👪

Inheritance

1

Autosomal dominant HP:0000006

Autosomal dominant transmission with high but incomplete penetrance. In the two large multigenerational families that established the D230N allele, penetrance was reported at 80%.

Autosomal dominant inheritance Penetrance %: 80

Show evidence (2 references)

PMID:23147248 SUPPORT Human Clinical

"Here we present a large four-generation family in which DCM is inherited as an autosomal dominant trait."

Autosomal dominant transmission across four generations.

PMID:20117437 SUPPORT Human Clinical

"Abnormal cardiac dimensions and contractile parameters were identified in 16 of 20 mutation carriers, indicating a penetrance of 80% for DCM in the 2 families."

The primary segregation study, giving the carrier count behind the 80% figure rather than the figure alone.

?

Discussions and Knowledge Gaps

2

Is TPM1-DCM a distinct disease entity, or is the moderate ClinGen classification telling us that some reported TPM1 DCM variants will not survive re-curation?

KNOWLEDGE GAP tpm1_dcm_gene_validity_asymmetry

Attached to

genetic#TPM1 disease#Dilated Cardiomyopathy 1Y

The evidence here is genuinely split and a curator should not paper over it. On one side, two large multigenerational families with linkage, 80% penetrance, a transgenic mouse that phenocopies the early-onset disease, and a coherent biophysical mechanism - that is a strong case for D230N specifically. On the other, ClinGen rates TPM1-DCM Moderate while rating TPM1-HCM Definitive, an expert panel places it in the moderate tier, and a case-control burden study finds enrichment only in specific patient subsets, possibly confined to early-onset disease. The likeliest reconciliation is that a small number of well-supported alleles are genuinely causative while the gene as a whole has been over-called in adult DCM panels, which would predict that a variant-level rather than gene-level re-curation resolves the discrepancy. Practically, this matters for how much weight a TPM1 variant of uncertain significance should carry in an adult DCM workup.

Show evidence (4 references)

CGGV:assertion_1173d239-23cf-4c9c-9ea5-f95d9356e6c7-2025-04-04T160000.000Z SUPPORT Other

The current ClinGen classification, which is the substance of the gap.

CGGV:assertion_32e7ed58-ee49-4719-b48e-7fad58012319-2023-12-18T170000.000Z SUPPORT Other

The other half of the asymmetry, and it belongs here rather than on the gene record. On the TPM1-DCM gene record it was evidence for a different disease and could only mislead an aggregator; here the asymmetry itself is the claim, so a Definitive classification for HCM alongside a Moderate one for DCM is direct SUPPORT for the question this discussion poses.

PMID:31983221 SUPPORT Human Clinical

"Variants in MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1, and VCL were significantly enriched in specific patient subsets, with the last 2 genes potentially contributing primarily to early-onset forms of DCM."

The subset-restricted enrichment that supports a narrower, early-onset role rather than a general adult DCM gene.

+ 1 more reference

Can tropomyosin pseudo-phosphorylation rescue TPM1 cardiomyopathy mutations in a whole heart, given that the same modification is itself cardiomyopathic when overexpressed?

KNOWLEDGE GAP tpm1_pseudophosphorylation_rescue

Attached to

pathophysiology#Altered Tropomyosin Flexibility and Actin Binding

Two results sit awkwardly together. In vitro, the phosphomimetic substitutions S283D and S61D reduce or eliminate the abnormal actin affinity caused by cardiomyopathy mutations, which the authors propose as a rescue strategy. But a transgenic mouse highly expressing the S283D phosphomimetic develops severe dilated cardiomyopathy and dies within a month, and even moderate expression causes myocyte hypertrophy and fibrosis with impaired diastolic function. So the modification that normalises a biophysical parameter in a test tube is itself pathogenic in a heart at high dose. The unresolved question is whether there is a therapeutic window - a level of phosphorylation high enough to correct the mutant filament but below the threshold at which it causes disease on its own - or whether the in vitro rescue simply does not translate. Notably the mouse showed no change in myofilament calcium sensitivity, so the actin-affinity correction and the whole-heart phenotype may not be connected at all.

Show evidence (3 references)

PMID:33129908 SUPPORT In Vitro

"The results indicate that Tpm pseudo-phosphorylation by mutations S283D or S61D can rescue the effects of mutations in the TPM1 gene encoding a cardiac isoform of Tpm that lead to the development of such severe inherited heart diseases as hypertrophic or dilated cardiomyopathies."

The in vitro rescue claim.

PMID:30567734 REFUTE Model Organism

"High expression of Tpm S283D variant in one transgenic mouse line resulted in an increased heart:body weight ratio, coupled with a severe dilated cardiomyopathic phenotype resulting in death within 1 month of birth."

Graded REFUTE against the rescue proposal as a therapeutic strategy - the same modification causes lethal DCM in vivo at high expression.

PMID:30567734 SUPPORT Model Organism

"Surprisingly, we observed no alterations in calcium sensitivity of the myofibers, cooperativity, or calcium-ATPase activity in the myofibers."

Shows the in vivo phenotype is not mediated by the calcium-sensitivity axis, which weakens the link between the in vitro actin-affinity correction and any whole-heart benefit.

⚙

Pathophysiology

4

TPM1 Missense Variant

Single missense substitutions in alpha-tropomyosin. The disease-causing alleles are scattered along the coiled-coil rather than confined to one domain, and which disease results depends on where the substitution sits and what it does to the molecule - different mutations cause HCM or DCM, so the gene is not simply dose-sensitive.

TPM1 hgnc:12010

Downstream

Altered Tropomyosin Flexibility and Actin Binding

Show evidence (4 references)

PMID:24005378 SUPPORT Other

"The inherited cardiac diseases hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) can both be caused by missense mutations in the TPM1 gene which encodes the thin filament regulatory protein α-tropomyosin."

Establishes that both diseases arise from missense change in the same gene. Graded OTHER because this is a structure-function review synthesising biophysical and animal-model work rather than reporting one study type.

PMID:24005378 SUPPORT Other

"Different mutations are responsible for either HCM or DCM, suggesting that distinct changes in tropomyosin structure and function can lead to the different diseases."

States that allele identity, not gene dosage, determines which phenotype results.

PMID:11273725 SUPPORT Human Clinical

"We identified two mutations that alter highly conserved residues and that, unlike hypertrophic cardiomyopathy-associated mutations, cause localized charge reversal on the surface of tropomyosin."

The first proposal of a physical rule separating the two phenotypes - DCM alleles reverse surface charge, HCM alleles do not. D230N fits it, losing a charge at a solvent-exposed f-position residue.

+ 1 more reference

Altered Tropomyosin Flexibility and Actin Binding

The primary biophysical lesion, and it differs between alleles. D230N increases the thermal stability of the C-terminal end of the coiled-coil, which decreases flexibility at the head-to-tail overlap - the joint the filament must flex about to move around actin. D84N instead weakens tropomyosin's binding to actin by 25% through lost charge-charge interaction. Both routes compromise the same regulatory function; neither is a simple loss of protein.

actin binding GO:0003779 ↓ DECREASED

striated muscle thin filament GO:0005865

Downstream

Decreased Myofilament Calcium Sensitivity

Show evidence (3 references)

PMID:28600229 SUPPORT In Vitro

"Measurements of the thermal unfolding of D230N-Tm vs WT-Tm revealed an increase in stability primarily affecting the C-terminus of the Tm coiled-coil."

The structural measurement behind the reduced-flexibility mechanism.

PMID:28600229 SUPPORT In Vitro

"the D230N-Tm mutation induces a decrease in flexibility of the C-terminus via propagation through the helical structure of the protein, thus decreasing the flexibility of the Tm overlap and impairing its ability to regulate contraction"

States the allosteric propagation from the substituted residue to the overlap region.

PMID:23147248 SUPPORT In Vitro

"The TPM1 p.D84N was the only mutation identified. The mutation co-segregates with all clinically affected family members and significantly weakens the binding of tropomyosin to actin by 25%."

The alternative biophysical route - quantified loss of actin binding rather than altered flexibility.

Decreased Myofilament Calcium Sensitivity

The functional consequence that defines the DCM direction. Across TPM1 alleles, DCM mutations generally decrease myofilament calcium sensitivity while HCM mutations increase it, and DCM mutations additionally uncouple troponin phosphorylation from calcium responsiveness - so the heart loses not only sensitivity but the ability to modulate it. In the D230N mouse the reduced calcium sensitivity of sliding velocity is accompanied by an increased peak amplitude of the calcium transient, which reads as compensation: the cell raises calcium because the filament responds to it less.

cardiac muscle cell CL:0000746

regulation of cardiac muscle contraction by calcium ion signaling GO:0010882 ↓ DECREASED

Animal models

D230N-Tm transgenic mouse Mouse measures Isolated myocytes from the model were used to measure calcium handling and myofilament activation, giving the reduced calcium sensitivity and raised transient amplitude.

Downstream

Systolic Dysfunction and Ventricular Dilation

Show evidence (4 references)

PMID:24005378 SUPPORT Other

"The latter changes have been found to be particularly consistent, with HCM mutations increasing Ca(2+) sensitivity and DCM mutations in general decreasing this parameter and uncoupling the effect of troponin phosphorylation upon Ca(2+) responsiveness."

The central directional claim separating TPM1-HCM from TPM1-DCM, described by the review as the most consistent of the reported effects.

PMID:28600229 SUPPORT In Vitro

"D230N-Tm filaments exhibited a reduced Ca2+ sensitivity of sliding velocity. This decrease in sensitivity was coupled to increase in the peak amplitude of Ca2+ transients."

Direct measurement of both the reduced sensitivity and the compensatory calcium transient.

PMID:20117437 SUPPORT In Vitro

"In vitro studies demonstrated major inhibitory effects on sarcomere function with reduced Ca(2+) sensitivity, maximum activation, and Ca(2+) affinity compared with wild-type TPM1."

The reconstituted-thin-filament measurements themselves, from the study that made them, across three related biophysical parameters.

+ 1 more reference

Systolic Dysfunction and Ventricular Dilation

The organ-level endpoint: reduced ejection fraction with left ventricular enlargement. In the D230N transgenic mouse significant systolic dysfunction is present by two months of age, phenocopying the early onset seen in the families.

heart left ventricle UBERON:0002084

Animal models

D230N-Tm transgenic mouse Mouse recapitulates Reproduces the early-onset systolic dysfunction of the human D230N families, with significant impairment by two months of age.

Show evidence (2 references)

PMID:20117437 SUPPORT Human Clinical

"Abnormal cardiac dimensions and contractile parameters were identified in 16 of 20 mutation carriers, indicating a penetrance of 80% for DCM in the 2 families."

The human phenotype the mechanism must explain - abnormal chamber dimensions and contractility in most carriers.

PMID:23147248 SUPPORT Human Clinical

"Dilated cardiomyopathy (DCM) is characterized by idiopathic dilatation and systolic contractile dysfunction of the ventricle(s) leading to an impaired systolic function."

Defines the clinical endpoint of the pathograph.

⬡

Pathograph

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

●

Phenotypes

4

Cardiovascular 3

Dilated Cardiomyopathy VERY_FREQUENT HP:0001644

Show evidence (1 reference)

PMID:20117437 SUPPORT Human Clinical

"TPM1 D230N segregated with DCM in 2 large unrelated families."

The segregation evidence establishing TPM1 as a DCM gene.

Reduced Left Ventricular Ejection Fraction VERY_FREQUENT HP:0012664

Show evidence (1 reference)

PMID:20117437 SUPPORT Human Clinical

"Two siblings, IV-5 and IV-8, presented with DCM and advanced HF at 5 months of age (LVEF 27% and 29%), and were given the presumptive diagnosis of myocarditis."

Measured ejection fractions in affected carriers. The misdiagnosis as myocarditis is quoted with them because it is how the phenotype presents before the family history is known.

Congestive Heart Failure FREQUENT HP:0001635

Graded FREQUENT rather than VERY_FREQUENT because the same cohort describes adults diagnosed on family screening with asymptomatic left ventricular dysfunction, who by definition were not in heart failure. The phenotype is age-dependent within the family.

Show evidence (2 references)

PMID:20117437 SUPPORT Human Clinical

"Clinical manifestations ranged from decompensated heart failure or sudden death in those presenting early in life to asymptomatic left ventricular dysfunction in those diagnosed during adulthood."

Both the presence of heart failure and the reason it is not graded universal - the same sentence gives the asymptomatic adult end of the range.

PMID:20117437 SUPPORT Human Clinical

"Presentation early in life, from infancy to adolescence, was not uncommon and was associated with severe, sometimes lethal outcomes, including SCD and refractory HF leading to death or transplantation."

The severity of the heart failure when it occurs, and its endpoints.

Other 1

Left Ventricular Noncompaction OCCASIONAL HP:0030682

Show evidence (2 references)

PMID:23147248 SUPPORT Human Clinical

"We show that a mutation in TPM1 is associated with DCM and a lethal, early onset form of NCCM, probably as a result of diminished actin binding caused by weakened charge-charge interactions."

Establishes the DCM/noncompaction overlap for TPM1 and attributes it to the same actin-binding defect.

PMID:23147248 SUPPORT Human Clinical

"The youngest affected was diagnosed with dilated and non-compaction cardiomyopathy (NCCM) and died at the age of five."

The index noncompaction case, showing both phenotypes in one individual.

🧬

Genetic Associations

1

TPM1

Gene: TPM1 hgnc:12010 relationship_type: CAUSATIVE

Show evidence (3 references)

CGGV:assertion_1173d239-23cf-4c9c-9ea5-f95d9356e6c7-2025-04-04T160000.000Z SUPPORT Other

ClinGen's current gene-disease validity classification for TPM1 in dilated cardiomyopathy is Moderate, not Definitive. Graded PARTIAL because that is exactly what a moderate classification asserts - real but not fully established.

PMID:33947203 SUPPORT Human Clinical

"Seven genes (14%; ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence."

Independent expert-panel curation placing TPM1 in the moderate tier for DCM, with the panel's own expectation that it will strengthen.

PMID:31983221 SUPPORT Human Clinical

"Variants in MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1, and VCL were significantly enriched in specific patient subsets, with the last 2 genes potentially contributing primarily to early-onset forms of DCM."

Case-control burden analysis showing TPM1 enrichment is restricted to specific patient subsets rather than DCM at large.

Variants (7)

D230N

The allele that defined this disease entity, identified by segregation in two large unrelated multigenerational families with severe, often early-onset DCM at 80% penetrance. It substitutes asparagine for aspartic acid at a solvent-exposed f-position residue near the C-terminus, losing a charge.

Show evidence (2 references)

PMID:20117437 SUPPORT Human Clinical

"Unlike previously reported TPM1 variants (E45K E40K) associated with DCM in isolated individuals (7), we demonstrate that dominant transmission of TPM1 D230N segregates with disease and deleteriously impacts in vitro assays of contractility, providing definitive evidence that TPM1 mutations cause DCM."

Identifies the founding allele and states what distinguishes it from the earlier single-patient TPM1 reports - dominant segregation, not just co-occurrence.

PMID:20117437 SUPPORT Human Clinical

"Presentation early in life, from infancy to adolescence, was not uncommon and was associated with severe, sometimes lethal outcomes, including SCD and refractory HF leading to death or transplantation."

The clinical severity of the allele, from the study that ascertained the families.

D84N

Causes dilated and non-compaction cardiomyopathy in a four-generation family, acting by weakening actin binding rather than by altering coiled-coil flexibility.

Show evidence (1 reference)

PMID:23147248 SUPPORT Human Clinical

"We mapped the phenotype to chromosome 15 and subsequently identified a missense mutation in TPM1, resulting in a p.D84N amino acid substitution."

Identification of the D84N allele by linkage and sequencing.

K30E

A de novo allele in a proband with DCM and left ventricular non-compaction who reached terminal heart failure before four years of age. The only reported de novo TPM1 variant in this entry, and the clearest evidence that a single TPM1 substitution is sufficient to cause paediatric DCM without a transmitted family history.

Show evidence (3 references)

PMID:39684770 SUPPORT Human Clinical

"We identified a novel de novo variant, c.88A>G (p.Lys30Glu, K30E), in the TPM1 gene encoding the major cardiac muscle tropomyosin (Tpm) isoform, Tpm1.1."

Identifies the allele and establishes that it arose de novo.

PMID:39684770 SUPPORT Human Clinical

"The variant was found in a proband with DCM and left ventricular non-compaction who progressed to terminal heart failure at the age of 3 years and 8 months."

The clinical course, and the second TPM1 allele in this entry to combine dilated cardiomyopathy with non-compaction.

PMID:39684770 SUPPORT In Vitro

"The K30E substitution decreased the thermal stability of Tpm and its complex with actin and significantly reduced the sliding velocity of the regulated thin filaments over a surface covered by ovine cardiac myosin in an in vitro motility assay across the entire physiological range of Ca2+ concentration."

Functional confirmation on the same two axes the D230N work uses - thermal stability of the coiled-coil and thin-filament sliding velocity - which is what makes the two alleles mechanistically comparable.

E114Q

A heterozygous missense allele in exon 3, reported in a Chinese Han family with DCM. Curated as an allele-spectrum entry: the report establishes the substitution and the family, but performs no functional assay, so no mechanism is asserted for it.

Show evidence (2 references)

PMID:35029218 SUPPORT Human Clinical

"This novel heterozygous mutation results in the substitution of glutamic acid with glutamine (p.E114Q)."

Identifies the allele and its zygosity.

PMID:35029218 SUPPORT Human Clinical

"A Chinese Han family with DCM phenotypes was examined."

Graded PARTIAL - a single family with no segregation statistics or functional work, which is the level of evidence this allele currently rests on.

M8R

A DCM-linked allele near the tropomyosin N-terminus, studied end to end from atomistic simulation through a Markov thin-filament model to human engineered heart tissue. It reaches the same hypocontractile endpoint as D230N by a different molecular route - by favouring the blocked state of tropomyosin on actin rather than by stiffening the overlap region.

Show evidence (2 references)

PMID:39282088 SUPPORT Computational

"Atomistic simulations predict that M8R increases flexibility of the tropomyosin chain and enhances affinity for the blocked or inactive state of tropomyosin on actin."

The predicted molecular mechanism. Note the direction is opposite to D230N, which decreases flexibility - so increased and decreased chain flexibility can both give a dilated phenotype, and flexibility alone is not the discriminator.

PMID:39282088 SUPPORT In Vitro

"The mutant tissues manifested depressed contractility and twitch duration that agreed in detail with model predictions."

Experimental confirmation in human engineered heart tissue, which is what lifts this above a purely computational claim.

E40K and E45K

The earliest reported TPM1 alleles associated with dilated cardiomyopathy, found in isolated individuals rather than in segregating families. Curated to record why TPM1 pathogenicity in DCM was considered unproven until D230N: the alleles existed, but without transmission data.

Show evidence (1 reference)

PMID:20117437 SUPPORT Human Clinical

"Unlike previously reported TPM1 variants (E45K E40K) associated with DCM in isolated individuals (7), we demonstrate that dominant transmission of TPM1 D230N segregates with disease and deleteriously impacts in vitro assays of contractility, providing definitive evidence that TPM1 mutations cause DCM."

Graded PARTIAL because the sentence names these alleles in order to say their evidence was weaker - association in single individuals without segregation.

E54K

A DCM-associated allele used as the comparator against the HCM allele E62Q in mechanistic work. Modelled as acting through long-range allosteric change in the association of the troponin I mobile domain with tropomyosin/actin.

Show evidence (1 reference)

PMID:39436707 SUPPORT In Vitro

"the E54K mutation appeared to act via long-range allosteric interactions to increase the association rate of the C-terminal troponin I mobile domain to tropomyosin/actin"

The proposed molecular mechanism distinguishing this DCM allele from the paired HCM allele.

💊

Medical Actions

3

Heart Failure Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: ACE inhibitor NCIT:C247

Standard heart-failure medical therapy, ACE inhibition in particular. It is not directed at the tropomyosin lesion and does not correct it, but in these families it was followed by recovery of ejection fraction in individual carriers, including one whose function improved from 39% to 55% on starting an ACE inhibitor.

Show evidence (3 references)

PMID:20117437 SUPPORT Human Clinical

"After an uncomplicated pregnancy, II-4 had mild further decline in LVEF from 48% to 39%, improving to 55% with institution of an ACE inhibitor."

A measured before-and-after in a carrier of the founding allele. Single-patient evidence, which is why the treatment is described as followed by recovery rather than as shown to cause it.

PMID:20117437 SUPPORT Human Clinical

"Cardiac studies revealed ventricular tachycardia and DCM (LVEF 25%) which improved with medical management."

Graded PARTIAL - improvement on unspecified medical management in one further carrier, with no agent named.

PMID:20117437 SUPPORT Human Clinical

"Moreover, although early presentation with DCM was typically severe, there was potential for remarkable improvement, as 3 of 5 affected infants with the TPM1 mutation had striking recovery of LV function."

Graded PARTIAL and included as a caution rather than as efficacy evidence. Infants with this allele can recover spontaneously, so an uncontrolled series cannot separate treatment effect from natural history.

Heart Transplantation

Action: heart transplantation Ontology label: Heart Transplantation NCIT:C15246

The endpoint for carriers whose heart failure becomes refractory. In these families it was reached in adolescence by a carrier who had been asymptomatic at diagnosis, which is the clearest statement of how fast the phenotype can move.

Show evidence (1 reference)

PMID:20117437 SUPPORT Human Clinical

"IV-1 was asymptomatic when diagnosed with DCM at 7 years during family screening, but developed severe HF at age 17 and underwent transplant at 18 years of age."

Documents transplantation in a carrier, and the decade-long interval between screen-detected asymptomatic disease and transplant.

Cascade Screening of At-Risk Relatives

Action: genetic screening of at-risk relatives Ontology label: Genetic Screening NCIT:C92803

Cardiac surveillance of first-degree relatives, with genetic testing where the familial variant is known. This is the intervention with the clearest rationale in TPM1-DCM: the phenotype is 80% penetrant, adults are often asymptomatic when detected, and the one carrier in these families whose course is documented from asymptomatic diagnosis onwards was found by family screening.

Show evidence (3 references)

PMID:20301486 SUPPORT Other

"Provide a basic view of genetic risk assessment of at-risk asymptomatic"

GeneReviews states risk assessment of asymptomatic relatives as one of the overview's four purposes. Quoted short because the cached GeneReviews record for this chapter holds only the front matter - the scope statement is the only assessable text in it, and the Management and Clinical Characteristics sections are not present to mine.

PMID:20117437 SUPPORT Human Clinical

"IV-1 was asymptomatic when diagnosed with DCM at 7 years during family screening, but developed severe HF at age 17 and underwent transplant at 18 years of age."

Screening detected disease a decade before it became symptomatic in this carrier, which is the concrete case for surveillance in an 80%-penetrant dominant condition.

PMID:20117437 SUPPORT Human Clinical

"These observations have implications for the management of familial DCM."

Graded PARTIAL - the authors draw a management implication from the natural history but state no protocol, so this supports screening as a direction rather than as a specified intervention.

🐁

Animal Models

1

D230N-Tm transgenic mouse

A transgenic mouse carrying the human D230N tropomyosin allele under an alpha-myosin-heavy-chain promoter, developed specifically to phenocopy the early-onset remodelling seen in the D230N families and to permit paired cellular and structural measurements in the same model.

Species

Mouse

Genotype

Heterozygous alpha-tropomyosin D230N transgenic (alpha-MHC promoter)

Genes

TPM1 hgnc:12010

Publication

PMID:28600229

Pathograph links

Systolic Dysfunction and Ventricular Dilation recapitulates fidelity: high Reproduces the early-onset systolic dysfunction of the human D230N families, with significant impairment by two months of age.

Limitations: A transgenic overexpression model driven by the alpha-MHC promoter rather than a knock-in at the endogenous locus, so the mutant-to-wild-type protein ratio is set by transgene expression rather than by heterozygosity. Since the mechanism turns on the biophysical properties of a coiled-coil that must dimerise and interdigitate, stoichiometry is not a neutral detail here.

Readouts

Left ventricular systolic function by echocardiography

Direction: DECREASED

Interpretation: Early-onset systolic dysfunction matching the human phenotype.

Show evidence (1 reference)

PMID:28600229 SUPPORT Model Organism

"The resultant mouse model strongly phenocopied the early onset of cardiomyopathic remodeling observed in patients as significant systolic dysfunction was observed by 2months of age."

The echocardiographic finding and its timing.

Show evidence (1 reference)

PMID:28600229 SUPPORT Model Organism

"To determine how a single amino acid mutation in α-tropomyosin (Tm) can lead to a highly penetrant DCM we generated a novel transgenic mouse model carrying the D230N mutation."

States the model's purpose and construction.

Decreased Myofilament Calcium Sensitivity measures fidelity: moderate Isolated myocytes from the model were used to measure calcium handling and myofilament activation, giving the reduced calcium sensitivity and raised transient amplitude.

Limitations: The authors judged these measurements to comprise complex inputs and to lack sufficient experimental resolution, which is why they turned to structural methods. The readouts are directionally informative but should not be treated as precise quantification of the myofilament defect. A readout named "Calcium sensitivity of sliding velocity" was previously curated here and has been moved off this link. That measurement is regulated in vitro motility of recombinant D230N tropomyosin - no mouse tissue is involved - so it was never a readout of this model, and its own evidence item was graded IN_VITRO, which was the tell. The sliding-velocity result is retained where it belongs, on the Decreased Myofilament Calcium Sensitivity pathophysiology node. A readout on a model link has to be a measurement made in that model, or the link overstates what the model has shown.

Readouts

Peak calcium transient amplitude in isolated myocytes

Direction: INCREASED

Interpretation: Raised calcium transients in myocytes from the model - the cell-level compensation for reduced myofilament calcium sensitivity, and the measurement that was actually made in this mouse.

Show evidence (1 reference)

PMID:28600229 SUPPORT Model Organism

"Peak amplitude Ca2+ transients were significantly increased in D230N-Tm myocytes compared to Non-Tg at baseline"

Measured in myocytes isolated from the transgenic mouse, which is what makes it a readout of this model rather than of the recombinant protein.

Rates of myocyte contraction and relaxation

Direction: INCREASED

Interpretation: Faster contraction and relaxation kinetics accompanying the raised transients, recorded in the same myocytes.

Show evidence (1 reference)

PMID:28600229 SUPPORT Model Organism

"The rates of contraction and relaxation in D230N-Tm myocytes were significantly increased compared to Non-Tg"

The paired kinetic measurement in the same isolated-myocyte experiment.

Show evidence (1 reference)

PMID:28600229 SUPPORT Model Organism

"we examined the effect of the mutation on Ca2+ handling in isolated myocytes and myofilament activation in vitro"

Establishes what the model was used to measure. Graded PARTIAL given the authors' own stated reservation about the resolution of these measurements.

{ }

Source YAML

click to show

name: Dilated Cardiomyopathy 1Y
category: Mendelian
creation_date: "2026-08-27T00:00:00Z"
synonyms:
- CMD1Y
- TPM1-related dilated cardiomyopathy
- Alpha-tropomyosin-related dilated cardiomyopathy
- Cardiomyopathy, dilated, 1Y
description: >-
  Dilated cardiomyopathy 1Y is the TPM1-related form of familial dilated cardiomyopathy.
  TPM1 encodes alpha-tropomyosin, the coiled-coil dimer that lies in the actin groove and
  acts as the gatekeeper of cross-bridge formation. Each dimer interdigitates head-to-tail
  with the next, so the thin filament is a continuous flexible cable whose azimuthal
  position - blocked, closed or open - sets whether myosin can engage actin as calcium
  rises.

  The point worth understanding is that TPM1 causes both hypertrophic and dilated
  cardiomyopathy, and the direction of the calcium-sensitivity change is what separates
  them. HCM mutations increase myofilament calcium sensitivity; DCM mutations in general
  decrease it, and additionally uncouple the effect of troponin phosphorylation on calcium
  responsiveness. This is not a difference of degree along one axis: recent work on the
  paired variants E62Q (HCM) and E54K (DCM) attributes them to different molecular events -
  reduced tropomyosin stiffness favouring the closed state in the HCM variant, versus a
  long-range allosteric change in troponin I mobile-domain association in the DCM variant.

  A curator should also know that the gene-disease validity is asymmetric. ClinGen
  classifies TPM1 for hypertrophic cardiomyopathy as Definitive but for dilated
  cardiomyopathy only as Moderate, and two independent large reappraisals of DCM gene
  validity place TPM1 in the moderate rather than definitive tier, with a suggestion that
  its contribution is concentrated in early-onset disease. TPM1-DCM is real but is not on
  the same evidential footing as LMNA or TTN.

  Phenotype extends beyond dilation. The D84N allele causes dilated and non-compaction
  cardiomyopathy in the same family, with a child diagnosed at five months who died at
  five, and MONDO lists left ventricular noncompaction among this term's parents.
disease_term:
  preferred_term: dilated cardiomyopathy 1Y
  term:
    id: MONDO:0012744
    label: dilated cardiomyopathy 1Y
parents:
- Dilated Cardiomyopathy
references:
- reference: PMID:20301486
  title: "Dilated Cardiomyopathy Overview."
  tags:
  - GeneReviews
inheritance:
- name: Autosomal dominant
  description: >-
    Autosomal dominant transmission with high but incomplete penetrance. In the two large
    multigenerational families that established the D230N allele, penetrance was reported
    at 80%.
  penetrance_percentage: "80"
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:23147248
    reference_title: "A novel alpha-tropomyosin mutation associates with dilated and non-compaction cardiomyopathy and diminishes actin binding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we present a large four-generation family in which DCM is inherited as an autosomal dominant trait."
    explanation: Autosomal dominant transmission across four generations.
  - reference: PMID:20117437
    reference_title: "Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormal cardiac dimensions and contractile parameters were identified in 16 of 20 mutation carriers, indicating a penetrance of 80% for DCM in the 2 families."
    explanation: >-
      The primary segregation study, giving the carrier count behind the 80% figure rather
      than the figure alone.
pathophysiology:
- name: TPM1 Missense Variant
  description: >-
    Single missense substitutions in alpha-tropomyosin. The disease-causing alleles are
    scattered along the coiled-coil rather than confined to one domain, and which disease
    results depends on where the substitution sits and what it does to the molecule -
    different mutations cause HCM or DCM, so the gene is not simply dose-sensitive.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: TPM1
    term:
      id: hgnc:12010
      label: TPM1
  downstream:
  - target: Altered Tropomyosin Flexibility and Actin Binding
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:24005378
    reference_title: "Alpha-tropomyosin mutations in inherited cardiomyopathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The inherited cardiac diseases hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) can both be caused by missense mutations in the TPM1 gene which encodes the thin filament regulatory protein α-tropomyosin."
    explanation: >-
      Establishes that both diseases arise from missense change in the same gene. Graded
      OTHER because this is a structure-function review synthesising biophysical and
      animal-model work rather than reporting one study type.
  - reference: PMID:24005378
    reference_title: "Alpha-tropomyosin mutations in inherited cardiomyopathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Different mutations are responsible for either HCM or DCM, suggesting that distinct changes in tropomyosin structure and function can lead to the different diseases."
    explanation: States that allele identity, not gene dosage, determines which phenotype results.
  - reference: PMID:11273725
    reference_title: "Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified two mutations that alter highly conserved residues and that, unlike hypertrophic cardiomyopathy-associated mutations, cause localized charge reversal on the surface of tropomyosin."
    explanation: >-
      The first proposal of a physical rule separating the two phenotypes - DCM alleles
      reverse surface charge, HCM alleles do not. D230N fits it, losing a charge at a
      solvent-exposed f-position residue.
  - reference: PMID:11273725
    reference_title: "Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "substitution of different amino acid residues in the same thin filament proteins is associated with the distinct phenotypes of cardiac hypertrophy or congestive heart failure"
    explanation: >-
      The same claim stated as a conclusion, and the earliest statement of the
      one-gene-two-diseases pattern this node rests on.
- name: Altered Tropomyosin Flexibility and Actin Binding
  description: >-
    The primary biophysical lesion, and it differs between alleles. D230N increases the
    thermal stability of the C-terminal end of the coiled-coil, which decreases flexibility
    at the head-to-tail overlap - the joint the filament must flex about to move around
    actin. D84N instead weakens tropomyosin's binding to actin by 25% through lost
    charge-charge interaction. Both routes compromise the same regulatory function; neither
    is a simple loss of protein.
  biological_scale: MOLECULAR
  molecular_functions:
  - preferred_term: actin binding
    modifier: DECREASED
    term:
      id: GO:0003779
      label: actin binding
  cellular_components:
  - preferred_term: striated muscle thin filament
    term:
      id: GO:0005865
      label: striated muscle thin filament
  downstream:
  - target: Decreased Myofilament Calcium Sensitivity
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:28600229
    reference_title: "The structural basis of alpha-tropomyosin linked (Asp230Asn) familial dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Measurements of the thermal unfolding of D230N-Tm vs WT-Tm revealed an increase in stability primarily affecting the C-terminus of the Tm coiled-coil."
    explanation: The structural measurement behind the reduced-flexibility mechanism.
  - reference: PMID:28600229
    reference_title: "The structural basis of alpha-tropomyosin linked (Asp230Asn) familial dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the D230N-Tm mutation induces a decrease in flexibility of the C-terminus via propagation through the helical structure of the protein, thus decreasing the flexibility of the Tm overlap and impairing its ability to regulate contraction"
    explanation: States the allosteric propagation from the substituted residue to the overlap region.
  - reference: PMID:23147248
    reference_title: "A novel alpha-tropomyosin mutation associates with dilated and non-compaction cardiomyopathy and diminishes actin binding."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The TPM1 p.D84N was the only mutation identified. The mutation co-segregates with all clinically affected family members and significantly weakens the binding of tropomyosin to actin by 25%."
    explanation: >-
      The alternative biophysical route - quantified loss of actin binding rather than
      altered flexibility.
- name: Decreased Myofilament Calcium Sensitivity
  description: >-
    The functional consequence that defines the DCM direction. Across TPM1 alleles, DCM
    mutations generally decrease myofilament calcium sensitivity while HCM mutations
    increase it, and DCM mutations additionally uncouple troponin phosphorylation from
    calcium responsiveness - so the heart loses not only sensitivity but the ability to
    modulate it. In the D230N mouse the reduced calcium sensitivity of sliding velocity is
    accompanied by an increased peak amplitude of the calcium transient, which reads as
    compensation: the cell raises calcium because the filament responds to it less.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: regulation of cardiac muscle contraction by calcium ion signaling
    modifier: DECREASED
    term:
      id: GO:0010882
      label: regulation of cardiac muscle contraction by calcium ion signaling
  downstream:
  - target: Systolic Dysfunction and Ventricular Dilation
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:24005378
    reference_title: "Alpha-tropomyosin mutations in inherited cardiomyopathies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The latter changes have been found to be particularly consistent, with HCM mutations increasing Ca(2+) sensitivity and DCM mutations in general decreasing this parameter and uncoupling the effect of troponin phosphorylation upon Ca(2+) responsiveness."
    explanation: >-
      The central directional claim separating TPM1-HCM from TPM1-DCM, described by the
      review as the most consistent of the reported effects.
  - reference: PMID:28600229
    reference_title: "The structural basis of alpha-tropomyosin linked (Asp230Asn) familial dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "D230N-Tm filaments exhibited a reduced Ca2+ sensitivity of sliding velocity. This decrease in sensitivity was coupled to increase in the peak amplitude of Ca2+ transients."
    explanation: Direct measurement of both the reduced sensitivity and the compensatory calcium transient.
  - reference: PMID:20117437
    reference_title: "Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In vitro studies demonstrated major inhibitory effects on sarcomere function with reduced Ca(2+) sensitivity, maximum activation, and Ca(2+) affinity compared with wild-type TPM1."
    explanation: >-
      The reconstituted-thin-filament measurements themselves, from the study that made
      them, across three related biophysical parameters.
  - reference: PMID:28600229
    reference_title: "The structural basis of alpha-tropomyosin linked (Asp230Asn) familial dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "While significant, and consistent with other DCMs, these measurements are comprised of complex inputs and did not provide sufficient experimental resolution."
    explanation: >-
      Graded PARTIAL and included deliberately - the authors themselves judged the calcium
      measurements insufficiently resolved, which is why they went on to the structural
      work. The calcium change is real but is not the whole account.
- name: Systolic Dysfunction and Ventricular Dilation
  description: >-
    The organ-level endpoint: reduced ejection fraction with left ventricular enlargement.
    In the D230N transgenic mouse significant systolic dysfunction is present by two months
    of age, phenocopying the early onset seen in the families.
  biological_scale: ORGANISM
  locations:
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:20117437
    reference_title: "Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Abnormal cardiac dimensions and contractile parameters were identified in 16 of 20 mutation carriers, indicating a penetrance of 80% for DCM in the 2 families."
    explanation: >-
      The human phenotype the mechanism must explain - abnormal chamber dimensions and
      contractility in most carriers.
  - reference: PMID:23147248
    reference_title: "A novel alpha-tropomyosin mutation associates with dilated and non-compaction cardiomyopathy and diminishes actin binding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dilated cardiomyopathy (DCM) is characterized by idiopathic dilatation and systolic contractile dysfunction of the ventricle(s) leading to an impaired systolic function."
    explanation: Defines the clinical endpoint of the pathograph.
phenotypes:
- name: Dilated Cardiomyopathy
  category: Cardiovascular
  description: Left ventricular dilation with systolic dysfunction, the defining phenotype.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:20117437
    reference_title: "Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TPM1 D230N segregated with DCM in 2 large unrelated families."
    explanation: The segregation evidence establishing TPM1 as a DCM gene.
- name: Reduced Left Ventricular Ejection Fraction
  category: Cardiovascular
  description: Reduced ejection fraction, the functional correlate of the systolic dysfunction.
  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:20117437
    reference_title: "Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two siblings, IV-5 and IV-8, presented with DCM and advanced HF at 5 months of age (LVEF 27% and 29%), and were given the presumptive diagnosis of myocarditis."
    explanation: >-
      Measured ejection fractions in affected carriers. The misdiagnosis as myocarditis is
      quoted with them because it is how the phenotype presents before the family history
      is known.
- name: Left Ventricular Noncompaction
  category: Cardiovascular
  description: >-
    Noncompaction cardiomyopathy, described with the D84N allele in the same family as
    dilated cardiomyopathy. MONDO lists left ventricular noncompaction among this term's
    parents, so the overlap is recognised at the ontology level as well as clinically.
  frequency: OCCASIONAL
  phenotype_term:
    preferred_term: Left ventricular noncompaction
    term:
      id: HP:0030682
      label: Left ventricular noncompaction
  evidence:
  - reference: PMID:23147248
    reference_title: "A novel alpha-tropomyosin mutation associates with dilated and non-compaction cardiomyopathy and diminishes actin binding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show that a mutation in TPM1 is associated with DCM and a lethal, early onset form of NCCM, probably as a result of diminished actin binding caused by weakened charge-charge interactions."
    explanation: >-
      Establishes the DCM/noncompaction overlap for TPM1 and attributes it to the same
      actin-binding defect.
  - reference: PMID:23147248
    reference_title: "A novel alpha-tropomyosin mutation associates with dilated and non-compaction cardiomyopathy and diminishes actin binding."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The youngest affected was diagnosed with dilated and non-compaction cardiomyopathy (NCCM) and died at the age of five."
    explanation: The index noncompaction case, showing both phenotypes in one individual.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    Decompensated heart failure, the clinical syndrome the systolic dysfunction produces.
    In the D230N families it was the presenting problem in those who presented early in
    life, and the route to death or transplantation.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  notes: >-
    Graded FREQUENT rather than VERY_FREQUENT because the same cohort describes adults
    diagnosed on family screening with asymptomatic left ventricular dysfunction, who by
    definition were not in heart failure. The phenotype is age-dependent within the family.
  evidence:
  - reference: PMID:20117437
    reference_title: "Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical manifestations ranged from decompensated heart failure or sudden death in those presenting early in life to asymptomatic left ventricular dysfunction in those diagnosed during adulthood."
    explanation: >-
      Both the presence of heart failure and the reason it is not graded universal - the
      same sentence gives the asymptomatic adult end of the range.
  - reference: PMID:20117437
    reference_title: "Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Presentation early in life, from infancy to adolescence, was not uncommon and was associated with severe, sometimes lethal outcomes, including SCD and refractory HF leading to death or transplantation."
    explanation: The severity of the heart failure when it occurs, and its endpoints.
genetic:
- name: TPM1
  notes: >-
    TPM1 encodes alpha-tropomyosin, a coiled-coil thin filament regulatory protein. The
    gene-disease validity is asymmetric between the two cardiomyopathies it causes:
    ClinGen classifies TPM1 as Definitive for hypertrophic cardiomyopathy but only
    Moderate for dilated cardiomyopathy. Two independent large reappraisals reach the same
    tier, one of them suggesting the TPM1 contribution to DCM may be concentrated in
    early-onset disease. Interpret a TPM1 variant reported in an adult DCM patient with
    that asymmetry in mind. The ClinGen TPM1/hypertrophic-cardiomyopathy Definitive
    assertion is deliberately not among this record's evidence items: it is a validity
    assertion for a different disease, so on a TPM1-DCM gene record any consumer
    aggregating the evidence list would count it as positive support for exactly the
    relationship this entry qualifies as only Moderate. It is curated in the
    tpm1_dcm_gene_validity_asymmetry discussion, where the asymmetry is the claim.
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: TPM1
    term:
      id: hgnc:12010
      label: TPM1
  evidence:
  - reference: CGGV:assertion_1173d239-23cf-4c9c-9ea5-f95d9356e6c7-2025-04-04T160000.000Z
    reference_title: "TPM1 / dilated cardiomyopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TPM1 | HGNC:12010 | dilated cardiomyopathy | MONDO:0005021 | AD | Moderate"
    explanation: >-
      ClinGen's current gene-disease validity classification for TPM1 in dilated
      cardiomyopathy is Moderate, not Definitive. Graded PARTIAL because that is exactly
      what a moderate classification asserts - real but not fully established.
  - reference: PMID:33947203
    reference_title: "Evidence-Based Assessment of Genes in Dilated Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Seven genes (14%; ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including 2 additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence."
    explanation: >-
      Independent expert-panel curation placing TPM1 in the moderate tier for DCM, with the
      panel's own expectation that it will strengthen.
  - reference: PMID:31983221
    reference_title: "Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants in MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1, and VCL were significantly enriched in specific patient subsets, with the last 2 genes potentially contributing primarily to early-onset forms of DCM."
    explanation: >-
      Case-control burden analysis showing TPM1 enrichment is restricted to specific
      patient subsets rather than DCM at large.
  variants:
  - name: D230N
    description: >-
      The allele that defined this disease entity, identified by segregation in two large
      unrelated multigenerational families with severe, often early-onset DCM at 80%
      penetrance. It substitutes asparagine for aspartic acid at a solvent-exposed
      f-position residue near the C-terminus, losing a charge.
    evidence:
    - reference: PMID:20117437
      reference_title: "Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Unlike previously reported TPM1 variants (E45K E40K) associated with DCM in isolated individuals (7), we demonstrate that dominant transmission of TPM1 D230N segregates with disease and deleteriously impacts in vitro assays of contractility, providing definitive evidence that TPM1 mutations cause DCM."
      explanation: >-
        Identifies the founding allele and states what distinguishes it from the earlier
        single-patient TPM1 reports - dominant segregation, not just co-occurrence.
    - reference: PMID:20117437
      reference_title: "Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Presentation early in life, from infancy to adolescence, was not uncommon and was associated with severe, sometimes lethal outcomes, including SCD and refractory HF leading to death or transplantation."
      explanation: The clinical severity of the allele, from the study that ascertained the families.
  - name: D84N
    description: >-
      Causes dilated and non-compaction cardiomyopathy in a four-generation family, acting
      by weakening actin binding rather than by altering coiled-coil flexibility.
    evidence:
    - reference: PMID:23147248
      reference_title: "A novel alpha-tropomyosin mutation associates with dilated and non-compaction cardiomyopathy and diminishes actin binding."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We mapped the phenotype to chromosome 15 and subsequently identified a missense mutation in TPM1, resulting in a p.D84N amino acid substitution."
      explanation: Identification of the D84N allele by linkage and sequencing.
  - name: K30E
    description: >-
      A de novo allele in a proband with DCM and left ventricular non-compaction who
      reached terminal heart failure before four years of age. The only reported de novo
      TPM1 variant in this entry, and the clearest evidence that a single TPM1 substitution
      is sufficient to cause paediatric DCM without a transmitted family history.
    evidence:
    - reference: PMID:39684770
      reference_title: "Novel Mutation Lys30Glu in the TPM1 Gene Leads to Pediatric Left Ventricular Non-Compaction and Dilated Cardiomyopathy via Impairment of Structural and Functional Properties of Cardiac Tropomyosin."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We identified a novel de novo variant, c.88A>G (p.Lys30Glu, K30E), in the TPM1 gene encoding the major cardiac muscle tropomyosin (Tpm) isoform, Tpm1.1."
      explanation: Identifies the allele and establishes that it arose de novo.
    - reference: PMID:39684770
      reference_title: "Novel Mutation Lys30Glu in the TPM1 Gene Leads to Pediatric Left Ventricular Non-Compaction and Dilated Cardiomyopathy via Impairment of Structural and Functional Properties of Cardiac Tropomyosin."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The variant was found in a proband with DCM and left ventricular non-compaction who progressed to terminal heart failure at the age of 3 years and 8 months."
      explanation: >-
        The clinical course, and the second TPM1 allele in this entry to combine dilated
        cardiomyopathy with non-compaction.
    - reference: PMID:39684770
      reference_title: "Novel Mutation Lys30Glu in the TPM1 Gene Leads to Pediatric Left Ventricular Non-Compaction and Dilated Cardiomyopathy via Impairment of Structural and Functional Properties of Cardiac Tropomyosin."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The K30E substitution decreased the thermal stability of Tpm and its complex with actin and significantly reduced the sliding velocity of the regulated thin filaments over a surface covered by ovine cardiac myosin in an in vitro motility assay across the entire physiological range of Ca2+ concentration."
      explanation: >-
        Functional confirmation on the same two axes the D230N work uses - thermal
        stability of the coiled-coil and thin-filament sliding velocity - which is what
        makes the two alleles mechanistically comparable.
  - name: E114Q
    description: >-
      A heterozygous missense allele in exon 3, reported in a Chinese Han family with DCM.
      Curated as an allele-spectrum entry: the report establishes the substitution and the
      family, but performs no functional assay, so no mechanism is asserted for it.
    evidence:
    - reference: PMID:35029218
      reference_title: "Identification of a novel missense mutation in the TPM1 gene via exome sequencing in a Chinese family with dilated cardiomyopathy: A case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This novel heterozygous mutation results in the substitution of glutamic acid with glutamine (p.E114Q)."
      explanation: Identifies the allele and its zygosity.
    - reference: PMID:35029218
      reference_title: "Identification of a novel missense mutation in the TPM1 gene via exome sequencing in a Chinese family with dilated cardiomyopathy: A case report and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "A Chinese Han family with DCM phenotypes was examined."
      explanation: >-
        Graded PARTIAL - a single family with no segregation statistics or functional work,
        which is the level of evidence this allele currently rests on.
  - name: M8R
    description: >-
      A DCM-linked allele near the tropomyosin N-terminus, studied end to end from atomistic
      simulation through a Markov thin-filament model to human engineered heart tissue. It
      reaches the same hypocontractile endpoint as D230N by a different molecular route -
      by favouring the blocked state of tropomyosin on actin rather than by stiffening the
      overlap region.
    evidence:
    - reference: PMID:39282088
      reference_title: "In silico and in vitro models reveal the molecular mechanisms of hypocontractility caused by TPM1 M8R."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "Atomistic simulations predict that M8R increases flexibility of the tropomyosin chain and enhances affinity for the blocked or inactive state of tropomyosin on actin."
      explanation: >-
        The predicted molecular mechanism. Note the direction is opposite to D230N, which
        decreases flexibility - so increased and decreased chain flexibility can both give
        a dilated phenotype, and flexibility alone is not the discriminator.
    - reference: PMID:39282088
      reference_title: "In silico and in vitro models reveal the molecular mechanisms of hypocontractility caused by TPM1 M8R."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The mutant tissues manifested depressed contractility and twitch duration that agreed in detail with model predictions."
      explanation: >-
        Experimental confirmation in human engineered heart tissue, which is what lifts this
        above a purely computational claim.
  - name: E40K and E45K
    description: >-
      The earliest reported TPM1 alleles associated with dilated cardiomyopathy, found in
      isolated individuals rather than in segregating families. Curated to record why TPM1
      pathogenicity in DCM was considered unproven until D230N: the alleles existed, but
      without transmission data.
    evidence:
    - reference: PMID:20117437
      reference_title: "Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Unlike previously reported TPM1 variants (E45K E40K) associated with DCM in isolated individuals (7), we demonstrate that dominant transmission of TPM1 D230N segregates with disease and deleteriously impacts in vitro assays of contractility, providing definitive evidence that TPM1 mutations cause DCM."
      explanation: >-
        Graded PARTIAL because the sentence names these alleles in order to say their
        evidence was weaker - association in single individuals without segregation.
  - name: E54K
    description: >-
      A DCM-associated allele used as the comparator against the HCM allele E62Q in
      mechanistic work. Modelled as acting through long-range allosteric change in the
      association of the troponin I mobile domain with tropomyosin/actin.
    evidence:
    - reference: PMID:39436707
      reference_title: "Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy-associated TPM1 variants."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the E54K mutation appeared to act via long-range allosteric interactions to increase the association rate of the C-terminal troponin I mobile domain to tropomyosin/actin"
      explanation: The proposed molecular mechanism distinguishing this DCM allele from the paired HCM allele.
treatments:
- name: Heart Failure Pharmacotherapy
  description: >-
    Standard heart-failure medical therapy, ACE inhibition in particular. It is not
    directed at the tropomyosin lesion and does not correct it, but in these families it
    was followed by recovery of ejection fraction in individual carriers, including one
    whose function improved from 39% to 55% on starting an ACE inhibitor.
  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
  evidence:
  - reference: PMID:20117437
    reference_title: "Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After an uncomplicated pregnancy, II-4 had mild further decline in LVEF from 48% to 39%, improving to 55% with institution of an ACE inhibitor."
    explanation: >-
      A measured before-and-after in a carrier of the founding allele. Single-patient
      evidence, which is why the treatment is described as followed by recovery rather
      than as shown to cause it.
  - reference: PMID:20117437
    reference_title: "Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac studies revealed ventricular tachycardia and DCM (LVEF 25%) which improved with medical management."
    explanation: >-
      Graded PARTIAL - improvement on unspecified medical management in one further
      carrier, with no agent named.
  - reference: PMID:20117437
    reference_title: "Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, although early presentation with DCM was typically severe, there was potential for remarkable improvement, as 3 of 5 affected infants with the TPM1 mutation had striking recovery of LV function."
    explanation: >-
      Graded PARTIAL and included as a caution rather than as efficacy evidence. Infants
      with this allele can recover spontaneously, so an uncontrolled series cannot
      separate treatment effect from natural history.
- name: Heart Transplantation
  description: >-
    The endpoint for carriers whose heart failure becomes refractory. In these families it
    was reached in adolescence by a carrier who had been asymptomatic at diagnosis, which
    is the clearest statement of how fast the phenotype can move.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  evidence:
  - reference: PMID:20117437
    reference_title: "Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IV-1 was asymptomatic when diagnosed with DCM at 7 years during family screening, but developed severe HF at age 17 and underwent transplant at 18 years of age."
    explanation: >-
      Documents transplantation in a carrier, and the decade-long interval between
      screen-detected asymptomatic disease and transplant.
- name: Cascade Screening of At-Risk Relatives
  description: >-
    Cardiac surveillance of first-degree relatives, with genetic testing where the familial
    variant is known. This is the intervention with the clearest rationale in TPM1-DCM: the
    phenotype is 80% penetrant, adults are often asymptomatic when detected, and the one
    carrier in these families whose course is documented from asymptomatic diagnosis
    onwards was found by family screening.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: genetic screening of at-risk relatives
    term:
      id: NCIT:C92803
      label: Genetic Screening
  evidence:
  - 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"
    explanation: >-
      GeneReviews states risk assessment of asymptomatic relatives as one of the overview's
      four purposes. Quoted short because the cached GeneReviews record for this chapter
      holds only the front matter - the scope statement is the only assessable text in it,
      and the Management and Clinical Characteristics sections are not present to mine.
  - reference: PMID:20117437
    reference_title: "Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IV-1 was asymptomatic when diagnosed with DCM at 7 years during family screening, but developed severe HF at age 17 and underwent transplant at 18 years of age."
    explanation: >-
      Screening detected disease a decade before it became symptomatic in this carrier,
      which is the concrete case for surveillance in an 80%-penetrant dominant condition.
  - reference: PMID:20117437
    reference_title: "Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These observations have implications for the management of familial DCM."
    explanation: >-
      Graded PARTIAL - the authors draw a management implication from the natural history
      but state no protocol, so this supports screening as a direction rather than as a
      specified intervention.
animal_models:
- name: D230N-Tm transgenic mouse
  species: Mouse
  genotype: Heterozygous alpha-tropomyosin D230N transgenic (alpha-MHC promoter)
  publication: PMID:28600229
  description: >-
    A transgenic mouse carrying the human D230N tropomyosin allele under an
    alpha-myosin-heavy-chain promoter, developed specifically to phenocopy the early-onset
    remodelling seen in the D230N families and to permit paired cellular and structural
    measurements in the same model.
  genes:
  - preferred_term: TPM1
    term:
      id: hgnc:12010
      label: TPM1
  modeled_mechanisms:
  - target: Systolic Dysfunction and Ventricular Dilation
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Reproduces the early-onset systolic dysfunction of the human D230N families, with
      significant impairment by two months of age.
    limitations: >-
      A transgenic overexpression model driven by the alpha-MHC promoter rather than a
      knock-in at the endogenous locus, so the mutant-to-wild-type protein ratio is set by
      transgene expression rather than by heterozygosity. Since the mechanism turns on the
      biophysical properties of a coiled-coil that must dimerise and interdigitate,
      stoichiometry is not a neutral detail here.
    readouts:
    - name: Left ventricular systolic function by echocardiography
      target: Systolic Dysfunction and Ventricular Dilation
      direction: DECREASED
      interpretation: Early-onset systolic dysfunction matching the human phenotype.
      evidence:
      - reference: PMID:28600229
        reference_title: "The structural basis of alpha-tropomyosin linked (Asp230Asn) familial dilated cardiomyopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The resultant mouse model strongly phenocopied the early onset of cardiomyopathic remodeling observed in patients as significant systolic dysfunction was observed by 2months of age."
        explanation: The echocardiographic finding and its timing.
    evidence:
    - reference: PMID:28600229
      reference_title: "The structural basis of alpha-tropomyosin linked (Asp230Asn) familial dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "To determine how a single amino acid mutation in α-tropomyosin (Tm) can lead to a highly penetrant DCM we generated a novel transgenic mouse model carrying the D230N mutation."
      explanation: States the model's purpose and construction.
  - target: Decreased Myofilament Calcium Sensitivity
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Isolated myocytes from the model were used to measure calcium handling and myofilament
      activation, giving the reduced calcium sensitivity and raised transient amplitude.
    limitations: >-
      The authors judged these measurements to comprise complex inputs and to lack
      sufficient experimental resolution, which is why they turned to structural methods.
      The readouts are directionally informative but should not be treated as precise
      quantification of the myofilament defect.

      A readout named "Calcium sensitivity of sliding velocity" was previously curated here
      and has been moved off this link. That measurement is regulated in vitro motility of
      recombinant D230N tropomyosin - no mouse tissue is involved - so it was never a
      readout of this model, and its own evidence item was graded IN_VITRO, which was the
      tell. The sliding-velocity result is retained where it belongs, on the Decreased
      Myofilament Calcium Sensitivity pathophysiology node. A readout on a model link has to
      be a measurement made in that model, or the link overstates what the model has shown.
    readouts:
    - name: Peak calcium transient amplitude in isolated myocytes
      target: Decreased Myofilament Calcium Sensitivity
      direction: INCREASED
      interpretation: >-
        Raised calcium transients in myocytes from the model - the cell-level compensation
        for reduced myofilament calcium sensitivity, and the measurement that was actually
        made in this mouse.
      evidence:
      - reference: PMID:28600229
        reference_title: "The structural basis of alpha-tropomyosin linked (Asp230Asn) familial dilated cardiomyopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Peak amplitude Ca2+ transients were significantly increased in D230N-Tm myocytes compared to Non-Tg at baseline"
        explanation: >-
          Measured in myocytes isolated from the transgenic mouse, which is what makes it a
          readout of this model rather than of the recombinant protein.
    - name: Rates of myocyte contraction and relaxation
      target: Decreased Myofilament Calcium Sensitivity
      direction: INCREASED
      interpretation: >-
        Faster contraction and relaxation kinetics accompanying the raised transients,
        recorded in the same myocytes.
      evidence:
      - reference: PMID:28600229
        reference_title: "The structural basis of alpha-tropomyosin linked (Asp230Asn) familial dilated cardiomyopathy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The rates of contraction and relaxation in D230N-Tm myocytes were significantly increased compared to Non-Tg"
        explanation: The paired kinetic measurement in the same isolated-myocyte experiment.
    evidence:
    - reference: PMID:28600229
      reference_title: "The structural basis of alpha-tropomyosin linked (Asp230Asn) familial dilated cardiomyopathy."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "we examined the effect of the mutation on Ca2+ handling in isolated myocytes and myofilament activation in vitro"
      explanation: >-
        Establishes what the model was used to measure. Graded PARTIAL given the authors'
        own stated reservation about the resolution of these measurements.
discussions:
- discussion_id: tpm1_dcm_gene_validity_asymmetry
  kind: KNOWLEDGE_GAP
  prompt: >-
    Is TPM1-DCM a distinct disease entity, or is the moderate ClinGen classification
    telling us that some reported TPM1 DCM variants will not survive re-curation?
  attaches_to:
  - genetic#TPM1
  - disease#Dilated Cardiomyopathy 1Y
  rationale: >-
    The evidence here is genuinely split and a curator should not paper over it. On one
    side, two large multigenerational families with linkage, 80% penetrance, a transgenic
    mouse that phenocopies the early-onset disease, and a coherent biophysical mechanism -
    that is a strong case for D230N specifically. On the other, ClinGen rates TPM1-DCM
    Moderate while rating TPM1-HCM Definitive, an expert panel places it in the moderate
    tier, and a case-control burden study finds enrichment only in specific patient
    subsets, possibly confined to early-onset disease. The likeliest reconciliation is that
    a small number of well-supported alleles are genuinely causative while the gene as a
    whole has been over-called in adult DCM panels, which would predict that a variant-level
    rather than gene-level re-curation resolves the discrepancy. Practically, this matters
    for how much weight a TPM1 variant of uncertain significance should carry in an adult
    DCM workup.
  evidence:
  - reference: CGGV:assertion_1173d239-23cf-4c9c-9ea5-f95d9356e6c7-2025-04-04T160000.000Z
    reference_title: "TPM1 / dilated cardiomyopathy (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TPM1 | HGNC:12010 | dilated cardiomyopathy | MONDO:0005021 | AD | Moderate"
    explanation: The current ClinGen classification, which is the substance of the gap.
  - reference: CGGV:assertion_32e7ed58-ee49-4719-b48e-7fad58012319-2023-12-18T170000.000Z
    reference_title: "TPM1 / hypertrophic cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TPM1 | HGNC:12010 | hypertrophic cardiomyopathy | MONDO:0005045 | AD | Definitive"
    explanation: >-
      The other half of the asymmetry, and it belongs here rather than on the gene record.
      On the TPM1-DCM gene record it was evidence for a different disease and could only
      mislead an aggregator; here the asymmetry itself is the claim, so a Definitive
      classification for HCM alongside a Moderate one for DCM is direct SUPPORT for the
      question this discussion poses.
  - reference: PMID:31983221
    reference_title: "Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants in MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1, and VCL were significantly enriched in specific patient subsets, with the last 2 genes potentially contributing primarily to early-onset forms of DCM."
    explanation: >-
      The subset-restricted enrichment that supports a narrower, early-onset role rather
      than a general adult DCM gene.
  - reference: PMID:20117437
    reference_title: "Familial dilated cardiomyopathy caused by an alpha-tropomyosin mutation: the distinctive natural history of sarcomeric dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Unlike previously reported TPM1 variants (E45K E40K) associated with DCM in isolated individuals (7), we demonstrate that dominant transmission of TPM1 D230N segregates with disease and deleteriously impacts in vitro assays of contractility, providing definitive evidence that TPM1 mutations cause DCM."
    explanation: >-
      The counterweight - allele-level evidence for D230N is strong, which is why the gap
      is about gene-level over-calling rather than about whether TPM1-DCM exists.
- discussion_id: tpm1_pseudophosphorylation_rescue
  kind: KNOWLEDGE_GAP
  prompt: >-
    Can tropomyosin pseudo-phosphorylation rescue TPM1 cardiomyopathy mutations in a whole
    heart, given that the same modification is itself cardiomyopathic when overexpressed?
  attaches_to:
  - pathophysiology#Altered Tropomyosin Flexibility and Actin Binding
  rationale: >-
    Two results sit awkwardly together. In vitro, the phosphomimetic substitutions S283D
    and S61D reduce or eliminate the abnormal actin affinity caused by cardiomyopathy
    mutations, which the authors propose as a rescue strategy. But a transgenic mouse
    highly expressing the S283D phosphomimetic develops severe dilated cardiomyopathy and
    dies within a month, and even moderate expression causes myocyte hypertrophy and
    fibrosis with impaired diastolic function. So the modification that normalises a
    biophysical parameter in a test tube is itself pathogenic in a heart at high dose.
    The unresolved question is whether there is a therapeutic window - a level of
    phosphorylation high enough to correct the mutant filament but below the threshold at
    which it causes disease on its own - or whether the in vitro rescue simply does not
    translate. Notably the mouse showed no change in myofilament calcium sensitivity, so
    the actin-affinity correction and the whole-heart phenotype may not be connected at
    all.
  evidence:
  - reference: PMID:33129908
    reference_title: "Tropomyosin pseudo-phosphorylation can rescue the effects of cardiomyopathy-associated mutations."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The results indicate that Tpm pseudo-phosphorylation by mutations S283D or S61D can rescue the effects of mutations in the TPM1 gene encoding a cardiac isoform of Tpm that lead to the development of such severe inherited heart diseases as hypertrophic or dilated cardiomyopathies."
    explanation: The in vitro rescue claim.
  - reference: PMID:30567734
    reference_title: "Tropomyosin pseudo-phosphorylation results in dilated cardiomyopathy."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "High expression of Tpm S283D variant in one transgenic mouse line resulted in an increased heart:body weight ratio, coupled with a severe dilated cardiomyopathic phenotype resulting in death within 1 month of birth."
    explanation: >-
      Graded REFUTE against the rescue proposal as a therapeutic strategy - the same
      modification causes lethal DCM in vivo at high expression.
  - reference: PMID:30567734
    reference_title: "Tropomyosin pseudo-phosphorylation results in dilated cardiomyopathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Surprisingly, we observed no alterations in calcium sensitivity of the myofibers, cooperativity, or calcium-ATPase activity in the myofibers."
    explanation: >-
      Shows the in vivo phenotype is not mediated by the calcium-sensitivity axis, which
      weakens the link between the in vitro actin-affinity correction and any whole-heart
      benefit.

📚

References & Deep Research

References

1

PMID:20301486

Dilated Cardiomyopathy Overview.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

Dilated Cardiomyopathy 1Y (CMD1Y / TPM1-Related Dilated Cardiomyopathy): Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 12 citations 2026-08-27T14:44:35.421562

Dilated Cardiomyopathy 1Y (CMD1Y / TPM1-Related Dilated Cardiomyopathy): Comprehensive Research Report

1. Disease Information

Overview. Dilated Cardiomyopathy 1Y (CMD1Y) is a monogenic, autosomal dominant subtype of primary/familial dilated cardiomyopathy (DCM) caused by heterozygous missense mutations in TPM1 (alpha-tropomyosin, tropomyosin-1), the gene encoding the major sarcomeric thin-filament protein that co-regulates calcium-dependent actin–myosin interaction with the troponin complex. The disease is characterized by left ventricular (and often biventricular) dilation with impaired systolic contractile function, leading to progressive congestive heart failure; some reported patients died in the third to sixth decades of life OMIM #611878. Ultrastructurally, electron microscopy of affected myocardium shows abnormal sarcomere structure OMIM #611878.

Key identifiers: - OMIM (phenotype): #611878 — CARDIOMYOPATHY, DILATED, 1Y; CMD1Y - OMIM (gene): 191010 — TROPOMYOSIN 1; TPM1 - HGNC: 12010 (TPM1) — thegencc.org/genes/HGNC:12010 - UniProt: P09493 (tropomyosin alpha-1 chain) - Locus: 15q22.1–q22.2 - MedGen: C2678476 — MedGen C2678476 / NIH GTR - Orphanet (broader entity): ORPHA:154 — Familial isolated dilated cardiomyopathy - Related MONDO/parent concept: primary/idiopathic dilated cardiomyopathy, MONDO:0005021 - Allelic disorders at the same TPM1 locus:* Familial Hypertrophic Cardiomyopathy 3 (HCM3), Left Ventricular Noncompaction 9 (LVNC9), and CMD1E (an earlier-numbered TPM1-linked DCM designation, illustrating that TPM1 maps to more than one historical CMD1x sub-label)

Synonyms/alternative names: Cardiomyopathy, dilated, 1Y; CMD1Y; TPM1-related dilated cardiomyopathy; alpha-tropomyosin cardiomyopathy; DCM type 1Y (DCM1Y).

Evidence basis: This entry is derived almost entirely from aggregated case-level and small-pedigree reports (individual families and probands identified through linkage analysis, targeted Sanger sequencing, or next-generation sequencing panels) rather than large disease registries — reflecting the rarity of TPM1-DCM as a cause of DCM overall. Functional/mechanistic characterization comes from in vitro biochemical, biophysical, and iPSC-cardiomyocyte/computational studies of specific variants.

2. Etiology

Disease-causal factor. CMD1Y is caused by heterozygous missense mutations in TPM1 on chromosome 15q22.1, inherited in an autosomal dominant pattern OMIM #611878. Approximately 30 distinct TPM1 variants have been reported in association with DCM1Y to date (per aggregated literature review) PMC8758022.

Genetic risk factors: - Causal missense variants cluster across the coiled-coil tropomyosin rod domain and disrupt either (a) surface charge distribution affecting actin binding, or (b) allosteric communication with the troponin complex. - Documented pathogenic/likely pathogenic DCM-causing TPM1 variants include: - E40K and E54K — the founding CMD1Y mutations, identified by Olson et al. via linkage analysis of two DCM pedigrees; described as altering the surface charge of alpha-tropomyosin (PMID: 11273725, J Mol Cell Cardiol, 2001). - D230N (Asp230Asn) — identified in two Caucasian probands and segregating with disease in 14 affected relatives; structural basis characterized by X-ray/biophysical study (PMID: 28600229); ClinVar RCV000036354. - M8R (Met8Arg) — DCM/LVNC-associated variant with in silico and in vitro modeling of hypocontractility mechanism (PMC11392859); ClinVar RCV000036318. - K30E (Lys30Glu) — de novo variant causing severe pediatric DCM with LV noncompaction; destabilizes the N-terminal tropomyosin domain (PMID: 39684770, 2024). - E114Q — novel missense variant (c.340G>C) identified in a Chinese Han family, segregating with maternal death from DCM at age 50 (PMID: 35029218, 2022). - T237S — reported as likely pathogenic in a DCM proband. - E62Q is the classic HCM-causing (not DCM) TPM1 variant, useful as a mechanistic contrast (see Section 6). - Allele frequency: DCM-causing TPM1 variants are absent or present at extremely low frequency in population reference databases (gnomAD), consistent with pathogenicity and highly penetrant dominant disease; TPM1 as a whole gene shows constraint against missense variation in its functional (coiled-coil) domains. - Modifier genes: No validated CMD1Y-specific modifier genes are established; general DCM modifier/second-hit loci (e.g., titin truncating variants) may exacerbate phenotype in digenic contexts, as recognized broadly in the DCM genetics literature (PMC4288017, "Genetic Causes of Dilated Cardiomyopathy").

Environmental/other risk factors: No disease-specific environmental triggers are established for CMD1Y; as with other genetic DCM, generic stressors that unmask or accelerate cardiomyopathy (pregnancy, alcohol, cardiotoxic chemotherapy, viral myocarditis, tachyarrhythmia) may in principle act as second hits, but this has not been specifically documented for TPM1 carriers in the literature reviewed.

Protective factors: None specifically documented for TPM1/CMD1Y.

Gene–environment interactions: Not specifically characterized for this subtype in the literature surveyed.

3. Phenotypes

Because DCM1Y is a form of DCM, its phenotype overlaps substantially with nonsyndromic/idiopathic DCM, with variable severity and age of onset reported across pedigrees — from neonatal-onset lethal disease (K30E case, onset at 2 weeks of life) to adult-onset disease with death in the third–sixth decades OMIM #611878.

Phenotype	Suggested HPO term	Notes
Dilated cardiomyopathy	HP:0001644	Core defining feature; LV (and often RV) chamber enlargement with reduced ejection fraction
Left ventricular dilation	HP:0002944 (or related LV dilation term)	Documented on echocardiography (e.g., LVEDD 33.6 mm/m² in E114Q case)
Reduced left ventricular ejection fraction	HP:0012664 (Decreased left ventricular ejection fraction)	EF 43.1% (E114Q, adult-onset), EF 20% (K30E, pediatric/severe)
Congestive heart failure	HP:0001635	Progressive; presenting symptom in most reported cases (dyspnea, chest tightness, abdominal distension/edema)
Cardiomegaly	HP:0001712	On physical exam/imaging
Sinus tachycardia	HP:0011703	e.g., HR 113 bpm in the E114Q proband
Left ventricular noncompaction	HP:0030702 (or "Left ventricular noncompaction cardiomyopathy")	Overlaps with the allelic LVNC9 phenotype; co-occurs with DCM in some TPM1 mutation carriers (K30E, M8R)
Cyanosis (infantile presentation)	HP:0000961	Reported in the neonatal-onset K30E case
Hypotonia (infantile)	HP:0001252	Reported in the neonatal-onset K30E case
Sudden cardiac death	HP:0001645	Risk in undiagnosed/advanced disease, as in general DCM
Abnormal sarcomere morphology	(no precise HPO term; describe via ultrastructural finding)	Seen on electron microscopy of myocardium OMIM #611878

Onset/severity/progression: Highly variable — reported onset spans neonatal to adult; disease course is generally progressive, with several reported deaths from heart failure ranging from early childhood (age 3 years 8 months, K30E) to middle adulthood (ages 27–50 across different variant carriers). Severity correlates loosely with the degree of hypocontractility produced by the specific variant (see Section 6).

Frequency among affected individuals: Given the small numbers of reported families (case reports/small pedigrees), formal phenotype-frequency statistics (percentage penetrance for each sub-phenotype) are not established; qualitative HPO frequency terms (e.g., "typical" for cardiac dilation, "occasional" for LV noncompaction overlap) would be more appropriate than numeric percentages.

Quality of life impact: Not separately quantified for CMD1Y specifically; as with general heart-failure populations, expect substantial QoL burden proportional to NYHA functional class, captured generically via tools like the Kansas City Cardiomyopathy Questionnaire (KCCQ) in broader DCM literature — no disease-specific QoL study identified for this subtype.

4. Genetic/Molecular Information

Causal gene: TPM1 (Tropomyosin 1, alpha), OMIM *191010, HGNC:12010, UniProt P09493, located at 15q22.1–q22.2, encoding the major cardiac/striated-muscle tropomyosin isoform (a ~284-amino-acid, highly alpha-helical coiled-coil protein that polymerizes head-to-tail along the actin thin filament).

Variant classification and type: All reported CMD1Y-causing variants to date are heterozygous missense mutations (no frameshift/nonsense/splice-site DCM1Y variants identified in the literature reviewed), consistent with a dominant-negative or altered-function mechanism rather than simple haploinsufficiency. Representative variants and their ClinVar classifications: - p.Asp230Asn (c.688G>A) — classified pathogenic for "Primary dilated cardiomyopathy" (ClinVar RCV000036354) - p.Met8Arg (c.23T>G) — ClinVar RCV000036318 - p.Glu40Lys, p.Glu54Lys — originally described by Olson et al. 2001 (PMID: 11273725) - p.Lys30Glu (c.88A>G) — de novo, functionally characterized 2024 (PMID: 39684770) - p.Glu114Gln (c.340G>C) — novel, 2022 Chinese pedigree (PMID: 35029218)

Population frequency: DCM-causing TPM1 missense variants are essentially absent from gnomAD/population databases, consistent with rarity and pathogenicity; TPM1 as a gene shows regional missense constraint concentrated in actin-binding and troponin-interacting surfaces of the coiled-coil.

Somatic vs. germline: All reported CMD1Y variants are germline; most are familial (autosomal dominant transmission with variable expressivity), though de novo occurrence has been documented (K30E case, PMID: 39684770).

Functional consequences — mechanism divides HCM vs. DCM at the same locus. A key mechanistic insight, established by direct comparison of an HCM-causing (E62Q) and a DCM-causing (E54K) TPM1 variant using iPSC-derived cardiomyocytes and computational modeling (PMID: 39436707, J Clin Invest, 2024): - DCM variant E54K: decreases calcium sensitivity and produces hypocontractility — via long-range allosteric effects that increase the association rate of the C-terminal troponin I mobile domain, yielding shorter-lived twitches, impaired length-dependent activation, and ~3-fold decreased peak force. Net effect: increased tissue compliance, chamber dilation without hypertrophy. - HCM variant E62Q (contrast case): increases calcium sensitivity, reduces tropomyosin molecular stiffness, favors the "closed" (activating) regulatory state, and produces hypercontractility (>3-fold increased peak force), driving hypertrophy. - This supports a unifying framework in which intrinsically decreased actomyosin contractility from TPM1 variants produces cardiomyocyte lengthening/dilation (DCM), while intrinsically increased contractility produces hypertrophy (HCM) — despite both classes of mutation affecting the same protein.

For the K30E variant specifically: differential scanning calorimetry showed decreased thermal/calorimetric stability of tropomyosin domains 2–3 and reduced thermal stability of the tropomyosin–actin complex; in vitro motility assays showed ~37% reduction in thin-filament sliding velocity across physiological calcium concentrations, with increased calcium sensitivity (pCa50 5.97 vs 5.83 WT) but impaired maximal force — indicating a complex, domain-destabilizing hypocontractile mechanism (PMID: 39684770).

For D230N: structural studies indicate the mutation perturbs local coiled-coil geometry, altering tropomyosin's positional regulation on the thin filament (PMID: 28600229).

Modifier genes / epigenetics / chromosomal abnormalities: None specifically reported for CMD1Y; not applicable as this is a single-gene missense disorder without described epigenetic modulation or chromosomal rearrangement mechanism in the literature surveyed.

Gene Ontology / pathway suggestions: - GO:0003779 — actin binding - GO:0005523 — tropomyosin binding - GO:0060048 — cardiac muscle contraction - GO:0086003 — cardiac muscle cell contraction - GO:0055010 — ventricular cardiac muscle tissue morphogenesis - GO Cellular Component: GO:0030017 — sarcomere; GO:0036379 — myofilament; GO:0005865 — striated muscle thin filament

5. Environmental Information

No disease-specific environmental, infectious, or occupational/toxin exposures are documented as causal for CMD1Y in the literature surveyed — it is a purely monogenic sarcomeric cardiomyopathy. As is generic to DCM broadly, comorbid exposures (alcohol, cardiotoxic chemotherapeutics, viral myocarditis) could theoretically modify phenotype expression/severity in a genetically susceptible carrier, but no CMD1Y-specific gene–environment study was identified.

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream): 1. Molecular trigger: Heterozygous TPM1 missense mutation alters the tropomyosin coiled-coil structure (surface charge, domain stability, or troponin-interaction interface). 2. Thin-filament regulatory defect: Mutant tropomyosin shows reduced calcium sensitivity and/or destabilized interaction with actin and the troponin complex, shifting the tropomyosin-actin regulatory equilibrium and altering cross-bridge cycling kinetics. 3. Cellular contractile defect: Reduced peak isometric force generation and impaired length-dependent activation in cardiomyocytes (demonstrated directly via in vitro motility assays and iPSC-CM/engineered heart tissue force measurements) — net hypocontractility. 4. Tissue/organ remodeling: Chronic hypocontractility drives compensatory cardiomyocyte lengthening (sarcomere addition in series rather than parallel, as in hypertrophy), increased ventricular compliance, and progressive chamber dilation without wall thickening. 5. Organism-level manifestation: Reduced systolic function → reduced cardiac output → neurohormonal activation (renin-angiotensin-aldosterone, sympathetic) → progressive congestive heart failure, arrhythmia risk, and in severe/pediatric-onset cases, rapid decompensation and death.

Molecular pathways: Sarcomeric thin-filament calcium-regulated contraction (troponin–tropomyosin–actin regulatory unit); secondary activation of cardiac stress/remodeling pathways typical of heart failure (natriuretic peptide signaling, RAAS, sympathetic/adrenergic signaling) as downstream consequences rather than primary drivers.

Cellular processes: Altered actomyosin cross-bridge cycling; impaired calcium-dependent activation of the thin filament; cardiomyocyte structural remodeling (elongation).

Protein dysfunction: Structural destabilization of the tropomyosin coiled-coil (loss of thermal/calorimetric stability in specific domains, e.g., K30E; altered coiled-coil geometry, e.g., D230N; altered surface charge affecting actin-binding affinity, e.g., E40K/E54K).

Biochemical/functional abnormalities: Decreased calcium sensitivity of force generation in some variants; reduced maximal force and reduced thin-filament sliding velocity in in vitro motility assays; altered troponin I C-terminal mobile-domain dynamics (E54K, allosteric mechanism).

Suggested ontology terms: - GO (biological process): GO:0060048 (cardiac muscle contraction), GO:0086001 (cardiac muscle cell action potential), GO:0055010 (ventricular cardiac muscle tissue morphogenesis), GO:0003009 (skeletal/cardiac muscle contraction - regulation of muscle contraction: GO:0006937) - GO (molecular function): GO:0003785 (actin monomer binding), GO:0005523 (tropomyosin binding) - CL (cell type): CL:0000746 (cardiac muscle cell); CL:0002098 (ventricular cardiac myocyte) - UBERON: UBERON:0002082 (cardiac ventricle); UBERON:0002080 (heart left ventricle)

Molecular profiling / advanced technologies: The most recent mechanistic dissection (PMID: 39436707, 2024) used human iPSC-derived cardiomyocytes, engineered heart tissue force measurements, and computational (myofilament) modeling to directly compare HCM (E62Q) vs. DCM (E54K) TPM1 variants — representative of state-of-the-art functional genomics approaches for sarcomeric cardiomyopathy variant interpretation. No transcriptomic/proteomic/single-cell dataset specific to CMD1Y myocardium was identified in this search.

7. Anatomical Structures Affected

Organ level: Heart (primary); specifically left ventricle (dilation, reduced EF) and frequently right ventricle/biventricular involvement; secondary systemic effects of heart failure (pulmonary congestion, hepatic congestion, renal hypoperfusion) as downstream complications. Body system: cardiovascular.
Tissue/cell level: Cardiac (striated) muscle tissue; ventricular cardiomyocytes (CL:0002098) are the principal affected cell population.
Subcellular level: Sarcomere/myofilament (GO:0030017 sarcomere; GO:0036379 myofilament) — specifically the thin filament (actin–tropomyosin–troponin complex).
Localization: Diffuse myocardial involvement (not focal); in the LVNC9-overlap phenotype, additional apex/mid-ventricular noncompaction of the left ventricular wall is described, sometimes with Ebstein anomaly of the tricuspid valve or mitral insufficiency in the allelic condition OMIM #611878.
UBERON terms: UBERON:0002079 (left cardiac ventricle), UBERON:0002080/UBERON:0002082 (cardiac ventricle), UBERON:0006566 (cardiac muscle tissue).

8. Temporal Development

Onset: Highly variable — documented range from neonatal (2 weeks of life, K30E case, PMID 39684770) to adult onset (40s, E114Q case, PMID 35029218); OMIM describes death "in the third to sixth decades of life in some patients," implying typical adult-onset presentation is common but pediatric/severe presentations occur with specific variants.
Progression: Generally progressive — chamber dilation and systolic dysfunction worsen over time; some patients decompensate despite guideline-directed medical therapy (e.g., the K30E infant died of progressive heart failure at 3 years 8 months despite treatment).
Disease course pattern: Chronic, progressive heart failure course typical of sarcomeric DCM, punctuated by risk of malignant arrhythmia/sudden death.
Critical periods: Neonatal/early-childhood presentation (as with de novo K30E) appears to portend a particularly aggressive, rapidly fatal course, suggesting these patients represent a high-risk subgroup warranting early transplant evaluation.

9. Inheritance and Population

Inheritance pattern: Autosomal dominant OMIM #611878.
Penetrance/expressivity: Variable expressivity is evident from the literature — the same gene (and even overlapping variant positions) can produce DCM, LVNC, or HCM phenotypes depending on the specific substitution and its biophysical effect on tropomyosin (see Section 6); within-family phenotypic variability is also described (e.g., D230N segregating across 14 affected relatives with presumably variable severity).
De novo occurrence: Documented (K30E, PMID 39684770), alongside clearly familial transmission (D230N in two large multigenerational families; E114Q in a Chinese Han pedigree with maternal death from DCM).
Genetic anticipation, germline mosaicism, founder effects, consanguinity: Not specifically documented for CMD1Y in the literature surveyed.
Epidemiology (broader DCM context, since CMD1Y-specific incidence/prevalence figures are not separately tabulated):
Overall DCM prevalence has historically been estimated at ~1:2,500, with more recent population-genomic reappraisals suggesting a substantially higher effective prevalence, potentially ≥1 in 250 individuals when including subclinical/genotype-positive cases (NCBI Bookshelf NBK553847).
Familial DCM accounts for roughly 20–50% of cases depending on screening rigor (historically underestimated at ~7%, revised upward to 30–60% of index cases with systematic family echocardiographic screening) (JACC: Heart Failure 2022).
Up to 40 genes are implicated in genetic DCM overall, of which TPM1 is a well-established but relatively rare cause (encoding the thin-filament, not the more commonly implicated genes TTN, LMNA, MYH7, or BAG3) (PMC4288017).
TPM1-specific prevalence among genotyped DCM cohorts is low (a minority contributor relative to titin-truncating variants, which are the single largest genetic cause of DCM); exact percentage contribution of TPM1 to genetic DCM was not precisely quantified in the sources reviewed here and would benefit from a dedicated cohort-frequency search if needed for curation.
Population demographics: No specific ethnic/geographic enrichment documented for TPM1-DCM; reported pedigrees span Caucasian (D230N families), Chinese Han (E114Q family), and other ancestries, consistent with a pan-ethnic distribution typical of private/rare sarcomeric variants rather than a founder mutation.
Sex ratio / age distribution: Not specifically reported for CMD1Y; general DCM has a male predominance in adult-onset disease, though pediatric/de novo cases (as in K30E) affected a female proband.

10. Diagnostics

Clinical/imaging tests:
Echocardiography — primary diagnostic modality; demonstrates LV (± RV) dilation, reduced ejection fraction/fractional shortening, and can detect associated LV noncompaction.
Cardiac MRI — for tissue characterization, fibrosis assessment (late gadolinium enhancement), and confirmation of noncompaction where suspected.
Electrocardiography — sinus tachycardia, conduction abnormalities, and arrhythmia surveillance.
Electron microscopy of myocardial biopsy — historically used to show abnormal sarcomere ultrastructure in early OMIM-cataloged cases, though endomyocardial biopsy is not standard first-line diagnostic practice today.
Biomarkers: Standard heart-failure biomarkers (BNP/NT-proBNP) apply generically; no CMD1Y-specific biomarker identified.
Genetic testing:
Clinical DCM gene panels commonly include TPM1 among ~40–100+ genes tested (panels of up to ~78 genes for hereditary DCM are commercially available).
Confirmatory approach in reported cases: next-generation sequencing (whole-exome or targeted panel) followed by Sanger sequencing confirmation and familial segregation analysis (as used for E114Q, PMID 35029218, and K30E, PMID 39684770).
Cascade/family genetic testing is recommended once a proband's causal variant is identified, given the autosomal dominant pattern.
Clinical criteria: Standard DCM diagnostic criteria (LV dilation adjusted for body size + LV systolic dysfunction not explained by abnormal loading conditions or coronary artery disease) apply; differential diagnosis must exclude ischemic cardiomyopathy, myocarditis, toxic/metabolic cardiomyopathy, and other genetic causes (LMNA, TTN, MYH7, BAG3, FLNC, etc.) before attributing disease to TPM1.
Screening: First-degree relatives of a confirmed CMD1Y proband should undergo clinical (echocardiographic) and/or genetic cascade screening given autosomal dominant inheritance and documented within-family segregation in reported pedigrees.

11. Outcome/Prognosis

CMD1Y carries a variable but potentially severe prognosis: OMIM describes death from progressive cardiac failure in the third to sixth decades in some patients OMIM #611878; the E54K variant was originally identified in a 27-year-old man who died awaiting cardiac transplantation (per OMIM/Olson et al. 2001); the K30E de novo variant caused death at 3 years 8 months in a pediatric patient despite treatment (PMID 39684770).
Complications: Progressive heart failure, arrhythmia (documented risk generically in DCM; specific arrhythmia burden not separately quantified for TPM1 carriers in this search), and need for advanced therapies (transplantation) in severe cases.
Prognostic factors: Age of onset appears prognostically important — neonatal/early pediatric onset (as with de novo K30E) is associated with rapid, fatal progression, whereas adult-onset cases (E114Q) can show symptomatic improvement with standard heart-failure pharmacotherapy (beta-blocker) at one-year follow-up.
No formal survival-curve or actuarial life-expectancy data specific to CMD1Y were identified; prognosis should be extrapolated cautiously from the general sarcomeric-DCM literature, where genotype (e.g., LMNA, FLNC, PLN, TTN) is increasingly used for arrhythmic risk stratification — TPM1 is not among the genes currently flagged for enhanced primary-prevention ICD thresholds in contemporary guidelines, unlike LMNA/FLNC/PLN.

12. Treatment

No CMD1Y-specific therapy exists; management follows standard guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction, as used in the reported cases:

Pharmacotherapy (documented in CMD1Y case reports):
Beta-blocker (metoprolol) — improved symptoms at 1-year follow-up in the E114Q adult case (NCIT:C15986 Pharmacotherapy; specific agent metoprolol)
ACE inhibitor (captopril) — used in the pediatric K30E case
Loop diuretic (furosemide) and mineralocorticoid receptor antagonist (spironolactone) — used in the K30E case for volume management
Digoxin — used in the K30E case
Electrolyte/cardioprotective supplementation (potassium, magnesium)
Broader GDMT framework applicable to DCM generally (not CMD1Y-specific but standard of care): ACE inhibitors/ARBs, beta-blockers, mineralocorticoid receptor antagonists, and angiotensin receptor–neprilysin inhibitor (ARNI), per contemporary heart-failure guidelines; SGLT2 inhibitors are now also part of standard quadruple therapy for HFrEF broadly (not specifically documented in the TPM1 case literature reviewed, but standard of care as of current guidelines).
Device therapy: Implantable cardioverter-defibrillator (ICD) for symptomatic ventricular arrhythmia, resuscitated sudden cardiac death, or per standard EF-based primary-prevention criteria; cardiac resynchronization therapy (CRT) as indicated by QRS/conduction criteria in advanced disease.
Advanced/end-stage therapy: Ventricular assist device (VAD) and/or cardiac transplantation for refractory heart failure — directly relevant, as the original E54K CMD1Y patient died awaiting transplantation.
Suggested NCIT terms:
NCIT:C15986 — Pharmacotherapy
NCIT:C15747 — Supportive Care
NCIT:C15289 — Organ Transplantation (cardiac transplantation)
Device-based therapy (ICD/CRT — no precise NCIT clinical-action term readily available; would need therapeutic_modality: DEVICE)
Experimental/precision approaches: No TPM1/CMD1Y-specific gene therapy, ASO, or targeted molecular therapy identified in current trials; myofilament-targeted small molecules (e.g., myosin modulators developed for HCM) are mechanistically informative but not established/approved therapies for TPM1-DCM specifically.
Genetic counseling: Recommended given autosomal dominant inheritance and demonstrated family segregation (NCIT:C15240 — Genetic Counseling).

13. Prevention

Primary prevention: Not applicable in the traditional sense (monogenic disease); the closest analog is genetic/family counseling to identify at-risk relatives before symptom onset.
Secondary prevention/screening: Cascade genetic testing of first-degree relatives once a proband's TPM1 variant is confirmed, paired with periodic clinical (echocardiographic) surveillance of genotype-positive, phenotype-negative relatives — standard practice for genetic DCM generally, though no CMD1Y-specific screening protocol/interval was identified in this search.
Tertiary prevention: Early initiation of GDMT in genotype-positive/pre-clinical individuals is an area of active general-DCM management interest but is not specifically validated for TPM1 carriers in the literature reviewed.
Reproductive options: Prenatal/preimplantation genetic testing could be considered for known familial variants, consistent with general practice for highly penetrant autosomal dominant cardiomyopathies, though not specifically documented for CMD1Y.

14. Other Species / Natural Disease

Taxonomy: TPM1 orthologs are broadly conserved across vertebrates. Mouse ortholog: Tpm1 (MGI:98809), "tropomyosin 1, alpha."
Natural disease in other species: No naturally occurring TPM1-associated cardiomyopathy in companion animals or wildlife was identified in this search (unlike, e.g., some MYBPC3-associated feline HCM); this appears to be an under-studied area for veterinary comparative pathology.
Comparative biology: The tropomyosin–troponin–actin regulatory apparatus is deeply conserved across striated muscle in all vertebrates, supporting strong evolutionary conservation of the core disease mechanism (calcium-regulated thin-filament activation).

15. Model Organisms

Cellular/in vitro models: The most current and mechanistically informative CMD1Y-relevant models are human iPSC-derived cardiomyocytes and engineered heart tissue, used to directly compare DCM-causing (E54K) versus HCM-causing (E62Q) TPM1 variants and demonstrate divergent contractile phenotypes (hypocontractility vs. hypercontractility) (PMID: 39436707, J Clin Invest, 2024). Recombinant mutant tropomyosin protein combined with in vitro motility assays and differential scanning calorimetry has also been used to characterize specific variants biophysically (e.g., K30E, PMID 39684770; D230N, PMID 28600229).
Computational models: Myofilament/sarcomere computational modeling has been used alongside iPSC-CM data to mechanistically dissect how TPM1 variants shift the contractile force–calcium relationship (PMID 39436707); separately, myofilament modeling approaches for predicting tropomyosin mutation effects on cardiac contraction have been described generally (PMC5081029).
Animal models: No CMD1Y (TPM1-DCM)-specific transgenic/knock-in mouse or zebrafish model was identified in this search (searches for TPM1 E54K/E40K knock-in mice or zebrafish models did not return a CMD1Y-specific in vivo model; the field currently relies predominantly on iPSC-CM and biophysical reconstitution systems for TPM1-DCM). This is a notable knowledge gap relative to other DCM genes (e.g., TNNT2 R141W, LMNA, and titin-based DCM, which all have established mouse knock-in models cited in the general DCM literature) — worth flagging explicitly as a HUMAN_MODEL_MISMATCH/knowledge-gap candidate in a dismech entry, since in vivo whole-organism validation of TPM1-DCM mechanisms is currently lacking relative to the strength of the in vitro/computational mechanistic data.
Model limitations: iPSC-CM/engineered heart tissue systems capture sarcomeric contractile mechanics well but do not recapitulate whole-organ chamber remodeling, neurohormonal compensation, or long-term arrhythmic risk — meaning the "hypocontractility → dilation" causal link, while mechanistically well-supported at the cell/tissue level, has not been confirmed in an intact-organ in vivo model specific to CMD1Y.

Summary of Key Ontology Term Suggestions for KB Curation

Category	Term
Disease (OMIM)	#611878 CMD1Y
Gene	HGNC:12010 (TPM1)
Causal variant examples	ClinVar RCV000036354 (D230N), RCV000036318 (M8R)
MONDO (parent)	MONDO:0005021 (dilated cardiomyopathy)
Orphanet	ORPHA:154 (Familial isolated dilated cardiomyopathy)
HP	HP:0001644 (Dilated cardiomyopathy), HP:0001635 (CHF), HP:0001712 (Cardiomegaly), HP:0012664 (Decreased LVEF), HP:0030702 (LV noncompaction)
GO (BP)	GO:0060048 (cardiac muscle contraction)
GO (MF)	GO:0005523 (tropomyosin binding), GO:0003779 (actin binding)
CL	CL:0002098 (ventricular cardiac myocyte)
UBERON	UBERON:0002079 (left cardiac ventricle)
NCIT (treatment)	C15986 (Pharmacotherapy), C15289 (Organ Transplantation), C15240 (Genetic Counseling)

Sources

OMIM #611878 — CARDIOMYOPATHY, DILATED, 1Y; CMD1Y
OMIM *191010 — TROPOMYOSIN 1; TPM1
MedGen C2678476 — Dilated cardiomyopathy 1Y
NIH GTR — Dilated cardiomyopathy 1Y
Olson TM et al., "Mutations that alter the surface charge of alpha-tropomyosin are associated with dilated cardiomyopathy," PMID: 11273725
"The structural basis of alpha-tropomyosin linked (Asp230Asn) familial dilated cardiomyopathy," PMID: 28600229
ClinVar RCV000036354 — TPM1 D230N / Primary dilated cardiomyopathy
ClinVar RCV000036318 — TPM1 M8R / Primary dilated cardiomyopathy
"Novel Mutation Lys30Glu in the TPM1 Gene Leads to Pediatric Left Ventricular Non-Compaction and Dilated Cardiomyopathy," PMID: 39684770
"Identification of a novel missense mutation in the TPM1 gene via exome sequencing in a Chinese family with dilated cardiomyopathy," PMID: 35029218
"Distinct mechanisms drive divergent phenotypes in hypertrophic and dilated cardiomyopathy–associated TPM1 variants," J Clin Invest, PMID: 39436707 (2024)
"In silico and in vitro models reveal the molecular mechanisms of hypocontractility caused by TPM1 M8R," PMC11392859
"GENETIC CAUSES OF DILATED CARDIOMYOPATHY," PMC4288017
"Epidemiology — Dilated Cardiomyopathy," NCBI Bookshelf NBK553847
"Family Screening in Dilated Cardiomyopathy: Prevalence, Incidence, and Potential for Limiting Follow-Up," JACC: Heart Failure (2022), https://www.jacc.org/doi/10.1016/j.jchf.2022.07.009
"Current Management and Treatment — Dilated Cardiomyopathy," NCBI Bookshelf NBK553842
Orphanet — TPM1 gene-disease associations (ORPHA:154, ORPHA:54260, ORPHA:155)
TPM1 gene, GenCC / ClinGen curation, https://thegencc.org/genes/HGNC:12010
MGI — Tpm1 mouse gene detail, MGI:98809

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	12
Resolved	12
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	12
On topic	11
Off topic	0

All extracted references resolved successfully.

Dilated Cardiomyopathy 1Y

Ask OpenScientist

OpenScientist Report

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Dilated Cardiomyopathy 1Y (CMD1Y / TPM1-Related Dilated Cardiomyopathy): Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Key Ontology Term Suggestions for KB Curation

Sources

Reference Validation