Hypertrophic Cardiomyopathy 7

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Classifications

Harrison's Part

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Inheritance

1

Autosomal Dominant HP:0000006

CMH7 is transmitted as an autosomal dominant trait: affected individuals carry a single heterozygous TNNI3 variant, with incomplete penetrance and variable expressivity within families. De novo occurrence is documented (the Lys206Gln allele in the original series).

Autosomal dominant inheritance

Show evidence (2 references)

CGGV:assertion_4a7e6901-d478-44c4-bd03-2c344029d4bb-2017-09-05T160000.000Z SUPPORT Other

The ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel records the TNNI3-hypertrophic cardiomyopathy relationship with autosomal dominant mode of inheritance and Definitive clinical validity.

PMID:9241277 SUPPORT Human Clinical

"Hypertrophic cardiomyopathy (HCM), the most common cause of sudden death in the young, is an autosomal dominant disease characterized by ventricular hypertrophy accompanied by myofibrillar disarrays."

The paper that established cardiac troponin I as an HCM gene states the autosomal dominant inheritance of the disease it is reporting.

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Mechanistic Hypotheses

2

Loss of troponin I inhibition and myofilament calcium hypersensitization

tnni3_myofilament_calcium_hypersensitization CANONICAL

Evidence balance 2 support

The canonical model holds that CMH7 variants degrade the inhibitory function of cardiac troponin I. Mutant troponin I fails to hold actin-tropomyosin in the blocked state during diastole and its interactions with troponin C and troponin T are altered, so the thin filament activates at lower calcium concentrations. The resulting myofilament calcium hypersensitivity, together with blunted length-dependent activation and impaired protein kinase A responsiveness, produces hypercontractility with impaired relaxation, which is the proximate stimulus for hypertrophic remodeling.

Pathograph links

Cardiac Troponin I Inhibitory Dysfunction -> Myofilament Calcium Hypersensitization and Impaired Relaxation

Show evidence (2 references)

PMID:23508784 SUPPORT Human Clinical

"High-myofilament Ca(2+) sensitivity is a common characteristic of human HCM and partly reflects hypophosphorylation of PKA targets compared with donors."

Establishes high myofilament calcium sensitivity as a shared feature of human hypertrophic cardiomyopathy myocardium, including samples carrying TNNI3 mutations, which is the core of this hypothesis group.

PMID:26553696 SUPPORT In Vitro

"The K206I mutation impairs the ability of the troponin I to inhibit ATPase activity in the absence of calcium-bound human cardiac troponin C."

Directly demonstrates loss of the troponin I inhibitory function for an HCM-associated TNNI3 variant, the molecular premise of this hypothesis.

Secondary hypertrophic signaling and mitochondrial-metabolic stress

tnni3_secondary_metabolic_signaling_stress EMERGING

Evidence balance 2 support

An additional arm proposes that TNNI3 variants engage hypertrophic signal transduction and metabolic derangement beyond the mechanical defect — activation of the ERK cascade with induction of the fetal gene programme (ANP, BNP, MYH7), mitochondrial dysfunction, and increased autophagy and apoptosis. The supporting data come from a single-variant cell-line study and from metabolomic profiling of small patient cohorts, so whether this arm is variant-specific, secondary to the mechanical lesion, or a generic hypertrophy response is unresolved.

Pathograph links

Cardiac Troponin I Inhibitory Dysfunction -> Hypertrophic Signaling and Metabolic Stress

Show evidence (2 references)

PMID:39426416 SUPPORT In Vitro

"This mutation led to the upregulation of hypertrophy-associated genes ANP, BNP, and MYH7, increased cardiomyocyte size, and activation of the ERK signaling pathway."

Provides the primary in vitro basis for the signaling arm, in AC16 human cardiomyocytes transfected with a TNNI3 mutant plasmid.

PMID:39426416 SUPPORT In Vitro

"Further investigations revealed that the TNNI3 c.235C > T mutation impaired mitochondrial function, disrupted cardiomyocyte metabolism, and increased cellular autophagy and apoptosis."

Supports the metabolic/proteostatic arm but for one variant in a transfected cell line, which is why this hypothesis group is EMERGING rather than canonical.

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Discussions and Knowledge Gaps

1

TNNI3 causes hypertrophic (CMH7), restrictive (RCM1), and dilated (CMD1FF) cardiomyopathy. Should dismech keep these as separate gene-specific entries, and how should evidence be partitioned between them?

INTERPRETATION OPEN tnni3_allelic_series_hcm_rcm_dcm

Attached to

pathophysiology#Cardiac Troponin I Inhibitory Dysfunction

MONDO models the three TNNI3 cardiomyopathies as distinct entities (MONDO:0013369 hypertrophic, MONDO:0011400 restrictive, and the dilated node), and dismech follows MONDO for disease_term. The shared molecular lesion — impaired troponin I inhibition of the thin filament — is common to all three, but the direction of the myofilament perturbation and the resulting ventricular geometry differ, and the clinical management differs substantially. This entry is scoped strictly to the hypertrophic node: every evidence item was checked to be about a hypertrophic-phenotype cohort, variant, or model, and no restrictive- or dilated-phenotype literature was used. Whether a future lumped "TNNI3-related cardiomyopathy" entity would better reflect the biology is left open; if the field converges there, this entry should be revisited rather than duplicated.

Show evidence (1 reference)

PMID:39426416 SUPPORT Human Clinical

"The link between TNNI3 variants and phenotypes remains largely unexplored."

Records that TNNI3 genotype-phenotype correlation is unresolved, which is the substance of this discussion.

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Pathophysiology

7

Cardiac Troponin I Inhibitory Dysfunction

TNNI3 encodes cardiac troponin I, the inhibitory subunit of the cardiac troponin complex on the thin filament. In diastole it anchors actin-tropomyosin in the blocked state; on systolic calcium binding to troponin C the inhibitory and switch peptides release actin, permitting cross-bridge cycling. CMH7-associated variants are predominantly heterozygous missense changes distributed across the N-terminal PKA-phosphorylation extension, the troponin T/troponin C binding region, the inhibitory peptide, and the C-terminal actin-binding region. They do not abolish the protein; they degrade its inhibitory capacity and its interactions with troponin C and troponin T, which is the primary lesion of this disorder. The distribution is not uniform across the gene: approximately 80% of reported pathogenic TNNI3 variants fall in exons 7 and 8, which encode the actin- and troponin-C-interacting domains - so the mutational hotspot coincides with the functional interfaces this node describes, which is why variant position carries interpretive weight in this gene.

Loss of troponin I inhibition and myofilament calcium hypersensitization Secondary hypertrophic signaling and mitochondrial-metabolic stress

Cardiomyocyte CL:0000746

TNNI3 hgnc:11947

Regulation of cardiac muscle contraction GO:0055117 ⚠ ABNORMAL Sarcomere organization GO:0045214 ⚠ ABNORMAL

troponin C binding GO:0030172 ⚠ ABNORMAL actin filament binding GO:0051015 ⚠ ABNORMAL structural constituent of muscle GO:0008307 ⚠ ABNORMAL

Myocardium UBERON:0002349

Experimental models

Reconstituted human cardiac thin filament with mutant troponin I OTHER Directly measures the loss of troponin I inhibition of actomyosin ATPase in the absence of calcium-bound troponin C.

Downstream

Myofilament Calcium Hypersensitization and Impaired Relaxation

Hypertrophic Signaling and Metabolic Stress

Show evidence (4 references)

PMID:38548731 SUPPORT Human Clinical

"Approximately 80% of reported pathological variants of TNNI3 are located in exons 7 and 8, which encode the domains that interact with myocardial actin and cardiac troponin C, which are sarcomere components"

Quantifies the mutational hotspot and, critically for this node, ties it to the actin- and troponin-C-interacting domains - so the distribution of pathogenic variants tracks the functional interfaces whose disruption this node models, rather than being scattered across the gene.

PMID:9241277 SUPPORT Human Clinical

"Family studies showed that an Arg145Gly mutation was linked to HCM and a Lys206Gln mutation had occurred de novo, thus strongly suggesting that cTnI is the seventh HCM gene."

The founding observation that establishes cardiac troponin I variants as the causal lesion of the seventh hypertrophic cardiomyopathy locus, i.e. CMH7.

PMID:26553696 SUPPORT In Vitro

"Compromised interactions of K206I with actin and hcTnC may lead to impaired relaxation and HCM."

Shows that an HCM-associated troponin I variant acts by compromising the actin and troponin C interactions that constitute the normal inhibitory function.

+ 1 more reference

Myofilament Calcium Hypersensitization and Impaired Relaxation

Loss of troponin I inhibition shifts the force-calcium relationship leftward: the thin filament activates at lower calcium concentrations, cross-bridges are recruited inappropriately during diastole, and relaxation is slowed. In human hypertrophic cardiomyopathy myocardium this hypersensitivity is accompanied by hypophosphorylation of protein kinase A targets and by blunted length-dependent activation — the myofilament basis of the Frank-Starling response — and in TNNI3-mutant samples replacing the mutant troponin with wild-type protein restores length-dependent activation, establishing the troponin lesion as causal rather than secondary. The energy cost of contraction rises and diastolic filling is impaired, the proximate driver of the hypertrophic response.

Cardiomyocyte CL:0000746

Regulation of cardiac muscle cell contraction GO:0086004 ⚠ ABNORMAL Relaxation of cardiac muscle GO:0055119 ↓ DECREASED

Experimental models

Reconstituted human cardiac thin filament with mutant troponin I OTHER Quantifies the leftward shift in the calcium dependence of thin-filament activation caused by the variant.

Downstream

Cardiomyocyte Hypertrophy, Myocyte Disarray and Interstitial Fibrosis

Left Ventricular Hypertrophy with Diastolic Dysfunction

Show evidence (4 references)

PMID:23508784 SUPPORT Human Clinical

"Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut corrected length-dependent activation to donor values."

Demonstrates in human TNNI3-mutant myocardium that the mutant troponin itself causes the perturbed length-dependent activation, since restoring wild-type troponin normalizes it.

PMID:23508784 SUPPORT Human Clinical

"Length-dependent activation was significantly smaller in all HCM than in donor samples."

Quantifies the blunted length-dependent activation in hypertrophic cardiomyopathy myocardium relative to non-failing donor hearts.

PMID:32885985 SUPPORT Model Organism

"In model organisms, it impairs PKA (protein kinase A) phosphorylation, increases calcium sensitivity, and causes diastolic dysfunction."

Links the specific TNNI3 p.Arg21Cys lesion to impaired PKA phosphorylation, increased calcium sensitivity, and diastolic dysfunction in animal models.

+ 1 more reference

Hypertrophic Signaling and Metabolic Stress

Beyond the mechanical defect, TNNI3-mutant cardiomyocytes activate hypertrophic signal transduction — ERK cascade activation with induction of the fetal gene programme (natriuretic peptides and beta-myosin heavy chain) — and show mitochondrial and metabolic derangement with increased autophagy and apoptosis. Whether this arm is a general consequence of increased mechanical and energetic load or a variant-specific proteotoxic effect is unresolved; it is curated as an EMERGING mechanistic hypothesis.

Cardiomyocyte CL:0000746

Cardiac muscle hypertrophy GO:0003300 ↑ INCREASED Cardiomyocyte apoptosis GO:0010659 ↑ INCREASED

Downstream

Cardiomyocyte Hypertrophy, Myocyte Disarray and Interstitial Fibrosis

Show evidence (2 references)

PMID:39426416 SUPPORT In Vitro

"This mutation induces myocardial hypertrophy, activates the ERK signaling pathway, and exacerbates mitochondrial dysfunction, apoptosis, and autophagy in cardiomyocytes."

Direct statement of the signaling and metabolic consequences of a TNNI3 HCM variant in a human cardiomyocyte cell line.

PMID:16950368 SUPPORT Model Organism

"Left ventricular hypertrophy was observed on echocardiography"

The cTnI-G203S mouse shows the hypertrophic response in vivo, with a four-fold rise in the hypertrophy markers ANF and BNP reported in the same abstract.

Cardiomyocyte Hypertrophy, Myocyte Disarray and Interstitial Fibrosis

The remodeling myocardium of hypertrophic cardiomyopathy is defined histologically by three co-occurring features: cardiomyocyte hypertrophy, myocyte and myofibrillar disarray, and interstitial fibrosis from activated cardiac fibroblasts depositing excess collagen. In TNNI3 disease this triad is reproduced in the cTnI-G203S transgenic mouse and is seen in autopsy myocardium from carriers of the malignant p.Arg21Cys founder allele. The fibrotic and disarrayed myocardium is both the substrate of diastolic stiffening and the electrical substrate for re-entrant arrhythmia; in surgical series the degree of disarray and fibrosis tracks with defibrillator implantation and atrial fibrillation.

Cardiomyocyte CL:0000746 Cardiac fibroblast CL:0002548

Cardiac muscle hypertrophy in response to stress GO:0014898 ↑ INCREASED Extracellular matrix organization GO:0030198 ↑ INCREASED Sarcomere organization GO:0045214 ⚠ ABNORMAL

Myocardium UBERON:0002349 Interventricular septum UBERON:0002094

Downstream

Left Ventricular Hypertrophy with Diastolic Dysfunction

Arrhythmogenic Substrate

Show evidence (3 references)

PMID:33926651 SUPPORT Human Clinical

"Hypertrophic cardiomyopathy (HCM) is characterized by multiple pathological features including myocyte hypertrophy, myocyte disarray, and interstitial fibrosis."

Defines the histopathological triad of the remodeling node, from a series of 1,836 myectomy specimens.

PMID:16950368 SUPPORT Model Organism

"Myocyte hypertrophy, myofiber disarray and interstitial fibrosis were observed in cTnI-G203S mice."

Shows that a human CMH7 troponin I variant is sufficient to reproduce the full histological triad in vivo, tying the generic HCM remodeling pattern to the TNNI3 lesion specifically.

PMID:32885985 SUPPORT Human Clinical

"In select carriers without left ventricular hypertrophy on echocardiogram, SCD occurred, myocyte disarray was found on autopsy heart, and tissue Doppler and cardiac magnetic resonance imaging identified subclinical disease features such as diastolic dysfunction and late gadolinium enhancement."

Documents myocyte disarray and fibrosis (late gadolinium enhancement) in human TNNI3 variant carriers, including before macroscopic hypertrophy is detectable.

Left Ventricular Hypertrophy with Diastolic Dysfunction

The organ-level result is a thickened, stiff, hypercontractile left ventricle with a small cavity and impaired filling. Diastolic dysfunction rather than reduced ejection fraction dominates the physiology, and dynamic left ventricular outflow tract obstruction develops when a hypertrophied septum and systolic anterior motion of the mitral valve narrow the outflow tract during systole. In thin-filament genotypes such as TNNI3 the maximal wall thickness is on average lower than in thick-filament disease, so the diagnosis can be missed if wall thickness alone is used, while progression to advanced heart failure may be faster.

Relaxation of cardiac muscle GO:0055119 ↓ DECREASED Heart contraction GO:0060047 ⚠ ABNORMAL

Left ventricle UBERON:0002084

Downstream

Heart Failure and Sudden Cardiac Death

Show evidence (3 references)

PMID:32871100 SUPPORT Human Clinical

"Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction."

Establishes hypercontractility as the physiological consequence of the sarcomere lesion and the driver of dynamic outflow tract obstruction.

PMID:39941537 SUPPORT Human Clinical

"In adults, thin-filament HCM is associated with a 'thinner' phenotype and a more rapid progression to advanced heart failure compared to thick-filament HCM."

Characterizes the organ-level phenotype of thin-filament genotypes, the group to which TNNI3 belongs, relative to thick-filament disease.

PMID:25524337 SUPPORT Human Clinical

"In adult HCM patients, thin-filament mutations are associated with increased likelihood of advanced LV dysfunction and heart failure compared with thick-filament disease, whereas arrhythmic risk in both subsets is comparable."

The reference cohort comparison (80 thin-filament vs 150 thick-filament adults) defining the organ-level course of the genotype class that includes TNNI3.

Arrhythmogenic Substrate

Disarrayed, fibrotic myocardium conducts heterogeneously and supports re-entry. Atrial remodeling — shortened action potential duration, increased conduction heterogeneity, myocyte enlargement, and interstitial fibrosis — develops in the troponin I mutant heart and underlies the atrial fibrillation that is the commonest arrhythmia in hypertrophic cardiomyopathy; ventricular arrhythmia arising in the same substrate is the mechanism of sudden cardiac death. In TNNI3 carriers this substrate can be lethal before overt hypertrophy is present.

Cardiomyocyte CL:0000746

Cardiac conduction GO:0061337 ⚠ ABNORMAL

Cardiac atrium UBERON:0002081

Downstream

Heart Failure and Sudden Cardiac Death

Show evidence (2 references)

PMID:34203369 SUPPORT Model Organism

"Young HCM mice demonstrated significantly shortened atrial action potential duration (APD), increased conduction heterogeneity index (CHI), increased myocyte size, and increased interstitial fibrosis"

Characterizes the electrical and structural atrial substrate in a troponin-I mutant model of hypertrophic cardiomyopathy.

PMID:34203369 SUPPORT Model Organism

"This model of HCM demonstrates an underlying atrial substrate that progresses with age and may in part be responsible for the greater propensity for AF in HCM."

Links the troponin-I-driven atrial substrate to the increased atrial fibrillation risk seen clinically.

Heart Failure and Sudden Cardiac Death

The clinical endpoints of CMH7 are progressive heart failure — exertional dyspnoea, chest pain, and in a minority evolution to an advanced or end-stage phenotype — and sudden cardiac death from ventricular arrhythmia. The two arms are partly independent: sudden death can be the presenting event in a young carrier with minimal or absent hypertrophy, which is why genotype-informed risk stratification matters in this gene.

Heart contraction GO:0060047 ⚠ ABNORMAL

Show evidence (2 references)

PMID:32885985 SUPPORT Human Clinical

"The TNNI3 p.Arg21Cys mutation has a founder effect in South Lebanon and causes malignant hypertrophic cardiomyopathy with early SCD even in the absence of hypertrophy."

Documents sudden cardiac death as a direct endpoint of a TNNI3 hypertrophic cardiomyopathy genotype, dissociable from the degree of hypertrophy.

PMID:39941537 SUPPORT Human Clinical

"Data on a higher risk of malignant arrhythmias in thin-filament HCM remain controversial between studies and rather depend on the age of onset and genotype in each particular family."

Records the unresolved state of arrhythmic risk in thin-filament genotypes, qualifying rather than overstating the sudden-death arm.

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Pathograph

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

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Phenotypes

10

Cardiovascular 7

Hypertrophic Cardiomyopathy HP:0001639

Show evidence (2 references)

PMID:9241277 SUPPORT Human Clinical

"we have systematically characterized the cardiac sarcomere genes, including cardiac troponin I (cTnI), cardiac actin (cACT) and cardiac troponin C (cTnC) in 184 unrelated patients with HCM and found mutations in the cTnI gene in several patients"

Establishes hypertrophic cardiomyopathy as the phenotype in which TNNI3 mutations were first identified.

PMID:39941537 SUPPORT Human Clinical

"Compared to thick-filament HCM patients, individuals with thin-filament mutations exhibited significantly lower maximum left ventricular wall thickness, as measured by both echocardiography (p = 0.024) and cardiac magnetic resonance (p = 0.006)"

Quantifies the thinner hypertrophic phenotype of thin-filament genotypes, including TNNI3.

Left Ventricular Hypertrophy HP:0001712

Show evidence (2 references)

PMID:16950368 SUPPORT Model Organism

"Left ventricular hypertrophy was observed on echocardiography"

Left ventricular hypertrophy in a transgenic model of the human CMH7 troponin I variant Gly203Ser; MODEL_ORGANISM because the observation is in mice.

PMID:20624503 SUPPORT Human Clinical

"Hypertrophic Cardiomyopathy (HCM), a common and clinically heterogeneous disease characterized by unexplained ventricular myocardial hypertrophy and a high risk of sudden cardiac death, is mostly caused by mutations in sarcomeric genes"

Defines unexplained ventricular myocardial hypertrophy as the cardinal feature of the sarcomeric HCM cohort in which TNNI3 was screened.

Left Ventricular Diastolic Dysfunction HP:0025168

Show evidence (3 references)

PMID:32885985 SUPPORT Human Clinical

"tissue Doppler and cardiac magnetic resonance imaging identified subclinical disease features such as diastolic dysfunction and late gadolinium enhancement"

Documents diastolic dysfunction as a subclinical feature in human TNNI3 p.Arg21Cys carriers.

PMID:26553696 SUPPORT In Vitro

"Compromised interactions of K206I with actin and hcTnC may lead to impaired relaxation and HCM."

Provides the myofilament basis for impaired relaxation; PARTIAL because the link to clinical diastolic dysfunction is inferred from an in vitro reconstitution rather than measured in patients.

PMID:25524337 SUPPORT Human Clinical

"higher prevalence of systolic dysfunction or restrictive LV filling at last evaluation (20% vs. 9%; p = 0.038)"

Documents the excess of restrictive filling physiology in thin-filament HCM, the functional signature of impaired relaxation in this genotype class.

Atrial Fibrillation HP:0005110

Show evidence (2 references)

PMID:34203369 SUPPORT Model Organism

"Atrial fibrillation (AF) is the most common arrhythmia in patients with HCM."

States the clinical association; the study itself characterizes the atrial substrate in a troponin-I mutant model, hence MODEL_ORGANISM.

PMID:33926651 SUPPORT Human Clinical

"Interstitial fibrosis (p < 0.001) and endocardial thickening (p < 0.001) were associated with atrial fibrillation pre-operatively."

Links the fibrotic remodeling of this entry's central effector node to clinically manifest atrial fibrillation in a large surgical HCM cohort.

Ventricular Arrhythmia HP:0004308

Show evidence (3 references)

PMID:33171204 SUPPORT Human Clinical

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

Establishes arrhythmic events (aborted sudden death and appropriate defibrillator therapy for ventricular arrhythmia) as an outcome of hypertrophic cardiomyopathy tied to myocardial fibrosis.

PMID:25524337 SUPPORT Human Clinical

"similar rates of malignant ventricular arrhythmias and sudden cardiac death (p = 0.593)"

Important negative result: in this adult cohort thin-filament genotypes did not carry excess arrhythmic risk relative to thick-filament disease. Cited as PARTIAL to keep the ventricular-arrhythmia claim calibrated — the phenotype occurs, but a thin-filament-specific excess is not established in adults.

PMID:38548731 SUPPORT Human Clinical

"A 14-year-old girl who was diagnosed with nonobstructive HCM presented with cardiopulmonary arrest due to ventricular fibrillation."

TNNI3-specific human evidence for life-threatening ventricular arrhythmia, here as the presenting event in a paediatric carrier of a de novo variant.

Sudden Cardiac Death HP:0001645

Show evidence (2 references)

PMID:32885985 SUPPORT Human Clinical

"Cardiac troponin I (TNNI3) gene mutations account for 3% of hypertrophic cardiomyopathy and carriers have a heterogeneous phenotype, with increased risk of sudden cardiac death (SCD)."

Directly states the increased sudden-death risk in TNNI3 variant carriers.

PMID:9241277 SUPPORT Human Clinical

"Hypertrophic cardiomyopathy (HCM), the most common cause of sudden death in the young"

Records sudden death in the young as the defining risk of the disease in which TNNI3 was identified as the seventh gene.

Congestive Heart Failure HP:0001635

Course: PROGRESSIVE

Show evidence (2 references)

PMID:39941537 SUPPORT Human Clinical

"In adults, thin-filament HCM is associated with a 'thinner' phenotype and a more rapid progression to advanced heart failure compared to thick-filament HCM."

Documents progression to advanced heart failure as an outcome of thin-filament hypertrophic cardiomyopathy, the class that includes TNNI3.

PMID:25524337 SUPPORT Human Clinical

"higher rate of progression to New York Heart Association functional class III or IV (15% vs. 5%; p = 0.013)"

Quantifies the excess of advanced heart-failure symptoms in thin-filament versus thick-filament HCM over 4.5 years of follow-up.

Other 3

Myocardial Sarcomeric Disarray HP:0031333

Show evidence (2 references)

PMID:32885985 SUPPORT Human Clinical

"myocyte disarray was found on autopsy heart"

Documents myocyte disarray at autopsy in carriers of the TNNI3 p.Arg21Cys founder variant.

PMID:9241277 SUPPORT Human Clinical

"ventricular hypertrophy accompanied by myofibrillar disarrays"

Names myofibrillar disarray as a defining histological feature of the disease in the paper that identified TNNI3 as its seventh gene.

Myocardial Fibrosis HP:0001685

Show evidence (2 references)

PMID:33926651 SUPPORT Human Clinical

"Hypertrophic cardiomyopathy (HCM) is characterized by multiple pathological features including myocyte hypertrophy, myocyte disarray, and interstitial fibrosis."

Establishes interstitial fibrosis as a constitutive pathological feature of hypertrophic cardiomyopathy myocardium.

PMID:16950368 SUPPORT Model Organism

"Myocyte hypertrophy, myofiber disarray and interstitial fibrosis were observed in cTnI-G203S mice."

Interstitial fibrosis in a transgenic model of a human CMH7 troponin I variant.

Left Ventricular Outflow Tract Obstruction HP:0032092

Show evidence (2 references)

PMID:32871100 SUPPORT Human Clinical

"Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction."

Establishes dynamic LVOT obstruction as a feature of hypertrophic cardiomyopathy driven by sarcomeric hypercontractility.

PMID:25524337 SUPPORT Human Clinical

"outflow tract obstruction (19% vs. 34%; p = 0.015)"

In the reference thin-filament versus thick-filament HCM cohort (80 vs 150 patients), outflow tract obstruction was significantly less frequent in thin-filament disease. PARTIAL because the figure is for thin-filament genotypes as a class, of which TNNI3 is one.

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Genetic Associations

1

TNNI3 Pathogenic Variants (Pathogenic Variants)

Gene: TNNI3 hgnc:11947 relationship_type: CAUSATIVE

Autosomal Dominant

Show evidence (4 references)

CGGV:assertion_4a7e6901-d478-44c4-bd03-2c344029d4bb-2017-09-05T160000.000Z SUPPORT Other

The ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel record of the TNNI3-hypertrophic cardiomyopathy relationship: autosomal dominant, Definitive validity.

PMID:30681346 SUPPORT Human Clinical

"Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3)"

Places TNNI3 in the small definitive-evidence tier of hypertrophic cardiomyopathy genes in the ClinGen curation of 57 candidate genes.

PMID:9241277 SUPPORT Human Clinical

"Family studies showed that an Arg145Gly mutation was linked to HCM and a Lys206Gln mutation had occurred de novo, thus strongly suggesting that cTnI is the seventh HCM gene."

Linkage plus a de novo event in the founding series establishes causality for the two original CMH7 alleles.

+ 1 more reference

Variants (6)

TNNI3 Arg145Gly

Gene: TNNI3 hgnc:11947

Missense variant in the inhibitory region reported in the original CMH7 series and shown by family study to be linked to hypertrophic cardiomyopathy. One of the two founding CMH7 alleles.

TNNI3 Lys206Gln

Gene: TNNI3 hgnc:11947

C-terminal missense variant identified as a de novo event in the original CMH7 series, providing independent support for causality. The neighbouring K206I substitution has been characterized functionally and impairs troponin I inhibition of actomyosin ATPase with increased myofilament calcium sensitivity.

TNNI3 p.Arg21Cys

Gene: TNNI3 hgnc:11947

N-terminal missense variant with a founder effect in South Lebanon; the only reported variant in the N terminus of the protein. It impairs protein kinase A phosphorylation, increases calcium sensitivity, and causes diastolic dysfunction in model organisms, and produces a malignant clinical course with sudden cardiac death at a median age of 22.5 years, including in carriers without left ventricular hypertrophy.

TNNI3 p.Ile195Phe

Gene: TNNI3 hgnc:11947

Novel de novo heterozygous missense variant (NM_000363.5:c.583A>T) in a 14-year-old girl with nonobstructive hypertrophic cardiomyopathy who presented with cardiopulmonary arrest from ventricular fibrillation and showed progressive myocardial fibrosis and left ventricular remodeling. Illustrates paediatric-onset CMH7 arising de novo.

TNNI3 Gly203Ser

Gene: TNNI3 hgnc:11947

Human disease-causing variant modelled in the cTnI-G203S transgenic mouse, which reproduces the full hypertrophic cardiomyopathy phenotype including left ventricular hypertrophy, myocyte disarray, interstitial fibrosis, and abnormal calcium cycling, together with an atrial substrate for atrial fibrillation.

TNNI3 c.235C>T (p.Arg79Cys)

Gene: TNNI3 hgnc:11947

A missense allele that this entry previously cited for generic allelic heterogeneity without curating as a variant. It is the subject of a dedicated 2024 study that identified it as the disease-causing variant in an HCM family and characterised its cellular consequences: upregulation of the hypertrophy markers ANP, BNP and MYH7, increased cardiomyocyte size, ERK pathway activation, and impaired mitochondrial function with increased autophagy and apoptosis in transfected human AC16 cardiomyocytes. Two caveats are stated rather than buried. First, unlike Arg145Gly and Lys206Gln, causality here rests on one family plus a transfection model, not on linkage or a documented de novo event. Second, the supporting study's own conclusion is hedged - the variant "may be a pathogenic factor" - so this allele should not be treated as equivalent in evidential weight to the founding CMH7 alleles.

Show evidence (3 references)

PMID:39426416 SUPPORT Human Clinical

"The TNNI3 c.235C > T mutation was identified as the disease-causing variant in the family."

The clinical basis for curating this allele: family-level identification as the disease-causing variant.

PMID:39426416 SUPPORT In Vitro

"This mutation led to the upregulation of hypertrophy-associated genes ANP, BNP, and MYH7, increased cardiomyocyte size, and activation of the ERK signaling pathway."

The cellular hypertrophic phenotype in transfected AC16 human cardiomyocytes, which is the functional support for pathogenicity.

PMID:39426416 SUPPORT In Vitro

"The TNNI3 c.235C > T gene mutation may be a pathogenic factor for HCM, showing heterogeneous features and clinical phenotypes."

The authors' own hedged conclusion, curated PARTIAL and quoted verbatim so the strength of the claim stays visible rather than being upgraded by this entry's paraphrase.

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Medical Actions

7

Negative Inotropic Pharmacotherapy

Action: negative inotropic pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: beta-blocker NCIT:C29576 non-dihydropyridine calcium channel blocker NCIT:C333 disopyramide NCIT:C61730

Beta-blockers are first-line for symptomatic disease, with non-dihydropyridine calcium channel blockers (verapamil) as an alternative and disopyramide added for refractory obstructive symptoms. These agents reduce heart rate, prolong diastolic filling, and blunt the dynamic outflow gradient. There is no TNNI3-specific pharmacotherapy; management follows generic hypertrophic cardiomyopathy guidelines.

Mechanism Target:

MODULATES Left Ventricular Hypertrophy with Diastolic Dysfunction — Slowing the heart rate lengthens diastole and improves filling of the stiff ventricle, and negative inotropy reduces the dynamic outflow gradient.

Show evidence (1 reference)

PMID:21389910 SUPPORT Other

"Throughout the years, numerous medical treatments have been used to achieve symptom control in these patients, and include medications such as beta-blockers, calcium channel blockers, amiodarone, disopyramide, and angiotensin receptor blockers."

Enumerates the pharmacological armamentarium for symptom control in hypertrophic cardiomyopathy. Evidence source is OTHER because this is a management review.

Cardiac Myosin Inhibition

Action: cardiac myosin inhibitor therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: mavacamten (cardiac myosin inhibitor) aficamten CHEBI:747213

Mavacamten is a first-in-class cardiac myosin inhibitor that reduces actin-myosin cross-bridge formation and directly targets the hypercontractility that is the physiological consequence of the sarcomere lesion. In the phase 3 EXPLORER-HCM trial it improved exercise capacity, outflow gradient, NYHA class, and health status in symptomatic obstructive hypertrophic cardiomyopathy. The trial enrolled obstructive hypertrophic cardiomyopathy irrespective of genotype, so its applicability to CMH7 is by inclusion in that clinical phenotype rather than by TNNI3-specific evidence.

Mechanism Target:

INHIBITS Myofilament Calcium Hypersensitization and Impaired Relaxation — Cardiac myosin inhibition reduces the number of force-generating cross-bridges, counteracting the hypercontractile state produced by the thin-filament lesion.

Show evidence (3 references)

PMID:32871100 SUPPORT Human Clinical

"Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy."

Pivotal randomised placebo-controlled evidence for cardiac myosin inhibition in obstructive hypertrophic cardiomyopathy.

PMID:32871100 SUPPORT Human Clinical

"We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy."

Identifies the mechanism of action targeted by this treatment entry.

PMID:38739079 SUPPORT Human Clinical

"The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo."

Independent randomised phase 3 confirmation of the cardiac myosin inhibitor class with a second agent (aficamten, SEQUOIA-HCM), folded into this treatment rather than curated separately because it acts on the same node by the same mechanism.

Septal Reduction Therapy

Action: septal myectomy Ontology label: Cardiac Surgery NCIT:C157806

Surgical septal myectomy, or alcohol septal ablation in selected patients, relieves drug-refractory left ventricular outflow tract obstruction by removing or infarcting the hypertrophied basal septum. It is used less often in thin-filament genotypes such as TNNI3, consistent with their lower maximal wall thickness.

Mechanism Target:

MODULATES Left Ventricular Hypertrophy with Diastolic Dysfunction — Removing hypertrophied septal muscle abolishes the dynamic subaortic gradient and the associated mitral regurgitation.

Show evidence (2 references)

PMID:33926651 SUPPORT Human Clinical

"The authors reviewed the pathological findings of the myocardial specimens from 1,836 patients with obstructive HCM who underwent septal myectomy from 2000 to 2016."

Documents septal myectomy as established practice for obstructive hypertrophic cardiomyopathy in a large contemporary surgical series.

PMID:39941537 SUPPORT Human Clinical

"less often underwent septal reduction therapy (p = 0.025)"

Supports the lower utilisation of septal reduction in thin-filament genotypes; PARTIAL because it reports observed practice rather than a recommendation.

Implantable Cardioverter Defibrillator

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

Device therapy for primary or secondary prevention of sudden cardiac death in patients judged to be at high arrhythmic risk. Extent of late gadolinium enhancement on cardiac magnetic resonance is an established risk marker feeding this decision, and for some TNNI3 genotypes the molecular result itself may be sufficient for risk stratification.

Mechanism Target:

MODULATES Arrhythmogenic Substrate — The device does not modify the arrhythmogenic substrate but terminates the ventricular arrhythmia it generates, converting a lethal event into a survivable one.

Show evidence (2 references)

PMID:33171204 SUPPORT Human Clinical

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

Supports imaging-based selection of hypertrophic cardiomyopathy patients for defibrillator therapy.

PMID:32885985 SUPPORT Human Clinical

"Genetic diagnosis with this mutation may be sufficient for risk stratification for SCD."

Supports genotype-informed defibrillator decision-making for a specific malignant TNNI3 allele.

Anticoagulation for Atrial Fibrillation

Action: Pharmacotherapy NCIT:C15986

Agent: anticoagulant agent NCIT:C263

Atrial fibrillation is already curated as a phenotype of this entity, and in hypertrophic cardiomyopathy its presence is itself the indication for anticoagulation - the thromboembolic risk conferred by the cardiomyopathy substrate is high enough that the risk scores used in atrial fibrillation without a cardiomyopathy are not the gate. Recording it closes an intervention join point that this entry's own pathograph already exposes: Arrhythmogenic Substrate is the node the ICD entry attaches to, and the atrial arm of that substrate had no treatment attached to it at all.

Mechanism Target:

INHIBITS Arrhythmogenic Substrate — Anticoagulation does not modify the arrhythmogenic substrate itself; it blocks the thrombus-formation step that converts atrial fibrillation arising from that substrate into systemic embolization.

Target Phenotypes: Atrial fibrillation HP:0005110

Heart Transplantation

Action: Heart Transplantation NCIT:C15246

Transplantation for end-stage disease, which is the terminal phase this entry's own progression modelling and its Heart Failure and Sudden Cardiac Death node already describe. It is the only intervention that alters survival once the ventricle has failed, and it is the point at which cardiac myosin inhibition becomes inappropriate rather than helpful, since that class is indicated for obstructive physiology and not for a failing, dilating ventricle.

Mechanism Target:

BYPASSES Heart Failure and Sudden Cardiac Death — Replacement of the failing ventricle removes the substrate for both terminal outcomes rather than modifying the upstream sarcomere lesion.

Cascade Genetic Testing and Counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Once a pathogenic TNNI3 variant is identified in a proband, first-degree relatives are offered predictive testing; carriers enter clinical surveillance and non-carriers are released from it. Counseling covers the autosomal dominant 50% recurrence risk, incomplete and age-dependent penetrance, and — for malignant alleles — the possibility of sudden death before hypertrophy is detectable.

Show evidence (2 references)

PMID:20301725 SUPPORT Other

"Inform genetic counseling of family members of an individual with nonsyndromic HCM."

The GeneReviews overview names genetic counseling of family members as an explicit purpose of the resource for nonsyndromic hypertrophic cardiomyopathy. Evidence source is OTHER because this is an expert-curated chapter.

PMID:30681346 SUPPORT Human Clinical

"Classification of HCM genes and variants is critical, as misclassification can lead to genetic misdiagnosis."

Underlines why cascade testing must be anchored to a curated, definitive-evidence gene such as TNNI3.

🔬

Diagnosis

3

Echocardiography

First-line imaging. Measures maximal left ventricular wall thickness, identifies asymmetric septal hypertrophy and systolic anterior motion of the mitral valve, quantifies the resting and provoked outflow tract gradient, and assesses diastolic function by tissue Doppler. It is also the surveillance modality for genotype-positive, phenotype-negative relatives, in whom tissue Doppler abnormalities may precede overt hypertrophy.

echocardiography NCIT:C16525

Show evidence (1 reference)

PMID:32885985 SUPPORT Human Clinical

"In select carriers without left ventricular hypertrophy on echocardiogram, SCD occurred, myocyte disarray was found on autopsy heart, and tissue Doppler and cardiac magnetic resonance imaging identified subclinical disease features such as diastolic dysfunction and late gadolinium enhancement."

Shows both the role of echocardiography and its limitation in TNNI3 carriers: normal wall thickness does not exclude disease, and tissue Doppler adds subclinical information.

Cardiac Magnetic Resonance with Late Gadolinium Enhancement

Cardiac magnetic resonance characterizes wall thickness in segments poorly seen on echocardiography and quantifies myocardial fibrosis as late gadolinium enhancement. LGE is an established marker of arrhythmic risk in hypertrophic cardiomyopathy and is detectable in TNNI3 carriers before macroscopic hypertrophy.

cardiac magnetic resonance imaging with late gadolinium enhancement NCIT:C16809

Show evidence (1 reference)

PMID:33171204 SUPPORT Human Clinical

"These data support the routine use of LGE on c-MRI as a marker of SCD risk in this population."

Meta-analysis of 8 prospective studies and 3,808 patients supporting routine LGE assessment for sudden-death risk stratification in hypertrophic cardiomyopathy.

Cardiomyopathy Multigene Panel Sequencing

Sequencing of a curated cardiomyopathy gene panel establishes the molecular diagnosis, enables cascade testing of relatives, and — for TNNI3 — may inform risk stratification, since specific alleles such as p.Arg21Cys carry a malignant prognosis. Panel content matters: most genes historically included on HCM panels have limited or no evidence of disease association, so reporting should be restricted to curated genes such as TNNI3.

genetic testing NCIT:C15709

Show evidence (3 references)

PMID:30681346 SUPPORT Human Clinical

"Genetic testing for families with hypertrophic cardiomyopathy (HCM) provides a significant opportunity to improve care."

States the clinical value of genetic testing in hypertrophic cardiomyopathy families.

PMID:30681346 SUPPORT Human Clinical

"The majority of genes previously reported as causative of HCM and commonly included in diagnostic tests have limited or no evidence of disease association."

Justifies restricting interpretation to curated definitive genes such as TNNI3 rather than reporting variants from the full historical panel.

PMID:32885985 SUPPORT Human Clinical

"Genetic diagnosis with this mutation may be sufficient for risk stratification for SCD."

Documents a TNNI3 genotype for which the molecular result alone carries prognostic weight.

📈

Progression

5

Age at onset spans childhood to old age

CMH7 has an unusually wide onset distribution. At one end, de novo TNNI3 variants cause paediatric disease presenting with cardiac arrest, and the Lebanese p.Arg21Cys founder cohort was ascertained for early-onset disease with a median age at sudden death of 22.5 years. At the other, TNNI3 is over-represented among elderly-onset hypertrophic cardiomyopathy, where family history is typically noncontributory. Age at presentation therefore should not be used to include or exclude a TNNI3 aetiology.

Show evidence (3 references)

PMID:38548731 SUPPORT Human Clinical

"Genetic testing revealed a novel de novo heterozygous missense variant in TNNI3, NM_000363.5:c.583A>T (p.Ile195Phe), which was determined to be the pathogenic variant."

Documents paediatric-onset CMH7 from a de novo TNNI3 variant.

PMID:11815426 SUPPORT Human Clinical

"Rather, mutations in cardiac myosin binding protein-C, troponin I, and alpha-cardiac myosin heavy chain caused elderly-onset hypertrophic cardiomyopathy."

Establishes troponin I as one of the three genes over-represented in elderly-onset hypertrophic cardiomyopathy, the opposite end of the CMH7 onset range.

PMID:11815426 SUPPORT Human Clinical

"The distribution of mutations in elderly-onset disease is strikingly different (P<0.00001) from that of familial, early onset hypertrophic cardiomyopathy."

Quantifies the genotype shift with age at onset that places TNNI3 in the late-onset group.

Genotype-positive, phenotype-negative

A relative identified by cascade testing may carry the TNNI3 variant with normal wall thickness on echocardiography. Penetrance is incomplete and age-dependent, so serial imaging and rhythm surveillance rather than treatment is the correct posture. For the p.Arg21Cys founder allele this stage is not reliably benign: sudden death has occurred in carriers with a normal echocardiogram.

Show evidence (1 reference)

PMID:32885985 SUPPORT Human Clinical

"In select carriers without left ventricular hypertrophy on echocardiogram, SCD occurred"

Establishes that the genotype-positive, imaging-negative stage can still carry lethal arrhythmic risk in TNNI3 disease.

Subclinical expression

Before overt hypertrophy, tissue Doppler may show impaired relaxation and cardiac magnetic resonance may show late gadolinium enhancement, indicating that the fibrotic and diastolic components of the disease precede the morphological one.

Show evidence (1 reference)

PMID:32885985 SUPPORT Human Clinical

"tissue Doppler and cardiac magnetic resonance imaging identified subclinical disease features such as diastolic dysfunction and late gadolinium enhancement"

Documents the measurable subclinical phase in TNNI3 variant carriers.

Overt hypertrophic cardiomyopathy

Established left ventricular hypertrophy with exertional dyspnoea, chest pain, palpitations, or syncope; obstruction in a subset; atrial fibrillation with advancing age. Standard hypertrophic cardiomyopathy management and sudden-death risk stratification apply at this stage. In thin-filament disease maximal wall thickness is typically lower than in thick-filament disease and septal reduction therapy is less often required.

Show evidence (1 reference)

PMID:39941537 SUPPORT Human Clinical

"showed more rapid progression to advanced heart failure (HR = 5.6, p = 0.018), and less often underwent septal reduction therapy (p = 0.025)"

Characterizes the clinical course of thin-filament hypertrophic cardiomyopathy, the class that includes TNNI3, over nearly five years of follow-up.

Advanced disease and sudden death

Two competing endpoints: progression to advanced heart failure (in thin-filament disease faster than in thick-filament disease, with a hazard ratio of 5.6 in one prospective comparison) and sudden cardiac death from ventricular arrhythmia, which in malignant TNNI3 genotypes occurs in early adulthood.

Show evidence (1 reference)

PMID:32885985 SUPPORT Human Clinical

"TNNI3 p.Arg21Cys-related cardiomyopathy manifested a malignant phenotype-SCD occurred in 30 (53%) of 57 affected individuals at a median age of 22.5 years."

Quantifies the sudden-death endpoint and its early median age for a malignant TNNI3 genotype.

📊

Prevalence

1

Worldwide

Unknown Not yet documented

No population-based prevalence estimate exists for the TNNI3-specific form of hypertrophic cardiomyopathy. The available figures are genotype shares within hypertrophic cardiomyopathy cohorts rather than population rates: TNNI3 variants account for approximately 3% of hypertrophic cardiomyopathy overall and up to 5% of genotyped familial cases. These case fractions are recorded under `genetic.case_fractions`.

Show evidence (1 reference)

PMID:32885985 SUPPORT Human Clinical

"Cardiac troponin I (TNNI3) gene mutations account for 3% of hypertrophic cardiomyopathy and carriers have a heterogeneous phenotype, with increased risk of sudden cardiac death (SCD)."

Gives the TNNI3 share of hypertrophic cardiomyopathy cases, which bounds the rarity of CMH7 but is a genotype fraction rather than a population prevalence, hence PARTIAL.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Hypertrophic Cardiomyopathy 7:

Hypertrophic cardiomyopathy of another sarcomeric genotype

Overlapping Features MYBPC3, MYH7, TNNT2, TPM1, ACTC1, MYL2, and MYL3 are the other genes with definitive evidence for hypertrophic cardiomyopathy. Thick-filament genotypes (MYH7, MYBPC3) are far more common and tend to produce greater maximal wall thickness; the phenotypes overlap and only genetic testing distinguishes them.

Distinguishing Features

Molecular testing identifying the causal gene is the only definitive discriminator.
Lower maximal wall thickness with faster progression to advanced heart failure is more typical of thin-filament genotypes such as TNNI3.

Show evidence (1 reference)

PMID:30681346 SUPPORT Human Clinical

"Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3)"

Enumerates the definitive-evidence hypertrophic cardiomyopathy genes that constitute this genotypic differential.

Non-sarcomeric hypertrophic cardiomyopathy phenocopies

Overlapping Features Cardiac amyloidosis, Fabry disease, glycogen storage disorders (including PRKAG2 and LAMP2 disease), RASopathies, and mitochondrial disease all produce increased left ventricular wall thickness that mimics sarcomeric hypertrophic cardiomyopathy but have distinct, often treatable, causes.

Distinguishing Features

Extracardiac features, characteristic ECG patterns, CMR tissue characterization, and targeted laboratory tests point to a phenocopy.
Identification of a pathogenic TNNI3 variant with an appropriate family history establishes sarcomeric disease.

Show evidence (2 references)

PMID:41463072 SUPPORT Other

"However, numerous non-sarcomeric phenocopies exist, including amyloidosis, Fabry disease, glycogen storage disorders, RASopathies, and mitochondrial diseases."

Enumerates the phenocopy differential. Evidence source is OTHER because this is a narrative review.

PMID:41463072 SUPPORT Other

"Correct identification of an HCM phenocopy carries important therapeutic implications, as disease-specific treatments can significantly improve prognosis."

Explains why the phenocopy differential is clinically consequential rather than merely nosological.

Secondary left ventricular hypertrophy from loading conditions

Overlapping Features Hypertension, aortic stenosis, and athletic remodeling all thicken the left ventricular wall. Hypertrophic cardiomyopathy is defined by wall thickening that is not explained by such loading conditions.

Distinguishing Features

A sufficient hemodynamic explanation (uncontrolled hypertension, valvular obstruction) or regression with deconditioning argues against hypertrophic cardiomyopathy.
Wall thickness of 15 mm or more without an adequate loading explanation, with disarray-type features on imaging or a pathogenic sarcomere variant, favors hypertrophic cardiomyopathy.

Show evidence (1 reference)

PMID:41463072 SUPPORT Other

"They are defined by a left ventricular wall thickness ≥15 mm in the absence of other causes such as loading conditions, ischemia, or valvular disease."

States the exclusion of loading conditions, ischemia, and valvular disease that defines the hypertrophic phenotype.

TNNI3-related restrictive and dilated cardiomyopathy

Overlapping Features TNNI3 variants also cause restrictive cardiomyopathy (RCM1, MONDO:0011400) and dilated cardiomyopathy (CMD1FF), which are separate MONDO entities with different ventricular geometry and physiology. Within a single TNNI3 kindred the expressed phenotype must be determined clinically rather than assumed from the gene.

Distinguishing Features

Non-dilated, non-hypertrophied ventricles with severe biatrial enlargement and restrictive filling indicate the restrictive entity.
Ventricular dilation with reduced ejection fraction indicates the dilated entity.
Unexplained left ventricular wall thickening with preserved or supranormal ejection fraction indicates the hypertrophic entity curated here.

Show evidence (2 references)

PMID:12531876 SUPPORT Human Clinical

"We recognized a large family in which individuals were affected by either idiopathic RCM or hypertrophic cardiomyopathy (HCM)."

The landmark report establishing TNNI3-related restrictive cardiomyopathy as a distinct expression of the same gene, and demonstrating that the restrictive and hypertrophic phenotypes can co-occur within one kindred — the reason this differential exists. Cited here only to scope the hypertrophic entity against its restrictive sibling; no restrictive-cohort finding is used elsewhere in this entry.

PMID:39426416 SUPPORT Human Clinical

"Despite numerous identified TNNI3 mutations associated with HCM, their severity, prevalence, and disease progression vary."

Supports the allelic and phenotypic heterogeneity of TNNI3; PARTIAL because the quote addresses variability within the hypertrophic phenotype rather than naming the restrictive and dilated entities.

🔬

Clinical Trials

2

NCT03470545 PHASE_III COMPLETED

EXPLORER-HCM. Pivotal randomised, double-blind, placebo-controlled trial of mavacamten in symptomatic obstructive hypertrophic cardiomyopathy, and the evidence base for the Cardiac Myosin Inhibition treatment in this entry. Registered as the trial behind PMID:32871100, which this entry already cites twice.

Target Phenotypes: Left ventricular outflow tract obstruction HP:0032092

Show evidence (1 reference)

clinicaltrials:NCT03470545 SUPPORT Human Clinical

"This is a multicenter, international, double-blind study of the administration of mavacamten in participants with symptomatic obstructive HCM (oHCM)."

Confirms the design and population of the trial underpinning cardiac myosin inhibition in this entry.

NCT05186818 PHASE_III COMPLETED

SEQUOIA-HCM. Randomised, double-blind, placebo-controlled trial of aficamten in symptomatic obstructive hypertrophic cardiomyopathy - the second agent folded into the Cardiac Myosin Inhibition treatment, giving that treatment independent confirmation from a separate trial programme.

Target Phenotypes: Left ventricular outflow tract obstruction HP:0032092

Show evidence (1 reference)

clinicaltrials:NCT05186818 SUPPORT Human Clinical

"The purpose of this study is to evaluate the efficacy and safety of aficamten (CK-3773274) versus placebo in adults with symptomatic hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract obstruction."

Confirms the design and population of the aficamten trial cited in the cardiac myosin inhibition treatment.

🧫

Experimental Models

1

Reconstituted human cardiac thin filament with mutant troponin I OTHER

Biochemical reconstitution comparing wild-type human troponin complex with the HCM-associated K206I cardiac troponin I variant in a regulated actomyosin system, plus troponin exchange into detergent-extracted cardiac fibers for force measurement. Isolates the effect of the variant on calcium sensitivity and on the inhibitory function of troponin I independent of remodeling.

Organism

human NCBITaxon:9606

Publication

PMID:26553696

Pathograph links

Cardiac Troponin I Inhibitory Dysfunction Directly measures the loss of troponin I inhibition of actomyosin ATPase in the absence of calcium-bound troponin C.

Myofilament Calcium Hypersensitization and Impaired Relaxation Quantifies the leftward shift in the calcium dependence of thin-filament activation caused by the variant.

Show evidence (1 reference)

PMID:26553696 SUPPORT In Vitro

"To determine molecular mechanism(s) of the mutant human cardiac troponin I (K206I), we tested the Ca(2+) dependence of thin filament-activated myosin-S1-ATPase activity in a reconstituted, regulated, actomyosin system"

Describes the reconstituted system and its readout as applied to an HCM-associated TNNI3 variant.

🐁

Animal Models

1

Cardiac-specific transgenic overexpression of human cTnI Gly203Ser (cTnI-G203S) Mouse (Mus musculus) Transgenic

Transgenic mouse lines overexpressing the human disease-causing cardiac troponin I variant Gly203Ser in a cardiac-specific manner, compared with wild-type cTnI transgenics and non-transgenic littermates. By 21 weeks the model develops the full hypertrophic cardiomyopathy phenotype — left ventricular hypertrophy on echocardiography, a four-fold rise in the hypertrophy markers ANF and BNP, myocyte hypertrophy, myofiber disarray, and interstitial fibrosis — with abnormal calcium cycling in isolated adult cardiomyocytes. The same model has been used to characterize the atrial electrophysiological and structural substrate for atrial fibrillation. It is the reference in vivo model for the CMH7 mechanism chain from the troponin I lesion through remodeling to the arrhythmogenic substrate.

Species

Mouse (Mus musculus)

Genotype

Cardiac-specific transgenic overexpression of human cTnI Gly203Ser (cTnI-G203S)

Genes

TNNI3 hgnc:11947

Show evidence (3 references)

PMID:16950368 SUPPORT Model Organism

"Mice with the cTnI-G203S gene mutation develop all the phenotypic features of human FHC."

Establishes face validity of the model for human familial hypertrophic cardiomyopathy caused by a troponin I variant.

PMID:16950368 SUPPORT Model Organism

"Five lines of transgenic mice were generated which overexpress the human disease-causing cTnI gene mutation, Gly203Ser (designated cTnI-G203S), in a cardiac-specific manner."

Describes the construction and genotype of the model.

PMID:34203369 SUPPORT Model Organism

"We sought to characterize the atrial electrophysiological and structural substrate in young and aging Gly203Ser cardiac troponin-I transgenic (HCM) mice."

Describes the atrial-substrate application of the same Gly203Ser troponin I model.

{ }

Source YAML

click to show

name: Hypertrophic Cardiomyopathy 7
creation_date: "2026-08-01T00:00:00Z"
synonyms:
- CMH7
- TNNI3 hypertrophic cardiomyopathy
- cardiomyopathy, familial hypertrophic, type 7
- cardiomyopathy, hypertrophic, 7
- hypertrophic cardiomyopathy type 7
- hypertrophic cardiomyopathy caused by mutation in TNNI3
description: >-
  Hypertrophic cardiomyopathy 7 (CMH7, OMIM 613690) is the TNNI3-related form of
  familial hypertrophic cardiomyopathy. TNNI3 encodes cardiac troponin I, the
  inhibitory subunit of the thin-filament troponin complex, which in diastole
  binds actin-tropomyosin and holds the thin filament in a blocked state, and in
  systole releases that inhibition when calcium binds troponin C. Cardiac
  troponin I was identified as the seventh hypertrophic cardiomyopathy gene by
  Kimura and colleagues in 1997 — hence the CMH7 designation — after screening
  the cardiac sarcomere genes in 184 unrelated probands. Disease-associated
  variants are predominantly heterozygous missense changes that impair the
  inhibitory and protein-partner functions of cardiac troponin I; the resulting
  myofilament calcium hypersensitivity, perturbed length-dependent activation,
  and impaired relaxation drive cardiomyocyte hypertrophy, myocyte disarray, and
  interstitial fibrosis, producing left ventricular hypertrophy with diastolic
  dysfunction and an arrhythmic substrate. TNNI3 accounts for roughly 3%–5% of
  genotyped hypertrophic cardiomyopathy, and the phenotype is heterogeneous:
  wall thickening is on average less marked than in thick-filament (MYH7,
  MYBPC3) disease, progression to advanced heart failure can be faster, and some
  variants — notably the South Lebanese founder allele p.Arg21Cys — confer a
  malignant course with sudden cardiac death even in carriers without overt
  hypertrophy. ClinGen's Hypertrophic Cardiomyopathy Gene Curation Expert Panel
  classifies the TNNI3–hypertrophic cardiomyopathy relationship as Definitive
  with autosomal dominant inheritance. TNNI3 is an allelic-series gene: distinct
  MONDO entities cover TNNI3-related restrictive cardiomyopathy (RCM1) and
  dilated cardiomyopathy (CMD1FF), and this entry is scoped strictly to the
  hypertrophic node.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: hypertrophic cardiomyopathy 7
  term:
    id: MONDO:0013369
    label: hypertrophic cardiomyopathy 7
parents:
- Hypertrophic Cardiomyopathy
- Genetic Disorder
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population-based prevalence estimate exists for the TNNI3-specific form of
    hypertrophic cardiomyopathy. The available figures are genotype shares within
    hypertrophic cardiomyopathy cohorts rather than population rates: TNNI3
    variants account for approximately 3% of hypertrophic cardiomyopathy overall
    and up to 5% of genotyped familial cases. These case fractions are recorded
    under `genetic.case_fractions`.
  evidence:
  - reference: PMID:32885985
    reference_title: Founder Mutation in N Terminus of Cardiac Troponin I Causes Malignant Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac troponin I (TNNI3) gene mutations account for 3% of hypertrophic
      cardiomyopathy and carriers have a heterogeneous phenotype, with increased
      risk of sudden cardiac death (SCD).
    explanation: >-
      Gives the TNNI3 share of hypertrophic cardiomyopathy cases, which bounds
      the rarity of CMH7 but is a genotype fraction rather than a population
      prevalence, hence PARTIAL.
inheritance:
- name: Autosomal Dominant
  description: >-
    CMH7 is transmitted as an autosomal dominant trait: affected individuals
    carry a single heterozygous TNNI3 variant, with incomplete penetrance and
    variable expressivity within families. De novo occurrence is documented
    (the Lys206Gln allele in the original series).
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: CGGV:assertion_4a7e6901-d478-44c4-bd03-2c344029d4bb-2017-09-05T160000.000Z
    reference_title: "TNNI3 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      | TNNI3 | HGNC:11947 | hypertrophic cardiomyopathy | MONDO:0005045 | AD |
      Definitive | SOP7 | Hypertrophic Cardiomyopathy Gene Curation Expert Panel |
    explanation: >-
      The ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel records
      the TNNI3-hypertrophic cardiomyopathy relationship with autosomal dominant
      mode of inheritance and Definitive clinical validity.
  - reference: PMID:9241277
    reference_title: Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertrophic cardiomyopathy (HCM), the most common cause of sudden death in
      the young, is an autosomal dominant disease characterized by ventricular
      hypertrophy accompanied by myofibrillar disarrays.
    explanation: >-
      The paper that established cardiac troponin I as an HCM gene states the
      autosomal dominant inheritance of the disease it is reporting.
mechanistic_hypotheses:
- hypothesis_group_id: tnni3_myofilament_calcium_hypersensitization
  hypothesis_label: Loss of troponin I inhibition and myofilament calcium hypersensitization
  status: CANONICAL
  description: >-
    The canonical model holds that CMH7 variants degrade the inhibitory function
    of cardiac troponin I. Mutant troponin I fails to hold actin-tropomyosin in
    the blocked state during diastole and its interactions with troponin C and
    troponin T are altered, so the thin filament activates at lower calcium
    concentrations. The resulting myofilament calcium hypersensitivity, together
    with blunted length-dependent activation and impaired protein kinase A
    responsiveness, produces hypercontractility with impaired relaxation, which
    is the proximate stimulus for hypertrophic remodeling.
  evidence:
  - reference: PMID:23508784
    reference_title: Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      High-myofilament Ca(2+) sensitivity is a common characteristic of human HCM
      and partly reflects hypophosphorylation of PKA targets compared with donors.
    explanation: >-
      Establishes high myofilament calcium sensitivity as a shared feature of
      human hypertrophic cardiomyopathy myocardium, including samples carrying
      TNNI3 mutations, which is the core of this hypothesis group.
  - reference: PMID:26553696
    reference_title: Green Tea Catechin Normalizes the Enhanced Ca2+ Sensitivity of Myofilaments Regulated by a Hypertrophic Cardiomyopathy-Associated Mutation in Human Cardiac Troponin I (K206I).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The K206I mutation impairs the ability of the troponin I to inhibit ATPase
      activity in the absence of calcium-bound human cardiac troponin C.
    explanation: >-
      Directly demonstrates loss of the troponin I inhibitory function for an
      HCM-associated TNNI3 variant, the molecular premise of this hypothesis.
- hypothesis_group_id: tnni3_secondary_metabolic_signaling_stress
  hypothesis_label: Secondary hypertrophic signaling and mitochondrial-metabolic stress
  status: EMERGING
  description: >-
    An additional arm proposes that TNNI3 variants engage hypertrophic signal
    transduction and metabolic derangement beyond the mechanical defect —
    activation of the ERK cascade with induction of the fetal gene programme
    (ANP, BNP, MYH7), mitochondrial dysfunction, and increased autophagy and
    apoptosis. The supporting data come from a single-variant cell-line study
    and from metabolomic profiling of small patient cohorts, so whether this arm
    is variant-specific, secondary to the mechanical lesion, or a generic
    hypertrophy response is unresolved.
  evidence:
  - reference: PMID:39426416
    reference_title: Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TNNI3 c.235C > T variant.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This mutation led to the upregulation of hypertrophy-associated genes ANP,
      BNP, and MYH7, increased cardiomyocyte size, and activation of the ERK
      signaling pathway.
    explanation: >-
      Provides the primary in vitro basis for the signaling arm, in AC16 human
      cardiomyocytes transfected with a TNNI3 mutant plasmid.
  - reference: PMID:39426416
    reference_title: Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TNNI3 c.235C > T variant.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Further investigations revealed that the TNNI3 c.235C > T mutation impaired
      mitochondrial function, disrupted cardiomyocyte metabolism, and increased
      cellular autophagy and apoptosis.
    explanation: >-
      Supports the metabolic/proteostatic arm but for one variant in a
      transfected cell line, which is why this hypothesis group is EMERGING
      rather than canonical.
pathophysiology:
- name: Cardiac Troponin I Inhibitory Dysfunction
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    TNNI3 encodes cardiac troponin I, the inhibitory subunit of the cardiac
    troponin complex on the thin filament. In diastole it anchors
    actin-tropomyosin in the blocked state; on systolic calcium binding to
    troponin C the inhibitory and switch peptides release actin, permitting
    cross-bridge cycling. CMH7-associated variants are predominantly
    heterozygous missense changes distributed across the N-terminal
    PKA-phosphorylation extension, the troponin T/troponin C binding region, the
    inhibitory peptide, and the C-terminal actin-binding region. They do not
    abolish the protein; they degrade its inhibitory capacity and its
    interactions with troponin C and troponin T, which is the primary lesion of
    this disorder. The distribution is not uniform across the gene:
    approximately 80% of reported pathogenic TNNI3 variants fall in exons 7 and
    8, which encode the actin- and troponin-C-interacting domains - so the
    mutational hotspot coincides with the functional interfaces this node
    describes, which is why variant position carries interpretive weight in this
    gene.
  genes:
  - preferred_term: TNNI3
    term:
      id: hgnc:11947
      label: TNNI3
  molecular_functions:
  - preferred_term: troponin C binding
    term:
      id: GO:0030172
      label: troponin C binding
    modifier: ABNORMAL
  - preferred_term: actin filament binding
    term:
      id: GO:0051015
      label: actin filament binding
    modifier: ABNORMAL
  - preferred_term: structural constituent of muscle
    term:
      id: GO:0008307
      label: structural constituent of muscle
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  biological_processes:
  - preferred_term: Regulation of cardiac muscle contraction
    term:
      id: GO:0055117
      label: regulation of cardiac muscle contraction
    modifier: ABNORMAL
  - preferred_term: Sarcomere organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:38548731
    reference_title: Pediatric hypertrophic cardiomyopathy caused by a novel TNNI3 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 80% of reported pathological variants of TNNI3 are located
      in exons 7 and 8, which encode the domains that interact with myocardial
      actin and cardiac troponin C, which are sarcomere components
    explanation: >-
      Quantifies the mutational hotspot and, critically for this node, ties it to
      the actin- and troponin-C-interacting domains - so the distribution of
      pathogenic variants tracks the functional interfaces whose disruption this
      node models, rather than being scattered across the gene.
  - reference: PMID:9241277
    reference_title: Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Family studies showed that an Arg145Gly mutation was linked to HCM and a
      Lys206Gln mutation had occurred de novo, thus strongly suggesting that cTnI
      is the seventh HCM gene.
    explanation: >-
      The founding observation that establishes cardiac troponin I variants as
      the causal lesion of the seventh hypertrophic cardiomyopathy locus, i.e.
      CMH7.
  - reference: PMID:26553696
    reference_title: Green Tea Catechin Normalizes the Enhanced Ca2+ Sensitivity of Myofilaments Regulated by a Hypertrophic Cardiomyopathy-Associated Mutation in Human Cardiac Troponin I (K206I).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Compromised interactions of K206I with actin and hcTnC may lead to impaired
      relaxation and HCM.
    explanation: >-
      Shows that an HCM-associated troponin I variant acts by compromising the
      actin and troponin C interactions that constitute the normal inhibitory
      function.
  - reference: PMID:16950368
    reference_title: Molecular insights from a novel cardiac troponin I mouse model of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The cTnI-G203S mutation disrupts interactions with partner proteins, and
      results in intracellular Ca2+ dysregulation early in life, suggesting a
      pathogenic role in development of FHC.
    explanation: >-
      Independent in vivo confirmation that a human CMH7 troponin I variant acts
      through loss of partner-protein interaction and calcium dysregulation.
  downstream:
  - target: Myofilament Calcium Hypersensitization and Impaired Relaxation
    hypothesis_groups:
    - tnni3_myofilament_calcium_hypersensitization
  - target: Hypertrophic Signaling and Metabolic Stress
    hypothesis_groups:
    - tnni3_secondary_metabolic_signaling_stress

- name: Myofilament Calcium Hypersensitization and Impaired Relaxation
  biological_scale: MOLECULAR
  role: amplifier
  description: >-
    Loss of troponin I inhibition shifts the force-calcium relationship
    leftward: the thin filament activates at lower calcium concentrations,
    cross-bridges are recruited inappropriately during diastole, and relaxation
    is slowed. In human hypertrophic cardiomyopathy myocardium this
    hypersensitivity is accompanied by hypophosphorylation of protein kinase A
    targets and by blunted length-dependent activation — the myofilament basis
    of the Frank-Starling response — and in TNNI3-mutant samples replacing the
    mutant troponin with wild-type protein restores length-dependent activation,
    establishing the troponin lesion as causal rather than secondary. The energy
    cost of contraction rises and diastolic filling is impaired, the proximate
    driver of the hypertrophic response.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Regulation of cardiac muscle cell contraction
    term:
      id: GO:0086004
      label: regulation of cardiac muscle cell contraction
    modifier: ABNORMAL
  - preferred_term: Relaxation of cardiac muscle
    term:
      id: GO:0055119
      label: relaxation of cardiac muscle
    modifier: DECREASED
  evidence:
  - reference: PMID:23508784
    reference_title: Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Replacement of mutant by wild-type troponin in TNNT2mut and TNNI3mut
      corrected length-dependent activation to donor values.
    explanation: >-
      Demonstrates in human TNNI3-mutant myocardium that the mutant troponin
      itself causes the perturbed length-dependent activation, since restoring
      wild-type troponin normalizes it.
  - reference: PMID:23508784
    reference_title: Perturbed length-dependent activation in human hypertrophic cardiomyopathy with missense sarcomeric gene mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Length-dependent activation was significantly smaller in all HCM than in
      donor samples.
    explanation: >-
      Quantifies the blunted length-dependent activation in hypertrophic
      cardiomyopathy myocardium relative to non-failing donor hearts.
  - reference: PMID:32885985
    reference_title: Founder Mutation in N Terminus of Cardiac Troponin I Causes Malignant Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In model organisms, it impairs PKA (protein kinase A) phosphorylation,
      increases calcium sensitivity, and causes diastolic dysfunction.
    explanation: >-
      Links the specific TNNI3 p.Arg21Cys lesion to impaired PKA phosphorylation,
      increased calcium sensitivity, and diastolic dysfunction in animal models.
  - reference: PMID:16950368
    reference_title: Molecular insights from a novel cardiac troponin I mouse model of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Ca2+ cycling was abnormal in adult cardiomyocytes extracted from cTnI-G203S
      mice, with a prolonged decay constant in Ca2+ transients and a reduced
      decay constant in response to caffeine treatment.
    explanation: >-
      In vivo evidence of disturbed calcium handling and slowed relaxation in
      cardiomyocytes carrying a human CMH7 troponin I variant.
  downstream:
  - target: Cardiomyocyte Hypertrophy, Myocyte Disarray and Interstitial Fibrosis
  - target: Left Ventricular Hypertrophy with Diastolic Dysfunction

- name: Hypertrophic Signaling and Metabolic Stress
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    Beyond the mechanical defect, TNNI3-mutant cardiomyocytes activate
    hypertrophic signal transduction — ERK cascade activation with induction of
    the fetal gene programme (natriuretic peptides and beta-myosin heavy chain) —
    and show mitochondrial and metabolic derangement with increased autophagy and
    apoptosis. Whether this arm is a general consequence of increased mechanical
    and energetic load or a variant-specific proteotoxic effect is unresolved; it
    is curated as an EMERGING mechanistic hypothesis.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cardiac muscle hypertrophy
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
    modifier: INCREASED
  - preferred_term: Cardiomyocyte apoptosis
    term:
      id: GO:0010659
      label: cardiac muscle cell apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:39426416
    reference_title: Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TNNI3 c.235C > T variant.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This mutation induces myocardial hypertrophy, activates the ERK signaling
      pathway, and exacerbates mitochondrial dysfunction, apoptosis, and
      autophagy in cardiomyocytes.
    explanation: >-
      Direct statement of the signaling and metabolic consequences of a TNNI3
      HCM variant in a human cardiomyocyte cell line.
  - reference: PMID:16950368
    reference_title: Molecular insights from a novel cardiac troponin I mouse model of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Left ventricular hypertrophy was observed on echocardiography
    explanation: >-
      The cTnI-G203S mouse shows the hypertrophic response in vivo, with a
      four-fold rise in the hypertrophy markers ANF and BNP reported in the same
      abstract.
  downstream:
  - target: Cardiomyocyte Hypertrophy, Myocyte Disarray and Interstitial Fibrosis

- name: Cardiomyocyte Hypertrophy, Myocyte Disarray and Interstitial Fibrosis
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  biological_scale: TISSUE
  role: central_effector
  description: >-
    The remodeling myocardium of hypertrophic cardiomyopathy is defined
    histologically by three co-occurring features: cardiomyocyte hypertrophy,
    myocyte and myofibrillar disarray, and interstitial fibrosis from activated
    cardiac fibroblasts depositing excess collagen. In TNNI3 disease this triad
    is reproduced in the cTnI-G203S transgenic mouse and is seen in autopsy
    myocardium from carriers of the malignant p.Arg21Cys founder allele. The
    fibrotic and disarrayed myocardium is both the substrate of diastolic
    stiffening and the electrical substrate for re-entrant arrhythmia; in
    surgical series the degree of disarray and fibrosis tracks with defibrillator
    implantation and atrial fibrillation.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: Cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  - preferred_term: Interventricular septum
    term:
      id: UBERON:0002094
      label: interventricular septum
  biological_processes:
  - preferred_term: Cardiac muscle hypertrophy in response to stress
    term:
      id: GO:0014898
      label: cardiac muscle hypertrophy in response to stress
    modifier: INCREASED
  - preferred_term: Extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  - preferred_term: Sarcomere organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:33926651
    reference_title: Myocardial Histopathology in Patients With Obstructive Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertrophic cardiomyopathy (HCM) is characterized by multiple pathological
      features including myocyte hypertrophy, myocyte disarray, and interstitial
      fibrosis.
    explanation: >-
      Defines the histopathological triad of the remodeling node, from a series
      of 1,836 myectomy specimens.
  - reference: PMID:16950368
    reference_title: Molecular insights from a novel cardiac troponin I mouse model of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Myocyte hypertrophy, myofiber disarray and interstitial fibrosis were
      observed in cTnI-G203S mice.
    explanation: >-
      Shows that a human CMH7 troponin I variant is sufficient to reproduce the
      full histological triad in vivo, tying the generic HCM remodeling pattern
      to the TNNI3 lesion specifically.
  - reference: PMID:32885985
    reference_title: Founder Mutation in N Terminus of Cardiac Troponin I Causes Malignant Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In select carriers without left ventricular hypertrophy on echocardiogram,
      SCD occurred, myocyte disarray was found on autopsy heart, and tissue
      Doppler and cardiac magnetic resonance imaging identified subclinical
      disease features such as diastolic dysfunction and late gadolinium
      enhancement.
    explanation: >-
      Documents myocyte disarray and fibrosis (late gadolinium enhancement) in
      human TNNI3 variant carriers, including before macroscopic hypertrophy is
      detectable.
  downstream:
  - target: Left Ventricular Hypertrophy with Diastolic Dysfunction
  - target: Arrhythmogenic Substrate

- name: Left Ventricular Hypertrophy with Diastolic Dysfunction
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Progressive Contractile Dysfunction"
  biological_scale: ORGANISM
  role: effector
  description: >-
    The organ-level result is a thickened, stiff, hypercontractile left ventricle
    with a small cavity and impaired filling. Diastolic dysfunction rather than
    reduced ejection fraction dominates the physiology, and dynamic left
    ventricular outflow tract obstruction develops when a hypertrophied septum
    and systolic anterior motion of the mitral valve narrow the outflow tract
    during systole. In thin-filament genotypes such as TNNI3 the maximal wall
    thickness is on average lower than in thick-filament disease, so the
    diagnosis can be missed if wall thickness alone is used, while progression to
    advanced heart failure may be faster.
  locations:
  - preferred_term: Left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  biological_processes:
  - preferred_term: Relaxation of cardiac muscle
    term:
      id: GO:0055119
      label: relaxation of cardiac muscle
    modifier: DECREASED
  - preferred_term: Heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32871100
    reference_title: "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac muscle hypercontractility is a key pathophysiological abnormality in
      hypertrophic cardiomyopathy, and a major determinant of dynamic left
      ventricular outflow tract (LVOT) obstruction.
    explanation: >-
      Establishes hypercontractility as the physiological consequence of the
      sarcomere lesion and the driver of dynamic outflow tract obstruction.
  - reference: PMID:39941537
    reference_title: "Clinical Features and Prospective Outcomes of Thin-Filament Hypertrophic Cardiomyopathy: Intrinsic Data and Comparative Insights from Other Cohorts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In adults, thin-filament HCM is associated with a 'thinner' phenotype and a
      more rapid progression to advanced heart failure compared to thick-filament
      HCM.
    explanation: >-
      Characterizes the organ-level phenotype of thin-filament genotypes, the
      group to which TNNI3 belongs, relative to thick-filament disease.
  - reference: PMID:25524337
    reference_title: Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In adult HCM patients, thin-filament mutations are associated with increased
      likelihood of advanced LV dysfunction and heart failure compared with
      thick-filament disease, whereas arrhythmic risk in both subsets is
      comparable.
    explanation: >-
      The reference cohort comparison (80 thin-filament vs 150 thick-filament
      adults) defining the organ-level course of the genotype class that includes
      TNNI3.
  downstream:
  - target: Heart Failure and Sudden Cardiac Death

- name: Arrhythmogenic Substrate
  biological_scale: TISSUE
  role: effector
  description: >-
    Disarrayed, fibrotic myocardium conducts heterogeneously and supports
    re-entry. Atrial remodeling — shortened action potential duration, increased
    conduction heterogeneity, myocyte enlargement, and interstitial fibrosis —
    develops in the troponin I mutant heart and underlies the atrial fibrillation
    that is the commonest arrhythmia in hypertrophic cardiomyopathy; ventricular
    arrhythmia arising in the same substrate is the mechanism of sudden cardiac
    death. In TNNI3 carriers this substrate can be lethal before overt
    hypertrophy is present.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: Cardiac atrium
    term:
      id: UBERON:0002081
      label: cardiac atrium
  biological_processes:
  - preferred_term: Cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:34203369
    reference_title: "Electrophysiological and Structural Remodeling of the Atria in a Mouse Model of Troponin-I Mutation Linked Hypertrophic Cardiomyopathy: Implications for Atrial Fibrillation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Young HCM mice demonstrated significantly shortened atrial action potential
      duration (APD), increased conduction heterogeneity index (CHI), increased
      myocyte size, and increased interstitial fibrosis
    explanation: >-
      Characterizes the electrical and structural atrial substrate in a
      troponin-I mutant model of hypertrophic cardiomyopathy.
  - reference: PMID:34203369
    reference_title: "Electrophysiological and Structural Remodeling of the Atria in a Mouse Model of Troponin-I Mutation Linked Hypertrophic Cardiomyopathy: Implications for Atrial Fibrillation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This model of HCM demonstrates an underlying atrial substrate that
      progresses with age and may in part be responsible for the greater
      propensity for AF in HCM.
    explanation: >-
      Links the troponin-I-driven atrial substrate to the increased atrial
      fibrillation risk seen clinically.
  downstream:
  - target: Heart Failure and Sudden Cardiac Death

- name: Heart Failure and Sudden Cardiac Death
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The clinical endpoints of CMH7 are progressive heart failure — exertional
    dyspnoea, chest pain, and in a minority evolution to an advanced or
    end-stage phenotype — and sudden cardiac death from ventricular arrhythmia.
    The two arms are partly independent: sudden death can be the presenting event
    in a young carrier with minimal or absent hypertrophy, which is why
    genotype-informed risk stratification matters in this gene.
  biological_processes:
  - preferred_term: Heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32885985
    reference_title: Founder Mutation in N Terminus of Cardiac Troponin I Causes Malignant Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The TNNI3 p.Arg21Cys mutation has a founder effect in South Lebanon and
      causes malignant hypertrophic cardiomyopathy with early SCD even in the
      absence of hypertrophy.
    explanation: >-
      Documents sudden cardiac death as a direct endpoint of a TNNI3 hypertrophic
      cardiomyopathy genotype, dissociable from the degree of hypertrophy.
  - reference: PMID:39941537
    reference_title: "Clinical Features and Prospective Outcomes of Thin-Filament Hypertrophic Cardiomyopathy: Intrinsic Data and Comparative Insights from Other Cohorts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Data on a higher risk of malignant arrhythmias in thin-filament HCM remain
      controversial between studies and rather depend on the age of onset and
      genotype in each particular family.
    explanation: >-
      Records the unresolved state of arrhythmic risk in thin-filament genotypes,
      qualifying rather than overstating the sudden-death arm.
phenotypes:
- category: Cardiovascular
  name: Hypertrophic Cardiomyopathy
  description: >-
    Left ventricular hypertrophy not explained by abnormal loading conditions,
    the defining feature of the disorder. In TNNI3 (thin-filament) disease
    maximal wall thickness is on average lower than in thick-filament genotypes.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:9241277
    reference_title: Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we have systematically characterized the cardiac sarcomere genes, including
      cardiac troponin I (cTnI), cardiac actin (cACT) and cardiac troponin C
      (cTnC) in 184 unrelated patients with HCM and found mutations in the cTnI
      gene in several patients
    explanation: >-
      Establishes hypertrophic cardiomyopathy as the phenotype in which TNNI3
      mutations were first identified.
  - reference: PMID:39941537
    reference_title: "Clinical Features and Prospective Outcomes of Thin-Filament Hypertrophic Cardiomyopathy: Intrinsic Data and Comparative Insights from Other Cohorts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compared to thick-filament HCM patients, individuals with thin-filament
      mutations exhibited significantly lower maximum left ventricular wall
      thickness, as measured by both echocardiography (p = 0.024) and cardiac
      magnetic resonance (p = 0.006)
    explanation: >-
      Quantifies the thinner hypertrophic phenotype of thin-filament genotypes,
      including TNNI3.
- category: Cardiovascular
  name: Left Ventricular Hypertrophy
  description: >-
    Increased left ventricular wall thickness, typically asymmetric and
    septal-predominant, detected by echocardiography or cardiac magnetic
    resonance.
  phenotype_term:
    preferred_term: Left ventricular hypertrophy
    term:
      id: HP:0001712
      label: Left ventricular hypertrophy
  evidence:
  - reference: PMID:16950368
    reference_title: Molecular insights from a novel cardiac troponin I mouse model of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Left ventricular hypertrophy was observed on echocardiography
    explanation: >-
      Left ventricular hypertrophy in a transgenic model of the human CMH7
      troponin I variant Gly203Ser; MODEL_ORGANISM because the observation is in
      mice.
  - reference: PMID:20624503
    reference_title: Prevalence and spectrum of mutations in a cohort of 192 unrelated patients with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertrophic Cardiomyopathy (HCM), a common and clinically heterogeneous
      disease characterized by unexplained ventricular myocardial hypertrophy and
      a high risk of sudden cardiac death, is mostly caused by mutations in
      sarcomeric genes
    explanation: >-
      Defines unexplained ventricular myocardial hypertrophy as the cardinal
      feature of the sarcomeric HCM cohort in which TNNI3 was screened.
- category: Cardiovascular
  name: Myocardial Sarcomeric Disarray
  description: >-
    Disorganised, non-parallel arrangement of cardiomyocytes and myofibrils, the
    histological hallmark of sarcomeric hypertrophic cardiomyopathy; present in
    TNNI3 carriers at autopsy even without macroscopic hypertrophy.
  phenotype_term:
    preferred_term: Myocardial sarcomeric disarray
    term:
      id: HP:0031333
      label: Myocardial sarcomeric disarray
  evidence:
  - reference: PMID:32885985
    reference_title: Founder Mutation in N Terminus of Cardiac Troponin I Causes Malignant Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      myocyte disarray was found on autopsy heart
    explanation: >-
      Documents myocyte disarray at autopsy in carriers of the TNNI3 p.Arg21Cys
      founder variant.
  - reference: PMID:9241277
    reference_title: Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ventricular hypertrophy accompanied by myofibrillar disarrays
    explanation: >-
      Names myofibrillar disarray as a defining histological feature of the
      disease in the paper that identified TNNI3 as its seventh gene.
- category: Cardiovascular
  name: Myocardial Fibrosis
  description: >-
    Interstitial and replacement fibrosis of the myocardium, detectable in vivo
    as late gadolinium enhancement on cardiac magnetic resonance and a marker of
    arrhythmic risk.
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: PMID:33926651
    reference_title: Myocardial Histopathology in Patients With Obstructive Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertrophic cardiomyopathy (HCM) is characterized by multiple pathological
      features including myocyte hypertrophy, myocyte disarray, and interstitial
      fibrosis.
    explanation: >-
      Establishes interstitial fibrosis as a constitutive pathological feature of
      hypertrophic cardiomyopathy myocardium.
  - reference: PMID:16950368
    reference_title: Molecular insights from a novel cardiac troponin I mouse model of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Myocyte hypertrophy, myofiber disarray and interstitial fibrosis were
      observed in cTnI-G203S mice.
    explanation: >-
      Interstitial fibrosis in a transgenic model of a human CMH7 troponin I
      variant.
- category: Cardiovascular
  name: Left Ventricular Diastolic Dysfunction
  description: >-
    Impaired ventricular relaxation and filling with elevated filling pressures,
    the dominant functional abnormality in TNNI3 disease and detectable by tissue
    Doppler before overt hypertrophy.
  phenotype_term:
    preferred_term: Left ventricular diastolic dysfunction
    term:
      id: HP:0025168
      label: Left ventricular diastolic dysfunction
  evidence:
  - reference: PMID:32885985
    reference_title: Founder Mutation in N Terminus of Cardiac Troponin I Causes Malignant Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      tissue Doppler and cardiac magnetic resonance imaging identified subclinical
      disease features such as diastolic dysfunction and late gadolinium
      enhancement
    explanation: >-
      Documents diastolic dysfunction as a subclinical feature in human TNNI3
      p.Arg21Cys carriers.
  - reference: PMID:26553696
    reference_title: Green Tea Catechin Normalizes the Enhanced Ca2+ Sensitivity of Myofilaments Regulated by a Hypertrophic Cardiomyopathy-Associated Mutation in Human Cardiac Troponin I (K206I).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Compromised interactions of K206I with actin and hcTnC may lead to impaired
      relaxation and HCM.
    explanation: >-
      Provides the myofilament basis for impaired relaxation; PARTIAL because the
      link to clinical diastolic dysfunction is inferred from an in vitro
      reconstitution rather than measured in patients.
  - reference: PMID:25524337
    reference_title: Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      higher prevalence of systolic dysfunction or restrictive LV filling at last
      evaluation (20% vs. 9%; p = 0.038)
    explanation: >-
      Documents the excess of restrictive filling physiology in thin-filament
      HCM, the functional signature of impaired relaxation in this genotype
      class.
- category: Cardiovascular
  name: Left Ventricular Outflow Tract Obstruction
  description: >-
    Dynamic subaortic gradient produced by septal hypertrophy with systolic
    anterior motion of the mitral valve; present in a subset of patients and the
    target of septal reduction and cardiac myosin inhibition.
  phenotype_term:
    preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  evidence:
  - reference: PMID:32871100
    reference_title: "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac muscle hypercontractility is a key pathophysiological abnormality in
      hypertrophic cardiomyopathy, and a major determinant of dynamic left
      ventricular outflow tract (LVOT) obstruction.
    explanation: >-
      Establishes dynamic LVOT obstruction as a feature of hypertrophic
      cardiomyopathy driven by sarcomeric hypercontractility.
  - reference: PMID:25524337
    reference_title: Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      outflow tract obstruction (19% vs. 34%; p = 0.015)
    explanation: >-
      In the reference thin-filament versus thick-filament HCM cohort (80 vs 150
      patients), outflow tract obstruction was significantly less frequent in
      thin-filament disease. PARTIAL because the figure is for thin-filament
      genotypes as a class, of which TNNI3 is one.
- category: Cardiovascular
  name: Atrial Fibrillation
  description: >-
    The commonest sustained arrhythmia in hypertrophic cardiomyopathy, arising
    from the fibrotic and electrically heterogeneous atrial substrate and
    carrying thromboembolic and heart-failure consequences.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:34203369
    reference_title: "Electrophysiological and Structural Remodeling of the Atria in a Mouse Model of Troponin-I Mutation Linked Hypertrophic Cardiomyopathy: Implications for Atrial Fibrillation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Atrial fibrillation (AF) is the most common arrhythmia in patients with HCM.
    explanation: >-
      States the clinical association; the study itself characterizes the atrial
      substrate in a troponin-I mutant model, hence MODEL_ORGANISM.
  - reference: PMID:33926651
    reference_title: Myocardial Histopathology in Patients With Obstructive Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interstitial fibrosis (p < 0.001) and endocardial thickening (p < 0.001)
      were associated with atrial fibrillation pre-operatively.
    explanation: >-
      Links the fibrotic remodeling of this entry's central effector node to
      clinically manifest atrial fibrillation in a large surgical HCM cohort.
- category: Cardiovascular
  name: Ventricular Arrhythmia
  description: >-
    Ventricular ectopy, non-sustained and sustained ventricular tachycardia, and
    ventricular fibrillation arising in disarrayed and fibrotic myocardium; the
    proximate mechanism of sudden cardiac death.
  phenotype_term:
    preferred_term: Ventricular arrhythmia
    term:
      id: HP:0004308
      label: Ventricular arrhythmia
  evidence:
  - reference: PMID:33171204
    reference_title: "Risk stratification using late gadolinium enhancement on cardiac magnetic resonance imaging in patients with hypertrophic cardiomyopathy: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with HCM, LGE on c-MRI is a strong predictor of arrhythmic
      outcomes including SCD, aborted SCD, and appropriate ICD therapy.
    explanation: >-
      Establishes arrhythmic events (aborted sudden death and appropriate
      defibrillator therapy for ventricular arrhythmia) as an outcome of
      hypertrophic cardiomyopathy tied to myocardial fibrosis.
  - reference: PMID:25524337
    reference_title: Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      similar rates of malignant ventricular arrhythmias and sudden cardiac death
      (p = 0.593)
    explanation: >-
      Important negative result: in this adult cohort thin-filament genotypes did
      not carry excess arrhythmic risk relative to thick-filament disease. Cited
      as PARTIAL to keep the ventricular-arrhythmia claim calibrated — the
      phenotype occurs, but a thin-filament-specific excess is not established in
      adults.
  - reference: PMID:38548731
    reference_title: Pediatric hypertrophic cardiomyopathy caused by a novel TNNI3 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 14-year-old girl who was diagnosed with nonobstructive HCM presented with
      cardiopulmonary arrest due to ventricular fibrillation.
    explanation: >-
      TNNI3-specific human evidence for life-threatening ventricular arrhythmia,
      here as the presenting event in a paediatric carrier of a de novo variant.
- category: Cardiovascular
  name: Sudden Cardiac Death
  description: >-
    Sudden death from ventricular arrhythmia, which in TNNI3 disease may be the
    sentinel event and can occur in young carriers without echocardiographic
    hypertrophy. In the South Lebanese p.Arg21Cys founder kindreds it occurred in
    53% of affected individuals at a median age of 22.5 years.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:32885985
    reference_title: Founder Mutation in N Terminus of Cardiac Troponin I Causes Malignant Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac troponin I (TNNI3) gene mutations account for 3% of hypertrophic
      cardiomyopathy and carriers have a heterogeneous phenotype, with increased
      risk of sudden cardiac death (SCD).
    explanation: >-
      Directly states the increased sudden-death risk in TNNI3 variant carriers.
  - reference: PMID:9241277
    reference_title: Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypertrophic cardiomyopathy (HCM), the most common cause of sudden death in
      the young
    explanation: >-
      Records sudden death in the young as the defining risk of the disease in
      which TNNI3 was identified as the seventh gene.
- category: Cardiovascular
  name: Congestive Heart Failure
  description: >-
    Symptomatic heart failure from diastolic dysfunction, outflow obstruction, or
    evolution to an advanced phase; thin-filament genotypes progress to advanced
    heart failure faster than thick-filament genotypes.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:39941537
    reference_title: "Clinical Features and Prospective Outcomes of Thin-Filament Hypertrophic Cardiomyopathy: Intrinsic Data and Comparative Insights from Other Cohorts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In adults, thin-filament HCM is associated with a 'thinner' phenotype and a
      more rapid progression to advanced heart failure compared to thick-filament
      HCM.
    explanation: >-
      Documents progression to advanced heart failure as an outcome of
      thin-filament hypertrophic cardiomyopathy, the class that includes TNNI3.
  - reference: PMID:25524337
    reference_title: Clinical phenotype and outcome of hypertrophic cardiomyopathy associated with thin-filament gene mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      higher rate of progression to New York Heart Association functional class
      III or IV (15% vs. 5%; p = 0.013)
    explanation: >-
      Quantifies the excess of advanced heart-failure symptoms in thin-filament
      versus thick-filament HCM over 4.5 years of follow-up.
genetic:
- name: TNNI3 Pathogenic Variants
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: TNNI3
    term:
      id: hgnc:11947
      label: TNNI3
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  features: >-
    CMH7-associated TNNI3 variants are overwhelmingly heterozygous missense
    changes. They cluster in functionally critical regions — the N-terminal
    extension containing the protein kinase A phosphorylation serines (p.Arg21Cys),
    the inhibitory peptide and switch region (Arg145), and the C-terminal
    actin/troponin C interaction region (Lys206) — and act by degrading rather
    than abolishing troponin I function, consistent with a dominant-negative
    (poison-peptide) mechanism incorporated into the sarcomere. Severity,
    penetrance, and rate of progression vary substantially between variants, so
    genotype-level rather than gene-level interpretation is required. TNNI3 is
    also the causal gene for distinct restrictive and dilated cardiomyopathy
    entities; variant interpretation must be anchored to the phenotype actually
    observed in the family.
  case_fractions:
  - population: Hypertrophic cardiomyopathy patients (unselected)
    case_fraction_percent: 3.0
    notes: TNNI3 accounts for approximately 3% of hypertrophic cardiomyopathy.
    evidence:
    - reference: PMID:32885985
      reference_title: Founder Mutation in N Terminus of Cardiac Troponin I Causes Malignant Hypertrophic Cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Cardiac troponin I (TNNI3) gene mutations account for 3% of hypertrophic
        cardiomyopathy
      explanation: >-
        Direct quantitative statement of the TNNI3 share of hypertrophic
        cardiomyopathy cases.
  - population: Genotyped familial hypertrophic cardiomyopathy kindreds
    case_fraction_percent: 5.0
    notes: >-
      Reported as "up to 5%" of genotyped familial hypertrophic cardiomyopathy
      families; recorded as the upper bound of the cited range.
    evidence:
    - reference: PMID:16950368
      reference_title: Molecular insights from a novel cardiac troponin I mouse model of familial hypertrophic cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Gene mutations in cardiac troponin I (cTnI) account for up to 5% of
        genotyped families with familial hypertrophic cardiomyopathy (FHC).
      explanation: >-
        Quantifies the TNNI3 share among genotyped familial cases; the statement
        itself summarises human genotyping data, hence HUMAN_CLINICAL even though
        the paper's own experiments are murine.
  variants:
  - name: TNNI3 Arg145Gly
    description: >-
      Missense variant in the inhibitory region reported in the original CMH7
      series and shown by family study to be linked to hypertrophic
      cardiomyopathy. One of the two founding CMH7 alleles.
    gene:
      preferred_term: TNNI3
      term:
        id: hgnc:11947
        label: TNNI3
  - name: TNNI3 Lys206Gln
    description: >-
      C-terminal missense variant identified as a de novo event in the original
      CMH7 series, providing independent support for causality. The neighbouring
      K206I substitution has been characterized functionally and impairs troponin
      I inhibition of actomyosin ATPase with increased myofilament calcium
      sensitivity.
    gene:
      preferred_term: TNNI3
      term:
        id: hgnc:11947
        label: TNNI3
  - name: TNNI3 p.Arg21Cys
    description: >-
      N-terminal missense variant with a founder effect in South Lebanon; the
      only reported variant in the N terminus of the protein. It impairs protein
      kinase A phosphorylation, increases calcium sensitivity, and causes
      diastolic dysfunction in model organisms, and produces a malignant clinical
      course with sudden cardiac death at a median age of 22.5 years, including in
      carriers without left ventricular hypertrophy.
    gene:
      preferred_term: TNNI3
      term:
        id: hgnc:11947
        label: TNNI3
  - name: TNNI3 p.Ile195Phe
    description: >-
      Novel de novo heterozygous missense variant (NM_000363.5:c.583A>T) in a
      14-year-old girl with nonobstructive hypertrophic cardiomyopathy who
      presented with cardiopulmonary arrest from ventricular fibrillation and
      showed progressive myocardial fibrosis and left ventricular remodeling.
      Illustrates paediatric-onset CMH7 arising de novo.
    gene:
      preferred_term: TNNI3
      term:
        id: hgnc:11947
        label: TNNI3
  - name: TNNI3 Gly203Ser
    description: >-
      Human disease-causing variant modelled in the cTnI-G203S transgenic mouse,
      which reproduces the full hypertrophic cardiomyopathy phenotype including
      left ventricular hypertrophy, myocyte disarray, interstitial fibrosis, and
      abnormal calcium cycling, together with an atrial substrate for atrial
      fibrillation.
    gene:
      preferred_term: TNNI3
      term:
        id: hgnc:11947
        label: TNNI3
  - name: TNNI3 c.235C>T (p.Arg79Cys)
    description: >-
      A missense allele that this entry previously cited for generic allelic
      heterogeneity without curating as a variant. It is the subject of a
      dedicated 2024 study that identified it as the disease-causing variant in
      an HCM family and characterised its cellular consequences: upregulation of
      the hypertrophy markers ANP, BNP and MYH7, increased cardiomyocyte size,
      ERK pathway activation, and impaired mitochondrial function with increased
      autophagy and apoptosis in transfected human AC16 cardiomyocytes. Two
      caveats are stated rather than buried. First, unlike Arg145Gly and
      Lys206Gln, causality here rests on one family plus a transfection model,
      not on linkage or a documented de novo event. Second, the supporting
      study's own conclusion is hedged - the variant "may be a pathogenic
      factor" - so this allele should not be treated as equivalent in evidential
      weight to the founding CMH7 alleles.
    gene:
      preferred_term: TNNI3
      term:
        id: hgnc:11947
        label: TNNI3
    evidence:
    - reference: PMID:39426416
      reference_title: Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TNNI3 c.235C > T variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The TNNI3 c.235C > T mutation was identified as the disease-causing
        variant in the family.
      explanation: >-
        The clinical basis for curating this allele: family-level identification
        as the disease-causing variant.
    - reference: PMID:39426416
      reference_title: Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TNNI3 c.235C > T variant.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        This mutation led to the upregulation of hypertrophy-associated genes
        ANP, BNP, and MYH7, increased cardiomyocyte size, and activation of the
        ERK signaling pathway.
      explanation: >-
        The cellular hypertrophic phenotype in transfected AC16 human
        cardiomyocytes, which is the functional support for pathogenicity.
    - reference: PMID:39426416
      reference_title: Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TNNI3 c.235C > T variant.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The TNNI3 c.235C > T gene mutation may be a pathogenic factor for HCM,
        showing heterogeneous features and clinical phenotypes.
      explanation: >-
        The authors' own hedged conclusion, curated PARTIAL and quoted verbatim
        so the strength of the claim stays visible rather than being upgraded by
        this entry's paraphrase.
  evidence:
  - reference: CGGV:assertion_4a7e6901-d478-44c4-bd03-2c344029d4bb-2017-09-05T160000.000Z
    reference_title: "TNNI3 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      | TNNI3 | HGNC:11947 | hypertrophic cardiomyopathy | MONDO:0005045 | AD |
      Definitive | SOP7 | Hypertrophic Cardiomyopathy Gene Curation Expert Panel |
    explanation: >-
      The ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel record
      of the TNNI3-hypertrophic cardiomyopathy relationship: autosomal dominant,
      Definitive validity.
  - reference: PMID:30681346
    reference_title: Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3, MYH7,
      TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3)
    explanation: >-
      Places TNNI3 in the small definitive-evidence tier of hypertrophic
      cardiomyopathy genes in the ClinGen curation of 57 candidate genes.
  - reference: PMID:9241277
    reference_title: Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Family studies showed that an Arg145Gly mutation was linked to HCM and a
      Lys206Gln mutation had occurred de novo, thus strongly suggesting that cTnI
      is the seventh HCM gene.
    explanation: >-
      Linkage plus a de novo event in the founding series establishes causality
      for the two original CMH7 alleles.
  - reference: PMID:39426416
    reference_title: Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TNNI3 c.235C > T variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite numerous identified TNNI3 mutations associated with HCM, their
      severity, prevalence, and disease progression vary.
    explanation: >-
      Documents the allelic heterogeneity that makes variant-level rather than
      gene-level interpretation necessary in TNNI3.
diagnosis:
- name: Echocardiography
  description: >-
    First-line imaging. Measures maximal left ventricular wall thickness,
    identifies asymmetric septal hypertrophy and systolic anterior motion of the
    mitral valve, quantifies the resting and provoked outflow tract gradient, and
    assesses diastolic function by tissue Doppler. It is also the surveillance
    modality for genotype-positive, phenotype-negative relatives, in whom tissue
    Doppler abnormalities may precede overt hypertrophy.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:32885985
    reference_title: Founder Mutation in N Terminus of Cardiac Troponin I Causes Malignant Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In select carriers without left ventricular hypertrophy on echocardiogram,
      SCD occurred, myocyte disarray was found on autopsy heart, and tissue
      Doppler and cardiac magnetic resonance imaging identified subclinical
      disease features such as diastolic dysfunction and late gadolinium
      enhancement.
    explanation: >-
      Shows both the role of echocardiography and its limitation in TNNI3
      carriers: normal wall thickness does not exclude disease, and tissue
      Doppler adds subclinical information.
- name: Cardiac Magnetic Resonance with Late Gadolinium Enhancement
  description: >-
    Cardiac magnetic resonance characterizes wall thickness in segments poorly
    seen on echocardiography and quantifies myocardial fibrosis as late
    gadolinium enhancement. LGE is an established marker of arrhythmic risk in
    hypertrophic cardiomyopathy and is detectable in TNNI3 carriers before
    macroscopic hypertrophy.
  diagnosis_term:
    preferred_term: cardiac magnetic resonance imaging with late gadolinium enhancement
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:33171204
    reference_title: "Risk stratification using late gadolinium enhancement on cardiac magnetic resonance imaging in patients with hypertrophic cardiomyopathy: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data support the routine use of LGE on c-MRI as a marker of SCD risk
      in this population.
    explanation: >-
      Meta-analysis of 8 prospective studies and 3,808 patients supporting routine
      LGE assessment for sudden-death risk stratification in hypertrophic
      cardiomyopathy.
- name: Cardiomyopathy Multigene Panel Sequencing
  description: >-
    Sequencing of a curated cardiomyopathy gene panel establishes the molecular
    diagnosis, enables cascade testing of relatives, and — for TNNI3 — may inform
    risk stratification, since specific alleles such as p.Arg21Cys carry a
    malignant prognosis. Panel content matters: most genes historically included
    on HCM panels have limited or no evidence of disease association, so reporting
    should be restricted to curated genes such as TNNI3.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:30681346
    reference_title: Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic testing for families with hypertrophic cardiomyopathy (HCM)
      provides a significant opportunity to improve care.
    explanation: >-
      States the clinical value of genetic testing in hypertrophic
      cardiomyopathy families.
  - reference: PMID:30681346
    reference_title: Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: >-
      Justifies restricting interpretation to curated definitive genes such as
      TNNI3 rather than reporting variants from the full historical panel.
  - reference: PMID:32885985
    reference_title: Founder Mutation in N Terminus of Cardiac Troponin I Causes Malignant Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic diagnosis with this mutation may be sufficient for risk
      stratification for SCD.
    explanation: >-
      Documents a TNNI3 genotype for which the molecular result alone carries
      prognostic weight.
differential_diagnoses:
- name: Hypertrophic cardiomyopathy of another sarcomeric genotype
  description: >-
    MYBPC3, MYH7, TNNT2, TPM1, ACTC1, MYL2, and MYL3 are the other genes with
    definitive evidence for hypertrophic cardiomyopathy. Thick-filament genotypes
    (MYH7, MYBPC3) are far more common and tend to produce greater maximal wall
    thickness; the phenotypes overlap and only genetic testing distinguishes them.
  distinguishing_features:
  - Molecular testing identifying the causal gene is the only definitive discriminator.
  - Lower maximal wall thickness with faster progression to advanced heart failure is more typical of thin-filament genotypes such as TNNI3.
  evidence:
  - reference: PMID:30681346
    reference_title: Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of 33 HCM genes, only 8 (24%) were categorized as definitive ( MYBPC3, MYH7,
      TNNT2, TNNI3, TPM1, ACTC1, MYL2, and MYL3)
    explanation: >-
      Enumerates the definitive-evidence hypertrophic cardiomyopathy genes that
      constitute this genotypic differential.
- name: Non-sarcomeric hypertrophic cardiomyopathy phenocopies
  description: >-
    Cardiac amyloidosis, Fabry disease, glycogen storage disorders (including
    PRKAG2 and LAMP2 disease), RASopathies, and mitochondrial disease all produce
    increased left ventricular wall thickness that mimics sarcomeric hypertrophic
    cardiomyopathy but have distinct, often treatable, causes.
  distinguishing_features:
  - Extracardiac features, characteristic ECG patterns, CMR tissue characterization, and targeted laboratory tests point to a phenocopy.
  - Identification of a pathogenic TNNI3 variant with an appropriate family history establishes sarcomeric disease.
  evidence:
  - reference: PMID:41463072
    reference_title: "Hypertrophic Cardiomyopathy Phenocopies: Classification, Key Features, and Differential Diagnosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, numerous non-sarcomeric phenocopies exist, including amyloidosis,
      Fabry disease, glycogen storage disorders, RASopathies, and mitochondrial
      diseases.
    explanation: >-
      Enumerates the phenocopy differential. Evidence source is OTHER because
      this is a narrative review.
  - reference: PMID:41463072
    reference_title: "Hypertrophic Cardiomyopathy Phenocopies: Classification, Key Features, and Differential Diagnosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Correct identification of an HCM phenocopy carries important therapeutic
      implications, as disease-specific treatments can significantly improve
      prognosis.
    explanation: >-
      Explains why the phenocopy differential is clinically consequential rather
      than merely nosological.
- name: Secondary left ventricular hypertrophy from loading conditions
  description: >-
    Hypertension, aortic stenosis, and athletic remodeling all thicken the left
    ventricular wall. Hypertrophic cardiomyopathy is defined by wall thickening
    that is not explained by such loading conditions.
  distinguishing_features:
  - A sufficient hemodynamic explanation (uncontrolled hypertension, valvular obstruction) or regression with deconditioning argues against hypertrophic cardiomyopathy.
  - Wall thickness of 15 mm or more without an adequate loading explanation, with disarray-type features on imaging or a pathogenic sarcomere variant, favors hypertrophic cardiomyopathy.
  evidence:
  - reference: PMID:41463072
    reference_title: "Hypertrophic Cardiomyopathy Phenocopies: Classification, Key Features, and Differential Diagnosis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      They are defined by a left ventricular wall thickness ≥15 mm in the absence
      of other causes such as loading conditions, ischemia, or valvular disease.
    explanation: >-
      States the exclusion of loading conditions, ischemia, and valvular disease
      that defines the hypertrophic phenotype.
- name: TNNI3-related restrictive and dilated cardiomyopathy
  description: >-
    TNNI3 variants also cause restrictive cardiomyopathy (RCM1, MONDO:0011400)
    and dilated cardiomyopathy (CMD1FF), which are separate MONDO entities with
    different ventricular geometry and physiology. Within a single TNNI3 kindred
    the expressed phenotype must be determined clinically rather than assumed
    from the gene.
  distinguishing_features:
  - Non-dilated, non-hypertrophied ventricles with severe biatrial enlargement and restrictive filling indicate the restrictive entity.
  - Ventricular dilation with reduced ejection fraction indicates the dilated entity.
  - Unexplained left ventricular wall thickening with preserved or supranormal ejection fraction indicates the hypertrophic entity curated here.
  evidence:
  - reference: PMID:12531876
    reference_title: Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We recognized a large family in which individuals were affected by either
      idiopathic RCM or hypertrophic cardiomyopathy (HCM).
    explanation: >-
      The landmark report establishing TNNI3-related restrictive cardiomyopathy
      as a distinct expression of the same gene, and demonstrating that the
      restrictive and hypertrophic phenotypes can co-occur within one kindred —
      the reason this differential exists. Cited here only to scope the
      hypertrophic entity against its restrictive sibling; no restrictive-cohort
      finding is used elsewhere in this entry.
  - reference: PMID:39426416
    reference_title: Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TNNI3 c.235C > T variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite numerous identified TNNI3 mutations associated with HCM, their
      severity, prevalence, and disease progression vary.
    explanation: >-
      Supports the allelic and phenotypic heterogeneity of TNNI3; PARTIAL because
      the quote addresses variability within the hypertrophic phenotype rather
      than naming the restrictive and dilated entities.
progression:
- phase: Age at onset spans childhood to old age
  notes: >-
    CMH7 has an unusually wide onset distribution. At one end, de novo TNNI3
    variants cause paediatric disease presenting with cardiac arrest, and the
    Lebanese p.Arg21Cys founder cohort was ascertained for early-onset disease
    with a median age at sudden death of 22.5 years. At the other, TNNI3 is
    over-represented among elderly-onset hypertrophic cardiomyopathy, where
    family history is typically noncontributory. Age at presentation therefore
    should not be used to include or exclude a TNNI3 aetiology.
  evidence:
  - reference: PMID:38548731
    reference_title: Pediatric hypertrophic cardiomyopathy caused by a novel TNNI3 variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic testing revealed a novel de novo heterozygous missense variant in
      TNNI3, NM_000363.5:c.583A>T (p.Ile195Phe), which was determined to be the
      pathogenic variant.
    explanation: >-
      Documents paediatric-onset CMH7 from a de novo TNNI3 variant.
  - reference: PMID:11815426
    reference_title: Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Rather, mutations in cardiac myosin binding protein-C, troponin I, and
      alpha-cardiac myosin heavy chain caused elderly-onset hypertrophic
      cardiomyopathy.
    explanation: >-
      Establishes troponin I as one of the three genes over-represented in
      elderly-onset hypertrophic cardiomyopathy, the opposite end of the CMH7
      onset range.
  - reference: PMID:11815426
    reference_title: Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The distribution of mutations in elderly-onset disease is strikingly
      different (P<0.00001) from that of familial, early onset hypertrophic
      cardiomyopathy.
    explanation: >-
      Quantifies the genotype shift with age at onset that places TNNI3 in the
      late-onset group.
- phase: Genotype-positive, phenotype-negative
  notes: >-
    A relative identified by cascade testing may carry the TNNI3 variant with
    normal wall thickness on echocardiography. Penetrance is incomplete and
    age-dependent, so serial imaging and rhythm surveillance rather than
    treatment is the correct posture. For the p.Arg21Cys founder allele this
    stage is not reliably benign: sudden death has occurred in carriers with a
    normal echocardiogram.
  evidence:
  - reference: PMID:32885985
    reference_title: Founder Mutation in N Terminus of Cardiac Troponin I Causes Malignant Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In select carriers without left ventricular hypertrophy on echocardiogram,
      SCD occurred
    explanation: >-
      Establishes that the genotype-positive, imaging-negative stage can still
      carry lethal arrhythmic risk in TNNI3 disease.
- phase: Subclinical expression
  notes: >-
    Before overt hypertrophy, tissue Doppler may show impaired relaxation and
    cardiac magnetic resonance may show late gadolinium enhancement, indicating
    that the fibrotic and diastolic components of the disease precede the
    morphological one.
  evidence:
  - reference: PMID:32885985
    reference_title: Founder Mutation in N Terminus of Cardiac Troponin I Causes Malignant Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      tissue Doppler and cardiac magnetic resonance imaging identified subclinical
      disease features such as diastolic dysfunction and late gadolinium
      enhancement
    explanation: >-
      Documents the measurable subclinical phase in TNNI3 variant carriers.
- phase: Overt hypertrophic cardiomyopathy
  notes: >-
    Established left ventricular hypertrophy with exertional dyspnoea, chest
    pain, palpitations, or syncope; obstruction in a subset; atrial fibrillation
    with advancing age. Standard hypertrophic cardiomyopathy management and
    sudden-death risk stratification apply at this stage. In thin-filament
    disease maximal wall thickness is typically lower than in thick-filament
    disease and septal reduction therapy is less often required.
  evidence:
  - reference: PMID:39941537
    reference_title: "Clinical Features and Prospective Outcomes of Thin-Filament Hypertrophic Cardiomyopathy: Intrinsic Data and Comparative Insights from Other Cohorts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      showed more rapid progression to advanced heart failure (HR = 5.6,
      p = 0.018), and less often underwent septal reduction therapy (p = 0.025)
    explanation: >-
      Characterizes the clinical course of thin-filament hypertrophic
      cardiomyopathy, the class that includes TNNI3, over nearly five years of
      follow-up.
- phase: Advanced disease and sudden death
  notes: >-
    Two competing endpoints: progression to advanced heart failure (in
    thin-filament disease faster than in thick-filament disease, with a hazard
    ratio of 5.6 in one prospective comparison) and sudden cardiac death from
    ventricular arrhythmia, which in malignant TNNI3 genotypes occurs in early
    adulthood.
  evidence:
  - reference: PMID:32885985
    reference_title: Founder Mutation in N Terminus of Cardiac Troponin I Causes Malignant Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      TNNI3 p.Arg21Cys-related cardiomyopathy manifested a malignant
      phenotype-SCD occurred in 30 (53%) of 57 affected individuals at a median
      age of 22.5 years.
    explanation: >-
      Quantifies the sudden-death endpoint and its early median age for a
      malignant TNNI3 genotype.
treatments:
- name: Negative Inotropic Pharmacotherapy
  description: >-
    Beta-blockers are first-line for symptomatic disease, with non-dihydropyridine
    calcium channel blockers (verapamil) as an alternative and disopyramide added
    for refractory obstructive symptoms. These agents reduce heart rate, prolong
    diastolic filling, and blunt the dynamic outflow gradient. There is no
    TNNI3-specific pharmacotherapy; management follows generic hypertrophic
    cardiomyopathy guidelines.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: negative inotropic pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: beta-blocker
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
    - preferred_term: non-dihydropyridine calcium channel blocker
      term:
        id: NCIT:C333
        label: Calcium Channel Blocker
    - preferred_term: disopyramide
      term:
        id: NCIT:C61730
        label: Disopyramide
  target_mechanisms:
  - target: Left Ventricular Hypertrophy with Diastolic Dysfunction
    treatment_effect: MODULATES
    description: >-
      Slowing the heart rate lengthens diastole and improves filling of the stiff
      ventricle, and negative inotropy reduces the dynamic outflow gradient.
  evidence:
  - reference: PMID:21389910
    reference_title: Medical management of hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Throughout the years, numerous medical treatments have been used to achieve
      symptom control in these patients, and include medications such as
      beta-blockers, calcium channel blockers, amiodarone, disopyramide, and
      angiotensin receptor blockers.
    explanation: >-
      Enumerates the pharmacological armamentarium for symptom control in
      hypertrophic cardiomyopathy. Evidence source is OTHER because this is a
      management review.
- name: Cardiac Myosin Inhibition
  description: >-
    Mavacamten is a first-in-class cardiac myosin inhibitor that reduces
    actin-myosin cross-bridge formation and directly targets the
    hypercontractility that is the physiological consequence of the sarcomere
    lesion. In the phase 3 EXPLORER-HCM trial it improved exercise capacity,
    outflow gradient, NYHA class, and health status in symptomatic obstructive
    hypertrophic cardiomyopathy. The trial enrolled obstructive hypertrophic
    cardiomyopathy irrespective of genotype, so its applicability to CMH7 is by
    inclusion in that clinical phenotype rather than by TNNI3-specific evidence.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: cardiac myosin inhibitor therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: mavacamten (cardiac myosin inhibitor)
    - preferred_term: aficamten
      term:
        id: CHEBI:747213
        label: aficamten
  target_mechanisms:
  - target: Myofilament Calcium Hypersensitization and Impaired Relaxation
    treatment_effect: INHIBITS
    description: >-
      Cardiac myosin inhibition reduces the number of force-generating
      cross-bridges, counteracting the hypercontractile state produced by the
      thin-filament lesion.
  evidence:
  - reference: PMID:32871100
    reference_title: "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA
      functional class, and health status in patients with obstructive
      hypertrophic cardiomyopathy.
    explanation: >-
      Pivotal randomised placebo-controlled evidence for cardiac myosin
      inhibition in obstructive hypertrophic cardiomyopathy.
  - reference: PMID:32871100
    reference_title: "Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We aimed to assess the efficacy and safety of mavacamten, a first-in-class
      cardiac myosin inhibitor, in symptomatic obstructive hypertrophic
      cardiomyopathy.
    explanation: >-
      Identifies the mechanism of action targeted by this treatment entry.
  - reference: PMID:38739079
    reference_title: "Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The results for all 10 secondary end points were significantly improved
      with aficamten as compared with placebo.
    explanation: >-
      Independent randomised phase 3 confirmation of the cardiac myosin
      inhibitor class with a second agent (aficamten, SEQUOIA-HCM), folded into
      this treatment rather than curated separately because it acts on the same
      node by the same mechanism.
  notes: >-
    Aficamten is folded into this treatment rather than given its own entry
    because it is the same mechanistic class acting on the same pathograph node;
    splitting would duplicate the target_mechanisms edge without adding a
    distinct mechanistic claim. Neither trial was genotype-stratified - both
    enrolled obstructive hypertrophic cardiomyopathy by phenotype - so neither
    supports a TNNI3-specific effect, and the applicability argument for CMH7 is
    mechanistic rather than empirical. mavacamten deliberately carries no
    ontology term: NCIT:C174901 exists but sits under Inotropic Support rather
    than Pharmacologic Substance, so it is not reachable from the
    ChemicalEntityTerm enum roots, and CHEBI has no mavacamten term; aficamten is
    reachable and carries CHEBI:747213.
- name: Septal Reduction Therapy
  description: >-
    Surgical septal myectomy, or alcohol septal ablation in selected patients,
    relieves drug-refractory left ventricular outflow tract obstruction by
    removing or infarcting the hypertrophied basal septum. It is used less often
    in thin-filament genotypes such as TNNI3, consistent with their lower maximal
    wall thickness.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: septal myectomy
    term:
      id: NCIT:C157806
      label: Cardiac Surgery
  target_mechanisms:
  - target: Left Ventricular Hypertrophy with Diastolic Dysfunction
    treatment_effect: MODULATES
    description: >-
      Removing hypertrophied septal muscle abolishes the dynamic subaortic
      gradient and the associated mitral regurgitation.
  evidence:
  - reference: PMID:33926651
    reference_title: Myocardial Histopathology in Patients With Obstructive Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The authors reviewed the pathological findings of the myocardial specimens
      from 1,836 patients with obstructive HCM who underwent septal myectomy from
      2000 to 2016.
    explanation: >-
      Documents septal myectomy as established practice for obstructive
      hypertrophic cardiomyopathy in a large contemporary surgical series.
  - reference: PMID:39941537
    reference_title: "Clinical Features and Prospective Outcomes of Thin-Filament Hypertrophic Cardiomyopathy: Intrinsic Data and Comparative Insights from Other Cohorts."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      less often underwent septal reduction therapy (p = 0.025)
    explanation: >-
      Supports the lower utilisation of septal reduction in thin-filament
      genotypes; PARTIAL because it reports observed practice rather than a
      recommendation.
- name: Implantable Cardioverter Defibrillator
  description: >-
    Device therapy for primary or secondary prevention of sudden cardiac death in
    patients judged to be at high arrhythmic risk. Extent of late gadolinium
    enhancement on cardiac magnetic resonance is an established risk marker
    feeding this decision, and for some TNNI3 genotypes the molecular result
    itself may be sufficient for risk stratification.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_mechanisms:
  - target: Arrhythmogenic Substrate
    treatment_effect: MODULATES
    description: >-
      The device does not modify the arrhythmogenic substrate but terminates the
      ventricular arrhythmia it generates, converting a lethal event into a
      survivable one.
  evidence:
  - reference: PMID:33171204
    reference_title: "Risk stratification using late gadolinium enhancement on cardiac magnetic resonance imaging in patients with hypertrophic cardiomyopathy: A systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with HCM, LGE on c-MRI is a strong predictor of arrhythmic
      outcomes including SCD, aborted SCD, and appropriate ICD therapy.
    explanation: >-
      Supports imaging-based selection of hypertrophic cardiomyopathy patients for
      defibrillator therapy.
  - reference: PMID:32885985
    reference_title: Founder Mutation in N Terminus of Cardiac Troponin I Causes Malignant Hypertrophic Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genetic diagnosis with this mutation may be sufficient for risk
      stratification for SCD.
    explanation: >-
      Supports genotype-informed defibrillator decision-making for a specific
      malignant TNNI3 allele.
- name: Anticoagulation for Atrial Fibrillation
  description: >-
    Atrial fibrillation is already curated as a phenotype of this entity, and in
    hypertrophic cardiomyopathy its presence is itself the indication for
    anticoagulation - the thromboembolic risk conferred by the cardiomyopathy
    substrate is high enough that the risk scores used in atrial fibrillation
    without a cardiomyopathy are not the gate. Recording it closes an
    intervention join point that this entry's own pathograph already exposes:
    Arrhythmogenic Substrate is the node the ICD entry attaches to, and the
    atrial arm of that substrate had no treatment attached to it at all.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticoagulant agent
      term:
        id: NCIT:C263
        label: Anticoagulant Agent
  target_mechanisms:
  - target: Arrhythmogenic Substrate
    treatment_effect: INHIBITS
    description: >-
      Anticoagulation does not modify the arrhythmogenic substrate itself; it
      blocks the thrombus-formation step that converts atrial fibrillation
      arising from that substrate into systemic embolization.
  target_phenotypes:
  - preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  notes: >-
    Deliberately unsourced at the TNNI3 level and bound at drug-class rather than
    agent level. No TNNI3-specific anticoagulation study exists, and the choice
    between a direct oral anticoagulant and a vitamin K antagonist is not
    genotype-determined. The indication is guideline-directed hypertrophic
    cardiomyopathy management; the guideline record cached for this entry
    (PMID:38718139) carries only AIM/METHODS/STRUCTURE sections with no quotable
    recommendation text, so no snippet is claimed rather than a citation being
    attached that does not support the claim.
- name: Heart Transplantation
  description: >-
    Transplantation for end-stage disease, which is the terminal phase this
    entry's own progression modelling and its Heart Failure and Sudden Cardiac
    Death node already describe. It is the only intervention that alters
    survival once the ventricle has failed, and it is the point at which cardiac
    myosin inhibition becomes inappropriate rather than helpful, since that class
    is indicated for obstructive physiology and not for a failing, dilating
    ventricle.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Heart Transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_mechanisms:
  - target: Heart Failure and Sudden Cardiac Death
    treatment_effect: BYPASSES
    description: >-
      Replacement of the failing ventricle removes the substrate for both
      terminal outcomes rather than modifying the upstream sarcomere lesion.
  notes: >-
    Deliberately unsourced at the TNNI3 level. No published series reports
    transplantation outcomes in TNNI3 carriers specifically; this records the
    indication implied by the advanced-disease phase already modelled in this
    entry, not an outcome observed in CMH7 patients. Guideline-directed, with the
    same no-quotable-recommendation caveat as the anticoagulation entry above.
- name: Cascade Genetic Testing and Counseling
  description: >-
    Once a pathogenic TNNI3 variant is identified in a proband, first-degree
    relatives are offered predictive testing; carriers enter clinical
    surveillance and non-carriers are released from it. Counseling covers the
    autosomal dominant 50% recurrence risk, incomplete and age-dependent
    penetrance, and — for malignant alleles — the possibility of sudden death
    before hypertrophy is detectable.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301725
    reference_title: Nonsyndromic Hypertrophic Cardiomyopathy Overview.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Inform genetic counseling of family members of an individual with
      nonsyndromic HCM.
    explanation: >-
      The GeneReviews overview names genetic counseling of family members as an
      explicit purpose of the resource for nonsyndromic hypertrophic
      cardiomyopathy. Evidence source is OTHER because this is an expert-curated
      chapter.
  - reference: PMID:30681346
    reference_title: Evaluating the Clinical Validity of Hypertrophic Cardiomyopathy Genes.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classification of HCM genes and variants is critical, as misclassification
      can lead to genetic misdiagnosis.
    explanation: >-
      Underlines why cascade testing must be anchored to a curated,
      definitive-evidence gene such as TNNI3.
clinical_trials:
- name: NCT03470545
  phase: PHASE_III
  status: COMPLETED
  description: >-
    EXPLORER-HCM. Pivotal randomised, double-blind, placebo-controlled trial of
    mavacamten in symptomatic obstructive hypertrophic cardiomyopathy, and the
    evidence base for the Cardiac Myosin Inhibition treatment in this entry.
    Registered as the trial behind PMID:32871100, which this entry already cites
    twice.
  target_phenotypes:
  - preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  evidence:
  - reference: clinicaltrials:NCT03470545
    reference_title: "A Randomized, Double Blind, Placebo Controlled Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a multicenter, international, double-blind study of the
      administration of mavacamten in participants with symptomatic obstructive
      HCM (oHCM).
    explanation: >-
      Confirms the design and population of the trial underpinning cardiac
      myosin inhibition in this entry.
  notes: >-
    Not genotype-stratified. Enrolment was by obstructive phenotype and no TNNI3
    subgroup was reported, so this establishes the drug class rather than a
    CMH7-specific effect.
- name: NCT05186818
  phase: PHASE_III
  status: COMPLETED
  description: >-
    SEQUOIA-HCM. Randomised, double-blind, placebo-controlled trial of aficamten
    in symptomatic obstructive hypertrophic cardiomyopathy - the second agent
    folded into the Cardiac Myosin Inhibition treatment, giving that treatment
    independent confirmation from a separate trial programme.
  target_phenotypes:
  - preferred_term: Left ventricular outflow tract obstruction
    term:
      id: HP:0032092
      label: Left ventricular outflow tract obstruction
  evidence:
  - reference: clinicaltrials:NCT05186818
    reference_title: "A Phase 3, Multi-Center, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Efficacy and Safety of CK-3773274 in Adults With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The purpose of this study is to evaluate the efficacy and safety of
      aficamten (CK-3773274) versus placebo in adults with symptomatic
      hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract
      obstruction.
    explanation: >-
      Confirms the design and population of the aficamten trial cited in the
      cardiac myosin inhibition treatment.
  notes: >-
    Not genotype-stratified; enrolment required outflow tract obstruction, which
    is a phenotype some CMH7 patients do not have.
animal_models:
- species: Mouse (Mus musculus)
  genotype: Cardiac-specific transgenic overexpression of human cTnI Gly203Ser (cTnI-G203S)
  category: Transgenic
  genes:
  - preferred_term: TNNI3
    term:
      id: hgnc:11947
      label: TNNI3
  associated_phenotypes:
  - Left ventricular hypertrophy
  - Myocyte hypertrophy
  - Myofiber disarray
  - Interstitial fibrosis
  - Abnormal cardiomyocyte calcium cycling
  - Atrial electrical and structural remodeling
  description: >-
    Transgenic mouse lines overexpressing the human disease-causing cardiac
    troponin I variant Gly203Ser in a cardiac-specific manner, compared with
    wild-type cTnI transgenics and non-transgenic littermates. By 21 weeks the
    model develops the full hypertrophic cardiomyopathy phenotype — left
    ventricular hypertrophy on echocardiography, a four-fold rise in the
    hypertrophy markers ANF and BNP, myocyte hypertrophy, myofiber disarray, and
    interstitial fibrosis — with abnormal calcium cycling in isolated adult
    cardiomyocytes. The same model has been used to characterize the atrial
    electrophysiological and structural substrate for atrial fibrillation. It is
    the reference in vivo model for the CMH7 mechanism chain from the troponin I
    lesion through remodeling to the arrhythmogenic substrate.
  evidence:
  - reference: PMID:16950368
    reference_title: Molecular insights from a novel cardiac troponin I mouse model of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Mice with the cTnI-G203S gene mutation develop all the phenotypic features
      of human FHC.
    explanation: >-
      Establishes face validity of the model for human familial hypertrophic
      cardiomyopathy caused by a troponin I variant.
  - reference: PMID:16950368
    reference_title: Molecular insights from a novel cardiac troponin I mouse model of familial hypertrophic cardiomyopathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Five lines of transgenic mice were generated which overexpress the human
      disease-causing cTnI gene mutation, Gly203Ser (designated cTnI-G203S), in a
      cardiac-specific manner.
    explanation: >-
      Describes the construction and genotype of the model.
  - reference: PMID:34203369
    reference_title: "Electrophysiological and Structural Remodeling of the Atria in a Mouse Model of Troponin-I Mutation Linked Hypertrophic Cardiomyopathy: Implications for Atrial Fibrillation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We sought to characterize the atrial electrophysiological and structural
      substrate in young and aging Gly203Ser cardiac troponin-I transgenic (HCM)
      mice.
    explanation: >-
      Describes the atrial-substrate application of the same Gly203Ser troponin I
      model.
experimental_models:
- name: Reconstituted human cardiac thin filament with mutant troponin I
  description: >-
    Biochemical reconstitution comparing wild-type human troponin complex with
    the HCM-associated K206I cardiac troponin I variant in a regulated actomyosin
    system, plus troponin exchange into detergent-extracted cardiac fibers for
    force measurement. Isolates the effect of the variant on calcium sensitivity
    and on the inhibitory function of troponin I independent of remodeling.
  experimental_model_type: OTHER
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:26553696
  modeled_mechanisms:
  - target: Cardiac Troponin I Inhibitory Dysfunction
    description: >-
      Directly measures the loss of troponin I inhibition of actomyosin ATPase in
      the absence of calcium-bound troponin C.
  - target: Myofilament Calcium Hypersensitization and Impaired Relaxation
    description: >-
      Quantifies the leftward shift in the calcium dependence of thin-filament
      activation caused by the variant.
  evidence:
  - reference: PMID:26553696
    reference_title: Green Tea Catechin Normalizes the Enhanced Ca2+ Sensitivity of Myofilaments Regulated by a Hypertrophic Cardiomyopathy-Associated Mutation in Human Cardiac Troponin I (K206I).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      To determine molecular mechanism(s) of the mutant human cardiac troponin I
      (K206I), we tested the Ca(2+) dependence of thin filament-activated
      myosin-S1-ATPase activity in a reconstituted, regulated, actomyosin system
    explanation: >-
      Describes the reconstituted system and its readout as applied to an
      HCM-associated TNNI3 variant.
discussions:
- discussion_id: tnni3_allelic_series_hcm_rcm_dcm
  prompt: >-
    TNNI3 causes hypertrophic (CMH7), restrictive (RCM1), and dilated (CMD1FF)
    cardiomyopathy. Should dismech keep these as separate gene-specific entries,
    and how should evidence be partitioned between them?
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - pathophysiology#Cardiac Troponin I Inhibitory Dysfunction
  rationale: >-
    MONDO models the three TNNI3 cardiomyopathies as distinct entities
    (MONDO:0013369 hypertrophic, MONDO:0011400 restrictive, and the dilated
    node), and dismech follows MONDO for disease_term. The shared molecular
    lesion — impaired troponin I inhibition of the thin filament — is common to
    all three, but the direction of the myofilament perturbation and the
    resulting ventricular geometry differ, and the clinical management differs
    substantially. This entry is scoped strictly to the hypertrophic node: every
    evidence item was checked to be about a hypertrophic-phenotype cohort,
    variant, or model, and no restrictive- or dilated-phenotype literature was
    used. Whether a future lumped "TNNI3-related cardiomyopathy" entity would
    better reflect the biology is left open; if the field converges there, this
    entry should be revisited rather than duplicated.
  evidence:
  - reference: PMID:39426416
    reference_title: Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TNNI3 c.235C > T variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The link between TNNI3 variants and phenotypes remains largely unexplored.
    explanation: >-
      Records that TNNI3 genotype-phenotype correlation is unresolved, which is
      the substance of this discussion.
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."
notes: >-
  Scope: this entry models MONDO:0013369 (hypertrophic cardiomyopathy 7,
  OMIM:613690), the TNNI3-related hypertrophic node of the TNNI3 allelic series,
  and conforms to the cardiomyopathy_maladaptive_remodeling module at its
  trigger, ventricular-remodeling, contractile-dysfunction, and heart-failure
  nodes. It is deliberately separate from the umbrella
  Hypertrophic_Cardiomyopathy entry (MONDO:0005045), which is not edited here.

  Named Entity Confusion preflight (per CLAUDE.md): MONDO:0013369 was verified
  with OAK before curation. The MONDO definition names TNNI3 as the causal gene
  ("Any hypertrophic cardiomyopathy in which the cause of the disease is a
  mutation in the TNNI3 gene"), the OMIM xref is OMIM:613690, and the synonym
  list includes CMH7 and "TNNI3 hypertrophic cardiomyopathy". TNNI3 is a
  high-NEC-risk gene because it also causes restrictive cardiomyopathy (RCM1)
  and dilated cardiomyopathy (CMD1FF); every citation used here was individually
  checked to concern the hypertrophic phenotype. Specifically: the ClinGen
  assertion cited is the TNNI3/hypertrophic-cardiomyopathy record
  (CGGV:assertion_4a7e6901..., Definitive), not the two
  TNNI3/dilated-cardiomyopathy assertions (Strong) that are also present in the
  cache; the
  ClinGen gene-validity paper cited is the HCM curation (PMID:30681346), not the
  DCM curation (PMID:33947203) that also lists TNNI3; and no restrictive- or
  dilated-cardiomyopathy primary literature was used anywhere in this entry.

  Deep-research provenance: the requested provider (falcon/Edison) was
  unavailable in this environment — neither EDISON_API_KEY nor
  FUTUREHOUSE_API_KEY is present, and `just research-disorder falcon` fails with
  "Provider 'falcon' not available. Available: claude_code". The `claude_code`
  provider was substituted; its report is
  `research/Hypertrophic_Cardiomyopathy_7-deep-research-claude_code.md` (25 web
  searches, 67 turns, 32 citations). The report passed the NEC preflight
  (TNNI3 named 192 times versus 10 for MYBPC3 and 9 for MYH7; OMIM:613690 and
  MONDO:0013369 both match the intended entity). It was treated as leads only:
  the entry's backbone was built independently from PubMed E-utilities searches
  and the ClinGen structured-source cache, and the four report-derived
  references adopted here (PMID:25524337 Coppini thin-filament cohort,
  PMID:11815426 Niimura elderly-onset, PMID:38548731 paediatric de novo case,
  PMID:12531876 Mogensen for the restrictive differential) were each fetched
  with `just fetch-reference` and quoted only from the cached record. One
  report suggestion was rejected on checking: it proposed Apical hypertrophic
  cardiomyopathy (HP:0031992) from the OMIM:613690 HPO annotation set, but the
  cited abstract does not support it and a genotype-morphology study
  (PMID:37561025) places TNNI3 hypertrophy in the anterior wall, interventricular
  septum, and lateral wall while attributing apical predominance to ALPK3, so no
  apical phenotype is curated. The report's Wolff-Parkinson-White suggestion was
  likewise dropped for lack of a quotable primary source.

  Evidence provenance caveats. (1) TNNI3-specific human cohort data are sparse,
  so several items are drawn from thin-filament-wide (PMID:39941537) or
  hypertrophic-cardiomyopathy-wide (PMID:33926651, PMID:33171204, PMID:32871100,
  PMID:41463072) studies; each such explanation states the scope explicitly and
  uses PARTIAL where the inference is indirect. (2) Mavacamten evidence comes
  from EXPLORER-HCM, which enrolled obstructive hypertrophic cardiomyopathy
  irrespective of genotype; there is no TNNI3-specific trial. (3) Mechanistic
  depth relies on the Gly203Ser transgenic mouse (PMID:16950368, PMID:34203369)
  and on reconstituted-myofilament biochemistry for K206I (PMID:26553696); these
  are tagged MODEL_ORGANISM and IN_VITRO respectively and are never the sole
  support for a human phenotype.

  GeneReviews baseline: there is no TNNI3-specific GeneReviews chapter, so the
  applicable resource is "Nonsyndromic Hypertrophic Cardiomyopathy Overview"
  (PMID:20301725), tagged accordingly in `references`. The indexed PubMed record
  contains only the chapter's six-clause purpose statement rather than the
  Clinical Characteristics or Management sections, so section-by-section
  GeneReviews mining is not possible from the cache; the one verbatim-quotable
  clause is cited on the cascade-testing treatment entry. Chapter-level
  phenotypes not quotable from the cached record (chest pain, syncope,
  palpitations, presyncope, exercise intolerance) are therefore not curated as
  separate phenotype entries rather than being supported by fabricated quotes.

  The 2024 AHA/ACC hypertrophic cardiomyopathy guideline (PMID:38718139) is
  listed in `references` for management provenance; its PubMed record is a
  structured AIM/METHODS/STRUCTURE abstract with no quotable clinical
  recommendations, so no evidence item quotes it.

📚

References & Deep Research

References

2

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.

Deep Research

1

Claude Code ▸

1. Disease Information

claude-haiku-4-5-20251001, claude-opus-5[1m] 32 citations 2026-08-01T21:21:38.105173

1. Disease Information

1.1 Overview

Hypertrophic cardiomyopathy 7 (CMH7) is the designation in the OMIM/MONDO numbered-series nosology for hypertrophic cardiomyopathy caused by heterozygous pathogenic variants in TNNI3, the gene encoding cardiac troponin I (cTnI), the inhibitory subunit of the cardiac thin-filament troponin complex. It is one of the "thin-filament" sarcomeric hypertrophic cardiomyopathies, mechanistically and prognostically distinguishable from the far more common "thick-filament" forms caused by MYBPC3 and MYH7.

TNNI3 was established as the seventh HCM disease gene by Kimura and colleagues in 1997 — hence the numeral in "CMH7" (Kimura et al., Nat Genet 1997;16(4):379-82; PMID:9241277):

[verbatim] "Because all the known disease genes encode major contractile elements in cardiac muscle, we have systematically characterized the cardiac sarcomere genes, including cardiac troponin I (cTnI), cardiac actin (cACT) and cardiac troponin C (cTnC) in 184 unrelated patients with HCM and found mutations in the cTnI gene in several patients. Family studies showed that an Arg145Gly mutation was linked to HCM and a Lys206Gln mutation had occurred de novo, thus strongly suggesting that cTnI is the seventh HCM gene."

CMH7 is not a clinically separable entity at the bedside — a patient with TNNI3-HCM presents as HCM. The entry's justification is genotype-anchored: TNNI3 variants carry a distinctive allelic-series signature (HCM ↔ restrictive cardiomyopathy ↔ dilated cardiomyopathy from the same gene, sometimes the same variant), a distinctive mechanistic signature (myofilament Ca²⁺ sensitization with impaired relaxation rather than primary hypercontractility), and, for at least one variant, a distinctive prognostic signature (malignant early sudden death).

1.2 Key Identifiers

Resource	Identifier	Notes
MONDO ✅	MONDO:0013369 — hypertrophic cardiomyopathy 7	Verified via OAK. Def: "Any hypertrophic cardiomyopathy in which the cause of the disease is a mutation in the TNNI3 gene." `is_a` MONDO:0024573 (familial hypertrophic cardiomyopathy); `RO:0004003` → HGNC:11947 (TNNI3); subsets: `rare`, `nord_rare`, `gard_rare`
OMIM (phenotype)	#613690 — CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 7; CMH7
OMIM (gene)	*191044 — TROPONIN I, CARDIAC; TNNI3
DOID	DOID:0110313	MONDO xref
MedGen / UMLS	C1860752 (MedGen UID 348695)
GARD	GARD:0024916
HGNC	HGNC:11947 (`hgnc:11947` in dismech lowercase convention)
NCBI Gene	7137
UniProt	P19429 (TNNI3_HUMAN)	210 aa, 24,008 Da
Cytogenetic location	19q13.42	OMIM renders as 19q13
Orphanet	No CMH7-specific ORPHA code. Parent: ORPHA:217569 (Familial isolated hypertrophic cardiomyopathy) — verify code before citing
ICD-10	I42.1 (obstructive HCM) / I42.2 (other HCM)	No CMH7-specific code
ICD-11	BC43.00 Hypertrophic cardiomyopathy (approximate; verify)
MeSH	D002312 (Cardiomyopathy, Hypertrophic) / D024741 (Cardiomyopathy, Hypertrophic, Familial)
ClinGen GCEP	TNNI3 — Definitive for autosomal dominant HCM

1.3 Synonyms and Alternative Names

From the verified MONDO record (OAK output): - CMH7 (EXACT; DOID:0110313, OMIM:613690) - TNNI3 hypertrophic cardiomyopathy (EXACT; MONDO design pattern) - hypertrophic cardiomyopathy caused by mutation in TNNI3 (EXACT) - cardiomyopathy, familial hypertrophic, type 7 (EXACT) - cardiomyopathy, hypertrophic, 7 (EXACT) - hypertrophic cardiomyopathy type 7 (EXACT) - cardiomyopathy, familial hypertrophic, 7 (RELATED)

Additional literature/GTR synonyms: TNNI3-related familial hypertrophic cardiomyopathy; cardiac troponin I–related HCM; thin-filament HCM (TNNI3 subtype). Note that GTR also lists "CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 7, MODIFIER OF" — a distinct OMIM concept for modifier alleles.

1.4 Provenance of the Information

Content for this entry derives from aggregated disease-level resources (OMIM, MONDO, ClinVar/ClinGen, HPO, UniProt) layered on primary human-clinical literature — family linkage studies (Kimura 1997; Mogensen 2003), multicenter genotype–phenotype cohorts (Coppini 2014; Pua 2020), and founder-population cascade screening (Fahed 2020) — plus model-organism (transgenic and knock-in mouse) and in vitro (skinned fiber, iPSC-CM, engineered heart tissue) mechanistic work. There is no EHR/individual-patient data source specific to CMH7 in this report; the population-scale genetic architecture data (Pua 2020) come from case–control sequencing rather than EHR phenotyping.

2. Etiology

2.1 Disease Causal Factors

CMH7 is a monogenic, autosomal dominant, primary sarcomeric disorder. The causal factor is a heterozygous (rarely homozygous/compound heterozygous) variant in TNNI3 that alters cardiac troponin I protein sequence. ClinGen's Hereditary Cardiovascular Disease GCEP classified the mechanism as "altered gene product sequence" with monoallelic inheritance — i.e., missense/in-frame variants acting through a poison-peptide / dominant-negative route, not haploinsufficiency. This is a crucial curation point: TNNI3 truncating variants are not an established cause of HCM (and where biallelic truncating variants occur, the phenotype is lethal infantile dilated cardiomyopathy, a different entity).

The 2025 ClinGen reappraisal (Hespe et al., J Am Coll Cardiol 2025;85(7):727-740; PMID:39971408; DOI:10.1016/j.jacc.2024.12.010) confirmed TNNI3 = Definitive for autosomal dominant HCM, one of only nine definitive sarcomere HCM genes.

There is no infectious, toxic, or acquired etiology for CMH7 itself. Environmental factors act only as modifiers/triggers (§2.3, §5).

2.2 Genetic Risk Factors

Primary causal variants (§4 for full detail). The dominant genetic risk factor is the TNNI3 variant.

Low-penetrance risk alleles. A distinct and curation-relevant category: some TNNI3 missense variants behave as population-enriched, low-penetrance risk alleles rather than high-penetrance Mendelian variants. Pua et al. (Circ Genom Precis Med 2020; PMID:32815737) reported:

[verbatim] "Two missense variants in thin filament encoding genes were commonly seen in Singaporean HCM (TNNI3:p.R79C, disease allele frequency [AF]=0.018; TNNT2:p.R286H, disease AF=0.022) and are enriched in Singaporean HCM when compared with Asian controls. Both variants have conflicting annotations in ClinVar and are of low penetrance but predicted deleterious."

[verbatim] "Chinese HCM patients commonly have low penetrance risk alleles in TNNT2 or TNNI3 but exhibit few clinically actionable HCM variants overall, highlighting the need for greater study of HCM genetics in non-White populations."

UniProt additionally annotates p.Pro82Ser (rs77615401) as a "CMH7 risk" allele rather than a fully penetrant causal variant.

Modifier genes and oligogenic burden. Multiple sarcomere variants (compound/double heterozygosity) confer earlier onset and worse outcomes in HCM generally; low-penetrance sarcomere variants contribute additively to HCM risk (see Circulation 2024/2025, "Low Penetrance Sarcomere Variants Contribute to Additive Risk in Hypertrophic Cardiomyopathy" — verify PMID before citing). HCM polygenic background scores modulate penetrance in genotype-positive individuals. No TNNI3-specific modifier locus has been established. OMIM does carry a separate concept "CARDIOMYOPATHY, FAMILIAL HYPERTROPHIC, 7, MODIFIER OF," reflecting variants that modify rather than cause.

Family history is the single strongest clinical genetic risk factor: first-degree relatives of a proband have a 50% prior probability of carrying the variant.

2.3 Environmental Risk Factors

No environmental exposure causes CMH7. Established phenotype modifiers / event triggers in HCM broadly, applicable to CMH7: - Intense competitive/burst exertion — historically the classic trigger for SCD in HCM; the 2024 AHA/ACC guideline substantially liberalized exercise restrictions relative to prior guidance (PMID:38718139). - Hypertension, obesity, and metabolic syndrome — amplify LV hypertrophy and accelerate progression to heart failure. - Male sex — associated with earlier diagnosis and greater hypertrophy in HCM generally. Notably, in the TNNI3 p.Arg21Cys founder cohort, no sex difference in SCD was observed (46.4% women vs 48.3% men) [paraphrase]. - Age — age-dependent penetrance; hypertrophy typically emerges during adolescent growth spurt or, for a TNNI3-enriched subset, in the sixth–seventh decade (§8). - Dehydration, vasodilators, and sudden preload reduction — provoke dynamic LVOT obstruction in the obstructive subset.

2.4 Protective Factors

Genetic: Being genotype-negative in a family with a known pathogenic TNNI3 variant is definitively protective; the 2024 AHA/ACC guideline recommends discharging such relatives from surveillance unless the variant is later reclassified. No established protective TNNI3 allele or protective modifier haplotype has been reported.
Environmental/therapeutic: Blood-pressure and weight control; avoidance of dehydration and volume depletion; ICD placement (secondary/primary prevention of arrhythmic death). Whether early disease-modifying pharmacotherapy in genotype-positive/phenotype-negative carriers prevents phenotype development remains unproven — this is the central open question of the VANISH-type trial paradigm (valsartan in early sarcomeric HCM) and of ongoing cardiac myosin inhibitor prevention studies.

2.5 Gene–Environment Interactions

The best-documented G×E axis in CMH7 is β-adrenergic signaling × the Ser23/Ser24 PKA phosphorylation site. cTnI Ser23/Ser24 phosphorylation by PKA is the molecular substrate of the β-adrenergic lusitropic (relaxation-enhancing) response: phosphorylation reduces myofilament Ca²⁺ sensitivity, accelerating relaxation during exercise/catecholamine surge. Variants in or near the RRRSS consensus motif (notably p.Arg21Cys) abolish this phosphorylation, so the carrier heart cannot mount the normal adrenergic relaxation response. The consequence is that catecholaminergic stress — exercise, emotion, illness — becomes selectively arrhythmogenic and diastolically decompensating in these carriers. Wang et al. showed the mouse counterpart directly:

[verbatim] "the R21C mutation abolished the in vivo phosphorylation of Ser(23)/Ser(24) in the mutant cTnI" (Wang et al., J Biol Chem 2012; PMID:22086914; DOI:10.1074/jbc.M111.294306)

and reported that isolated myocytes from older R21C mice show significant delays in Ca²⁺ decay and sarcomere relaxation only in the presence of isoproterenol — an explicitly stress-conditional phenotype [paraphrase — verify exact wording].

A second G×E consideration: afterload (hypertension) × sarcomere Ca²⁺ sensitization compounds the energetic mismatch (§6.4).

3. Phenotypes

3.1 HPO Annotations Curated to OMIM:613690

Retrieved from the HPO annotation API (ontology.jax.org/api/network/annotation/OMIM:613690). All HP IDs below verified with OAK ✅.

HP ID	Term	Frequency (as annotated)	Source
HP:0001639 ✅	Hypertrophic cardiomyopathy	2/2	PMID:11815426
HP:0031992 ✅	Apical hypertrophic cardiomyopathy	3/6	PMID:9241277
HP:0001716 ✅	Wolff-Parkinson-White syndrome	3/6	PMID:9241277
HP:0001714 ✅	Ventricular hypertrophy	(unspecified)	OMIM:613690
HP:0005110 ✅	Atrial fibrillation	Occasional	OMIM:613690
HP:0003581 ✅	Adult onset	6/6	PMID:11815426
HP:0000006	Autosomal dominant inheritance	—	PMID:9241277

Important caveat on the HPO frequency denominators: these are tiny (2/2, 3/6, 6/6) and derive from two specific papers. PMID:11815426 is Niimura et al., Circulation 2002, "Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly" — a late-onset cohort (symptoms at 59.3 ± 12.3 y, diagnosis at 62.8 ± 10.8 y). The "Adult onset 6/6" annotation therefore reflects an ascertainment-biased elderly-onset series, not the natural onset distribution of TNNI3-HCM, which includes pediatric and adolescent presentations (see §3.3, §8.1). Do not propagate "adult onset, 6/6" as a general CMH7 frequency claim.

3.2 Additional Phenotypes Documented in the CMH7 Literature (HPO Suggestions)

These are well-documented for TNNI3-HCM in the primary literature but are not in the OMIM:613690 HPO annotation set. All HP IDs verified with OAK ✅.

Structural / cardiac morphology | HP ID | Term | Comment | |---|---|---| | HP:0001670 ✅ | Asymmetric septal hypertrophy | Classic HCM morphology | | HP:0005144 ✅ | Ventricular septal hypertrophy | | | HP:0031333 ✅ | Myocardial sarcomeric disarray | Histopathological hallmark; documented on autopsy in p.Arg21Cys carriers without gross LVH | | HP:0031318 ✅ | Myofiber disarray | Broader parent | | HP:0001685 ✅ | Myocardial fibrosis | Progressive; LGE on CMR | | HP:0032092 ✅ | Left ventricular outflow tract obstruction | Less common in thin-filament HCM (19% vs 34% thick-filament, Coppini 2014) | | HP:0001723 ✅ | Restrictive cardiomyopathy | Allelic/overlap phenotype (§3.4) |

Functional | HP ID | Term | Comment | |---|---|---| | HP:0025168 ✅ | Left ventricular diastolic dysfunction | The core functional lesion of CMH7 | | HP:0001635 ✅ | Congestive heart failure | Thin-filament HCM progresses to advanced HF more often |

Arrhythmic | HP ID | Term | Comment | |---|---|---| | HP:0011675 ✅ | Arrhythmia | | | HP:0004308 ✅ | Ventricular arrhythmia | | | HP:0004756 ✅ | Ventricular tachycardia | NSVT more common in pediatric thin-filament HCM | | HP:0001645 ✅ | Sudden cardiac death | 53% of affected p.Arg21Cys carriers | | HP:0001695 ✅ | Cardiac arrest | | | HP:0005110 ✅ | Atrial fibrillation | | | HP:0001716 ✅ | Wolff-Parkinson-White syndrome | Specifically associated with the p.Gly203Ser variant (all 3 carriers in Kimura's series) |

Symptoms | HP ID | Term | |---|---| | HP:0002094 ✅ | Dyspnea | | HP:0001279 ✅ | Syncope | | HP:0100749 ✅ | Chest pain | | HP:0001962 ✅ | Palpitations |

OMIM's clinical synopsis for CMH7 describes ventricular hypertrophy that is "usually asymmetric and often involves the interventricular septum," with "dyspnea, syncope, collapse, palpitations, and chest pain; symptoms can be readily provoked by exercise" [paraphrase from OMIM summary — OMIM is not a PMID-citable evidence source in dismech; find a primary reference for each of these].

3.3 Phenotype Characteristics

Age of onset — genuinely bimodal/variable. - Pediatric/adolescent: Documented and clinically important. Fahed 2020's Lebanese founder cohort was ascertained specifically for pediatric-onset disease; median age at SCD was 22.5 years. A 2024 case report describes a 14-year-old girl with de novo TNNI3 c.583A>T (p.Ile195Phe) presenting with nonobstructive HCM and cardiopulmonary arrest from ventricular fibrillation (PMID:38548731). Norrish et al. (J Med Genet 2024;61(5):420-2; PMID:38296631) report a childhood-onset thin-filament HCM cohort. - Adult (typical): Second–fourth decade, as for HCM generally. - Elderly-onset: TNNI3 is over-represented among late-onset HCM. Niimura et al. found cTnI missense variants among 8 sarcomere variants in 31 patients diagnosed at 62.8 ± 10.8 y:

[verbatim] "Whereas defects in beta-cardiac myosin heavy chain, cardiac troponin T, and alpha-tropomyosin account for > 45% of familial hypertrophic cardiomyopathy, none were found here. Rather, mutations in cardiac myosin binding protein-C, troponin I, and alpha-cardiac myosin heavy chain caused elderly-onset hypertrophic cardiomyopathy." (PMID:11815426)

Severity — highly variable, both inter- and intrafamilial. OMIM notes disease expression "ranging from benign forms to malignant forms with high risk of cardiac failure and sudden cardiac death" [paraphrase]. Twin siblings homozygous for the same TNNI3 variant have been reported with restrictive and hypertrophic phenotypes respectively [paraphrase — locate and verify the primary report].

Progression — progressive. Documented progression to myocardial fibrosis, LV remodeling, and advanced heart failure. Coppini 2014 found thin-filament HCM (which includes TNNI3) had more frequent progression to NYHA III-IV / advanced HF (15% vs 5%) and more systolic dysfunction or restrictive filling (20% vs 9%) than thick-filament HCM [paraphrase — the JACC abstract numbers must be re-verified verbatim].

Frequency among affected individuals. Aside from the small HPO denominators above, the most robustly quantified phenotype frequency in a TNNI3 cohort is from Fahed 2020's p.Arg21Cys founder families (n=57 affected) [all paraphrase — re-verify]: - SCD: 30/57 (53%), median age 22.5 y - SCD as the first presentation: 25/30 (83.3%) - LVH on echocardiography among carriers: 19/30 (63.3%) - No LVH on echocardiography among carriers who nonetheless had events: 9/30 (30%)

3.4 The `TNNI3` Allelic Phenotype Spectrum (critical for entry scoping)

TNNI3 is unusual among sarcomere genes for producing four distinct cardiomyopathy phenotypes, which UniProt's variant table catalogues explicitly:

Phenotype	OMIM	Representative UniProt-annotated variants
CMH7 — hypertrophic	#613690	R141Q, R145G, A157V, R162P/Q, S166F, K177del, R186Q, D190H, D196N, R204H, K206Q; P82S (risk allele)
RCM1 — restrictive	#115210	L144Q, R145W, A171T, K178E, D190H, R192H
CMD1FF / CMD2A — dilated	#613286 / #611880	A2V, K36Q, A116G, N185K

Note R145 and D190 appear in both the HCM and RCM columns — the same residue (and in D190H's case the same substitution) can produce either phenotype. This is why Restrictive cardiomyopathy (HP:0001723) belongs in the CMH7 phenotype list as an overlap/spectrum finding, and why Mogensen's landmark paper is required reading:

[verbatim] "We recognized a large family in which individuals were affected by either idiopathic RCM or hypertrophic cardiomyopathy (HCM). Linkage analysis to selected sarcomeric contractile protein genes identified cardiac troponin I (TNNI3) as the likely disease gene. Subsequent mutation analysis revealed a novel missense mutation, which cosegregated with the disease in the family (lod score: 4.8). To determine if idiopathic RCM is part of the clinical expression of TNNI3 mutations, genetic investigations of the gene were performed in an additional nine unrelated RCM patients with restrictive filling patterns, bi-atrial dilatation, normal systolic function, and normal wall thickness. TNNI3 mutations were identified in six of these nine RCM patients. Two of the mutations identified in young individuals were de novo mutations. All mutations appeared in conserved and functionally important domains of the gene." (Mogensen et al., J Clin Invest 2003;111(2):209-16; PMID:12531876; DOI:10.1172/JCI16336)

Curation guidance: keep CMH7 (MONDO:0013369) distinct from TNNI3-related RCM (RCM1, MONDO term for OMIM:115210) and TNNI3-related DCM, but cross-reference them and document the shared mechanism. This is a natural candidate for a Grouping (grouping_basis: SHARED_GENE_FAMILY + SHARED_MECHANISM) over the TNNI3 allelic series.

3.5 Quality-of-Life Impact

No CMH7-specific QoL literature exists. HCM-general instruments and findings: - KCCQ-CSS (Kansas City Cardiomyopathy Questionnaire – Clinical Summary Score) and HCMSQ-SoB (HCM Symptom Questionnaire, Shortness-of-Breath subscore) are the validated, regulatory-accepted HCM PROs. EXPLORER-HCM showed mavacamten improved KCCQ-CSS by +9.1 points (95% CI 5.5 to 12.7) and HCMSQ-SoB by −1.8 (−2.4 to −1.2), p<0.0001 [verbatim from abstract]. - Per-phenotype QoL drivers in TNNI3-HCM specifically: exertional dyspnea and diastolic heart failure (the dominant symptomatic burden given the thin-filament restrictive physiology), ICD-related anxiety and shock burden, exercise restriction, and family/reproductive anxiety given the 50% transmission risk and the documented pattern of SCD as first presentation.

4. Genetic / Molecular Information

4.1 Causal Gene

TNNI3 — troponin I3, cardiac type. - HGNC:11947 · NCBI Gene 7137 · Ensembl ENSG00000129991 · UniProt P19429 - Cytogenetic location 19q13.42 - Reference transcript for HGVS: NM_000363.5 (protein NP_000354.4) - 8 exons; protein 210 aa, 24,008 Da - OMIM gene entry *191044 - Aliases (per NCBI Gene): cTnI, CMH7, RCM1, CMD1FF, CMD2A

Protein architecture (UniProt P19429, verified): | Region | Residues | Function | |---|---|---| | Cardiac-specific N-terminal extension | 1–43 (disordered) | Unique to the cardiac isoform; the β-adrenergic regulatory module | | PKA phosphorylation sites | Ser23, Ser24 | PKA/PKD1-mediated phosphorylation reduces Ca²⁺ sensitivity (lusitropy) | | PKC phosphorylation sites | Ser42, Ser44 | PKC/PRKCE-dependent | | TnC-binding region | 32–79 | | | TnI–TnT interaction | ~80, ~97 | IT-arm coiled coil | | Inhibitory region + actin/TnC-binding ("switch") region | ~129–149 | The Ca²⁺-dependent actin/TnC switch; the HCM/RCM mutation hotspot | | C-terminal mobile domain | ~150–210 | Second actin-binding site; modulates the inhibitory region | | Additional kinase sites | Thr31, Thr51, Thr129, Thr143 (STK4/MST1); Ser5/6, Tyr26, Ser77, Thr78, Ser166, Thr181, Ser199 | |

Function (UniProt): [verbatim] "Inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity."

Subcellular localization: cardiac myofibril; sarcomere; troponin complex (GO:0005861 ✅; cardiac troponin complex GO:1990584 ✅).

4.2 Variant Spectrum

Positional clustering. From the pediatric case report (PMID:38548731):

[verbatim] "Approximately 80% of reported pathological variants of TNNI3 are located in exons 7 and 8, which encode the domains that interact with myocardial actin and cardiac troponin C, which are sarcomere components"

This maps precisely onto the inhibitory/switch region and C-terminal mobile domain (residues ~130–210).

CMH7 variants annotated in UniProt P19429 (position → substitution, dbSNP):

Protein change	dbSNP	Phenotype per UniProt
p.Arg21Cys	rs104894723 (verify)	CMH7 — the only N-terminal-extension HCM variant
p.Pro82Ser	rs77615401	CMH7 risk allele
p.Arg141Gln	rs397516347	CMH7
p.Arg145Gly	rs104894724	CMH7 (Kimura's linked variant)
p.Arg145Trp	rs104894724	RCM1 (same residue, different substitution)
p.Leu144Gln	rs121917760	RCM1
p.Ala157Val	rs397516353	CMH7
p.Arg162Pro / p.Arg162Gln	rs397516354	CMH7
p.Ser166Phe	rs727504242	CMH7
p.Ala171Thr	rs121917761	RCM1
p.Lys177del	—	CMH7 (in-frame deletion)
p.Lys178Glu	rs104894730	RCM1
p.Arg186Gln	rs397516357	CMH7
p.Asp190His	—	*CMH7 and* RCM1**
p.Arg192His	rs104894729	RCM1
p.Asp196Asn	rs104894727	CMH7
p.Arg204His	rs727504275	CMH7
p.Lys206Gln	rs104894725	CMH7 (Kimura's de novo variant)

Additional literature-reported CMH7 variants not in the above extract: p.Gly203Ser (associated with WPW in all 3 carriers, Kimura 1997), p.Ile195Phe (c.583A>T, de novo, pediatric VF; PMID:38548731), p.Arg79Cys (c.235C>T, low-penetrance risk allele enriched in Chinese populations; PMID:32815737), p.Lys183del (Japanese apical HCM — verify primary source), p.Arg170Trp/Gly (infantile RCM).

Variant type / class: overwhelmingly missense, with occasional in-frame single-codon deletions (K177del, K183del, R170 region). Splice-site and frameshift/nonsense TNNI3 variants are not an established HCM mechanism; biallelic truncating variants cause lethal infantile DCM instead (see PMC11196996 — homozygous TNNI3 frameshift in a consanguineous family with lethal infantile DCM; verify PMID).

Variant classification (ACMG/AMP). ClinGen has a TNNI3-specific variant curation specification: CSpec GN098 (cspec.genome.network/cspec/ui/svi/doc/GN098), developed under the Hypertrophic Cardiomyopathy / Cardiomyopathy VCEP. Curators should apply gene-specific PM1 (hotspot = exons 7–8 / inhibitory-switch region), calibrated PS4/PM2 population thresholds, and functional-assay PS3 criteria per that spec rather than generic ACMG rules.

Allele frequency. Pathogenic TNNI3 variants are individually ultra-rare (typically absent from gnomAD or at AF < 1×10⁻⁵). Exceptions that matter: - p.Arg79Cys — enriched in East/Southeast Asian populations, HCM disease AF = 0.018 (PMID:32815737); present in gnomAD East Asian controls at appreciable frequency → PM2 does not apply, and conflicting ClinVar annotations abound. - rs397516354 (p.Arg162Gln/Pro) — reported gnomAD frequency ~0.006% [paraphrase — verify against gnomAD directly]. - p.Arg21Cys — founder allele in South Lebanon (see §9).

Somatic vs germline: germline exclusively. TNNI3 is not a somatic cancer gene; COSMIC/TCGA are not relevant. De novo germline variants are well documented (Kimura's K206Q; two of Mogensen's RCM variants; the p.Ile195Phe pediatric case).

Functional consequence class: Gain-of-function / dominant-negative (poison peptide). The mutant cTnI incorporates into the thin filament alongside wild-type protein and actively corrupts regulation; there is no evidence for a haploinsufficiency mechanism. Wang 2012 measured ~25% mutant cTnI incorporation in heterozygous knock-in mouse hearts [paraphrase] — a small mutant fraction sufficient to produce a phenotype, consistent with dominant negativity. ClinGen's dosage-sensitivity curation for TNNI3 (HGNC:11947) should be consulted before asserting any haploinsufficiency claim.

4.3 Modifier Genes

No TNNI3-specific modifier gene is established. General HCM modifiers that plausibly apply: - Second sarcomere variants (compound/double heterozygosity) → earlier onset, worse outcome. - HCM polygenic risk score background. - Candidate (weak evidence) modifiers reported in HCM broadly: ACE I/D, endothelin-1, angiotensinogen polymorphisms — historically reported, poorly replicated; do not curate as established. - OMIM's separate "CMH7, MODIFIER OF" concept implies at least one curated modifier allele in TNNI3 itself; verify against the OMIM entry before curating.

4.4 Epigenetic Information

No CMH7-specific epigenetic data exist. Established for HCM/hypertrophied myocardium generally (and therefore downstream-consequence rather than cause): - Fetal gene program reactivation (NPPA, NPPB, MYH7/MYH6 isoform switch) — Wang 2012 explicitly reports that R21C knock-in mice "activated the fetal gene program" [paraphrase]. - Differential DNA methylation and histone acetylation signatures in HCM myectomy tissue; HDAC inhibition has been explored preclinically as an antihypertrophic strategy. - Search resources: GEO (myectomy tissue datasets), ENCODE, Roadmap Epigenomics heart samples. No TNNI3-genotype-stratified epigenomic dataset is known.

4.5 Chromosomal Abnormalities

Not applicable. CMH7 is caused by point/in-frame variants. Chromosomal microarray, karyotype, and FISH have no diagnostic role for CMH7 and should be flagged as not indicated. Large deletions/duplications of TNNI3 are not an established HCM mechanism (consistent with the non-haploinsufficiency mechanism), though most clinical panels include del/dup analysis (31 of 47 GTR-listed TNNI3 tests offer it).

5. Environmental Information

Environmental toxins / radiation / occupational exposure: No established causal or modifying role specific to CMH7. CTD/TOXNET yield no TNNI3-HCM–specific exposure associations.
Lifestyle factors: As in §2.3 — high-intensity burst exercise (arrhythmic trigger), obesity and hypertension (phenotype amplifiers), dehydration and alcohol (LVOT gradient provocation in the obstructive subset). Anabolic-androgenic steroid use is a recognized HCM-phenocopy/aggravating exposure and must be excluded in differential diagnosis.
Infectious agents: Not applicable. No pathogen causes or triggers CMH7. (Concurrent myocarditis is a differential-diagnosis consideration for acute decompensation, not an etiology.)

6. Mechanism / Pathophysiology

6.1 The Causal Chain (upstream → downstream)

This is the recommended pathograph for a dismech pathophysiology: block. Nodes are annotated with biological_scale per the dismech enum.

Node 1 — TNNI3 missense variant in cardiac troponin I · biological_scale: MOLECULAR Heterozygous missense (or in-frame indel) variant, predominantly in exons 7–8 encoding the inhibitory/switch and C-terminal mobile domains. Mutant cTnI is expressed and incorporates into the sarcomeric thin filament alongside wild-type protein (~25% mutant fraction in heterozygous knock-in mice). - Gene: hgnc:11947 (TNNI3) - GO CC: GO:1990584 ✅ cardiac Troponin complex; GO:0030017 ✅ sarcomere - ↓ downstream

Node 2 — Impaired Ca²⁺-dependent thin-filament inhibition · biological_scale: MOLECULAR Two distinguishable molecular lesions, depending on variant location: - (a) Switch/inhibitory-region variants (R145G, R162Q, D190H, K206Q, I195F…) — the mutant inhibitory region fails to hold the tropomyosin–actin filament in the blocked state at low Ca²⁺, and the actin/TnC switch is biased toward the activated conformation. Wen et al. demonstrated this directly:

[verbatim] "The addition of 3 mm 2,3-butanedione monoxime at pCa 9.0 showed that there was approximately 2-4% of force generating cross-bridges attached in Tg-R145G fibers compared with less than 1.0% in Tg-WT fibers, suggesting that the mutation impairs the ability of the cardiac troponin complex to fully inhibit cross-bridge attachment under relaxing conditions." (PMID:18430738) - (b) N-terminal extension variant (R21C) — destroys the PKA phosphorylation consensus, locking the filament in the unphosphorylated, high-Ca²⁺-sensitivity state and abolishing β-adrenergic lusitropy. - GO BP: GO:0032971 ✅ regulation of muscle filament sliding; GO:1904114 ✅ positive regulation of muscle filament sliding; GO:0055117 ✅ regulation of cardiac muscle contraction - ↓

Node 3 — Increased myofilament Ca²⁺ sensitivity · biological_scale: MOLECULAR The unifying biophysical signature of TNNI3 cardiomyopathy variants, measured as a leftward shift of the force–pCa and ATPase–pCa relationships in skinned fibers.

[verbatim] "Simultaneous measurements of ATPase activity and force in skinned papillary fibers from hcTnI R145G transgenic mice (Tg-R145G) versus hcTnI wild type transgenic mice (Tg-WT) showed a significant decrease in the maximal Ca(2+)-activated force without changes in the maximal ATPase activity and an increase in the Ca(2+) sensitivity of both ATPase and force development." (PMID:18430738)

Note the mechanistically important dissociation: Ca²⁺ sensitivity ↑ but maximal force ↓. TNNI3-HCM is therefore not simply "hypercontractility" in the MYH7 R403Q sense — it is a regulatory/relaxation defect. This is the mechanistic root of the thin-filament clinical phenotype (mild hypertrophy, prominent diastolic/restrictive physiology). - GO BP: GO:0010882 ✅ regulation of cardiac muscle contraction by calcium ion signaling - ↓ (branches to Nodes 4a, 4b, 4c)

Node 4a — Impaired diastolic relaxation (incomplete cross-bridge detachment) · biological_scale: CELLULAR Residual force-generating cross-bridges persist at diastolic [Ca²⁺]; force and Ca²⁺ transients are prolonged.

[verbatim] "Prolonged force and intracellular [Ca(2+)] transients in electrically stimulated intact papillary muscles were observed in Tg-R145G compared with Tg-WT." (PMID:18430738) - Cell type: CL:2000046 ✅ ventricular cardiac muscle cell (parent CL:0000746 ✅ cardiac muscle cell) - Phenotype: HP:0025168 ✅ Left ventricular diastolic dysfunction - ↓

Node 4b — Myocardial energetic mismatch (increased tension cost) · biological_scale: CELLULAR Ca²⁺ sensitization plus reduced force-per-cross-bridge means more ATP consumed per unit of force generated.

[verbatim] "Energy cost calculations demonstrated higher energy consumption in Tg-R145G fibers compared with Tg-WT fibers." (PMID:18430738)

This is the mechano-energetic uncoupling paradigm central to modern HCM pathophysiology: excess ATP demand exceeds mitochondrial supply, depleting the phosphocreatine/ATP ratio, driving oxidative stress, and activating hypertrophic (ERK) and fibrotic signaling [paraphrase from recent reviews — verify a specific PMID before curating]. - GO BP: GO:0006936 muscle contraction (verify); ATP metabolic process GO:0046034 (verify) - ↓

Node 4c — Ca²⁺-handling remodeling and arrhythmogenic substrate · biological_scale: CELLULAR High myofilament Ca²⁺ buffering alters cytosolic Ca²⁺ transient shape and decay; the resulting Ca²⁺ mishandling, combined with disarray-generated conduction heterogeneity, creates the substrate for triggered activity and reentry. This is why TNNI3 carriers can die suddenly before developing hypertrophy. - Phenotypes: HP:0004308 ✅ Ventricular arrhythmia; HP:0001645 ✅ Sudden cardiac death - ↓

Node 5 — Compensatory hypertrophic and fibrotic remodeling · biological_scale: TISSUE Energetic stress and altered mechanotransduction activate the hypertrophic program (fetal gene reactivation) in cardiomyocytes and a fibrogenic program in cardiac fibroblasts.

[verbatim] "These results suggest that the phenotype of hypertrophic cardiomyopathy is most likely caused by the compensatory mechanisms in the cardiovascular system that are activated by 1) higher energy cost in the heart resulting from a significant decrease in average force per cross-bridge, 2) slowed relaxation (diastolic dysfunction) caused by prolonged [Ca(2+)] and force transients, and 3) an inability of the cardiac TnI to completely inhibit activation in the absence of Ca(2+) in Tg-R145G mice." (PMID:18430738)

Wang 2012 confirmed in the knock-in (rather than transgenic-overexpression) context: R21C⁺/⁻ and R21C⁺/⁺ mice "activated the fetal gene program and developed a remarkable degree of cardiac hypertrophy and fibrosis" [paraphrase]. - Cell types: CL:2000046 ✅ ventricular cardiac muscle cell; CL:0002548 ✅ fibroblast of cardiac tissue - GO BP: GO:0003300 ✅ cardiac muscle hypertrophy; GO:0014898 ✅ cardiac muscle hypertrophy in response to stress; GO:0010613 ✅ positive regulation of cardiac muscle hypertrophy - Phenotypes: HP:0001639 ✅ HCM; HP:0001670 ✅ Asymmetric septal hypertrophy; HP:0001685 ✅ Myocardial fibrosis; HP:0031333 ✅ Myocardial sarcomeric disarray - ↓

Node 6 — Clinical disease: diastolic heart failure, arrhythmia, sudden death · biological_scale: ORGANISM Restrictive filling physiology → elevated filling pressures → exertional dyspnea → progression to advanced heart failure; independently, arrhythmic death. - Phenotypes: HP:0001635 ✅ Congestive heart failure; HP:0002094 ✅ Dyspnea; HP:0001279 ✅ Syncope; HP:0001645 ✅ Sudden cardiac death; HP:0001723 ✅ Restrictive cardiomyopathy (in the RCM-overlap arm)

6.2 Molecular Pathways

Ca²⁺-troponin–tropomyosin thin-filament regulation (the primary lesion) — Reactome R-HSA-390522 "Striated Muscle Contraction"; KEGG hsa04260 "Cardiac muscle contraction"; KEGG hsa05410 "Hypertrophic cardiomyopathy (HCM)" — the most directly relevant curated pathway map.
β-adrenergic / PKA signaling (Ser23/Ser24 lusitropic axis) — KEGG hsa04261 "Adrenergic signaling in cardiomyocytes".
Downstream hypertrophic signaling: ERK1/2-MAPK, calcineurin–NFAT, and AMPK (energy-sensing) are implicated in the compensatory arm; PI3K-AKT-mTOR in growth. These are inferred from HCM-general literature, not TNNI3-specific data — curate with appropriate hedging.
TGF-β–driven interstitial fibrosis in the remodeling arm — a plausible conforms_to target for the dismech fibrotic_response module.

6.3 Cellular Processes

Excitation–contraction coupling; excitation–contraction uncoupling (the term used by Wang and colleagues for the chronic PKA-ablated state); cardiomyocyte hypertrophy; cardiac fibroblast activation and myofibroblast transition; cardiomyocyte oxidative stress; mitochondrial dysfunction. Cardiomyocyte apoptosis is a late/end-stage contributor.

6.4 Protein Dysfunction

The dysfunction is conformational/regulatory, not degradative. Mutant cTnI folds, is stably expressed, and integrates into the troponin complex — this is precisely what makes it a dominant-negative poison peptide. There is no misfolding, no aggregation, no proteasomal loss-of-protein mechanism. Three distinguishable structural failure modes: 1. Inhibitory/switch-region variants — the mutant fails to anchor the inhibitory region on actin at low Ca²⁺. 2. C-terminal mobile-domain variants — loss of the second actin-binding site that normally modulates the inhibitory region; also implicated in thin-filament structural integrity (the infantile RCM cTnI-R170G/W work shows impaired interplay of sarcomeric proteins and loss of thin-filament integrity). 3. N-terminal extension variant (R21C) — loss of the PKA phospho-switch; a regulatory-input failure rather than a filament-mechanics failure.

Structural resources: PDB 1J1E (human cardiac troponin core complex in the Ca²⁺-saturated state) is the canonical structure for mapping variants; AlphaFold DB entry for P19429 covers the disordered N-terminal extension not resolved crystallographically.

6.5 Metabolic Changes

Increased tension cost / ATP consumption per unit force (directly measured, PMID:18430738) → reduced myocardial phosphocreatine/ATP ratio; substrate shift from fatty-acid oxidation toward glucose utilization; creatine kinase system dysfunction. These are documented for HCM broadly (including in ³¹P-MRS studies of sarcomere-variant carriers) and mechanistically predicted for CMH7, but no TNNI3-genotype-specific human metabolomic study is known. Resources: HMDB, Metabolomics Workbench.

6.6 Immune System Involvement

Minimal and non-primary. CMH7 is not autoimmune, not immunodeficient, and not driven by chronic inflammation. Low-grade macrophage infiltration accompanies interstitial fibrosis in remodeling myocardium, as in other cardiomyopathies. Do not curate immune involvement as a mechanism node.

6.7 Tissue Damage Mechanisms

Myocyte disarray — the histopathological hallmark; loss of parallel myofiber alignment with whorled/interlacing architecture. Critically, disarray was found on autopsy in TNNI3 p.Arg21Cys carriers who had normal echocardiograms, establishing that the tissue lesion precedes gross hypertrophy [paraphrase].
Interstitial and replacement fibrosis — progressive; the CMR late-gadolinium-enhancement substrate; the arrhythmic substrate.
Microvascular ischemia — small-vessel dysplasia with medial hypertrophy and reduced capillary density relative to myocyte mass → supply-demand mismatch, compounding the energetic lesion of Node 4b.
Oxidative stress — downstream of mitochondrial overwork.

6.8 Biochemical Abnormalities

The defect is in a contractile regulatory protein, not an enzyme, receptor, or ion channel. There is no enzyme deficiency to assay. The measurable biochemical abnormalities are: - Reduced/abolished PKA phosphorylation of cTnI Ser23/Ser24 (R21C and, secondarily, in end-stage failing myocardium generally). - Leftward-shifted force–pCa relationship (ΔpCa₅₀) in skinned myocardium — the standard functional assay and the basis for ACMG PS3 in the TNNI3 CSpec. - Increased tension cost (ATPase/force ratio). - Circulating cardiac troponin I elevation — clinically, chronically mildly elevated hs-cTnI is common in HCM and prognostically adverse. LOINC: 89579-7 (Troponin I, cardiac, high sensitivity, serum/plasma) and 10839-9 (Troponin I, cardiac, serum/plasma) — verify LOINC codes before curating a reference_ranges block. Note the pleasing but non-causal irony: the mutated gene product is itself the standard clinical biomarker of myocardial injury. - NT-proBNP / BNP elevation tracks filling pressures and prognosis. LOINC 33762-6 (NT-proBNP) — verify.

6.9 Epigenetic Changes

See §4.4. Fetal gene program reactivation is the best-documented transcriptional-reprogramming event in the TNNI3 knock-in model.

6.10 Molecular Profiling

Modality	Status for CMH7	Notes / resources
Transcriptomics	HCM myectomy bulk and single-nucleus RNA-seq datasets exist in GEO; not `TNNI3`-genotype-stratified. GTEx provides `TNNI3` baseline expression (heart LV/AA-restricted).	GEO, GTEx, Human Cell Atlas
Proteomics	Sarcomere phospho-proteomics of human HCM myectomy tissue documents cTnI hypophosphorylation in disease. Wang 2012 used top-down MS to quantify cTnI phospho-status in R21C mice.	PRIDE, ProteomeXchange, Human Protein Atlas
Metabolomics	No CMH7-specific study. HCM-general FFA-metabolism abnormalities reported.	MetaboLights, Metabolomics Workbench
Lipidomics	No data.	LIPID MAPS
Genomic structural features	`TNNI3` is a small, compact, highly constrained gene; no recurrent SV.	Ensembl, dbVar, DGV

6.11 Advanced Technologies

Single-cell / single-nucleus: snRNA-seq of HCM myectomy tissue has resolved cardiomyocyte, fibroblast, and immune compartment shifts. Not yet TNNI3-stratified.
Spatial transcriptomics: applied to human HCM septal tissue to map disarray/fibrosis regions transcriptionally. Not TNNI3-specific.
iPSC-CM and engineered heart tissue (EHT) — this is where CMH7-adjacent single-variant work is strongest. Hasegawa et al. (Dev Growth Differ 2024; PMID:38193576; DOI:10.1111/dgd.12909) generated iPSCs from a patient with early-childhood-onset RCM carrying TNNI3 R170W, and compared them to an isogenic CRISPR-corrected line. R170W iPSC-CMs showed altered Ca²⁺ kinetics including prolonged tau, and R170W EHTs showed an increased ratio of relaxation force to contractile force; both were reversed in the isogenic control, and overexpression of wild-type TNNI3 rescued impaired relaxation [all paraphrase — verify against the abstract]. This is a direct in vitro demonstration of (i) mechanism, (ii) isogenic causality, and (iii) a gene-therapy rationale. A companion study (J Am Heart Assoc 2024, "Impaired Relaxation in Induced Pluripotent Stem Cell-Derived Cardiomyocytes with Pathogenic TNNI3 Mutation of Pediatric Restrictive Cardiomyopathy") reports the same lesion — verify PMID.
Multiparametric iPSC-CM phenotyping: a 2025 preprint ("Multiparametric Assessment of TNNI3 Variant Phenotypes in Human iPSC-Cardiomyocytes Correlates with Disease Severity in Patients", bioRxiv) reports variant-level in vitro phenotype correlating with clinical severity — preprint, not peer-reviewed; do not curate as evidence yet.
Functional genomics screens (CRISPR/RNAi): No TNNI3-HCM-specific screen. DepMap is not informative (non-essential in cancer lines).

7. Anatomical Structures Affected

7.1 Organ Level

Primary organ: the heart (UBERON:0000948 — verify), specifically the left ventricle. - UBERON:0002084 ✅ heart left ventricle — the primary site of hypertrophy - UBERON:0002094 ✅ interventricular septum — the classic maximal-hypertrophy site in asymmetric septal HCM - UBERON:0004667 ✅ interventricular septum muscular part - UBERON:0002349 ✅ myocardium - UBERON:0001083 ✅ myocardium of ventricle - Left ventricular apex — the distinctive site in "Japanese-type" apical HCM, over-represented in TNNI3 carriers (Kimura found 3/36 = 8.3% of apical HCM patients carried TNNI3 variants; HP:0031992 ✅ annotated 3/6 for CMH7)

Secondary involvement: - Left atrium (UBERON:0002079 — verify) — dilates secondary to chronic elevated filling pressures; substrate for atrial fibrillation (HP:0005110 ✅). Bi-atrial dilatation is a defining feature of the TNNI3 restrictive-overlap phenotype (Mogensen 2003). - Mitral valve / mitral apparatus — systolic anterior motion (SAM) and secondary mitral regurgitation in the obstructive subset (58% SAM in Niimura's late-onset series). - Pulmonary circulation — post-capillary pulmonary hypertension from chronically elevated left-heart filling pressures. - Right ventricle — involved in advanced/restrictive disease. Note that the R21C knock-in model showed differential contractile force generation between left and right ventricles (PMC4415466), an interesting chamber-asymmetry finding. - Systemic circulation / brain — cardioembolic stroke risk from AF.

Body systems: cardiovascular (primary and, essentially, exclusive). CMH7 is a non-syndromic, organ-restricted disorder — there is no skeletal muscle, CNS, renal, or dermatologic involvement, because TNNI3 expression is cardiac-restricted. This is a useful discriminator from HCM phenocopies (Fabry, Danon, Pompe, amyloidosis, RASopathies), all of which are multisystem.

7.2 Tissue and Cell Level

Tissue: cardiac muscle tissue (striated, involuntary); cardiac interstitium/connective tissue (fibrosis); intramural coronary microvasculature.

Cell populations: | CL ID | Cell type | Role | |---|---|---| | CL:2000046 ✅ | ventricular cardiac muscle cell | Primary affected cell — expresses mutant cTnI; site of Ca²⁺ sensitization, energetic stress, hypertrophy, disarray | | CL:0000746 ✅ | cardiac muscle cell | Broader parent | | CL:0002548 ✅ | fibroblast of cardiac tissue | Secondary effector — activated to myofibroblast, deposits interstitial/replacement fibrosis | | CL:0000115 | endothelial cell of vascular tree (verify) | Microvascular dysfunction/rarefaction | | CL:0000235 | macrophage (verify) | Minor; accompanies fibrotic remodeling |

Cell type NOT affected: skeletal muscle cells — TNNI3 is cardiac-specific (the skeletal paralogs are TNNI1 slow and TNNI2 fast). Atrial cardiomyocytes do express cTnI, so atrial myopathy is mechanistically expected and clinically observed as the AF substrate.

7.3 Subcellular Level

GO CC	Term	Relevance
GO:1990584 ✅	cardiac Troponin complex	The direct molecular site of the lesion
GO:0005861 ✅	troponin complex	Parent
GO:0030017 ✅	sarcomere
GO:0030016	myofibril (verify)
GO:0005865	striated muscle thin filament (verify)	The specific filament corrupted
GO:0005739	mitochondrion (verify)	Secondary — energetic stress / oxidative damage
GO:0016529	sarcoplasmic reticulum (verify)	Secondary — Ca²⁺-handling remodeling

7.4 Localization and Lateralization

Predominantly left-sided (left ventricle), with a strong predilection for the basal anterior interventricular septum; asymmetric by definition in the classic morphology (HP:0001670 ✅ Asymmetric septal hypertrophy).
Apical variant — a distinctive TNNI3-enriched morphology; hypertrophy confined to the LV apex, producing the classic "ace of spades" LV cavity on ventriculography/CMR and giant negative T waves in precordial leads.
Concentric or nonobstructive patterns are also seen; the pediatric p.Ile195Phe case was nonobstructive HCM.
In the restrictive-overlap arm, hypertrophy may be absent entirely with bi-atrial (bilateral) dilatation as the dominant morphologic finding.

8. Temporal Development

8.1 Onset

Typical age: Genuinely broad and trimodal in the literature, which is itself a curation-worthy fact: 1. Pediatric/adolescent (first–second decade) — documented in founder cohorts and de novo cases; associated with worse outcomes. 2. Young to middle adult (second–fourth decade) — the modal HCM presentation. 3. Elderly-onset (sixth–seventh decade) — TNNI3 is disproportionately represented here (Niimura 2002: symptoms at 59.3 ± 12.3 y, diagnosis at 62.8 ± 10.8 y, no family history of cardiomyopathy in any of the 31 patients).

For HPO curation, this means HP:0003581 (Adult onset) alone is insufficient; consider also HP:0011462 (Young adult onset), HP:0003621 (Juvenile onset), and HP:0003584 (Late onset) as a spread, with explicit frequency omission per the dismech frequency-evidence SOP unless a quantitative source supports each band.

Onset pattern: Insidious and chronic. Hypertrophy develops gradually, typically becoming echocardiographically detectable during adolescent somatic growth or in mid-to-late adulthood. The catastrophic exception: sudden cardiac death as the first manifestation — 83.3% of SCD events in the p.Arg21Cys founder cohort were the presenting event [paraphrase].

Critically: the genotype–phenotype latency is real and dangerous. Fahed 2020's central finding was that SCD occurred in carriers with entirely normal echocardiograms, with myocyte disarray found only at autopsy. Advanced imaging (tissue Doppler, CMR with LGE) detected subclinical disease in genotype-positive/phenotype-negative carriers [paraphrase]. This defines a preclinical stage with real event risk — a strong argument for TNNI3 genotype itself as a risk-stratification variable.

8.2 Progression

Disease stages (adapting the HCM natural-history framework): 1. Genotype-positive / phenotype-negative (G+/P−) — normal wall thickness; may show subtle diastolic abnormalities on tissue Doppler, ECG changes, or LGE. Not risk-free in TNNI3. 2. Classic hypertrophic phenotype — LVH ± obstruction, preserved EF, diastolic dysfunction. Most patients remain here lifelong. 3. Adverse remodeling — progressive fibrosis, atrial dilation, AF onset, worsening diastolic function, restrictive filling. 4. End-stage / "burnt-out" HCM (HCM with LV systolic dysfunction) — wall thinning, cavity dilation, EF < 50%. Thin-filament genotypes are over-represented here: Coppini 2014 reported progression to advanced HF in 15% of thin-filament vs 5% of thick-filament patients over 4.5 years mean follow-up [paraphrase]. 5. Restrictive phenotype — for the TNNI3 allelic-series arm; may bypass the hypertrophic stage entirely.

Progression rate: Slow and variable over decades in most patients; rapid in pediatric-onset and de novo cases (the p.Ile195Phe girl arrested ~1 year after diagnosis).

Course pattern: Chronic and progressive, punctuated by episodic arrhythmic events. Never relapsing-remitting.

Duration: Lifelong. No spontaneous resolution.

8.3 Patterns

Remission: No spontaneous remission. Treatment-induced regression of the LVOT gradient and symptoms occurs with mavacamten, myectomy, or ablation — but these relieve obstruction and symptoms; they are not demonstrated to reverse the underlying disarray/fibrosis in TNNI3-HCM, and CMH7 is less often obstructive than thick-filament HCM, making these interventions less frequently applicable.
Critical periods:
Adolescence — the window of most rapid hypertrophy development; also the peak age of exertional SCD in HCM. Justifies 1–2-yearly imaging in at-risk children (2024 AHA/ACC).
The G+/P− window — theoretically the optimal intervention point for disease modification, but no therapy is proven to prevent phenotype development.
Pre-conception / prenatal — the window for reproductive genetic counseling and PGT.

9. Inheritance and Population

9.1 Epidemiology

HCM overall: - Classic clinically-ascertained prevalence: ~1 in 500 (0.2%; 200 per 100,000) — the CARDIA-derived figure that dominated for two decades. - Revised, genotype- and imaging-inclusive estimate: ~1 in 200 (0.5%; 500 per 100,000) (Semsarian, Ingles, Maron & Maron, J Am Coll Cardiol 2015; PMID:25814232) — this figure includes G+/P− individuals at risk of developing disease. Also cited in the 2025 ClinGen reappraisal as "~1 in 500" [verbatim from that abstract], showing both figures remain in circulation; state which you mean.

CMH7 / TNNI3-HCM specifically: - TNNI3 accounts for ~3% of HCM (Fahed et al., Circ Genom Precis Med 2020; PMID:32885985): [verbatim] "Cardiac troponin I (TNNI3) gene mutations account for 3% of hypertrophic cardiomyopathy and carriers have a heterogeneous phenotype, with increased risk of sudden cardiac death (SCD)." - Alternative framing: <5% of cardiomyopathy patients carry pathogenic TNNI3 variants (PMID:38548731) [verbatim] "The prevalence of pathological variants of TNNI3 is reportedly less than 5% in patients with cardiomyopathies, with a relatively low penetrance of approximately 50%" - Within sarcomere-positive HCM specifically, one cohort reported 18/342 = 5.3% of single-variant Sarc+ patients had TNNI3 variants (vs MYBPC3 57.3%, MYH7 30.7%) [paraphrase — locate and verify the primary source].

Derived CMH7 prevalence estimate (for a dismech Prevalence record): Taking HCM point prevalence at 200 per 100,000 and TNNI3 at 3% of HCM → ~6 per 100,000 (≈1 in 17,000); using the 1-in-200 figure → ~15 per 100,000. This is a derived, not directly measured, figure — curate as:

population: Worldwide
measure_type: POINT_PREVALENCE
prevalence_class: BAND_1_9_PER_100000
rate_per_100000: 6.0
notes: >-
  Derived, not directly measured: HCM clinical point prevalence ~1/500
  (200/100,000) × TNNI3 attributable fraction ~3% (PMID:32885985).

Incidence: No CMH7-specific incidence data. Birth incidence equals variant transmission rate; clinical incidence is diagnosis-driven and highly ascertainment-dependent.

9.2 Inheritance Genetics

Pattern: Autosomal dominant (HP:0000006). Rare biallelic (homozygous/compound heterozygous) cases occur — typically in consanguineous families, typically with a severe infantile RCM or DCM phenotype rather than classic HCM. Recessive TNNI3 RCM is documented (BMC Med Genet 2019 — verify PMID).

For a dismech Inheritance block:

inheritance:
- inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance

Penetrance: Incomplete and age-dependent. The most-cited TNNI3 figure is ~50% (PMID:38548731, [verbatim] "with a relatively low penetrance of approximately 50%"). Penetrance is variant-dependent and spans nearly the whole range: - p.Arg21Cys — very high effective penetrance for events: 53% of affected individuals died suddenly (though note ascertainment bias in a pedigree study). - p.Arg79Cys — explicitly a low-penetrance risk allele (PMID:32815737). - p.Pro82Ser — UniProt-annotated "CMH7 risk," not fully penetrant.

Expressivity: Highly variable, both between and within families. The same variant can produce apical HCM, asymmetric septal HCM, restrictive physiology, or no detectable phenotype. Documented intrafamilial discordance includes homozygous twin siblings with divergent RCM vs HCM phenotypes.

Genetic anticipation: Not applicable — TNNI3 is not a repeat-expansion locus. Apparent anticipation in HCM pedigrees is ascertainment bias.

Germline mosaicism: Not specifically documented for TNNI3. De novo variants are well documented (K206Q, 2 of Mogensen's RCM variants, p.Ile195Phe), so parental gonadal mosaicism is a theoretical recurrence-risk consideration in de novo cases and should be mentioned in counseling (empirical recurrence risk after an apparently de novo variant is conventionally quoted as ~1%).

Founder effects — well documented for TNNI3: - TNNI3 p.Arg21Cys in South Lebanon. Fahed et al. sequenced 29 HCM families enriched for pediatric-onset disease, found 5 families with p.Arg21Cys, and established a founder haplotype (LOD 4.38; probability of 5 unrelated families by chance 5×10⁻¹⁵) [paraphrase]. Conclusion [verbatim]: "The TNNI3 p.Arg21Cys mutation has a founder effect in South Lebanon and causes malignant hypertrophic cardiomyopathy with early SCD even in the absence of hypertrophy." - TNNI3 p.Arg79Cys in Chinese/Southeast Asian populations — a common, population-enriched, low-penetrance allele (disease AF 0.018 in Singaporean HCM; PMID:32815737). - The p.Lys183del variant has been associated with Japanese apical HCM — verify the primary source before curating.

Consanguinity: Relevant only for the rare biallelic TNNI3 cardiomyopathies (infantile RCM/DCM), reported in consanguineous families including South African and Middle Eastern series. Not relevant to typical AD CMH7.

Carrier frequency: The term does not apply in the recessive sense. The relevant analogue — population frequency of pathogenic TNNI3 variants — is very low for high-penetrance alleles (individually <1×10⁻⁵ in gnomAD; most absent), with the population-enriched exceptions noted above.

9.3 Population Demographics

Affected populations: Worldwide, no overall ethnic predilection for TNNI3-HCM. Population-specific enrichments: South Lebanese (p.Arg21Cys), Chinese/Singaporean (p.Arg79Cys), Japanese (apical morphology among TNNI3 carriers, per Kimura's Japanese cohort). Note a major equity gap: [verbatim] "highlighting the need for greater study of HCM genetics in non-White populations" (PMID:32815737) — Singaporean HCM patients had significantly fewer confidently interpreted variants (P/LP 18% vs 31% in Whites) and an excess of VUS (24% vs 7%) [verbatim].
Geographic distribution: Global; no endemic pattern. Variant-level geography as above.
Sex ratio: No established sex bias in TNNI3 variant carriage (Mendelian autosomal). HCM diagnosis overall skews male (~60:40), reflecting ascertainment and hypertrophy magnitude rather than transmission. Fahed 2020 found no sex difference in SCD among p.Arg21Cys carriers (46.4% women vs 48.3% men) [paraphrase] — worth curating, since it contradicts the general HCM pattern.
Age distribution: Trimodal as in §8.1.

10. Diagnostics

10.1 Clinical Tests

Imaging (the diagnostic cornerstone): | Test | Findings in CMH7 | Notes | |---|---|---| | Transthoracic echocardiography (TTE) | Maximal LV wall thickness ≥15 mm (unexplained), or ≥13 mm with family history; asymmetric septal or apical distribution; diastolic dysfunction; LA dilation; SAM and LVOT gradient (less common in thin-filament HCM: 19% vs 34%) | First-line. LOINC/RadLex terms available | | Cardiac MRI with LGE | Gold standard for wall thickness, apical variants (often missed on TTE), and fibrosis burden. LGE detects subclinical disease in TNNI3 G+/P− carriers | Critical for the apical variant that TNNI3 favors | | Exercise stress echo | Unmasks provocable LVOT obstruction | | | Tissue Doppler imaging | Detects preclinical diastolic abnormality in G+/P− TNNI3 carriers (Fahed 2020) | High-yield in this genotype |

Electrophysiology: - 12-lead ECG — abnormal in >90% of HCM; LVH voltage, repolarization abnormality, pathological Q waves. Giant negative T waves in precordial leads are the signature of the apical variant. Ventricular pre-excitation (delta wave) should prompt consideration of TNNI3 p.Gly203Ser (all 3 carriers in Kimura's series had WPW) — as well as the metabolic phenocopies (PRKAG2, Danon, Pompe). - Ambulatory ECG (48-h Holter) — mandatory for NSVT detection; class I for SCD risk stratification. NSVT is more common in pediatric thin-filament HCM (PMID:38296631). - Implantable loop recorder — for unexplained syncope.

Laboratory / biomarkers: - hs-cTnI and NT-proBNP — prognostic, not diagnostic. - Phenocopy exclusion panel (essential): alpha-galactosidase A activity (males) and GLA sequencing (females) for Fabry; serum/urine free light chains + immunofixation and ⁹⁹ᵐTc-PYP scintigraphy for transthyretin amyloidosis; alpha-glucosidase for Pompe; LAMP2 for Danon; CK, lactate, ammonia for metabolic myopathies.

Biopsy / pathology: - Endomyocardial biopsy is NOT indicated for HCM diagnosis — it is reserved for suspected infiltrative phenocopy (amyloid, sarcoid) when non-invasive workup is equivocal. - Histopathology (from myectomy specimens or autopsy): myocyte disarray (HP:0031333 ✅) — whorled/interlacing myofiber architecture; cardiomyocyte hypertrophy with bizarre nuclei; interstitial and replacement fibrosis (HP:0001685 ✅); intramural coronary small-vessel dysplasia with medial hypertrophy and luminal narrowing. Autopsy in TNNI3 p.Arg21Cys SCD victims showed disarray without gross hypertrophy.

10.2 Genetic Testing

Recommended approach: A multigene HCM/cardiomyopathy NGS panel including at minimum the nine ClinGen-definitive sarcomere genes (MYBPC3, MYH7, TNNT2, TNNI3, TPM1, ACTC1, MYL2, MYL3, plus the definitive additions from the 2025 reappraisal) and the phenocopy genes (GLA, LAMP2, PRKAG2, TTR, PTPN11/RASopathies, GAA, FHL1). Testing is a class I recommendation for HCM probands (2024 AHA/ACC, PMID:38718139).

Diagnostic yield: ~40% of probands receive a P/LP variant on a modern panel ([verbatim] from the ClinGen reappraisal preprint: "the yield of identifying a likely pathogenic or pathogenic variant in a proband is ~40%"). Yield is substantially lower in non-White populations (18% in Singaporean patients, PMID:32815737).

Modality	Utility for CMH7
Gene panel	Preferred first-line. GTR lists 137 clinical tests for `TNNI3`; 48 for the CMH7 condition (47 with full coding-region sequencing, 31 with del/dup, 5 targeted, 1 select-exon)
Single-gene `TNNI3` testing	Appropriate only for cascade testing of a known familial variant, or for targeted testing of a founder allele (e.g. p.Arg21Cys in South Lebanese families)
WES	Second-line when panel is negative and the phenotype is atypical/syndromic
WGS	Research/tertiary setting; can capture deep-intronic and structural variants. Not standard of care
CMA / karyotype / FISH	Not indicated — no established SV mechanism for CMH7
mtDNA testing	Indicated only to exclude mitochondrial phenocopy (MELAS, MERRF) when extracardiac features are present. MITOMAP/MSeqDR
Repeat expansion testing	Not applicable (except Friedreich ataxia `FXN` GAA repeat as a hypertrophy phenocopy in the appropriate neurological context)

Variant interpretation: Apply the ClinGen TNNI3 variant curation specification (CSpec GN098) rather than generic ACMG/AMP rules. Key gene-specific points: PM1 hotspot = exons 7–8 (inhibitory/switch and C-terminal mobile domains, ~80% of pathogenic variants); PVS1 (null variant) does not apply — truncating TNNI3 variants are not an established AD-HCM mechanism; PM2 must be relaxed for population-enriched alleles (p.Arg79Cys). The 2024 AHA/ACC guideline recommends reconfirming reported pathogenicity every 2–3 years.

10.3 Omics-Based Diagnostics

RNA-seq: Not clinically used for CMH7; potential research role in resolving splice-affecting VUS.
Proteomics / metabolomics / epigenomics / liquid biopsy: No clinical diagnostic role. hs-cTnI is a single-analyte prognostic marker, not an omics diagnostic.

10.4 Clinical Criteria

Diagnostic criteria (2024 AHA/ACC, PMID:38718139; and 2023 ESC cardiomyopathy guideline): - Adults: LV wall thickness ≥15 mm in any segment, unexplained by loading conditions; ≥13 mm in a first-degree relative of an HCM proband or a genotype-positive individual. - Children: wall thickness >2 SD above the predicted mean (z-score >2), and in relatives z-score >2. - Diagnosis requires exclusion of secondary causes (hypertension, aortic stenosis, athlete's heart) and phenocopies.

Differential diagnosis (with discriminators): | Condition | Discriminating features | |---|---| | Athlete's heart | Wall thickness usually ≤15 mm, symmetric, dilated LV cavity, normal/supranormal diastolic function, regression on detraining, no LGE | | Hypertensive heart disease | Concentric, symmetric, proportional to BP burden, regresses with BP control | | Cardiac amyloidosis (ATTR/AL) | Low ECG voltage despite thick walls, granular sparkling myocardium, diffuse subendocardial LGE, ⁹⁹ᵐTc-PYP uptake, monoclonal protein | | Fabry disease | X-linked, low/absent α-Gal A, angiokeratomas, acroparesthesias, proteinuria, short PR, basal inferolateral LGE | | Danon disease (LAMP2) | X-linked, WPW, intellectual disability, skeletal myopathy, marked LVH in young males | | PRKAG2 glycogen storage | WPW + conduction disease + progressive AV block; sinus bradycardia | | Pompe (GAA) | Infantile: profound hypotonia, macroglossia, low α-glucosidase | | RASopathies (Noonan/LEOPARD, PTPN11, RAF1) | Dysmorphology, short stature, pulmonic stenosis, lentigines | | Friedreich ataxia | Concentric LVH + progressive ataxia, FXN GAA expansion | | Mitochondrial cardiomyopathy | Maternal inheritance, lactic acidosis, multisystem | | TNNI3-RCM | Same gene — normal or near-normal wall thickness, bi-atrial dilatation, restrictive filling, preserved systolic function |

The TNNI3-specific discriminator — the reason CMH7 deserves its own entry — is that these phenocopies are all multisystem, whereas TNNI3 disease is strictly cardiac; and among sarcomeric HCMs, TNNI3 skews toward milder hypertrophy with disproportionate diastolic/restrictive physiology and apical morphology.

10.5 Screening

Cascade genetic testing (2024 AHA/ACC, class I): offer to first-degree relatives only if a P/LP variant is identified in the proband [paraphrase]. A VUS is not actionable for cascade testing.
Clinical screening of first-degree relatives where genotype is unknown or a VUS: TTE + ECG, every 1–2 years in children/adolescents and every 3–5 years in adults [paraphrase]; screening may begin at any age based on family history and preference. In a family with a documented malignant TNNI3 variant (e.g. p.Arg21Cys), earlier and more intensive screening — plus consideration of CMR — is justified.
Genotype-negative relatives in a family with an established P/LP variant: discharge from surveillance, unless the variant is subsequently downgraded [paraphrase].
Newborn screening: Not applicable — CMH7 is not on the RUSP and there is no biochemical marker.
Population carrier screening: Not recommended. However, TNNI3 is on the ACMG SF v3.x secondary-findings list (as an HCM/cardiomyopathy gene), so P/LP TNNI3 variants are actionable incidental findings from clinical exome/genome sequencing — an important ascertainment route.

11. Outcome / Prognosis

11.1 Survival and Mortality

HCM overall: contemporary HCM-attributable annual mortality at specialist centers is ~0.5%/year, a marked improvement over historical (~3–6%/year) estimates driven by ICD therapy and referral-center care.

TNNI3-specific — this is the section where CMH7 genuinely diverges: - p.Arg21Cys (South Lebanese founder): SCD in 30/57 (53%) of affected individuals at median age 22.5 years; SCD was the first presentation in 83.3%; 30% of carriers who had events had no LVH on echocardiography [all paraphrase]. Conclusion [verbatim]: "causes malignant hypertrophic cardiomyopathy with early SCD even in the absence of hypertrophy." - Thin-filament HCM generally (TNNI3/TNNT2/TPM1/ACTC1, n=80 vs 150 thick-filament, mean 4.5 y follow-up; Coppini 2014, PMID:25524337): arrhythmic risk comparable between thin- and thick-filament, but advanced heart failure markedly more common in thin-filament (15% vs 5%) [paraphrase]. Verbatim conclusion: "thin-filament mutations are associated with increased likelihood of advanced LV dysfunction and heart failure". - Pediatric TNNI3: [verbatim] "Patients with pathological variants of TNNI3 reportedly experience severe clinical outcomes, such as fatal arrhythmias and sudden death, even in children" (PMID:38548731).

Life expectancy: Near-normal for the majority with mild/nonprogressive disease and appropriate ICD protection; markedly reduced in malignant-variant families and in pediatric-onset/restrictive-phenotype disease. Restrictive-phenotype TNNI3 disease in children has a poor prognosis and frequently requires transplantation.

Disease-specific mortality modes: (1) sudden arrhythmic death; (2) progressive heart failure; (3) stroke/thromboembolism from AF.

11.2 Morbidity and Function

Symptomatic burden: exertional dyspnea (dominant, from diastolic dysfunction), chest pain, palpitations, presyncope/syncope, fatigue.
Disability outcomes: exercise limitation; occupational restriction (commercial driving, aviation, some emergency services); ICD-related activity and psychological restriction; NYHA III–IV in the ~15% of thin-filament patients who progress.
QoL instruments: KCCQ-CSS, HCMSQ, SF-36, EQ-5D, PROMIS. See §3.5 for EXPLORER-HCM effect sizes.

11.3 Disease Course — Complications

Atrial fibrillation (HP:0005110 ✅) with cardioembolic stroke; progressive diastolic then systolic heart failure (HP:0001635 ✅); end-stage "burnt-out" HCM requiring transplant; ventricular arrhythmias and SCD (HP:0001645 ✅); infective endocarditis (rare, obstructive subset); post-capillary pulmonary hypertension; procedural complications (complete heart block after alcohol septal ablation; inappropriate ICD shocks and lead complications).

Recovery potential: None in the sense of disease reversal. Symptomatic recovery with septal reduction or mavacamten in the obstructive subset is substantial but is less often applicable in CMH7, which is disproportionately nonobstructive.

11.4 Prognostic Factors

Established HCM SCD risk markers (feed the HCM Risk-SCD calculator and the AHA/ACC major risk factor list): prior cardiac arrest/sustained VT; unexplained syncope; family history of SCD; maximal wall thickness ≥30 mm; LV apical aneurysm; LV EF <50%; extensive LGE (≥15% of LV mass) on CMR; NSVT on Holter; abnormal BP response to exercise (younger patients); young age.

TNNI3-genotype-specific prognostic considerations: - Genotype itself as a risk marker. Fahed and colleagues concluded that genetic diagnosis of TNNI3 p.Arg21Cys may be sufficient for SCD risk stratification independent of conventional markers [paraphrase] — a genuinely unusual and clinically consequential claim, because it means the standard wall-thickness- and LGE-based calculators underestimate risk in this genotype (their carriers died with normal echocardiograms). This should be curated as a distinct, high-value claim. - Thin-filament genotype predicts heart-failure progression more than arrhythmic risk (Coppini 2014). - Sarcomere-positive status generally predicts earlier onset, more fibrosis, and worse composite outcomes than sarcomere-negative HCM (SHaRe registry). - Multiple sarcomere variants predict worse outcomes.

Prognostic biomarkers: hs-cTnI and NT-proBNP (both associated with adverse outcomes in HCM); LGE extent on CMR is the strongest imaging prognostic marker.

12. Treatment

There is no TNNI3-specific or genotype-directed therapy in clinical use. Management follows the 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR HCM guideline (PMID:38718139; DOI:10.1161/CIR.0000000000001250 and 10.1016/j.jacc.2024.02.014). Two genotype-relevant caveats deserve prominence in a CMH7 entry: (i) CMH7 is more often nonobstructive, so the obstruction-directed armamentarium (disopyramide, myectomy, alcohol ablation, mavacamten) applies to a smaller fraction of these patients than in thick-filament HCM; and (ii) the diastolic/restrictive physiology and, for at least one variant, the hypertrophy-independent SCD risk shift management emphasis toward heart-failure care and toward a lower ICD threshold.

12.1 Pharmacotherapy

Treatment	Class / MoA	Indication in CMH7	NCIT
Beta blockers (metoprolol, bisoprolol, propranolol, atenolol)	β₁-adrenergic antagonist; negative inotropy/chronotropy, prolongs diastolic filling	First-line for symptomatic obstructive and nonobstructive HCM	`NCIT:C15986` Pharmacotherapy ✅ + `therapeutic_agent` NCIT:C61845 Metoprolol ✅
Non-dihydropyridine CCBs (verapamil, diltiazem)	L-type Ca²⁺ channel blockade; negative inotropy, improved relaxation	Alternative first-line when β-blockers not tolerated. Caution/contraindicated with severe obstruction + hypotension	`NCIT:C15986` ✅ + NCIT:C928 Verapamil ✅
Disopyramide	Class Ia antiarrhythmic; potent negative inotrope	Add-on for obstructive HCM refractory to β-blocker/CCB. Anticholinergic side effects	`NCIT:C15986` ✅ + NCIT:C61730 Disopyramide ✅
Mavacamten	Cardiac myosin inhibitor — allosterically reduces actin–myosin cross-bridge formation, decreasing hypercontractility	Obstructive HCM with inadequate response to first-line therapy (2024 guideline). FDA-approved. REMS program — echo monitoring of LVEF required	`NCIT:C15986` ✅ + `therapeutic_agent` NCIT:C174901 Mavacamten ✅ ; `therapeutic_modality: SMALL_MOLECULE`
Aficamten	Next-generation cardiac myosin inhibitor (SEQUOIA-HCM)	Obstructive HCM; FDA review/approval status should be verified as of 2026	Verify NCIT term
Diuretics	Loop/thiazide	Cautious use for congestion; avoid over-diuresis in obstruction	`NCIT:C15986` ✅
Anticoagulation (DOACs preferred; warfarin)	Factor Xa / thrombin inhibition	AF in HCM — anticoagulate regardless of CHA₂DS₂-VASc score (class I). Highly relevant given LA dilation in CMH7	`NCIT:C15986` ✅
Amiodarone / sotalol	Antiarrhythmics	AF rhythm control; VT suppression adjunct to ICD	`NCIT:C15986` ✅

Drugs to avoid: pure vasodilators (dihydropyridine CCBs, nitrates, ACE-I/ARB in significant obstruction), high-dose diuretics, digoxin, and positive inotropes in obstructive disease — all worsen the LVOT gradient.

Pharmacogenomics: - Mavacamten is a CYP2C19 substrate. Dose titration and the labeled dosing algorithm are CYP2C19 phenotype-dependent; poor metabolizers have substantially higher exposure and require dose adjustment. Check PharmGKB and the FDA label for the current genotype-guided dosing table. This is the single most clinically actionable PGx interaction in HCM care. - Metoprolol is a CYP2D6 substrate — CPIC has a metoprolol/CYP2D6 guideline; poor metabolizers experience greater bradycardia. - Warfarin — CYP2C9/VKORC1 (CPIC), though DOACs are now preferred.

12.2 Advanced Therapeutics

Gene therapy: No clinical gene therapy for TNNI3 exists. Strong preclinical rationale from the isogenic EHT work: AAV-mediated wild-type TNNI3 overexpression rescued impaired relaxation in R170W iPSC-CMs and EHTs [paraphrase, PMID:38193576] — the authors explicitly note "the possible benefits of gene therapies for patients with RCM." Because the mechanism is dominant-negative (poison peptide), an allele-specific silencing or base/prime-editing correction strategy is theoretically more attractive than simple gene addition; wild-type overexpression works in the dish by dilution of the mutant fraction. Contrast with MYBPC3, where haploinsufficiency makes gene replacement (currently in clinical trials, e.g. TN-201) mechanistically straightforward — that approach does not transfer to TNNI3.
Gene editing: Preclinical only. CRISPR correction of the TNNI3 variant in patient iPSCs has been demonstrated (the isogenic control lines in PMID:38193576).
Cell therapy: No role.
RNA-based therapies: No TNNI3 ASO or siRNA in development. An allele-selective ASO/siRNA is a logical but unrealized target given the dominant-negative mechanism.
Targeted therapy: Mavacamten and aficamten are the only mechanism-targeted agents. Note a conceptual mismatch worth curating: myosin inhibitors target hypercontractility, but the TNNI3 lesion is Ca²⁺ sensitization with reduced maximal force (PMID:18430738). Whether myosin inhibition is the mechanistically optimal intervention for thin-filament HCM — as opposed to a Ca²⁺-desensitizing thin-filament–directed agent — is an open and genuinely interesting question. Troponin-targeting agents that modulate thin-filament Ca²⁺ sensitivity have been shown in vitro to modulate the effects of de novo TNNC1/TNNI3 infantile cardiomyopathy variants (PMC8431798 — verify PMID) but none has reached the clinic.
Immunotherapy: Not applicable.

12.3 Surgical and Interventional

Intervention	Role	NCIT
Surgical septal myectomy (extended Morrow)	Gold standard for drug-refractory severe obstruction at experienced centers. Less often applicable in CMH7 (nonobstructive predominance)	NCIT term for septal myectomy not resolved in this session — verify; fall back to `NCIT:C15329` Surgical Procedure with a specific `preferred_term`
Alcohol septal ablation	Catheter alternative for suitable anatomy in older/higher-surgical-risk patients. Risk of complete heart block	Verify NCIT
ICD implantation	Primary prevention per risk stratification; secondary prevention (class I) after cardiac arrest/sustained VT. Threshold should be lower in malignant `TNNI3` genotypes. Subcutaneous ICD used in the pediatric p.Ile195Phe case	NCIT:C80435 Implantable Cardioverter-Defibrillator Placement ✅ ; `therapeutic_modality: DEVICE`
Catheter ablation	AF rhythm control	Verify NCIT
Dual-chamber pacing	Legacy/limited role for obstruction; used for bradycardia	Verify NCIT
Heart transplantation	End-stage HCM, restrictive-phenotype `TNNI3` disease, or intractable arrhythmia. Disproportionately relevant in CMH7 given restrictive/HF progression	`NCIT:C15289` Organ Transplantation ✅ ; `therapeutic_modality: SURGERY`
Mechanical circulatory support (LVAD)	Technically difficult in a small, stiff, non-dilated ventricle; restrictive `TNNI3` physiology is a relative contraindication. ECMO has been used as a bridge in pediatric `TNNI3` RCM with reported difficulty (PMC11157066 — verify PMID)	Verify NCIT

12.4 Supportive and Rehabilitative

Heart-failure symptom management; AF rate/rhythm control and stroke prophylaxis; cardiac rehabilitation — the 2024 guideline endorses moderate-intensity recreational exercise as beneficial for most HCM patients, a significant liberalization from prior restriction-heavy guidance (NCIT:C15315 Rehabilitation ✅); psychological support for ICD recipients and for families with a history of sudden death; palliative care in end-stage disease (NCIT:C15747 Supportive Care ✅).

12.5 Experimental / Clinical Trials

NCT03470545 — EXPLORER-HCM (mavacamten, phase 3, completed). Registered per the abstract [verbatim]: "This study is registered with ClinicalTrials.gov, NCT03470545."
MAVERICK-HCM — mavacamten in nonobstructive HCM (phase 2; the population most relevant to CMH7) — verify NCT.
ODYSSEY-HCM — mavacamten in nonobstructive HCM (phase 3) — verify NCT and status.
SEQUOIA-HCM / ACACIA-HCM — aficamten — verify NCT.
VALOR-HCM — mavacamten as an alternative to septal reduction therapy — verify NCT.
VANISH — valsartan in early sarcomeric HCM (disease-modification in G+/P− and early-phenotype carriers) — verify NCT; directly relevant to the CMH7 preclinical window.
No TNNI3-specific trial exists. TNNI3 carriers are enrolled within general HCM trials.

(Per dismech convention, each of these requires just fetch-reference NCT####### before curation, with the snippet quoted from the cached ClinicalTrials.gov record.)

12.6 Treatment Outcomes

EXPLORER-HCM efficacy [all verbatim from the abstract]: - Primary endpoint: 45/123 (37%) mavacamten vs 22/128 (17%) placebo (difference +19.4%, 95% CI 8.7 to 30.1; p=0.0005) - Post-exercise LVOT gradient: −36 mm Hg (95% CI −43.2 to −28.1; p<0.0001) - pVO₂: +1.4 mL/kg per min (0.6 to 2.1; p=0.0006) - NYHA class improvement ≥1: 80/123 vs 40/128 (34% more; 95% CI 22.2 to 45.4; p<0.0001) - "Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group."

Adverse events of note: mavacamten — reversible reduction in LVEF / systolic dysfunction (the class effect driving the REMS echo-monitoring requirement), atrial fibrillation, heart failure; disopyramide — anticholinergic effects, QT prolongation; alcohol septal ablation — complete heart block (~10%); myectomy at expert centers — <1% mortality. Resources: FAERS, MedWatch.

12.7 Treatment Strategy

Algorithm (2024 AHA/ACC, adapted for CMH7): 1. All patients: confirm diagnosis and exclude phenocopies → genetic testing → SCD risk stratification (with the explicit CMH7 caveat that conventional risk calculators may under-call risk in malignant TNNI3 genotypes) → cascade family screening → exercise counseling (permissive for moderate recreational activity) → AF surveillance. 2. Asymptomatic: no pharmacotherapy indicated; surveillance imaging. 3. Symptomatic + obstructive (the minority in CMH7): β-blocker → add/switch verapamil → add disopyramide or mavacamten → septal reduction therapy if refractory. 4. Symptomatic + nonobstructive (the CMH7-typical path): β-blocker or verapamil for diastolic filling; treat congestion cautiously; this is the therapeutic gap — no proven disease-modifying therapy for nonobstructive HCM, which is precisely where thin-filament patients concentrate. Advanced HF → transplant evaluation. 5. AF: anticoagulate regardless of CHA₂DS₂-VASc; rate or rhythm control. 6. High arrhythmic risk: ICD.

Personalized medicine: currently limited to (i) genotype-driven cascade screening, (ii) genotype-informed SCD risk stratification in specific TNNI3 variants, and (iii) CYP2C19-guided mavacamten dosing. Genotype-directed disease-modifying therapy for TNNI3 remains aspirational.

13. Prevention

13.1 Prevention Levels

Primary prevention (preventing the disease): Not achievable for variant carriage. The only true primary prevention is reproductive: preimplantation genetic testing for monogenic disease (PGT-M) or prenatal diagnosis, following genetic counseling. Whether early pharmacotherapy in G+/P− carriers prevents phenotype conversion is unproven (the VANISH question).
Secondary prevention (early detection): Cascade genetic testing of first-degree relatives is the highest-yield intervention in CMH7 — it identifies at-risk individuals before phenotype and, in malignant TNNI3 genotypes, before an event that would otherwise be first-and-fatal. Coupled with serial TTE/ECG (1–2 y children, 3–5 y adults) and CMR where LGE detection matters.
Tertiary prevention (preventing complications): ICD for SCD; anticoagulation for AF-related stroke; blood-pressure and weight control to limit remodeling; heart-failure therapy; endocarditis awareness in the obstructive subset; avoidance of contraindicated vasodilators/inotropes.

13.2 Immunization

Not applicable as disease prevention. Standard influenza, COVID-19, and pneumococcal vaccination are appropriate for patients with structural heart disease to reduce decompensation from intercurrent infection.

13.3 Screening and Early Detection

Population screening: not recommended. Neither newborn nor general-population genetic screening for HCM genes is endorsed. Pre-participation athletic screening (ECG-inclusive in the Italian/European model, history-and-exam in the US model) remains contested and is not CMH7-specific.
Genetic screening: cascade testing (§10.5); PGT-M and prenatal testing available for known familial variants; both require formal genetic counseling.
Secondary-findings reporting: TNNI3 is on the ACMG SF v3.x list, so P/LP variants are reported from clinical ES/GS regardless of indication — an unavoidable and deliberate ascertainment channel.
Risk stratification: HCM Risk-SCD calculator (ESC) and AHA/ACC major risk factors; with the CMH7-specific proviso that both underweight genotype and may miss the hypertrophy-negative TNNI3 carrier at risk.

13.4 Behavioral Interventions

Moderate-intensity recreational exercise is now endorsed (2024 guideline) rather than broadly restricted; competitive/high-intensity athletics require shared decision-making with an HCM specialist. Weight management, blood-pressure control, adequate hydration, avoidance of alcohol excess and stimulants (including anabolic steroids and high-dose sympathomimetics).

13.5 Genetic Counseling

Essential and non-optional in CMH7. NCIT:C15240 Genetic Counseling ✅. Content: - 50% transmission risk per pregnancy (autosomal dominant). - Incomplete (~50%) and age-dependent penetrance, and highly variable expressivity — a positive genotype is not a diagnosis, and a normal echocardiogram is not reassurance in a malignant-variant family. - The TNNI3 allelic spectrum: relatives may develop HCM, RCM, or (rarely) DCM. - The reality of SCD as a first presentation, and the case for a low ICD threshold in high-risk families. - Reproductive options: PGT-M, prenatal diagnosis, donor gametes, adoption, or unassisted conception with cascade screening of offspring. - ~1% empirical recurrence risk after an apparently de novo variant (gonadal mosaicism). - VUS management and the 2–3-yearly reinterpretation cadence. - Psychosocial support, insurance/GINA considerations, and family communication about a heritable sudden-death risk.

Resources: NSGC, ACMG, GeneReviews "Hypertrophic Cardiomyopathy Overview".

13.6 Public Health and Environmental Interventions

Not applicable in the classical sense. Relevant public-health measures: AED availability and CPR training in schools, sports venues, and public spaces (this is the highest-impact population intervention for HCM-related SCD); cardiac-arrest registries; molecular autopsy programs for sudden unexplained death in the young, which are a major route to identifying TNNI3 families retrospectively (exactly the mechanism by which the Lebanese founder families were characterized).

13.7 Prophylaxis

ICD (device prophylaxis against SCD); anticoagulation (prophylaxis against AF-related stroke). Infective endocarditis antibiotic prophylaxis is NOT routinely recommended for HCM in current guidelines.

14. Other Species / Natural Disease

14.1 Taxonomy and Orthologs

Species	NCBI Taxon	Gene	NCBI Gene ID	Notes
Homo sapiens	NCBITaxon:9606	`TNNI3`	7137
Mus musculus	NCBITaxon:10090	`Tnni3`	21954 (verify)	Primary disease model species; chromosome 7
Rattus norvegicus	NCBITaxon:10116	`Tnni3`	24837 (verify)	Physiology model
Felis catus	NCBITaxon:9685	`TNNI3`	—	Naturally occurring HCM species (see below)
Canis lupus familiaris	NCBITaxon:9615	`TNNI3`	—
Danio rerio	NCBITaxon:7955	`tnni1b`/`tnnt2a`	—	Cardiac troponin orthology in zebrafish is complicated by teleost genome duplication; `tnni3` is not a clean 1:1 ortholog. Verify with Alliance of Genome Resources before curating

The cardiac-specific N-terminal extension with the PKA Ser23/Ser24 site is a mammalian/amniote innovation and is highly conserved — the reason R21C is mechanistically interpretable across species and the reason mouse models of it are informative. See "TNNI1, TNNI2 and TNNI3: Evolution, Regulation, and Protein Structure-Function Relationships" (PMC5798203) for the comparative/evolutionary treatment.

14.2 Naturally Occurring Disease in Other Species

Feline HCM is the flagship naturally occurring animal HCM — the most common feline heart disease and a genuine spontaneous model. However, the established feline HCM genes are MYBPC3 and MYH7, not TNNI3: - OMIA:002951-9685 — Cardiomyopathy, hypertrophic, MYBPC3-related, autosomal dominant, Felis catus - OMIA:002952-9685 — Cardiomyopathy, hypertrophic, MYBPC3-related, autosomal recessive, Felis catus - OMIA:002212-9685 — Cardiomyopathy, hypertrophic, MYH7-related, Felis catus

Causal variants: MYBPC3 p.A31P in Maine Coon cats (Meurs et al. 2005) and MYBPC3 p.R820W in Ragdoll cats (Meurs et al. 2007) [paraphrase — verify PMIDs]. Feline HCM recapitulates human disease closely, including LVH, diastolic dysfunction, LA enlargement, arterial thromboembolism, and sudden death. VBO identifiers exist for Maine Coon and Ragdoll breeds — look them up before curating.

A TNNI3 variant has not been established as a cause of naturally occurring feline HCM. A 2024 Frontiers in Veterinary Science paper applied ACMG criteria to feline HCM-associated gene variants (including thin-filament genes) — verify PMID and findings before asserting any TNNI3 claim. Curation guidance: do not assert a feline TNNI3 natural disease. Curate feline HCM as a comparative-pathology analogue of the human disease, explicitly noting the gene mismatch.

Naturally occurring HCM is also described in dogs (rare), pigs, and non-human primates; genes are largely uncharacterized.

14.3 Comparative Biology

Comparative pathology: feline HCM shows the same triad — myocyte hypertrophy, myofiber disarray, and interstitial fibrosis — plus intramural arteriosclerosis, and shares the SCD and heart-failure endpoints. The key feline-specific difference is the prominence of aortic thromboembolism ("saddle thrombus"), far more common than in human HCM.
Evolutionary conservation: the troponin regulatory mechanism is conserved across striated muscle in bilaterians; the cardiac isoform's N-terminal β-adrenergic phospho-switch is a vertebrate/mammalian specialization. Resources: Alliance of Genome Resources, HomoloGene, OrthoDB.

14.4 Transmission

Not applicable. CMH7 is a germline genetic disease. Zero zoonotic potential; no cross-species transmission.

15. Model Organisms

15.1 Mouse Models — the Primary Evidence Base

(a) Transgenic Tg-R145G (overexpression) — Wen et al. 2008, PMID:18430738 Cardiac-specific overexpression of human cTnI R145G. Best-characterized biophysical model of a CMH7 variant. Findings (verbatim quotes in §6.1): increased Ca²⁺ sensitivity of both ATPase and force; decreased maximal Ca²⁺-activated force; unchanged cross-bridge turnover; higher energy consumption; 2–4% residual attached cross-bridges at pCa 9.0 vs <1% in WT; prolonged force and [Ca²⁺] transients. - Recapitulation: excellent for the molecular and myofilament phenotype (Ca²⁺ sensitization, impaired relaxation, energetic cost). This model established the mechanistic chain from variant to diastolic dysfunction. - Limitations: transgenic overexpression (non-physiological mutant:WT stoichiometry) rather than knock-in; readouts are largely ex vivo skinned-fiber/papillary muscle; the abstract's conclusion about hypertrophy is inferential ("most likely caused by compensatory mechanisms") rather than directly demonstrated. - Evidence classification: MODEL_ORGANISM (in vivo mouse) for the papillary-muscle work; skinned-fiber measurements arguably IN_VITRO — split evidence items accordingly per the dismech SOP.

(b) Knock-in Tnni3^R21C — Wang et al. 2012, PMID:22086914 The gold-standard genetic model — the mutation at the endogenous locus, in heterozygous (R21C⁺/⁻) and homozygous (R21C⁺/⁺) states. - [verbatim] "the R21C mutation abolished the in vivo phosphorylation of Ser(23)/Ser(24) in the mutant cTnI" - Heterozygous hearts incorporated ~25% mutant cTnI [paraphrase] — a physiologically faithful allelic ratio. - Both genotypes "activated the fetal gene program and developed a remarkable degree of cardiac hypertrophy and fibrosis" [paraphrase]. - PKA treatment of skinned fibers "reduced (R21C⁺/⁻) or abolished (R21C⁺/⁺) the well known decrease in the Ca²⁺ sensitivity of tension" [paraphrase] — a direct demonstration of the lost lusitropic reserve. - Longitudinal echo: hypertrophy after 12 months, with longer filling times and impaired relaxation; isoproterenol-conditional delays in Ca²⁺ decay and sarcomere relaxation appearing at older but not 6-month ages [paraphrase]. - Recapitulation: excellent — reproduces the human hypertrophy, fibrosis, diastolic dysfunction, and the specific molecular lesion (loss of PKA phospho-switch). - Limitations: the human p.Arg21Cys phenotype is dominated by early sudden arrhythmic death, which the mouse does not straightforwardly reproduce; mouse cardiac physiology (heart rate ~600 bpm, α-MHC-dominant ventricle vs human β-MHC) limits translation of relaxation kinetics; the late (12-month) hypertrophy onset compresses awkwardly against a human disease that can kill at 22. - Follow-on: PMC4415466 — the R21C knock-in shows left–right ventricular differences in contractile force generation, a chamber-asymmetry finding with no established human counterpart.

(c) Other relevant mouse models - Tg-R146G (=R145G in human numbering) and comparative R21C/R146G studies — "Troponin I Mutations R146G and R21C Alter Cardiac Troponin Function, Contractile Properties, and Modulation by Protein Kinase A (PKA)-mediated Phosphorylation" (J Biol Chem) — verify PMID. - Long-term PKA-phosphorylation-ablation models — "Long Term Ablation of PKA-mediated Cardiac Troponin I Phosphorylation Leads to Excitation-Contraction Uncoupling and Diastolic Dysfunction in a Knock-in Mouse Model of Hypertrophic Cardiomyopathy" (J Biol Chem) — verify PMID. Directly relevant to the R21C mechanism. - cTnI R193H (mouse) / R192H (human) RCM knock-in — the restrictive arm of the allelic series; see "Restrictive Cardiomyopathy Caused by Troponin Mutations: Application of Disease Animal Models in Translational Studies" (PMC5165243) for the review. - Tnni3 null (knockout) mice die of acute heart failure in the neonatal period as the fetal ssTnI isoform is replaced — a loss-of-function phenotype confirming that TNNI3 is essential but not a model of CMH7 (which is dominant-negative, not haploinsufficient). Verify the primary reference before curating.

Model resources: MGI (Tnni3; search alleles at informatics.jax.org — note the MGI ID was not correctly resolved in this session and must be verified), IMPC/KOMP (null alleles), IMSR (strain availability), MMRRC, EMMA.

15.2 In Vitro / Cellular Models

(a) Patient-derived iPSC-cardiomyocytes and engineered heart tissue (EHT) — the highest-value modern platform. Hasegawa et al. 2024 (PMID:38193576; DOI:10.1111/dgd.12909) — patient iPSC line carrying TNNI3 R170W vs isogenic CRISPR-corrected control [all paraphrase]: - R170W iPSC-CMs: altered Ca²⁺ kinetics, prolonged tau (relaxation time constant) - R170W EHTs: increased ratio of relaxation force to contractile force - Both phenotypes reversed in the isogenic corrected line — establishing variant causality - Wild-type TNNI3 overexpression rescued impaired relaxation — establishing a gene-therapy rationale - Evidence classification: IN_VITRO

Companion: J Am Heart Assoc 2024, "Impaired Relaxation in Induced Pluripotent Stem Cell-Derived Cardiomyocytes with Pathogenic TNNI3 Mutation of Pediatric Restrictive Cardiomyopathy" — verify PMID.

(b) Skinned fiber / reconstituted thin-filament biochemistry. Human and mouse skinned papillary/trabecular preparations; recombinant troponin exchange into demembranated fibers; in vitro motility assays; ATPase assays. These generate the force–pCa ΔpCa₅₀ measurement that anchors ACMG PS3 for TNNI3 variants.

(c) Human myectomy tissue. Ex vivo trabeculae from HCM myectomy specimens (Coppini's group is the principal source) allow direct measurement of human TNNI3-carrier myofilament function — the closest thing to a human "model system." - Note: "Restrictive Cardiomyopathy Troponin I R145W Mutation Does Not Perturb Myofilament Length-dependent Activation in Human Cardiac Sarcomeres" (PMC5076848) — a useful negative result showing that not every myofilament property is disturbed, which is worth curating as a scope constraint on the mechanism.

(d) Structural/computational. Molecular dynamics on the troponin core complex (PDB 1J1E) to predict variant effects; AlphaFold for the disordered N-terminal extension. Evidence classification: COMPUTATIONAL.

15.3 Model Characteristics Summary

Aspect of human CMH7	Mouse R21C KI	Mouse Tg-R145G	iPSC-CM/EHT	Feline HCM
Ca²⁺ sensitization	✅	✅	✅	n/a
Impaired relaxation / diastolic dysfunction	✅	✅	✅	✅
Loss of PKA lusitropic reserve	✅ (definitive)	—	—	—
Increased tension cost / energetic mismatch	—	✅	~	—
Cardiac hypertrophy	✅ (late, 12 mo)	inferred	✗ (immature CMs)	✅
Myocyte disarray	~	~	✗	✅
Interstitial fibrosis	✅	—	✗ (unless multicellular EHT)	✅
Sudden arrhythmic death	✗	✗	✗	✅
Restrictive/RCM phenotype	(R193H model)	—	✅ (R170W)	—
Correct allelic stoichiometry	✅ (~25% mutant)	✗ (overexpression)	✅ (patient-derived)	✅ (natural)

The dominant translational gap — flag as a dismech HUMAN_MODEL_MISMATCH discussion, not a generic KNOWLEDGE_GAP: the defining and lethal feature of human TNNI3 p.Arg21Cys disease is sudden arrhythmic death in the absence of hypertrophy at a median age of 22.5 years, whereas the corresponding knock-in mouse develops hypertrophy slowly (after 12 months) without a comparable arrhythmic-death phenotype. Evidence exists in the model; its fidelity to the human arrhythmic mechanism is the open question. Proposed resolving experiments: programmed electrical stimulation and telemetric arrhythmia monitoring in R21C knock-in mice under β-adrenergic challenge; optical mapping of the R21C heart; arrhythmia phenotyping of R21C iPSC-CM monolayers and EHTs; and human tissue/CMR studies of the disarray–arrhythmia relationship in hypertrophy-negative carriers.

15.4 Research Applications

Myofilament Ca²⁺-sensitivity pharmacology (Ca²⁺ desensitizers as a mechanistically rational TNNI3-directed drug class); β-adrenergic/PKA signaling and lusitropic reserve; cardiac energetics and mechano-energetic uncoupling; hypertrophic and fibrotic signaling; gene-therapy and gene-editing proof-of-concept (the isogenic EHT rescue); variant functional classification for ACMG PS3.

Appendix A — Master Reference List with PMIDs

#	Citation	PMID	Evidence source	Verbatim quote available?
1	Kimura A, et al. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat Genet 1997;16(4):379-82. DOI:10.1038/ng0897-379	9241277	HUMAN_CLINICAL	✅ Yes — full abstract
2	Mogensen J, et al. Idiopathic restrictive cardiomyopathy is part of the clinical expression of cardiac troponin I mutations. J Clin Invest 2003;111(2):209-16. DOI:10.1172/JCI16336	12531876	HUMAN_CLINICAL	✅ Yes — full abstract
3	Niimura H, et al. Sarcomere protein gene mutations in hypertrophic cardiomyopathy of the elderly. Circulation 2002	11815426	HUMAN_CLINICAL	✅ Yes — full abstract
4	Wen Y, et al. Functional consequences of the human cardiac troponin I hypertrophic cardiomyopathy mutation R145G in transgenic mice. J Biol Chem 2008;283(29):20484-94. DOI:10.1074/jbc.M801661200	18430738	MODEL_ORGANISM / IN_VITRO	✅ Yes — full abstract
5	Wang Y, et al. Generation and functional characterization of knock-in mice harboring the cardiac troponin I-R21C mutation. J Biol Chem 2012. DOI:10.1074/jbc.M111.294306	22086914	MODEL_ORGANISM	⚠️ Partial verbatim; re-fetch
6	Coppini R, et al. Clinical phenotype and outcome of HCM associated with thin-filament gene mutations. J Am Coll Cardiol 2014;64(24):2589-2600. DOI:10.1016/j.jacc.2014.09.059	25524337	HUMAN_CLINICAL	⚠️ Partial verbatim; re-fetch
7	Fahed AC, et al. Founder Mutation in N Terminus of Cardiac Troponin I Causes Malignant HCM. Circ Genom Precis Med 2020;13(5). DOI:10.1161/CIRCGEN.120.002991. PMC7676616	32885985	HUMAN_CLINICAL	⚠️ Partial verbatim; re-fetch
8	Pua CJ, et al. Genetic Studies of HCM in Singaporeans Identify Variants in TNNI3 and TNNT2 That Are Common in Chinese Patients. Circ Genom Precis Med 2020	32815737	HUMAN_CLINICAL	✅ Yes — full abstract
9	Hespe S, et al. Genes Associated With HCM: A Reappraisal by the ClinGen Hereditary Cardiovascular Disease GCEP. J Am Coll Cardiol 2025;85(7):727-740. DOI:10.1016/j.jacc.2024.12.010	39971408	OTHER (expert panel)	⚠️ Re-fetch; preprint PMID 39132495 / PMC11312670
10	Ommen SR, et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of HCM. Circulation/JACC 2024. DOI:10.1161/CIR.0000000000001250	38718139	OTHER (guideline)	⚠️ Re-fetch
11	Olivotto I, et al. Mavacamten for treatment of symptomatic obstructive HCM (EXPLORER-HCM). Lancet 2020;396(10253):759-769. DOI:10.1016/S0140-6736(20)31792-X	32871100	HUMAN_CLINICAL	✅ Yes — full abstract
12	Semsarian C, Ingles J, Maron MS, Maron BJ. New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol 2015	25814232	HUMAN_CLINICAL	⚠️ Re-fetch
13	Pediatric HCM caused by a novel TNNI3 variant (p.Ile195Phe). Hum Genome Var 2024. DOI:10.1038/s41439-024-00272-1. PMC10978967	38548731	HUMAN_CLINICAL	✅ Yes — full abstract + 3 key claims
14	Norrish G, et al. Childhood-onset HCM caused by thin-filament sarcomeric variants. J Med Genet 2024;61(5):420-422	38296631	HUMAN_CLINICAL	⚠️ Re-fetch
15	Hasegawa A, et al. Gene correction and overexpression of TNNI3 improve impaired relaxation in EHT model of pediatric RCM. Dev Growth Differ 2024. DOI:10.1111/dgd.12909. PMC11457505	38193576	IN_VITRO	⚠️ Re-fetch

Structured-source references usable directly as dismech evidence: - CGGV: (ClinGen Gene-Disease Validity) — the TNNI3–HCM Definitive assertion. Locate the assertion ID via just clingen-list and cite the validity table row. - ORPHA: — the Orphanet familial isolated HCM record (definition, epidemiology class, HPO phenotype table with frequencies, gene table). This is likely the highest-yield structured source for the phenotype-frequency and prevalence sections of this entry, since HPO's OMIM:613690 annotations have such small denominators. - NCIT:C174901 (Mavacamten) — check for an Accepted_Therapeutic_Use_For (P302) edge to cite the indication.

Appendix B — Verified Ontology Terms Ready for Curation

All terms below were resolved and label-verified with OAK against the repository's configured adapters during this session.

MONDO: MONDO:0013369 hypertrophic cardiomyopathy 7

Gene: hgnc:11947 TNNI3

HPO: HP:0001639 Hypertrophic cardiomyopathy · HP:0031992 Apical hypertrophic cardiomyopathy · HP:0001714 Ventricular hypertrophy · HP:0001670 Asymmetric septal hypertrophy · HP:0005144 Ventricular septal hypertrophy · HP:0025168 Left ventricular diastolic dysfunction · HP:0032092 Left ventricular outflow tract obstruction · HP:0001723 Restrictive cardiomyopathy · HP:0031333 Myocardial sarcomeric disarray · HP:0031318 Myofiber disarray · HP:0001685 Myocardial fibrosis · HP:0005110 Atrial fibrillation · HP:0001716 Wolff-Parkinson-White syndrome · HP:0004308 Ventricular arrhythmia · HP:0004756 Ventricular tachycardia · HP:0011675 Arrhythmia · HP:0001645 Sudden cardiac death · HP:0001695 Cardiac arrest · HP:0001635 Congestive heart failure · HP:0002094 Dyspnea · HP:0001279 Syncope · HP:0100749 Chest pain · HP:0001962 Palpitations · HP:0003581 Adult onset · HP:0000006 Autosomal dominant inheritance

GO (BP): GO:0060048 cardiac muscle contraction · GO:0055117 regulation of cardiac muscle contraction · GO:0010882 regulation of cardiac muscle contraction by calcium ion signaling · GO:0032971 regulation of muscle filament sliding · GO:1904114 positive regulation of muscle filament sliding · GO:0003300 cardiac muscle hypertrophy · GO:0014898 cardiac muscle hypertrophy in response to stress · GO:0010613 positive regulation of cardiac muscle hypertrophy · GO:0045214 sarcomere organization

GO (CC): GO:1990584 cardiac Troponin complex · GO:0005861 troponin complex · GO:0030017 sarcomere

CL: CL:2000046 ventricular cardiac muscle cell · CL:0000746 cardiac muscle cell · CL:0002548 fibroblast of cardiac tissue

UBERON: UBERON:0002084 heart left ventricle · UBERON:0002094 interventricular septum · UBERON:0004667 interventricular septum muscular part · UBERON:0002349 myocardium · UBERON:0001083 myocardium of ventricle

NCIT: NCIT:C15986 Pharmacotherapy · NCIT:C174901 Mavacamten · NCIT:C61845 Metoprolol · NCIT:C928 Verapamil · NCIT:C61730 Disopyramide · NCIT:C80435 Implantable Cardioverter-Defibrillator Placement · NCIT:C15289 Organ Transplantation · NCIT:C15240 Genetic Counseling · NCIT:C15315 Rehabilitation · NCIT:C15747 Supportive Care · NCIT:C15329 Surgical Procedure

Not resolved in this session — verify before use: NCIT terms for septal myectomy, alcohol septal ablation, catheter ablation, echocardiography, cardiac MRI; UBERON terms for heart (UBERON:0000948) and left atrium (UBERON:0002079); GO terms for myofibril, striated muscle thin filament, mitochondrion, sarcoplasmic reticulum; CL terms for endothelial cell and macrophage; LOINC codes for hs-cTnI and NT-proBNP; the Orphanet code for familial isolated HCM; NCT identifiers for MAVERICK-HCM, ODYSSEY-HCM, SEQUOIA-HCM, VALOR-HCM, and VANISH.

Appendix C — Curation Notes and Cautions

Do not blindly propagate the HPO frequency denominators for OMIM:613690. "Adult onset 6/6" derives from an elderly-onset-ascertained cohort (PMID:11815426) and directly contradicts the documented pediatric presentations. Per the dismech frequency-evidence SOP, omit frequency: rather than fabricate justification for most CMH7 phenotypes; the Orphanet HPO table (ORPHA: structured source) is a better-denominated alternative for the parent HCM entity.
Scope decision: keep CMH7 separate from TNNI3-RCM and TNNI3-DCM, but cross-reference. They have distinct MONDO/OMIM identities and distinct clinical management, yet share a gene, a mechanism (Ca²⁺ sensitization), and even individual variants (R145, D190). A Grouping over the TNNI3 allelic series (grouping_basis: [SHARED_GENE_FAMILY, SHARED_MECHANISM], criteria_semantics: NECESSARY with a HAS_GENE leaf on TNNI3) would capture this cleanly and is the natural home for the lump-vs-split reasoning.
Module conformance opportunities. CMH7 is a strong candidate conformer for cardiomyopathy_maladaptive_remodeling (#Ventricular Remodeling) and plausibly for fibrotic_response (the interstitial fibrosis arm). It is not a good fit for cardiac_ion_channel_repolarization, despite the arrhythmic phenotype — that module is scoped to structurally normal hearts with primary channel/Ca²⁺-handling variants, whereas CMH7's arrhythmia arises from a sarcomeric lesion with disarray. If the arrhythmia-without-hypertrophy finding in p.Arg21Cys carriers is curated, it should be a CMH7-local node, not a channelopathy-module conformance claim. There is a real gap here: no dismech module currently captures the sarcomeric myofilament Ca²⁺-sensitization → impaired relaxation → energetic mismatch chain, which recurs across thin-filament HCM (TNNI3, TNNT2, TPM1, ACTC1) and thin-filament RCM. That is a well-justified new-module candidate — consider the create-module skill.
The most distinctive, entry-justifying claims (rank these first in the pathophysiology narrative): (i) Ca²⁺ sensitization with reduced maximal force — mechanistically opposite to the MYH7 hypercontractility paradigm, and a direct challenge to the assumption that myosin inhibitors are the right drug class here; (ii) SCD without hypertrophy in p.Arg21Cys carriers, with disarray only at autopsy — genotype may outperform imaging for risk stratification; (iii) the R21C loss of the PKA lusitropic switch as a clean gene–environment (adrenergic stress) interaction; (iv) TNNI3 as the principal RCM gene and the resulting one-gene-three-cardiomyopathies allelic series; (v) TNNI3 over-representation in both apical and elderly-onset HCM.
Verbatim-quote status. Five abstracts were retrieved with full verbatim text (Kimura 1997, Mogensen 2003, Niimura 2002, Wen 2008, Pua 2020, Olivotto 2020 — six, in fact). The remainder were summarized by an intermediary. Every snippet must pass just fetch-reference + just validate-references before commit; the paraphrased items in particular will fail substring matching as written here.
Publisher access. ahajournals.org, jacc.org, and omim.org all returned HTTP 403 during this session. PubMed (pubmed.ncbi.nlm.nih.gov), PMC, NCBI eutils, HPO's ontology.jax.org API, GTR, and rest.uniprot.org were all accessible. Route reference fetching through those.

Sources: OMIM #613690 CMH7 · OMIM *191044 TNNI3 · Kimura 1997, PMID:9241277 · Mogensen 2003, PMID:12531876 · Niimura 2002, PMID:11815426 · Wen 2008, PMID:18430738 · Wang 2012, PMID:22086914 · Coppini 2014, PMID:25524337 · Fahed 2020, PMC7676616 · Pua 2020, PMID:32815737 · Olivotto 2020 EXPLORER-HCM, PMID:32871100 · Hespe 2025 ClinGen reappraisal, PMC11312670 · ClinGen HCM gene validity · ClinGen TNNI3 CSpec GN098 · 2024 AHA/ACC HCM Guideline, PMID:38718139 · UniProt P19429 · HPO annotations OMIM:613690 · GTR Hypertrophic cardiomyopathy 7 · Pediatric TNNI3 p.Ile195Phe, PMC10978967 · Hasegawa 2024 EHT, PMC11457505 · Norrish 2024, PMID:38296631 · Semsarian 2015, PMID:25814232 · OMIA:002951-9685 feline MYBPC3 HCM · OMIA:002212-9685 feline MYH7 HCM · Genetic Basis of HCM in Cats, PMC11352635 · TNNI1/2/3 evolution & structure-function, PMC5798203 · cTnI R145W human sarcomeres, PMC5076848 · Infantile RCM cTnI-R170G/W, PMC7077804 · Troponin RCM animal models review, PMC5165243 · R21C knock-in LV/RV differences, PMC4415466 · ClinVar TNNI3 pathogenic variants (ClinVar Miner) · Hypertrophic cardiomyopathy, Nat Rev Dis Primers 2025

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OpenScientist Report

Classifications

Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Progression

Prevalence

Differential Diagnoses

Clinical Trials

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

1. Disease Information

1.1 Overview

1.2 Key Identifiers

1.3 Synonyms and Alternative Names

1.4 Provenance of the Information

2. Etiology

2.1 Disease Causal Factors

2.2 Genetic Risk Factors

2.3 Environmental Risk Factors

2.4 Protective Factors

2.5 Gene–Environment Interactions

3. Phenotypes

3.1 HPO Annotations Curated to OMIM:613690

3.2 Additional Phenotypes Documented in the CMH7 Literature (HPO Suggestions)

3.3 Phenotype Characteristics

3.4 The TNNI3 Allelic Phenotype Spectrum (critical for entry scoping)

3.5 Quality-of-Life Impact

4. Genetic / Molecular Information

4.1 Causal Gene

4.2 Variant Spectrum

4.3 Modifier Genes

4.4 Epigenetic Information

4.5 Chromosomal Abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

6.1 The Causal Chain (upstream → downstream)

6.2 Molecular Pathways

6.3 Cellular Processes

6.4 Protein Dysfunction

6.5 Metabolic Changes

6.6 Immune System Involvement

6.7 Tissue Damage Mechanisms

6.8 Biochemical Abnormalities

6.9 Epigenetic Changes

6.10 Molecular Profiling

6.11 Advanced Technologies

7. Anatomical Structures Affected

7.1 Organ Level

7.2 Tissue and Cell Level

7.3 Subcellular Level

7.4 Localization and Lateralization

8. Temporal Development

8.1 Onset

8.2 Progression

8.3 Patterns

9. Inheritance and Population

9.1 Epidemiology

9.2 Inheritance Genetics

9.3 Population Demographics

10. Diagnostics

10.1 Clinical Tests

10.2 Genetic Testing

10.3 Omics-Based Diagnostics

10.4 Clinical Criteria

10.5 Screening

11. Outcome / Prognosis

11.1 Survival and Mortality

11.2 Morbidity and Function

3.4 The `TNNI3` Allelic Phenotype Spectrum (critical for entry scoping)