pair for any CMH14 variant.

Anfinson et al. state the scope of the whole field plainly:

"To date, zebrafish embryos are the only animal model that has been used to study human MYH6 variants." — PMID:35621855

and

"Relative to the large body of literature assessing MYH7 variants, few studies have sought to understand MYH6 variant pathology at the molecular level."

Resources

MGI (Myh6, MGI:97255) and IMPC/KOMP for mouse alleles; ZFIN for myh6/wea; Alliance of Genome Resources for orthology; Cellosaurus/hPSCreg for the patient iPSC line from PMID:33385793; IMSR/MMRRC for mouse strain distribution.

Curation summary for the dismech entry

The placeholder file currently asserts a pathophysiology node "MYH6 Missense Variant in Alpha-Myosin Heavy Chain" and a Left Ventricular Hypertrophy phenotype. Both are defensible, but the entry's substance should be the epistemic situation, not a borrowed MYH7 causal chain. Concretely:

1. Rewrite description to state that MYH6–HCM is ClinGen-Disputed and that the mechanism is unknown.
2. Keep the pathophysiology graph short and honest. One or two nodes, with biological_scale: MOLECULAR on the variant node. Do not build a 7-node MYH7-style chain; the check-causal-targets gate will happily accept a fabricated chain, and nothing else will catch it.
3. Lead evidence with CGGV:assertion_ee5380a4-0dee-49aa-b911-141502648144-2023-07-12T020000.000Z (already cached, quotable by row: MYH6 | HGNC:7576 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Disputed | SOP9 | Hereditary Cardiovascular Disease Gene Curation Expert Panel | 2023-07-12T02:00:00.000Z) and PMID:39971408.
4. Add a discussions: entry, kind: HUMAN_MODEL_MISMATCH, for the mouse αMHC-403 problem — the model exists and is famous, and its inapplicability to MYH6 is the substantive point.
5. Add a discussions: entry, kind: KNOWLEDGE_GAP, attaches_to: pathophysiology#…, for the unmeasured biophysics of R795Q and Q1065H.
6. Leave datasets: empty unless a genuinely CMH14-relevant accession survives manual relevance triage. I found none.
7. Record the atrial-isoform argument (Branch B) — Gorza 1984 + Berdougo 2003 + Anfinson 2022 — as the positive mechanistic content of the entry. It is the one thing here that is both well-evidenced and explanatory.
8. conforms_to candidates: check just list-modules for a cardiomyopathy remodeling module before conforming. cardiomyopathy_maladaptive_remodeling is the likely target for a fibrosis/remodeling node — but conform only if the entry ends up carrying such a node, which on the evidence it may not.

References fetched into references_cache/ during this work: PMID:11815426, 15998695, 27483260, 33385793, 34087240, 35911064, 21378987, 10388558, 6234108, 8614836, 24092743, 15735645, 26085007, 35621855, 14573521, 39971408, 30681346, 38718139, 37622657, 32871100, 38739079, 27532257, 23074333. Two mis-targeted fetches (PMID:14568893, PMID:35544178) are stale and should be deleted before committing; I did not remove them, as the deletion command needed approval this session.

Sources: - OMIM #613251 — CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 14 - OMIM #160710 — MYH6 - ClinGen MYH6 curation results (HGNC:7576) - ClinGen gene-validity assertion — MYH6 / hypertrophic cardiomyopathy (Disputed) - Hespe et al., JACC 2025 — Genes Associated With HCM: A Reappraisal (PMID:39971408) · PMC preprint - Ingles et al. 2019 — Evaluating the Clinical Validity of HCM Genes (PMID:30681346) - Niimura et al., Circulation 2002 (PMID:11815426) - Carniel et al., Circulation 2005 (PMID:15998695) - Rubattu et al. 2016 (PMID:27483260) - Walsh et al., Genet Med 2017 (PMID:27532257) - Holm et al., Nat Genet 2011 (PMID:21378987) - Ching et al., Nat Genet 2005 (PMID:15735645) - Theis et al., Circ Cardiovasc Genet 2015 (PMID:26085007) - Anfinson et al., J Cardiovasc Dev Dis 2022 (PMID:35621855) - Berdougo et al., Development 2003 (PMID:14573521) - Gorza et al., Circ Res 1984 (PMID:6234108) - Geisterfer-Lowrance et al., Science 1996 (PMID:8614836) - Weiss et al., J Mol Biol 1999 (PMID:10388558) - Liu et al., Clin Chim Acta 2021 (PMID:34087240) - Suzuki et al., J Cardiol Cases 2022 (PMID:35911064) - Wang et al. 2021 iPSC line (PMID:33385793) - Ommen et al., 2024 AHA/ACC HCM Guideline (PMID:38718139) - Arbelo et al., 2023 ESC Cardiomyopathy Guideline (PMID:37622657) - ClinVar VCV000014147 — MYH6 p.Arg795Gln - ClinVar VCV000014149 — MYH6 p.Gln1065His - gnomAD v4.0 gene constraint

Next step: tell me whether you want the entry curated as a disputed-entity Disease file (my recommendation, and I'd write it against the evidence above), or whether the lump/split call should go the other way — a SUBTYPE/OUT_OF_SCOPE disposition on Hypertrophic_Cardiomyopathy with the stub deleted and the reasoning recorded in notes.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

All extracted references resolved successfully.

Term Validation

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

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:

• MONDO:0013197 (2 mentions) - the report calls it "Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the MYH6 gene"; MONDO calls it hypertrophic cardiomyopathy 14, and lists "hypertrophic cardiomyopathy caused by mutation in MYH6" among its other names
• GO:0030017 (2 mentions) - the report calls it "sarcomere (CC)"; GO calls it sarcomere
• GO:0032982 (2 mentions) - the report calls it "myosin filament (CC)"; GO calls it myosin filament

Terms named inconsistently

The report gives these identifiers more than one name of its own:

• MONDO:0005045 - called "hypertrophic cardiomyopathy", "Hypertrophic cardiomyopathy"

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: ORPHA, MGI.

79 of 82 terms resolved to a current term; the rest could not be looked up either way.