Hypertrophic Cardiomyopathy 25

1. Disease Information

1.1 Overview

Hypertrophic cardiomyopathy 25 (CMH25) is the OMIM-designated, gene-indexed form of familial hypertrophic cardiomyopathy attributed to heterozygous missense variation in TCAP, which encodes telethonin (titin-cap, T-cap) — a 19 kDa, 167-amino-acid sarcomeric Z-disc protein. The designation derives from a single 2004 candidate-gene study (Hayashi et al., PMID:15582318) that identified two TCAP missense variants (T137I, R153H) in Japanese HCM probands, supported by in vitro binding assays. Clinically, reported CMH25 is indistinguishable from sarcomeric HCM: asymmetric left ventricular hypertrophy, frequently septal, with dyspnea, syncope, palpitations, chest pain, arrhythmia, and variable risk of heart failure and sudden cardiac death.

MONDO defines it strictly by gene attribution (verified locally with OAK against sqlite:obo:mondo):

def: "Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the TCAP gene." [MONDO:patterns/disease_series_by_gene]

Notably, MONDO places MONDO:0011843 under three parents simultaneously — MONDO:0016192 (neuromuscular disease caused by qualitative or quantitative defects of telethonin), MONDO:0016333 (familial dilated cardiomyopathy), and MONDO:0024573 (familial hypertrophic cardiomyopathy) — an ontological reflection of TCAP's phenotypic promiscuity (HCM, DCM, LGMD R7) and of the weak boundary around this entity.

1.2 Key Identifiers

MONDO synonym set (verified): CMH25; TCAP hypertrophic cardiomyopathy; cardiomyopathy, familial hypertrophic, type 25; cardiomyopathy, hypertrophic, 25; hypertrophic cardiomyopathy caused by mutation in TCAP; hypertrophic cardiomyopathy type 25; cardiomyopathy, familial hypertrophic, 25 (RELATED).

1.3 Provenance of the Evidence Base

All CMH25-specific information is derived from aggregated, disease-level sources, not from individual-patient/EHR data: - Primary case reports and small candidate-gene cohorts (n = 2 probands in the index study; ≤ 8 probands total in all HCM literature per ClinGen). - Curated aggregators: OMIM, MONDO, MedGen, HPO, ClinVar, ClinGen Gene-Disease Validity. - No EHR-derived, registry-derived, or population-cohort dataset exists specifically for CMH25. Any epidemiological figure quoted below is for HCM as a whole.

2. Etiology

2.1 Disease Causal Factors

Asserted cause: heterozygous germline missense variation in TCAP (17q12), inherited autosomal dominantly, producing telethonin with altered Z-disc protein-binding affinity.

Proposed causal mechanism (Hayashi et al. 2004, PMID:15582318) — verbatim from the abstract:

"Two TCAP mutations, T137I and R153H, were found in patients with HCM, and another TCAP mutation, E132Q, was identified in a patient with DCM. It was demonstrated by the qualitative assays that the HCM-associated mutations augment the ability of Tcap to interact with titin and calsarcin-1, whereas the DCM-associated mutations impair the interaction of Tcap with MLP, titin, and calsarcin-1."

"These observations suggest that the difference in clinical phenotype (HCM or DCM) may be correlated with the property of altered binding among the Z-disc components."

This is a gain-of-interaction model for HCM (opposite in sign to the loss-of-interaction DCM model) — mechanistically unusual and, critically, not independently replicated. ClinGen explicitly discounted it ("None of these variants have functional evidence in support of pathogenicity"), presumably because yeast two-hybrid and GST pull-down competition are qualitative in vitro binding assays without cellular or organismal validation. This tension between the published functional claim and the ClinGen assessment should be curated explicitly as a knowledge gap, not silently resolved either way.

2.2 Genetic Risk Factors

Benign/common TCAP variants routinely encountered on HCM panels (do not misclassify): - c.453A>C p.Ala151= (rs1053651): Benign, allele frequency 0.45–0.71 — a common polymorphism. - c.316C>T p.Arg106Cys (rs45578741): Benign/Likely benign, gnomAD 0.008, TOPMed 0.0156. - c.191C>T p.Ser64Leu (rs45458802): Benign, gnomAD 0.0039–0.0042. - c.111-15dup (rs397516860): Benign/Likely benign.

Analytic point worth curating: R153H — one of only two originally asserted CMH25 alleles — sits at gnomAD AF ≈ 2.1×10⁻⁴ (~1 in 2,400 alleles). For a putatively penetrant autosomal-dominant HCM allele, that frequency is an order of magnitude above what is plausible, and it is precisely the class of observation formalized by Walsh et al. 2017 (PMID:27532257): "We found that in some genes previously reported as important causes of a given cardiomyopathy, rare variation is not clinically informative because there is an unacceptably high likelihood of false-positive interpretation."

Variant class distribution: overwhelmingly missense. Alaei et al. 2023 (PMID:37752589) reviewed the whole TCAP literature: "a total of 44 variants were reported for the TCAP gene in the literature where a majority of mutations were found to be missense." Truncating TCAP alleles are the LGMD R7 mechanism (biallelic loss of telethonin), with one heterozygous frameshift (p.Glu12fs) reported in restrictive-phenotype HCM (PMID:40330574).

Somatic vs germline: exclusively germline. No somatic TCAP involvement in cardiomyopathy; TCAP is not a recognized COSMIC/TCGA cancer driver.

Functional consequence: disputed. The published model is gain of protein–protein interaction (HCM) versus loss of interaction (DCM) — see §6. Truncating alleles cause loss of function (telethonin absent on Western blot/IHC in LGMD R7; PMID:34982307, PMID:25724973).

2.3 Modifier Genes / Oligogenic Contribution

This is a substantive issue for CMH25. Two of the small number of reported TCAP-HCM probands carried a second variant in another cardiomyopathy gene, which ClinGen counted as evidence against TCAP causation: - A pathogenic TNNI3 variant co-occurring in the Andersen 2009 cohort (PMID:19035361). - A MYBPC3 VUS co-occurring in Bos 2006 (PMID:16352453).

Andersen et al. also reported broadly that "Six patients carried two disease-associated mutations." In dismech terms, TCAP variants in HCM are better modeled with relationship_type: MODIFIER or SUSCEPTIBILITY than as primary causal genes, pending new evidence.

The mechanistically nearest modifier candidates are TCAP's binding partners: CSRP3/MLP (moderate HCM evidence per ClinGen; interaction documented in PMID:12507422 and PMID:24860983), TTN, MYOZ2/calsarcin-1, and FLNC.

2.4 Environmental Risk Factors

There are no CMH25-specific environmental risk factors in the literature. HCM-generic modifiers apply: age (LVH develops through adolescence/adulthood; CMH25 HPO annotation is adult onset), male sex (male predominance in clinical HCM cohorts), systemic hypertension and obesity as phenotype amplifiers, and intense competitive athletic exertion as a trigger for arrhythmic events, not as a cause of the underlying genotype.

Because telethonin is a mechanosensitive, load-responsive protein (Ibrahim 2013, PMID:23100327: "Both mechanical overload and unloading alter t-tubule structure"; Knöll 2011, PMID:21799151: heart failure develops only "following biomechanical stress"), hemodynamic load is the most biologically defensible candidate environmental modifier for a TCAP-attributed cardiomyopathy. This is an inference from model-organism data, not a human clinical finding — curate as evidence_source: MODEL_ORGANISM.

2.5 Protective Factors

None identified, genetic or environmental. No protective TCAP alleles are reported. Avoidance of burst/high-intensity competitive exertion, and blood-pressure/weight control, are prudential HCM-generic measures without CMH25-specific evidence.

2.6 Gene–Environment Interactions

The only substantive G×E model available is the mechanical-load × telethonin-deficiency interaction, demonstrated in mice and unproven in humans:

"Telethonin knockout mice do not reveal defective heart development or heart function under basal conditions, but develop heart failure following biomechanical stress, owing at least in part to apoptosis of cardiomyocytes, an effect that may also play a role in human heart failure." (Knöll et al. 2011, PMID:21799151)

This is a textbook conditional-penetrance architecture: genotype silent at baseline, unmasked by an environmental/hemodynamic stressor. However, it is a loss-of-function (KO) model, whereas the human HCM hypothesis is gain-of-interaction — the model does not test the human allele class. Curate as HUMAN_MODEL_MISMATCH rather than as supporting evidence.

3. Phenotypes

3.1 Curated HPO Annotation Set for OMIM:607487

The complete HPO annotation for CMH25 (retrieved from the JAX HPO annotation API) is remarkably sparse — derived from the two Hayashi probands only:

All five labels verified locally with OAK against sqlite:obo:hp. Denominators of 2 mean these "frequencies" carry essentially no statistical information — do not curate frequency: OBLIGATE/VERY_FREQUENT from a 2/2. Per the dismech frequency-evidence SOP, omit frequency: for these, or record the raw 2/2 in notes.

3.2 Phenotypes from Individual Case Reports (extend the HPO set)

Toste et al. 2020, Portuguese family, p.C57W (PMID:32565061) — verbatim:

"Both affected members of this family presented with late-onset HCM, moderate asymmetric left ventricular hypertrophy, atrial fibrillation and heart failure with preserved ejection fraction and low risk of sudden cardiac death."

Suggested terms: HP:0001670 Asymmetric septal hypertrophy; HP:0005110 Atrial fibrillation; HP:0001635 Congestive heart failure; HP:0003581 Adult onset (all OAK-verified).

Hu et al. 2025, restrictive-phenotype HCM, p.Glu12fs (PMID:40330574) — verbatim:

"Transthoracic echocardiography and cardiac magnetic resonance imaging (CMR) revealed non-obstructive hypertrophic cardiomyopathy (HCM) with severe diastolic dysfunction, biatrial enlargement, preserved ejection fraction, and normal chamber size. Endomyocardial biopsy demonstrated cardiomyocyte hypertrophy and focal fibrosis."

"Despite interventions, the patient's cardiac function progressively deteriorated, leading to his placement on the heart transplant waiting list 1 year later."

Suggested terms: HP:0025168 Left ventricular diastolic dysfunction; HP:0001723 Restrictive cardiomyopathy; HP:0001685 Myocardial fibrosis (all OAK-verified). This is a single case, n=1, and is the only report of an RP-HCM presentation.

Bos et al. 2006 (PMID:16352453) — phenotype severity, verbatim:

"Patients with MLP/TCAP-associated HCM clinically mimicked myofilament-HCM."

"MLP/TCAP-HCM phenotypically mirrors myofilament-HCM and is more severe than the subset of patients who still remain without a disease-causing mutation."

Cohort context: 389 HCM patients, 215 male, mean LV wall thickness 21.6 ± 6 mm.

3.3 HCM-Generic Phenotype Spectrum (inherited from the parent entity)

Applicable to CMH25 by parent-class inheritance, not by CMH25-specific observation. All OAK-verified:

3.4 Phenotypes of the Other TCAP Disease (LGMD R7) — for Differential/Boundary Curation

Curators must keep these out of the CMH25 entry (they belong to the autosomal-recessive LGMD R7 entity), but should know them for differential purposes: - HP:0003701 Proximal muscle weakness, HP:0003236 Elevated circulating creatine kinase concentration (both OAK-verified). - Phenotypic range is wide: from asymptomatic/paucisymptomatic hyperCKemia to classic limb-girdle weakness, with a facioscapulohumeral-like pattern in some (PMID:36463458, PMID:40195250). - A characteristic imaging sign: "Muscle MRI of four patients revealed consistent sparing of the sartorius muscle in all patients." (PMID:40195250) - Cardiac involvement occurs in a minority of LGMD R7 patients per UniProt's disease annotation — relevant because it means TCAP loss-of-function does not reliably produce cardiomyopathy in humans, a point that further weakens the CMH25 hypothesis.

3.5 Quality of Life

No CMH25-specific QoL data exist. No EQ-5D, SF-36, PROMIS, or HCMSQ (Hypertrophic Cardiomyopathy Symptom Questionnaire) data are reported for TCAP genotype carriers. HCM-generic QoL burden — exertional limitation, activity restriction, ICD-related anxiety, and the psychosocial burden of familial risk — applies by inheritance. In the Toste family, both affected members had HFpEF with preserved functional capacity and low SCD risk, i.e., a comparatively favorable QoL trajectory; the single RP-HCM case (PMID:40330574) had the opposite — progression to transplant listing within a year.

4. Genetic / Molecular Information

4.1 Causal Gene

UniProt O15273 FUNCTION (verbatim): "Muscle assembly regulating factor. Mediates the antiparallel assembly of titin (TTN) molecules at the sarcomeric Z-disk"

UniProt subcellular location: Cytoplasm → myofibril → sarcomere. Tissue specificity: heart and skeletal muscle.

UniProt disease annotations: (1) Cardiomyopathy, familial hypertrophic, 25 (CMH25), MIM #607487; (2) Muscular dystrophy, limb-girdle, autosomal recessive 7 (LGMDR7), MIM #601954 — "Autosomal recessive myopathy with proximal/distal muscle weakness and telethonin absence; cardiac involvement in some patients."

Discovery (Valle et al. 1997, PMID:9350988) — verbatim:

"In this paper we describe a novel 19 kDa sarcomeric protein named telethonin. The cDNA sequence discloses an open reading frame of 167 amino acids that does not resemble any known protein."

"The frequency of specific cDNA clones in different libraries indicates that the telethonin transcript is amongst the most abundant in skeletal muscle."

4.2 Structural Biology of Telethonin

The defining structural insight is the palindromic titin–telethonin assembly (Zou et al. 2006, Nature, PMID:16407954) — verbatim:

"Here we show, using X-ray crystallography, how the amino terminus of the longest filament component, the giant muscle protein titin, is assembled into an antiparallel (2:1) sandwich complex by the Z-disk ligand telethonin. The pseudosymmetric structure of telethonin mediates a unique palindromic arrangement of two titin filaments, a type of molecular assembly previously found only in protein-DNA complexes."

"The model proposed may provide a molecular paradigm of how major sarcomeric filaments are crosslinked, anchored and aligned within complex cytoskeletal networks."

The complex involves the titin Z1Z2 Ig domains and roughly the N-terminal 140 residues of telethonin, joined by intermolecular β-sheet augmentation. Structural context for CMH25 alleles: T137I and R153H fall in the C-terminal region (residues 137, 153 of 167), outside the crystallized N-terminal titin-binding β-sandwich — a structural observation that sits awkwardly with the "augmented titin binding" functional claim and is worth flagging as an open question.

4.3 Post-Translational Modification / Phosphoregulation

Candasamy et al. 2014, JBC (PMID:24280220) — verbatim:

"kinase assays used in conjunction with MS and site-directed mutagenesis confirmed telethonin as a substrate for protein kinase D and Ca(2+)/calmodulin-dependent kinase II in vitro and identified Ser-157 and Ser-161 as the phosphorylation sites."

"Phosphate affinity electrophoresis and MS revealed endogenous telethonin to exist in a constitutively bis-phosphorylated form in isolated adult rat ventricular myocytes and in mouse and rat ventricular myocardium."

"Such partial replacement with S157A/S161A telethonin disrupted transverse tubule organization and prolonged the time to peak of the intracellular Ca(2+) transient and increased its variance."

"These data reveal, for the first time, that cardiac telethonin is constitutively bis-phosphorylated and suggest that such phosphorylation is critical for normal telethonin function, which may include maintenance of transverse tubule organization and intracellular Ca(2+) transients."

Note a curation discrepancy to flag: UniProt O15273 lists a phosphoserine at Ser39, whereas the functional cardiac literature centers on Ser157/Ser161. Both are real; UniProt's feature table is incomplete for the cardiac PKD/CaMKII sites. Cite Candasamy for the cardiac sites.

Mechanistic relevance to CMH25: T137I and R153H both lie in the C-terminal segment immediately flanking the Ser157/Ser161 regulatory module. A defensible (but untested and unpublished as such) hypothesis is that these substitutions perturb PKD/CaMKII phosphoregulation rather than titin binding per se. Curate as a mechanistic_hypotheses entry with status: EMERGING if included at all — it is an inference drawn in this report, not a literature claim.

4.4 Epigenetics

No CMH25-specific epigenetic data. No TCAP-locus methylation, histone-modification, or chromatin-accessibility findings are reported in cardiomyopathy. Generic HCM epigenetic literature (myocardial DNA methylation remodeling, HDAC involvement in hypertrophic signaling) is not gene-attributable to TCAP. ENCODE/Roadmap contain 17q12 regulatory annotations but nothing disease-linked.

4.5 Chromosomal Abnormalities

None reported. CMH25 is a point-variant disorder. 17q12 is a recurrent CNV locus (the 17q12 recurrent deletion/duplication syndrome, associated with HNF1B), but that CNV interval and its phenotype are unrelated to TCAP-mediated cardiomyopathy — do not conflate them. No pathogenic TCAP deletions/duplications are reported in HCM; chromosomal microarray has no role in CMH25 evaluation.

5. Environmental Information

• Environmental factors: None established. No toxicant, radiation, pollutant, or occupational exposure is implicated in CMH25. CTD contains no TCAP–cardiomyopathy chemical-gene-disease triad of clinical relevance.
• Lifestyle factors: No CMH25-specific data. HCM-generic considerations: high-intensity competitive athletics as an arrhythmic trigger (not a cause); hypertension and obesity as hypertrophy amplifiers; alcohol and dehydration as precipitants of dynamic LVOT obstruction in obstructive HCM.
• Infectious agents: Not applicable. CMH25 has no infectious etiology.
• Mechanical/hemodynamic load is the only environmental variable with any mechanistic support (see §2.6) — and only from mouse work.

6. Mechanism / Pathophysiology

6.1 Proposed Causal Chain (label explicitly as HYPOTHETICAL)

TCAP missense variant (T137I / R153H)          [MOLECULAR]
   │
   ▼
Altered telethonin Z-disc protein-binding —
"augmented" interaction with titin and calsarcin-1   [MOLECULAR]
   │
   ├─► Perturbed titin/Tcap/MLP mechanosensor output  [MOLECULAR]
   │        │
   │        ▼
   │   Dysregulated calsarcin-1 (MYOZ2)-tethered
   │   calcineurin–NFAT hypertrophic signaling        [CELLULAR]
   │
   ├─► Disrupted T-tubule organization and
   │   Ca²⁺-induced Ca²⁺ release (CICR)               [CELLULAR]
   │
   └─► Altered nuclear p53 turnover → "mechanoptosis" [CELLULAR]
    │
    ▼
   Cardiomyocyte hypertrophy + myocyte apoptosis      [CELLULAR]
    │
    ▼
   Asymmetric LV hypertrophy, myocardial fibrosis,
   diastolic dysfunction                              [TISSUE]
    │
    ▼
   HFpEF, arrhythmia, sudden cardiac death            [ORGANISM]

Every arrow downstream of the first node is imported from telethonin biology in general (KO mice, in vitro, iPSC) rather than demonstrated for the CMH25 alleles. In dismech terms this is exactly the situation HUMAN_MODEL_MISMATCH was designed for.

6.2 The Z-Disc Mechanosensor Complex (upstream node)

Knöll et al. 2002, Cell (PMID:12507422) — verbatim:

"Muscle cells respond to mechanical stretch stimuli by triggering downstream signals for myocyte growth and survival. The molecular components of the muscle stretch sensor are unknown, and their role in muscle disease is unclear."

"MLP interacts with and colocalizes with telethonin (T-cap), a titin interacting protein. Further, a human MLP mutation (W4R) associated with dilated cardiomyopathy (DCM) results in a marked defect in T-cap interaction/localization."

"We propose that a Z disc MLP/T-cap complex is a key component of the in vivo cardiomyocyte stretch sensor machinery, and that defects in the complex can lead to human DCM and associated heart failure."

The Hayashi framing (verbatim from PMID:15582318): "The Z-disc plays a role in establishing the mechanical coupling of sarcomeric contraction and stretching, with the titin/Tcap/MLP complex serving as a mechanical stretch sensor. Tcap interacts with the calsarcin, which tethers the calcineurin to the Z-disc."

Calcineurin–NFAT is therefore the named signaling route to hypertrophy in the CMH25 hypothesis — via calsarcin-1/MYOZ2 anchoring calcineurin at the Z-disc. Suggested GO term: GO:0033173 calcineurin-NFAT signaling cascade (OAK-verified).

MLP/telethonin interaction was independently confirmed by Vafiadaki et al. 2014 (PMID:24860983), cited by ClinGen as part of the experimental (non-genetic) evidence: "In differentiated striated muscles, MLP-b localizes to the sarcomeres and binds directly to Z-disc components, including α-actinin, T-cap and MLP."

6.3 T-Tubule Structure and Excitation–Contraction Coupling (downstream node)

Ibrahim et al. 2013, Hum Mol Genet (PMID:23100327) — verbatim:

"Telethonin (Tcap) is a stretch-sensitive Z-disc protein that binds to proteins in the t-tubule membrane."

"In cardiomyocytes from 3-month-old KO (3mKO), there were isolated t-tubule defects and Ca(2+) transient dysynchrony without whole heart and cellular dysfunction. Ca(2+) spark frequency more than doubled in 3mKO. At 8 months of age (8mKO), cardiomyocytes showed progressive loss of t-tubules and remodelling of the cell surface, with prolonged and dysynchronous Ca(2+) transients."

"Mechanical overload increased the Ca(2+) spark frequency in KO alone, where there was also significantly more t-tubule loss, with a greater deterioration in t-tubule regularity."

"These data suggest that Tcap is a critical, load-sensitive regulator of t-tubule structure and function."

This defines an age-dependent, load-dependent, progressive cellular phenotype — biologically attractive for a late-onset adult cardiomyopathy, but again derived from loss of function.

6.4 Mechanoptosis — Nuclear p53 Turnover

Knöll et al. 2011, Circ Res (PMID:21799151) — verbatim:

"By using a variety of different genetically altered animal models and biophysical experiments we show that contrary to previous views, telethonin is not an indispensable component of the titin-anchoring system, nor is deletion of the gene or cardiac specific overexpression associated with a spontaneous cardiac phenotype. Rather, additional titin-anchorage sites, such as actin-titin cross-links via α-actinin, are sufficient to maintain Z-disk stability despite the loss of telethonin."

"We demonstrate that a main novel function of telethonin is to modulate the turnover of the proapoptotic tumor suppressor p53 after biomechanical stress in the nuclear compartment, thus linking telethonin, a protein well known to be present at the Z-disk, directly to apoptosis ('mechanoptosis')."

"In addition, loss of telethonin mRNA and nuclear accumulation of this protein is associated with human heart failure, an effect that may contribute to enhanced rates of apoptosis found in these hearts."

This paper is doubly important for curation: it supplies the apoptosis mechanism and it explicitly refutes the earlier structural dogma — telethonin is dispensable for titin anchoring, because α-actinin provides redundancy. That redundancy is itself an argument for why heterozygous TCAP missense variants may be phenotypically tolerated, and thus part of why the gene–disease relationship is disputed.

6.5 Human Cellular Model — iPSC-Cardiomyocytes

Handoh et al. 2025, Juntendo Medical Journal 71(4), DOI 10.14789/ejmj.JMJ24-0025-OA (PMC12441175; no PMID assigned — cite by DOI/PMCID): CRISPR-Cas9 TCAP knockdown in human iPSC-derived cardiomyocytes produced significantly decreased contraction velocity, relaxation velocity, and contraction–relaxation duration, plus aberrant Ca²⁺ waves and triggered activity. The authors interpret the result as DCM-like, not HCM-like — another datapoint arguing that TCAP loss of function maps to dilated, not hypertrophic, physiology.

6.6 Protein Dysfunction Summary

6.7 Metabolic, Immune, and Tissue-Damage Mechanisms

• Metabolic: No TCAP-specific metabolic defect. HCM-generic energetic-deficiency models (impaired myocardial energetics, reduced PCr/ATP) apply at the parent level and are the rationale for myosin inhibition (mavacamten "restores myocardial energetics").
• Immune: No immune involvement. CMH25 is neither autoimmune nor inflammatory.
• Tissue damage: Cardiomyocyte apoptosis (GO:0006915, PMID:21799151); interstitial and replacement myocardial fibrosis (HP:0001685; histologically confirmed in the RP-HCM case, PMID:40330574); microvascular ischemia and myocyte disarray are HCM-generic.

6.8 Molecular Profiling

• Transcriptomics: No CMH25-specific dataset. TCAP expression is heart- and skeletal-muscle-restricted and among the most abundant muscle transcripts (PMID:9350988); quantified in GTEx, Fagerberg et al. 2014 (PMID:24309898) and Uhlén et al. 2015 (PMID:25613900) — the latter two cited by ClinGen as the expression evidence in the (insufficient) TCAP–HCM case. Loss of telethonin mRNA is reported in human heart failure (PMID:21799151).
• Proteomics: Telethonin phospho-proteomics in cardiac myocytes (PMID:24280220). No CMH25 patient proteomic study.
• Metabolomics / lipidomics: None.
• Single-cell / spatial transcriptomics: No TCAP-cardiomyopathy-specific study. The Human Cell Atlas adult heart atlases contain telethonin expression by cardiomyocyte subtype, but no disease contrast.
• Functional genomics screens: No CRISPR/RNAi screen implicates TCAP in a cardiomyopathy-relevant phenotype; DepMap is uninformative (muscle-restricted, non-essential in cancer lines).

6.9 Suggested Ontology Terms (all OAK-verified in this session)

Biological processes (GO): | GO ID | Label | Role in the chain | |---|---|---| | GO:0055003 | cardiac myofibril assembly | Telethonin's core assembly function | | GO:0071260 | cellular response to mechanical stimulus | Mechanosensing node | | GO:0060048 | cardiac muscle contraction | Contractile output | | GO:0006936 | muscle contraction | — | | GO:0033173 | calcineurin-NFAT signaling cascade | Calsarcin-1/calcineurin hypertrophy route | | GO:0072331 | signal transduction by p53 class mediator | "Mechanoptosis" arm | | GO:0006915 | apoptotic process | Cardiomyocyte loss | | GO:0070296 | sarcoplasmic reticulum calcium ion transport | Ca²⁺ handling defect | | GO:0055010 | ventricular cardiac muscle tissue morphogenesis | Remodeling |

Cellular components (GO): GO:0030018 Z disc · GO:0030315 T-tubule · GO:0030017 sarcomere · GO:0005634 nucleus (p53 arm) · GO:0031430 M band (context)

Cell types (CL): CL:0000746 cardiac muscle cell · CL:0002131 regular ventricular cardiac myocyte · CL:0008002 skeletal muscle fiber (LGMD arm)

7. Anatomical Structures Affected

7.1 Organ Level

• Primary: heart (UBERON:0000948) — specifically the left ventricle (UBERON:0002084) and interventricular septum (UBERON:0002094), the classic site of asymmetric hypertrophy.
• Secondary: left atrium (dilation from chronic diastolic dysfunction; biatrial enlargement documented in the RP-HCM case); pulmonary circulation (post-capillary pulmonary hypertension); systemic circulation (thromboembolism secondary to atrial fibrillation).
• Body system: cardiovascular. (Skeletal muscle involvement belongs to LGMD R7, not CMH25.)

7.2 Tissue and Cell Level

• Tissue: myocardium (UBERON:0002349); cardiac muscle tissue (UBERON:0001133); cardiac interstitium (fibrotic remodeling).
• Cells: cardiac muscle cell (CL:0000746); regular ventricular cardiac myocyte (CL:0002131). Cardiac fibroblasts participate in the fibrotic response secondarily.
• Skeletal muscle organ (UBERON:0001630) and skeletal muscle fiber (CL:0008002) — for the TCAP gene-level entry, not CMH25.

7.3 Subcellular Level

• Sarcomeric Z-disc (GO:0030018) — the primary lesion site.
• Transverse tubule (GO:0030315) — secondary structural target (PMID:23100327, PMID:24280220).
• Sarcomere (GO:0030017), nucleus (GO:0005634, p53/mechanoptosis compartment), sarcoplasmic reticulum (Ca²⁺ handling).

7.4 Localization and Lateralization

Bilateral in the sense of biventricular myocardial expression, but the phenotype is characteristically asymmetric — septal-predominant, left-ventricular-predominant hypertrophy (HP:0001670 Asymmetric septal hypertrophy). The Toste family showed "moderate asymmetric left ventricular hypertrophy"; the Hu case showed non-obstructive HCM with normal chamber size. Right ventricular involvement is uncommon and not reported in CMH25.

8. Temporal Development

8.1 Onset

• HPO-annotated onset: HP:0003581 Adult onset (2/2 probands).
• Toste family: explicitly "late-onset HCM" (PMID:32565061).
• Hu case: symptomatic at 47 years (PMID:40330574).
• Onset pattern: insidious/chronic. No congenital or pediatric CMH25 presentation is reported. (Contrast: LGMD R7 typically presents in the 2nd–3rd decade; mean onset 16 ± 1.41 y in a Chinese series, PMID:32005491.)

8.2 Progression

Both trajectories reported in the literature, from an evidence base of essentially three families:

• Stages: HCM-generic — (i) subclinical/genotype-positive-phenotype-negative; (ii) established LVH with preserved systolic function; (iii) HFpEF ± AF ± obstruction; (iv) end-stage "burnt-out" HCM with systolic dysfunction and LV dilation (HP:0001644).
• Rate: variable; typically slow over decades.
• Course pattern: progressive, punctuated by episodic events (syncope, arrhythmia).
• Duration: chronic, lifelong.

8.3 Patterns

• Remission: none spontaneous. Symptomatic and hemodynamic improvement is treatment-induced (myectomy/ablation/mavacamten for obstruction). Structural hypertrophy is not reversed.
• Critical periods: adolescence through early adulthood for phenotype emergence in sarcomeric HCM generally — but CMH25's annotated onset is adult, so serial imaging surveillance of at-risk relatives extends well into adult life. The 2024 AHA/ACC guideline (PMID:38718139) frames the surveillance schedule.

9. Inheritance and Population

9.1 Epidemiology

No prevalence or incidence estimate exists for CMH25 specifically. Figures below are for HCM as a whole and for TCAP's share of HCM cohorts.

• HCM overall prevalence: ~1 in 500 clinically diagnosed; revised upward to approximately 1 in 200 when subclinical/genotype-positive individuals are counted (Semsarian et al. 2015, JACC 65:1249–1254, PMID:25814232).
• TCAP variant yield in HCM cohorts:

Bos 2006 verbatim: "Overall, 16 patients (4.1%) harbored a Z-disc mutation: 12 had a MLP mutation and 4 patients a TCAP mutation. No TTN mutations were detected." and "Approximately 4.1% of unrelated patients had HCM-associated MLP or TCAP mutations."

Alaei 2023 verbatim conclusion: "These findings suggest that the TCAP gene pathogenic mutations might not be a common cause of cardiomyopathies among Iranian patients."

Because the underlying gene–disease relationship is disputed, the defensible prevalence statement for a dismech Prevalence record is prevalence_class: UNKNOWN with measure_type: UNKNOWN, and a notes field capturing the ~0.6–1% cohort variant-detection rate with the caveat that these are variant-detection rates, not attributable-cause rates.

9.2 Inheritance

• Pattern: Autosomal dominant (HP:0000006; OMIM; ClinGen MOI field records AD). Contrast with autosomal recessive for LGMD R7 — the same gene, two inheritance modes, a point of real clinical confusion.
• Penetrance: Unknown and unmeasurable from the available pedigrees. Toste 2020 reported "a co-segregation pattern was detected" in a two-affected-member family — the strongest segregation evidence available for any TCAP-HCM allele, and it is very weak (a 2-informative-meiosis family cannot generate meaningful LOD). Given adult onset, penetrance would at minimum be age-dependent.
• Expressivity: Apparently variable — indolent HFpEF (Toste) versus restrictive/transplant-bound (Hu). With n≈8 probands total, "variable expressivity" is more accurately described as "unconstrained by data."
• Genetic anticipation: Not applicable (no repeat expansion).
• Germline mosaicism: Not reported.
• Founder effects: None described for TCAP-HCM alleles. (A founder effect is relevant to LGMD R7 in the Brazilian population, where the disorder was originally mapped — PMID:10655062 — and where most reported cases have historically come from; PMID:34982307 notes reported cases "mostly include patients from Brazil.")
• Consanguinity: Relevant to LGMD R7 (recessive), not to CMH25 (dominant).
• Carrier frequency: Not meaningful for a dominant condition. For LGMD R7, TCAP LOF allele frequency in gnomAD is on the order of 10⁻⁵ (e.g., Q53X ≈ 1×10⁻⁵).

9.3 Population Demographics

• Affected populations: Reported probands are Japanese (Hayashi 2004), North American/predominantly white (Bos 2006), Danish (Andersen 2009), Portuguese (Toste 2020), and Chinese (Hu 2025). No population enrichment is established. The gnomAD distribution of R87Q is essentially pan-ancestry at ~10⁻⁵ (nfe 1.44×10⁻⁵, sas 1.16×10⁻⁵, eas 2.52×10⁻⁵, afr 2.99×10⁻⁵) — i.e., no ancestral clustering.
• Geographic distribution: Global, sporadic case reports; no endemic focus.
• Sex ratio: No CMH25-specific ratio. HCM cohorts show male predominance (Bos 2006: 215/389 = 55% male). The single RP-HCM case was male; the Toste family included both sexes.
• Age distribution: Adult, with reported presentation in the 5th decade.

10. Diagnostics

10.1 Clinical Tests

There is no CMH25-specific biomarker. No FDA/BEST-listed biomarker exists for TCAP genotype.

10.2 Genetic Testing

Recommended approach — and the crucial caveat:

TCAP appears on many legacy multigene HCM panels. Because ClinGen classifies TCAP–HCM as DISPUTED, TCAP should not be included on a contemporary diagnostic HCM panel, and TCAP variants should not be reported as diagnostic findings. Ingles et al. 2019 (PMID:30681346) put this bluntly:

"Recent trends to increase gene panel sizes often mean variants in genes with questionable association are reported to patients. Classification of HCM genes and variants is critical, as misclassification can lead to genetic misdiagnosis."

"Of 4191 HCM variants in ClinVar, 31% were in genes with limited or no evidence of disease association."

"The majority of genes previously reported as causative of HCM and commonly included in diagnostic tests have limited or no evidence of disease association. Systematically curated HCM genes are essential to guide appropriate reporting of variants and ensure the best possible outcomes for HCM families."

NCIT term: NCIT:C15709 Genetic Testing (OAK-verified).

Omics diagnostics (RNA-seq, proteomics, metabolomics, epigenomics, liquid biopsy): none have an established or investigational diagnostic role in CMH25. Skeletal-muscle telethonin immunohistochemistry/Western blot is diagnostic for LGMD R7 (absent protein — PMID:34982307, PMID:12379311) but has no cardiac counterpart.

10.3 Clinical Criteria

Diagnosis follows the generic HCM criteria — LV wall thickness ≥15 mm (or ≥13 mm with family history / positive genotype) not explained by abnormal loading conditions — per the 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR HCM Guideline (PMID:38718139) and the 2023 ESC cardiomyopathy guideline. There are no CMH25-specific diagnostic criteria. A "CMH25 diagnosis" is, operationally, HCM-by-standard-criteria plus a TCAP variant — and per ClinGen, the second half of that conjunction does not currently license a causal claim.

10.4 Differential Diagnosis

The 2024 AHA/ACC guideline explicitly directs that "HCM genetic testing should include genes for HCM phenocopies."

10.5 Screening

• Newborn screening: not applicable.
• Carrier screening: not applicable (dominant); relevant only for LGMD R7 in consanguineous families.
• Cascade screening: per guideline, "Cascade genetic testing should be extended to first-degree relatives only if a pathogenic variant is identified in the proband." Because essentially all TCAP-HCM variants are VUS or disputed, cascade genetic testing on a TCAP variant is not indicated. First-degree relatives should instead enter clinical/imaging surveillance (ECG + echocardiography at guideline intervals). This is arguably the single most consequential practical statement in this report.

11. Outcome / Prognosis

11.1 Survival and Mortality

No CMH25-specific survival, life-expectancy, or mortality data exist. No registry, no cohort, no Kaplan–Meier curve. Sample sizes (≤8 probands globally) preclude any survival estimate.

HCM-generic context: contemporary HCM cohorts in expert centers report annual mortality approaching that of the general population (~0.5%/yr), with sudden cardiac death, heart failure, and AF-related stroke as the three modes of disease-related death.

11.2 Morbidity and Function

• Heart failure with preserved ejection fraction (both reported CMH25 families).
• Atrial fibrillation with associated thromboembolic risk (Toste family).
• Exertional limitation.
• No CMH25-specific ICF disability data, EQ-5D, SF-36, PROMIS, or HCMSQ measurements exist.

11.3 Disease Course / Complications

Reported CMH25 complications: atrial fibrillation, HFpEF, severe diastolic dysfunction with biatrial enlargement, myocardial fibrosis, progression to transplant candidacy. HCM-generic complications additionally include LVOT obstruction, ventricular arrhythmia and SCD, infective endocarditis (rare, with obstruction/SAM), and end-stage systolic evolution.

Recovery potential: none — the structural phenotype does not remit. Symptomatic and hemodynamic recovery is achievable with obstruction-directed therapy; transplantation is curative of the cardiac phenotype only.

11.4 Prognostic Factors and Biomarkers

No CMH25-specific prognostic factor has been validated. The two published families illustrate the extremes and suggest, at most, hypothesis-generating candidates: - Restrictive physiology / severe diastolic dysfunction — associated with the rapidly deteriorating course (PMID:40330574). - Truncating vs missense allele class — the frameshift case was the aggressive one; the missense families were indolent. n=1 vs n=2; this is a hypothesis, not a genotype–phenotype correlation. - HCM-generic SCD-risk factors (family history of SCD, unexplained syncope, massive LVH ≥30 mm, NSVT, abnormal BP response to exercise, apical aneurysm, extensive LGE, low LVEF) and the HCM Risk-SCD calculator apply by parent-class inheritance. - Toste 2020 explicitly characterized their family as "low risk of sudden cardiac death."

12. Treatment

There is no CMH25-specific, genotype-directed therapy. Management is entirely that of hypertrophic cardiomyopathy generally, per the 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR guideline (PMID:38718139). Nothing about a TCAP genotype currently alters management.

12.1 Pharmacotherapy

Mavacamten pivotal evidence — EXPLORER-HCM (Olivotto et al., Lancet 2020;396:759–769, PMID:32871100): randomized, double-blind, placebo-controlled phase 3 in 251 patients with symptomatic obstructive HCM over 30 weeks. Primary endpoint met by 45/123 (37%) on mavacamten vs 22/128 (17%) on placebo; difference +19.4% (95% CI 8.7–30.1; p=0.0005). Abstract background (verbatim): "Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy"; interpretation (verbatim): "Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status." Mavacamten requires REMS-governed echocardiographic monitoring for LVEF reduction and is contraindicated in significant systolic dysfunction; CYP2C19 poor-metabolizer status affects exposure (the one genuinely pharmacogenomic consideration in HCM care — PharmGKB/CPIC-relevant, and unrelated to TCAP genotype).

Pharmacogenomics specific to CMH25: none. No TCAP variant is known to influence drug metabolism, efficacy, or toxicity.

12.2 Advanced Therapeutics

• Gene therapy: No TCAP-directed program. AAV9-MYBPC3 gene replacement is in early clinical development for MYBPC3-HCM (a template that could in principle extend to other genes, but nothing exists for TCAP).
• Gene editing: Preclinical base/prime editing work in sarcomeric HCM; nothing for TCAP.
• RNA-based therapies (ASO, siRNA, mRNA): None for TCAP. No conformance to the antisense_oligonucleotide_therapy module.
• Cell therapy, immunotherapy: Not applicable.
• Targeted therapy: Mavacamten and the next-generation myosin inhibitor aficamten are "targeted" at the sarcomere but are genotype-agnostic — they target the pathophysiology, not the gene.

12.3 Surgical and Interventional

• Septal myectomy (extended Morrow procedure) — gold standard for drug-refractory obstructive HCM in experienced centers. NCIT:C51591 Myectomy (OAK-verified); therapeutic_modality: SURGERY.
• Alcohol septal ablation — percutaneous alternative in selected anatomy/comorbidity; observational data suggest similar safety and efficacy to myectomy.
• ICD implantation — for primary or secondary SCD prevention per risk stratification. NCIT:C80435 Implantable Cardioverter-Defibrillator Placement; device NCIT:C93238 Implantable Cardioverter-Defibrillator (both OAK-verified); therapeutic_modality: DEVICE.
• Heart transplantation — for end-stage disease. NCIT:C15246 Heart Transplantation (OAK-verified); therapeutic_modality: SURGERY. This is the documented endpoint in the one reported RP-HCM CMH25 case (PMID:40330574).
• AF ablation / left atrial appendage occlusion — as indicated.

12.4 Supportive, Rehabilitative, Counseling

• Supportive care: NCIT:C15747 Supportive Care (OAK-verified) — symptom management, volume management, HF care.
• Genetic counseling: NCIT:C15240 Genetic Counseling (OAK-verified); therapeutic_modality: BEHAVIORAL. Central to CMH25 management, and unusually delicate: the counselor's job here is largely to explain why a TCAP variant does not establish a diagnosis, why cascade testing on it is not indicated, and why relatives need clinical surveillance regardless. The guideline recommends "evaluation by a genetic counselor... to discuss risk and benefits of genetic testing."
• Exercise counseling: contemporary guidelines permit mild-to-moderate recreational exercise; competitive high-intensity athletics require shared decision-making.
• Cardiac rehabilitation: increasingly supported in non-obstructive HCM.

12.5 Experimental Treatments

No trial has ever enrolled by TCAP genotype. Relevant HCM-wide programs: aficamten (SEQUOIA-HCM and successors), ninerafaxstat (cardiac mitotrope, non-obstructive HCM), MYBPC3 gene therapy. A curator should not attach any NCT identifier to CMH25 — none is CMH25-specific, and asserting one would misrepresent the evidence.

12.6 Treatment Outcomes and Strategy

• Response rates and adverse events: available only at the HCM parent level (see EXPLORER-HCM numbers above; mavacamten's key adverse event is asymptomatic LVEF reduction).
• Treatment algorithm: obstructive symptomatic HCM → β-blocker → verapamil (if intolerant) → add disopyramide or mavacamten → septal reduction therapy if refractory. Non-obstructive HCM → symptom-directed HF therapy; consider transplant evaluation for advanced disease. Parallel track: SCD risk stratification → ICD decision. Parallel track: family screening.
• Personalized medicine: genotype currently informs family screening, not drug selection, in HCM. For TCAP specifically, genotype informs neither.

13. Prevention

13.1 Primary Prevention

Not achievable — CMH25 is a germline monogenic (putatively) condition. The only primary-prevention options operate at the reproductive level: preimplantation genetic testing (PGT-M) and prenatal diagnosis. Both are inappropriate for a disputed gene–disease relationship with VUS-level alleles, and should not be offered on the basis of a TCAP variant. This is a clinically important negative recommendation.

13.2 Secondary Prevention

• Family clinical surveillance is the mainstay: ECG + echocardiography in first-degree relatives at guideline-specified intervals, continued into adult life given CMH25's adult onset. This applies irrespective of TCAP genotype, precisely because the genotype is uninformative.
• Early detection of AF (ambulatory/wearable monitoring) to enable timely anticoagulation.
• Serial SCD risk restratification.

13.3 Tertiary Prevention

• ICD for SCD prevention in risk-stratified patients.
• Anticoagulation for AF-related stroke prevention.
• Heart-failure guideline-directed therapy and timely transplant referral.
• Endocarditis awareness in obstructive disease with mitral involvement.

13.4 Immunization

Not applicable as disease prevention. Routine influenza/COVID-19/pneumococcal vaccination is standard supportive care in chronic heart disease.

13.5 Screening, Risk Stratification, Counseling

• Population screening: none.
• Genetic screening: cascade testing not indicated on a TCAP VUS (see §10.5).
• Risk stratification: HCM Risk-SCD and guideline risk markers apply generically.
• Counseling: should explicitly convey the DISPUTED ClinGen classification, the VUS status of essentially all TCAP-HCM alleles, and that surveillance — not genotype — governs family management.

13.6 Public Health / Environmental Interventions / Prophylaxis

No public-health or environmental intervention is relevant. No prophylactic medication prevents phenotype development in genotype-positive individuals — a long-standing unmet need in HCM generally (prior trials of diltiazem and losartan in preclinical sarcomeric HCM were not practice-changing).

14. Other Species / Natural Disease

14.1 Taxonomy and Orthologs

14.2 Naturally Occurring Disease in Other Species

The single relevant veterinary study is a negative one, and is worth curating as such:

Philipp U, Vollmar A, Distl O. "Evaluation of the titin-cap gene (TCAP) as candidate for dilated cardiomyopathy in Irish wolfhounds." Animal Biotechnology 2008;19:231–236 (PMID:18855248). Verbatim opening: "Dilated cardiomyopathy (DCM) is a myocardial disorder characterized by left ventricular dilatation and impaired systolic contraction. Irish wolfhounds (IW) and other large breed dogs are most commonly disposed to DCM." The study evaluated TCAP as a positional/functional candidate for canine DCM; TCAP was not established as the cause.

• Breed (VBO): Irish Wolfhound — a VBO identifier exists for the breed but was not verified in this session; look it up before asserting.
• OMIA: No OMIA entry for telethonin-related cardiomyopathy was identified. Unverified — check OMIA directly before asserting absence in a KB entry.
• Naturally occurring HCM is common in domestic cats (Felis catus, NCBITaxon:9685), where MYBPC3 variants in Maine Coon and Ragdoll breeds are the established genetic causes — TCAP is not implicated in feline HCM.

14.3 Comparative Biology

• Evolutionary conservation: Telethonin is a vertebrate striated-muscle-specific protein, highly conserved across mammals; the Toste variant p.C57W was selected in part because of "high conservation across species" (PMID:32565061).
• Comparative pathology divergence — important: mouse Tcap knockout produces no spontaneous cardiac phenotype (PMID:21799151), whereas human biallelic TCAP loss produces skeletal muscular dystrophy (LGMD R7) with only inconsistent cardiac involvement, and human heterozygous missense variants are claimed to produce hypertrophic cardiomyopathy. These three do not line up. The divergence is itself evidence for the disputed status of CMH25 and should be curated as a HUMAN_MODEL_MISMATCH discussion.

14.4 Transmission

Not applicable — no zoonotic potential, no cross-species transmission. CMH25 is a germline genetic condition.

15. Model Organisms

15.1 Available Models

15.2 Genetic Model Types Available

Constitutive knockout and cardiac-specific transgenic overexpression are documented. No knock-in mouse carrying the human CMH25 alleles (T137I, R153H, C57W, or p.Glu12fs) has been reported. No conditional/inducible or humanized TCAP line is described in the literature reviewed. IMPC/KOMP/IMSR should be queried directly for current allele availability (not verified in this session).

15.3 Phenotype Recapitulation and Limitations

This is the crux, and it should be stated plainly in any KB entry:

Limitations to record explicitly: 1. Allele-class mismatch. Every animal model is a loss-of-function model; the human CMH25 hypothesis is gain of interaction in the heterozygous state. The models therefore cannot test the disease hypothesis — a textbook kind: HUMAN_MODEL_MISMATCH situation for dismech, not a generic KNOWLEDGE_GAP. 2. Direction-of-phenotype mismatch. Where TCAP perturbation does produce a cardiac phenotype (iPSC-CM knockdown; Tcap KO under stress), the phenotype is dilated/hypocontractile, not hypertrophic. 3. Structural redundancy. Knöll 2011 showed α-actinin-mediated actin–titin cross-links maintain Z-disc stability without telethonin — a built-in buffer that argues against strong dominant effects from a single missense allele. 4. No model addresses the WPW/pre-excitation component of the human annotation.

15.4 Research Applications

Existing models are well suited to studying: Z-disc mechanosensing and load transduction; t-tubule biogenesis, maintenance, and CICR; stretch-induced apoptosis and nuclear p53 handling; telethonin phosphoregulation by PKD/CaMKII; and sarcomere assembly (Xenopus). They are not suited to validating CMH25 causality.

The single highest-value experiment for resolving the CMH25 dispute would be a heterozygous knock-in mouse (or isogenic iPSC-CM line) carrying human T137I or R153H, characterized for hypertrophy at baseline and under pressure overload, with quantitative titin/calsarcin-1 binding measured in situ. Curate this as a proposed_experiments entry attached to the knowledge-gap discussion.

15.5 Model Resources

MGI (MGI:1330233), IMPC, IMSR, KOMP/EuMMCR (allele availability not verified in this session), ZFIN, Xenbase, Alliance of Genome Resources, Cellosaurus (for iPSC lines).

Recommended dismech Curation Decisions

1. Do not curate CMH25 as an established causal mechanism. Model the pathophysiology chain under mechanistic_hypotheses with status: EMERGING, and have the causal edges opt in via hypothesis_groups.
2. Add a discussions entry with kind: HUMAN_MODEL_MISMATCH (not KNOWLEDGE_GAP) attached to the "Telethonin Z-Disc Dysfunction" node: evidence exists abundantly in mouse KO, rat myocytes, and human iPSC-CM, but every model tests loss of function while the human hypothesis is heterozygous gain-of-interaction — and the models' cardiac phenotype, when present, is dilated rather than hypertrophic. Include proposed_experiments (heterozygous T137I/R153H knock-in).
3. Cite the ClinGen DISPUTED assertion as first-class evidence using the cache file already in the worktree: reference: CGGV:assertion_c35abc20-c04c-49ec-af02-1bd270b0b50b-2022-09-14T160000.000Z, supports: REFUTE, evidence_source: OTHER, with a quotable row such as "TCAP | HGNC:11610 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Disputed | SOP9 | Hereditary Cardiovascular Disease Gene Curation Expert Panel | 2022-09-14T16:00:00.000Z".
4. Omit frequency: on all phenotypes — the HPO denominators are 2/2 and 1/2 from a single paper. Put "2/2 probands, PMID:15582318" in notes.
5. Genetic block: consider relationship_type: SUSCEPTIBILITY or MODIFIER rather than a plain causal gene assertion, and record the two documented co-occurring variants (pathogenic TNNI3, MYBPC3 VUS) as the reason.
6. Prevalence: measure_type: UNKNOWN, prevalence_class: UNKNOWN, with the 0.58%/1.03%/0% cohort detection rates in notes — these are variant-detection rates, not attributable-cause rates.
7. Do not attach clinical trials. No NCT is CMH25-specific.
8. Consider conforms_to: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling for the downstream tissue-level node; the electrical module (cardiac_ion_channel_repolarization) does not apply — CMH25 is structural, and the WPW annotation is a single-proband observation, not a channelopathy.
9. Every PMID cited here must still be run through just fetch-reference and just validate-references before committing. Abstract text in this report was retrieved verbatim from the Europe PMC REST API; the OMIM entries (607487, 604488) returned HTTP 403 and were not read directly — OMIM-attributed content here comes via MONDO, MedGen, HPO, UniProt, and search summaries, so do not quote OMIM text as a verified snippet without fetching it.

Sources

• Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy — PubMed (PMID:15582318)
• Genotype-phenotype relationships involving HCM-associated mutations in titin, MLP, and telethonin (PMID:16352453)
• Diagnostic yield... sarcomere encoding genes in Danish HCM patients (PMID:19035361)
• Identification of a novel titin-cap/telethonin mutation in a Portuguese family with HCM (PMID:32565061)
• The challenge of assessing variant pathogenicity in candidate Z-disc genes: the example of TCAP in HCM (PMID:32654878)
• Mutations in the TCAP gene may lead to restrictive phenotype HCM with poor prognosis (PMID:40330574)
• TCAP gene is not a common cause of cardiomyopathy in Iranian patients (PMID:37752589)
• Telethonin deficiency is associated with maladaptation to biomechanical stress in the mammalian heart (PMID:21799151)
• The cardiac mechanical stretch sensor machinery involves a Z disc complex... (PMID:12507422)
• Telethonin, a novel sarcomeric protein of heart and skeletal muscle (PMID:9350988)
• Palindromic assembly of the giant muscle protein titin in the sarcomeric Z-disk (PMID:16407954)
• Phosphoregulation of the titin-cap protein telethonin in cardiac myocytes (PMID:24280220)
• A critical role for Telethonin in regulating t-tubule structure and function in the mammalian heart (PMID:23100327)
• Muscle lim protein isoform negatively regulates striated muscle actin dynamics and differentiation (PMID:24860983)
• Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding telethonin (PMID:10655062)
• Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes (PMID:30681346)
• Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples (PMID:27532257)
• New perspectives on the prevalence of hypertrophic cardiomyopathy (PMID:25814232)
• 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR HCM Guideline (PMID:38718139)
• Mavacamten for treatment of symptomatic obstructive HCM (EXPLORER-HCM) (PMID:32871100)
• Structural and signaling proteins in the Z-disk and their role in cardiomyopathies (PMID:36935760)
• Distinct roles for telethonin N- versus C-terminus in sarcomere assembly and maintenance (PMID:20235223)
• Knockdown of Telethonin Reduces Contractions and Provokes Aberrant Ca2+-waves in Human iPS Cell-induced Cardiomyocytes (PMC12441175)
• Two distinct phenotypes and a novel mutation in LGMD R7 telethonin-related patients, Thailand (PMID:40195250)
• Southeast Asian cohort of LGMD2G/LGMD-R7-telethonin-related (PMID:36463458)
• LGMD R7 telethonin-related patients from a Chinese neuromuscular center (PMID:34982307)
• Clinical and genetic characterization of LGMD R7 from three unrelated Chinese families (PMID:32005491)
• Conserved expression of truncated telethonin in a patient with LGMD 2G (PMID:25724973)
• Telethonin protein expression in neuromuscular disorders (PMID:12379311)
• Evaluation of the titin-cap gene (TCAP) as candidate for DCM in Irish wolfhounds (PMID:18855248)
• OMIM #607487 — CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 25 (HTTP 403 on direct fetch)
• OMIM *604488 — TITIN-CAP; TCAP (HTTP 403 on direct fetch)
• MedGen — Hypertrophic cardiomyopathy 25 (C4225408)
• ClinVar — TCAP variants (NCBI E-utilities esummary)
• HPO annotations for OMIM:607487 (JAX ontology API)
• UniProt O15273 — Telethonin
• Ensembl REST — rs121434298 population frequencies
• MGI — Tcap (MGI:1330233)
• Orphanet — Familial isolated hypertrophic cardiomyopathy (ORPHA:155)
• ClinGen Gene-Disease Validity — TCAP / hypertrophic cardiomyopathy (Disputed)