Dilated Cardiomyopathy 1FF

Genetic MONDO:0013211 Pathograph 16 Show in embeddings browser Dilated Cardiomyopathy Genetic Disorder

Dilated cardiomyopathy 1FF (CMD1FF, OMIM 613286) is the autosomal dominant, TNNI3-related form of familial isolated dilated cardiomyopathy. TNNI3 encodes cardiac troponin I (cTnI), the inhibitory subunit of the sarcomeric troponin complex that holds the actin-tropomyosin thin filament in its "off" state until calcium binding to troponin C releases the inhibition. CMD1FF is caused by a single heterozygous TNNI3 allele — classically a missense variant that is incorporated into the troponin complex and alters thin-filament calcium regulation from within it, and in at least one studied family a truncating allele acting through haploinsufficiency. The entity exists as a separate dismech entry because it contrasts on mechanism, not merely on OMIM number, with Dilated_Cardiomyopathy_2A (CMD2A, OMIM 611880), the recessive TNNI3 dilated cardiomyopathy. In CMD2A both alleles are null, no cardiac troponin I is made, and the disease is timed by the perinatal troponin I isoform switch: a well neonate decompensates within the first year with refractory heart failure. In CMD1FF a normal allele is always present and a mutant cTnI protein is present in the thin filament, so there is no null state and no isoform-switch clock. The dominant missense alleles instead alter what the troponin complex does — reconstituted mutant troponin gives lower maximum actin-tropomyosin-activated myosin ATPase rates, lower calcium sensitivity, and reduced thin-filament calcium affinity — which is the thin-filament signature shared with dominant DCM alleles in TNNT2, TPM1, TNNC1 and ACTC1, and is directionally opposite to the calcium-sensitizing TNNI3 missense alleles that cause hypertrophic (CMH7) and restrictive (RCM1) cardiomyopathy. Onset is correspondingly different: variable and incompletely penetrant rather than obligate and neonatal, though severe early-onset disease is well documented — three of the five carriers in the founding families were transplanted at ages 6, 15 and 24. Recurrence risk and cascade-screening practice differ for the same reason (50% per offspring with surveillance of first-degree relatives, versus 25% per sibship with carrier testing in CMD2A). ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies the autosomal dominant TNNI3-DCM relationship as Strong, curated separately from its Strong autosomal recessive classification.

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Inheritance
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Pathophys.
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Phenotypes
3
Hypotheses
3
Gaps
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Pathograph
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Genes
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Variants
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Medical Actions
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Differentials
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Models
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References
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Deep Research
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Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
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Inheritance

1
Autosomal Dominant HP:0000006
CMD1FF is transmitted as an autosomal dominant trait: a single heterozygous TNNI3 allele is sufficient, transmission follows the classic vertical pattern, and each offspring of a carrier has a 50% recurrence risk. Penetrance is incomplete and expressivity variable, so a genotype-positive relative may be phenotype-negative for years — which is what makes longitudinal cascade surveillance, rather than a single screening echocardiogram, the appropriate family strategy. This dominant mode is the axis on which CMD1FF separates from CMD2A, where two loss-of-function alleles are required and heterozygous parents are typically unaffected.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:19590045 SUPPORT Human Clinical
"These are the first reported autosomal dominant DCM-causing mutations in TNNI3, and so the findings expand the spectrum of disease-causing genes that lead to either hypertrophic cardiomyopathy or DCM depending on the specific mutation."
The founding CMD1FF report explicitly establishes TNNI3 as an autosomal dominant dilated cardiomyopathy gene, distinct from its long-known hypertrophic role.
CGGV:assertion_668087ea-0d2f-42c2-a291-f73400d34023-2025-04-18T160000.000Z SUPPORT Other
"TNNI3 | HGNC:11947 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel records an autosomal dominant TNNI3-DCM gene-disease relationship with Strong clinical validity, curated separately from the recessive relationship.
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Mechanistic Hypotheses

3
Altered thin-filament calcium regulation by mutant cTnI
tnni3_ad_altered_thin_filament_regulation CANONICAL
Evidence balance 2 support
The canonical model holds that a heterozygous TNNI3 missense allele produces a full-length but functionally altered cardiac troponin I that is incorporated into the thin filament alongside the wild-type protein, and changes what the troponin complex does rather than how much of it there is. Reconstitution of troponin with either founding mutant (Lys36Gln, Asn185Lys) lowers the maximum actin-tropomyosin-activated myosin ATPase rate and lowers calcium sensitivity, and the resulting thin filaments have reduced calcium affinity. This is the same functional signature carried by proven dominant DCM alleles in the other thin-filament proteins, and it is directionally opposite to the calcium-sensitizing TNNI3 alleles that cause hypertrophic and restrictive cardiomyopathy — which is the mechanistic reason one gene produces three dominant cardiomyopathies. The consequence at the cell level is a weaker, slower contraction with a suppressed systolic calcium transient.
Pathograph links
Heterozygous TNNI3 Variant Altering Cardiac Troponin I -> Altered Thin-Filament Calcium Regulation DIRECT A mutant or under-supplied troponin I changes the calcium-regulatory behaviour of the thin filament it sits in.
Altered Thin-Filament Calcium Regulation -> Reduced Cardiomyocyte Contractility and Systolic Calcium Transient DIRECT
Reduced Cardiomyocyte Contractility and Systolic Calcium Transient -> Calcineurin-NFAT and Akt Signaling Activation DIRECT
Calcineurin-NFAT and Akt Signaling Activation -> Adverse Ventricular Remodeling DIRECT
Show evidence (2 references)
PMID:19590045 SUPPORT In Vitro
"Analysis of Ca(2+) regulation of actin-tropomyosin-activated myosin ATPase by troponin revealed that troponin reconstituted with either mutant troponin I gave lower maximum ATPase rates and lower Ca(2+) sensitivity than wild type."
Supplies the direct functional measurement on which this model rests, for the two founding CMD1FF alleles. Classified IN_VITRO because it is a reconstituted-protein ATPase assay rather than a patient observation.
PMID:32278834 SUPPORT Other
"HCM and RCM models tended to have increased calcium sensitivity and DCM decreased sensitivity (P < .001)."
Establishes across the pooled troponin-variant literature that the calcium-sensitivity direction separates dilated from hypertrophic and restrictive disease, which is the generalization this model places CMD1FF inside. Evidence source is OTHER because it is a meta-analysis of previously published functional models rather than a single study type.
Uncoupling of myofilament calcium sensitivity from troponin I phosphorylation
tnni3_ad_pka_uncoupling ALTERNATIVE
Evidence balance 2 support
A competing, more specific proposal is that the primary defect is not the change in baseline calcium sensitivity at all, but the loss of its regulation. In normal thin filaments, protein kinase A phosphorylation of troponin I desensitizes the myofilament two- to three-fold, which is how beta-adrenergic stimulation accelerates relaxation. In thin filaments containing any of a panel of dominant DCM alleles — including the CMD1FF allele K36Q — calcium sensitivity no longer moves with troponin I phosphorylation at all. On this model the heart's inotropic and lusitropic reserve is what is lost, and chronic failure follows from the blunted beta-adrenergic response rather than from the resting sensitivity shift. It is recorded as ALTERNATIVE rather than CANONICAL because it has been demonstrated in vitro across mutant thin filaments but not yet shown to be the rate-limiting lesion in a CMD1FF patient or animal.
Pathograph links
Heterozygous TNNI3 Variant Altering Cardiac Troponin I -> Uncoupling of Calcium Sensitivity from Troponin I Phosphorylation DIRECT On the alternative model, the primary consequence of the mutant allele is loss of phosphorylation control over calcium sensitivity rather than a shift in its resting value.
Uncoupling of Calcium Sensitivity from Troponin I Phosphorylation -> Reduced Cardiomyocyte Contractility and Systolic Calcium Transient INDIRECT UNKNOWN INTERMEDIATES Loss of phosphorylation-dependent desensitization is proposed to degrade contractile and relaxation reserve over time rather than instantaneously, hence an indirect link.
Show evidence (2 references)
PMID:23539503 SUPPORT In Vitro
"We conclude that DCM-causing mutations in thin filament proteins abolish the relationship between myofilament Ca(2+) sensitivity and troponin I phosphorylation by PKA."
States the uncoupling hypothesis as the paper's conclusion, from quantitative in vitro motility assays on native mutant thin filaments.
PMID:23539503 SUPPORT In Vitro
"However, Ca(2+) sensitivity did not change with the level of troponin I phosphorylation in any of the DCM-mutant containing thin filaments (E40K, E54K, and D230N in α-tropomyosin; R141W and ΔK210 in cardiac troponin T; K36Q in cardiac troponin I; G159D in cardiac troponin C, and E361G in cardiac..."
Names K36Q in cardiac troponin I — one of the two founding CMD1FF alleles — among the mutant thin filaments showing the uncoupling, which is what makes this model applicable to this entity rather than to DCM generally.
Haploinsufficiency from a heterozygous truncating allele
tnni3_ad_haploinsufficiency EMERGING
Evidence balance 2 support
A third route to dominant TNNI3 dilated cardiomyopathy has been described in human explanted myocardium: a heterozygous truncating allele (p.98trunc) that produces no altered protein but simply too little of the normal one. Troponin I fell to 39% of control with distorted stoichiometry across the three troponin subunits, and exchanging in recombinant wild-type troponin both restored protein levels and normalized every functional deficit — establishing the lesion as troponin-intrinsic rather than end-stage remodeling. Notably the functional consequence here ran in the opposite direction to the missense model: calcium sensitivity was increased, not decreased, with impaired length-dependent activation. Recorded as EMERGING because it rests on one studied heart, and because that directional discrepancy is unresolved (see the corresponding discussion).
Pathograph links
Heterozygous TNNI3 Variant Altering Cardiac Troponin I -> Altered Thin-Filament Calcium Regulation DIRECT A mutant or under-supplied troponin I changes the calcium-regulatory behaviour of the thin filament it sits in.
Show evidence (2 references)
DOI:10.1113/jp274145 SUPPORT In Vitro
"The TNNI3p.98trunc and TNNT2p.K217del mutation showed reduced expression of troponin I to 39% and 51%, troponin T to 64% and 53%, and troponin C to 73% and 97% of controls, respectively, and altered stoichiometry between the three cardiac troponin subunits."
Quantifies the reduced troponin I abundance and subunit stoichiometry imbalance that define the haploinsufficiency route. Classified IN_VITRO because the measurements are on membrane-permeabilized cardiomyocytes from explanted tissue.
DOI:10.1113/jp274145 SUPPORT In Vitro
"Moreover, upon exchange all functional deficits in the TNNI3p.98trunc and TNNT2p.K217del samples were normalized to control values confirming the pathogenic effects of the troponin mutations."
The troponin-exchange rescue is what establishes that the contractile defect is caused by the troponin lesion itself rather than by secondary end-stage remodeling in an explanted failing heart.
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Discussions and Knowledge Gaps

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Is dominant TNNI3 dilated cardiomyopathy (CMD1FF) a separate dismech entity from recessive TNNI3 dilated cardiomyopathy (CMD2A), or should it be a subtype of it?
INTERPRETATION RESOLVED cmd1ff_versus_cmd2a_split
Attached to
pathophysiology#Heterozygous TNNI3 Variant Altering Cardiac Troponin I
The two share a gene and an organ-level phenotype, so the split needs a reason beyond having two OMIM numbers. Four independent axes support it. Mechanism: CMD2A abolishes cardiac troponin I, whereas CMD1FF always retains a wild-type allele and — for the founding missense alleles — puts an altered protein into the troponin complex, so the lesion is a change in what the thin filament does rather than an absence of it. Direction of functional effect: the CMD1FF alleles lower maximum ATPase and calcium sensitivity, whereas the troponin I-null heart is characterized by global regulatory failure timed by a developmental isoform switch, a clock that has no meaning when one allele is intact. Natural history: obligate neonatal-to-infantile and near-uniformly severe in CMD2A, versus variable, incompletely penetrant, childhood-to-adult onset in CMD1FF. Clinical action: 50% per-offspring recurrence with longitudinal surveillance of first-degree relatives, versus 25% per sibship with carrier testing and reproductive counselling. ClinGen's Dilated Cardiomyopathy GCEP reinforces this by issuing two separate TNNI3-DCM assertions differing only in mode of inheritance, both rated Strong. Recorded as RESOLVED in favour of a separate entry; if MONDO or ClinGen later collapses the two, this entry and CMD2A should be merged rather than left to duplicate each other.
Show evidence (2 references)
CGGV:assertion_668087ea-0d2f-42c2-a291-f73400d34023-2025-04-18T160000.000Z SUPPORT Other
"TNNI3 | HGNC:11947 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
The dominant assertion, curated separately from the recessive one on the same day by the same expert panel — the external evidence that the two relationships are treated as distinct curatable claims.
PMID:36981019 SUPPORT Human Clinical
"In recent years, however, an increasing amount of evidence has validated the hypothesis that biallelic TNNI3 null mutations cause a severe form of neonatal dilated cardiomyopathy."
Establishes the recessive entity's distinct genotype and neonatal course, which is the contrast this split rests on.
Do all dominant TNNI3 dilated-cardiomyopathy alleles decrease myofilament calcium sensitivity, given that the one heterozygous truncating allele studied in human myocardium increased it?
KNOWLEDGE GAP OPEN cmd1ff_calcium_sensitivity_direction_conflict
Attached to
pathophysiology#Altered Thin-Filament Calcium Regulation mechanistic_hypotheses#tnni3_ad_haploinsufficiency
The organising generalization for dominant thin-filament dilated cardiomyopathy is that its alleles desensitize the myofilament to calcium, opposite to the sensitizing hypertrophic and restrictive alleles — and the two founding CMD1FF missense alleles behave that way on reconstitution. But the single heterozygous TNNI3 truncating allele characterized in explanted human myocardium showed pure haploinsufficiency with *increased* calcium sensitivity and impaired length-dependent activation. Both results are credible and neither is a measurement error: they differ in allele class (altered-function missense versus reduced-quantity truncation), in preparation (reconstituted proteins versus permeabilized human cardiomyocytes), and in whether secondary remodeling of an end-stage explanted heart could contribute. Whether the two allele classes reach the same disease by opposite myofilament routes, or whether one of them belongs to a different mechanism entirely, is unresolved — and it matters, because a calcium-sensitizer or -desensitizer therapy would be predicted to help one group and harm the other.
Proposed experiments
Paired calcium-sensitivity measurement across CMD1FF missense and truncating alleles
exp_cmd1ff_allele_class_calcium_sensitivity_series
Measure myofilament calcium sensitivity and length-dependent activation in one preparation across a panel of heterozygous TNNI3 dilated-cardiomyopathy alleles spanning both classes, so the direction of effect is not confounded by differences in assay system.
Isogenic human iPSC-cardiomyocyte comparison of missense versus truncating TNNI3 alleles
exp_cmd1ff_isogenic_ipsc_allele_comparison
Introduce K36Q, N185K, and a truncating TNNI3 allele into a single isogenic human iPSC background and compare calcium sensitivity, contractility, and length-dependent activation, removing both the species and the end-stage remodeling confounds.
Show evidence (2 references)
PMID:19590045 SUPPORT In Vitro
"Analysis of Ca(2+) regulation of actin-tropomyosin-activated myosin ATPase by troponin revealed that troponin reconstituted with either mutant troponin I gave lower maximum ATPase rates and lower Ca(2+) sensitivity than wild type."
One side of the discrepancy: the founding missense alleles reduce calcium sensitivity.
DOI:10.1113/jp274145 REFUTE In Vitro
"The TNNI3p.98trunc showed pure haploinsufficiency, increased Ca2+‐sensitivity and impaired length‐dependent activation."
The other side: a heterozygous TNNI3 truncating allele in human myocardium raised calcium sensitivity. Graded REFUTE against the claim that all dominant TNNI3 dilated-cardiomyopathy alleles are calcium-desensitizing, which is the generalization this gap questions.
Does any whole-animal model of dominant TNNI3 dilated cardiomyopathy exist, and what does its absence cost the mechanistic account?
KNOWLEDGE GAP OPEN cmd1ff_no_animal_model
Attached to
pathophysiology#Adverse Ventricular Remodeling
Every functional result behind this entry comes from reconstituted proteins, permeabilized human cardiomyocytes, or acutely transduced isolated myocytes. No knock-in animal carrying a CMD1FF allele has been reported, in contrast to the thin-filament DCM field generally, where knock-in mouse models exist for TNNT2 and TPM1 alleles and where the Tnni3-null mouse anchors the recessive entity. Consequently the steps from myofilament defect through remodeling to a dilated ventricle are asserted here from dilated cardiomyopathy as a class rather than demonstrated for this genotype, and questions that need an intact circulation — penetrance, the trigger for conversion from latent to manifest disease, and whether beta-blockade acts differently when phosphorylation-sensitivity coupling is lost — cannot currently be addressed.
Proposed experiments
Tnni3 K36Q or N185K knock-in mouse
exp_cmd1ff_knockin_mouse
Generate a heterozygous knock-in carrying a CMD1FF allele at the endogenous locus and characterize penetrance, age of onset, ventricular geometry, fibrosis and response to beta-blockade, to test whether the in vitro myofilament defect is sufficient for the disease.
Show evidence (1 reference)
PMID:32618513 SUPPORT Other
"To date, five gene-targeted knock-in mouse models of DCM carrying thin-filament mutations have been characterized: TnT ΔK210 (10), R141W (36), and R134W (15); actin E99K (46); and αTM E54K (35)."
Enumerates the existing thin-filament DCM knock-in models — none of them a TNNI3 allele — which is the gap this discussion records. Evidence source is OTHER because the sentence surveys prior literature rather than reporting this paper's results.
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Pathophysiology

7
Heterozygous TNNI3 Variant Altering Cardiac Troponin I
TNNI3 encodes cardiac troponin I, the inhibitory subunit of the troponin complex and one of the three regulatory proteins (with troponin C and troponin T) that confer calcium sensitivity on the sarcomeric thin filament. CMD1FF arises from a single heterozygous TNNI3 allele. The founding alleles are missense (Lys36Gln, Asn185Lys), which produce a full-length mutant cTnI that assembles into the troponin complex beside the wild-type protein; a heterozygous truncating allele acting by haploinsufficiency has also been documented in explanted human myocardium. Either way a wild-type allele remains, so — unlike the biallelic null genotype of CMD2A — the myocardium is never troponin I-free, and the disease is not gated by the perinatal troponin I isoform switch.
Altered thin-filament calcium regulation by mutant cTnI Haploinsufficiency from a heterozygous truncating allele Uncoupling of myofilament calcium sensitivity from troponin I phosphorylation
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
TNNI3 hgnc:11947 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TNNI3 (hgnc:11947). hgnc:11947 is a gene from the HUGO Gene Nomenclature Committee.
Sarcomere organization GO:0045214 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Sarcomere organization (GO:0045214). GO:0045214 is a biological process from the Gene Ontology. ⚠ ABNORMAL
actin binding GO:0003779 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves abnormal actin binding (GO:0003779). GO:0003779 is a molecular function from the Gene Ontology. ⚠ ABNORMAL
troponin complex GO:0005861 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves abnormal troponin complex (GO:0005861). GO:0005861 is a cellular component from the Gene Ontology.
Myocardium UBERON:0002349 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Myocardium (UBERON:0002349). UBERON:0002349 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Altered Thin-Filament Calcium Regulation A mutant or under-supplied troponin I changes the calcium-regulatory behaviour of the thin filament it sits in. Altered thin-filament calcium regulation by mutant cTnI Haploinsufficiency from a heterozygous truncating allele
Uncoupling of Calcium Sensitivity from Troponin I Phosphorylation On the alternative model, the primary consequence of the mutant allele is loss of phosphorylation control over calcium sensitivity rather than a shift in its resting value. Uncoupling of myofilament calcium sensitivity from troponin I phosphorylation
Show evidence (2 references)
PMID:19590045 SUPPORT Human Clinical
"We report 2 novel TNNI3 missense mutations, Lys36Gln and Asn185Lys, each associated with severe and early onset familial DCM."
Identifies the two founding heterozygous missense alleles and their segregation with familial dilated cardiomyopathy — the causal claim of this node.
DOI:10.1113/jp274145 SUPPORT In Vitro
"The TNNI3p.98trunc showed pure haploinsufficiency, increased Ca2+‐sensitivity and impaired length‐dependent activation."
Documents the second allele class reaching this node — a heterozygous truncation acting by haploinsufficiency in human left ventricular tissue. Classified IN_VITRO because the measurement is on permeabilized cardiomyocytes.
Altered Thin-Filament Calcium Regulation
With a mutant cTnI in the troponin complex, the thin filament's translation of calcium binding into cross-bridge activation is degraded. For the founding CMD1FF missense alleles this takes the form of a lower maximum actin-tropomyosin-activated myosin ATPase rate, lower calcium sensitivity, and reduced calcium affinity of the mutant thin filaments — a coordinated loss of activation rather than a leak of inhibition. This calcium-desensitizing direction is what places CMD1FF with the other dominant thin-filament dilated cardiomyopathies and separates it from the calcium-sensitizing TNNI3 alleles of hypertrophic and restrictive disease. In the reported haploinsufficient truncating case the measured direction was the opposite, which this entry records as an unresolved discrepancy rather than smoothing over.
Altered thin-filament calcium regulation by mutant cTnI
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Regulation of cardiac muscle contraction GO:0055117 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Regulation of cardiac muscle contraction (GO:0055117). GO:0055117 is a biological process from the Gene Ontology. ⚠ ABNORMAL Regulation of striated muscle contraction GO:0006942 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Regulation of striated muscle contraction (GO:0006942). GO:0006942 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Reduced Cardiomyocyte Contractility and Systolic Calcium Transient Altered thin-filament calcium regulation by mutant cTnI
Show evidence (2 references)
PMID:19590045 SUPPORT In Vitro
"Furthermore, mutant thin filaments had reduced Ca(2+) affinity compared with normal."
Supplies the thin-filament-level calcium affinity measurement this node asserts, for the CMD1FF alleles themselves.
PMID:32618513 SUPPORT Other
"Previous work has shown that changes to myofilament Ca2+ sensitivity caused by DCM mutations are qualitatively opposite from hypertrophic cardiomyopathy (HCM) mutations in the same genes."
States the directional contrast between dilated and hypertrophic alleles in the same genes, which is the discriminating claim of this node. Evidence source is OTHER because this sentence summarises the prior literature rather than reporting this paper's own cardiomyocyte experiments.
Uncoupling of Calcium Sensitivity from Troponin I Phosphorylation
Beta-adrenergic stimulation normally accelerates cardiac relaxation by having protein kinase A phosphorylate troponin I, which desensitizes the myofilament to calcium two- to three-fold. In thin filaments carrying a dominant DCM allele — the CMD1FF allele K36Q among them — calcium sensitivity no longer tracks troponin I phosphorylation at all. The regulatory link is severed rather than the set point moved, so the myocardium loses the ability to change its calcium sensitivity on demand. This node is the substrate of the alternative mechanistic hypothesis: it predicts a blunted response to sympathetic drive as the operative deficit, which would show first as loss of contractile and relaxation reserve under stress rather than at rest.
Uncoupling of myofilament calcium sensitivity from troponin I phosphorylation
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Regulation of cardiac muscle cell contraction GO:0086004 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Regulation of cardiac muscle cell contraction (GO:0086004). GO:0086004 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Reduced Cardiomyocyte Contractility and Systolic Calcium Transient Loss of phosphorylation-dependent desensitization is proposed to degrade contractile and relaxation reserve over time rather than instantaneously, hence an indirect link. Uncoupling of myofilament calcium sensitivity from troponin I phosphorylation
Show evidence (2 references)
PMID:23539503 SUPPORT In Vitro
"In thin filaments from normal human and mouse heart, protein kinase A (PKA) phosphorylation of troponin I caused a two- to three-fold decrease in myofibrillar Ca(2+) sensitivity."
Establishes the normal phosphorylation-sensitivity relationship that this node asserts is lost.
PMID:23539503 SUPPORT In Vitro
"We propose that this blunts the response to β-adrenergic stimulation and could be the cause of DCM in the long term."
States the proposed downstream consequence — loss of beta-adrenergic responsiveness — that this node contributes to the pathograph.
Reduced Cardiomyocyte Contractility and Systolic Calcium Transient
At the level of the single myocyte the thin-filament lesion produces significantly reduced fractional shortening together with a reduced systolic calcium transient, with slowed contraction and slowed calcium reuptake. Sarcoplasmic reticulum calcium load rises while fractional release falls, reflecting reduced SERCA activity and increased sodium-calcium exchanger activity. These changes were shown for the CMD1FF allele K36Q alongside dominant DCM alleles in troponin T and tropomyosin, and were common to all three — evidence that this node is a shared convergence point of thin-filament dilated cardiomyopathy rather than an idiosyncrasy of one variant.
Altered thin-filament calcium regulation by mutant cTnI
Cardiac ventricular myocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiac ventricular myocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Cardiac muscle cell contraction GO:0086003 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Cardiac muscle cell contraction (GO:0086003). GO:0086003 is a biological process from the Gene Ontology. ↓ DECREASED Intracellular calcium ion homeostasis GO:0006874 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Intracellular calcium ion homeostasis (GO:0006874). GO:0006874 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Experimental models
Adenovirally transduced adult guinea pig left ventricular cardiomyocytes expressing TNNI3 K36Q OTHER The model's central result is reduced fractional shortening with a suppressed systolic calcium transient in cells carrying the CMD1FF allele.
Downstream
Calcineurin-NFAT and Akt Signaling Activation Altered thin-filament calcium regulation by mutant cTnI
Adverse Ventricular Remodeling
Show evidence (2 references)
PMID:32618513 SUPPORT In Vitro
"In this work we have studied the functional consequences of mutations in cardiac troponin T (R131W), cardiac troponin I (K36Q) and α-tropomyosin (E40K) using adenovirally transduced isolated guinea pig left ventricular cardiomyocytes. We find significantly reduced fractional shortening with..."
Directly measures the two properties this node asserts — reduced shortening and reduced systolic calcium — in cardiomyocytes expressing the CMD1FF allele K36Q. Classified IN_VITRO because the system is isolated, adenovirally transduced cardiomyocytes.
PMID:32618513 SUPPORT In Vitro
"These changes in Ca2+ handling and signaling are common to all three mutations, indicating an analogous pathway of disease pathogenesis in thin-filament sarcomeric DCM."
Establishes that the calcium-handling changes are shared across dominant thin-filament DCM alleles, which is why this node is modeled as a convergence point rather than an allele-specific finding.
Calcineurin-NFAT and Akt Signaling Activation
Chronically paced cardiomyocytes expressing dominant thin-filament DCM mutations, including TNNI3 K36Q, show dephosphorylation and nuclear translocation of NFAT with concordant Akt phosphorylation, and no change in ERK activation. This is the link between an altered myofilament and a transcriptional remodeling program: the mutant sarcomere does not merely contract badly, it changes the calcium-dependent signalling that instructs the cell to remodel. Note that NFAT activation is not specific to the dilated direction — it is also a hypertrophic cardiomyopathy hallmark — so this node is a shared remodeling entry point rather than a discriminating feature of CMD1FF.
Altered thin-filament calcium regulation by mutant cTnI
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Calcineurin-NFAT signaling cascade GO:0033173 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Calcineurin-NFAT signaling cascade (GO:0033173). GO:0033173 is a biological process from the Gene Ontology. ↑ INCREASED
Experimental models
Adenovirally transduced adult guinea pig left ventricular cardiomyocytes expressing TNNI3 K36Q OTHER The model supplies the signalling readouts linking the mutant myofilament to a remodeling transcriptional program.
Downstream
Adverse Ventricular Remodeling Altered thin-filament calcium regulation by mutant cTnI
Show evidence (1 reference)
PMID:32618513 SUPPORT In Vitro
"We also observe dephosphorylation and nuclear translocation of the nuclear factor of activated T cells (NFAT), with concordant RAC-α-serine/threonine protein kinase (Akt) phosphorylation but no change to extracellular signal-regulated kinase activation in chronically paced cardiomyocytes..."
Supplies the specific signalling readout this node asserts, in cardiomyocytes carrying the CMD1FF allele among others.
Adverse Ventricular Remodeling
Sustained contractile inefficiency and the remodeling signalling it drives convert a molecular lesion into a structurally altered ventricle: cardiomyocyte loss by apoptosis, interstitial fibrosis from activated cardiac fibroblasts, and progressive chamber enlargement with rising wall stress. This node is the generic dilated-cardiomyopathy remodeling program rather than a TNNI3-specific process, and is curated as such — no CMD1FF-specific histopathological series exists, and the fibrosis branch is asserted from dilated cardiomyopathy as a class.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology. Cardiac fibroblast CL:0002548 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiac fibroblast, annotated with fibroblast of cardiac tissue (CL:0002548). CL:0002548 is a cell type from the Cell Ontology.
Extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ↑ INCREASED Cardiomyocyte apoptosis GO:0010659 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Cardiomyocyte apoptosis, annotated with cardiac muscle cell apoptotic process (GO:0010659). GO:0010659 is a biological process from the Gene Ontology. ↑ INCREASED
Myocardium UBERON:0002349 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Myocardium (UBERON:0002349). UBERON:0002349 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Left Ventricular Dilation and Systolic Failure
Show evidence (2 references)
PMID:32618513 SUPPORT Other
"Dilated cardiomyopathy (DCM) is a disease of the myocardium characterized by dilatation of the left ventricle, impaired systolic function, evidence of cellular apoptosis, and interstitial fibrosis."
Establishes apoptosis and interstitial fibrosis as constituents of the dilated-cardiomyopathy remodeling phenotype this node describes. Evidence source is OTHER because the sentence is a review statement in the paper's introduction, not a result of its cardiomyocyte experiments.
PMID:31073128 SUPPORT Other
"Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling"
Names adverse myocardial remodelling as the process that imaging is deployed to assess in dilated cardiomyopathy, supporting its place in the causal chain. Evidence source is OTHER because this is a Nature Reviews Disease Primers review.
Left Ventricular Dilation and Systolic Failure
The organ-level endpoint: left ventricular or biventricular chamber enlargement with impaired contraction, not explained by loading conditions or coronary disease, progressing to congestive heart failure. In the founding CMD1FF families this was severe and early — three of five carriers required cardiac transplantation, at ages 6, 15 and 24 — but expressivity is variable and a genotype-positive relative may sit for years in a phenotype-negative or subclinical state, which is the clinical difference from the obligate, uniformly severe infantile course of the recessive entity.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Cardiac muscle contraction GO:0060048 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Cardiac muscle contraction (GO:0060048). GO:0060048 is a biological process from the Gene Ontology. ↓ DECREASED
Left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Left ventricle, annotated with heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Congestive heart failure
Sudden cardiac death Structural and electrical remodeling of the dilated ventricle carries arrhythmic risk; no CMD1FF-specific event rate is available.
Show evidence (2 references)
PMID:19590045 SUPPORT Human Clinical
"Of the 5 mutation carriers, cardiac transplantation was required in 3, at ages 6, 15, and 24 years."
Quantifies the severity of organ-level failure in the founding CMD1FF families and the age range over which it presented.
PMID:31073128 SUPPORT Other
"Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease."
Supplies the definition of the organ-level phenotype this node represents. Evidence source is OTHER because this is a Nature Reviews Disease Primers review.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Dilated Cardiomyopathy 1FF Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Dilated cardiomyopathy VERY_FREQUENT Cardiovascular HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644), qualified as course progressive. HP:0001644 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:19590045 SUPPORT Human Clinical
"We report 2 novel TNNI3 missense mutations, Lys36Gln and Asn185Lys, each associated with severe and early onset familial DCM."
Dilated cardiomyopathy is the obligate phenotype of the heterozygous TNNI3 genotype in this entity, and is characterized as severe and early onset, supporting the VERY_FREQUENT band.
Left ventricular dilatation VERY_FREQUENT Cardiovascular HP:4000141 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular dilatation (HP:4000141). HP:4000141 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31073128 SUPPORT Other
"Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease."
Chamber dilation is constitutive of the diagnosis CMD1FF carriers receive. Evidence source is OTHER because this is a review; no CMD1FF-specific echocardiographic series exists to quantify the dimension.
Left ventricular systolic dysfunction VERY_FREQUENT Cardiovascular HP:0025169 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular systolic dysfunction (HP:0025169). HP:0025169 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1002/ejhf.3657 SUPPORT Human Clinical
"family history of arrhythmia and being carrier of a pathogenic/likely pathogenic variant are the main risk factors for LV systolic dysfunction"
Establishes carriage of a pathogenic variant as a principal risk factor for developing left ventricular systolic dysfunction among relatives in DCM family screening — the situation a CMD1FF kindred is in. The cohort is DCM/NDLVC relatives generally, not TNNI3 carriers specifically.
Reduced left ventricular ejection fraction VERY_FREQUENT Cardiovascular HP:0012664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced left ventricular ejection fraction (HP:0012664). HP:0012664 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32618513 SUPPORT Other
"Dilated cardiomyopathy (DCM) is clinically characterized by dilated ventricular cavities and reduced ejection fraction, leading to heart failure and increased thromboembolic risk."
Establishes reduced ejection fraction as a defining clinical feature of the disease class this entity belongs to. Evidence source is OTHER because the sentence is the paper's framing of dilated cardiomyopathy rather than one of its experimental results.
Congestive heart failure FREQUENT Cardiovascular HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:19590045 SUPPORT Human Clinical
"Of the 5 mutation carriers, cardiac transplantation was required in 3, at ages 6, 15, and 24 years."
Transplantation in three of five carriers documents progression to end-stage heart failure in this entity. The FREQUENT rather than VERY_FREQUENT band reflects that not every reported carrier reached this endpoint.
Sudden cardiac death Cardiovascular HP:0001645 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sudden cardiac death (HP:0001645). HP:0001645 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32618513 SUPPORT Other
"Clinically, it is associated with chronic heart failure, sudden cardiac death, and cardioembolic stroke."
Names sudden cardiac death among the clinical associations of dilated cardiomyopathy. Frequency is deliberately omitted — the quote is about the disease class, and no source quantifies arrhythmic death in the TNNI3 dominant subset. Evidence source is OTHER because the sentence is background framing rather than an experimental result.
Arrhythmia Cardiovascular HP:0011675 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arrhythmia (HP:0011675). HP:0011675 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
DOI:10.1002/ejhf.3657 SUPPORT Human Clinical
"Secondary heart failure (HF) and arrhythmic outcomes were also included."
Documents arrhythmic outcomes as a tracked endpoint in relatives of DCM probands. No frequency is asserted: the quote establishes that arrhythmia is part of the outcome set in DCM family screening, not its rate in TNNI3 carriers.
🧬

Genetic Associations

1
TNNI3 Heterozygous Function-Altering Variants (Heterozygous Missense and Truncating Variants)
Gene: TNNI3 hgnc:11947 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is TNNI3 (hgnc:11947). hgnc:11947 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Autosomal Dominant
Show evidence (3 references)
CGGV:assertion_668087ea-0d2f-42c2-a291-f73400d34023-2025-04-18T160000.000Z SUPPORT Other
"TNNI3 | HGNC:11947 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies the autosomal dominant TNNI3-DCM gene-disease relationship as Strong under SOP10.
PMID:19590045 SUPPORT Human Clinical
"One contractile protein gene well known as a hypertrophic cardiomyopathy disease gene, but with no reported mutation in autosomal dominant DCM, is TNNI3 which encodes cardiac troponin I."
States the gene's prior standing as a hypertrophic cardiomyopathy gene, which is the background against which the dominant DCM relationship curated here was established.
PMID:36981019 SUPPORT Human Clinical
"While heterozygous TNNI3 missense mutations have long been associated with autosomal dominant hypertrophic and restrictive cardiomyopathies, the role of TNNI3 null mutations has been more debated"
States the zygosity-and-variant-class landscape that a TNNI3 variant must be placed within before an entity is assigned — the heterozygous missense side of which is where CMD1FF sits.
Variants (3)
TNNI3 p.Lys36Gln (K36Q)
Gene: TNNI3 hgnc:11947 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TNNI3 (hgnc:11947). hgnc:11947 is a gene from the HUGO Gene Nomenclature Committee.
N-terminal missense allele, one of the two founding CMD1FF variants. Reconstituted troponin carrying it gives reduced maximum ATPase and reduced calcium sensitivity, and thin filaments containing it lose the normal coupling between calcium sensitivity and troponin I phosphorylation. It is also the allele carried into the isolated-cardiomyocyte studies that demonstrate reduced fractional shortening, suppressed systolic calcium, and NFAT activation, making it the best functionally characterized CMD1FF variant.
Show evidence (1 reference)
PMID:19590045 SUPPORT Human Clinical
"We report 2 novel TNNI3 missense mutations, Lys36Gln and Asn185Lys, each associated with severe and early onset familial DCM."
Identifies this allele and its association with severe early-onset familial dilated cardiomyopathy.
TNNI3 p.Asn185Lys (N185K)
Gene: TNNI3 hgnc:11947 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TNNI3 (hgnc:11947). hgnc:11947 is a gene from the HUGO Gene Nomenclature Committee.
C-terminal missense allele, the second founding CMD1FF variant, segregating with severe early-onset familial dilated cardiomyopathy and producing the same reduced-ATPase, reduced-calcium-sensitivity signature on reconstitution.
Show evidence (1 reference)
PMID:19590045 SUPPORT In Vitro
"Analysis of Ca(2+) regulation of actin-tropomyosin-activated myosin ATPase by troponin revealed that troponin reconstituted with either mutant troponin I gave lower maximum ATPase rates and lower Ca(2+) sensitivity than wild type."
Records the functional consequence measured for both founding alleles, including this one. Classified IN_VITRO because it is a reconstituted protein assay.
TNNI3 p.98trunc (heterozygous)
Gene: TNNI3 hgnc:11947 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in TNNI3 (hgnc:11947). hgnc:11947 is a gene from the HUGO Gene Nomenclature Committee.
Heterozygous truncating allele studied in explanted left ventricular tissue from a transplanted DCM patient. Troponin I fell to 39% of control with distorted subunit stoichiometry, and exchange with recombinant wild-type troponin restored protein levels and normalized the functional deficits. It is the evidence that haploinsufficiency, not only altered function, is a route to dominant TNNI3 dilated cardiomyopathy.
Show evidence (1 reference)
DOI:10.1113/jp274145 SUPPORT In Vitro
"Exchange with wild‐type troponin complex corrected troponin protein levels to 83% of controls in the TNNI3p.98trunc sample."
The exchange experiment establishing that the deficit in this heterozygous truncating genotype is a troponin-quantity problem correctable in vitro.
💊

Medical Actions

3
Guideline-Directed Heart Failure Pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ACE inhibitor NCIT:C247 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses ACE inhibitor (NCIT:C247). NCIT:C247 is a therapeutic agent from the NCI Thesaurus. beta-blocker NCIT:C29576 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses beta-blocker, annotated with Beta-Adrenergic Antagonist (NCIT:C29576). NCIT:C29576 is a therapeutic agent from the NCI Thesaurus. mineralocorticoid receptor antagonist (spironolactone as the class exemplar) NCIT:C840 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses mineralocorticoid receptor antagonist (spironolactone as the class exemplar), annotated with Spironolactone (NCIT:C840). NCIT:C840 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Standard anti-remodeling heart-failure therapy — renin-angiotensin system blockade, a beta-blocker, and a mineralocorticoid receptor antagonist — targeting the neurohormonal and remodeling amplifier downstream of the myofilament lesion. There is no TNNI3-directed or myofilament-correcting therapy for CMD1FF, so management is the generic dilated-cardiomyopathy regimen. One caveat is worth recording: if the uncoupling hypothesis is correct, the myofilament in this disease no longer responds to phosphorylation-mediated calcium desensitization, which is the arm of beta-adrenergic signalling that beta-blockade modulates — a reason to expect generic therapy to work through remodeling rather than through restoring myofilament regulation.
Mechanism Target:
INHIBITS Adverse Ventricular Remodeling — Neurohormonal blockade slows the remodeling program that converts the myofilament lesion into a dilated ventricle; it does not correct the mutant troponin.
Show evidence (1 reference)
PMID:31073128 SUPPORT Other
"As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM."
Establishes standard heart-failure therapy as first-line management for dilated cardiomyopathy, of which CMD1FF is a genetic form. Evidence source is OTHER because this is a Nature Reviews Disease Primers review.
Heart Transplantation
Action: heart transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is heart transplantation (NCIT:C15246). NCIT:C15246 is a clinical intervention from the NCI Thesaurus. Ontology label: Heart Transplantation NCIT:C15246
Platform: Surgery
The definitive therapy for end-stage disease, and a documented outcome in this entity: three of the five carriers in the founding families were transplanted, the youngest at age 6. Because the lesion is a constitutional sarcomeric protein defect rather than a reversible insult, recovery of native ventricular function is not expected once end-stage failure is established.
Mechanism Target:
INHIBITS Left Ventricular Dilation and Systolic Failure — Transplantation replaces the failing ventricle outright; it is the only intervention that removes the mutant myocardium.
Show evidence (1 reference)
PMID:19590045 SUPPORT Human Clinical
"Of the 5 mutation carriers, cardiac transplantation was required in 3, at ages 6, 15, and 24 years."
Documents transplantation as the realized endpoint in the majority of reported CMD1FF carriers.
Genetic Counseling and Cascade Screening
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Platform: Behavioral / lifestyle
Counseling for a 50% per-offspring recurrence risk, predictive testing of first-degree relatives, and enrolment of genotype-positive relatives in longitudinal cardiac surveillance. The counseling content differs materially from CMD2A's: there the conversation is about a 25% sibship risk and unaffected carrier parents, here it is about vertical transmission, incomplete penetrance, and the fact that a normal echocardiogram today does not discharge a carrier. Genetic counseling is one of the few points on which international DCM guidelines already agree.
Show evidence (2 references)
DOI:10.1093/ehjqcco/qcae109 SUPPORT Other
"Our review revealed consensus on several key aspects: the definition of DCM, the use of B-type natriuretic peptides and high-sensitivity troponin in laboratory testing, the essential role of multimodality cardiovascular imaging for initial diagnosis, genetic counselling, and the management of..."
Records genetic counselling as an area of cross-guideline consensus in dilated cardiomyopathy management. Evidence source is OTHER because this is a systematic review of guidelines.
PMID:20301486 SUPPORT Other
"Provide a basic view of genetic risk assessment of at-risk asymptomatic relatives of a proband with DCM to inform cardiac surveillance and allow early detection and treatment of DCM to improve long-term outcome."
The GeneReviews DCM overview frames genetic risk assessment of asymptomatic relatives as a route to earlier detection and better outcome, which is the rationale for cascade screening in a dominant entity. Evidence source is OTHER because GeneReviews is an expert-curated reference work. The quote is drawn from the chapter's stated purpose — the only prose in the PubMed record — rather than from a counseling section, and it is generic DCM guidance rather than CMD1FF-specific.
🔬

Diagnosis

3
Echocardiography
First-line and usually diagnostic: left ventricular internal dimensions and ejection fraction establish the dilated, hypocontractile phenotype. In a CMD1FF kindred echocardiography also carries the surveillance load, since a genotype-positive relative may convert from phenotype-negative to systolic dysfunction years after the first normal study.
echocardiography NCIT:C16525 NCI Thesaurus (NCIT)
Show evidence (1 reference)
DOI:10.1093/ehjqcco/qcae109 SUPPORT Other
"Our review revealed consensus on several key aspects: the definition of DCM, the use of B-type natriuretic peptides and high-sensitivity troponin in laboratory testing, the essential role of multimodality cardiovascular imaging for initial diagnosis, genetic counselling, and the management of..."
Records cross-guideline consensus that multimodality cardiovascular imaging is essential for the initial diagnosis of dilated cardiomyopathy, of which CMD1FF is a genetic form. Evidence source is OTHER because this is a systematic review of guidelines rather than a primary study.
Molecular Genetic Testing
Cardiomyopathy-panel or exome sequencing establishes the diagnosis and, as importantly, its zygosity. A heterozygous TNNI3 variant in a proband with a dilated ventricle points at CMD1FF; two loss-of-function alleles point at CMD2A; and a heterozygous missense allele must still be weighed against the much larger TNNI3 hypertrophic and restrictive literature before a dilated entity is assigned. Segregation in the family is what converts a plausible variant into a diagnosis, which is why the founding report evaluated its candidates by segregation analysis and control screening rather than by computational prediction.
cardiomyopathy gene panel or exome sequencing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:19590045 SUPPORT Human Clinical
"Genomic DNA was isolated and TNNI3 exons screened by heteroduplex analysis. Exons with aberrant profiles were sequenced and variants evaluated by segregation analysis and study of normal controls."
Documents segregation analysis plus control screening as the evidence standard applied to candidate TNNI3 variants in this entity.
DOI:10.1093/ehjqcco/qcae109 SUPPORT Other
"Nonetheless, notable areas of variation included the formation of multidisciplinary management teams, the role of cascade genetic testing, pathways for arrhythmic risk stratification, and the criteria for prophylactic defibrillator implantation."
Records that the role of cascade genetic testing is an area where DCM guidelines diverge — relevant because cascade testing is the practical consequence of a CMD1FF diagnosis. Evidence source is OTHER because this is a systematic review of guidelines.
Family Screening of First-Degree Relatives
Because the trait is dominant with incomplete and age-dependent penetrance, the diagnostic unit is the family rather than the proband. Longitudinal screening of first-degree relatives detects left ventricular systolic dysfunction before it declares itself clinically, and detection through a screening programme is associated with better outcomes than detection outside one. Carriage of a pathogenic variant is one of the main risk factors for developing dysfunction, so a CMD1FF genotype identifies precisely the relatives who need continuing rather than one-off evaluation.
cascade family screening for dilated cardiomyopathy NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
DOI:10.1002/ejhf.3657 SUPPORT Human Clinical
"Baseline and follow-up data of first-degree relatives of probands affected by DCM/NDLVC were collected."
Establishes longitudinal evaluation of first-degree relatives as the design of DCM family screening, which is the practice a dominant CMD1FF genotype triggers. The cohort is DCM/NDLVC relatives generally rather than TNNI3 carriers.
DOI:10.1002/ejhf.3657 SUPPORT Human Clinical
"family history of arrhythmia and being carrier of a pathogenic/likely pathogenic variant are the main risk factors for LV systolic dysfunction"
Identifies pathogenic-variant carriage as a main risk factor for developing systolic dysfunction, which is what makes genotype-directed surveillance of CMD1FF relatives worthwhile.
📈

Progression

3
Genotype-positive, phenotype-negative
Because penetrance is incomplete and age-dependent, a carrier may have a structurally normal, normally contracting ventricle for years or decades. This phase has no counterpart in the recessive entity, where the null genotype declares itself in infancy. It is the phase that makes longitudinal cascade surveillance of first-degree relatives, rather than a single screening study, the appropriate family strategy, and it is why relatives found to carry a pathogenic variant are followed rather than discharged.
Show evidence (1 reference)
DOI:10.1002/ejhf.3657 SUPPORT Human Clinical
"During a median follow-up of 110 months (interquartile range 57–188 months), only subjects that previously developed LV systolic dysfunction had primary outcomes (19 vs. 0, p"
Documents a screened relative population followed for a median of nine years in which the emergence of systolic dysfunction, not carrier status alone, marks the transition to adverse outcomes — the latent-then-manifest pattern this phase describes. The cohort is DCM/NDLVC relatives generally.
Manifest left ventricular systolic dysfunction
Onset of measurable systolic dysfunction and chamber dilation, which may be detected on surveillance before symptoms. In the founding CMD1FF families this stage was reached in childhood or early adulthood in the severely affected carriers. Detection at this point is what family screening exists to achieve, because it opens the window for anti-remodeling therapy before symptomatic failure.
Show evidence (1 reference)
PMID:19590045 SUPPORT Human Clinical
"We report 2 novel TNNI3 missense mutations, Lys36Gln and Asn185Lys, each associated with severe and early onset familial DCM."
Characterizes the manifest disease in the founding families as severe and early in onset.
Advanced heart failure, transplantation, or death
In the severe end of the reported spectrum the disease progresses to end-stage heart failure requiring cardiac transplantation — three of the five carriers in the founding families, at ages 6, 15 and 24. There is no TNNI3-directed therapy, so progression is modified only by generic heart-failure management, and transplantation remains the definitive option.
Show evidence (1 reference)
PMID:19590045 SUPPORT Human Clinical
"Of the 5 mutation carriers, cardiac transplantation was required in 3, at ages 6, 15, and 24 years."
Documents progression to transplantation and the ages at which it occurred in this entity.
📊

Prevalence

1
Worldwide
Cases In Literature Not yet documented
No population-based prevalence estimate exists for the dominant TNNI3 form of dilated cardiomyopathy specifically. The entity was defined from a screen of 96 DCM probands that found two novel missense alleles, and the reported literature has remained at the level of individual families and cohort fractions. For scale: dilated cardiomyopathy as a whole affects roughly 1 in 500 people with 30-40% of cases familial, and TNNI3 accounts for a small minority of gene-positive familial DCM. Any CMD1FF-specific rate quoted elsewhere should be treated as an extrapolation.
Show evidence (2 references)
PMID:19590045 SUPPORT Human Clinical
"To test TNNI3 as a candidate gene, a panel of 96 probands with DCM was analyzed."
Establishes the ascertainment behind this entity — a 96-proband DCM panel screen yielding two families — which is why no population frequency is available.
PMID:32618513 SUPPORT Other
"DCM affects roughly 1 in 500 people globally (49). Approximately 30–40% of cases are found to be familial (19)"
Supplies the denominator this entity sits inside — dilated cardiomyopathy prevalence and its familial fraction. Evidence source is OTHER because the quoted sentences are background review statements in the paper's introduction rather than results of its own experiments, which are graded IN_VITRO elsewhere in this entry.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Dilated Cardiomyopathy 1FF:

Dilated cardiomyopathy 2A (recessive TNNI3 disease)
Overlapping Features The same gene, the opposite zygosity, and a different mechanism. CMD2A requires two loss-of-function alleles, abolishes cardiac troponin I entirely, and presents in the neonatal period or first year with refractory heart failure once the perinatal troponin I isoform switch withdraws the substituting slow skeletal isoform. Heterozygous parents are typically unaffected. A biallelic truncating genotype in an infant is CMD2A, not CMD1FF, and the recurrence risk and reproductive counselling that follow are different (25% per sibship rather than 50% per offspring).
Show evidence (1 reference)
PMID:36981019 SUPPORT Human Clinical
"In recent years, however, an increasing amount of evidence has validated the hypothesis that biallelic TNNI3 null mutations cause a severe form of neonatal dilated cardiomyopathy."
States the recessive entity's defining genotype and its neonatal presentation, which is what distinguishes it from the entity curated here.
Other genetic and acquired causes of dilated cardiomyopathy
Overlapping Features Dilated cardiomyopathy is genetically heterogeneous — titin, lamin A/C, MYH7, TNNT2, FLNC, RBM20, BAG3 and others — and roughly 30-40% of cases are familial, so a TNNI3 variant must compete with alternative genetic explanations in a gene-positive proband. Non-genetic causes (myocarditis, alcohol and other cardiotoxins, anthracyclines, peripartum, tachycardia-mediated, endocrine) must be excluded before a familial label is applied, and can also coexist with and unmask a genetic substrate.
Show evidence (2 references)
PMID:31073128 SUPPORT Other
"Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases."
Enumerates the acquired differential that must be excluded before a familial DCM diagnosis. Evidence source is OTHER because this is a review.
PMID:32618513 SUPPORT Other
"Causative genes have substantial overlap with other cardiac conditions, such as arrhythmogenic right ventricular cardiomyopathy (ARVC) and hypertrophic cardiomyopathy (HCM); however, it is far more genetically heterogeneous than both of these, with over 30 potential disease genes characterized..."
Quantifies the genetic heterogeneity a TNNI3 variant must be weighed against. Evidence source is OTHER because the sentence is a review statement in the paper's introduction.
🧫

Experimental Models

1
Adenovirally transduced adult guinea pig left ventricular cardiomyocytes expressing TNNI3 K36Q OTHER
Isolated adult guinea pig left ventricular myocytes transduced with FLAG-tagged K36Q cardiac troponin I alongside wild-type controls, paced and assayed for sarcomere shortening, calcium transients, sarcoplasmic reticulum load, and signalling. Guinea pig was chosen because its calcium handling resembles the human more closely than the mouse does. The design isolates the primary effect of the mutant protein before secondary remodeling, which is exactly what a patient-derived explant cannot do — and it studies the actual CMD1FF allele rather than a proxy.
Cardiac ventricular myocyte CL:0000746 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses Cardiac ventricular myocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Organism
domestic guinea pig NCBITaxon:10141 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in domestic guinea pig, annotated with Cavia porcellus (NCBITaxon:10141). NCBITaxon:10141 is an organism from the NCBI Taxonomy.
Publication
PMID:32618513
Pathograph links
Reduced Cardiomyocyte Contractility and Systolic Calcium Transient recapitulates fidelity: moderate The model's central result is reduced fractional shortening with a suppressed systolic calcium transient in cells carrying the CMD1FF allele.
Limitations: Acute adenoviral overexpression in a non-human myocyte is not the same as lifelong heterozygous expression in a human heart: mutant and wild-type protein ratios are set by transduction rather than by allele dosage, and the 48-hour timescale excludes chronic adaptation. Guinea pig calcium handling is closer to human than murine but is still not human.
Readouts
Fractional sarcomere shortening
Direction: DECREASED
Interpretation: Contractile output of the single myocyte carrying the mutant allele.
Show evidence (1 reference)
PMID:32618513 SUPPORT In Vitro
"We find significantly reduced fractional shortening with reduced systolic Ca2+."
Reports the shortening and systolic calcium measurements behind these readouts.
Systolic calcium transient amplitude
Direction: DECREASED
Interpretation: Calcium available to activate the myofilament, measured by fura-2 ratiometry in the same cells.
Show evidence (1 reference)
PMID:32618513 SUPPORT In Vitro
"We also observe increased sarcoplasmic reticulum (SR) Ca2+ load and smaller fractional SR Ca2+ release."
Supplies the sarcoplasmic-reticulum handling result that accompanies the reduced systolic transient in this model.
Calcineurin-NFAT and Akt Signaling Activation measures fidelity: moderate The model supplies the signalling readouts linking the mutant myofilament to a remodeling transcriptional program.
Limitations: NFAT and Akt were assayed in chronically paced isolated cells over hours; no remodeling phenotype develops in this system, so the link from signalling to tissue remodeling is inferred rather than observed here.
Readouts
NFAT nuclear translocation
Direction: INCREASED
Interpretation: Activation of calcium-dependent remodeling signalling.
Show evidence (1 reference)
PMID:32618513 SUPPORT In Vitro
"We also observe dephosphorylation and nuclear translocation of the nuclear factor of activated T cells (NFAT), with concordant RAC-α-serine/threonine protein kinase (Akt) phosphorylation but no change to extracellular signal-regulated kinase activation in chronically paced cardiomyocytes..."
The measurement of NFAT dephosphorylation and nuclear translocation that this readout records.
Show evidence (1 reference)
PMID:32618513 SUPPORT In Vitro
"In this study we set out to investigate the functional effect of DCM-causing mutations in three separate thin-filament regulatory proteins: TnT R131W, TnI K36Q, and α-TM E40K, using our established adult guinea pig left ventricular cardiomyocyte model (39)."
Describes the model system and confirms that the CMD1FF allele K36Q is among the mutations it carries, which is what makes it informative for this entry.
{ }

Source YAML

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name: Dilated Cardiomyopathy 1FF
creation_date: "2026-09-02T18:30:00Z"
synonyms:
- CMD1FF
- DCM1FF
- cardiomyopathy, dilated, 1FF
- dilated cardiomyopathy type 1FF
- TNNI3-related autosomal dominant dilated cardiomyopathy
description: >-
  Dilated cardiomyopathy 1FF (CMD1FF, OMIM 613286) is the autosomal dominant,
  TNNI3-related form of familial isolated dilated cardiomyopathy. TNNI3 encodes
  cardiac troponin I (cTnI), the inhibitory subunit of the sarcomeric troponin
  complex that holds the actin-tropomyosin thin filament in its "off" state until
  calcium binding to troponin C releases the inhibition. CMD1FF is caused by a
  single heterozygous TNNI3 allele — classically a missense variant that is
  incorporated into the troponin complex and alters thin-filament calcium
  regulation from within it, and in at least one studied family a truncating
  allele acting through haploinsufficiency.

  The entity exists as a separate dismech entry because it contrasts on mechanism,
  not merely on OMIM number, with Dilated_Cardiomyopathy_2A (CMD2A, OMIM 611880),
  the recessive TNNI3 dilated cardiomyopathy. In CMD2A both alleles are null, no
  cardiac troponin I is made, and the disease is timed by the perinatal troponin I
  isoform switch: a well neonate decompensates within the first year with
  refractory heart failure. In CMD1FF a normal allele is always present and a
  mutant cTnI protein is present in the thin filament, so there is no null state
  and no isoform-switch clock. The dominant missense alleles instead alter what the
  troponin complex does — reconstituted mutant troponin gives lower maximum
  actin-tropomyosin-activated myosin ATPase rates, lower calcium sensitivity, and
  reduced thin-filament calcium affinity — which is the thin-filament signature
  shared with dominant DCM alleles in TNNT2, TPM1, TNNC1 and ACTC1, and is
  directionally opposite to the calcium-sensitizing TNNI3 missense alleles that
  cause hypertrophic (CMH7) and restrictive (RCM1) cardiomyopathy. Onset is
  correspondingly different: variable and incompletely penetrant rather than
  obligate and neonatal, though severe early-onset disease is well documented —
  three of the five carriers in the founding families were transplanted at ages 6,
  15 and 24. Recurrence risk and cascade-screening practice differ for the same
  reason (50% per offspring with surveillance of first-degree relatives, versus
  25% per sibship with carrier testing in CMD2A). ClinGen's Dilated Cardiomyopathy
  Gene Curation Expert Panel classifies the autosomal dominant TNNI3-DCM
  relationship as Strong, curated separately from its Strong autosomal recessive
  classification.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: dilated cardiomyopathy 1FF
  term:
    id: MONDO:0013211
    label: dilated cardiomyopathy 1FF
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population-based prevalence estimate exists for the dominant TNNI3 form of
    dilated cardiomyopathy specifically. The entity was defined from a screen of
    96 DCM probands that found two novel missense alleles, and the reported
    literature has remained at the level of individual families and cohort
    fractions. For scale: dilated cardiomyopathy as a whole affects roughly 1 in
    500 people with 30-40% of cases familial, and TNNI3 accounts for a small
    minority of gene-positive familial DCM. Any CMD1FF-specific rate quoted
    elsewhere should be treated as an extrapolation.
  evidence:
  - reference: PMID:19590045
    reference_title: Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To test TNNI3 as a candidate gene, a panel of 96 probands with DCM was
      analyzed.
    explanation: >-
      Establishes the ascertainment behind this entity — a 96-proband DCM panel
      screen yielding two families — which is why no population frequency is
      available.
  - reference: PMID:32618513
    reference_title: "Dilated cardiomyopathy mutations in thin-filament regulatory proteins reduce contractility, suppress systolic Ca(2+), and activate NFAT and Akt signaling."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      DCM affects roughly 1 in 500 people globally (49). Approximately 30–40% of
      cases are found to be familial (19)
    explanation: >-
      Supplies the denominator this entity sits inside — dilated cardiomyopathy
      prevalence and its familial fraction. Evidence source is OTHER because the
      quoted sentences are background review statements in the paper's
      introduction rather than results of its own experiments, which are graded
      IN_VITRO elsewhere in this entry.
inheritance:
- name: Autosomal Dominant
  description: >-
    CMD1FF is transmitted as an autosomal dominant trait: a single heterozygous
    TNNI3 allele is sufficient, transmission follows the classic vertical pattern,
    and each offspring of a carrier has a 50% recurrence risk. Penetrance is
    incomplete and expressivity variable, so a genotype-positive relative may be
    phenotype-negative for years — which is what makes longitudinal cascade
    surveillance, rather than a single screening echocardiogram, the appropriate
    family strategy. This dominant mode is the axis on which CMD1FF separates from
    CMD2A, where two loss-of-function alleles are required and heterozygous
    parents are typically unaffected.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:19590045
    reference_title: Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These are the first reported autosomal dominant DCM-causing mutations in
      TNNI3, and so the findings expand the spectrum of disease-causing genes that
      lead to either hypertrophic cardiomyopathy or DCM depending on the specific
      mutation.
    explanation: >-
      The founding CMD1FF report explicitly establishes TNNI3 as an autosomal
      dominant dilated cardiomyopathy gene, distinct from its long-known
      hypertrophic role.
  - reference: CGGV:assertion_668087ea-0d2f-42c2-a291-f73400d34023-2025-04-18T160000.000Z
    reference_title: "TNNI3 / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TNNI3 | HGNC:11947 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong
    explanation: >-
      ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel records an
      autosomal dominant TNNI3-DCM gene-disease relationship with Strong clinical
      validity, curated separately from the recessive relationship.
mechanistic_hypotheses:
- hypothesis_group_id: tnni3_ad_altered_thin_filament_regulation
  hypothesis_label: Altered thin-filament calcium regulation by mutant cTnI
  status: CANONICAL
  description: >-
    The canonical model holds that a heterozygous TNNI3 missense allele produces a
    full-length but functionally altered cardiac troponin I that is incorporated
    into the thin filament alongside the wild-type protein, and changes what the
    troponin complex does rather than how much of it there is. Reconstitution of
    troponin with either founding mutant (Lys36Gln, Asn185Lys) lowers the maximum
    actin-tropomyosin-activated myosin ATPase rate and lowers calcium sensitivity,
    and the resulting thin filaments have reduced calcium affinity. This is the
    same functional signature carried by proven dominant DCM alleles in the other
    thin-filament proteins, and it is directionally opposite to the
    calcium-sensitizing TNNI3 alleles that cause hypertrophic and restrictive
    cardiomyopathy — which is the mechanistic reason one gene produces three
    dominant cardiomyopathies. The consequence at the cell level is a weaker,
    slower contraction with a suppressed systolic calcium transient.
  evidence:
  - reference: PMID:19590045
    reference_title: Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Analysis of Ca(2+) regulation of actin-tropomyosin-activated myosin ATPase
      by troponin revealed that troponin reconstituted with either mutant troponin
      I gave lower maximum ATPase rates and lower Ca(2+) sensitivity than wild
      type.
    explanation: >-
      Supplies the direct functional measurement on which this model rests, for
      the two founding CMD1FF alleles. Classified IN_VITRO because it is a
      reconstituted-protein ATPase assay rather than a patient observation.
  - reference: PMID:32278834
    reference_title: Meta-analysis of cardiomyopathy-associated variants in troponin genes identifies loci and intragenic hot spots that are associated with worse clinical outcomes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      HCM and RCM models tended to have increased calcium sensitivity and DCM
      decreased sensitivity (P < .001).
    explanation: >-
      Establishes across the pooled troponin-variant literature that the
      calcium-sensitivity direction separates dilated from hypertrophic and
      restrictive disease, which is the generalization this model places CMD1FF
      inside. Evidence source is OTHER because it is a meta-analysis of
      previously published functional models rather than a single study type.
- hypothesis_group_id: tnni3_ad_pka_uncoupling
  hypothesis_label: Uncoupling of myofilament calcium sensitivity from troponin I phosphorylation
  status: ALTERNATIVE
  description: >-
    A competing, more specific proposal is that the primary defect is not the
    change in baseline calcium sensitivity at all, but the loss of its regulation.
    In normal thin filaments, protein kinase A phosphorylation of troponin I
    desensitizes the myofilament two- to three-fold, which is how beta-adrenergic
    stimulation accelerates relaxation. In thin filaments containing any of a panel
    of dominant DCM alleles — including the CMD1FF allele K36Q — calcium
    sensitivity no longer moves with troponin I phosphorylation at all. On this
    model the heart's inotropic and lusitropic reserve is what is lost, and chronic
    failure follows from the blunted beta-adrenergic response rather than from the
    resting sensitivity shift. It is recorded as ALTERNATIVE rather than CANONICAL
    because it has been demonstrated in vitro across mutant thin filaments but not
    yet shown to be the rate-limiting lesion in a CMD1FF patient or animal.
  evidence:
  - reference: PMID:23539503
    reference_title: Familial dilated cardiomyopathy mutations uncouple troponin I phosphorylation from changes in myofibrillar Ca²⁺ sensitivity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We conclude that DCM-causing mutations in thin filament proteins abolish the
      relationship between myofilament Ca(2+) sensitivity and troponin I
      phosphorylation by PKA.
    explanation: >-
      States the uncoupling hypothesis as the paper's conclusion, from quantitative
      in vitro motility assays on native mutant thin filaments.
  - reference: PMID:23539503
    reference_title: Familial dilated cardiomyopathy mutations uncouple troponin I phosphorylation from changes in myofibrillar Ca²⁺ sensitivity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      However, Ca(2+) sensitivity did not change with the level of troponin I
      phosphorylation in any of the DCM-mutant containing thin filaments (E40K,
      E54K, and D230N in α-tropomyosin; R141W and ΔK210 in cardiac troponin T; K36Q
      in cardiac troponin I; G159D in cardiac troponin C, and E361G in cardiac
      α-actin).
    explanation: >-
      Names K36Q in cardiac troponin I — one of the two founding CMD1FF alleles —
      among the mutant thin filaments showing the uncoupling, which is what makes
      this model applicable to this entity rather than to DCM generally.
- hypothesis_group_id: tnni3_ad_haploinsufficiency
  hypothesis_label: Haploinsufficiency from a heterozygous truncating allele
  status: EMERGING
  description: >-
    A third route to dominant TNNI3 dilated cardiomyopathy has been described in
    human explanted myocardium: a heterozygous truncating allele (p.98trunc) that
    produces no altered protein but simply too little of the normal one. Troponin I
    fell to 39% of control with distorted stoichiometry across the three troponin
    subunits, and exchanging in recombinant wild-type troponin both restored
    protein levels and normalized every functional deficit — establishing the
    lesion as troponin-intrinsic rather than end-stage remodeling. Notably the
    functional consequence here ran in the opposite direction to the missense
    model: calcium sensitivity was increased, not decreased, with impaired
    length-dependent activation. Recorded as EMERGING because it rests on one
    studied heart, and because that directional discrepancy is unresolved (see the
    corresponding discussion).
  evidence:
  - reference: DOI:10.1113/jp274145
    reference_title: Genotype-specific pathogenic effects in human dilated cardiomyopathy
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The TNNI3p.98trunc and TNNT2p.K217del mutation showed reduced expression of
      troponin I to 39% and 51%, troponin T to 64% and 53%, and troponin C to 73%
      and 97% of controls, respectively, and altered stoichiometry between the
      three cardiac troponin subunits.
    explanation: >-
      Quantifies the reduced troponin I abundance and subunit stoichiometry
      imbalance that define the haploinsufficiency route. Classified IN_VITRO
      because the measurements are on membrane-permeabilized cardiomyocytes from
      explanted tissue.
  - reference: DOI:10.1113/jp274145
    reference_title: Genotype-specific pathogenic effects in human dilated cardiomyopathy
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Moreover, upon exchange all functional deficits in the TNNI3p.98trunc and
      TNNT2p.K217del samples were normalized to control values confirming the
      pathogenic effects of the troponin mutations.
    explanation: >-
      The troponin-exchange rescue is what establishes that the contractile defect
      is caused by the troponin lesion itself rather than by secondary end-stage
      remodeling in an explanted failing heart.
pathophysiology:
- name: Heterozygous TNNI3 Variant Altering Cardiac Troponin I
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    TNNI3 encodes cardiac troponin I, the inhibitory subunit of the troponin
    complex and one of the three regulatory proteins (with troponin C and troponin
    T) that confer calcium sensitivity on the sarcomeric thin filament. CMD1FF
    arises from a single heterozygous TNNI3 allele. The founding alleles are
    missense (Lys36Gln, Asn185Lys), which produce a full-length mutant cTnI that
    assembles into the troponin complex beside the wild-type protein; a
    heterozygous truncating allele acting by haploinsufficiency has also been
    documented in explanted human myocardium. Either way a wild-type allele
    remains, so — unlike the biallelic null genotype of CMD2A — the myocardium is
    never troponin I-free, and the disease is not gated by the perinatal troponin I
    isoform switch.
  genes:
  - preferred_term: TNNI3
    term:
      id: hgnc:11947
      label: TNNI3
  molecular_functions:
  - preferred_term: actin binding
    term:
      id: GO:0003779
      label: actin binding
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: troponin complex
    term:
      id: GO:0005861
      label: troponin complex
    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: Sarcomere organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:19590045
    reference_title: Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report 2 novel TNNI3 missense mutations, Lys36Gln and Asn185Lys, each
      associated with severe and early onset familial DCM.
    explanation: >-
      Identifies the two founding heterozygous missense alleles and their
      segregation with familial dilated cardiomyopathy — the causal claim of this
      node.
  - reference: DOI:10.1113/jp274145
    reference_title: Genotype-specific pathogenic effects in human dilated cardiomyopathy
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The TNNI3p.98trunc showed pure haploinsufficiency, increased Ca2+‐sensitivity
      and impaired length‐dependent activation.
    explanation: >-
      Documents the second allele class reaching this node — a heterozygous
      truncation acting by haploinsufficiency in human left ventricular tissue.
      Classified IN_VITRO because the measurement is on permeabilized
      cardiomyocytes.
  downstream:
  - target: Altered Thin-Filament Calcium Regulation
    causal_link_type: DIRECT
    hypothesis_groups:
    - tnni3_ad_altered_thin_filament_regulation
    - tnni3_ad_haploinsufficiency
    description: >-
      A mutant or under-supplied troponin I changes the calcium-regulatory
      behaviour of the thin filament it sits in.
  - target: Uncoupling of Calcium Sensitivity from Troponin I Phosphorylation
    causal_link_type: DIRECT
    hypothesis_groups:
    - tnni3_ad_pka_uncoupling
    description: >-
      On the alternative model, the primary consequence of the mutant allele is
      loss of phosphorylation control over calcium sensitivity rather than a shift
      in its resting value.

- name: Altered Thin-Filament Calcium Regulation
  biological_scale: MOLECULAR
  role: intermediate
  description: >-
    With a mutant cTnI in the troponin complex, the thin filament's translation of
    calcium binding into cross-bridge activation is degraded. For the founding
    CMD1FF missense alleles this takes the form of a lower maximum
    actin-tropomyosin-activated myosin ATPase rate, lower calcium sensitivity, and
    reduced calcium affinity of the mutant thin filaments — a coordinated loss of
    activation rather than a leak of inhibition. This calcium-desensitizing
    direction is what places CMD1FF with the other dominant thin-filament dilated
    cardiomyopathies and separates it from the calcium-sensitizing TNNI3 alleles of
    hypertrophic and restrictive disease. In the reported haploinsufficient
    truncating case the measured direction was the opposite, which this entry
    records as an unresolved discrepancy rather than smoothing over.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Regulation of cardiac muscle contraction
    term:
      id: GO:0055117
      label: regulation of cardiac muscle contraction
    modifier: ABNORMAL
  - preferred_term: Regulation of striated muscle contraction
    term:
      id: GO:0006942
      label: regulation of striated muscle contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:19590045
    reference_title: Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, mutant thin filaments had reduced Ca(2+) affinity compared with
      normal.
    explanation: >-
      Supplies the thin-filament-level calcium affinity measurement this node
      asserts, for the CMD1FF alleles themselves.
  - reference: PMID:32618513
    reference_title: "Dilated cardiomyopathy mutations in thin-filament regulatory proteins reduce contractility, suppress systolic Ca(2+), and activate NFAT and Akt signaling."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Previous work has shown that changes to myofilament Ca2+ sensitivity caused
      by DCM mutations are qualitatively opposite from hypertrophic cardiomyopathy
      (HCM) mutations in the same genes.
    explanation: >-
      States the directional contrast between dilated and hypertrophic alleles in
      the same genes, which is the discriminating claim of this node. Evidence
      source is OTHER because this sentence summarises the prior literature rather
      than reporting this paper's own cardiomyocyte experiments.
  downstream:
  - target: Reduced Cardiomyocyte Contractility and Systolic Calcium Transient
    causal_link_type: DIRECT
    hypothesis_groups:
    - tnni3_ad_altered_thin_filament_regulation

- name: Uncoupling of Calcium Sensitivity from Troponin I Phosphorylation
  biological_scale: MOLECULAR
  role: modifier
  description: >-
    Beta-adrenergic stimulation normally accelerates cardiac relaxation by having
    protein kinase A phosphorylate troponin I, which desensitizes the myofilament
    to calcium two- to three-fold. In thin filaments carrying a dominant DCM
    allele — the CMD1FF allele K36Q among them — calcium sensitivity no longer
    tracks troponin I phosphorylation at all. The regulatory link is severed rather
    than the set point moved, so the myocardium loses the ability to change its
    calcium sensitivity on demand. This node is the substrate of the alternative
    mechanistic hypothesis: it predicts a blunted response to sympathetic drive as
    the operative deficit, which would show first as loss of contractile and
    relaxation reserve under stress rather than at rest.
  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
  evidence:
  - reference: PMID:23539503
    reference_title: Familial dilated cardiomyopathy mutations uncouple troponin I phosphorylation from changes in myofibrillar Ca²⁺ sensitivity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In thin filaments from normal human and mouse heart, protein kinase A (PKA)
      phosphorylation of troponin I caused a two- to three-fold decrease in
      myofibrillar Ca(2+) sensitivity.
    explanation: >-
      Establishes the normal phosphorylation-sensitivity relationship that this
      node asserts is lost.
  - reference: PMID:23539503
    reference_title: Familial dilated cardiomyopathy mutations uncouple troponin I phosphorylation from changes in myofibrillar Ca²⁺ sensitivity.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We propose that this blunts the response to β-adrenergic stimulation and
      could be the cause of DCM in the long term.
    explanation: >-
      States the proposed downstream consequence — loss of beta-adrenergic
      responsiveness — that this node contributes to the pathograph.
  downstream:
  - target: Reduced Cardiomyocyte Contractility and Systolic Calcium Transient
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - tnni3_ad_pka_uncoupling
    description: >-
      Loss of phosphorylation-dependent desensitization is proposed to degrade
      contractile and relaxation reserve over time rather than instantaneously,
      hence an indirect link.

- name: Reduced Cardiomyocyte Contractility and Systolic Calcium Transient
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Progressive Contractile Dysfunction"
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    At the level of the single myocyte the thin-filament lesion produces
    significantly reduced fractional shortening together with a reduced systolic
    calcium transient, with slowed contraction and slowed calcium reuptake.
    Sarcoplasmic reticulum calcium load rises while fractional release falls,
    reflecting reduced SERCA activity and increased sodium-calcium exchanger
    activity. These changes were shown for the CMD1FF allele K36Q alongside
    dominant DCM alleles in troponin T and tropomyosin, and were common to all
    three — evidence that this node is a shared convergence point of thin-filament
    dilated cardiomyopathy rather than an idiosyncrasy of one variant.
  cell_types:
  - preferred_term: Cardiac ventricular myocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cardiac muscle cell contraction
    term:
      id: GO:0086003
      label: cardiac muscle cell contraction
    modifier: DECREASED
  - preferred_term: Intracellular calcium ion homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32618513
    reference_title: "Dilated cardiomyopathy mutations in thin-filament regulatory proteins reduce contractility, suppress systolic Ca(2+), and activate NFAT and Akt signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In this work we have studied the functional consequences of mutations in
      cardiac troponin T (R131W), cardiac troponin I (K36Q) and α-tropomyosin
      (E40K) using adenovirally transduced isolated guinea pig left ventricular
      cardiomyocytes. We find significantly reduced fractional shortening with
      reduced systolic Ca2+.
    explanation: >-
      Directly measures the two properties this node asserts — reduced shortening
      and reduced systolic calcium — in cardiomyocytes expressing the CMD1FF allele
      K36Q. Classified IN_VITRO because the system is isolated, adenovirally
      transduced cardiomyocytes.
  - reference: PMID:32618513
    reference_title: "Dilated cardiomyopathy mutations in thin-filament regulatory proteins reduce contractility, suppress systolic Ca(2+), and activate NFAT and Akt signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      These changes in Ca2+ handling and signaling are common to all three
      mutations, indicating an analogous pathway of disease pathogenesis in
      thin-filament sarcomeric DCM.
    explanation: >-
      Establishes that the calcium-handling changes are shared across dominant
      thin-filament DCM alleles, which is why this node is modeled as a convergence
      point rather than an allele-specific finding.
  downstream:
  - target: Calcineurin-NFAT and Akt Signaling Activation
    causal_link_type: DIRECT
    hypothesis_groups:
    - tnni3_ad_altered_thin_filament_regulation
  - target: Adverse Ventricular Remodeling
    causal_link_type: DIRECT

- name: Calcineurin-NFAT and Akt Signaling Activation
  biological_scale: CELLULAR
  role: intermediate
  description: >-
    Chronically paced cardiomyocytes expressing dominant thin-filament DCM
    mutations, including TNNI3 K36Q, show dephosphorylation and nuclear
    translocation of NFAT with concordant Akt phosphorylation, and no change in ERK
    activation. This is the link between an altered myofilament and a transcriptional
    remodeling program: the mutant sarcomere does not merely contract badly, it
    changes the calcium-dependent signalling that instructs the cell to remodel.
    Note that NFAT activation is not specific to the dilated direction — it is also
    a hypertrophic cardiomyopathy hallmark — so this node is a shared remodeling
    entry point rather than a discriminating feature of CMD1FF.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Calcineurin-NFAT signaling cascade
    term:
      id: GO:0033173
      label: calcineurin-NFAT signaling cascade
    modifier: INCREASED
  evidence:
  - reference: PMID:32618513
    reference_title: "Dilated cardiomyopathy mutations in thin-filament regulatory proteins reduce contractility, suppress systolic Ca(2+), and activate NFAT and Akt signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We also observe dephosphorylation and nuclear translocation of the nuclear
      factor of activated T cells (NFAT), with concordant RAC-α-serine/threonine
      protein kinase (Akt) phosphorylation but no change to extracellular
      signal-regulated kinase activation in chronically paced cardiomyocytes
      expressing DCM mutations.
    explanation: >-
      Supplies the specific signalling readout this node asserts, in cardiomyocytes
      carrying the CMD1FF allele among others.
  downstream:
  - target: Adverse Ventricular Remodeling
    causal_link_type: DIRECT
    hypothesis_groups:
    - tnni3_ad_altered_thin_filament_regulation

- name: Adverse Ventricular Remodeling
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  biological_scale: TISSUE
  role: central_effector
  description: >-
    Sustained contractile inefficiency and the remodeling signalling it drives
    convert a molecular lesion into a structurally altered ventricle: cardiomyocyte
    loss by apoptosis, interstitial fibrosis from activated cardiac fibroblasts,
    and progressive chamber enlargement with rising wall stress. This node is the
    generic dilated-cardiomyopathy remodeling program rather than a
    TNNI3-specific process, and is curated as such — no CMD1FF-specific
    histopathological series exists, and the fibrosis branch is asserted from
    dilated cardiomyopathy as a class.
  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
  biological_processes:
  - preferred_term: Extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  - preferred_term: Cardiomyocyte apoptosis
    term:
      id: GO:0010659
      label: cardiac muscle cell apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:32618513
    reference_title: "Dilated cardiomyopathy mutations in thin-filament regulatory proteins reduce contractility, suppress systolic Ca(2+), and activate NFAT and Akt signaling."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dilated cardiomyopathy (DCM) is a disease of the myocardium characterized by
      dilatation of the left ventricle, impaired systolic function, evidence of
      cellular apoptosis, and interstitial fibrosis.
    explanation: >-
      Establishes apoptosis and interstitial fibrosis as constituents of the
      dilated-cardiomyopathy remodeling phenotype this node describes. Evidence
      source is OTHER because the sentence is a review statement in the paper's
      introduction, not a result of its cardiomyocyte experiments.
  - reference: PMID:31073128
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Echocardiography and other imaging techniques are required to assess
      ventricular dysfunction and adverse myocardial remodelling
    explanation: >-
      Names adverse myocardial remodelling as the process that imaging is deployed
      to assess in dilated cardiomyopathy, supporting its place in the causal chain.
      Evidence source is OTHER because this is a Nature Reviews Disease Primers
      review.
  downstream:
  - target: Left Ventricular Dilation and Systolic Failure
    causal_link_type: DIRECT

- name: Left Ventricular Dilation and Systolic Failure
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The organ-level endpoint: left ventricular or biventricular chamber
    enlargement with impaired contraction, not explained by loading conditions or
    coronary disease, progressing to congestive heart failure. In the founding
    CMD1FF families this was severe and early — three of five carriers required
    cardiac transplantation, at ages 6, 15 and 24 — but expressivity is variable
    and a genotype-positive relative may sit for years in a phenotype-negative or
    subclinical state, which is the clinical difference from the obligate,
    uniformly severe infantile course of the recessive entity.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: Left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  biological_processes:
  - preferred_term: Cardiac muscle contraction
    term:
      id: GO:0060048
      label: cardiac muscle contraction
    modifier: DECREASED
  evidence:
  - reference: PMID:19590045
    reference_title: Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 5 mutation carriers, cardiac transplantation was required in 3, at
      ages 6, 15, and 24 years.
    explanation: >-
      Quantifies the severity of organ-level failure in the founding CMD1FF
      families and the age range over which it presented.
  - reference: PMID:31073128
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left
      ventricular or biventricular dilation and impaired contraction that is not
      explained by abnormal loading conditions (for example, hypertension and
      valvular heart disease) or coronary artery disease.
    explanation: >-
      Supplies the definition of the organ-level phenotype this node represents.
      Evidence source is OTHER because this is a Nature Reviews Disease Primers
      review.
  downstream:
  - target: Congestive heart failure
    causal_link_type: DIRECT
  - target: Sudden cardiac death
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Structural and electrical remodeling of the dilated ventricle carries
      arrhythmic risk; no CMD1FF-specific event rate is available.
phenotypes:
- category: Cardiovascular
  name: Dilated cardiomyopathy
  description: >-
    The defining phenotype: a dilated, poorly contracting left ventricle in the
    absence of abnormal loading conditions or coronary disease. In CMD1FF it is
    familial and dominantly transmitted, and although onset is variable the
    reported families included severe childhood-onset disease.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:19590045
    reference_title: Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report 2 novel TNNI3 missense mutations, Lys36Gln and Asn185Lys, each
      associated with severe and early onset familial DCM.
    explanation: >-
      Dilated cardiomyopathy is the obligate phenotype of the heterozygous TNNI3
      genotype in this entity, and is characterized as severe and early onset,
      supporting the VERY_FREQUENT band.
- category: Cardiovascular
  name: Left ventricular dilatation
  description: >-
    Enlargement of the left ventricular cavity — the structural half of the dilated
    phenotype, and the finding that establishes it on echocardiography.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Left ventricular dilatation
    term:
      id: HP:4000141
      label: Left ventricular dilatation
  evidence:
  - reference: PMID:31073128
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left
      ventricular or biventricular dilation and impaired contraction that is not
      explained by abnormal loading conditions (for example, hypertension and
      valvular heart disease) or coronary artery disease.
    explanation: >-
      Chamber dilation is constitutive of the diagnosis CMD1FF carriers receive.
      Evidence source is OTHER because this is a review; no CMD1FF-specific
      echocardiographic series exists to quantify the dimension.
- category: Cardiovascular
  name: Left ventricular systolic dysfunction
  description: >-
    Impaired systolic performance of the left ventricle, the functional counterpart
    of chamber dilation and the phenotype that family screening programmes look for
    in genotype-positive relatives.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Left ventricular systolic dysfunction
    term:
      id: HP:0025169
      label: Left ventricular systolic dysfunction
  evidence:
  - reference: DOI:10.1002/ejhf.3657
    reference_title: Prediction and Prognostic Role of Left Ventricular Systolic Dysfunction in Family Screening for Dilated Cardiomyopathy and Non-Dilated Left Ventricular Cardiomyopathy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      family history of arrhythmia and being carrier of a pathogenic/likely
      pathogenic variant are the main risk factors for LV systolic dysfunction
    explanation: >-
      Establishes carriage of a pathogenic variant as a principal risk factor for
      developing left ventricular systolic dysfunction among relatives in DCM
      family screening — the situation a CMD1FF kindred is in. The cohort is
      DCM/NDLVC relatives generally, not TNNI3 carriers specifically.
- category: Cardiovascular
  name: Reduced left ventricular ejection fraction
  description: >-
    Depressed ejection fraction is the quantitative expression of the systolic
    defect and the measure on which heart-failure therapy and advanced-therapy
    referral are staged.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  evidence:
  - reference: PMID:32618513
    reference_title: "Dilated cardiomyopathy mutations in thin-filament regulatory proteins reduce contractility, suppress systolic Ca(2+), and activate NFAT and Akt signaling."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dilated cardiomyopathy (DCM) is clinically characterized by dilated
      ventricular cavities and reduced ejection fraction, leading to heart failure
      and increased thromboembolic risk.
    explanation: >-
      Establishes reduced ejection fraction as a defining clinical feature of the
      disease class this entity belongs to. Evidence source is OTHER because the
      sentence is the paper's framing of dilated cardiomyopathy rather than one of
      its experimental results.
- category: Cardiovascular
  name: Congestive heart failure
  description: >-
    Clinical heart failure is the syndrome that brings CMD1FF patients to
    attention and the endpoint that medical therapy is aimed at; in the founding
    families it progressed to transplantation in three of five carriers.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:19590045
    reference_title: Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 5 mutation carriers, cardiac transplantation was required in 3, at
      ages 6, 15, and 24 years.
    explanation: >-
      Transplantation in three of five carriers documents progression to end-stage
      heart failure in this entity. The FREQUENT rather than VERY_FREQUENT band
      reflects that not every reported carrier reached this endpoint.
- category: Cardiovascular
  name: Sudden cardiac death
  description: >-
    Arrhythmic death is a recognized outcome of dilated cardiomyopathy as a class
    and is the reason defibrillator criteria form part of DCM guideline debate. No
    CMD1FF-specific event rate has been reported, so no frequency is asserted here.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:32618513
    reference_title: "Dilated cardiomyopathy mutations in thin-filament regulatory proteins reduce contractility, suppress systolic Ca(2+), and activate NFAT and Akt signaling."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinically, it is associated with chronic heart failure, sudden cardiac
      death, and cardioembolic stroke.
    explanation: >-
      Names sudden cardiac death among the clinical associations of dilated
      cardiomyopathy. Frequency is deliberately omitted — the quote is about the
      disease class, and no source quantifies arrhythmic death in the TNNI3
      dominant subset. Evidence source is OTHER because the sentence is background
      framing rather than an experimental result.
- category: Cardiovascular
  name: Arrhythmia
  description: >-
    Atrial and ventricular arrhythmia complicate the structurally and electrically
    remodeled ventricle. Family history of arrhythmia is itself one of the main
    predictors of developing systolic dysfunction among relatives screened in DCM
    families, which is why arrhythmic history is collected during cascade
    evaluation rather than only after a phenotype appears.
  phenotype_term:
    preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: DOI:10.1002/ejhf.3657
    reference_title: Prediction and Prognostic Role of Left Ventricular Systolic Dysfunction in Family Screening for Dilated Cardiomyopathy and Non-Dilated Left Ventricular Cardiomyopathy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Secondary heart failure (HF) and arrhythmic outcomes were also included.
    explanation: >-
      Documents arrhythmic outcomes as a tracked endpoint in relatives of DCM
      probands. No frequency is asserted: the quote establishes that arrhythmia is
      part of the outcome set in DCM family screening, not its rate in TNNI3
      carriers.
genetic:
- name: TNNI3 Heterozygous Function-Altering Variants
  association: Heterozygous Missense and Truncating 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
    evidence:
    - reference: CGGV:assertion_668087ea-0d2f-42c2-a291-f73400d34023-2025-04-18T160000.000Z
      reference_title: "TNNI3 / dilated cardiomyopathy (Strong)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        TNNI3 | HGNC:11947 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong
      explanation: >-
        ClinGen records AD as the mode of inheritance for this TNNI3-DCM
        gene-disease relationship, separately from its AR assertion.
  features: >-
    CMD1FF genotypes are monoallelic. The founding alleles are missense (Lys36Gln
    in the N-terminal region, Asn185Lys in the C-terminal region), each segregating
    with severe early-onset familial disease and each shown to alter thin-filament
    calcium regulation on reconstitution. A heterozygous truncating allele
    (p.98trunc) has additionally been characterized in explanted human myocardium
    and behaves as pure haploinsufficiency rather than as an altered-function
    allele. A TNNI3 variant list cannot be interpreted without its zygosity and
    variant class: the same gene's heterozygous missense alleles more commonly
    cause hypertrophic (CMH7) and restrictive (RCM1) cardiomyopathy, and its
    biallelic null genotypes cause the recessive infantile entity CMD2A. Note that
    the p.Arg98* nonsense allele appears on both sides of that line — homozygous in
    reported CMD2A patients, and studied heterozygously as a haploinsufficient DCM
    allele — so allele identity alone does not assign an entity.
  variants:
  - name: TNNI3 p.Lys36Gln (K36Q)
    description: >-
      N-terminal missense allele, one of the two founding CMD1FF variants.
      Reconstituted troponin carrying it gives reduced maximum ATPase and reduced
      calcium sensitivity, and thin filaments containing it lose the normal
      coupling between calcium sensitivity and troponin I phosphorylation. It is
      also the allele carried into the isolated-cardiomyocyte studies that
      demonstrate reduced fractional shortening, suppressed systolic calcium, and
      NFAT activation, making it the best functionally characterized CMD1FF
      variant.
    gene:
      preferred_term: TNNI3
      term:
        id: hgnc:11947
        label: TNNI3
    evidence:
    - reference: PMID:19590045
      reference_title: Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We report 2 novel TNNI3 missense mutations, Lys36Gln and Asn185Lys, each
        associated with severe and early onset familial DCM.
      explanation: >-
        Identifies this allele and its association with severe early-onset familial
        dilated cardiomyopathy.
  - name: TNNI3 p.Asn185Lys (N185K)
    description: >-
      C-terminal missense allele, the second founding CMD1FF variant, segregating
      with severe early-onset familial dilated cardiomyopathy and producing the
      same reduced-ATPase, reduced-calcium-sensitivity signature on reconstitution.
    gene:
      preferred_term: TNNI3
      term:
        id: hgnc:11947
        label: TNNI3
    evidence:
    - reference: PMID:19590045
      reference_title: Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Analysis of Ca(2+) regulation of actin-tropomyosin-activated myosin ATPase
        by troponin revealed that troponin reconstituted with either mutant
        troponin I gave lower maximum ATPase rates and lower Ca(2+) sensitivity
        than wild type.
      explanation: >-
        Records the functional consequence measured for both founding alleles,
        including this one. Classified IN_VITRO because it is a reconstituted
        protein assay.
  - name: TNNI3 p.98trunc (heterozygous)
    description: >-
      Heterozygous truncating allele studied in explanted left ventricular tissue
      from a transplanted DCM patient. Troponin I fell to 39% of control with
      distorted subunit stoichiometry, and exchange with recombinant wild-type
      troponin restored protein levels and normalized the functional deficits. It
      is the evidence that haploinsufficiency, not only altered function, is a
      route to dominant TNNI3 dilated cardiomyopathy.
    gene:
      preferred_term: TNNI3
      term:
        id: hgnc:11947
        label: TNNI3
    evidence:
    - reference: DOI:10.1113/jp274145
      reference_title: Genotype-specific pathogenic effects in human dilated cardiomyopathy
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Exchange with wild‐type troponin complex corrected troponin protein
        levels to 83% of controls in the TNNI3p.98trunc sample.
      explanation: >-
        The exchange experiment establishing that the deficit in this heterozygous
        truncating genotype is a troponin-quantity problem correctable in vitro.
  evidence:
  - reference: CGGV:assertion_668087ea-0d2f-42c2-a291-f73400d34023-2025-04-18T160000.000Z
    reference_title: "TNNI3 / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TNNI3 | HGNC:11947 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong
    explanation: >-
      ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies the
      autosomal dominant TNNI3-DCM gene-disease relationship as Strong under SOP10.
  - reference: PMID:19590045
    reference_title: Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One contractile protein gene well known as a hypertrophic cardiomyopathy
      disease gene, but with no reported mutation in autosomal dominant DCM, is
      TNNI3 which encodes cardiac troponin I.
    explanation: >-
      States the gene's prior standing as a hypertrophic cardiomyopathy gene, which
      is the background against which the dominant DCM relationship curated here
      was established.
  - reference: PMID:36981019
    reference_title: "Homozygous TNNI3 Mutations and Severe Early Onset Dilated Cardiomyopathy: Patient Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While heterozygous TNNI3 missense mutations have long been associated with
      autosomal dominant hypertrophic and restrictive cardiomyopathies, the role of
      TNNI3 null mutations has been more debated
    explanation: >-
      States the zygosity-and-variant-class landscape that a TNNI3 variant must be
      placed within before an entity is assigned — the heterozygous missense side
      of which is where CMD1FF sits.
diagnosis:
- name: Echocardiography
  description: >-
    First-line and usually diagnostic: left ventricular internal dimensions and
    ejection fraction establish the dilated, hypocontractile phenotype. In a CMD1FF
    kindred echocardiography also carries the surveillance load, since a
    genotype-positive relative may convert from phenotype-negative to systolic
    dysfunction years after the first normal study.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: DOI:10.1093/ehjqcco/qcae109
    reference_title: "Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Our review revealed consensus on several key aspects: the definition of DCM,
      the use of B-type natriuretic peptides and high-sensitivity troponin in
      laboratory testing, the essential role of multimodality cardiovascular
      imaging for initial diagnosis, genetic counselling, and the management of
      advanced disease.
    explanation: >-
      Records cross-guideline consensus that multimodality cardiovascular imaging
      is essential for the initial diagnosis of dilated cardiomyopathy, of which
      CMD1FF is a genetic form. Evidence source is OTHER because this is a
      systematic review of guidelines rather than a primary study.
- name: Molecular Genetic Testing
  description: >-
    Cardiomyopathy-panel or exome sequencing establishes the diagnosis and, as
    importantly, its zygosity. A heterozygous TNNI3 variant in a proband with a
    dilated ventricle points at CMD1FF; two loss-of-function alleles point at
    CMD2A; and a heterozygous missense allele must still be weighed against the
    much larger TNNI3 hypertrophic and restrictive literature before a dilated
    entity is assigned. Segregation in the family is what converts a plausible
    variant into a diagnosis, which is why the founding report evaluated its
    candidates by segregation analysis and control screening rather than by
    computational prediction.
  diagnosis_term:
    preferred_term: cardiomyopathy gene panel or exome sequencing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:19590045
    reference_title: Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Genomic DNA was isolated and TNNI3 exons screened by heteroduplex analysis.
      Exons with aberrant profiles were sequenced and variants evaluated by
      segregation analysis and study of normal controls.
    explanation: >-
      Documents segregation analysis plus control screening as the evidence
      standard applied to candidate TNNI3 variants in this entity.
  - reference: DOI:10.1093/ehjqcco/qcae109
    reference_title: "Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Nonetheless, notable areas of variation included the formation of
      multidisciplinary management teams, the role of cascade genetic testing,
      pathways for arrhythmic risk stratification, and the criteria for prophylactic
      defibrillator implantation.
    explanation: >-
      Records that the role of cascade genetic testing is an area where DCM
      guidelines diverge — relevant because cascade testing is the practical
      consequence of a CMD1FF diagnosis. Evidence source is OTHER because this is a
      systematic review of guidelines.
- name: Family Screening of First-Degree Relatives
  description: >-
    Because the trait is dominant with incomplete and age-dependent penetrance, the
    diagnostic unit is the family rather than the proband. Longitudinal screening
    of first-degree relatives detects left ventricular systolic dysfunction before
    it declares itself clinically, and detection through a screening programme is
    associated with better outcomes than detection outside one. Carriage of a
    pathogenic variant is one of the main risk factors for developing dysfunction,
    so a CMD1FF genotype identifies precisely the relatives who need continuing
    rather than one-off evaluation.
  diagnosis_term:
    preferred_term: cascade family screening for dilated cardiomyopathy
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: DOI:10.1002/ejhf.3657
    reference_title: Prediction and Prognostic Role of Left Ventricular Systolic Dysfunction in Family Screening for Dilated Cardiomyopathy and Non-Dilated Left Ventricular Cardiomyopathy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Baseline and follow-up data of first-degree relatives of probands affected by
      DCM/NDLVC were collected.
    explanation: >-
      Establishes longitudinal evaluation of first-degree relatives as the design of
      DCM family screening, which is the practice a dominant CMD1FF genotype
      triggers. The cohort is DCM/NDLVC relatives generally rather than TNNI3
      carriers.
  - reference: DOI:10.1002/ejhf.3657
    reference_title: Prediction and Prognostic Role of Left Ventricular Systolic Dysfunction in Family Screening for Dilated Cardiomyopathy and Non-Dilated Left Ventricular Cardiomyopathy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      family history of arrhythmia and being carrier of a pathogenic/likely
      pathogenic variant are the main risk factors for LV systolic dysfunction
    explanation: >-
      Identifies pathogenic-variant carriage as a main risk factor for developing
      systolic dysfunction, which is what makes genotype-directed surveillance of
      CMD1FF relatives worthwhile.
differential_diagnoses:
- name: Dilated cardiomyopathy 2A (recessive TNNI3 disease)
  description: >-
    The same gene, the opposite zygosity, and a different mechanism. CMD2A requires
    two loss-of-function alleles, abolishes cardiac troponin I entirely, and
    presents in the neonatal period or first year with refractory heart failure
    once the perinatal troponin I isoform switch withdraws the substituting slow
    skeletal isoform. Heterozygous parents are typically unaffected. A biallelic
    truncating genotype in an infant is CMD2A, not CMD1FF, and the recurrence risk
    and reproductive counselling that follow are different (25% per sibship rather
    than 50% per offspring).
  evidence:
  - reference: PMID:36981019
    reference_title: "Homozygous TNNI3 Mutations and Severe Early Onset Dilated Cardiomyopathy: Patient Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In recent years, however, an increasing amount of evidence has validated the
      hypothesis that biallelic TNNI3 null mutations cause a severe form of neonatal
      dilated cardiomyopathy.
    explanation: >-
      States the recessive entity's defining genotype and its neonatal presentation,
      which is what distinguishes it from the entity curated here.
- name: TNNI3-related hypertrophic and restrictive cardiomyopathy (CMH7, RCM1)
  description: >-
    The other dominant TNNI3 diseases, and the harder differential because they
    share both gene and zygosity with CMD1FF. They are separated on phenotype and
    on the direction of the functional lesion: hypertrophic and restrictive TNNI3
    alleles increase myofilament calcium sensitivity, while dilated alleles decrease
    it. A heterozygous TNNI3 missense variant reported in a hypertrophic or
    restrictive family does not by itself establish CMD1FF causality in a dilated
    proband.
  evidence:
  - reference: PMID:32278834
    reference_title: Meta-analysis of cardiomyopathy-associated variants in troponin genes identifies loci and intragenic hot spots that are associated with worse clinical outcomes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      HCM and RCM models tended to have increased calcium sensitivity and DCM
      decreased sensitivity (P < .001).
    explanation: >-
      Supplies the functional axis that separates dilated from hypertrophic and
      restrictive troponin disease. Evidence source is OTHER because it aggregates
      functional models from the published literature.
  - reference: PMID:32278834
    reference_title: Meta-analysis of cardiomyopathy-associated variants in troponin genes identifies loci and intragenic hot spots that are associated with worse clinical outcomes.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The inhibitory region and C-terminal region in TNNI3 exhibited increased
      restrictive cardiomyopathy (P =.008).
    explanation: >-
      Identifies TNNI3 regions enriched for restrictive rather than dilated
      phenotypes, which is positional information a curator can use when triaging a
      heterozygous TNNI3 variant.
- name: Other genetic and acquired causes of dilated cardiomyopathy
  description: >-
    Dilated cardiomyopathy is genetically heterogeneous — titin, lamin A/C, MYH7,
    TNNT2, FLNC, RBM20, BAG3 and others — and roughly 30-40% of cases are familial,
    so a TNNI3 variant must compete with alternative genetic explanations in a
    gene-positive proband. Non-genetic causes (myocarditis, alcohol and other
    cardiotoxins, anthracyclines, peripartum, tachycardia-mediated, endocrine)
    must be excluded before a familial label is applied, and can also coexist with
    and unmask a genetic substrate.
  evidence:
  - reference: PMID:31073128
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Nongenetic forms of DCM can result from different aetiologies, including
      inflammation of the myocardium due to an infection (mostly viral); exposure to
      drugs, toxins or allergens; and systemic endocrine or autoimmune diseases.
    explanation: >-
      Enumerates the acquired differential that must be excluded before a familial
      DCM diagnosis. Evidence source is OTHER because this is a review.
  - reference: PMID:32618513
    reference_title: "Dilated cardiomyopathy mutations in thin-filament regulatory proteins reduce contractility, suppress systolic Ca(2+), and activate NFAT and Akt signaling."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Causative genes have substantial overlap with other cardiac conditions, such
      as arrhythmogenic right ventricular cardiomyopathy (ARVC) and hypertrophic
      cardiomyopathy (HCM); however, it is far more genetically heterogeneous than
      both of these, with over 30 potential disease genes characterized to date
      (53).
    explanation: >-
      Quantifies the genetic heterogeneity a TNNI3 variant must be weighed against.
      Evidence source is OTHER because the sentence is a review statement in the
      paper's introduction.
progression:
- phase: Genotype-positive, phenotype-negative
  notes: >-
    Because penetrance is incomplete and age-dependent, a carrier may have a
    structurally normal, normally contracting ventricle for years or decades. This
    phase has no counterpart in the recessive entity, where the null genotype
    declares itself in infancy. It is the phase that makes longitudinal cascade
    surveillance of first-degree relatives, rather than a single screening study,
    the appropriate family strategy, and it is why relatives found to carry a
    pathogenic variant are followed rather than discharged.
  evidence:
  - reference: DOI:10.1002/ejhf.3657
    reference_title: Prediction and Prognostic Role of Left Ventricular Systolic Dysfunction in Family Screening for Dilated Cardiomyopathy and Non-Dilated Left Ventricular Cardiomyopathy
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During a median follow-up of 110 months (interquartile range 57–188 months),
      only subjects that previously developed LV systolic dysfunction had primary
      outcomes (19 vs. 0, p
    explanation: >-
      Documents a screened relative population followed for a median of nine years
      in which the emergence of systolic dysfunction, not carrier status alone,
      marks the transition to adverse outcomes — the latent-then-manifest pattern
      this phase describes. The cohort is DCM/NDLVC relatives generally.
- phase: Manifest left ventricular systolic dysfunction
  notes: >-
    Onset of measurable systolic dysfunction and chamber dilation, which may be
    detected on surveillance before symptoms. In the founding CMD1FF families this
    stage was reached in childhood or early adulthood in the severely affected
    carriers. Detection at this point is what family screening exists to achieve,
    because it opens the window for anti-remodeling therapy before symptomatic
    failure.
  evidence:
  - reference: PMID:19590045
    reference_title: Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report 2 novel TNNI3 missense mutations, Lys36Gln and Asn185Lys, each
      associated with severe and early onset familial DCM.
    explanation: >-
      Characterizes the manifest disease in the founding families as severe and
      early in onset.
- phase: Advanced heart failure, transplantation, or death
  notes: >-
    In the severe end of the reported spectrum the disease progresses to end-stage
    heart failure requiring cardiac transplantation — three of the five carriers in
    the founding families, at ages 6, 15 and 24. There is no TNNI3-directed therapy,
    so progression is modified only by generic heart-failure management, and
    transplantation remains the definitive option.
  evidence:
  - reference: PMID:19590045
    reference_title: Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 5 mutation carriers, cardiac transplantation was required in 3, at
      ages 6, 15, and 24 years.
    explanation: >-
      Documents progression to transplantation and the ages at which it occurred in
      this entity.
treatments:
- name: Guideline-Directed Heart Failure Pharmacotherapy
  description: >-
    Standard anti-remodeling heart-failure therapy — renin-angiotensin system
    blockade, a beta-blocker, and a mineralocorticoid receptor antagonist —
    targeting the neurohormonal and remodeling amplifier downstream of the
    myofilament lesion. There is no TNNI3-directed or myofilament-correcting
    therapy for CMD1FF, so management is the generic dilated-cardiomyopathy
    regimen. One caveat is worth recording: if the uncoupling hypothesis is
    correct, the myofilament in this disease no longer responds to
    phosphorylation-mediated calcium desensitization, which is the arm of
    beta-adrenergic signalling that beta-blockade modulates — a reason to expect
    generic therapy to work through remodeling rather than through restoring
    myofilament regulation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: beta-blocker
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
    - preferred_term: mineralocorticoid receptor antagonist (spironolactone as the class exemplar)
      term:
        id: NCIT:C840
        label: Spironolactone
  target_mechanisms:
  - target: Adverse Ventricular Remodeling
    treatment_effect: INHIBITS
    description: >-
      Neurohormonal blockade slows the remodeling program that converts the
      myofilament lesion into a dilated ventricle; it does not correct the mutant
      troponin.
  evidence:
  - reference: PMID:31073128
    reference_title: Dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      As DCM eventually leads to impaired contractility, standard approaches to
      prevent or treat heart failure are the first-line treatment for patients with
      DCM.
    explanation: >-
      Establishes standard heart-failure therapy as first-line management for
      dilated cardiomyopathy, of which CMD1FF is a genetic form. Evidence source is
      OTHER because this is a Nature Reviews Disease Primers review.
- name: Heart Transplantation
  description: >-
    The definitive therapy for end-stage disease, and a documented outcome in this
    entity: three of the five carriers in the founding families were transplanted,
    the youngest at age 6. Because the lesion is a constitutional sarcomeric
    protein defect rather than a reversible insult, recovery of native ventricular
    function is not expected once end-stage failure is established.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_mechanisms:
  - target: Left Ventricular Dilation and Systolic Failure
    treatment_effect: INHIBITS
    description: >-
      Transplantation replaces the failing ventricle outright; it is the only
      intervention that removes the mutant myocardium.
  evidence:
  - reference: PMID:19590045
    reference_title: Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Of the 5 mutation carriers, cardiac transplantation was required in 3, at
      ages 6, 15, and 24 years.
    explanation: >-
      Documents transplantation as the realized endpoint in the majority of
      reported CMD1FF carriers.
- name: Genetic Counseling and Cascade Screening
  description: >-
    Counseling for a 50% per-offspring recurrence risk, predictive testing of
    first-degree relatives, and enrolment of genotype-positive relatives in
    longitudinal cardiac surveillance. The counseling content differs materially
    from CMD2A's: there the conversation is about a 25% sibship risk and unaffected
    carrier parents, here it is about vertical transmission, incomplete penetrance,
    and the fact that a normal echocardiogram today does not discharge a carrier.
    Genetic counseling is one of the few points on which international DCM
    guidelines already agree.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: DOI:10.1093/ehjqcco/qcae109
    reference_title: "Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Our review revealed consensus on several key aspects: the definition of DCM,
      the use of B-type natriuretic peptides and high-sensitivity troponin in
      laboratory testing, the essential role of multimodality cardiovascular
      imaging for initial diagnosis, genetic counselling, and the management of
      advanced disease.
    explanation: >-
      Records genetic counselling as an area of cross-guideline consensus in
      dilated cardiomyopathy management. Evidence source is OTHER because this is a
      systematic review of guidelines.
  - reference: PMID:20301486
    reference_title: Dilated Cardiomyopathy Overview.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Provide a basic view of genetic risk assessment of at-risk asymptomatic
      relatives of a proband with DCM to inform cardiac surveillance and allow
      early detection and treatment of DCM to improve long-term outcome.
    explanation: >-
      The GeneReviews DCM overview frames genetic risk assessment of asymptomatic
      relatives as a route to earlier detection and better outcome, which is the
      rationale for cascade screening in a dominant entity. Evidence source is
      OTHER because GeneReviews is an expert-curated reference work. The quote is
      drawn from the chapter's stated purpose — the only prose in the PubMed
      record — rather than from a counseling section, and it is generic DCM
      guidance rather than CMD1FF-specific.
experimental_models:
- name: Adenovirally transduced adult guinea pig left ventricular cardiomyocytes expressing TNNI3 K36Q
  description: >-
    Isolated adult guinea pig left ventricular myocytes transduced with FLAG-tagged
    K36Q cardiac troponin I alongside wild-type controls, paced and assayed for
    sarcomere shortening, calcium transients, sarcoplasmic reticulum load, and
    signalling. Guinea pig was chosen because its calcium handling resembles the
    human more closely than the mouse does. The design isolates the primary effect
    of the mutant protein before secondary remodeling, which is exactly what a
    patient-derived explant cannot do — and it studies the actual CMD1FF allele
    rather than a proxy.
  experimental_model_type: OTHER
  organism:
    preferred_term: domestic guinea pig
    term:
      id: NCBITaxon:10141
      label: Cavia porcellus
  cell_types:
  - preferred_term: Cardiac ventricular myocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  publication: PMID:32618513
  modeled_mechanisms:
  - target: Reduced Cardiomyocyte Contractility and Systolic Calcium Transient
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The model's central result is reduced fractional shortening with a suppressed
      systolic calcium transient in cells carrying the CMD1FF allele.
    limitations: >-
      Acute adenoviral overexpression in a non-human myocyte is not the same as
      lifelong heterozygous expression in a human heart: mutant and wild-type
      protein ratios are set by transduction rather than by allele dosage, and the
      48-hour timescale excludes chronic adaptation. Guinea pig calcium handling is
      closer to human than murine but is still not human.
    readouts:
    - name: Fractional sarcomere shortening
      target: Reduced Cardiomyocyte Contractility and Systolic Calcium Transient
      direction: DECREASED
      interpretation: Contractile output of the single myocyte carrying the mutant allele.
      evidence:
      - reference: PMID:32618513
        reference_title: "Dilated cardiomyopathy mutations in thin-filament regulatory proteins reduce contractility, suppress systolic Ca(2+), and activate NFAT and Akt signaling."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          We find significantly reduced fractional shortening with reduced systolic
          Ca2+.
        explanation: >-
          Reports the shortening and systolic calcium measurements behind these
          readouts.
    - name: Systolic calcium transient amplitude
      target: Reduced Cardiomyocyte Contractility and Systolic Calcium Transient
      direction: DECREASED
      interpretation: >-
        Calcium available to activate the myofilament, measured by fura-2 ratiometry
        in the same cells.
      evidence:
      - reference: PMID:32618513
        reference_title: "Dilated cardiomyopathy mutations in thin-filament regulatory proteins reduce contractility, suppress systolic Ca(2+), and activate NFAT and Akt signaling."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          We also observe increased sarcoplasmic reticulum (SR) Ca2+ load and
          smaller fractional SR Ca2+ release.
        explanation: >-
          Supplies the sarcoplasmic-reticulum handling result that accompanies the
          reduced systolic transient in this model.
  - target: Calcineurin-NFAT and Akt Signaling Activation
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      The model supplies the signalling readouts linking the mutant myofilament to a
      remodeling transcriptional program.
    limitations: >-
      NFAT and Akt were assayed in chronically paced isolated cells over hours; no
      remodeling phenotype develops in this system, so the link from signalling to
      tissue remodeling is inferred rather than observed here.
    readouts:
    - name: NFAT nuclear translocation
      target: Calcineurin-NFAT and Akt Signaling Activation
      direction: INCREASED
      interpretation: Activation of calcium-dependent remodeling signalling.
      evidence:
      - reference: PMID:32618513
        reference_title: "Dilated cardiomyopathy mutations in thin-filament regulatory proteins reduce contractility, suppress systolic Ca(2+), and activate NFAT and Akt signaling."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          We also observe dephosphorylation and nuclear translocation of the nuclear
          factor of activated T cells (NFAT), with concordant RAC-α-serine/threonine
          protein kinase (Akt) phosphorylation but no change to extracellular
          signal-regulated kinase activation in chronically paced cardiomyocytes
          expressing DCM mutations.
        explanation: >-
          The measurement of NFAT dephosphorylation and nuclear translocation that
          this readout records.
  evidence:
  - reference: PMID:32618513
    reference_title: "Dilated cardiomyopathy mutations in thin-filament regulatory proteins reduce contractility, suppress systolic Ca(2+), and activate NFAT and Akt signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In this study we set out to investigate the functional effect of DCM-causing
      mutations in three separate thin-filament regulatory proteins: TnT R131W, TnI
      K36Q, and α-TM E40K, using our established adult guinea pig left ventricular
      cardiomyocyte model (39).
    explanation: >-
      Describes the model system and confirms that the CMD1FF allele K36Q is among
      the mutations it carries, which is what makes it informative for this entry.
discussions:
- discussion_id: cmd1ff_versus_cmd2a_split
  prompt: >-
    Is dominant TNNI3 dilated cardiomyopathy (CMD1FF) a separate dismech entity
    from recessive TNNI3 dilated cardiomyopathy (CMD2A), or should it be a subtype
    of it?
  kind: INTERPRETATION
  status: RESOLVED
  attaches_to:
  - pathophysiology#Heterozygous TNNI3 Variant Altering Cardiac Troponin I
  rationale: >-
    The two share a gene and an organ-level phenotype, so the split needs a reason
    beyond having two OMIM numbers. Four independent axes support it. Mechanism:
    CMD2A abolishes cardiac troponin I, whereas CMD1FF always retains a wild-type
    allele and — for the founding missense alleles — puts an altered protein into
    the troponin complex, so the lesion is a change in what the thin filament does
    rather than an absence of it. Direction of functional effect: the CMD1FF alleles
    lower maximum ATPase and calcium sensitivity, whereas the troponin I-null heart
    is characterized by global regulatory failure timed by a developmental isoform
    switch, a clock that has no meaning when one allele is intact. Natural history:
    obligate neonatal-to-infantile and near-uniformly severe in CMD2A, versus
    variable, incompletely penetrant, childhood-to-adult onset in CMD1FF. Clinical
    action: 50% per-offspring recurrence with longitudinal surveillance of
    first-degree relatives, versus 25% per sibship with carrier testing and
    reproductive counselling. ClinGen's Dilated Cardiomyopathy GCEP reinforces this
    by issuing two separate TNNI3-DCM assertions differing only in mode of
    inheritance, both rated Strong. Recorded as RESOLVED in favour of a separate
    entry; if MONDO or ClinGen later collapses the two, this entry and CMD2A should
    be merged rather than left to duplicate each other.
  evidence:
  - reference: CGGV:assertion_668087ea-0d2f-42c2-a291-f73400d34023-2025-04-18T160000.000Z
    reference_title: "TNNI3 / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      TNNI3 | HGNC:11947 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong
    explanation: >-
      The dominant assertion, curated separately from the recessive one on the same
      day by the same expert panel — the external evidence that the two
      relationships are treated as distinct curatable claims.
  - reference: PMID:36981019
    reference_title: "Homozygous TNNI3 Mutations and Severe Early Onset Dilated Cardiomyopathy: Patient Report and Review of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In recent years, however, an increasing amount of evidence has validated the
      hypothesis that biallelic TNNI3 null mutations cause a severe form of neonatal
      dilated cardiomyopathy.
    explanation: >-
      Establishes the recessive entity's distinct genotype and neonatal course,
      which is the contrast this split rests on.
- discussion_id: cmd1ff_calcium_sensitivity_direction_conflict
  prompt: >-
    Do all dominant TNNI3 dilated-cardiomyopathy alleles decrease myofilament
    calcium sensitivity, given that the one heterozygous truncating allele studied
    in human myocardium increased it?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Altered Thin-Filament Calcium Regulation
  - mechanistic_hypotheses#tnni3_ad_haploinsufficiency
  rationale: >-
    The organising generalization for dominant thin-filament dilated cardiomyopathy
    is that its alleles desensitize the myofilament to calcium, opposite to the
    sensitizing hypertrophic and restrictive alleles — and the two founding CMD1FF
    missense alleles behave that way on reconstitution. But the single heterozygous
    TNNI3 truncating allele characterized in explanted human myocardium showed pure
    haploinsufficiency with *increased* calcium sensitivity and impaired
    length-dependent activation. Both results are credible and neither is a
    measurement error: they differ in allele class (altered-function missense versus
    reduced-quantity truncation), in preparation (reconstituted proteins versus
    permeabilized human cardiomyocytes), and in whether secondary remodeling of an
    end-stage explanted heart could contribute. Whether the two allele classes reach
    the same disease by opposite myofilament routes, or whether one of them belongs
    to a different mechanism entirely, is unresolved — and it matters, because a
    calcium-sensitizer or -desensitizer therapy would be predicted to help one group
    and harm the other.
  proposed_experiments:
  - experiment_id: exp_cmd1ff_allele_class_calcium_sensitivity_series
    name: Paired calcium-sensitivity measurement across CMD1FF missense and truncating alleles
    description: >-
      Measure myofilament calcium sensitivity and length-dependent activation in one
      preparation across a panel of heterozygous TNNI3 dilated-cardiomyopathy
      alleles spanning both classes, so the direction of effect is not confounded by
      differences in assay system.
  - experiment_id: exp_cmd1ff_isogenic_ipsc_allele_comparison
    name: Isogenic human iPSC-cardiomyocyte comparison of missense versus truncating TNNI3 alleles
    description: >-
      Introduce K36Q, N185K, and a truncating TNNI3 allele into a single isogenic
      human iPSC background and compare calcium sensitivity, contractility, and
      length-dependent activation, removing both the species and the end-stage
      remodeling confounds.
  evidence:
  - reference: PMID:19590045
    reference_title: Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Analysis of Ca(2+) regulation of actin-tropomyosin-activated myosin ATPase by
      troponin revealed that troponin reconstituted with either mutant troponin I
      gave lower maximum ATPase rates and lower Ca(2+) sensitivity than wild type.
    explanation: >-
      One side of the discrepancy: the founding missense alleles reduce calcium
      sensitivity.
  - reference: DOI:10.1113/jp274145
    reference_title: Genotype-specific pathogenic effects in human dilated cardiomyopathy
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      The TNNI3p.98trunc showed pure haploinsufficiency, increased Ca2+‐sensitivity
      and impaired length‐dependent activation.
    explanation: >-
      The other side: a heterozygous TNNI3 truncating allele in human myocardium
      raised calcium sensitivity. Graded REFUTE against the claim that all dominant
      TNNI3 dilated-cardiomyopathy alleles are calcium-desensitizing, which is the
      generalization this gap questions.
- discussion_id: cmd1ff_no_animal_model
  prompt: >-
    Does any whole-animal model of dominant TNNI3 dilated cardiomyopathy exist, and
    what does its absence cost the mechanistic account?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Adverse Ventricular Remodeling
  rationale: >-
    Every functional result behind this entry comes from reconstituted proteins,
    permeabilized human cardiomyocytes, or acutely transduced isolated myocytes. No
    knock-in animal carrying a CMD1FF allele has been reported, in contrast to the
    thin-filament DCM field generally, where knock-in mouse models exist for TNNT2
    and TPM1 alleles and where the Tnni3-null mouse anchors the recessive entity.
    Consequently the steps from myofilament defect through remodeling to a dilated
    ventricle are asserted here from dilated cardiomyopathy as a class rather than
    demonstrated for this genotype, and questions that need an intact circulation —
    penetrance, the trigger for conversion from latent to manifest disease, and
    whether beta-blockade acts differently when phosphorylation-sensitivity coupling
    is lost — cannot currently be addressed.
  proposed_experiments:
  - experiment_id: exp_cmd1ff_knockin_mouse
    name: Tnni3 K36Q or N185K knock-in mouse
    description: >-
      Generate a heterozygous knock-in carrying a CMD1FF allele at the endogenous
      locus and characterize penetrance, age of onset, ventricular geometry, fibrosis
      and response to beta-blockade, to test whether the in vitro myofilament defect
      is sufficient for the disease.
  evidence:
  - reference: PMID:32618513
    reference_title: "Dilated cardiomyopathy mutations in thin-filament regulatory proteins reduce contractility, suppress systolic Ca(2+), and activate NFAT and Akt signaling."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      To date, five gene-targeted knock-in mouse models of DCM carrying
      thin-filament mutations have been characterized: TnT ΔK210 (10), R141W (36),
      and R134W (15); actin E99K (46); and αTM E54K (35).
    explanation: >-
      Enumerates the existing thin-filament DCM knock-in models — none of them a
      TNNI3 allele — which is the gap this discussion records. Evidence source is
      OTHER because the sentence surveys prior literature rather than reporting this
      paper's results.
references:
- reference: PMID:20301486
  title: Dilated Cardiomyopathy Overview.
  tags:
  - GeneReviews
notes: >-
  Scope. This entry covers the dominant, heterozygous TNNI3 dilated cardiomyopathy
  (OMIM 613286, MONDO:0013211). The recessive TNNI3 dilated entity is
  Dilated_Cardiomyopathy_2A; the dominant TNNI3 hypertrophic and restrictive
  diseases (CMH7, RCM1) appear here only as differential diagnoses. TNNI3 is the
  most heavily represented gene in this corner of the KB, so a TNNI3 citation must
  be checked for zygosity, variant class, and cardiomyopathy subtype before it is
  reused across these entries. In particular the p.Arg98* allele occurs on both
  sides of the dominant/recessive line and is not by itself diagnostic of either
  entity.

  Grouping. This entry was added as a member of the Familial_Dilated_Cardiomyopathy
  grouping, and that grouping's curation-gaps note — which previously read "TNNI3
  is represented by the recessive CMD2A entity" — was updated in the same change,
  since TNNI3 is now represented by both its dominant and its recessive entity.

  GeneReviews baseline: no CMD1FF- or TNNI3-specific GeneReviews chapter exists.
  The applicable chapter is the generic "Dilated Cardiomyopathy Overview"
  (PMID:20301486), tagged above; its PubMed record carries only the chapter's
  stated purpose and no Clinical Characteristics text, so it could not serve as a
  phenotype baseline. The phenotype set here is built from the founding Carballo
  families plus the dilated-cardiomyopathy class literature, and phenotypes taken
  from the class rather than from this entity say so in their explanations.

  Deliberately not curated. No prevalence figure is asserted for CMD1FF: the
  Chmielewski Polish genetic-DCM cohort attributing about 1% of gene findings to
  TNNI3 is cited in the deep-research report, but its cached reference file carries
  no abstract body, so no exact snippet could be verified and the claim was left
  out rather than paraphrased. No animal model is recorded because none carrying a
  CMD1FF allele has been reported (see the corresponding discussion). No
  environmental section is curated: the report's list of second hits (alcohol,
  anthracyclines, peripartum stress, myocarditis) is general genetic-DCM biology
  with no TNNI3-specific evidence, and asserting it here would attach an
  unevidenced exposure to a mechanism node. No clinical trials are recorded — none
  is registered for this entity — and no datasets block was added, as no
  CMD1FF-specific dataset was identified.

  Deep-research provenance: Edison/FutureHouse Falcon
  (research/Dilated_Cardiomyopathy_1FF-deep-research-falcon.md). `just preflight-dr`
  passed against MONDO:0013211 with TNNI3 mentioned 51 times and the report's OMIM
  set covering 613286. The report was used as a lead-generation source only. It
  correctly separates CMD1FF from CMD2A and correctly corrects a nomenclature error
  it found in the literature (OMIM 617047 is FLNC-related restrictive
  cardiomyopathy, not CMD1FF). Two of its claims were checked and not carried over:
  it reports being unable to establish a MONDO identifier for CMD1FF and suggests
  mapping to parent concepts, whereas MONDO:0013211 exists and was resolved
  directly with OAK; and its suggested HPO term "Left ventricular dilatation
  (HP:0001712)" is wrong — HP:0001712 is Left ventricular hypertrophy, and the
  correct term HP:4000141 was used instead. Its founding-literature coverage was
  incomplete: the Carballo 2009 Circulation Research report that defines this
  entity and is the OMIM 613286 anchor is not among its citations and was found
  independently, as were the Memo 2013 uncoupling study, the Robinson 2020
  cardiomyocyte study of the K36Q allele, and the Tadros 2020 troponin-variant
  meta-analysis.
📚

References & Deep Research

References

1
PMID:20301486
Dilated Cardiomyopathy Overview.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Record notes

Scope. This entry covers the dominant, heterozygous TNNI3 dilated cardiomyopathy (OMIM 613286, MONDO:0013211). The recessive TNNI3 dilated entity is Dilated_Cardiomyopathy_2A; the dominant TNNI3 hypertrophic and restrictive diseases (CMH7, RCM1) appear here only as differential diagnoses. TNNI3 is the most heavily represented gene in this corner of the KB, so a TNNI3 citation must be checked for zygosity, variant class, and cardiomyopathy subtype before it is reused across these entries. In particular the p.Arg98* allele occurs on both sides of the dominant/recessive line and is not by itself diagnostic of either entity. Grouping. This entry was added as a member of the Familial_Dilated_Cardiomyopathy grouping, and that grouping's curation-gaps note — which previously read "TNNI3 is represented by the recessive CMD2A entity" — was updated in the same change, since TNNI3 is now represented by both its dominant and its recessive entity. GeneReviews baseline: no CMD1FF- or TNNI3-specific GeneReviews chapter exists. The applicable chapter is the generic "Dilated Cardiomyopathy Overview" (PMID:20301486), tagged above; its PubMed record carries only the chapter's stated purpose and no Clinical Characteristics text, so it could not serve as a phenotype baseline. The phenotype set here is built from the founding Carballo families plus the dilated-cardiomyopathy class literature, and phenotypes taken from the class rather than from this entity say so in their explanations. Deliberately not curated. No prevalence figure is asserted for CMD1FF: the Chmielewski Polish genetic-DCM cohort attributing about 1% of gene findings to TNNI3 is cited in the deep-research report, but its cached reference file carries no abstract body, so no exact snippet could be verified and the claim was left out rather than paraphrased. No animal model is recorded because none carrying a CMD1FF allele has been reported (see the corresponding discussion). No environmental section is curated: the report's list of second hits (alcohol, anthracyclines, peripartum stress, myocarditis) is general genetic-DCM biology with no TNNI3-specific evidence, and asserting it here would attach an unevidenced exposure to a mechanism node. No clinical trials are recorded — none is registered for this entity — and no datasets block was added, as no CMD1FF-specific dataset was identified. Deep-research provenance: Edison/FutureHouse Falcon (research/Dilated_Cardiomyopathy_1FF-deep-research-falcon.md). `just preflight-dr` passed against MONDO:0013211 with TNNI3 mentioned 51 times and the report's OMIM set covering 613286. The report was used as a lead-generation source only. It correctly separates CMD1FF from CMD2A and correctly corrects a nomenclature error it found in the literature (OMIM 617047 is FLNC-related restrictive cardiomyopathy, not CMD1FF). Two of its claims were checked and not carried over: it reports being unable to establish a MONDO identifier for CMD1FF and suggests mapping to parent concepts, whereas MONDO:0013211 exists and was resolved directly with OAK; and its suggested HPO term "Left ventricular dilatation (HP:0001712)" is wrong — HP:0001712 is Left ventricular hypertrophy, and the correct term HP:4000141 was used instead. Its founding-literature coverage was incomplete: the Carballo 2009 Circulation Research report that defines this entity and is the OMIM 613286 anchor is not among its citations and was found independently, as were the Memo 2013 uncoupling study, the Robinson 2020 cardiomyocyte study of the K36Q allele, and the Tadros 2020 troponin-variant meta-analysis.

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Disease Characteristics Research Template
Edison Scientific Literature 11 citations 2026-09-02T17:45:18.254439

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Dilated Cardiomyopathy 1FF
  • MONDO ID: (if available)
  • Category: Cardiovascular

Research Objectives

Please provide a comprehensive research report on Dilated Cardiomyopathy 1FF covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Dilated Cardiomyopathy 1FF: comprehensive disease-characteristics report

Executive summary and scope

Dilated cardiomyopathy 1FF (DCM1FF) is the autosomal-dominant TNNI3-associated dilated-cardiomyopathy phenotype, OMIM #613286. It must not be conflated with DCM2A (OMIM #611880), the increasingly well-supported, usually severe neonatal/infantile cardiomyopathy caused by biallelic TNNI3 loss-of-function (LoF) variants. It must also be separated from TNNI3-associated hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), and left-ventricular noncompaction (LVNC). This distinction is clinically important because variant mechanism, inheritance, penetrance, onset, and recurrence risk differ. Heterozygous TNNI3 variants can act through haploinsufficiency, altered thin-filament regulation, or dominant-negative/gain-of-function effects; biallelic null variants can nearly abolish cardiac troponin-I expression. (sorrentino2023homozygoustnni3mutations pages 1-2, sorrentino2023homozygoustnni3mutations pages 5-8, sorrentino2023homozygoustnni3mutations pages 2-4, bollen2017genotype‐specificpathogeniceffects pages 1-4)

The evidence base for narrowly defined DCM1FF remains small. Consequently, exact disease-specific prevalence, penetrance, sex ratio, survival, phenotype frequencies, environmental modifiers, and treatment-response rates are not established. Where necessary, this report identifies evidence as DCM1FF-specific, TNNI3-spectrum, or general genetic DCM rather than extrapolating silently.

Entity Inheritance / variant mechanism Typical onset / phenotype Key example variants Evidence caveat
DCM1FF (OMIM 613286) Autosomal dominant; heterozygous TNNI3 variants, including function-altering missense variants and reported truncation-associated haploinsufficiency Variable-onset dilated cardiomyopathy with ventricular dilation and systolic dysfunction; penetrance and expressivity can vary within and between families p.Arg98Ter (p.98trunc); p.Glu182Lys and p.Glu184Lys have also been listed with DCM Very rare, with uneven variant-level evidence. Pathogenicity requires ACMG/AMP assessment using population frequency, segregation, and functional evidence. Must not be conflated with recessive infantile DCM.
DCM2A (OMIM 611880) Autosomal recessive; biallelic TNNI3 loss-of-function variants causing markedly reduced or absent cardiac troponin I Severe neonatal or infantile DCM, often presenting in the first year with ventricular dilation, very low LVEF, rapidly progressive heart failure, transplantation, or death Homozygous c.292C>T (p.Arg98Ter); c.204del (p.Arg69AlafsTer8); c.150G>A (p.Lys50=), causing abnormal splicing; contiguous deletion involving TNNI3 Strongest loss-of-function evidence concerns biallelic disease. Heterozygous carrier parents may be unaffected; recessive cases must not be classified as autosomal-dominant DCM1FF.
Other TNNI3 cardiomyopathies: HCM, RCM, and LVNC Usually autosomal-dominant missense disease in HCM or RCM through gain-of-function or dominant-negative effects; recessive missense and splice variants also occur; mechanism is variant-dependent HCM and RCM may begin in childhood or adulthood; pediatric RCM can progress rapidly and have poor prognosis. LVNC has been reported with biallelic splice variation. Intermediate and overlapping phenotypes occur. HCM: p.Arg21Cys and p.Arg79Cys; RCM: p.Arg192Cys and homozygous p.Asp196His; LVNC: homozygous c.24+2T>A The same gene can cause distinct phenotypes. HCM, RCM, or LVNC evidence does not automatically establish DCM1FF causality; some reported alleles remain VUS or show low penetrance.

Table: This table separates autosomal-dominant DCM1FF from biallelic TNNI3 loss-of-function DCM2A and other TNNI3-associated cardiomyopathies. Evidence comes from human cases, myocardial functional studies, and reviews. (sorrentino2023homozygoustnni3mutations pages 1-2, sorrentino2023homozygoustnni3mutations pages 4-5, sorrentino2023homozygoustnni3mutations pages 5-8, sorrentino2023homozygoustnni3mutations pages 2-4, bollen2017genotype‐specificpathogeniceffects pages 1-4, bollen2017genotype‐specificpathogeniceffects pages 14-18, han2025troponini– pages 7-8)

1. Disease information

Definition

DCM is conventionally defined by left-ventricular or biventricular dilation and systolic dysfunction that cannot be explained solely by coronary artery disease, hypertension, valvular disease, congenital heart disease, or other abnormal loading conditions. DCM1FF is the subset attributed to a pathogenic heterozygous variant in TNNI3, which encodes cardiac troponin I (cTnI), an inhibitory component of the sarcomeric thin-filament troponin complex. (sorrentino2023homozygoustnni3mutations pages 2-4, scolari2024geneticsofthe pages 3-3, sorella2025diagnosisandmanagement pages 1-2)

Identifiers and synonyms

  • Preferred name: Dilated cardiomyopathy 1FF
  • OMIM phenotype: 613286
  • Gene: TNNI3, cardiac troponin I; chromosome 19q13.4. (sorrentino2023homozygoustnni3mutations pages 2-4)
  • Synonyms: DCM1FF; TNNI3-related autosomal-dominant dilated cardiomyopathy; cardiac troponin-I–related DCM; familial dilated cardiomyopathy due to TNNI3.
  • MONDO: A distinct DCM1FF MONDO identifier was not established from the retrieved sources. Parent concepts appropriate for mapping are dilated cardiomyopathy, MONDO:0005021, and familial dilated cardiomyopathy, MONDO:0016333. The retrieved Open Targets result supports those parent disease records but should not be used as proof of a DCM1FF-specific MONDO mapping. (OpenTargets Search: dilated cardiomyopathy-FLNC)
  • ICD-10: No genotype-specific code; use the jurisdiction-appropriate DCM code, commonly I42.0.
  • ICD-11: No TNNI3/DCM1FF-specific code was identified; map to the dilated-cardiomyopathy category.
  • MeSH: Cardiomyopathy, Dilated.
  • Orphanet: No disease-specific ORPHA identifier was verified in the retrieved evidence; do not assign one without direct ORDO/Orphanet confirmation.

This report uses aggregated disease resources, published families, case reports, explanted myocardial tissue, and cohort studies—not individual EHR data. Recent HPO work supports standardized rare-disease phenotyping and EHR integration, but it does not itself supply DCM1FF phenotype frequencies.

Critical nomenclature correction

OMIM #617047 is not DCM1FF; retrieved current literature uses it for FLNC-associated familial restrictive cardiomyopathy 5. DCM1FF is #613286 and TNNI3-associated. This correction prevents erroneous attribution of FLNC’s high arrhythmic-risk phenotype to DCM1FF.

2. Etiology

Causal factors and genetic risk

The primary lesion is a germline TNNI3 variant affecting cTnI quantity or function. Heterozygous missense variants can alter interactions with troponin C, troponin T, tropomyosin, or actin and may exert dominant-negative or gain-of-function effects. A heterozygous p.Arg98Ter/p.98truncation allele has been studied as haploinsufficiency in human myocardium. (sorrentino2023homozygoustnni3mutations pages 2-4, bollen2017genotype‐specificpathogeniceffects pages 1-4)

Variant interpretation must be phenotype- and mechanism-specific. The same gene causes DCM, HCM, RCM, LVNC, and intermediate phenotypes; therefore, a TNNI3 variant reported in HCM or RCM does not automatically establish DCM1FF. Variants should be assessed under ACMG/AMP principles using rarity, segregation, allelic state, functional evidence, phenotype match, and competing causes. (han2025troponini– pages 7-8, mestre2025predictionandprognostic pages 9-9, scolari2024geneticsofthe pages 3-3)

Environmental and clinical risk modifiers

No DCM1FF-specific environmental-risk study was identified. In genetic DCM generally, pregnancy/peripartum stress, alcohol, cardiotoxic chemotherapy, and myocarditis can reveal or amplify disease in genetically predisposed people. These are plausible “second hits,” not demonstrated TNNI3-specific causal modifiers. (scolari2024geneticsofthe pages 3-3)

Other clinically relevant stressors include uncontrolled hypertension, tachyarrhythmia, ischemia, endocrine/metabolic disease, nutritional deficiency, and cardiotoxic drugs. They should be excluded as alternative or additive causes rather than assumed to be part of DCM1FF.

Protective factors

No reproducible genetic protective variant, diet, supplement, medication, or exposure has been demonstrated specifically for DCM1FF. Potentially protective clinical practices are avoidance of cardiotoxins and excessive alcohol, control of blood pressure and arrhythmias, timely heart-failure therapy, and surveillance of genotype-positive relatives. These reduce acquired cardiac stress or identify disease earlier; they do not prevent inheritance.

Gene–environment interaction

A biologically reasonable model is that impaired sarcomeric reserve reduces tolerance to hemodynamic, inflammatory, toxic, or pregnancy-associated stress, accelerating remodeling. This remains inferred for DCM1FF. A neonatal case was initially suspected to have myocarditis, illustrating diagnostic overlap rather than proving infection-triggered TNNI3 disease. (sorrentino2023homozygoustnni3mutations pages 4-5)

3. Phenotypes

Because no large DCM1FF natural-history cohort was found, frequencies below are qualitative unless otherwise stated.

  • Ventricular dilation—clinical sign/imaging abnormality; usually left ventricular and potentially biventricular; variable onset and progressive in symptomatic disease. Suggested HPO: Dilated cardiomyopathy (HP:0001644), Left ventricular dilatation (HP:0001712).
  • Reduced systolic function/LVEF—imaging/functional abnormality; mild to severe. General DCM descriptions use LVEF below approximately 40–50% as impaired, depending on diagnostic framework. Suggested HPO: Decreased left ventricular ejection fraction (HP:0012664), Left ventricular systolic dysfunction (HP:0025169). (sorrentino2023homozygoustnni3mutations pages 1-2)
  • Heart failure—syndrome/signs and symptoms; exertional dyspnea, fatigue, exercise intolerance, orthopnea, edema, feeding difficulty or tachypnea in infants. Suggested HPO: Congestive heart failure (HP:0001635), Dyspnea (HP:0002094), Exercise intolerance (HP:0003546), Peripheral edema (HP:0012398).
  • Arrhythmia or conduction disease—possible DCM complication, but DCM1FF-specific frequency and arrhythmic risk are not defined. Suggested HPO: Cardiac arrhythmia (HP:0011675), Ventricular arrhythmia (HP:0031677), Palpitations (HP:0001962), Syncope (HP:0001279). (sorrentino2023homozygoustnni3mutations pages 1-2)
  • Functional mitral/tricuspid regurgitation—secondary to chamber/annular dilation; HPO: Mitral regurgitation (HP:0001653) and Tricuspid regurgitation (HP:0005180). Both occurred in severe biallelic infantile cases but are not quantified in DCM1FF. (sorrentino2023homozygoustnni3mutations pages 4-5)
  • Thromboembolism/stroke—advanced HF/device-associated complication rather than a defining phenotype. One biallelic infantile case developed ischemic stroke during mechanical support. HPO: Thromboembolism (HP:0001907) and Ischemic stroke (HP:0002140). (sorrentino2023homozygoustnni3mutations pages 4-5)
  • Sudden cardiac death—recognized in DCM generally, but a TNNI3-DCM1FF-specific rate is unavailable. HPO: Sudden cardiac death (HP:0001645).

Age, severity, and progression

AD DCM1FF may have variable onset and penetrance. In contrast, biallelic TNNI3-null DCM commonly presents in the first year and can progress rapidly to transplant or death. Recent examples presented at six to seven months with LVEF 25%; both required transplantation, while a separate de novo p.Glu182Lys neonatal case died shortly after discharge. (sorrentino2023homozygoustnni3mutations pages 1-2, sorrentino2023homozygoustnni3mutations pages 4-5, han2025troponini– pages 7-8)

Quality of life

No DCM1FF-specific EQ-5D, SF-36, Kansas City Cardiomyopathy Questionnaire, or pediatric quality-of-life dataset was found. Expected burdens follow symptomatic DCM: restricted exercise and employment/school activity, recurrent hospitalization, medication and device burden, anxiety about sudden death and relatives, and transplant-related morbidity. These should be captured with validated HF instruments rather than entered as measured DCM1FF effects.

4. Genetic and molecular information

Causal gene

  • TNNI3; cardiac troponin I.
  • Protein role: approximately 24-kDa inhibitory troponin subunit that suppresses actin–myosin interaction at low cytosolic calcium and participates in calcium-dependent activation/relaxation. (sorrentino2023homozygoustnni3mutations pages 2-4)
  • HGNC/NCBI/UniProt identifiers: should be populated by direct database import in a production knowledge base; they were not independently verified in the retrieved excerpts.

Variant classes and consequences

  1. Heterozygous missense: may alter thin-filament protein interactions, calcium sensitivity, or phosphorylation-dependent regulation; mechanism can be dominant-negative or gain-of-function. Penetrance may be incomplete and variable. (sorrentino2023homozygoustnni3mutations pages 2-4)
  2. Heterozygous truncating p.Arg98Ter/p.98truncation: human myocardium supports haploinsufficiency with reduced troponin-complex abundance and abnormal myofilament physiology. (bollen2017genotype‐specificpathogeniceffects pages 1-4, bollen2017genotype‐specificpathogeniceffects pages 14-18)
  3. Biallelic LoF: causes a separate recessive, severe early-onset disease. Homozygous c.204del, p.Arg69AlafsTer8 produced markedly reduced TNNI3 RNA and absent protein, supporting nonsense-mediated decay. (sorrentino2023homozygoustnni3mutations pages 5-8)
  4. Splice/synonymous LoF: biallelic splice-disrupting or intron-retaining variants can cause pediatric DCM or LVNC. (sorrentino2023homozygoustnni3mutations pages 5-8, sorrentino2023homozygoustnni3mutations pages 10-11)

Reported DCM-associated alleles in retrieved sources include p.Arg98Ter/p.98truncation, p.Glu182Lys, and p.Glu184Lys. The latter two were listed in a review-derived table, and p.Glu182Lys was reported de novo in a neonate; each requires transcript-specific HGVS normalization and ClinVar reassessment before clinical use. (bollen2017genotype‐specificpathogeniceffects pages 1-4, han2025troponini– pages 7-8)

For recessive infantile DCM, examples include NM_000363.5:c.292C>T, p.Arg98Ter; c.204del, p.Arg69AlafsTer8; c.150G>A, p.Lys50= with splice effect; and a contiguous deletion involving TNNI3. (sorrentino2023homozygoustnni3mutations pages 4-5, sorrentino2023homozygoustnni3mutations pages 5-8)

Allele frequency and origin

Pathogenic Mendelian DCM alleles should generally be absent or extremely rare in ancestry-matched population databases. Exact gnomAD/TOPMed frequencies were not supplied by the retrieved evidence and should be imported variant by variant. DCM1FF variants are constitutional germline, not somatic cancer mutations. Both inherited and de novo TNNI3 variants occur across the broader spectrum.

Modifier, epigenetic, and chromosomal information

No validated DCM1FF modifier gene or disease-specific DNA-methylation, histone, or chromatin signature was identified. The contiguous TNNT1/TNNI3 deletion is relevant to recessive syndromic infantile disease, not typical AD DCM1FF. Large structural variants remain possible and may require copy-number/WGS analysis when panel testing is negative.

5. Environmental information

No toxin, pathogen, radiation exposure, occupation, smoking pattern, diet, or lifestyle factor is sufficient to cause genetically defined DCM1FF. General DCM evaluation should nevertheless assess:

  • alcohol and stimulants;
  • anthracyclines and other cardiotoxic therapies;
  • pregnancy/peripartum timing;
  • viral or immune-mediated myocarditis;
  • sustained tachyarrhythmia;
  • endocrine, nutritional, metabolic, and autoimmune causes;
  • hypertension and coronary disease.

Myocarditis-like episodes or infections can mimic inherited DCM, and genetic susceptibility can coexist with acquired injury. Evidence for a TNNI3-specific infectious trigger is unavailable. (sorrentino2023homozygoustnni3mutations pages 4-5, scolari2024geneticsofthe pages 3-3)

6. Mechanism and pathophysiology

Ordered causal chain

  1. A pathogenic germline TNNI3 variant leads to reduced cTnI abundance or altered cTnI structure/function.
  2. Abnormal cTnI leads to disturbed interaction among troponin I, troponin C, troponin T, actin, tropomyosin, and the thin filament.
  3. Disturbed troponin regulation results in abnormal calcium sensitivity, phosphorylation response, and/or inhibitory control of actomyosin cycling.
  4. These myofilament defects lead to inefficient contraction/relaxation and impaired length-dependent activation; the exact balance is variant-specific.
  5. Chronic cardiomyocyte mechanical and energetic inefficiency is inferred to cause cellular stress and reduced contractile reserve.
  6. This stress leads to adverse myocardial remodeling—myocyte dysfunction/loss, extracellular-matrix remodeling and fibrosis, and ventricular wall stress. The fibrosis branch is general DCM biology rather than directly demonstrated for every DCM1FF allele.
  7. Remodeling results in ventricular dilation and reduced LVEF.
  8. Dilation and systolic failure lead to neurohormonal activation, functional valve regurgitation, congestion, and clinical heart failure.
  9. Branch: structural/electrical remodeling and calcium-handling abnormalities may lead to atrial or ventricular arrhythmia, syncope, thromboembolism, and sudden death; DCM1FF-specific event rates remain unknown.
  10. Biallelic branch: two TNNI3 LoF alleles lead to nonsense-mediated decay or severely reduced/absent cTnI, resulting in much earlier, often infantile, severe DCM. (sorrentino2023homozygoustnni3mutations pages 4-5, sorrentino2023homozygoustnni3mutations pages 5-8, bollen2017genotype‐specificpathogeniceffects pages 1-4)

Direct mechanistic evidence

Human explanted-myocardium evidence: in p.98trunc cardiomyocytes, troponin I, T, and C abundance was approximately 39%, 64%, and 73% of control, respectively. Skinned cardiomyocytes had increased Ca²⁺ sensitivity and impaired length-dependent activation. Exogenous PKA did not normalize the defect, whereas exchange with recombinant wild-type troponin partly restored protein levels and normalized functional abnormalities. This supports a direct, genotype-specific troponin-complex mechanism rather than secondary end-stage remodeling alone. (bollen2017genotype‐specificpathogeniceffects pages 1-4, bollen2017genotype‐specificpathogeniceffects pages 14-18)

Human biopsy evidence, recessive disease: homozygous p.Arg69AlafsTer8 was associated with markedly reduced transcript and complete absence of cTnI protein, with increased fetal TNNI1 expression—consistent with nonsense-mediated decay and incomplete isoform compensation. (sorrentino2023homozygoustnni3mutations pages 5-8)

A useful short quotation from the 2017 study abstract is: “different gene mutations induce dilated cardiomyopathy via diverse cellular pathways.” (bollen2017genotype‐specificpathogeniceffects pages 1-4)

Pathways, processes, cells, and ontology suggestions

  • Thin-filament contraction and calcium regulation: GO:0006941 striated muscle contraction, GO:0055008 cardiac muscle contraction, GO:0006936 muscle contraction, GO:0003009 skeletal muscle contraction only if skeletal involvement is documented.
  • Calcium regulation/excitation–contraction coupling: GO:0006874 cellular calcium ion homeostasis, GO:0010880 regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum, GO:0086001 cardiac muscle cell action potential.
  • Sarcomere organization/remodeling: GO:0045214 sarcomere organization, GO:0060048 cardiac muscle contraction, GO:0048738 cardiac muscle tissue development.
  • Downstream remodeling: hypertrophy, apoptosis, autophagy, oxidative stress, fibrosis, and inflammatory signaling are plausible general DCM processes but were not directly resolved in DCM1FF-specific single-cell data.
  • Principal cell: cardiac muscle cell/cardiomyocyte (CL:0000746). Secondary cells include cardiac fibroblasts, vascular endothelial cells, smooth-muscle cells, macrophages, and conduction-system cardiomyocytes; involvement is inferred from remodeling.

No DCM1FF-specific Wnt, MAPK, mTOR, or PI3K–AKT initiating pathway has been demonstrated. These may be downstream remodeling pathways, not the primary biochemical lesion.

Molecular profiling and advanced technologies

Available disease-specific profiling is limited to myocardial RNA/protein abundance and contractile physiology. No validated DCM1FF-specific plasma metabolomic, lipidomic, proteomic, epigenomic, single-cell, spatial-transcriptomic, or integrated multi-omic signature was identified. Thus, such profiles should not be entered as established disease features.

7. Anatomical structures affected

  • Primary organ: heart, particularly ventricular myocardium; UBERON:0000948 heart, UBERON:0002084 heart left ventricle, UBERON:0002080 heart right ventricle, UBERON:0002349 myocardium.
  • Tissue: cardiac muscle tissue, ventricular wall, sarcomeres and thin filaments.
  • Cells: cardiomyocytes, especially ventricular working myocytes (CL:0000746).
  • Subcellular: sarcomere (GO:0030017), myofibril (GO:0030016), actin cytoskeleton (GO:0015629), troponin complex (GO:0005861), thin filament.
  • Secondary organs: lungs in pulmonary congestion; liver, kidneys, and peripheral tissues in advanced low-output/congestive HF; brain after embolic stroke. These are complications, not primary TNNI3 targets.
  • Lateralization: not applicable. Disease is not unilateral; left ventricular predominance is anatomical rather than body-side lateralization.

8. Temporal development

AD DCM1FF appears chronic and variably penetrant, with onset potentially from childhood to adulthood, but robust gene-specific age distributions are lacking. Disease may pass through a genotype-positive/phenotype-negative phase, subtle strain or ECG abnormalities, overt LV systolic dysfunction/dilation, symptomatic HF, and advanced HF/transplantation.

The biallelic form is different: most reported severe cases present in infancy, sometimes after apparently normal birth. In the 2023 report, symptoms began at six or seven months, followed by LVEF 25%, rapid deterioration, mechanical support, and transplant by eight months or within four months of presentation. (sorrentino2023homozygoustnni3mutations pages 4-5)

Recovery is possible through reverse remodeling under HF therapy in DCM generally, but no DCM1FF-specific remission rate exists. Even after normalized LVEF, genetic substrate persists; surveillance and usually continued therapy are prudent. Critical intervention windows are (1) presymptomatic familial surveillance, (2) early asymptomatic LV dysfunction, and (3) rapid referral for advanced HF when severe pediatric or adult deterioration occurs.

9. Inheritance and population

Inheritance

  • DCM1FF: autosomal dominant; recurrence risk is nominally 50% for each child of a heterozygous carrier, before accounting for penetrance and variant classification.
  • Biallelic TNNI3-null DCM/DCM2A: autosomal recessive; when both parents are carriers, each pregnancy has 25% affected, 50% carrier, and 25% noncarrier risk.
  • Penetrance: incomplete/variable and likely age-dependent for heterozygous TNNI3 variants; precise DCM1FF penetrance is unknown. (sorrentino2023homozygoustnni3mutations pages 2-4)
  • Expressivity: variable, spanning asymptomatic carriage, DCM, HCM, RCM, or overlapping phenotypes depending on allele and mechanism.
  • Anticipation: not established.
  • Germline mosaicism: theoretically possible after an apparently de novo finding but not quantified.
  • Consanguinity: relevant mainly to biallelic recessive disease. (sorrentino2023homozygoustnni3mutations pages 4-5, sorrentino2023homozygoustnni3mutations pages 5-8)

Epidemiology

No population prevalence or incidence is available for DCM1FF itself. In genetic DCM generally, plausible genetic causes are found in approximately 10–40% of cases; guideline synthesis estimates familial DCM at 30–50%, with an identifiable cause in roughly 30–40% of familial cases. Estimates vary with ascertainment and gene curation. (scolari2024geneticsofthe pages 3-3, sorella2025diagnosisandmanagement pages 1-2)

A recent Polish genetic DCM cohort attributed about 1% of identified gene findings to TNNI3, compared with TTN 38%, MYH7 7%, FLNC and DMD 5% each, and TNNT2 3%. This is cohort composition—not TNNI3 prevalence in the general population. (chmielewski2025geneticarchitectureof pages 2-2)

No reliable DCM1FF sex ratio, ethnic disparity, geographic distribution, or carrier frequency was identified. Founder effects are established for certain TNNI3 HCM/RCM alleles, but not for DCM1FF in the reviewed evidence.

10. Diagnostics

Clinical diagnostic pathway

  1. History and pedigree: three-generation cardiac history, sudden death, transplant, HF, arrhythmia, neuromuscular disease, alcohol/toxin exposure, pregnancy, infection, and cardiotoxic treatment.
  2. Examination: congestion, murmurs of functional regurgitation, low output, edema, hepatomegaly, growth/feeding assessment in children.
  3. ECG and ambulatory monitoring: conduction disease, ectopy, atrial fibrillation, nonsustained ventricular tachycardia.
  4. Echocardiography: LV and RV size/function, LVEF, global longitudinal strain, valve regurgitation, filling pressures.
  5. Cardiac MRI: volumes, function, edema and late gadolinium enhancement/fibrosis; useful for phenotyping, differential diagnosis, and risk assessment.
  6. Laboratory tests: BNP/NT-proBNP and high-sensitivity troponin are guideline-consensus biomarkers; CBC, electrolytes, renal/liver function, thyroid, iron, and cause-directed metabolic/infectious testing. (sorella2025diagnosisandmanagement pages 1-2)
  7. Coronary and loading-condition exclusion: based on age/risk and clinical context.
  8. Endomyocardial biopsy: not routine; reserve for suspected myocarditis, infiltrative/storage disease, or rapidly progressive unexplained HF when results would change management.

A 2024 ESC-guideline commentary quotes cardiomyopathies as myocardial disorders structurally and functionally abnormal “in the absence of coronary artery disease, hypertension, valvular disease, and congenital heart disease sufficient to cause the observed myocardial abnormality.”

Genetic testing

Use a curated cardiomyopathy multigene panel including TNNI3, with deletion/duplication analysis and appropriate coverage. Trio testing is valuable in severe pediatric disease. WES/WGS is appropriate when panel testing is negative, onset is very early, the presentation is syndromic, structural/deep-intronic variants are suspected, or recessive disease is possible. Confirm clinically actionable variants by an orthogonal method and perform segregation testing. (sorrentino2023homozygoustnni3mutations pages 2-4, scolari2024geneticsofthe pages 3-3)

Do not use a VUS for predictive testing, irreversible treatment, or reproductive decisions. Reanalyze periodically as ClinVar, gnomAD, functional data, and gene-specific curation evolve. RNA studies can establish splice effects; myocardial or iPSC functional studies remain research tools.

CMA/karyotype/FISH are not first-line for isolated DCM1FF but may be appropriate for congenital anomalies, developmental delay, or suspected copy-number/chromosomal disease. Mitochondrial and repeat-expansion testing are phenotype-driven, not routine TNNI3 tests.

Family screening

Offer genetic counseling and targeted testing to first-degree relatives after a pathogenic/likely pathogenic familial variant is established. Genotype-positive relatives require serial ECG and imaging even when asymptomatic; Holter monitoring and strain imaging can add predictive information. Genotype-negative relatives in a well-characterized P/LP family can often be released from serial genetic-family surveillance, subject to clinical judgment. A recent Dutch program found DCM in 9% at baseline and another 10% of reevaluated relatives over a median five years; none of 128 relatives lacking the familial P/LP variant developed DCM. These are general DCM data, not TNNI3-specific.

Differential diagnosis

Exclude ischemic cardiomyopathy, hypertensive or valvular remodeling, myocarditis, tachycardia-induced cardiomyopathy, peripartum cardiomyopathy, alcohol/toxin/chemotherapy injury, endocrine/metabolic/mitochondrial disease, neuromuscular disease, arrhythmogenic cardiomyopathy, LVNC, and TNNI3-related HCM/RCM. Distinguishing the latter requires imaging phenotype, diastolic physiology, allelic state, and variant-level evidence.

11. Outcome and prognosis

No valid DCM1FF-specific five- or ten-year survival curve exists in the retrieved literature. Prognosis should therefore be estimated from phenotype: LVEF/RV function, NYHA/Ross class, congestion, fibrosis, ventricular arrhythmia, syncope, biomarkers, treatment response, and need for mechanical support.

General pediatric cardiomyopathy data provide context only: one 2024 cohort reported DCM survival of 75.5% at five years and 60.1% at ten years, with NYHA/Ross III–IV predicting mortality. These figures cannot be assigned specifically to TNNI3 disease.

The recessive infantile form is often severe. In two 2023 cases, both had LVEF 25% and required transplant in infancy; one suffered stroke during support. In another neonatal p.Glu182Lys case, the child died after discharge. (sorrentino2023homozygoustnni3mutations pages 4-5, han2025troponini– pages 7-8)

Prognostic complications include progressive HF, ventricular and atrial arrhythmias, sudden death, functional regurgitation, intracardiac thrombosis/embolism, multiorgan congestion, mechanical support, and transplantation. Improvement under treatment is possible, but genetic status remains lifelong.

12. Treatment

Current standard care

There is no approved TNNI3- or DCM1FF-specific drug, RNA therapy, gene therapy, or cell therapy. Treatment follows age-appropriate DCM/HFrEF guidelines:

  • ARNI or ACE inhibitor/ARB;
  • evidence-based beta blocker;
  • mineralocorticoid-receptor antagonist;
  • SGLT2 inhibitor in eligible HFrEF patients;
  • loop diuretic for congestion;
  • iron replacement for documented iron deficiency;
  • anticoagulation only for standard indications such as atrial fibrillation, intracardiac thrombus, or prior embolism;
  • ivabradine, hydralazine/isosorbide dinitrate, vericiguat, or digoxin in selected patients.

Suggested NCIt intervention mappings include Pharmacologic Therapy (C15986), Angiotensin Receptor–Neprilysin Inhibitor, Beta Adrenergic Blocker, Mineralocorticoid Receptor Antagonist, Sodium-Glucose Cotransporter 2 Inhibitor, and Diuretic Therapy; production IDs should be verified against the current NCIt release.

Devices and advanced care

  • ICD for secondary prevention and phenotype-based primary prevention after individualized assessment; TNNI3 alone currently lacks a validated gene-specific ICD threshold.
  • CRT for standard electrical/mechanical criteria.
  • LVAD/ECMO for refractory shock or bridge to transplant/recovery.
  • Heart transplantation for end-stage HF; the 2023 biallelic cases illustrate successful real-world use. (sorrentino2023homozygoustnni3mutations pages 4-5)
  • Suggested NCIt terms: Implantable Cardioverter-Defibrillator, Cardiac Resynchronization Therapy, Ventricular Assist Device, Extracorporeal Membrane Oxygenation, Heart Transplantation.

Rehabilitation and supportive care

Multidisciplinary HF/cardiogenetics care, sodium/fluid advice individualized to congestion, vaccination, supervised exercise/cardiac rehabilitation when stable, psychosocial care, school/work accommodations, and reproductive counseling are appropriate. Competitive/intense exercise advice should be individualized by phenotype and arrhythmia burden rather than genotype alone.

Experimental therapy and trials

Troponin-complex replacement normalized contractile abnormalities in an ex-vivo human cardiomyocyte experiment, providing proof of mechanism—not a deliverable therapy. (bollen2017genotype‐specificpathogeniceffects pages 1-4, bollen2017genotype‐specificpathogeniceffects pages 14-18)

A ClinicalTrials.gov search retrieved no relevant TNNI3/DCM1FF-directed interventional trial. The one gene-therapy trial returned concerned Friedreich-ataxia cardiomyopathy and is not applicable. Gene replacement, allele-specific silencing, editing, and sarcomere/calcium modulators remain preclinical concepts. For dominant missense disease, the correct strategy would depend on whether the allele acts by haploinsufficiency, dominant-negative effect, or gain of function.

13. Prevention

Primary prevention

The inherited allele cannot presently be prevented after conception. Reduce avoidable myocardial stress: avoid cocaine/amphetamines and cardiotoxic supplements, minimize excessive alcohol, control blood pressure and metabolic disease, review cardiotoxic chemotherapy risk, and seek early assessment for pregnancy-associated or infectious cardiac symptoms. Evidence is general DCM prevention, not DCM1FF-specific.

Secondary prevention

  • Cascade genetic testing after identification of a familial P/LP variant.
  • Serial ECG, echocardiography/strain, and rhythm monitoring in carriers.
  • Prompt therapy for asymptomatic LV dysfunction or overt HF.
  • Consider CMR for uncertain or evolving phenotype.

Family-screening evidence indicates earlier detected LV dysfunction has better outcomes than disease detected outside screening programs, supporting surveillance as a clinically meaningful preventive implementation. (mestre2025predictionandprognostic pages 9-9)

Tertiary prevention

Continue guideline-directed therapy, prevent decompensation, treat arrhythmias and thromboembolic risk, vaccinate against respiratory infections, provide rehabilitation, and refer early for device or advanced-HF evaluation when indicated.

Reproductive prevention/counseling

Offer preconception counseling, prenatal diagnosis, or PGT-M after a familial pathogenic variant is established. Counseling must distinguish the 50% transmission risk of AD DCM1FF from the 25% affected risk when both parents carry a recessive TNNI3 LoF allele. A VUS is inadequate for PGT-M or predictive testing.

14. Other species and natural disease

  • Human: Homo sapiens, NCBI Taxon 9606.
  • Common research ortholog systems include mouse (Mus musculus, 10090), rat (Rattus norvegicus, 10116), and zebrafish (Danio rerio, 7955).

TNNI3/cardiac troponin-I function is evolutionarily conserved across vertebrates, supporting mechanistic models. However, no well-validated naturally occurring companion-animal or livestock disease specifically homologous to human DCM1FF was identified. Accordingly, no breed/VBO association should be assigned. The disorder is not infectious, transmissible, or zoonotic.

15. Model organisms and experimental systems

Human myocardial models

The strongest DCM1FF mechanism evidence comes from explanted human LV tissue and membrane-permeabilized cardiomyocytes carrying p.98trunc. Strengths are native adult sarcomere context and direct contractile measurement; limitations include end-stage remodeling, small sample size, and inability to model presymptomatic progression. Recombinant wild-type troponin exchange supplied a causal rescue experiment. (bollen2017genotype‐specificpathogeniceffects pages 1-4, bollen2017genotype‐specificpathogeniceffects pages 14-18)

Human biopsy models of recessive disease

RNA and protein studies in p.Arg69AlafsTer8 myocardium showed reduced transcript and absent cTnI, directly demonstrating LoF. This models DCM2A, not AD DCM1FF. (sorrentino2023homozygoustnni3mutations pages 5-8)

iPSC-derived cardiomyocytes and engineered tissue

TNNI3-mutant iPSC-cardiomyocytes and engineered heart tissues can examine calcium sensitivity, relaxation, contractile force, sarcomere organization, drug response, and gene correction. Advantages include human genetic background and isogenic CRISPR controls. Limitations include fetal-like maturation, altered TNNI isoform expression, lack of adult loading and multicellular architecture, and incomplete modeling of fibrosis, immunity, and long-term arrhythmia.

Mouse and zebrafish models

Transgenic/knock-in mice and zebrafish are used across the TNNI3/troponin cardiomyopathy spectrum. They permit in-vivo hemodynamic, arrhythmic, developmental, and survival studies, but phenotype direction can differ by variant, species, dosage, developmental stage, and background. No single model retrieved here fully recapitulates human AD DCM1FF natural history. (han2025troponini– pages 7-8)

Omics/model gaps

No DCM1FF-specific organoid, single-cell atlas, spatial transcriptomic map, systematic CRISPR screen, or validated multi-omic biomarker panel was identified. These are high-priority research gaps, along with prospective registries that separate heterozygous DCM1FF from biallelic DCM2A and other TNNI3 phenotypes.

Evidence appraisal and current research priorities

The most persuasive disease-specific evidence is human myocardial physiology demonstrating p.98trunc-associated haploinsufficiency and functional rescue. Recent 2023 literature substantially strengthens a different relationship—biallelic TNNI3 LoF with lethal or transplant-requiring infantile DCM. (sorrentino2023homozygoustnni3mutations pages 4-5, sorrentino2023homozygoustnni3mutations pages 5-8, bollen2017genotype‐specificpathogeniceffects pages 1-4)

Priority needs are: a curated transcript-specific variant registry; segregation and penetrance studies; ancestry-diverse population controls; longitudinal ECG/CMR/strain phenotyping; direct comparison of AD missense, AD truncating, and biallelic LoF mechanisms; mature isogenic engineered-heart-tissue models; and genotype-specific therapeutic studies. Until those data exist, diagnosis should be variant-level and phenotype-led, and management should follow contemporary inherited-DCM and HF guidance rather than assuming a uniform “TNNI3 cardiomyopathy” prognosis.

References

  1. (sorrentino2023homozygoustnni3mutations pages 1-2): Ugo Sorrentino, Ilaria Gabbiato, Chiara Canciani, Davide Calosci, Chiara Rigon, Daniela Zuccarello, and Matteo Cassina. Homozygous tnni3 mutations and severe early onset dilated cardiomyopathy: patient report and review of the literature. Mar 2023. URL: https://doi.org/10.3390/genes14030748, doi:10.3390/genes14030748. This article has 19 citations.

  2. (sorrentino2023homozygoustnni3mutations pages 5-8): Ugo Sorrentino, Ilaria Gabbiato, Chiara Canciani, Davide Calosci, Chiara Rigon, Daniela Zuccarello, and Matteo Cassina. Homozygous tnni3 mutations and severe early onset dilated cardiomyopathy: patient report and review of the literature. Mar 2023. URL: https://doi.org/10.3390/genes14030748, doi:10.3390/genes14030748. This article has 19 citations.

  3. (sorrentino2023homozygoustnni3mutations pages 2-4): Ugo Sorrentino, Ilaria Gabbiato, Chiara Canciani, Davide Calosci, Chiara Rigon, Daniela Zuccarello, and Matteo Cassina. Homozygous tnni3 mutations and severe early onset dilated cardiomyopathy: patient report and review of the literature. Mar 2023. URL: https://doi.org/10.3390/genes14030748, doi:10.3390/genes14030748. This article has 19 citations.

  4. (bollen2017genotype‐specificpathogeniceffects pages 1-4): Ilse A. E. Bollen, Maike Schuldt, Magdalena Harakalova, Aryan Vink, Folkert W. Asselbergs, Jose R. Pinto, Martina Krüger, Diederik W. D. Kuster, and Jolanda van der Velden. Genotype‐specific pathogenic effects in human dilated cardiomyopathy. The Journal of Physiology, 595:4677-4693, Jun 2017. URL: https://doi.org/10.1113/jp274145, doi:10.1113/jp274145. This article has 50 citations.

  5. (sorrentino2023homozygoustnni3mutations pages 4-5): Ugo Sorrentino, Ilaria Gabbiato, Chiara Canciani, Davide Calosci, Chiara Rigon, Daniela Zuccarello, and Matteo Cassina. Homozygous tnni3 mutations and severe early onset dilated cardiomyopathy: patient report and review of the literature. Mar 2023. URL: https://doi.org/10.3390/genes14030748, doi:10.3390/genes14030748. This article has 19 citations.

  6. (bollen2017genotype‐specificpathogeniceffects pages 14-18): Ilse A. E. Bollen, Maike Schuldt, Magdalena Harakalova, Aryan Vink, Folkert W. Asselbergs, Jose R. Pinto, Martina Krüger, Diederik W. D. Kuster, and Jolanda van der Velden. Genotype‐specific pathogenic effects in human dilated cardiomyopathy. The Journal of Physiology, 595:4677-4693, Jun 2017. URL: https://doi.org/10.1113/jp274145, doi:10.1113/jp274145. This article has 50 citations.

  7. (han2025troponini– pages 7-8): Dongju Han, Younghyun Lim, Soah Lee, and Seong-il Eyun. Troponin i – a comprehensive review of its function, structure, evolution, and role in muscle diseases. Animal Cells and Systems, 29:446-468, Jul 2025. URL: https://doi.org/10.1080/19768354.2025.2533821, doi:10.1080/19768354.2025.2533821. This article has 9 citations and is from a peer-reviewed journal.

  8. (scolari2024geneticsofthe pages 3-3): Fernando Luis Scolari, Henrique Iahnke Garbin, Thais Mariel Andara Beuren, Felipe Cerqueira Matheus, Ricardo Mourilhe-Rocha, and Marcelo Imbroinise Bittencourt. Genetics of the cardiomyopathies: a review for the cardiologist. ABC Heart Fail Cardiomyop, Oct 2024. URL: https://doi.org/10.36660/abchf.20240047i, doi:10.36660/abchf.20240047i. This article has 3 citations.

  9. (sorella2025diagnosisandmanagement pages 1-2): Anna Sorella, Kristian Galanti, Lorena Iezzi, Sabina Gallina, Selma F Mohammed, Neha Sekhri, Mohammed Majid Akhtar, Sanjay K Prasad, Choudhary Anwar Ahmed Chahal, Fabrizio Ricci, and Mohammed Yunus Khanji. Diagnosis and management of dilated cardiomyopathy: a systematic review of clinical practice guidelines and recommendations. European Heart Journal. Quality of Care & Clinical Outcomes, 11:206-222, Dec 2025. URL: https://doi.org/10.1093/ehjqcco/qcae109, doi:10.1093/ehjqcco/qcae109. This article has 45 citations.

  10. (OpenTargets Search: dilated cardiomyopathy-FLNC): Open Targets Query (dilated cardiomyopathy-FLNC, 7 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  11. (mestre2025predictionandprognostic pages 9-9): Eva Del Mestre, Alessia Paldino, Carola Pio Loco Detto Gava, Ilaria Gandin, Marta Gigli, Davide Stolfo, Martina Setti, Giovanni Maria Severini, Beatrice Spedicati, Stefania Lenarduzzi, Giorgia Girotto, Alessandro Folgheraiter, Jacopo Giulio Rizzi, Renata Korcova, Luisa Mestroni, Marco Merlo, Matteo Dal Ferro, and Gianfranco Sinagra. Prediction and prognostic role of left ventricular systolic dysfunction in family screening for dilated cardiomyopathy and non-dilated left ventricular cardiomyopathy. European journal of heart failure, Apr 2025. URL: https://doi.org/10.1002/ejhf.3657, doi:10.1002/ejhf.3657. This article has 6 citations and is from a highest quality peer-reviewed journal.

  12. (sorrentino2023homozygoustnni3mutations pages 10-11): Ugo Sorrentino, Ilaria Gabbiato, Chiara Canciani, Davide Calosci, Chiara Rigon, Daniela Zuccarello, and Matteo Cassina. Homozygous tnni3 mutations and severe early onset dilated cardiomyopathy: patient report and review of the literature. Mar 2023. URL: https://doi.org/10.3390/genes14030748, doi:10.3390/genes14030748. This article has 19 citations.

  13. (chmielewski2025geneticarchitectureof pages 2-2): P. Chmielewski, G. Truszkowska, G. Kostrzewa, Ewa Michalak, P. Stawiński, Ilona Kowalik, Ilona Minota, Przemysław Leszek, Łukasz Mazurkiewicz, Jolanta Krzysztoń-Russjan, Rafał Płoski, and Z. Bilińska. Genetic architecture of dilated cardiomyopathy in poland: variant distribution, clinical characteristics and prognosis. Polish archives of internal medicine, Aug 2025. URL: https://doi.org/10.20452/pamw.17083, doi:10.20452/pamw.17083. This article has 4 citations.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 7
Resolved 7
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 7
On topic 3
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 38
Resolved 38
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0
Terms whose name was checked 1
Terms named correctly 0
Terms named as a different term 0
Terms whose name is worth a second look 1

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • CL:0000746 (2 mentions) - the report calls it "Principal cell: cardiac muscle cell/cardiomyocyte"; CL calls it cardiac muscle cell**

Every term resolved, and every label the report gave matched.