Hypertrophic Cardiomyopathy 9

Genetic MONDO:0013412 Pathograph 5 Show in embeddings browser Hypertrophic Cardiomyopathy autosomal dominant titinopathy Cardiomyopathy hereditary disease

Hypertrophic cardiomyopathy 9 (CMH9; OMIM 613765) is the OMIM/MONDO designation for hypertrophic cardiomyopathy (HCM) attributed to variants in TTN, which encodes titin. The entity originates from a single 1999 report of an Arg740Leu substitution identified in one of 82 HCM probands who lacked mutations in the then-known sarcomere genes. The TTN-HCM gene-disease relationship is disputed. ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel classifies TTN-hypertrophic cardiomyopathy as Limited (SOP11, 2025-10-28), and cohort studies find titin-truncating variants (TTNtv) no more frequently in HCM patients than in controls. This contrasts sharply with TTN-dilated cardiomyopathy, which ClinGen classifies as Definitive and for which TTNtv are the single commonest genetic cause; the large DCM literature is NOT transferable to this entity and is deliberately excluded here. dismech therefore models CMH9 as a nominal disease entity carrying a disputed causal gene rather than an established mechanism. The two proposed molecular mechanisms — altered titin Z-disc binding to alpha-actinin, and perturbed titin/MURF1 interaction with enhanced titin degradation near the M-line — are recorded as explicitly hypothetical mechanistic hypotheses, each anchored to a small primary study, and the outstanding validity question is recorded as a knowledge gap.

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Inheritance
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Pathophys.
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Phenotypes
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Hypotheses
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Gaps
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Pathograph
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Genes
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Differentials
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Models
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References
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Deep Research
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Inheritance

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Autosomal dominant inheritance HP:0000006
The reported mode of inheritance for the TTN-HCM relationship is autosomal dominant, as recorded in the ClinGen curation. Note that this records the mode asserted for the claimed relationship; because the relationship itself is classified Limited, published segregation evidence supporting dominant transmission of an HCM phenotype with a TTN variant is minimal rather than absent: the index CMH9 observation was a single proband, not a segregating pedigree, and the one published pedigree (PMID:39895828) is a single three-generation family in which the variant tracked with three affected members and was absent from healthy adults, with one unaffected 3-year-old carrier. Under ACMG that is PP1 at supporting strength only.
Autosomal dominant inheritance
Show evidence (2 references)
CGGV:assertion_c17e22eb-c6fc-487d-bcf6-001bb85fdabd-2025-10-28T160000.000Z SUPPORT Other
"TTN | HGNC:12403 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Limited"
The ClinGen row records autosomal dominant as the asserted mode of inheritance, but simultaneously classifies the underlying gene-disease relationship as Limited; support is therefore partial.
PMID:10462489 SUPPORT Human Clinical
"A G to T transversion in codon 740, from CGC to CTC, replacing Arginine with Leucine was found in a patient."
The founding CMH9 report describes a heterozygous missense change in a single patient. It is consistent with dominant action but provides no family segregation data, which is why support is recorded as partial.
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Mechanistic Hypotheses

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Altered titin Z-disc binding to alpha-actinin
ttn_zdisc_actinin_binding EMERGING
Evidence balance 1 support
The original CMH9 proposal: a missense substitution in the titin Z-repeat region increases the binding affinity of titin for alpha-actinin, perturbing Z-disc assembly or Z-disc mechanical signalling and thereby producing hypertrophic remodelling. The supporting data are one proband plus a yeast two-hybrid binding assay; no animal model, no segregation data, and no replication in an independent HCM cohort have been reported for the Arg740Leu variant specifically. (Segregation has since been reported for a different TTN allele, p.Arg6745Cys, in one family - see the genetic section - but that does not replicate this variant or this mechanism.)
Status is EMERGING rather than CANONICAL or ALTERNATIVE because no independent replication has been published in the 25+ years since the original report.
Pathograph links
Rare TTN Variants in Sarcomere-Negative Hypertrophic Cardiomyopathy -> Altered Titin Z-Disc Binding to Alpha-Actinin UNKNOWN Proposed consequence of the Z-repeat-region Arg740Leu substitution. Directness is UNKNOWN because the link rests on a single in vitro binding assay.
Altered Titin Z-Disc Binding to Alpha-Actinin -> Hypertrophic Remodeling of the Left Ventricle INDIRECT UNKNOWN INTERMEDIATES The step from altered Z-disc protein binding to clinical hypertrophy is entirely unbridged for this variant; no intermediate mechanism has been demonstrated.
Show evidence (1 reference)
PMID:10462489 SUPPORT In Vitro
"This mutation was not found in more than 500 normal chromosomes and increased the binding affinity of titin to alpha-actitin in the yeast two-hybrid assay."
Provides the in vitro binding result on which the hypothesis rests. It is an interaction assay in yeast, not a demonstration of cardiac pathogenesis, so it supports the hypothesis only partially. (The abstract contains the typographical error "alpha-actitin" for alpha-actinin; the snippet is quoted verbatim.)
Perturbed titin/MURF1 interaction with enhanced titin ubiquitination
ttn_murf1_degradation EMERGING
Evidence balance 2 support
A later proposal derived from a medaka fish mutant (non-spring heart) with hypertrophic myocardium and diastolic dysfunction caused by a missense change in a titin immunoglobulin domain at the M-line/A-band transition. Screening 96 familial HCM patients without known sarcomeric mutations identified two further M-line-proximal Ig domain variants; in vitro, both the fish and human variants increased titin binding to MURF1 and enhanced ubiquitin-mediated titin degradation. This remains a model-organism plus in vitro hypothesis and has not established clinical validity for TTN as an HCM gene.
Deliberately not merged with the Z-disc/alpha-actinin hypothesis: the two implicate different titin regions (Z-repeat versus M-line-proximal Ig domains) and different partner proteins.
Pathograph links
Rare TTN Variants in Sarcomere-Negative Hypertrophic Cardiomyopathy -> Perturbed Titin-MURF1 Interaction and Enhanced Titin Degradation UNKNOWN Proposed consequence of M-line-proximal Ig domain substitutions, supported by fish-model and in vitro data only.
Perturbed Titin-MURF1 Interaction and Enhanced Titin Degradation -> Hypertrophic Remodeling of the Left Ventricle INDIRECT UNKNOWN INTERMEDIATES Demonstrated in a fish model; the corresponding chain in human myocardium carrying these variants has not been shown.
Show evidence (2 references)
PMID:31628103 SUPPORT Model Organism
"These findings implicate an impaired interaction between titin and MURF1 as a novel mechanism underlying the pathogenesis of HCM."
States the hypothesis. The primary evidence is a medaka fish mutant, so translational validity to human HCM is not established; support is partial.
PMID:39132495 SUPPORT Other
"in a medaka mutagenesis fish model with diastolic dysfunction, highlighting this as an important region"
ClinGen's expert panel explicitly acknowledges the M-line/A-band transition region finding as noteworthy while still holding the overall gene-disease relationship at Limited — which is precisely the epistemic status this hypothesis is recorded with.
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Discussions and Knowledge Gaps

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Is TTN a genuine hypertrophic cardiomyopathy gene at all, or is CMH9 a historical entity that should be retired?
KNOWLEDGE GAP OPEN ttn_hcm_gene_disease_validity
ClinGen classifies TTN-HCM as Limited. The entity rests on one 1999 proband plus two variants in a later 96-patient screen, with segregation reported in only one small three-generation family (PMID:39895828, p.Arg6745Cys, with one unaffected 3-year-old carrier), no independent replication of the index variant, a targeted 389-patient study that was negative across the four exons it examined, and TTNtv frequencies in HCM that match controls. Note that the ClinGen assertion is dated 2025-10-28 and that segregation report is from February 2025, so the expert panel plausibly had it available and still classified the relationship as Limited - which is a stronger argument for the classification than an absence of segregation would have been. What is missing is precisely the evidence class that would settle it: large-cohort case-control burden testing of rare TTN MISSENSE variation (not truncating variation) in HCM against gnomAD-scale controls, plus segregation in multiplex families. Until that exists, dismech records CMH9 as a disputed entity and declines to assert a mechanism.
Proposed experiments
Region-stratified rare TTN missense burden test in HCM
ttn_hcm_rare_missense_burden
Case-control burden analysis of rare TTN missense variation in a large sarcomere-negative HCM cohort against population reference data, stratified by Z-disc, I-band, A-band, and M-line domains. Truncating variation is explicitly not the variable of interest here, since it has already been shown not to be enriched in HCM.
Supporting outcome
  • Significant excess of rare missense variation in a specific titin region in HCM cases would support a genuine, region-restricted TTN-HCM relationship and could move the ClinGen classification above Limited.
Refuting outcome
  • No regional excess over population expectation would support retiring CMH9 as a distinct disease entity.
Segregation analysis of the reported CMH9 variants
ttn_hcm_variant_segregation
Recontact and genotype extended pedigrees, where available, for the Arg740Leu Z-repeat variant and the two M-line-proximal Ig-domain variants, testing co-segregation with an HCM phenotype.
Supporting outcome
  • Co-segregation with HCM across multiple informative meioses would supply the evidence class most conspicuously missing from the current curation.
Isogenic iPSC-cardiomyocyte modelling of reported TTN variants
ttn_hcm_ipsc_cardiomyocyte_model
Introduce the reported TTN variants into isogenic human iPSC-derived cardiomyocytes and assess hypertrophic growth, sarcomere organisation, titin turnover, and diastolic relaxation against isogenic controls.
Supporting outcome
  • A reproducible hypertrophic and diastolic phenotype in human cardiomyocytes would provide the human-cell functional evidence that the yeast two-hybrid and medaka data currently substitute for.
Show evidence (3 references)
CGGV:assertion_c17e22eb-c6fc-487d-bcf6-001bb85fdabd-2025-10-28T160000.000Z SUPPORT Other
"TTN | HGNC:12403 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Limited"
The Limited classification is the formal statement of the gap.
PMID:28822653 SUPPORT Human Clinical
"However, their significance in hypertrophic cardiomyopathy (HCM) is still unclear."
Contemporary authors state the uncertainty explicitly.
PMID:39132495 SUPPORT Other
"Clinical laboratories are discouraged from reporting variants in genes with disputed HCM-association"
Frames the clinical stakes of leaving this gap unresolved. TTN was held at Limited rather than downgraded to Disputed, so it sits just above the threshold at which the panel advises laboratories not to report variants at all.
If TTN variants are not a cause of hypertrophic cardiomyopathy, are titin-truncating variants nonetheless a prognostic modifier within established HCM?
CONTROVERSY OPEN ttn_hcm_cause_versus_modifier
Attached to
genetic#TTN
These are separable claims and the evidence points in opposite directions for each. TTNtv prevalence in HCM equals that in controls (arguing against causation), yet in the same cohort TTNtv carriers had a markedly higher rate of cardiovascular death during follow-up (adjusted hazard ratio 6.88). A modifier effect would not make TTN an HCM gene, but would make TTN genotype clinically meaningful in HCM. The finding is single-cohort, rests on 3 deaths among 13 carriers, and has not been replicated.
Proposed experiments
Independent replication of the TTNtv-cardiovascular-mortality signal in HCM
ttntv_hcm_mortality_replication
Prospective or retrospective replication of the association between titin-truncating variant carrier status and cardiovascular death within an independent, ancestrally distinct HCM cohort powered for an adequate number of events.
Supporting outcome
  • Replication would establish TTN genotype as a prognostic modifier in HCM even though TTN is not an HCM disease gene.
Refuting outcome
  • Failure to replicate would leave the single-cohort finding as an unconfirmed signal likely inflated by the small number of events.
Show evidence (1 reference)
PMID:28822653 SUPPORT Human Clinical
"Our study suggests that TTNtv might be a genetic modifier of HCM and confer an increased risk for cardiovascular death."
States the modifier hypothesis that this controversy is about.
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Pathophysiology

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Rare TTN Variants in Sarcomere-Negative Hypertrophic Cardiomyopathy
The proximal node of the claimed CMH9 mechanism: a rare heterozygous TTN variant in a patient with hypertrophic cardiomyopathy who has no variant in an established sarcomere gene. Both reported series ascertained patients this way — by residual, gene-elusive HCM — which is a candidate-gene design that cannot by itself establish causality. Titin is the largest human protein and carries a high background burden of rare variation, so rare TTN variants are expected in any sufficiently large cohort. This node is tagged HYPOTHETICAL because its causal link to the downstream hypertrophic phenotype is exactly what remains unproven.
Altered titin Z-disc binding to alpha-actinin Perturbed titin/MURF1 interaction with enhanced titin ubiquitination
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
TTN hgnc:12403 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TTN (hgnc:12403). hgnc:12403 is a gene from the HUGO Gene Nomenclature Committee.
structural constituent of muscle GO:0008307 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves structural constituent of muscle (GO:0008307). GO:0008307 is a molecular function from the Gene Ontology.
Downstream
Altered Titin Z-Disc Binding to Alpha-Actinin Proposed consequence of the Z-repeat-region Arg740Leu substitution. Directness is UNKNOWN because the link rests on a single in vitro binding assay. Altered titin Z-disc binding to alpha-actinin
Perturbed Titin-MURF1 Interaction and Enhanced Titin Degradation Proposed consequence of M-line-proximal Ig domain substitutions, supported by fish-model and in vitro data only. Perturbed titin/MURF1 interaction with enhanced titin ubiquitination
Show evidence (3 references)
PMID:10462489 SUPPORT Human Clinical
"we searched for a disease-associated mutation in the titin gene in 82 HCM patients who had no mutation in the known disease genes"
Documents the sarcomere-negative ascertainment design of the founding CMH9 study and the single variant it yielded.
PMID:31628103 SUPPORT Human Clinical
"Screening of mutations in 96 unrelated patients with familial HCM, who had no previously implicated mutations in known sarcomeric gene candidates, identified two mutations in Ig domains close to the M-line region of titin."
The only independent human series reporting candidate TTN variants in HCM, again using sarcomere-negative ascertainment; two variants in 96 patients.
PMID:16352453 REFUTE Human Clinical
"No TTN mutations were detected."
A targeted resequencing study in 389 unrelated HCM patients found no TTN mutations, weakening the claim that TTN is a recurrent HCM disease gene. Not "no mutations at all": only exons 2, 3, 4 and 14 were sequenced - the regions previously implicated in HCM or DCM - so this is a negative result over four of TTN's 364 exons and refutes recurrence at the known sites rather than excluding TTN involvement across the gene. The same caveat is stated on this study's other use in the genetic section, so the two explanations agree.
Altered Titin Z-Disc Binding to Alpha-Actinin
Increased affinity of the titin Z-repeat region for alpha-actinin, reported in a yeast two-hybrid assay for the Arg740Leu variant. The proposal is that abnormally tight Z-disc anchoring perturbs sarcomere assembly or Z-disc mechanosensing. No cardiac cell, tissue, or animal data have been published for this variant, and the functional direction (gain of binding) has not been connected experimentally to a hypertrophic response.
Altered titin Z-disc binding to alpha-actinin
Cardiac myofibril assembly GO:0055003 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves Cardiac myofibril assembly (GO:0055003). GO:0055003 is a biological process from the Gene Ontology.
actinin binding GO:0042805 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased actinin binding (GO:0042805). GO:0042805 is a molecular function from the Gene Ontology. ↑ INCREASED
Downstream
Hypertrophic Remodeling of the Left Ventricle The step from altered Z-disc protein binding to clinical hypertrophy is entirely unbridged for this variant; no intermediate mechanism has been demonstrated. Altered titin Z-disc binding to alpha-actinin
Show evidence (2 references)
PMID:10462489 SUPPORT In Vitro
"This mutation was not found in more than 500 normal chromosomes and increased the binding affinity of titin to alpha-actitin in the yeast two-hybrid assay."
Direct in vitro support for the altered-binding claim itself (as distinct from any claim that the altered binding causes HCM).
PMID:10462489 SUPPORT Human Clinical
"These observations suggest that the titin mutation may cause HCM in this patient via altered affinity to alpha-actinin."
The authors' own framing is explicitly hedged ("may cause ... in this patient"), which is the level of confidence this node carries.
Perturbed Titin-MURF1 Interaction and Enhanced Titin Degradation
Missense substitutions in titin immunoglobulin domains near the M-line increase titin binding to muscle-specific RING finger protein 1 (MURF1), an E3 ubiquitin ligase, and enhance ubiquitin-mediated titin degradation. In the medaka model this was accompanied by fewer myofibrils, disrupted sarcomeres, pathologically stiff titin isoforms, and M-line disassembly. Human support is limited to two variants found in a 96-patient sarcomere-negative familial HCM screen plus in vitro assays.
Perturbed titin/MURF1 interaction with enhanced titin ubiquitination
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
TTN hgnc:12403 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TTN (hgnc:12403). hgnc:12403 is a gene from the HUGO Gene Nomenclature Committee.
Protein ubiquitination GO:0016567 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Protein ubiquitination (GO:0016567). GO:0016567 is a biological process from the Gene Ontology. ↑ INCREASED Myofibril assembly GO:0030239 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Myofibril assembly (GO:0030239). GO:0030239 is a biological process from the Gene Ontology. ↓ DECREASED
Experimental models
non-spring heart (nsh) medaka fish titin Ig-domain mutant OTHER Reproduces a hypertrophic, diastolically impaired myocardium from a titin Ig-domain missense change, which is the mechanism this node proposes.
Downstream
Hypertrophic Remodeling of the Left Ventricle Demonstrated in a fish model; the corresponding chain in human myocardium carrying these variants has not been shown. Perturbed titin/MURF1 interaction with enhanced titin ubiquitination
Show evidence (2 references)
PMID:31628103 SUPPORT In Vitro
"In vitro studies revealed that the mutations found both in medaka fish and in familial HCM increased binding of titin to muscle-specific ring finger protein 1 (MURF1) and enhanced titin degradation by ubiquitination."
Direct in vitro support for increased MURF1 binding and enhanced ubiquitin-mediated titin degradation.
PMID:31628103 SUPPORT Model Organism
"The nsh homozygotes had fewer myofibrils, disrupted sarcomeres and expressed pathologically stiffer titin isoforms."
Model-organism support for disrupted sarcomere and myofibril assembly. It is a medaka fish phenotype, so it is partial support for a human mechanism.
Hypertrophic Remodeling of the Left Ventricle
The shared clinical endpoint of all hypertrophic cardiomyopathy: left ventricular wall thickening with myocyte disarray and impaired diastolic filling. This node is well established as the phenotype of HCM in general; it is tagged HYPOTHETICAL here only in the sense that its attribution to a TTN variant in this entity is unproven. The conserved downstream remodeling chain is modelled generically in the kb/modules/ cardiomyopathy_maladaptive_remodeling module; no conforms_to link is declared from this entry because the disease-specific causal edges into this node are themselves hypothetical.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Cardiac muscle hypertrophy in response to stress GO:0014898 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Cardiac muscle hypertrophy in response to stress (GO:0014898). GO:0014898 is a biological process from the Gene Ontology. ↑ INCREASED
Show evidence (1 reference)
PMID:10462489 SUPPORT Other
"Hypertrophic cardiomyopathy (HCM) is characterized by ventricular hypertrophy accompanied by myofibrillar disarrays."
Defines the hypertrophy-plus-disarray endpoint that CMH9, as a subtype label of HCM, is asserted to produce.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Hypertrophic Cardiomyopathy 9 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

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Cardiovascular 2
Left Ventricular Hypertrophy HP:0001712 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular hypertrophy (HP:0001712). HP:0001712 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:10462489 SUPPORT Other
"Hypertrophic cardiomyopathy (HCM) is characterized by ventricular hypertrophy accompanied by myofibrillar disarrays."
Establishes ventricular hypertrophy as the defining phenotype of the disease category to which the reported TTN patient belonged.
PMID:39895828 SUPPORT Human Clinical
"the thickness of the basal interventricular septum was approximately 32 mm, middle interventricular septum was approximately 34 mm, and apical interventricular septum was approximately 24 mm"
The only measured hypertrophy data in a reported TTN-variant HCM carrier, and therefore the entry's one genuinely HUMAN_CLINICAL observation for this phenotype rather than a disease definition. PARTIAL because it is a single proband and the variant's causality is not established.
Left Ventricular Diastolic Dysfunction HP:0025168 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular diastolic dysfunction (HP:0025168). HP:0025168 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31628103 SUPPORT Other
"Hypertrophic cardiomyopathy (HCM) is a hereditary disease characterized by cardiac hypertrophy with diastolic dysfunction."
Supports diastolic dysfunction as a feature of HCM generally; it is not a TTN-specific observation, hence PARTIAL. evidence_source is OTHER, not HUMAN_CLINICAL: the quoted sentence is the paper's opening definition of the disease, not a measurement it reports.
Other 1
Myocardial Sarcomeric Disarray HP:0031333 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myocardial sarcomeric disarray (HP:0031333). HP:0031333 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10462489 SUPPORT Other
"Hypertrophic cardiomyopathy (HCM) is characterized by ventricular hypertrophy accompanied by myofibrillar disarrays."
Names myofibrillar disarray as a defining feature of HCM.
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Genetic Associations

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TTN (Disputed causal gene. ClinGen classifies TTN-hypertrophic cardiomyopathy as Limited. The claimed causal alleles are rare missense substitutions (Arg740Leu in the Z-repeat region; two Ig-domain variants near the M-line), each reported once in sarcomere-negative HCM cohorts. Titin-truncating variants — the mechanism that makes TTN the commonest dilated cardiomyopathy gene — are NOT enriched in HCM relative to controls, and a separate line of evidence instead suggests TTNtv may act as an outcome modifier in established HCM rather than as a cause of it.)
Gene: TTN hgnc:12403 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TTN (hgnc:12403). hgnc:12403 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: DISPUTED
Show evidence (10 references)
PMID:39895828 SUPPORT Human Clinical
"WES combined with Sanger sequencing results showed that the other two HCM patients in this family carried this TTN mutation, while none of the healthy family members carried the mutation except for a 3 years old girl."
The only published segregation evidence for any TTN allele in hypertrophic cardiomyopathy: a fourth allele, p.Arg6745Cys, tracking with disease across a three-generation Chinese Han family. Curated PARTIAL, and it does not overturn the Limited classification - it is one small family, ACMG PP1 counts only at supporting strength, there is no functional work, and the authors themselves note the Ig49 domain has no known protein binding site nearby. One unaffected 3-year-old carrier is uninformative given age-dependent penetrance rather than evidence against segregation. This allele is recorded because omitting it would leave the entry asserting an absence a reader could falsify in one search, and because the ClinGen assertion post-dates it (2025-10-28 versus February 2025), which makes the Limited classification more persuasive rather than less.
CGGV:assertion_c17e22eb-c6fc-487d-bcf6-001bb85fdabd-2025-10-28T160000.000Z SUPPORT Other
"TTN | HGNC:12403 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Limited"
The authoritative gene-disease validity classification: Limited, from ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel.
PMID:39132495 SUPPORT Other
"TTN 1.2 5.5 6.7 Limited"
The expert panel's own scoring row for TTN in the HCM reappraisal: 1.2 genetic evidence points plus 5.5 experimental evidence points, total 6.7, yielding a Limited classification. Note the evidence is weighted toward experimental rather than genetic (case/segregation) support — the pattern expected of a gene with a plausible biology but no case-level proof.
+ 7 more references
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External Assertions

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ClinGen TTN-hypertrophic cardiomyopathy gene-disease validity assertion
ClinGen gene disease validity CGGV:assertion_c17e22eb-c6fc-487d-bcf6-001bb85fdabd-2025-10-28T160000.000Z
ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel classifies the autosomal dominant TTN-hypertrophic cardiomyopathy (MONDO:0005045) relationship as Limited under SOP11, classified 2025-10-28. This is the authoritative external judgement on the validity of the CMH9 entity and is the reason this entry does not assert an established disease mechanism.
Show evidence (1 reference)
CGGV:assertion_c17e22eb-c6fc-487d-bcf6-001bb85fdabd-2025-10-28T160000.000Z SUPPORT Other
"TTN | HGNC:12403 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Limited"
ClinGen classifies the TTN-hypertrophic cardiomyopathy gene-disease relationship as Limited with autosomal dominant inheritance.
ClinGen TTN-dilated cardiomyopathy gene-disease validity assertion
ClinGen gene disease validity CGGV:assertion_1ec53217-814e-44b3-a7b7-0f18311c20f3-2025-05-30T160000.000Z
Recorded here only as a contrast and as an explicit anti-conflation guard: the well-validated TTN cardiomyopathy association is with DILATED cardiomyopathy (Definitive), not hypertrophic cardiomyopathy. Evidence and mechanism from the TTN-DCM literature must not be imported into this HCM entry.
Show evidence (2 references)
CGGV:assertion_1ec53217-814e-44b3-a7b7-0f18311c20f3-2025-05-30T160000.000Z SUPPORT Other
"TTN | HGNC:12403 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
ClinGen classifies TTN-dilated cardiomyopathy as Definitive, in contrast to the Limited classification for TTN-hypertrophic cardiomyopathy, establishing that the two TTN-cardiomyopathy relationships are of very different evidentiary standing.
PMID:39132495 SUPPORT Other
"TTN has definitive gene-disease validity for dilated cardiomyopathy"
The HCM expert panel itself draws the DCM/HCM distinction explicitly, confirming that the strong TTN evidence base belongs to dilated, not hypertrophic, cardiomyopathy.
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Diagnosis

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Multigene HCM panel, with TTN not reportable as an established cause
This is the clinically actionable output of the entry, and it is a reporting rule rather than a testing indication. TTN is on many cardiomyopathy panels because of its Definitive relationship with DILATED cardiomyopathy; a rare TTN variant returned in a patient being investigated for hypertrophic cardiomyopathy must not be reported as an established cause of that phenotype, must not drive predictive cascade testing in relatives, and does not end the search for a variant in a gene with adequate validity. The empirical basis is that TTN variant carriage in HCM runs at control frequency, and that in the one study that checked, every HCM subject with a TTN variant also carried a pathogenic variant in an established HCM gene - so finding TTN and stopping risks missing the actual cause.
Multigene hypertrophic cardiomyopathy panel testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: A rare TTN variant in an HCM workup is an uncertain finding at gene level, not a molecular diagnosis. Continue interpreting the panel as though TTN were absent from it.
This rule previously existed only as free text in the genetic section's notes. It is promoted here so it is machine-readable, since it is the single most useful output of a disputed-validity entry.
Show evidence (1 reference)
PMID:22335739 SUPPORT Human Clinical
"each subject with hypertrophic cardiomyopathy who had a TTN variant also had a pathogenic mutation in an established hypertrophic cardiomyopathy gene, suggesting that TTN truncations rarely, if ever, cause hypertrophic cardiomyopathy."
The direct basis for the reporting rule: TTN variants in HCM patients co-occurred with a genuine cause every time, so reporting TTN would have been wrong in every case examined.
📊

Prevalence

1
Published TTN-attributed hypertrophic cardiomyopathy probands worldwide
Cases In Literature Not yet documented
No prevalence can be stated for CMH9, and the reason is the entity's own disputed status rather than a gap in ascertainment: counting cases requires a rule for deciding which TTN variant carriers have the disease, and that is exactly what is unsettled. The published case base is roughly four probands - the 1999 Arg740Leu index case, two Ig-domain variants from a 96-patient screen, and the 2025 p.Arg6745Cys family - none independently replicated. By contrast, TTN variant carriage among HCM patients is well measured and runs at control frequency, which is the finding that makes the case count uninterpretable rather than merely small.
Show evidence (1 reference)
PMID:22335739 SUPPORT Human Clinical
"The frequency of TTN truncating variants identified by next-generation sequencing of samples from subjects with hypertrophic cardiomyopathy and controls was similar (1% and 3%, respectively; P = 0.34)."
Supplies the carriage-versus-control comparison that makes a CMH9 case count uninterpretable. PARTIAL because it measures truncating variants rather than the missense alleles this entity is built on.
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Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Hypertrophic Cardiomyopathy 9:

Sarcomeric hypertrophic cardiomyopathy Not Yet Curated MONDO:0024573
Overlapping Features The differential that matters most for this entity, because it is not merely an alternative but the likelier explanation in any patient where a TTN variant is found. The definitive HCM genes - MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, MYL3 - account for the great majority of genotype-positive HCM, and in the one systematic comparison every HCM patient carrying a TTN variant also carried a pathogenic variant in one of them.
Distinguishing Features
  • Sarcomeric HCM: a pathogenic variant in a gene with definitive HCM validity. CMH9: a TTN variant whose gene-disease relationship is classified Limited, frequently alongside an unrecognised sarcomeric variant.
Show evidence (1 reference)
PMID:30681346 SUPPORT Other
"Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3)"
Names the definitive-validity genes that constitute this differential, and by omission places TTN outside them.
Non-sarcomeric phenocopies of left ventricular hypertrophy
Overlapping Features Phenocopy exclusion carries extra weight in a sarcomere-negative HCM patient, which is by definition the population in which TTN variants were sought - the founding CMH9 cohort consisted of probands without mutations in the then-known sarcomere genes. Fabry disease, ATTR and AL amyloidosis, Danon disease, PRKAG2 glycogen storage cardiomyopathy, and the RASopathies all produce unexplained left ventricular hypertrophy, several are treatable, and all are better-established explanations than a Limited-validity TTN variant. Athlete's heart and hypertensive hypertrophy account for the non-genetic end of the differential.
🧫

Experimental Models

1
non-spring heart (nsh) medaka fish titin Ig-domain mutant OTHER
The primary experimental support for the titin/MURF1 hypothesis, and the only whole-organism model in this entry. A cardiovascular-mutant medaka carrying a missense change in an Ig domain at the M-line-A-band transition zone of titin shows diastolic dysfunction and hypertrophic myocardium; homozygotes have fewer myofibrils, disrupted sarcomeres and stiffer titin isoforms, while heterozygotes show M-line disassembly resembling the human pathology. Positional cloning of that mutation is what directed the screen of 96 sarcomere-negative familial HCM patients in which the two human Ig-domain alleles curated here were found.
Organism
Japanese medaka NCBITaxon:8090 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Japanese medaka, annotated with Oryzias latipes (NCBITaxon:8090). NCBITaxon:8090 is an organism from the NCBI Taxonomy.
Publication
PMID:31628103
Pathograph links
Perturbed Titin-MURF1 Interaction and Enhanced Titin Degradation partially recapitulates fidelity: low Reproduces a hypertrophic, diastolically impaired myocardium from a titin Ig-domain missense change, which is the mechanism this node proposes.
Limitations: Fidelity is LOW and deliberately so. This is a fish, the causal direction in the model runs from a mutation found in fish to a human screen rather than from a validated human allele, the human phenotype is dominant while the fish structural phenotype is clearest in homozygotes, and no mammalian model of any TTN HCM allele exists. The model motivates the hypothesis; it does not establish the human mechanism, which is why every node in this entry remains HYPOTHETICAL.
Show evidence (1 reference)
PMID:31628103 SUPPORT Model Organism
"The nsh homozygotes had fewer myofibrils, disrupted sarcomeres and expressed pathologically stiffer titin isoforms."
The structural phenotype of the model, and the observation that ties a titin Ig-domain lesion to sarcomeric disruption.
Show evidence (1 reference)
PMID:31628103 SUPPORT Model Organism
"we generated a cardiovascular-mutant medaka fish, non-spring heart (nsh), which showed diastolic dysfunction and hypertrophic myocardium."
Describes the model and its cardiac phenotype.
{ }

Source YAML

click to show 
name: Hypertrophic Cardiomyopathy 9
creation_date: "2026-08-01T00:00:00Z"
description: >-
  Hypertrophic cardiomyopathy 9 (CMH9; OMIM 613765) is the OMIM/MONDO
  designation for hypertrophic cardiomyopathy (HCM) attributed to variants in
  TTN, which encodes titin. The entity originates from a single 1999 report of
  an Arg740Leu substitution identified in one of 82 HCM probands who lacked
  mutations in the then-known sarcomere genes.

  The TTN-HCM gene-disease relationship is disputed. ClinGen's Hereditary
  Cardiovascular Disease Gene Curation Expert Panel classifies
  TTN-hypertrophic cardiomyopathy as Limited (SOP11, 2025-10-28), and cohort
  studies find titin-truncating variants (TTNtv) no more frequently in HCM
  patients than in controls. This contrasts sharply with TTN-dilated
  cardiomyopathy, which ClinGen classifies as Definitive and for which TTNtv
  are the single commonest genetic cause; the large DCM literature is NOT
  transferable to this entity and is deliberately excluded here.

  dismech therefore models CMH9 as a nominal disease entity carrying a disputed
  causal gene rather than an established mechanism. The two proposed molecular
  mechanisms — altered titin Z-disc binding to alpha-actinin, and perturbed
  titin/MURF1 interaction with enhanced titin degradation near the M-line — are
  recorded as explicitly hypothetical mechanistic hypotheses, each anchored to
  a small primary study, and the outstanding validity question is recorded as a
  knowledge gap.
synonyms:
- CMH9
- TTN hypertrophic cardiomyopathy
- cardiomyopathy, familial hypertrophic, 9
- hypertrophic cardiomyopathy type 9
- hypertrophic cardiomyopathy caused by mutation in TTN
category: Genetic
parents:
- Hypertrophic Cardiomyopathy
- autosomal dominant titinopathy
- Cardiomyopathy
- hereditary disease
disease_term:
  preferred_term: hypertrophic cardiomyopathy 9
  term:
    id: MONDO:0013412
    label: hypertrophic cardiomyopathy 9
references:
- reference: PMID:20301725
  title: "Nonsyndromic Hypertrophic Cardiomyopathy Overview."
  tags:
  - GeneReviews
- reference: PMID:38718139
  title: "2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines."
- reference: PMID:39132495
  title: "ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy."
external_assertions:
- name: ClinGen TTN-hypertrophic cardiomyopathy gene-disease validity assertion
  source: ClinGen
  assertion_type: gene_disease_validity
  external_id: "CGGV:assertion_c17e22eb-c6fc-487d-bcf6-001bb85fdabd-2025-10-28T160000.000Z"
  url: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c17e22eb-c6fc-487d-bcf6-001bb85fdabd-2025-10-28T160000.000Z
  description: >-
    ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel
    classifies the autosomal dominant TTN-hypertrophic cardiomyopathy
    (MONDO:0005045) relationship as Limited under SOP11, classified
    2025-10-28. This is the authoritative external judgement on the validity
    of the CMH9 entity and is the reason this entry does not assert an
    established disease mechanism.
  evidence:
  - reference: CGGV:assertion_c17e22eb-c6fc-487d-bcf6-001bb85fdabd-2025-10-28T160000.000Z
    reference_title: "TTN / hypertrophic cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TTN | HGNC:12403 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Limited"
    explanation: >-
      ClinGen classifies the TTN-hypertrophic cardiomyopathy gene-disease
      relationship as Limited with autosomal dominant inheritance.
- name: ClinGen TTN-dilated cardiomyopathy gene-disease validity assertion
  source: ClinGen
  assertion_type: gene_disease_validity
  external_id: "CGGV:assertion_1ec53217-814e-44b3-a7b7-0f18311c20f3-2025-05-30T160000.000Z"
  url: https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_1ec53217-814e-44b3-a7b7-0f18311c20f3-2025-05-30T160000.000Z
  description: >-
    Recorded here only as a contrast and as an explicit anti-conflation guard:
    the well-validated TTN cardiomyopathy association is with DILATED
    cardiomyopathy (Definitive), not hypertrophic cardiomyopathy. Evidence and
    mechanism from the TTN-DCM literature must not be imported into this HCM
    entry.
  evidence:
  - reference: CGGV:assertion_1ec53217-814e-44b3-a7b7-0f18311c20f3-2025-05-30T160000.000Z
    reference_title: "TTN / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TTN | HGNC:12403 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
    explanation: >-
      ClinGen classifies TTN-dilated cardiomyopathy as Definitive, in contrast
      to the Limited classification for TTN-hypertrophic cardiomyopathy,
      establishing that the two TTN-cardiomyopathy relationships are of very
      different evidentiary standing.
  - reference: PMID:39132495
    reference_title: "ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TTN has definitive gene-disease validity for dilated cardiomyopathy"
    explanation: >-
      The HCM expert panel itself draws the DCM/HCM distinction explicitly,
      confirming that the strong TTN evidence base belongs to dilated, not
      hypertrophic, cardiomyopathy.
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    The reported mode of inheritance for the TTN-HCM relationship is autosomal
    dominant, as recorded in the ClinGen curation. Note that this records the
    mode asserted for the claimed relationship; because the relationship itself
    is classified Limited, published segregation evidence supporting dominant
    transmission of an HCM phenotype with a TTN variant is minimal rather than
    absent: the index CMH9 observation was a single proband, not a segregating
    pedigree, and the one published pedigree (PMID:39895828) is a single
    three-generation family in which the variant tracked with three affected
    members and was absent from healthy adults, with one unaffected 3-year-old
    carrier. Under ACMG that is PP1 at supporting strength only.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: CGGV:assertion_c17e22eb-c6fc-487d-bcf6-001bb85fdabd-2025-10-28T160000.000Z
    reference_title: "TTN / hypertrophic cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TTN | HGNC:12403 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Limited"
    explanation: >-
      The ClinGen row records autosomal dominant as the asserted mode of
      inheritance, but simultaneously classifies the underlying gene-disease
      relationship as Limited; support is therefore partial.
  - reference: PMID:10462489
    reference_title: "Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A G to T transversion in codon 740, from CGC to CTC, replacing Arginine
      with Leucine was found in a patient.
    explanation: >-
      The founding CMH9 report describes a heterozygous missense change in a
      single patient. It is consistent with dominant action but provides no
      family segregation data, which is why support is recorded as partial.
mechanistic_hypotheses:
- hypothesis_group_id: ttn_zdisc_actinin_binding
  hypothesis_label: Altered titin Z-disc binding to alpha-actinin
  status: EMERGING
  description: >-
    The original CMH9 proposal: a missense substitution in the titin Z-repeat
    region increases the binding affinity of titin for alpha-actinin, perturbing
    Z-disc assembly or Z-disc mechanical signalling and thereby producing
    hypertrophic remodelling. The supporting data are one proband plus a yeast
    two-hybrid binding assay; no animal model, no segregation data, and no
    replication in an independent HCM cohort have been reported for the
    Arg740Leu variant specifically. (Segregation has since been reported for a
    different TTN allele, p.Arg6745Cys, in one family - see the genetic section
    - but that does not replicate this variant or this mechanism.)
  evidence:
  - reference: PMID:10462489
    reference_title: "Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This mutation was not found in more than 500 normal chromosomes and
      increased the binding affinity of titin to alpha-actitin in the yeast
      two-hybrid assay.
    explanation: >-
      Provides the in vitro binding result on which the hypothesis rests. It is
      an interaction assay in yeast, not a demonstration of cardiac
      pathogenesis, so it supports the hypothesis only partially. (The abstract
      contains the typographical error "alpha-actitin" for alpha-actinin; the
      snippet is quoted verbatim.)
  notes: >-
    Status is EMERGING rather than CANONICAL or ALTERNATIVE because no
    independent replication has been published in the 25+ years since the
    original report.
- hypothesis_group_id: ttn_murf1_degradation
  hypothesis_label: Perturbed titin/MURF1 interaction with enhanced titin ubiquitination
  status: EMERGING
  description: >-
    A later proposal derived from a medaka fish mutant (non-spring heart) with
    hypertrophic myocardium and diastolic dysfunction caused by a missense
    change in a titin immunoglobulin domain at the M-line/A-band transition.
    Screening 96 familial HCM patients without known sarcomeric mutations
    identified two further M-line-proximal Ig domain variants; in vitro, both
    the fish and human variants increased titin binding to MURF1 and enhanced
    ubiquitin-mediated titin degradation. This remains a model-organism plus
    in vitro hypothesis and has not established clinical validity for TTN as an
    HCM gene.
  evidence:
  - reference: PMID:31628103
    reference_title: "Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These findings implicate an impaired interaction between titin and MURF1
      as a novel mechanism underlying the pathogenesis of HCM.
    explanation: >-
      States the hypothesis. The primary evidence is a medaka fish mutant, so
      translational validity to human HCM is not established; support is
      partial.
  - reference: PMID:39132495
    reference_title: "ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      in a medaka mutagenesis fish model with diastolic dysfunction,
      highlighting this as an important region
    explanation: >-
      ClinGen's expert panel explicitly acknowledges the M-line/A-band
      transition region finding as noteworthy while still holding the overall
      gene-disease relationship at Limited — which is precisely the epistemic
      status this hypothesis is recorded with.
  notes: >-
    Deliberately not merged with the Z-disc/alpha-actinin hypothesis: the two
    implicate different titin regions (Z-repeat versus M-line-proximal Ig
    domains) and different partner proteins.
pathophysiology:
- name: Rare TTN Variants in Sarcomere-Negative Hypertrophic Cardiomyopathy
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The proximal node of the claimed CMH9 mechanism: a rare heterozygous TTN
    variant in a patient with hypertrophic cardiomyopathy who has no variant in
    an established sarcomere gene. Both reported series ascertained patients
    this way — by residual, gene-elusive HCM — which is a candidate-gene design
    that cannot by itself establish causality. Titin is the largest human
    protein and carries a high background burden of rare variation, so rare
    TTN variants are expected in any sufficiently large cohort. This node is
    tagged HYPOTHETICAL because its causal link to the downstream hypertrophic
    phenotype is exactly what remains unproven.
  genes:
  - preferred_term: TTN
    term:
      id: hgnc:12403
      label: TTN
  molecular_functions:
  - preferred_term: structural constituent of muscle
    term:
      id: GO:0008307
      label: structural constituent of muscle
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:10462489
    reference_title: "Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we searched for a disease-associated mutation in the titin gene in 82 HCM
      patients who had no mutation in the known disease genes
    explanation: >-
      Documents the sarcomere-negative ascertainment design of the founding
      CMH9 study and the single variant it yielded.
  - reference: PMID:31628103
    reference_title: "Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Screening of mutations in 96 unrelated patients with familial HCM, who had
      no previously implicated mutations in known sarcomeric gene candidates,
      identified two mutations in Ig domains close to the M-line region of titin.
    explanation: >-
      The only independent human series reporting candidate TTN variants in HCM,
      again using sarcomere-negative ascertainment; two variants in 96 patients.
  - reference: PMID:16352453
    reference_title: "Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "No TTN mutations were detected."
    explanation: >-
      A targeted resequencing study in 389 unrelated HCM patients found no TTN
      mutations, weakening the claim that TTN is a recurrent HCM disease gene.
      Not "no mutations at all": only exons 2, 3, 4 and 14 were sequenced - the
      regions previously implicated in HCM or DCM - so this is a negative result
      over four of TTN's 364 exons and refutes recurrence at the known sites
      rather than excluding TTN involvement across the gene. The same caveat is
      stated on this study's other use in the genetic section, so the two
      explanations agree.
  downstream:
  - target: Altered Titin Z-Disc Binding to Alpha-Actinin
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - ttn_zdisc_actinin_binding
    description: >-
      Proposed consequence of the Z-repeat-region Arg740Leu substitution.
      Directness is UNKNOWN because the link rests on a single in vitro binding
      assay.
    evidence:
    - reference: PMID:10462489
      reference_title: "Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        These observations suggest that the titin mutation may cause HCM in this
        patient via altered affinity to alpha-actinin.
      explanation: >-
        The only published statement linking this variant to altered
        alpha-actinin affinity; explicitly hedged by its authors.
  - target: Perturbed Titin-MURF1 Interaction and Enhanced Titin Degradation
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - ttn_murf1_degradation
    description: >-
      Proposed consequence of M-line-proximal Ig domain substitutions, supported
      by fish-model and in vitro data only.
    evidence:
    - reference: PMID:31628103
      reference_title: "Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In vitro studies revealed that the mutations found both in medaka fish
        and in familial HCM increased binding of titin to muscle-specific ring
        finger protein 1 (MURF1) and enhanced titin degradation by
        ubiquitination.
      explanation: >-
        Links the reported human HCM variants to the MURF1 binding and
        degradation change, in vitro.
- name: Altered Titin Z-Disc Binding to Alpha-Actinin
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Increased affinity of the titin Z-repeat region for alpha-actinin, reported
    in a yeast two-hybrid assay for the Arg740Leu variant. The proposal is that
    abnormally tight Z-disc anchoring perturbs sarcomere assembly or Z-disc
    mechanosensing. No cardiac cell, tissue, or animal data have been published
    for this variant, and the functional direction (gain of binding) has not
    been connected experimentally to a hypertrophic response.
  molecular_functions:
  - preferred_term: actinin binding
    term:
      id: GO:0042805
      label: actinin binding
    modifier: INCREASED
  biological_processes:
  - preferred_term: Cardiac myofibril assembly
    term:
      id: GO:0055003
      label: cardiac myofibril assembly
  evidence:
  - reference: PMID:10462489
    reference_title: "Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This mutation was not found in more than 500 normal chromosomes and
      increased the binding affinity of titin to alpha-actitin in the yeast
      two-hybrid assay.
    explanation: >-
      Direct in vitro support for the altered-binding claim itself (as distinct
      from any claim that the altered binding causes HCM).
  - reference: PMID:10462489
    reference_title: "Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These observations suggest that the titin mutation may cause HCM in this
      patient via altered affinity to alpha-actinin.
    explanation: >-
      The authors' own framing is explicitly hedged ("may cause ... in this
      patient"), which is the level of confidence this node carries.
  downstream:
  - target: Hypertrophic Remodeling of the Left Ventricle
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - ttn_zdisc_actinin_binding
    description: >-
      The step from altered Z-disc protein binding to clinical hypertrophy is
      entirely unbridged for this variant; no intermediate mechanism has been
      demonstrated.
- name: Perturbed Titin-MURF1 Interaction and Enhanced Titin Degradation
  biological_scale: MOLECULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Missense substitutions in titin immunoglobulin domains near the M-line
    increase titin binding to muscle-specific RING finger protein 1 (MURF1), an
    E3 ubiquitin ligase, and enhance ubiquitin-mediated titin degradation. In
    the medaka model this was accompanied by fewer myofibrils, disrupted
    sarcomeres, pathologically stiff titin isoforms, and M-line disassembly.
    Human support is limited to two variants found in a 96-patient
    sarcomere-negative familial HCM screen plus in vitro assays.
  genes:
  - preferred_term: TTN
    term:
      id: hgnc:12403
      label: TTN
  biological_processes:
  - preferred_term: Protein ubiquitination
    term:
      id: GO:0016567
      label: protein ubiquitination
    modifier: INCREASED
  - preferred_term: Myofibril assembly
    term:
      id: GO:0030239
      label: myofibril assembly
    modifier: DECREASED
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:31628103
    reference_title: "Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro studies revealed that the mutations found both in medaka fish and
      in familial HCM increased binding of titin to muscle-specific ring finger
      protein 1 (MURF1) and enhanced titin degradation by ubiquitination.
    explanation: >-
      Direct in vitro support for increased MURF1 binding and enhanced
      ubiquitin-mediated titin degradation.
  - reference: PMID:31628103
    reference_title: "Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The nsh homozygotes had fewer myofibrils, disrupted sarcomeres and
      expressed pathologically stiffer titin isoforms.
    explanation: >-
      Model-organism support for disrupted sarcomere and myofibril assembly. It
      is a medaka fish phenotype, so it is partial support for a human
      mechanism.
  downstream:
  - target: Hypertrophic Remodeling of the Left Ventricle
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - ttn_murf1_degradation
    description: >-
      Demonstrated in a fish model; the corresponding chain in human myocardium
      carrying these variants has not been shown.
    evidence:
    - reference: PMID:31628103
      reference_title: "Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        we generated a cardiovascular-mutant medaka fish, non-spring heart
        (nsh), which showed diastolic dysfunction and hypertrophic myocardium
      explanation: >-
        The titin-mutant medaka develops hypertrophic myocardium with diastolic
        dysfunction, supporting the edge in a model organism only. Human
        evidence for this step is absent, so support is partial.
- name: Hypertrophic Remodeling of the Left Ventricle
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The shared clinical endpoint of all hypertrophic cardiomyopathy: left
    ventricular wall thickening with myocyte disarray and impaired diastolic
    filling. This node is well established as the phenotype of HCM in general;
    it is tagged HYPOTHETICAL here only in the sense that its attribution to a
    TTN variant in this entity is unproven. The conserved downstream remodeling
    chain is modelled generically in the kb/modules/
    cardiomyopathy_maladaptive_remodeling module; no conforms_to link is
    declared from this entry because the disease-specific causal edges into
    this node are themselves hypothetical.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  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
  evidence:
  - reference: PMID:10462489
    reference_title: "Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hypertrophic cardiomyopathy (HCM) is characterized by ventricular
      hypertrophy accompanied by myofibrillar disarrays.
    explanation: >-
      Defines the hypertrophy-plus-disarray endpoint that CMH9, as a subtype
      label of HCM, is asserted to produce.
phenotypes:
- category: Clinical
  name: Left Ventricular Hypertrophy
  description: >-
    Ventricular wall thickening is the defining feature of the HCM phenotype
    that CMH9 is nominally a subtype of. No TTN-variant-specific hypertrophy
    pattern, severity, or distribution has been described. The one measured
    observation available in a TTN-variant carrier comes from the p.Arg6745Cys
    proband, with basal, mid and apical interventricular septal thicknesses of
    approximately 32, 34 and 24 mm - severe asymmetric hypertrophy, but in a
    single individual whose variant is not established as causal.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:10462489
    reference_title: "Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hypertrophic cardiomyopathy (HCM) is characterized by ventricular
      hypertrophy accompanied by myofibrillar disarrays.
    explanation: >-
      Establishes ventricular hypertrophy as the defining phenotype of the
      disease category to which the reported TTN patient belonged.
  - reference: PMID:39895828
    reference_title: "A Case Study Identified a New Mutation in the TTN Gene for Inherited Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the thickness of the basal interventricular septum was approximately 32
      mm, middle interventricular septum was approximately 34 mm, and apical
      interventricular septum was approximately 24 mm
    explanation: >-
      The only measured hypertrophy data in a reported TTN-variant HCM carrier,
      and therefore the entry's one genuinely HUMAN_CLINICAL observation for
      this phenotype rather than a disease definition. PARTIAL because it is a
      single proband and the variant's causality is not established.
- category: Histologic
  name: Myocardial Sarcomeric Disarray
  description: >-
    Myofibrillar/myocyte disarray is the histological hallmark of HCM. It is
    inherited by this entry from the HCM phenotype definition rather than from
    any TTN-specific pathology series.
  phenotype_term:
    preferred_term: Myocardial sarcomeric disarray
    term:
      id: HP:0031333
      label: Myocardial sarcomeric disarray
  evidence:
  - reference: PMID:10462489
    reference_title: "Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hypertrophic cardiomyopathy (HCM) is characterized by ventricular
      hypertrophy accompanied by myofibrillar disarrays.
    explanation: >-
      Names myofibrillar disarray as a defining feature of HCM.
- category: Clinical
  name: Left Ventricular Diastolic Dysfunction
  description: >-
    Impaired diastolic filling accompanies the hypertrophic phenotype. In the
    medaka titin model that motivates the MURF1 hypothesis, diastolic
    dysfunction was the presenting cardiac abnormality.
  phenotype_term:
    preferred_term: Left ventricular diastolic dysfunction
    term:
      id: HP:0025168
      label: Left ventricular diastolic dysfunction
  evidence:
  - reference: PMID:31628103
    reference_title: "Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hypertrophic cardiomyopathy (HCM) is a hereditary disease characterized by
      cardiac hypertrophy with diastolic dysfunction.
    explanation: >-
      Supports diastolic dysfunction as a feature of HCM generally; it is not a
      TTN-specific observation, hence PARTIAL. evidence_source is OTHER, not
      HUMAN_CLINICAL: the quoted sentence is the paper's opening definition of
      the disease, not a measurement it reports.
genetic:
- name: TTN
  gene_term:
    preferred_term: TTN
    term:
      id: hgnc:12403
      label: TTN
  relationship_type: DISPUTED
  association: >-
    Disputed causal gene. ClinGen classifies TTN-hypertrophic cardiomyopathy as
    Limited. The claimed causal alleles are rare missense substitutions
    (Arg740Leu in the Z-repeat region; two Ig-domain variants near the M-line),
    each reported once in sarcomere-negative HCM cohorts. Titin-truncating
    variants — the mechanism that makes TTN the commonest dilated cardiomyopathy
    gene — are NOT enriched in HCM relative to controls, and a separate line of
    evidence instead suggests TTNtv may act as an outcome modifier in
    established HCM rather than as a cause of it.
  evidence:
  - reference: PMID:39895828
    reference_title: "A Case Study Identified a New Mutation in the TTN Gene for Inherited Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES combined with Sanger sequencing results showed that the other two HCM
      patients in this family carried this TTN mutation, while none of the
      healthy family members carried the mutation except for a 3 years old girl.
    explanation: >-
      The only published segregation evidence for any TTN allele in hypertrophic
      cardiomyopathy: a fourth allele, p.Arg6745Cys, tracking with disease
      across a three-generation Chinese Han family. Curated PARTIAL, and it does
      not overturn the Limited classification - it is one small family, ACMG PP1
      counts only at supporting strength, there is no functional work, and the
      authors themselves note the Ig49 domain has no known protein binding site
      nearby. One unaffected 3-year-old carrier is uninformative given
      age-dependent penetrance rather than evidence against segregation. This
      allele is recorded because omitting it would leave the entry asserting an
      absence a reader could falsify in one search, and because the ClinGen
      assertion post-dates it (2025-10-28 versus February 2025), which makes the
      Limited classification more persuasive rather than less.
  - reference: CGGV:assertion_c17e22eb-c6fc-487d-bcf6-001bb85fdabd-2025-10-28T160000.000Z
    reference_title: "TTN / hypertrophic cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TTN | HGNC:12403 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Limited"
    explanation: >-
      The authoritative gene-disease validity classification: Limited, from
      ClinGen's Hereditary Cardiovascular Disease Gene Curation Expert Panel.
  - reference: PMID:39132495
    reference_title: "ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TTN 1.2 5.5 6.7 Limited"
    explanation: >-
      The expert panel's own scoring row for TTN in the HCM reappraisal: 1.2
      genetic evidence points plus 5.5 experimental evidence points, total 6.7,
      yielding a Limited classification. Note the evidence is weighted toward
      experimental rather than genetic (case/segregation) support — the pattern
      expected of a gene with a plausible biology but no case-level proof.
  - reference: PMID:39132495
    reference_title: "ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy."
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      No excess TTN variants were noted in cases compared to controls in two
      studies.
    explanation: >-
      The expert panel's summary of the case-control evidence: no enrichment of
      TTN variants in HCM cases over controls, the core reason the relationship
      does not rise above Limited.
  - reference: PMID:22335739
    reference_title: "Truncations of titin causing dilated cardiomyopathy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The frequency of TTN truncating variants identified by next-generation
      sequencing of samples from subjects with hypertrophic cardiomyopathy and
      controls was similar (1% and 3%, respectively; P = 0.34).
    explanation: >-
      The directly on-point refutation: truncating TTN variants were no more
      common in hypertrophic cardiomyopathy than in controls - numerically
      slightly less common - so a truncating-variant mechanism does not account
      for HCM. This entry previously quoted the study's dilated-cardiomyopathy
      result here, which supported a claim about DCM while the machine-readable
      assertion was about HCM; the HCM comparison is quoted instead.
  - reference: PMID:22335739
    reference_title: "Truncations of titin causing dilated cardiomyopathy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      each subject with hypertrophic cardiomyopathy who had a TTN variant also
      had a pathogenic mutation in an established hypertrophic cardiomyopathy
      gene, suggesting that TTN truncations rarely, if ever, cause hypertrophic
      cardiomyopathy.
    explanation: >-
      The strongest single datum against this entity in the literature. Every
      TTN variant found in an HCM subject was accompanied by a pathogenic
      variant in a gene with established HCM validity - so the TTN variants were
      bystanders in genotype-explained patients, not the cause. Its force is
      that it removes the alternative reading in which TTN variants are rare but
      real HCM causes.
  - reference: PMID:28822653
    reference_title: "Titin-Truncating Variants Increase the Risk of Cardiovascular Death in Patients With Hypertrophic Cardiomyopathy."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of TTNtv in patients with HCM and in healthy controls was
      comparable
    explanation: >-
      In 529 Chinese HCM patients versus 307 controls, TTNtv prevalence was
      indistinguishable (2.5% vs 2.6%), independently refuting TTN truncating
      variants as a cause of HCM.
  - reference: PMID:28822653
    reference_title: "Titin-Truncating Variants Increase the Risk of Cardiovascular Death in Patients With Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study suggests that TTNtv might be a genetic modifier of HCM and
      confer an increased risk for cardiovascular death.
    explanation: >-
      Supports the alternative reading of the TTN-HCM relationship — modifier of
      outcome rather than cause of disease. Hedged by the authors and based on 3
      events among 13 TTNtv carriers, so support is partial.
  - reference: PMID:16352453
    reference_title: "Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "No TTN mutations were detected."
    explanation: >-
      Targeted analysis in 389 unrelated HCM patients yielded no TTN mutations,
      providing negative replication for the founding CMH9 report. The scope
      caveat matters and is stated rather than left implicit: only exons 2, 3, 4
      and 14 were sequenced - the regions previously implicated in HCM or DCM -
      which is four of TTN's 364 exons. This is a negative result over roughly
      1% of the gene, so it refutes recurrence at the known sites rather than
      excluding TTN involvement generally.
  - reference: PMID:30681346
    reference_title: "Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The majority of genes previously reported as causative of HCM and commonly
      included in diagnostic tests have limited or no evidence of disease
      association.
    explanation: >-
      Provides the general context in which the TTN-HCM claim sits: a systematic
      ClinGen-methodology curation found that only 8 of 33 curated HCM genes had
      definitive evidence, with 22 having limited or no evidence. Partial because
      this quoted conclusion is a summary statement rather than the TTN-specific
      row.
  notes: >-
    Practical consequence for variant interpretation: a rare TTN variant found
    on a multigene HCM panel should not be reported as an established cause of
    the patient's hypertrophy.
prevalence:
- population: Published TTN-attributed hypertrophic cardiomyopathy probands worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No prevalence can be stated for CMH9, and the reason is the entity's own
    disputed status rather than a gap in ascertainment: counting cases requires
    a rule for deciding which TTN variant carriers have the disease, and that is
    exactly what is unsettled. The published case base is roughly four probands
    - the 1999 Arg740Leu index case, two Ig-domain variants from a 96-patient
    screen, and the 2025 p.Arg6745Cys family - none independently replicated. By
    contrast, TTN variant carriage among HCM patients is well measured and runs
    at control frequency, which is the finding that makes the case count
    uninterpretable rather than merely small.
  evidence:
  - reference: PMID:22335739
    reference_title: "Truncations of titin causing dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The frequency of TTN truncating variants identified by next-generation
      sequencing of samples from subjects with hypertrophic cardiomyopathy and
      controls was similar (1% and 3%, respectively; P = 0.34).
    explanation: >-
      Supplies the carriage-versus-control comparison that makes a CMH9 case
      count uninterpretable. PARTIAL because it measures truncating variants
      rather than the missense alleles this entity is built on.
diagnosis:
- name: Multigene HCM panel, with TTN not reportable as an established cause
  diagnosis_term:
    preferred_term: Multigene hypertrophic cardiomyopathy panel testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    This is the clinically actionable output of the entry, and it is a reporting
    rule rather than a testing indication. TTN is on many cardiomyopathy panels
    because of its Definitive relationship with DILATED cardiomyopathy; a rare
    TTN variant returned in a patient being investigated for hypertrophic
    cardiomyopathy must not be reported as an established cause of that
    phenotype, must not drive predictive cascade testing in relatives, and does
    not end the search for a variant in a gene with adequate validity. The
    empirical basis is that TTN variant carriage in HCM runs at control
    frequency, and that in the one study that checked, every HCM subject with a
    TTN variant also carried a pathogenic variant in an established HCM gene -
    so finding TTN and stopping risks missing the actual cause.
  results: >-
    A rare TTN variant in an HCM workup is an uncertain finding at gene level,
    not a molecular diagnosis. Continue interpreting the panel as though TTN
    were absent from it.
  evidence:
  - reference: PMID:22335739
    reference_title: "Truncations of titin causing dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      each subject with hypertrophic cardiomyopathy who had a TTN variant also
      had a pathogenic mutation in an established hypertrophic cardiomyopathy
      gene, suggesting that TTN truncations rarely, if ever, cause hypertrophic
      cardiomyopathy.
    explanation: >-
      The direct basis for the reporting rule: TTN variants in HCM patients
      co-occurred with a genuine cause every time, so reporting TTN would have
      been wrong in every case examined.
  notes: >-
    This rule previously existed only as free text in the genetic section's
    notes. It is promoted here so it is machine-readable, since it is the single
    most useful output of a disputed-validity entry.
differential_diagnoses:
- name: Sarcomeric hypertrophic cardiomyopathy
  disease_term:
    preferred_term: familial hypertrophic cardiomyopathy
    term:
      id: MONDO:0024573
      label: familial hypertrophic cardiomyopathy
  description: >-
    The differential that matters most for this entity, because it is not merely
    an alternative but the likelier explanation in any patient where a TTN
    variant is found. The definitive HCM genes - MYBPC3, MYH7, TNNT2, TNNI3,
    TPM1, ACTC1, MYL2, MYL3 - account for the great majority of genotype-positive
    HCM, and in the one systematic comparison every HCM patient carrying a TTN
    variant also carried a pathogenic variant in one of them.
  distinguishing_features:
  - 'Sarcomeric HCM: a pathogenic variant in a gene with definitive HCM validity.
    CMH9: a TTN variant whose gene-disease relationship is classified Limited,
    frequently alongside an unrecognised sarcomeric variant.'
  evidence:
  - reference: PMID:30681346
    reference_title: "Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3,
      MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3)
    explanation: >-
      Names the definitive-validity genes that constitute this differential, and
      by omission places TTN outside them.
- name: TTN-related dilated cardiomyopathy
  description: >-
    The most consequential confusion risk for this entity, and the reason the
    entry carries an external_assertions contrast. TTN-dilated cardiomyopathy is
    ClinGen Definitive and titin-truncating variants are its commonest genetic
    cause; TTN-hypertrophic cardiomyopathy is Limited. A curator or clinician
    encountering "TTN cardiomyopathy" in the literature is far more likely to be
    reading about the dilated entity, and that literature is not transferable
    here.
  distinguishing_features:
  - 'TTN-DCM: truncating variants, ClinGen Definitive, ventricular dilation with
    systolic impairment. CMH9: rare missense variants, ClinGen Limited,
    hypertrophy - and truncating variants occur at control frequency.'
  evidence:
  - reference: PMID:22335739
    reference_title: "Truncations of titin causing dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The frequency of TTN truncating variants identified by next-generation
      sequencing of samples from subjects with hypertrophic cardiomyopathy and
      controls was similar (1% and 3%, respectively; P = 0.34).
    explanation: >-
      The same study that established the DCM association found no HCM
      association, which is the cleanest single demonstration that the two
      entities must be kept apart.
- name: Non-sarcomeric phenocopies of left ventricular hypertrophy
  description: >-
    Phenocopy exclusion carries extra weight in a sarcomere-negative HCM patient,
    which is by definition the population in which TTN variants were sought - the
    founding CMH9 cohort consisted of probands without mutations in the
    then-known sarcomere genes. Fabry disease, ATTR and AL amyloidosis, Danon
    disease, PRKAG2 glycogen storage cardiomyopathy, and the RASopathies all
    produce unexplained left ventricular hypertrophy, several are treatable, and
    all are better-established explanations than a Limited-validity TTN variant.
    Athlete's heart and hypertensive hypertrophy account for the non-genetic end
    of the differential.
  notes: >-
    Deliberately carries no evidence item. The phenocopy list is standard
    practice for unexplained left ventricular hypertrophy rather than a
    TTN-specific finding, and no cached source for this entity enumerates it;
    stating that is preferable to attaching a citation that does not support it.
experimental_models:
- name: non-spring heart (nsh) medaka fish titin Ig-domain mutant
  description: >-
    The primary experimental support for the titin/MURF1 hypothesis, and the
    only whole-organism model in this entry. A cardiovascular-mutant medaka
    carrying a missense change in an Ig domain at the M-line-A-band transition
    zone of titin shows diastolic dysfunction and hypertrophic myocardium;
    homozygotes have fewer myofibrils, disrupted sarcomeres and stiffer titin
    isoforms, while heterozygotes show M-line disassembly resembling the human
    pathology. Positional cloning of that mutation is what directed the screen of
    96 sarcomere-negative familial HCM patients in which the two human Ig-domain
    alleles curated here were found.
  experimental_model_type: OTHER
  organism:
    preferred_term: Japanese medaka
    term:
      id: NCBITaxon:8090
      label: Oryzias latipes
  publication: PMID:31628103
  modeled_mechanisms:
  - target: Perturbed Titin-MURF1 Interaction and Enhanced Titin Degradation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Reproduces a hypertrophic, diastolically impaired myocardium from a titin
      Ig-domain missense change, which is the mechanism this node proposes.
    limitations: >-
      Fidelity is LOW and deliberately so. This is a fish, the causal direction
      in the model runs from a mutation found in fish to a human screen rather
      than from a validated human allele, the human phenotype is dominant while
      the fish structural phenotype is clearest in homozygotes, and no mammalian
      model of any TTN HCM allele exists. The model motivates the hypothesis; it
      does not establish the human mechanism, which is why every node in this
      entry remains HYPOTHETICAL.
    evidence:
    - reference: PMID:31628103
      reference_title: "Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The nsh homozygotes had fewer myofibrils, disrupted sarcomeres and
        expressed pathologically stiffer titin isoforms.
      explanation: >-
        The structural phenotype of the model, and the observation that ties a
        titin Ig-domain lesion to sarcomeric disruption.
  evidence:
  - reference: PMID:31628103
    reference_title: "Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we generated a cardiovascular-mutant medaka fish, non-spring heart (nsh),
      which showed diastolic dysfunction and hypertrophic myocardium.
    explanation: >-
      Describes the model and its cardiac phenotype.
discussions:
- discussion_id: ttn_hcm_gene_disease_validity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is TTN a genuine hypertrophic cardiomyopathy gene at all, or is CMH9 a
    historical entity that should be retired?
  rationale: >-
    ClinGen classifies TTN-HCM as Limited. The entity rests on one 1999 proband
    plus two variants in a later 96-patient screen, with segregation reported in
    only one small three-generation family (PMID:39895828, p.Arg6745Cys, with
    one unaffected 3-year-old carrier), no independent replication of the index
    variant, a targeted 389-patient study that was negative across the four
    exons it examined, and TTNtv frequencies in HCM that match controls. Note
    that the ClinGen assertion is dated 2025-10-28 and that segregation report
    is from February 2025, so the expert panel plausibly had it available and
    still classified the relationship as Limited - which is a stronger argument
    for the classification than an absence of segregation would have been. What is missing is precisely the evidence class that would settle
    it: large-cohort case-control burden testing of rare TTN MISSENSE variation
    (not truncating variation) in HCM against gnomAD-scale controls, plus
    segregation in multiplex families. Until that exists, dismech records CMH9
    as a disputed entity and declines to assert a mechanism.
  proposed_experiments:
  - experiment_id: ttn_hcm_rare_missense_burden
    name: Region-stratified rare TTN missense burden test in HCM
    description: >-
      Case-control burden analysis of rare TTN missense variation in a large
      sarcomere-negative HCM cohort against population reference data,
      stratified by Z-disc, I-band, A-band, and M-line domains. Truncating
      variation is explicitly not the variable of interest here, since it has
      already been shown not to be enriched in HCM.
    supporting_outcome:
    - >-
        Significant excess of rare missense variation in a specific titin region
        in HCM cases would support a genuine, region-restricted TTN-HCM
        relationship and could move the ClinGen classification above Limited.
    refuting_outcome:
    - >-
        No regional excess over population expectation would support retiring
        CMH9 as a distinct disease entity.
  - experiment_id: ttn_hcm_variant_segregation
    name: Segregation analysis of the reported CMH9 variants
    description: >-
      Recontact and genotype extended pedigrees, where available, for the
      Arg740Leu Z-repeat variant and the two M-line-proximal Ig-domain variants,
      testing co-segregation with an HCM phenotype.
    supporting_outcome:
    - >-
        Co-segregation with HCM across multiple informative meioses would supply
        the evidence class most conspicuously missing from the current curation.
  - experiment_id: ttn_hcm_ipsc_cardiomyocyte_model
    name: Isogenic iPSC-cardiomyocyte modelling of reported TTN variants
    description: >-
      Introduce the reported TTN variants into isogenic human iPSC-derived
      cardiomyocytes and assess hypertrophic growth, sarcomere organisation,
      titin turnover, and diastolic relaxation against isogenic controls.
    supporting_outcome:
    - >-
        A reproducible hypertrophic and diastolic phenotype in human
        cardiomyocytes would provide the human-cell functional evidence that the
        yeast two-hybrid and medaka data currently substitute for.
  evidence:
  - reference: CGGV:assertion_c17e22eb-c6fc-487d-bcf6-001bb85fdabd-2025-10-28T160000.000Z
    reference_title: "TTN / hypertrophic cardiomyopathy (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TTN | HGNC:12403 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Limited"
    explanation: >-
      The Limited classification is the formal statement of the gap.
  - reference: PMID:28822653
    reference_title: "Titin-Truncating Variants Increase the Risk of Cardiovascular Death in Patients With Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, their significance in hypertrophic cardiomyopathy (HCM) is still
      unclear.
    explanation: >-
      Contemporary authors state the uncertainty explicitly.
  - reference: PMID:39132495
    reference_title: "ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinical laboratories are discouraged from reporting variants in genes
      with disputed HCM-association
    explanation: >-
      Frames the clinical stakes of leaving this gap unresolved. TTN was held at
      Limited rather than downgraded to Disputed, so it sits just above the
      threshold at which the panel advises laboratories not to report variants
      at all.
- discussion_id: ttn_hcm_cause_versus_modifier
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    If TTN variants are not a cause of hypertrophic cardiomyopathy, are
    titin-truncating variants nonetheless a prognostic modifier within
    established HCM?
  rationale: >-
    These are separable claims and the evidence points in opposite directions
    for each. TTNtv prevalence in HCM equals that in controls (arguing against
    causation), yet in the same cohort TTNtv carriers had a markedly higher rate
    of cardiovascular death during follow-up (adjusted hazard ratio 6.88).
    A modifier effect would not make TTN an HCM gene, but would make TTN
    genotype clinically meaningful in HCM. The finding is single-cohort, rests
    on 3 deaths among 13 carriers, and has not been replicated.
  attaches_to:
  - "genetic#TTN"
  proposed_experiments:
  - experiment_id: ttntv_hcm_mortality_replication
    name: Independent replication of the TTNtv-cardiovascular-mortality signal in HCM
    description: >-
      Prospective or retrospective replication of the association between
      titin-truncating variant carrier status and cardiovascular death within an
      independent, ancestrally distinct HCM cohort powered for an adequate
      number of events.
    supporting_outcome:
    - >-
        Replication would establish TTN genotype as a prognostic modifier in HCM
        even though TTN is not an HCM disease gene.
    refuting_outcome:
    - >-
        Failure to replicate would leave the single-cohort finding as an
        unconfirmed signal likely inflated by the small number of events.
  evidence:
  - reference: PMID:28822653
    reference_title: "Titin-Truncating Variants Increase the Risk of Cardiovascular Death in Patients With Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study suggests that TTNtv might be a genetic modifier of HCM and
      confer an increased risk for cardiovascular death.
    explanation: >-
      States the modifier hypothesis that this controversy is about.
notes: >-
  Scope decision versus the existing titinopathy entry. MONDO:0013412 has two
  parents: MONDO:0024573 (familial hypertrophic cardiomyopathy, not curated) and
  MONDO:0100494 (autosomal dominant titinopathy, which IS curated as
  kb/disorders/TTN_Related_Myopathy_Dominant_Negative_TTNsv.yaml). A
  parent-term duplicate check was therefore run before creating this file. The
  two entries are distinct sibling entities, not duplicates: the existing entry
  covers a SKELETAL MUSCLE myopathy (distal weakness, contractures) caused by
  heterozygous multi-exon IN-FRAME STRUCTURAL VARIANTS acting by a
  dominant-negative internally-deleted titin protein, and it explicitly states
  that it "does not attempt to cover the full TTN disease spectrum"; it never
  mentions hypertrophic cardiomyopathy. This entry covers a CARDIAC hypertrophic
  phenotype attributed to rare MISSENSE substitutions (Z-repeat Arg740Leu;
  M-line-proximal Ig domains) with entirely different proposed mechanisms
  (alpha-actinin binding, MURF1-mediated titin degradation), a different OMIM
  number (613765), and its own exact MONDO term — which the titinopathy entry
  lacks and only approximates via its parent. Because MONDO:0013412 exists as an
  exact term, no `mappings` block is needed here.

  Curation guard (Named Entity Confusion): TTN's dominant cardiomyopathy
  association is with DILATED cardiomyopathy (MONDO:0005021, ClinGen
  Definitive), where truncating variants explain roughly a quarter of familial
  cases. That literature is far larger than the HCM literature and is easy to
  import by mistake. It is intentionally excluded from this entry; see
  kb/disorders/Dilated_Cardiomyopathy.yaml for the DCM entity. The umbrella
  entry kb/disorders/Hypertrophic_Cardiomyopathy.yaml (MONDO:0005045) already
  lists TTN among HCM panel genes and cites the same ClinGen Limited assertion.

  Reference-mining note, recorded so it is not re-litigated: PMID:20301725
  (GeneReviews Nonsyndromic Hypertrophic Cardiomyopathy Overview) and
  PMID:38718139 (2024 AHA/ACC guideline) are both cached as abstract_only, and
  neither record contains minable content - GeneReviews carries only its
  six-point "purpose of this overview" list, and the guideline abstract carries
  only AIM/METHODS/STRUCTURE sections. No evidence item cites either, and none
  can without fabrication. In particular, the penetrance figures that circulate
  for HCM generally must not be attributed to PMID:20301725 from this entry -
  that text is not in the cached record and would fail reference validation.

  ClinVar caveat for Arg740Leu: the ClinVar record for this allele
  (VCV000012649) is a 0-star, OMIM-derived "Pathogenic" assertion dated
  1999-08-27 with no assertion criteria provided, predating the ACMG/AMP
  framework by 16 years. It is the same 1999 report this entity rests on, not
  independent confirmation of it, and a reader who checks ClinVar and sees
  "Pathogenic" should know that. This is directly relevant to why the
  gene-disease relationship is disputed while a variant-level database still
  reads as settled.

  Treatments are deliberately absent, and this is a scoping decision rather than
  an omission. No TTN-genotype-directed therapy exists, and every management
  option that would appear here - negative inotropes, myosin inhibitors,
  ICD, septal reduction, transplantation - is indicated on the hypertrophic
  cardiomyopathy phenotype irrespective of genotype. Curating them under a
  Limited-validity entity would imply that a TTN variant carries management
  consequences, which is the opposite of this entry's central claim. See
  kb/disorders/Hypertrophic_Cardiomyopathy.yaml for genotype-agnostic
  management.
📚

References & Deep Research

References

3
PMID:20301725
Nonsyndromic Hypertrophic Cardiomyopathy Overview.
No top-level findings curated for this source.
PMID:38718139
2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.
No top-level findings curated for this source.
PMID:39132495
ClinGen Hereditary Cardiovascular Disease Gene Curation Expert Panel: Reappraisal of Genes associated with Hypertrophic Cardiomyopathy.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
1. Disease Information
claude-haiku-4-5-20251001, claude-opus-5[1m] 30 citations 2026-08-01T21:15:02.874464

1. Disease Information

1.1 Overview

Hypertrophic cardiomyopathy 9 (CMH9) is the OMIM disease-series designation for hypertrophic cardiomyopathy (HCM) attributed to heterozygous variants in TTN (titin) on chromosome 2q31.2. MONDO defines it purely by gene attribution, not by any distinguishing clinical or mechanistic feature:

"Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the TTN gene." — MONDO:0013412 definition (MONDO:patterns/disease_series_by_gene)

The entity originates from Satoh et al. (1999), who screened TTN in 82 HCM probands negative for the then-known sarcomere genes and found one heterozygous c.2219G>T, p.Arg740Leu substitution (PMID:10462489, Biochem Biophys Res Commun 262:411‑7):

"A G to T transversion in codon 740, from CGC to CTC, replacing Arginine with Leucine was found in a patient. This mutation was not found in more than 500 normal chromosomes and increased the binding affinity of titin to alpha‑actitin [sic] in the yeast two‑hybrid assay. These observations suggest that the titin mutation may cause HCM in this patient via altered affinity to alpha‑actinin." (HUMAN_CLINICAL + IN_VITRO; note the authors' own hedge)

There is no CMH9-specific clinical syndrome. Reported patients present as ordinary nonsyndromic HCM. No TTN-specific hypertrophy pattern, age of onset, arrhythmic profile, or treatment response has ever been described.

1.2 Key identifiers

Resource Identifier
OMIM #613765 (CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 9; CMH9)
MONDO MONDO:0013412 (hypertrophic cardiomyopathy 9)
DOID DOID:0110315
MedGen / UMLS MEDGEN:348780 / UMLS:C1861065
MeSH (supplementary concept) MESH:C566044
GARD GARD:0024921
GTR condition C1861065 ("Hypertrophic cardiomyopathy 9")
Gene TTN, HGNC:12403, OMIM *188840, NCBI Gene 7273, Ensembl ENSG00000155657, UniProt Q8WZ42
Parent MONDO classes MONDO:0024573 (familial hypertrophic cardiomyopathy); MONDO:0100494 (autosomal dominant titinopathy); equivalent to MONDO:0005045 ∧ (RO:0004003 some HGNC:12403)
ICD‑10‑CM I42.1 (obstructive HCM) / I42.2 (other HCM) — no CMH9-specific code
ICD‑11 BC43 hypertrophic cardiomyopathy block (familial‑genetic and non‑obstructive subcategories BC43.10 / BC43.11) — no CMH9-specific code
Orphanet No dedicated ORPHA code. Familial isolated HCM (ORPHA:155) is flagged "NON RARE IN EUROPE" and is outside the Orphanet rare-disease nomenclature; ORPHA:217569 ("rare hypertrophic cardiomyopathy") is a group-of-disorders node with prevalence/inheritance "not specified"

Ontology suggestion for the KB disease_term: MONDO:0013412 (exact). Do not substitute MONDO:0005045 (hypertrophic cardiomyopathy) — that is the umbrella entity.

1.3 Synonyms

CMH9; cardiomyopathy, familial hypertrophic, 9 (or type 9); hypertrophic cardiomyopathy type 9; TTN hypertrophic cardiomyopathy; hypertrophic cardiomyopathy caused by mutation in TTN. (All are EXACT synonyms in MONDO.)

1.4 Provenance of information

Disease-level aggregated resources only (OMIM, MONDO, ClinGen, ClinVar, GeneReviews) plus a handful of small primary case series. No EHR/registry-derived, patient-level CMH9 cohort exists. Because the entity is defined by gene attribution rather than a distinguishable phenotype, any EHR case-finding for "CMH9" would in practice retrieve generic HCM cases (I42.1/I42.2) plus a TTN genotype.

2. Etiology

2.1 Disease causal factors

Claimed cause: heterozygous rare missense variation in TTN — a disputed causal claim.

Three lines of causal claim exist, all thin:

  1. Z‑repeat missense (p.Arg740Leu) — one proband, 1999 (PMID:10462489). Never replicated, never segregated.
  2. M‑line/A‑band‑transition Ig‑domain missense — two variants in 96 sarcomere‑negative Japanese familial HCM probands, plus a medaka fish mutant (PMID:31628103).
  3. Titin‑truncating variants (TTNtv) — the DCM mechanism — explicitly not supported for HCM (see §4.4).

Counter-evidence is stronger than the positive evidence:

  • Herman et al. 2012, N Engl J Med 366:619‑28 (PMID:22335739): "the frequency of TTN mutations was significantly higher among subjects with dilated cardiomyopathy (54 of 203 [27%]) than among subjects with hypertrophic cardiomyopathy (3 of 231 [1%], P=3×10⁻¹⁶) or controls (7 of 249 [3%], P=9×10⁻¹⁴)." Note HCM (1%) was below controls (3%). Also: "Mutations associated with dilated cardiomyopathy were overrepresented in the titin A‑band but were absent from the Z‑disk and M‑band regions of titin" — i.e., precisely the two regions the CMH9 hypotheses invoke. (HUMAN_CLINICAL)
  • Bos et al. 2006, Mol Genet Metab 88:78‑85 (PMID:16352453): 389 unrelated HCM patients, targeted analysis of the HCM‑associated TTN exons (2, 3, 4, 14) — "No TTN mutations were detected." (HUMAN_CLINICAL; negative replication)
  • Wang et al. 2017, Can J Cardiol 33:1292‑7 (PMID:28822653): 529 Chinese HCM vs 307 controls — "We identified 13 and 8 TTNtv in patients with HCM (13 of 529 [2.5%]) and controls (8 of 307 [2.6%]) … The prevalence of TTNtv in patients with HCM and in healthy controls was comparable (P = 0.895)." (HUMAN_CLINICAL)
  • ClinGen HCM GCEP reappraisal (Hespe, Waddell, Asatryan et al., JACC 2025;85(7):727‑740, doi:10.1016/j.jacc.2024.12.010; preprint PMID:39132495 / PMC11312670): TTN scored 1.2 genetic + 5.5 experimental = 6.7 points → Limited. Panel narrative: "the majority are missense without functional data or located in an exon with low percent spliced in (PSI) cardiac tissue"; "no excess TTN variants were noted in cases compared to controls in 2 studies"; "evidence for TTN variants causing HCM remained limited, rather than being reclassified as disputed." (OTHER / expert-panel curation)

Interpretation for the KB: model TTN with relationship_type: DISPUTED, and record the mechanism nodes at mechanism_confidence: HYPOTHETICAL.

2.2 Risk factors

Genetic. - TTN rare missense variation — disputed (above). - Background rare-variant burden is the confounder. Titin is the largest human protein (~34,350 aa canonical; up to ~35,991 aa inferred‑complete isoform; ~364 exons in the meta‑transcript NM_001267550). Every genome carries multiple rare TTN missense alleles; ~2–3% of unselected individuals carry a truncating allele (3% of controls in PMID:22335739). Any sufficiently large candidate-gene screen will therefore find rare TTN variants irrespective of causality — the core methodological problem with CMH9. - Real HCM risk factors (parent phenotype): pathogenic variants in the 8 definitive sarcomere genes — MYBPC3 (~50% of genotype‑positive), MYH7 (~33%), TNNI3 (~5%), TNNT2 (~4%), then TPM1, ACTC1, MYL2, MYL3 (<3% each) (GeneReviews, PMID:20301725). The 2025 ClinGen reappraisal recognises 29 genes at moderate/strong/definitive for HCM or isolated LVH (MYBPC3, MYH7, TNNT2, TNNI3, TNNC1, TPM1, ACTC1, MYL2, MYL3, ACTN2, CSRP3, FHOD3, FLNC, PRKAG2, PLN, DES, FHL1, LAMP2, GLA, CACNA1C, TTR, PTPN11, RAF1, RIT1, and others). - Polygenic background modulates penetrance and expressivity in HCM generally; low-penetrance sarcomere variants contribute additive risk (Circulation 2025, "Low Penetrance Sarcomere Variants Contribute to Additive Risk in Hypertrophic Cardiomyopathy"). - Modifier claim specific to TTN: TTNtv may be an outcome modifier rather than a cause — see §4.5.

Environmental / demographic (parent phenotype; none TTN‑specific). - Age (penetrance is age-dependent; typical onset adolescence–early adulthood). - Male sex (over-represented in HCM cohorts; adverse events occur earlier in male TTN carriers in the DCM setting, PMID:22335739). - Intense competitive athletic training — a trigger for arrhythmic events and a differential-diagnosis confounder ("athlete's heart"), not an initiating cause. - Hypertension and aortic stenosis are phenocopy causes of LVH, not CMH9 risk factors. - No toxin, infectious, occupational, or dietary exposure has ever been linked to CMH9. Not applicable / no data.

2.3 Protective factors

No CMH9-specific protective genetic or environmental factor has been reported. For HCM generally: avoidance of burst/extreme exertion and of dehydration/volume depletion in LVOT-obstructive physiology; blood-pressure control; avoidance of pure vasodilators and high-dose diuretics in obstructive disease. These are management rather than validated primary prevention. No protective allele is documented in gnomAD-scale data.

2.4 Gene–environment interactions

No CMH9-specific GxE data. In the broader titin field, the best-characterised GxE is in DCM, not HCM: TTNtv carriers show a stress- or exposure-dependent phenotype (alcohol, peripartum, chemotherapy, atrial fibrillation, hypertension; e.g. Nat Cardiovasc Res 2024, "Titin truncating variants, cardiovascular risk factors and the risk of atrial fibrillation and heart failure"), and heterozygous Ttn-truncation mice are normal at baseline but decompensate under angiotensin II/isoproterenol or transverse aortic constriction (PMID:26504781; MODEL_ORGANISM). Do not transfer this to CMH9 — it is DCM biology.

3. Phenotypes

No phenotype in this list is TTN-specific; all are inherited from the HCM parent phenotype, with the exception of the diastolic-dysfunction emphasis that comes from the medaka model. Frequencies below are HCM-cohort figures (GeneReviews PMID:20301725; 2024 AHA/ACC guideline PMID:38718139) and should be curated as parent-phenotype frequencies, not CMH9 frequencies.

Phenotype HPO term Type Onset Course Frequency (HCM overall)
Left ventricular hypertrophy (LV wall ≥15 mm adults; z>3 children) HP:0001712 Left ventricular hypertrophy Clinical sign / imaging Adolescence–early adulthood typical; any age Progressive then plateau Obligate (defining)
Asymmetric septal hypertrophy HP:0001670 Asymmetric septal hypertrophy Imaging as above Stable/progressive Most
Myocardial sarcomeric (myofibrillar) disarray HP:0031333 Myocardial sarcomeric disarray Histologic — — Histological hallmark
LV diastolic dysfunction HP:0025168 Left ventricular diastolic dysfunction Functional Early, often pre-hypertrophic Progressive Very frequent
LV outflow tract obstruction HP:0031573 Left ventricular outflow tract obstruction Hemodynamic Adult Dynamic/provocable 25–30% at rest
Exertional dyspnea HP:0002875 Exertional dyspnea Symptom Adult Progressive Common (leading symptom)
Chest pain / angina HP:0100749 Chest pain Symptom Adult Episodic Common
Palpitations HP:0001962 Palpitations Symptom Adult Episodic Common
Syncope / presyncope HP:0001279 Syncope Symptom Adolescent–adult Episodic Important SCD risk marker
Atrial fibrillation HP:0005110 Atrial fibrillation Arrhythmia Adult Recurrent→permanent ~60% by age 60 if diagnosed by 40
Ventricular tachycardia HP:0004756 Ventricular tachycardia Arrhythmia Any Episodic Substantial minority
Sudden cardiac death HP:0001645 Sudden cardiac death Outcome Adolescent–young adult peak Catastrophic ~6% of cohorts experience SCD/aborted arrest/appropriate ICD therapy; HCM = 5–14% of SCD in competitive athletes
Systolic dysfunction / "burnt-out" end-stage phase HP:0001635 Congestive heart failure; HP:0012722? (use HP:0005162 Abnormal left ventricular function) Clinical Late Progressive LV systolic dysfunction ~8%
Myocardial fibrosis (LGE on CMR) HP:0001637 Abnormal myocardium morphology (no precise HP term for LGE) Imaging/histology Mid Progressive Common; prognostic
Mitral regurgitation (SAM-mediated) HP:0001653 Mitral regurgitation Clinical Adult Dynamic Common in obstructive HCM
Elevated NT‑proBNP / troponin HP:0031185 Abnormal circulating creatine kinase?—prefer LOINC (NT‑proBNP LOINC:33762‑6; hs‑cTnT LOINC:67151‑1) Laboratory — — Common; prognostic

Quality-of-life impact. No CMH9-specific QoL data. In HCM generally, exertional dyspnea, chest pain and fatigue drive impairment; the SEQUOIA‑HCM aficamten trial used the Kansas City Cardiomyopathy Questionnaire (KCCQ) and pVO₂ as functional endpoints, with ~60% of aficamten-treated vs 24% of placebo patients improving NYHA class. Additional QoL burdens: exercise restriction counselling, ICD-related anxiety, and cascade-screening implications for relatives. Instruments in use: KCCQ, SF‑36, EQ‑5D, HCM Symptom Questionnaire (HCMSQ).

Severity/progression descriptors (HCM parent). Severity: variable, from lifelong asymptomatic to end-stage HF. Progression: slow and progressive with an episodic arrhythmic overlay. Penetrance 50–62% in P/LP heterozygotes, gene-dependent (~32% MYL3 to ~69% ACTC1) (PMID:20301725). None of these figures has ever been measured for TTN carriers.

4. Genetic / Molecular Information

4.1 Causal gene

TTN (titin), HGNC:12403, OMIM *188840, 2q31.2, UniProt Q8WZ42. Encodes the giant sarcomeric filament spanning the half-sarcomere from Z‑disc to M‑band (>1 µm), 3–4.2 MDa depending on splice isoform (N2B, N2BA, novex isoforms). Functional segments: Z‑disc (Z‑repeats binding α‑actinin, telethonin/TCAP anchoring), I‑band (elastic spring: tandem Ig, N2B/N2BA, PEVK), A‑band (super-repeats binding myosin/MyBP‑C), M‑band (titin kinase domain, MURF1/MURF2 binding, obscurin/myomesin interface).

GO annotations to use: GO:0008307 structural constituent of muscle; GO:0042805 actinin binding; GO:0031430 M band; GO:0030018 Z disc; GO:0030016 myofibril; GO:0055003 cardiac myofibril assembly; GO:0016567 protein ubiquitination; GO:0014898 cardiac muscle hypertrophy in response to stress.

4.2 The reported CMH9 alleles

Variant HGVS Location Reported Evidence ClinVar
p.Arg740Leu NM_001267550.2:c.2219G>T; NP_001254479.2:p.Arg740Leu; NC_000002.12:g.178785999C>A; rs28933405 Z‑disc Z‑repeat region Satoh 1999, 1 proband/82 (PMID:10462489) Absent from >500 normal chromosomes; ↑α‑actinin binding (~40%) in yeast two‑hybrid VCV000012649, "Pathogenic", review status 0 stars — "no assertion criteria provided", single OMIM submission, last evaluated 1999‑08‑27; no population frequency displayed
p.Ser30186Ala exon 301, TCT→GCT Ig domain near M‑line/A‑band transition Medaka/human study (PMID:31628103), 96 familial HCM probands ↑MURF1 binding; ↑ubiquitin-mediated titin degradation (IN_VITRO) —
p.Asp30994Asn exon 306, GAT→AAT Ig domain within the MURF1‑binding site same same —
p.Arg6745Cys c.20233C>T, exon 80 I‑band region Chinese family, WES, Int J Gen Med 2025 (PMID:39895828) Present in affected relatives, absent in healthy relatives except one young child Novel; classification not established

Critical caveat on the R740L ClinVar record: its "Pathogenic" label is a 0‑star OMIM-derived assertion from 1999 predating ACMG/AMP criteria. Under ACMG/AMP 2015 rules the variant would today, at best, be a VUS: PS3 is weak (yeast two‑hybrid interaction assay, not a disease-relevant functional readout), PM2 support was "absent from 500 chromosomes" (not gnomAD-scale), and there is no PP1 segregation and no PS4 case-control enrichment. gnomAD frequency is not displayed on the ClinVar record and could not be retrieved programmatically for this report — flag as a gap to fill before curating any allele-frequency claim.

4.3 Variant classes and functional consequences

  • Type: all CMH9 claims are missense. This matters: the disease-validated TTN mechanism (DCM) is truncating (nonsense/frameshift/canonical splice) with haploinsufficiency/poison-peptide effects in high‑PSI A‑band exons (Roberts et al. 2015, Sci Transl Med, PMID:25589632).
  • Proposed functional consequence #1 (gain of function / altered binding): R740L increases titin–α‑actinin affinity (~40%) — an unusual "too‑tight" gain-of-binding, not loss of function.
  • Proposed functional consequence #2 (enhanced degradation): M‑line‑proximal Ig missense increases MURF1 binding and ubiquitin-mediated titin turnover — effectively a localised loss of titin protein.
  • These two proposals are mechanistically incompatible with each other and implicate opposite ends of the molecule. They should be curated as two separate, non-merged mechanistic_hypotheses groups.
  • Germline in all cases. Somatic TTN variation is irrelevant here (TTN is a well-known false-positive "long gene" hit in tumour mutation datasets — do not cite COSMIC/TCGA for this entity).

4.4 Why truncating variants are excluded

TTNtv frequencies: DCM 27% vs HCM 1% vs controls 3% (PMID:22335739); HCM 2.5% vs controls 2.6% (PMID:28822653). PSI/exon-usage analysis (PMID:25589632) established that only constitutively expressed (high‑PSI) A‑band TTNtv are DCM-relevant — "the most common genetic cause of DCM in ambulant patients in the community." The ClinGen panel found the only truncating-type HCM case evidence to be one A‑band frameshift (PSI 100%) and one I‑band termination (PSI 100%) — two isolated observations against a high background rate.

4.5 Modifier hypothesis (a separable claim)

Wang et al. 2017 (PMID:28822653): among 529 HCM patients, TTNtv carriers had cardiovascular death in 3/13 (23.1%) vs 39/516 (7.6%) in non-carriers, adjusted HR 6.88 (95% CI 2.04–23.20; P=0.002). Authors: "Our study suggests that TTNtv might be a genetic modifier of HCM and confers increased risk for cardiovascular death." Single cohort, 3 events, unreplicated. Curate as CONTROVERSY, not as a causal mechanism. Note the logical structure: TTN can be simultaneously (a) not an HCM gene and (b) a prognostic modifier within HCM.

4.6 Modifier genes, epigenetics, chromosomal abnormalities

  • Modifier genes for CMH9: none identified. No data.
  • Epigenetics: no CMH9-specific methylation/histone data. Generic HCM myocardium shows DNA methylation and ncRNA remodelling, but nothing titin- or CMH9-specific is published. No data.
  • Chromosomal abnormalities: not a mechanism here. Large TTN CNVs are rare; GeneReviews states "large deletions and duplications are not a major cause of nonsyndromic HCM." Chromosomal microarray/karyotype have no role.

5. Environmental Information

  • Environmental factors: none established for CMH9. Not applicable.
  • Lifestyle factors: relevant only as symptom/arrhythmia modifiers of the HCM phenotype (exertion, dehydration, alcohol, stimulants). For titin biology generally, mechanical/haemodynamic load is the physiologically meaningful "environment" — titin is a load-sensing molecule — but no CMH9 load-interaction study exists.
  • Infectious agents: Not applicable. No infectious trigger implicated.

6. Mechanism / Pathophysiology

6.1 Causal chain — as claimed, with confidence labels

[HYPOTHETICAL, MOLECULAR]
Rare heterozygous TTN missense variant in a sarcomere-negative HCM patient
   │  (ascertainment: residual, gene-elusive HCM — candidate-gene design)
   ├──► HYPOTHESIS A (Z-disc):  ↑ titin Z-repeat binding to α-actinin (~40%, Y2H)
   │        └─► perturbed Z-disc assembly / Z-disc mechanosensing  [UNBRIDGED]
   │                └─► ??? ─────────────────────────┐
   └──► HYPOTHESIS B (M-line):  ↑ titin Ig-domain binding to MURF1  │
    └─► ↑ ubiquitin-mediated titin degradation              │
 └─► M-line disassembly, fewer myofibrils,          │
     stiffer (N2B-shifted) titin isoforms  [fish]   │
          └─► ??? ────────────────────────────────► │
                                                    ▼
                          [TISSUE] Hypertrophic remodeling of the LV
                          (wall thickening + myocyte disarray +
                           impaired diastolic filling)
                                    │
                                    ▼
                    Generic HCM downstream cascade
            (see kb/modules/cardiomyopathy_maladaptive_remodeling)

The step marked ??? is entirely unbridged in both hypotheses. No intermediate signalling has been demonstrated linking either binding perturbation to a hypertrophic transcriptional program in human cardiomyocytes.

6.2 Hypothesis A — altered Z‑disc / α‑actinin interaction

Titin's N‑terminus spans the Z‑disc; the central Z‑repeats bind the C‑terminal calmodulin-like domain of α‑actinin‑2 (ACTN2), anchoring the filament and creating a mechanosensing hot spot. Arg740 lies in this Z‑repeat region. The 1999 claim is that a ~40% affinity increase alters Z‑disc assembly or mechanotransduction.

Evidence base: one yeast two-hybrid experiment. No cardiac cell, tissue, or animal data for this variant. Independent support that Z‑disc/α‑actinin‑2 disruption can cause human myocardial mechanical dysfunction exists (e.g., Circ Heart Fail/PMC10572656, "Disruption of Z‑Disc Function Promotes Mechanical Dysfunction in Human Myocardium: Evidence for a Dual Myofilament Modulatory Role by Alpha‑Actinin 2"), and ACTN2 itself is a ClinGen-recognised HCM gene — but that supports the pathway's plausibility, not this variant's causality. Notably, Herman 2012 found DCM-associated truncations were absent from the Z‑disc region, and Bos 2006 found nothing at all when directly resequencing the Z‑disc-encoding exons in 389 HCM patients.

GO: GO:0042805 actinin binding (modifier INCREASED); GO:0030018 Z disc; GO:0055003 cardiac myofibril assembly.

6.3 Hypothesis B — titin/MURF1 signalling and enhanced titin turnover

The titin M‑band harbours the titin kinase domain, now understood to be a catalytically inactive pseudokinase scaffold that recruits the E3 ubiquitin ligases MURF1 (TRIM63) and MURF2, coupling sarcomeric mechanics to ubiquitin-dependent turnover and myofibril trophicity (Bogomolovas et al., Open Biol 2014;4:140041, doi:10.1098/rsob.140041). TRIM63 is itself a recognised HCM-associated gene.

The medaka non‑spring heart (nsh) mutant carries an Ig-domain missense (D23186V, exon 204) at the M‑line/A‑band transition (PMID:31628103, Dis Model Mech 12:dmm041103):

"The nsh homozygotes had fewer myofibrils, disrupted sarcomeres and expressed pathologically stiffer titin isoforms. In addition, the nsh heterozygotes showed M‑line disassembly that is similar to the pathological changes found in HCM." (MODEL_ORGANISM)

"Screening of mutations in 96 unrelated patients with familial HCM, who had no previously implicated mutations in known sarcomeric gene candidates, identified two mutations in Ig domains close to the M‑line region of titin. In vitro studies revealed that the mutations found both in medaka fish and in familial HCM increased binding of titin to muscle‑specific ring finger protein 1 (MURF1) and enhanced titin degradation by ubiquitination. These findings implicate an impaired interaction between titin and MURF1 as a novel mechanism underlying the pathogenesis of HCM." (IN_VITRO + MODEL_ORGANISM)

Mechanistic details from the full text: atrial systolic/diastolic velocities fell from ~183 µm/s (WT) to ~64 µm/s (nsh); N2B (stiff) isoform expression increased, i.e., reduced elasticity and increased passive stiffness — a biophysically coherent route to diastolic dysfunction; MURF1/MURF2 catalysed multi-ubiquitination of the titin fragment in vitro; mutant constructs showed lower steady-state protein levels. The authors state a key limitation: "since the medaka TTN gene is very large, we were unable to clone the full-length cDNA (~15 kb) to perform the rescue experiments" — the model lacks genetic rescue. The human arm presents family pedigrees, but ClinGen's independent assessment of the total case-level evidence remained Limited.

GO: GO:0016567 protein ubiquitination (INCREASED); GO:0030239 myofibril assembly (DECREASED); GO:0031430 M band; GO:0061077 chaperone-mediated protein folding (n/a); GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process.

6.4 Downstream (inherited from the HCM parent phenotype, not TTN-specific)

Increased sarcomeric energetic cost and Ca²⁺ sensitisation → myocyte hypertrophy and disarray → interstitial and replacement fibrosis → microvascular dysfunction/ischemia → impaired relaxation and elevated filling pressures → LVOT obstruction (± SAM of the mitral valve) → arrhythmogenic substrate → AF, VT, SCD, and in a minority the end-stage systolic ("burnt-out") phase. This is exactly the chain captured by the dismech module cardiomyopathy_maladaptive_remodeling; a conforms_to link from CMH9 is not warranted because the disease-specific edges into that chain are hypothetical.

6.5 Cell types, compartments, metabolism, immunity

  • Cell types: CL:0000746 cardiac muscle cell (cardiomyocyte); secondarily CL:0002548 fibroblast of cardiac tissue (fibrotic remodelling), CL:0002144 capillary endothelial cell (microvascular dysfunction).
  • Subcellular: GO:0030017 sarcomere; GO:0030018 Z disc; GO:0031430 M band; GO:0030016 myofibril; GO:0005634 nucleus (titin N‑terminus/Z‑disc mechanosignalling relays, e.g., MLP/CSRP3 shuttling); GO:0005739 mitochondrion (energetic stress, downstream).
  • Metabolic changes: no CMH9-specific metabolomics. HCM generally shows impaired myocardial energetics (reduced PCr/ATP by ³¹P‑MRS), a shift toward glucose utilisation, and increased ATP cost of tension. No titin-specific data.
  • Immune involvement: none primary. Sterile inflammation accompanies fibrotic remodelling but is not disease-defining. Not applicable as a mechanism.
  • Tissue damage mechanisms: myocyte hypertrophy/disarray, interstitial + replacement fibrosis, microvascular ischemia. Generic.
  • Molecular profiling (transcriptomics/proteomics/metabolomics/lipidomics/single-cell/spatial/CRISPR screens): No CMH9-specific dataset exists in GEO, ArrayExpress, PRIDE, MetaboLights, HCA, or DepMap. Titin exon-usage/PSI resources from the DCM field (PMID:25589632; Inferring disease course from differential exon usage in the wide titinopathy spectrum, PMC11514934) are methodologically relevant for interpreting TTN variants but are not CMH9 data. This is a genuine and complete gap.

7. Anatomical Structures Affected

Organ level - Primary: heart — UBERON:0000948; specifically left ventricle UBERON:0002084 and interventricular septum UBERON:0002094 (asymmetric septal hypertrophy). - Secondary: left atrium UBERON:0002079 (dilation, AF substrate); mitral valve UBERON:0002135 (SAM, regurgitation); cardiac conduction system UBERON:0004146; pulmonary circulation (post-capillary pulmonary hypertension); systemic embolic targets — brain UBERON:0000955 (cardioembolic stroke). - Body systems: cardiovascular primary. Note that titin is also expressed in skeletal muscle UBERON:0001134 — skeletal myopathy is not a feature of CMH9 as reported, but is central to other titinopathies (HMERF, LGMD R10, Salih myopathy) under the shared MONDO parent autosomal dominant titinopathy (MONDO:0100494). No skeletal-muscle phenotype has been described in CMH9 patients.

Tissue / cell level - Cardiac muscle tissue UBERON:0001133 / myocardium UBERON:0002349. - CL:0000746 cardiac muscle cell — the primary affected population; CL:0002548 cardiac fibroblast; CL:0002144 capillary endothelial cell.

Subcellular — GO:0030017 sarcomere, GO:0030018 Z disc, GO:0031430 M band, GO:0030016 myofibril.

Localization / lateralization — Bilateral in the sense of biventricular potential, but the phenotype is characteristically left-sided and regionally asymmetric (basal anteroseptal predominance; apical, midventricular, and concentric variants occur). Right ventricular involvement is possible but secondary. Use HP:0001670 (asymmetric septal hypertrophy) to capture asymmetry.

8. Temporal Development

Onset. No CMH9-specific onset data (n≈4 reported probands). HCM parent phenotype: onset typically adolescence or early adulthood, but ranges from infancy to the eighth decade; onset is insidious, detected on screening ECG/echo or after a symptomatic/arrhythmic event. HPO onset terms: HP:0003581 Adult onset / HP:0011462 Young adult onset / HP:0003621 Juvenile onset (choose per case; for CMH9 the honest annotation is variable/unknown).

Progression / staging. Recognised HCM stages: (1) genotype‑positive/phenotype‑negative (subclinical; may show impaired relaxation, ECG changes, crypts before hypertrophy); (2) classic phenotype with preserved EF ± obstruction; (3) adverse remodelling with AF, progressive fibrosis, worsening diastolic failure; (4) end-stage/"burnt-out" with systolic dysfunction (~8% of cohorts) requiring advanced therapies. Rate is slow and variable over decades, punctuated by episodic arrhythmic events. Duration: chronic, lifelong (HP:0003679 progressive; HP:0003676 progressive disorder).

Patterns. No spontaneous remission. Treatment-induced symptomatic remission is achievable (myectomy, alcohol septal ablation, cardiac myosin inhibitors) but does not reverse the genotype; regression of hypertrophy with myosin inhibitors is partial and drug-dependent. Critical periods: adolescence/young adulthood (peak SCD risk, athletic exposure) and the period around phenotype conversion in genotype-positive relatives — the rationale for serial screening every 1–2 years (see §13).

9. Inheritance and Population

9.1 Epidemiology

CMH9-specific: unquantifiable. Cumulative published cases ≈ 4 probands worldwide (1 Japanese in 1999; 2 Japanese in 2019; 1 Chinese family in 2025). Appropriate prevalence_class: CASES_IN_LITERATURE with measure_type: CASES_IN_LITERATURE and a note that the entity's validity is disputed. Do not assign a numeric rate.

HCM parent phenotype (for context only): - Classic estimate 1 in 500 (~200 per 100,000) from echocardiographic screening (CARDIA). - Contemporary US administrative-claims estimate (JACC: Advances 2025, "Epidemiology of Hypertrophic Cardiomyopathy in the United States From 2016 to 2023"): 1 in 327, ~832,956 US cases — higher than classic estimates, reflecting ascertainment and awareness. - Range across literature 1:500–1:3,000 depending on method; genotype-based estimates (P/LP variant carriage) suggest higher latent carriage with incomplete penetrance.

9.2 Genetic parameters

  • Inheritance: autosomal dominant — HP:0000006. Recorded as such in ClinGen's TTN‑HCM assertion and asserted by OMIM. But note: the index CMH9 observation was a single proband with no segregation data; support for dominance in this specific entity is PARTIAL, inherited from HCM generally rather than demonstrated for TTN.
  • Penetrance: unknown for CMH9. HCM overall: 50–62% in P/LP heterozygotes, age-dependent, gene-specific (~32% MYL3 to ~69% ACTC1) (PMID:20301725). Population-based genotype-first studies show substantially lower penetrance than clinic-ascertained estimates.
  • Expressivity: highly variable with marked intrafamilial variability (HCM generally).
  • Anticipation: Not applicable — no repeat expansion mechanism.
  • Germline mosaicism: possible in principle for HCM (parental gonadal mosaicism reported); no CMH9 report.
  • Founder effects: none for CMH9. (Contrast: founder TTNtv exist for DCM, e.g. TTN:c.12478del in Slovenia — DCM, not HCM.)
  • Consanguinity: no role established; dominant mechanism.
  • Carrier frequency: not a meaningful parameter for a dominant, disputed entity. gnomAD frequency of R740L was not retrievable for this report — explicit gap.

9.3 Population demographics

  • Affected populations: the three primary reports are East Asian (2 Japanese cohorts, 1 Chinese family). This almost certainly reflects ascertainment by the research groups involved, not a genuine ancestry effect, and should be curated as such rather than as a population-prevalence claim.
  • Geographic distribution: none established. No variant shows geographic clustering.
  • Sex ratio: no CMH9 data. HCM cohorts are male-predominant (~60:40) with women diagnosed later and often more symptomatic.
  • Age distribution: no CMH9 data; HCM parent as in §8.

10. Diagnostics

There is no CMH9-specific diagnostic test or pathway. Diagnosis is (1) diagnose HCM, then (2) genotype — and the TTN finding, if any, is currently not reportable as causal.

10.1 Clinical tests (HCM parent; 2024 AHA/ACC guideline, PMID:38718139)

Modality Findings Codes
Transthoracic echocardiography (first-line) LV wall ≥15 mm (adults) or ≥13 mm with family history; z>3 in children; SAM; dynamic LVOT gradient (rest + Valsalva + exercise provocation); diastolic indices NCIT:C16816 (Echocardiography)
Cardiac MRI with LGE Hypertrophy distribution, apical/mid variants, myocardial fibrosis burden (prognostic), phenocopy discrimination (e.g., amyloid, Fabry) NCIT:C16809 (Magnetic Resonance Imaging)
12-lead ECG LVH voltage, repolarisation abnormalities, deep T inversions (apical HCM), pathologic Q waves; often abnormal before hypertrophy NCIT:C38053 (Electrocardiography)
Ambulatory ECG (24–48 h Holter) NSVT (SCD risk marker), AF detection NCIT:C38050? — use NCIT:C38053 with modifier
Exercise testing / CPET Functional capacity, pVO₂, exercise-provocable obstruction, blood-pressure response (SCD risk) NCIT:C38082 (Exercise Stress Test)
Biomarkers NT‑proBNP (LOINC:33762‑6), hs‑troponin T (LOINC:67151‑1) — prognostic, not diagnostic. Rule out phenocopies: α‑galactosidase A activity/GLA for Fabry; serum/urine free light chains + technetium‑pyrophosphate scintigraphy for ATTR amyloid; creatine kinase for Danon/glycogenoses LOINC as listed
Endomyocardial biopsy Rarely needed; shows myocyte hypertrophy, myofibrillar disarray (HP:0031333), interstitial fibrosis. Used mainly to confirm infiltrative phenocopies NCIT:C15680 (Biopsy)

10.2 Genetic testing

  • Recommended approach (2024 AHA/ACC): HCM-focused multigene panel in the proband, with evaluation by a genetic counsellor before and after testing; panels should include phenocopy genes (GLA, LAMP2, PRKAG2, TTR, PTPN11/RASopathies, FHL1, DES, CACNA1C, ACTN2, FLNC, FHOD3, ALPK3). Diagnostic yield ~30% in unselected HCM, ~60% in familial cases.
  • Cascade testing: offered to first-degree relatives only when a P/LP variant is identified in the proband. Genotype-positive/phenotype-negative relatives get serial imaging; ICDs are not indicated for them, and they may participate in competitive sport.
  • WES/WGS: second-line when panels are negative and a syndromic/phenocopy diagnosis is suspected; WGS adds little for TTN interpretation given the background variant burden.
  • Single-gene testing: appropriate only for a known familial variant.
  • CMA / karyotype / FISH: not indicated — large CNVs are not a significant cause of nonsyndromic HCM.
  • mtDNA testing: consider for maternally inherited LVH (MT‑TI and other mt‑tRNA variants).
  • Repeat expansion testing: not applicable, except Friedreich ataxia (FXN GAA) in the syndromic differential.
  • The TTN-specific interpretive rule: a rare TTN variant on an HCM panel should not be reported as an established cause of the patient's hypertrophy. For any TTN variant, evaluate exon PSI (percent-spliced-in) and domain location — but note that even high‑PSI TTNtv are DCM-, not HCM-, associated.

10.3 Omics-based diagnostics

RNA-seq on blood/muscle can resolve splice-impact of candidate TTN variants and is the one omics modality with real utility here. Proteomics, metabolomics, epigenomics, liquid biopsy: no established diagnostic role. Not applicable.

10.4 Clinical criteria and differential diagnosis

Diagnostic criterion (2024 AHA/ACC): maximal LV wall thickness ≥15 mm in any myocardial segment (or ≥13 mm with a positive family history or positive genotype), by any imaging modality, not explained solely by abnormal loading conditions. Pediatric: z-score >3 (or >2 with family history/genotype).

Differential (all must be excluded): - Hypertensive heart disease, aortic stenosis — loading-condition LVH. - Athlete's heart — concentric mild LVH with increased LV cavity size, normal diastolic function, regression with deconditioning. - Cardiac amyloidosis (ATTR/AL) — low voltage with LVH, apical sparing on strain, positive PYP scan. - Fabry disease (GLA) — low α‑Gal A, prominent inferolateral LGE, extracardiac features. - Danon disease (LAMP2), PRKAG2 glycogen storage — pre-excitation, conduction disease. - RASopathies (Noonan/PTPN11, RAF1, RIT1; Costello) — dysmorphology, pulmonary valve stenosis. - Pompe disease, Friedreich ataxia, desminopathy, mitochondrial cardiomyopathy, Timothy syndrome (CACNA1C).

10.5 Screening

  • Cascade clinical screening of first-degree relatives with ECG + echo, repeated every 1–2 years (more often in adolescence), regardless of genotype availability.
  • Newborn screening: not applicable.
  • Population carrier screening: not applicable for a dominant, low-penetrance, disputed entity.

11. Outcome / Prognosis

No CMH9-specific outcome data exist. All figures below are for HCM overall and must be curated as parent-phenotype prognosis.

  • Mortality: contemporary HCM-related mortality in specialist centres is ~0.5–1%/year, far below the 2–4%/year of older referral-bias-era series. HCM remains a leading cause of SCD in young athletes (5–14% of cases).
  • Survival: with modern management, life expectancy in many HCM patients approaches that of the general population; the end-stage phase (~8% with systolic dysfunction) carries substantially worse survival and may require transplant.
  • Composite burden: SHaRe registry (Ho et al., Circulation 2018;138:1387‑1398, PMID:30297972; 4,591 patients, 2,763 genotyped, mean follow-up 5.4±6.9 y) established that sarcomere-variant-positive patients have earlier onset and a higher lifetime burden of adverse events (arrhythmias, HF, AF, stroke, death) than sarcomere-negative patients. This is directly relevant framing for CMH9: the reported CMH9 patients are by definition sarcomere-negative on established genes, which is the lower-risk SHaRe stratum — another reason not to assume a distinct severe TTN-HCM phenotype.
  • Morbidity/disability: exercise intolerance, AF (up to ~60% by age 60 in early-diagnosed patients) with elevated stroke risk requiring anticoagulation irrespective of CHA₂DS₂‑VASc, ICD-related morbidity, and activity restriction.
  • QoL instruments: KCCQ, SF‑36, EQ‑5D, HCMSQ. No CMH9-specific QoL study.
  • Complications: SCD/VT, AF and cardioembolic stroke, progressive HF, infective endocarditis (rare, with SAM/MR), pregnancy-related decompensation (maternal mortality is nonetheless low, 0.2%, GeneReviews PMID:20301725).
  • Prognostic factors (HCM): maximal wall thickness, LV apical aneurysm, extensive LGE on CMR, unexplained syncope, NSVT, family history of SCD, abnormal BP response to exercise, LVEF <50%, left atrial size — all integrated in the ESC HCM Risk‑SCD calculator and the AHA/ACC risk-marker approach.
  • TTN-specific prognostic claim: the single unreplicated finding that TTNtv carriage predicts cardiovascular death within HCM (adjusted HR 6.88) (PMID:28822653). Treat as hypothesis-generating.

12. Treatment

No CMH9-specific, genotype-directed therapy exists. Management is standard HCM management (2024 AHA/ACC/AMSSM/HRS/PACES/SCMR guideline, PMID:38718139).

12.1 Pharmacotherapy

Therapy Mechanism Indication NCIT suggestion
Beta-blockers (metoprolol, bisoprolol, atenolol) β₁-adrenergic blockade → ↓ contractility, ↓ HR, ↑ diastolic filling First-line for symptomatic obstructive and non-obstructive HCM NCIT:C15986 Pharmacotherapy + therapeutic_agent NCIT:C2019 Adrenergic beta-Antagonist
Non-dihydropyridine CCBs (verapamil, diltiazem) L-type Ca²⁺ channel blockade Beta-blocker intolerance/failure; avoid in severe obstruction + hypotension NCIT:C15986 + CHEBI:9948 verapamil
Disopyramide Class Ia antiarrhythmic, negative inotrope Add-on for refractory obstruction (with AV-nodal blocker) NCIT:C15986 + CHEBI:4657 disopyramide
Mavacamten First-in-class cardiac myosin inhibitor; reduces actin–myosin cross-bridge formation → ↓ hypercontractility, ↓ LVOT gradient Symptomatic obstructive HCM (FDA 2022); REMS due to systolic-dysfunction risk NCIT:C15986 + NCIT term for mavacamten; therapeutic_modality: SMALL_MOLECULE
Aficamten (MYQORZO) Allosteric, reversible cardiac myosin inhibitor Symptomatic obstructive HCM — FDA approved 2025, EU February 2026; based on phase 3 SEQUOIA‑HCM (NCT05186818): ~60% vs 24% placebo improved NYHA class; Boxed Warning for heart failure; MYQORZO REMS. (Aficamten: First Approval, PMID:41941083) NCIT:C15986 + therapeutic_modality: SMALL_MOLECULE
Oral anticoagulation (DOAC preferred) Thromboembolism prevention Any AF in HCM, regardless of CHA₂DS₂‑VASc NCIT:C15986
Antiarrhythmics (amiodarone, sotalol) Rhythm control AF/VT NCIT:C15986
Diuretics (cautious) Preload reduction Congestion in non-obstructive HCM; caution in obstruction NCIT:C15986

Avoid: pure vasodilators (nitrates, dihydropyridines), high-dose diuretics, digoxin, and positive inotropes in obstructive physiology.

Pharmacogenomics: mavacamten is a CYP2C19 substrate — dosing and titration are CYP2C19-phenotype-informed (poor metabolisers require dose caps); aficamten has a less CYP2C19-dependent profile. No TTN-genotype-directed pharmacogenomics exists. PharmGKB/CPIC have no CMH9 entry.

12.2 Advanced therapeutics

  • Gene therapy: active for MYBPC3-related HCM (AAV9 gene replacement, e.g., TN‑201 and related programs). Nothing for TTN — and TTN's ~100 kb coding sequence makes conventional AAV gene replacement structurally impossible. Base/prime editing of specific TTN alleles is conceivable but entirely preclinical. Not applicable to CMH9 today.
  • Cell therapy, RNA therapies (ASO/siRNA), targeted therapy, immunotherapy: none for CMH9. (Note: TTN exon-skipping ASO strategies are being explored preclinically for TTN-DCM, not HCM.)

12.3 Surgical / interventional

  • Septal myectomy (extended transaortic) — gold standard for drug-refractory obstructive HCM in experienced centres; NCIT:C15329 Surgical Procedure.
  • Alcohol septal ablation — catheter alternative for selected anatomy/comorbidity; NCIT:C49236 Therapeutic Procedure.
  • ICD implantation — primary prevention per risk stratification; secondary prevention after arrest/sustained VT; NCIT:C50040? (use NCIT:C49236 with a device descriptor; therapeutic_modality: DEVICE).
  • Catheter ablation for AF; cardiac transplantation (NCIT:C15289 Organ Transplantation) for end-stage disease.

12.4 Supportive, rehabilitative, and lifestyle

Symptom-directed care; moderate-intensity exercise is now endorsed (a change from historical blanket restriction), with shared decision-making for competitive/high-intensity sport; cardiac rehabilitation (NCIT:C15315 Rehabilitation); genetic counselling (NCIT:C15240); pre-conception and prenatal counselling.

12.5 Experimental / trials

No trial has ever enrolled by TTN genotype in HCM. Relevant HCM trials: SEQUOIA‑HCM (NCT05186818, aficamten, completed), MAPLE‑HCM (aficamten monotherapy vs metoprolol), ACACIA‑HCM (non-obstructive HCM), ODYSSEY‑HCM, VALOR‑HCM (mavacamten vs septal reduction therapy), and the MYBPC3 gene-therapy programs. Any clinical_trials block for CMH9 must be annotated as parent-phenotype trials, not CMH9-specific.

12.6 Treatment strategy

Algorithm: confirm HCM and exclude phenocopies → risk-stratify for SCD (ICD decision) → if obstructive and symptomatic: beta-blocker → ±verapamil/disopyramide → cardiac myosin inhibitor (mavacamten or aficamten, with echo surveillance and REMS) → septal reduction therapy if refractory. If non-obstructive: symptom-directed HF therapy, AF management, transplant evaluation at end stage. Genotype currently informs family screening, not drug choice — and a TTN variant informs neither.

13. Prevention

  • Primary prevention (preventing the disease): not possible — germline, dominant. No modifiable exposure initiates CMH9.
  • Secondary prevention (early detection): the core intervention. Cascade clinical screening (ECG + echo) of first-degree relatives every 1–2 years; cascade genetic testing only if a P/LP variant is identified in the proband. A rare TTN variant does not meet this bar and should not be used to include or exclude relatives from surveillance — the practically important consequence of the Limited classification.
  • Tertiary prevention (preventing complications): ICD for high SCD risk; anticoagulation for any AF; endocarditis awareness; avoidance of dehydration/vasodilators in obstruction; blood-pressure control; individualised exercise prescription; pregnancy planning and monitoring.
  • Immunization: not disease-specific; standard influenza/COVID/pneumococcal vaccination as for any cardiac patient.
  • Genetic screening: PGD/PGT‑M and prenatal diagnosis are technically available for a known P/LP familial variant — not appropriate for a Limited-validity TTN variant.
  • Risk stratification: ESC HCM Risk‑SCD model; AHA/ACC major risk markers; CMR‑LGE burden.
  • Counselling: genetic counselling before and after testing is a guideline recommendation (NCIT:C15240 Genetic Counseling); counselling for CMH9 specifically must convey uncertain gene–disease validity.
  • Public health / environmental interventions: pre-participation athletic screening programs (contested cost-effectiveness), AED availability at sporting venues. Not CMH9-specific.

14. Other Species / Natural Disease

  • Taxonomy: naturally occurring HCM is well described in domestic cat, Felis catus (NCBITaxon:9685) — the single most important spontaneous animal model of HCM — and less commonly in dog (Canis lupus familiaris, NCBITaxon:9615), pig, and some non-human primates.
  • Breeds (VBO): Maine Coon and Ragdoll cats are the classic HCM breeds, with MYBPC3 founder variants (A31P in Maine Coon; R820W in Ragdoll) — see OMIA. Sphynx and British Shorthair have breed-associated HCM without a fully defined gene.
  • Critically: feline HCM is a MYBPC3 story, not a TTN story. There is no OMIA entry, and no naturally occurring animal disease, attributed to TTN in hypertrophic cardiomyopathy. TTN variants in animals are associated with DCM (e.g., reports in Doberman-type DCM genetics remain contested) and with muscular phenotypes.
  • Orthologues: mouse Ttn (NCBI Gene 22138, MGI:98864); rat Ttn (NCBI Gene 84005); zebrafish ttn.1/ttn.2; medaka ttn. Titin's Z‑disc α‑actinin interface, A‑band super-repeats, and M‑band kinase/MURF1 module are deeply conserved across vertebrates — the premise on which the medaka model rests.
  • Comparative pathology: the medaka nsh mutant reproduces hypertrophic myocardium, diastolic dysfunction, sarcomeric disarray, and M‑line disassembly — a genuine cross-species mechanistic parallel, but in a two-chambered fish heart without the coronary microcirculation, fibrotic remodelling, or LVOT obstruction that dominate human HCM.
  • Zoonotic potential / transmission: not applicable.

15. Model Organisms

Model Type Construct Recapitulation Limitations Resource
Medaka non‑spring heart (nsh) — Oryzias latipes Vertebrate, in vivo ENU/positional-cloned missense D23186V, exon 204, Ig domain at M‑line/A‑band transition The only in vivo model of a CMH9-type allele. Homozygotes: fewer myofibrils, disrupted sarcomeres, stiffer (N2B-shifted) titin isoforms, atrial velocities ↓ from ~183 to ~64 µm/s. Heterozygotes: M‑line disassembly "similar to the pathological changes found in HCM" No genetic rescue ("we were unable to clone the full-length cDNA (~15 kb) to perform the rescue experiments"); fish two-chambered heart; homozygous phenotype is largely hypoplastic/dysmorphic rather than hypertrophic in the mammalian sense; the human variants tested are different residues from the fish one PMID:31628103 (Dis Model Mech 2019); bioRxiv 680579; PMC6899042
Ttn knock-in / truncation mice Mammalian, in vivo M‑line/other targeted alleles; heterozygous truncations Homozygotes die ~E9.0 with severe sarcomere-assembly defects; heterozygotes normal at baseline but develop DCM under angiotensin II/isoproterenol, and maladaptive hypertrophy under transverse aortic constriction (PMID:26504781) Models DCM, not CMH9. Load-dependent hypertrophy in a TTNtv mouse is not evidence for TTN-HCM MGI (MGI:98864), IMSR, IMPC
MURF1/Trim63 knockout mouse Mammalian, in vivo Constitutive KO Exaggerated cardiac hypertrophy after pressure overload — establishes MURF1 as a brake on hypertrophic growth, supporting the pathway invoked by Hypothesis B Pathway-level plausibility only; not a TTN-variant model MGI
Yeast two-hybrid titin–α‑actinin assay In vitro Z‑repeat fragment + α‑actinin CaM-like domain The entire experimental basis of Hypothesis A (~40% affinity increase for R740L) Heterologous, non-cardiac, interaction-only; no functional or cellular readout PMID:10462489
In vitro MURF1 binding + ubiquitination assays In vitro Recombinant titin Ig fragments + MURF1/MURF2 Increased MURF1 binding, multi-ubiquitination, reduced mutant protein levels Fragment-based; does not establish myocardial consequence PMID:31628103
Human iPSC-derived cardiomyocytes (isogenic) In vitro, human Does not yet exist for CMH9 alleles — — This is the single highest-value missing experiment (see below)

Overall model-system verdict: CMH9 has no mammalian genetic model, no genetic rescue in the one model that exists, and no human-cell model. In dismech terms, this warrants a HUMAN_MODEL_MISMATCH discussion alongside the KNOWLEDGE_GAP: evidence exists (medaka, yeast two-hybrid), but its translational validity to human HCM is precisely the unresolved question.

16. Synthesis: Knowledge Gaps and the Experiments That Would Settle Them

Open question 1 (KNOWLEDGE_GAP): Is TTN a hypertrophic cardiomyopathy gene at all, or should CMH9 be retired as a disease entity?

What is missing is a specific evidence class: large-cohort, region-stratified case-control burden testing of rare TTN missense variation (Z‑disc / I‑band / A‑band / M‑band strata) in HCM against gnomAD-scale controls, plus segregation in multiplex families. Note that truncating-variant burden has already been tested and is negative — the burden question that remains open is missense-specific, and it has not been properly asked. Proposed experiments:

  1. Region-stratified rare TTN missense burden test in a large sarcomere-negative HCM cohort vs population reference, stratified by domain and PSI. Supports CMH9 if a regional excess emerges; refutes it if the burden matches population expectation.
  2. Segregation analysis of p.Arg740Leu, p.Ser30186Ala, p.Asp30994Asn (and now p.Arg6745Cys) in extended pedigrees. This is the evidence class most conspicuously absent from the founding report.
  3. Isogenic human iPSC-cardiomyocyte modelling of the reported alleles: hypertrophic growth, sarcomere organisation, titin turnover/half-life, passive stiffness, and relaxation kinetics vs isogenic controls — replacing yeast two-hybrid and fish data with human cardiac cell data.

Open question 2 (CONTROVERSY): If TTN does not cause HCM, do TTNtv nonetheless modify outcome within established HCM? The two claims are logically separable and the evidence points in opposite directions: prevalence data argue against causation, while the same cohort reports adjusted HR 6.88 for cardiovascular death (PMID:28822653; 3 deaths among 13 carriers, unreplicated). Resolution requires replication in an independent, ancestrally distinct HCM cohort with adequate event numbers — e.g., within SHaRe or a national registry with linked TTN sequencing.

Curation guard (Named Entity Confusion risk — high). TTN's dominant, well-validated cardiomyopathy association is with dilated cardiomyopathy (MONDO:0005021; ClinGen Definitive; TTNtv in ~25% of familial DCM). That literature is an order of magnitude larger than the HCM literature and is trivially easy to import by mistake — including via search engines and deep-research tools that will happily return DCM content for a "TTN cardiomyopathy" query. Every claim in a CMH9 entry must be checked against the question: does this source's cohort have hypertrophic, or dilated, cardiomyopathy?

Reference list (with evidence-source classification)

PMID / ID Citation Evidence source Use
10462489 Satoh M, et al. Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. Biochem Biophys Res Commun 1999;262:411‑7 HUMAN_CLINICAL + IN_VITRO Founding CMH9 report; R740L; α‑actinin binding
31628103 Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients. Dis Model Mech 2019;12:dmm041103 MODEL_ORGANISM + IN_VITRO + HUMAN_CLINICAL Medaka nsh; 2 human M‑line Ig variants; MURF1
22335739 Herman DS, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med 2012;366:619‑28 HUMAN_CLINICAL TTNtv: DCM 27% vs HCM 1% vs controls 3%; Z‑disk/M‑band absence
28822653 Titin-truncating variants increase the risk of cardiovascular death in patients with hypertrophic cardiomyopathy. Can J Cardiol 2017;33:1292‑7 HUMAN_CLINICAL TTNtv 2.5% HCM vs 2.6% controls; modifier HR 6.88
16352453 Bos JM, et al. Genotype-phenotype relationships involving HCM-associated mutations in titin, muscle LIM protein, and telethonin. Mol Genet Metab 2006;88:78‑85 HUMAN_CLINICAL "No TTN mutations were detected" in 389 HCM
30681346 Ingles J, et al. Evaluating the clinical validity of hypertrophic cardiomyopathy genes. Circ Genom Precis Med 2019;12:e002460 OTHER (expert curation) 8/33 definitive; 22/33 limited or no evidence
39132495 / doi:10.1016/j.jacc.2024.12.010 Hespe S, Waddell A, Asatryan B, et al. Genes associated with hypertrophic cardiomyopathy: a reappraisal by the ClinGen HCVD GCEP. JACC 2025;85(7):727‑740 (preprint PMC11312670) OTHER (expert curation) TTN 1.2+5.5=6.7 → Limited; PSI rationale; 29 genes at moderate+
CGGV assertion c17e22eb-…-2025-10-28 ClinGen: TTN / hypertrophic cardiomyopathy (MONDO:0005045), AD, Limited OTHER Authoritative validity call
CGGV assertion 1ec53217-…-2025-05-30 ClinGen: TTN / dilated cardiomyopathy (MONDO:0005021), AD, Definitive OTHER Anti-conflation contrast
25589632 Roberts AM, et al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med 2015 HUMAN_CLINICAL + COMPUTATIONAL PSI framework for TTNtv interpretation
20301725 Cirino AL, Channaoui N, Ho C. Nonsyndromic Hypertrophic Cardiomyopathy Overview. GeneReviews [updated 2025‑03‑06] OTHER (review) HCM clinical characteristics, penetrance, gene table, management. Note: does not list TTN as an HCM gene
38718139 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy. Circulation 2024 OTHER (guideline) Diagnosis, risk stratification, treatment, cascade screening
30297972 Ho CY, et al. Genotype and lifetime burden of disease in hypertrophic cardiomyopathy: insights from SHaRe. Circulation 2018;138:1387‑1398 HUMAN_CLINICAL Sarcomere-positive vs -negative outcomes
39895828 A case study identified a new mutation in the TTN gene for inherited hypertrophic cardiomyopathy. Int J Gen Med 2025 HUMAN_CLINICAL Chinese family, TTN c.20233C>T p.R6745C, exon 80
26504781 Pressure overload by transverse aortic constriction induces maladaptive hypertrophy in a titin-truncated mouse model. 2015 MODEL_ORGANISM DCM/load model — contextual only
41941083 Aficamten: First Approval. Drugs OTHER Aficamten (MYQORZO) FDA 2025 / EU Feb 2026
doi:10.1098/rsob.140041 Bogomolovas J, et al. Titin kinase is an inactive pseudokinase scaffold that supports MuRF1 recruitment to the sarcomeric M-line. Open Biol 2014;4:140041 IN_VITRO Titin kinase–MURF1 scaffold biology
doi:10.1016/j.jacadv.2025.102552 Epidemiology of hypertrophic cardiomyopathy in the United States from 2016 to 2023. JACC: Advances 2025 HUMAN_CLINICAL US HCM prevalence 1 in 327
ClinVar VCV000012649 NM_001267550.2(TTN):c.2219G>T (p.Arg740Leu), rs28933405 OTHER 0‑star "Pathogenic", OMIM submission, evaluated 1999‑08‑27
MONDO:0013412 MONDO ontology record OTHER Definition, synonyms, xrefs, logical axioms

Unresolved retrieval gaps in this report (flagged rather than guessed): (1) gnomAD v4 allele frequency for TTN p.Arg740Leu could not be retrieved programmatically (gnomAD is a client-rendered app; ClinVar shows no frequency) — verify via the gnomAD GraphQL API or browser before curating any frequency claim; (2) the full-text TTN paragraph of the final JACC 2025 reappraisal was accessible only via the medRxiv/PMC preprint — verify wording against the published version before quoting it as an evidence snippet; (3) whether the two 2019 M‑line Ig variants segregated in their families is asserted in that paper's pedigrees but was judged insufficient by ClinGen — read the primary figures before making a segregation claim either way.

Sources: - OMIM #613765 — CMH9 · OMIM *188840 — TTN · Clinical Synopsis 613765 - GTR: Hypertrophic cardiomyopathy 9 (C1861065) · ClinVar VCV000012649 · ClinVar RCV000013484 - ClinGen HCM gene reappraisal (JACC 2025) · preprint PMC11312670 · ClinGen summary page · GenCC TTN–HCM submission - Evaluating the Clinical Validity of HCM Genes (Circ Genom Precis Med 2019) · SHaRe: Genotype and Lifetime Burden of Disease in HCM - Titin/MURF1 medaka + human HCM study (PMC6899042) · PMID 28822653 · Titin-truncated mouse TAC model · Titin kinase pseudokinase / MuRF1 scaffold · α-actinin-2 Z-disc dysfunction in human myocardium - GeneReviews: Nonsyndromic HCM Overview (NBK1768) · 2024 AHA/ACC HCM Guideline · ACC Key Points - US HCM epidemiology 2016–2023 (JACC Advances) · Orphanet: rare hypertrophic cardiomyopathy (ORPHA:217569) · Orphanet: familial isolated HCM (ORPHA:155) - Cytokinetics: FDA approval of MYQORZO (aficamten) · TCTMD coverage · Aficamten: First Approval (PMID 41941083) - TTN A Case Study, Int J Gen Med 2025 (PMID 39895828) · ICD-10-CM I42.1 · ICD-10-CM I42.2 · ICD-11 HCM block