🏷

Classifications

Harrison's Part

👪

Inheritance

1

Autosomal dominant HP:0000006

CMD1NN is classified as an autosomal dominant trait (OMIM 615916). The reported alleles are heterozygous and predominantly missense substitutions in RAF1, with one frameshift truncation (p.R254fs) reported in the North Indian cohort of the discovery study, and the disease is described in the RASopathy cardiomyopathy literature as an inherited RAF1 phenotype. The direct evidence for the mode of inheritance is weaker than for the mechanism: the discovery report was a case-control resequencing study rather than a large pedigree study, and no penetrance estimate specific to RAF1 dilated cardiomyopathy has been published, so no penetrance value is recorded here.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:26380542 SUPPORT INDIRECT Human Clinical

"In addition, inherited abnormalities in one pathway gene, RAF1, cause pediatric-onset dilated cardiomyopathy."

States that the RAF1 dilated cardiomyopathy alleles are inherited rather than exclusively de novo, which is the part of the dominant-transmission claim this review directly supports. It is INDIRECT for the dominant mode itself, which the sentence does not name.

PMID:26380542 SUPPORT INDIRECT Human Clinical

"Noonan syndrome and related disorders (Noonan syndrome with multiple lentigines, Costello syndrome, cardiofaciocutaneous syndrome, Noonan syndrome with loose anagen hair, and other related traits) are autosomal dominant traits."

Establishes autosomal dominant transmission for heterozygous RAF1-pathway alleles generally. It is INDIRECT because the sentence enumerates the syndromic RASopathies, not CMD1NN, and is cited here only as the pathway-level precedent for a heterozygous missense allele acting dominantly.

?

Discussions and Knowledge Gaps

2

Would RAF1-dilated cardiomyopathy survive a formal ClinGen gene-disease validity curation as an entity distinct from RAF1-Noonan syndrome?

KNOWLEDGE GAP OPEN cmd1nn_gene_disease_validity_unadjudicated

Attached to

genetic#RAF1

ClinGen's RASopathy Gene Curation Expert Panel has curated RAF1 against Noonan syndrome and classified it Definitive. No ClinGen assertion exists for RAF1 against dilated cardiomyopathy, so the entity's gene-disease validity has never been graded by the body whose gradings this knowledge base otherwise treats as authoritative. The supporting human genetic evidence is concentrated in a single 2014 case-control resequencing report, and a subsequent clinical panel cohort found pathogenic RASopathy-gene variants only among patients tested for hypertrophic cardiomyopathy. This is a gap in adjudication rather than a positive refutation - the mechanism evidence is strong and independent - but it is the reason this entry does not describe the gene-disease relationship as definitive.

Show evidence (1 reference)

CGGV:assertion_85645d27-2056-4ad3-9593-8d7739aa4121-2024-10-23T160000.000Z SUPPORT DIRECT Other

Shows the disease against which ClinGen has actually curated RAF1. The absence of a corresponding dilated-cardiomyopathy row is the gap.

Does transient mRNA overexpression of a RAF1 mutant in a zebrafish embryo model what a single heterozygous RAF1 missense allele does to a human ventricle?

HUMAN MODEL MISMATCH OPEN cmd1nn_zebrafish_overexpression_mismatch

Attached to

pathophysiology#mTOR Pathway Activation animal_models#Zebrafish

The only in vivo evidence for the AKT-mTOR mechanism comes from constitutive expression of the mutants in zebrafish embryos. Human CMD1NN is heterozygosity for a missense allele at endogenous dosage in a four-chambered, non-regenerative heart that dilates over years. Overexpression can drive signalling outputs that a heterozygous allele does not, and the zebrafish readout was heart failure in an embryo rather than progressive chamber dilation. The mismatch matters specifically for the therapeutic inference: the rapamycin rescue is the strongest reason to think mTOR inhibition might be disease-modifying in patients, and it is exactly the result the model's non-physiological expression level puts most at risk.

Proposed experiments

Isogenic human cardiomyocyte comparison of DCM and HCM RAF1 alleles

exp_cmd1nn_isogenic_ipsc_allele_comparison

Introduce the reported CMD1NN alleles into human iPSC-derived cardiomyocytes or engineered cardiac tissue at endogenous dosage, alongside isogenic controls and a Noonan hotspot allele, and measure AKT, mTOR and ERK signalling together with contractile function. This is the experiment that would show whether the AKT-over-ERK split holds at heterozygous dosage in human myocardium, and it has already been done for the Noonan p.Ser257Leu allele but not for the dilated-cardiomyopathy alleles.

Would support

pathophysiology#BRAF-Dependent AKT Hyperactivation pathophysiology#mTOR Pathway Activation

Would refute

pathophysiology#BRAF-Dependent AKT Hyperactivation

Supporting outcome

Heterozygous CMD1NN alleles raise AKT and mTOR pathway activity without substantially raising ERK activity, and impair contractile function, in isogenic human cardiomyocytes.

Refuting outcome

At endogenous heterozygous dosage the CMD1NN alleles produce no measurable AKT or mTOR change relative to isogenic controls, indicating the signalling phenotype was an artefact of overexpression.

⚙

Pathophysiology

5

RAF1 Variant Altering Kinase Activity

The initiating lesion is a rare heterozygous RAF1 variant - in most reported cases a missense substitution, and in one North Indian case a frameshift truncation (p.R254fs) - in the gene encoding the RAF-1 (CRAF) serine/threonine kinase of the RAS-MAPK pathway. What distinguishes the dilated-cardiomyopathy alleles from the Noonan-syndrome ones is not merely their position but the direction of their effect on the kinase. The Noonan hotspots flank Ser259 and raise kinase activity; the dilated-cardiomyopathy alleles have been reported to have reduced kinase activity relative to the hypertrophic-cardiomyopathy alleles and to leave the residues critical to regulation unaltered. Molecular dynamics of the C-terminal variants makes the same point at residue resolution: the DCM-associated p.Leu603Pro substitution drives the kinase domain into an inactive conformation, while the HCM-associated S612T and L613V substitutions - only a few residues away - stabilise an active one. A single gain-of-function or loss-of-function label is therefore not warranted across the reported CMD1NN allele set, and none is asserted here.

Cardiomyocyte CL:0000746

RAF1 hgnc:9829

RAF-1 serine/threonine kinase activity GO:0004674 ⚠ ABNORMAL

Downstream

BRAF-Dependent AKT Hyperactivation The altered RAF-1 kinase redirects signalling into the AKT arm rather than amplifying ERK.

Show evidence (6 references)

PMID:24777450 SUPPORT DIRECT Human Clinical

"On the basis of resequencing of 513 DCM cases and 1,150 matched controls from various cohorts of distinct ancestry, we discovered rare, functional RAF1 mutations in 3 of the cohorts (South Indian, North Indian and Japanese)."

Establishes the trigger lesion - rare functional RAF1 variants - and the case-control ascertainment in three independent cohorts that supports it.

PMID:24777450 SUPPORT DIRECT Human Clinical

"In Group 2, two additional RAF1 sequence variants were identified: a single base-pair deletion leading to a protein truncation (p.R254fs) and a missense mutation predicting a p.Thr641Met substitution."

Records the one reported allele that is not a missense substitution, which is why this node is not scoped to missense alleles. A frameshift truncation is the reason the allele set cannot be given a single gain-of-function or loss-of-function label.

PMID:24777450 SUPPORT DIRECT In Vitro

"One DCM-associated missense mutant (p.Leu603Pro) showed impaired kinase activity and reduced ERK activation as did the truncated RAF1 protein (p.R254fs)."

Shows the truncating allele was functionally characterised alongside the missense alleles and behaves like the kinase-impairing one, so it belongs to this node's lesion class rather than being an incidental finding. Graded IN_VITRO because the kinase-activity and ERK-activation measurements are cell-based assays, not observations in patients.

+ 3 more references

BRAF-Dependent AKT Hyperactivation

In cells expressing the dilated-cardiomyopathy RAF1 mutants, AKT is hyperactivated, and that hyperactivation depends on BRAF - the paralogous RAF kinase - rather than on RAF-1 acting directly. ERK activation is largely unaltered. This is the node that separates CMD1NN from RAF1 Noonan syndrome at the level of signalling: the Noonan hotspot mutants show increased kinase activity with enhanced ERK activation, and it is that ERK amplification that the RASopathy literature implicates in pathological cardiomyocyte hypertrophy.

Cardiomyocyte CL:0000746

AKT signaling GO:0043491 ↑ INCREASED ERK1/ERK2 cascade GO:0070371

Downstream

mTOR Pathway Activation Hyperactive AKT drives the downstream mTOR growth and protein-synthesis program.

Show evidence (2 references)

PMID:24777450 SUPPORT DIRECT In Vitro

"Biochemical studies showed that DCM-associated RAF1 mutants had altered kinase activity, resulting in largely unaltered ERK activation but in AKT that was hyperactivated in a BRAF-dependent manner."

The primary evidence for this node, including the BRAF dependence and the absence of a substantial ERK effect. The ERK1/ERK2 cascade term is bound without a modifier for exactly that reason - no directional change is claimed.

PMID:17603483 SUPPORT INDIRECT In Vitro

"Ectopically expressed RAF1 mutants from the two HCM hotspots had increased kinase activity and enhanced ERK activation, whereas non-HCM-associated mutants were kinase impaired."

The contrasting Noonan-syndrome result. Cited as INDIRECT support because it characterises a different allele class; it is what establishes that the absence of ERK amplification in the dilated-cardiomyopathy mutants is a genuine discriminator rather than an assay limitation.

mTOR Pathway Activation

Increased signalling through mTOR reprograms cardiomyocyte growth, protein synthesis and autophagic turnover. The evidence that this step is load-bearing in CMD1NN is pharmacological rather than observational: rapamycin, an mTOR inhibitor, rescued the cardiac phenotype produced by the mutants in zebrafish. This is the step that makes the disease mechanistically interesting - and, in principle, druggable in a way the RASopathy hypertrophic cardiomyopathies are not, since those are targeted at the MEK/ERK arm instead.

Cardiomyocyte CL:0000746

TOR signaling GO:0031929 ↑ INCREASED

Animal models

Zebrafish cardiac expression of DCM-associated RAF1 mutants Zebrafish recapitulates The model reproduces the AKT-hyperactivated, mTOR-dependent cardiac failure that this node asserts, and the rapamycin rescue establishes the dependence rather than merely the correlation.

Downstream

Ventricular Dilation and Systolic Dysfunction Dysregulated growth and remodelling signalling in the cardiomyocyte culminates in chamber dilation and falling contractile performance. The intermediate sarcomeric and metabolic lesions in CMD1NN have not been demonstrated, which is why this edge is not marked DIRECT.

Show evidence (1 reference)

PMID:24777450 SUPPORT INDIRECT Model Organism

"Constitutive expression of these mutants in zebrafish embryos resulted in a heart failure phenotype with AKT hyperactivation that was rescued by treatment with rapamycin."

Rapamycin rescue is the evidence that mTOR signalling mediates the cardiac phenotype. INDIRECT because mTOR involvement is inferred from the target of the rescuing drug.

Ventricular Dilation and Systolic Dysfunction

The defining structural lesion: left ventricular or biventricular enlargement with impaired contraction, not explained by abnormal loading conditions or coronary artery disease. In CMD1NN this is reached from a signalling lesion rather than from a sarcomeric or cytoskeletal one, which is unusual within the numbered dilated cardiomyopathy series, where the causal lesion is more often sarcomeric, Z-disc, nuclear-envelope, proteostatic or post-transcriptional.

Cardiomyocyte CL:0000746 Cardiac Fibroblast CL:0002548

Heart Contraction GO:0060047 ↓ DECREASED Extracellular Matrix Organization GO:0030198 ↑ INCREASED

Left ventricle UBERON:0002084 Myocardium UBERON:0002349

Downstream

Heart Failure The dilated, poorly contracting ventricle fails to maintain output.

Show evidence (2 references)

PMID:31073128 SUPPORT DIRECT Other

"Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease."

States the structural and exclusionary definition this node represents. Evidence source is OTHER because this is a Nature Reviews Disease Primers review rather than a primary study.

PMID:24777450 SUPPORT INDIRECT Model Organism

"Constitutive expression of these mutants in zebrafish embryos resulted in a heart failure phenotype with AKT hyperactivation that was rescued by treatment with rapamycin."

In vivo demonstration that the mutant alleles are sufficient to produce a failing heart. INDIRECT for the human ventricular phenotype because the readout is an mRNA-injected zebrafish embryo, not a patient ventricle.

Heart Failure

Progressive systolic heart failure is the clinical endpoint. Onset in the reported CMD1NN cases was predominantly in childhood, and childhood cardiomyopathies are the most common cause of heart failure in children and are frequently transplantation-requiring.

Cardiomyocyte CL:0000746

Show evidence (1 reference)

PMID:30384889 SUPPORT INDIRECT Human Clinical

"Childhood cardiomyopathies are progressive and often lethal disorders, forming the most common cause of heart failure in children."

Establishes the severity and heart-failure burden of the childhood-onset cardiomyopathy class to which CMD1NN belongs. INDIRECT because the cohort is childhood cardiomyopathy generally, not RAF1 carriers.

⬡

Pathograph

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

●

Phenotypes

3

Dilated Cardiomyopathy OBLIGATE Cardiovascular HP:0001644

Onset: CHILDHOOD

Show evidence (2 references)

PMID:26380542 SUPPORT DIRECT Human Clinical

"In addition, inherited abnormalities in one pathway gene, RAF1, cause pediatric-onset dilated cardiomyopathy."

States both the phenotype and its pediatric onset for the RAF1 dilated cardiomyopathy entity.

PMID:24777450 SUPPORT DIRECT Human Clinical

"The prevalence of RAF1 mutations was ~9% in childhood-onset DCM cases in these three cohorts."

Anchors the phenotype to childhood-onset dilated cardiomyopathy, the ascertainment category in which the RAF1 alleles were found.

Reduced Left Ventricular Ejection Fraction Cardiovascular HP:0012664

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:31073128 SUPPORT INDIRECT Other

"Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease."

Impaired contraction is part of the definition of the phenotype CMD1NN manifests. INDIRECT because this is the general DCM definition, not a CMD1NN measurement.

Congestive Heart Failure Cardiovascular HP:0001635

Show evidence (1 reference)

PMID:30384889 SUPPORT INDIRECT Human Clinical

"Childhood cardiomyopathies are progressive and often lethal disorders, forming the most common cause of heart failure in children."

Documents heart failure as the dominant clinical consequence of the childhood cardiomyopathy class. INDIRECT for CMD1NN specifically.

🧬

Genetic Associations

1

RAF1

Gene: RAF1 hgnc:9829 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:24777450 SUPPORT DIRECT Human Clinical

"These findings provide new mechanistic insights and potential therapeutic targets for RAF1-associated DCM and further expand the clinical spectrum of RAF1-related human disorders."

The discovery report's own causal conclusion, and its framing of the entity as an expansion of the RAF1 clinical spectrum rather than a form of Noonan syndrome.

PMID:30762279 REFUTE INDIRECT Human Clinical

"We identified four patients (5.41%) with pathogenic or likely pathogenic variants in HRAS, PTPN11 and RAF1 (two individuals). Indication for testing for all four individuals was HCM."

Counter-evidence recorded deliberately. In a clinical cardiomyopathy panel cohort that included 24 dilated cardiomyopathy cases and 9 with combined noncompaction and dilated disease, every pathogenic RASopathy-gene finding came from a patient tested for hypertrophic cardiomyopathy. It does not refute the gene-disease relationship, but it refutes any expectation that RAF1 is a frequent yield in unselected dilated cardiomyopathy, and it is why the discovery case fraction is not generalised.

💊

Medical Actions

2

Heart Failure Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: ACE inhibitor NCIT:C247 angiotensin receptor-neprilysin inhibitor NCIT:C190796 beta-blocker NCIT:C29576 mineralocorticoid receptor antagonist NCIT:C101255 SGLT2 inhibitor NCIT:C98083

Platform: Small molecule

Guideline-directed heart-failure therapy for the manifest phenotype, dosed for age. There is no RAF1-directed or CMD1NN-specific approved therapy, so management is phenotype-based and identical to that for other genetic dilated cardiomyopathies: renin-angiotensin blockade with an ACE inhibitor or an angiotensin receptor-neprilysin inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist, and, in eligible patients, an SGLT2 inhibitor. A loop diuretic is used for congestion but is symptomatic rather than disease-modifying, and is not bound here because no cited source in this entry states that indication for dilated cardiomyopathy specifically. Nothing in this regimen acts on the RAF1 lesion; it acts on the neurohormonal remodelling downstream of it.

Mechanism Target:

MODULATES Ventricular Dilation and Systolic Dysfunction — Neurohormonal blockade opposes the maladaptive remodelling that carries the dilated, hypocontractile ventricle forward, rather than correcting the upstream RAF1 kinase lesion or the AKT-mTOR signalling it drives. The link is therefore placed at the chamber-remodelling node and not at the molecular trigger.

Show evidence (2 references)

PMID:39064249 SUPPORT INDIRECT Other

"The standard treatment of HF includes angiotensin-converting enzyme inhibitors, angiotensin receptor-neprilysin inhibitors, mineralocorticoid-receptor antagonists, beta-blockers, and sodium-glucose-co-transporter 2 inhibitors."

Names the four-pillar class set bound above as standard therapy for the reduced-ejection-fraction phenotype this node describes. INDIRECT and OTHER because it is a narrative review's statement of standard of care in heart failure generally, not a trial result in CMD1NN, whose management is extrapolated from that guidance.

PMID:37876955 SUPPORT INDIRECT Human Clinical

"Seventy-two percent of this cohort were on angiotensin-converting-enzyme inhibitors, 40% on aldosterone antagonists, and 47% on beta-blockers."

Documents that the same neurohormonal classes are what childhood dilated cardiomyopathy is actually treated with, which is the age group CMD1NN presents in. INDIRECT because the cohort is childhood dilated cardiomyopathy of mixed cause, not a RAF1-genotyped series.

Heart Transplantation

Action: organ transplantation Ontology label: Organ Transplantation NCIT:C15289

Platform: Surgery

Advanced, refractory disease is an indication for transplantation, which is a common outcome in severe childhood-onset cardiomyopathy.

Mechanism Target:

BYPASSES Heart Failure — Transplantation replaces the failing organ rather than acting anywhere in the RAF1 causal chain, so it resolves the terminal node without correcting the kinase lesion, the AKT-mTOR signalling, or the remodelling upstream of it. It is the endpoint of the pathograph, not an intervention in it.

Show evidence (1 reference)

PMID:37876955 SUPPORT INDIRECT Human Clinical

"Dilated cardiomyopathy (DCM) remains the most common form of cardiomyopathy and the reason for cardiac transplantation among children."

Establishes that transplantation is the standard destination for childhood dilated cardiomyopathy that reaches refractory heart failure, which is the node this link points at. INDIRECT because the statement is about childhood DCM as a class rather than RAF1-associated cases.

Show evidence (1 reference)

PMID:30384889 SUPPORT INDIRECT Human Clinical

"Childhood cardiomyopathies are progressive and often lethal disorders, forming the most common cause of heart failure in children."

Supports the severity that makes transplantation a realistic endpoint in this disease class. INDIRECT because the cohort is childhood cardiomyopathy generally.

🔬

Diagnosis

2

Echocardiography

First-line and usually diagnostic: left ventricular internal dimensions and ejection fraction establish the dilated, hypocontractile phenotype. Nothing about the imaging is RAF1-specific, and the echocardiogram is also where the principal differential call is made - wall hypertrophy rather than dilation points to the RASopathy phenotype instead.

echocardiography NCIT:C16525

Show evidence (1 reference)

PMID:31073128 SUPPORT DIRECT Other

"Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling"

Establishes imaging as the required modality for assessing the ventricular dysfunction that defines the phenotype.

Cardiomyopathy Gene Panel Including RASopathy Genes

Molecular confirmation requires a cardiomyopathy panel that actually contains RAF1. This is not automatic: RASopathy genes were historically absent from cardiomyopathy panels, and the case for including them was made on the strength of the hypertrophic phenotype, where the yield is highest. The evidence for this route in dilated phenotypes is in fact negative: the one clinical service that prospectively tested 11 RASopathy genes in 419 referrals for dilated cardiomyopathy found no variant of clinical significance and concluded against testing in DCM. So the panel is the practical route to a molecular diagnosis of CMD1NN only because RAF1 happens to be carried on it, not because unselected DCM referrals are a productive place to look. A RAF1 variant of uncertain significance does not establish CMD1NN; phenotype fit, population frequency, segregation, allele class and functional data all have to be weighed, and the historical CMD1NN allele list carries mixed in-silico predictions.

genetic testing NCIT:C15709

Show evidence (4 references)

PMID:29696744 SUPPORT INDIRECT Human Clinical

"was recently associated with pediatric-onset dilated cardiomyopathy (DCM) (Dhandapany et al., 2014)"

Records why RAF1 is on a RASopathy gene set applied to dilated as well as hypertrophic referrals. This is a background sentence attributing the DCM association to Dhandapany et al. 2014, not a result of this study - the same paper's own DCM result is negative and is cited below. INDIRECT because it establishes the gene-disease association that motivates panel inclusion rather than the diagnostic performance of the panel itself.

PMID:29696744 REFUTE DIRECT Human Clinical

"No variants of clinical significance were identified in the DCM sub-cohort"

The diagnostic yield of RASopathy-gene testing in this study's 419 dilated cardiomyopathy referrals was zero, which argues against the panel as a productive route to a molecular diagnosis in unselected DCM.

PMID:29696744 REFUTE DIRECT Human Clinical

"there appears little, if any, benefit to testing individuals with DCM"

The study's own recommendation is against RASopathy-gene testing in dilated cardiomyopathy. Kept as an explicit REFUTE so this diagnostic entry is not read as endorsed by a paper that argues the opposite.

+ 1 more reference

📊

Prevalence

1

Worldwide

Unknown Unknown

No population prevalence has been established for CMD1NN. The frequently quoted "~9%" figure is a case fraction among childhood-onset dilated cardiomyopathy in the three discovery cohorts, not a population rate, and is recorded as such under `genetic` rather than here.

🐁

Animal Models

1

Zebrafish cardiac expression of DCM-associated RAF1 mutants

The in vivo model behind the CMD1NN mechanism. Zebrafish embryos constitutively expressing the dilated-cardiomyopathy RAF1 mutants developed a heart failure phenotype accompanied by AKT hyperactivation, and treatment with rapamycin rescued it. The rescue arm is what makes this model do mechanistic work rather than merely demonstrate toxicity: it places mTOR in the causal path.

Species

Zebrafish

Genotype

Constitutive embryonic expression of human dilated-cardiomyopathy-associated RAF1 missense mutants

Publication

PMID:24777450

Pathograph links

mTOR Pathway Activation recapitulates fidelity: moderate The model reproduces the AKT-hyperactivated, mTOR-dependent cardiac failure that this node asserts, and the rapamycin rescue establishes the dependence rather than merely the correlation.

Limitations: Transient mRNA overexpression is not the human genetic situation, which is a single heterozygous missense allele at endogenous dosage; overexpression can produce signalling phenotypes that a heterozygous allele would not. The zebrafish heart is two-chambered and regenerative, so chamber dilation, chronic fibrosis and the human developmental timescale are not modelled.

Readouts

Rapamycin rescue of the cardiac failure phenotype

Direction: RESTORED

Interpretation: Pharmacological mTOR inhibition reverses the mutant phenotype, which is the measurement that places mTOR signalling in the causal chain.

Show evidence (1 reference)

PMID:24777450 SUPPORT DIRECT Model Organism

"Constitutive expression of these mutants in zebrafish embryos resulted in a heart failure phenotype with AKT hyperactivation that was rescued by treatment with rapamycin."

Reports the rescue measurement behind this readout.

Show evidence (1 reference)

PMID:24777450 SUPPORT DIRECT Model Organism

"Constitutive expression of these mutants in zebrafish embryos resulted in a heart failure phenotype with AKT hyperactivation that was rescued by treatment with rapamycin."

Supports treating this model as informative for the AKT-mTOR node, since it reproduces both the signalling abnormality and a cardiac failure phenotype.

{ }

Source YAML

click to show

name: Dilated Cardiomyopathy 1NN
creation_date: "2026-09-02T00:00:00Z"
synonyms:
- CMD1NN
- DCM1NN
- dilated cardiomyopathy type 1NN
- cardiomyopathy, dilated, 1NN
- RAF1 familial isolated dilated cardiomyopathy
- RAF1-related childhood-onset dilated cardiomyopathy
description: >-
  Dilated cardiomyopathy 1NN (CMD1NN, OMIM 615916) is the RAF1-related member of
  the numbered familial isolated dilated cardiomyopathy series. It is the
  mechanistically awkward member of that series and the reason it is curated
  separately: RAF1 is a RASopathy gene, and the phenotype normally produced by a
  disease-causing RAF1 allele is the opposite one. Noonan-syndrome RAF1 alleles
  cluster in two hotspots around Ser259, raise kinase activity, enhance ERK
  activation, and produce hypertrophic cardiomyopathy in 95% of hotspot carriers.
  The alleles reported in CMD1NN behave differently. Dhandapany and colleagues
  resequenced 513 dilated cardiomyopathy cases against 1,150 matched controls
  across South Indian, North Indian and Japanese cohorts, found rare functional
  RAF1 variants in all three, and showed biochemically that these mutants left
  ERK activation largely unaltered while hyperactivating AKT in a BRAF-dependent
  manner. Cardiac expression of the mutants in zebrafish produced heart failure
  with AKT hyperactivation that rapamycin rescued, implicating the AKT-mTOR arm
  rather than the ERK arm that drives the RASopathy hypertrophic phenotype. The
  disease presents as isolated, predominantly childhood-onset left ventricular
  dilation with systolic dysfunction, without the facial, growth or developmental
  features of Noonan syndrome. Evidence rests almost entirely on that 2014
  discovery report and its models; ClinGen has curated RAF1 for Noonan syndrome
  (Definitive) but has no gene-disease validity assertion for RAF1-dilated
  cardiomyopathy, and that gap is recorded explicitly below rather than papered
  over.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: dilated cardiomyopathy 1NN
  term:
    id: MONDO:0014396
    label: dilated cardiomyopathy 1NN
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
inheritance:
- name: Autosomal dominant
  description: >-
    CMD1NN is classified as an autosomal dominant trait (OMIM 615916). The
    reported alleles are heterozygous and predominantly missense substitutions in
    RAF1, with one frameshift truncation (p.R254fs) reported in the North Indian
    cohort of the discovery study, and the
    disease is described in the RASopathy cardiomyopathy literature as an
    inherited RAF1 phenotype. The direct evidence for the mode of inheritance is
    weaker than for the mechanism: the discovery report was a case-control
    resequencing study rather than a large pedigree study, and no
    penetrance estimate specific to RAF1 dilated cardiomyopathy has been
    published, so no penetrance value is recorded here.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:26380542
    reference_title: "Cardiomyopathies in Noonan syndrome and the other RASopathies."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, inherited abnormalities in one pathway gene, RAF1, cause
      pediatric-onset dilated cardiomyopathy.
    explanation: >-
      States that the RAF1 dilated cardiomyopathy alleles are inherited rather
      than exclusively de novo, which is the part of the dominant-transmission
      claim this review directly supports. It is INDIRECT for the dominant mode
      itself, which the sentence does not name.
  - reference: PMID:26380542
    reference_title: "Cardiomyopathies in Noonan syndrome and the other RASopathies."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Noonan syndrome and related disorders (Noonan syndrome with multiple
      lentigines, Costello syndrome, cardiofaciocutaneous syndrome, Noonan
      syndrome with loose anagen hair, and other related traits) are autosomal
      dominant traits.
    explanation: >-
      Establishes autosomal dominant transmission for heterozygous RAF1-pathway
      alleles generally. It is INDIRECT because the sentence enumerates the
      syndromic RASopathies, not CMD1NN, and is cited here only as the pathway-level
      precedent for a heterozygous missense allele acting dominantly.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >-
    No population prevalence has been established for CMD1NN. The frequently
    quoted "~9%" figure is a case fraction among childhood-onset dilated
    cardiomyopathy in the three discovery cohorts, not a population rate, and is
    recorded as such under `genetic` rather than here.
pathophysiology:
- name: RAF1 Variant Altering Kinase Activity
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The initiating lesion is a rare heterozygous RAF1 variant - in most reported
    cases a missense substitution, and in one North Indian case a frameshift
    truncation (p.R254fs) - in the gene
    encoding the RAF-1 (CRAF) serine/threonine kinase of the RAS-MAPK pathway.
    What distinguishes the dilated-cardiomyopathy alleles from the
    Noonan-syndrome ones is not merely their position but the direction of their
    effect on the kinase. The Noonan hotspots flank Ser259 and raise kinase
    activity; the dilated-cardiomyopathy alleles have been reported to have
    reduced kinase activity relative to the hypertrophic-cardiomyopathy alleles
    and to leave the residues critical to regulation unaltered. Molecular
    dynamics of the C-terminal variants makes the same point at residue
    resolution: the DCM-associated p.Leu603Pro substitution drives the kinase
    domain into an inactive conformation, while the HCM-associated S612T and
    L613V substitutions - only a few residues away - stabilise an active one. A
    single gain-of-function or loss-of-function label is therefore not warranted
    across the reported CMD1NN allele set, and none is asserted here.
  genes:
  - preferred_term: RAF1
    term:
      id: hgnc:9829
      label: RAF1
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: RAF-1 serine/threonine kinase activity
    term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
    modifier: ABNORMAL
  evidence:
  - reference: PMID:24777450
    reference_title: "RAF1 mutations in childhood-onset dilated cardiomyopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On the basis of resequencing of 513 DCM cases and 1,150 matched controls
      from various cohorts of distinct ancestry, we discovered rare, functional
      RAF1 mutations in 3 of the cohorts (South Indian, North Indian and
      Japanese).
    explanation: >-
      Establishes the trigger lesion - rare functional RAF1 variants - and the
      case-control ascertainment in three independent cohorts that supports it.
  - reference: PMID:24777450
    reference_title: "RAF1 mutations in childhood-onset dilated cardiomyopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In Group 2, two additional RAF1 sequence variants were identified: a
      single base-pair deletion leading to a protein truncation (p.R254fs) and a
      missense mutation predicting a p.Thr641Met substitution.
    explanation: >-
      Records the one reported allele that is not a missense substitution, which
      is why this node is not scoped to missense alleles. A frameshift
      truncation is the reason the allele set cannot be given a single
      gain-of-function or loss-of-function label.
  - reference: PMID:24777450
    reference_title: "RAF1 mutations in childhood-onset dilated cardiomyopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      One DCM-associated missense mutant (p.Leu603Pro) showed impaired kinase
      activity and reduced ERK activation as did the truncated RAF1 protein
      (p.R254fs).
    explanation: >-
      Shows the truncating allele was functionally characterised alongside the
      missense alleles and behaves like the kinase-impairing one, so it belongs
      to this node's lesion class rather than being an incidental finding.
      Graded IN_VITRO because the kinase-activity and ERK-activation
      measurements are cell-based assays, not observations in patients.
  - reference: PMID:36927384
    reference_title: "Molecular analyses of the C-terminal CRAF variants associated with cardiomyopathy reveal their opposing impacts on the active conformation of the kinase domain."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      The experimental data suggest that genetic alternation at position 603
      impairs, while those at positions 612/613 enhance the CRAF kinase activity.
    explanation: >-
      States the opposing directional effect of neighbouring C-terminal CRAF
      substitutions, which is the residue-level basis for treating the
      dilated-cardiomyopathy alleles as a distinct functional class rather than
      as more RASopathy gain-of-function alleles. Graded IN_VITRO rather than
      COMPUTATIONAL because this sentence summarises the prior kinase-activity
      measurements the paper sets out to explain; the simulation is what the
      authors then contribute, and is cited separately below.
  - reference: PMID:36927384
    reference_title: "Molecular analyses of the C-terminal CRAF variants associated with cardiomyopathy reveal their opposing impacts on the active conformation of the kinase domain."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: >-
      the substitution of Leucine 603 for proline transits the kinase domain to a
      state that exhibits the molecular hallmarks of an inactive kinase, for
      example, a closed activation loop
    explanation: >-
      Gives the structural mechanism by which the DCM-associated p.Leu603Pro
      allele impairs the kinase. INDIRECT because it is a molecular dynamics
      simulation rather than a measurement in patient tissue.
  - reference: PMID:29696744
    reference_title: "NGS testing for cardiomyopathy: Utility of adding RASopathy-associated genes."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      variants have been reported to be functionally distinct, with the
      DCM-associated variants having reduced kinase activity compared to
      HCM-associated variants and unaltered residues critical to regulation
      (Dhandapany et al., 2014)
    explanation: >-
      Restates the functional distinction between the dilated- and
      hypertrophic-cardiomyopathy RAF1 alleles. Not independent corroboration:
      the sentence attributes the claim to Dhandapany et al. 2014, the discovery
      paper already cited on this node. Graded IN_VITRO because the underlying
      measurement being restated is kinase biochemistry, not a clinical
      observation from this sequencing cohort, and INDIRECT because it reaches
      the claim through that citation rather than reporting it.
  downstream:
  - target: BRAF-Dependent AKT Hyperactivation
    causal_link_type: DIRECT
    description: >-
      The altered RAF-1 kinase redirects signalling into the AKT arm rather than
      amplifying ERK.
    evidence:
    - reference: PMID:24777450
      reference_title: "RAF1 mutations in childhood-onset dilated cardiomyopathy."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: IN_VITRO
      snippet: >-
        Biochemical studies showed that DCM-associated RAF1 mutants had altered
        kinase activity, resulting in largely unaltered ERK activation but in AKT
        that was hyperactivated in a BRAF-dependent manner.
      explanation: >-
        Directly links the mutant kinase to AKT hyperactivation and records that
        ERK activation was largely unaltered, which is the edge this node asserts.
- name: BRAF-Dependent AKT Hyperactivation
  biological_scale: MOLECULAR
  role: effector
  description: >-
    In cells expressing the dilated-cardiomyopathy RAF1 mutants, AKT is
    hyperactivated, and that hyperactivation depends on BRAF - the paralogous RAF
    kinase - rather than on RAF-1 acting directly. ERK activation is largely
    unaltered. This is the node that separates CMD1NN from RAF1 Noonan syndrome
    at the level of signalling: the Noonan hotspot mutants show increased kinase
    activity with enhanced ERK activation, and it is that ERK amplification that
    the RASopathy literature implicates in pathological cardiomyocyte
    hypertrophy.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: AKT signaling
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    modifier: INCREASED
  - preferred_term: ERK1/ERK2 cascade
    term:
      id: GO:0070371
      label: ERK1 and ERK2 cascade
  evidence:
  - reference: PMID:24777450
    reference_title: "RAF1 mutations in childhood-onset dilated cardiomyopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Biochemical studies showed that DCM-associated RAF1 mutants had altered
      kinase activity, resulting in largely unaltered ERK activation but in AKT
      that was hyperactivated in a BRAF-dependent manner.
    explanation: >-
      The primary evidence for this node, including the BRAF dependence and the
      absence of a substantial ERK effect. The ERK1/ERK2 cascade term is bound
      without a modifier for exactly that reason - no directional change is claimed.
  - reference: PMID:17603483
    reference_title: "Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    snippet: >-
      Ectopically expressed RAF1 mutants from the two HCM hotspots had increased
      kinase activity and enhanced ERK activation, whereas non-HCM-associated
      mutants were kinase impaired.
    explanation: >-
      The contrasting Noonan-syndrome result. Cited as INDIRECT support because it
      characterises a different allele class; it is what establishes that the
      absence of ERK amplification in the dilated-cardiomyopathy mutants is a
      genuine discriminator rather than an assay limitation.
  downstream:
  - target: mTOR Pathway Activation
    causal_link_type: DIRECT
    description: >-
      Hyperactive AKT drives the downstream mTOR growth and protein-synthesis
      program.
    evidence:
    - reference: PMID:24777450
      reference_title: "RAF1 mutations in childhood-onset dilated cardiomyopathy."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Constitutive expression of these mutants in zebrafish embryos resulted in
        a heart failure phenotype with AKT hyperactivation that was rescued by
        treatment with rapamycin.
      explanation: >-
        Rapamycin is an mTOR inhibitor, so rescue of the AKT-hyperactivated
        phenotype by rapamycin places mTOR downstream of AKT in this disease. It
        is INDIRECT because the mTOR step is inferred from the pharmacology of the
        rescuing agent rather than measured directly in the report abstract.
- name: mTOR Pathway Activation
  biological_scale: CELLULAR
  role: effector
  description: >-
    Increased signalling through mTOR reprograms cardiomyocyte growth, protein
    synthesis and autophagic turnover. The evidence that this step is load-bearing
    in CMD1NN is pharmacological rather than observational: rapamycin, an mTOR
    inhibitor, rescued the cardiac phenotype produced by the mutants in zebrafish.
    This is the step that makes the disease mechanistically interesting - and, in
    principle, druggable in a way the RASopathy hypertrophic cardiomyopathies are
    not, since those are targeted at the MEK/ERK arm instead.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: TOR signaling
    term:
      id: GO:0031929
      label: TOR signaling
    modifier: INCREASED
  evidence:
  - reference: PMID:24777450
    reference_title: "RAF1 mutations in childhood-onset dilated cardiomyopathy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Constitutive expression of these mutants in zebrafish embryos resulted in a
      heart failure phenotype with AKT hyperactivation that was rescued by
      treatment with rapamycin.
    explanation: >-
      Rapamycin rescue is the evidence that mTOR signalling mediates the cardiac
      phenotype. INDIRECT because mTOR involvement is inferred from the target of
      the rescuing drug.
  downstream:
  - target: Ventricular Dilation and Systolic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Dysregulated growth and remodelling signalling in the cardiomyocyte
      culminates in chamber dilation and falling contractile performance. The
      intermediate sarcomeric and metabolic lesions in CMD1NN have not been
      demonstrated, which is why this edge is not marked DIRECT.
- name: Ventricular Dilation and Systolic Dysfunction
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    The defining structural lesion: left ventricular or biventricular enlargement
    with impaired contraction, not explained by abnormal loading conditions or
    coronary artery disease. In CMD1NN this is reached from a signalling lesion
    rather than from a sarcomeric or cytoskeletal one, which is unusual within the
    numbered dilated cardiomyopathy series, where the causal lesion is more often
    sarcomeric, Z-disc, nuclear-envelope, proteostatic or post-transcriptional.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: Cardiac Fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: Heart Contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: DECREASED
  - preferred_term: Extracellular Matrix Organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  locations:
  - preferred_term: Left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  evidence:
  - reference: PMID:31073128
    reference_title: "Dilated cardiomyopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: >-
      Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left
      ventricular or biventricular dilation and impaired contraction that is not
      explained by abnormal loading conditions (for example, hypertension and
      valvular heart disease) or coronary artery disease.
    explanation: >-
      States the structural and exclusionary definition this node represents.
      Evidence source is OTHER because this is a Nature Reviews Disease Primers
      review rather than a primary study.
  - reference: PMID:24777450
    reference_title: "RAF1 mutations in childhood-onset dilated cardiomyopathy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Constitutive expression of these mutants in zebrafish embryos resulted in a
      heart failure phenotype with AKT hyperactivation that was rescued by
      treatment with rapamycin.
    explanation: >-
      In vivo demonstration that the mutant alleles are sufficient to produce a
      failing heart. INDIRECT for the human ventricular phenotype because the
      readout is an mRNA-injected zebrafish embryo, not a patient ventricle.
  downstream:
  - target: Heart Failure
    causal_link_type: DIRECT
    description: >-
      The dilated, poorly contracting ventricle fails to maintain output.
- name: Heart Failure
  biological_scale: ORGANISM
  role: consequence
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >-
    Progressive systolic heart failure is the clinical endpoint. Onset in the
    reported CMD1NN cases was predominantly in childhood, and childhood
    cardiomyopathies are the most common cause of heart failure in children and are
    frequently transplantation-requiring.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:30384889
    reference_title: "Genetic Basis of Severe Childhood-Onset Cardiomyopathies."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Childhood cardiomyopathies are progressive and often lethal disorders,
      forming the most common cause of heart failure in children.
    explanation: >-
      Establishes the severity and heart-failure burden of the childhood-onset
      cardiomyopathy class to which CMD1NN belongs. INDIRECT because the cohort is
      childhood cardiomyopathy generally, not RAF1 carriers.
phenotypes:
- name: Dilated Cardiomyopathy
  category: Cardiovascular
  description: >-
    Left ventricular or biventricular dilation with systolic dysfunction is the
    defining and obligate feature.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
    onset:
      onset_category: CHILDHOOD
      notes: >-
        Onset in the reported CMD1NN cases was predominantly in childhood; the
        alleles were found by resequencing childhood-onset dilated cardiomyopathy
        cases. Later-onset presentation has not been excluded.
  frequency: OBLIGATE
  evidence:
  - reference: PMID:26380542
    reference_title: "Cardiomyopathies in Noonan syndrome and the other RASopathies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, inherited abnormalities in one pathway gene, RAF1, cause
      pediatric-onset dilated cardiomyopathy.
    explanation: >-
      States both the phenotype and its pediatric onset for the RAF1 dilated
      cardiomyopathy entity.
  - reference: PMID:24777450
    reference_title: "RAF1 mutations in childhood-onset dilated cardiomyopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The prevalence of RAF1 mutations was ~9% in childhood-onset DCM cases in
      these three cohorts.
    explanation: >-
      Anchors the phenotype to childhood-onset dilated cardiomyopathy, the
      ascertainment category in which the RAF1 alleles were found.
- name: Reduced Left Ventricular Ejection Fraction
  category: Cardiovascular
  description: >-
    Impaired systolic performance is the functional counterpart of the structural
    dilation and is the measurement on which the diagnosis is made
    echocardiographically. No CMD1NN-specific ejection-fraction distribution has
    been published.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:31073128
    reference_title: "Dilated cardiomyopathy."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left
      ventricular or biventricular dilation and impaired contraction that is not
      explained by abnormal loading conditions (for example, hypertension and
      valvular heart disease) or coronary artery disease.
    explanation: >-
      Impaired contraction is part of the definition of the phenotype CMD1NN
      manifests. INDIRECT because this is the general DCM definition, not a
      CMD1NN measurement.
- name: Congestive Heart Failure
  category: Cardiovascular
  description: >-
    Progressive pump failure with congestion, exercise intolerance and, in
    children, feeding and growth difficulty.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:30384889
    reference_title: "Genetic Basis of Severe Childhood-Onset Cardiomyopathies."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Childhood cardiomyopathies are progressive and often lethal disorders,
      forming the most common cause of heart failure in children.
    explanation: >-
      Documents heart failure as the dominant clinical consequence of the
      childhood cardiomyopathy class. INDIRECT for CMD1NN specifically.
diagnosis:
- name: Echocardiography
  description: >-
    First-line and usually diagnostic: left ventricular internal dimensions and
    ejection fraction establish the dilated, hypocontractile phenotype. Nothing
    about the imaging is RAF1-specific, and the echocardiogram is also where the
    principal differential call is made - wall hypertrophy rather than dilation
    points to the RASopathy phenotype instead.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:31073128
    reference_title: "Dilated cardiomyopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: >-
      Echocardiography and other imaging techniques are required to assess
      ventricular dysfunction and adverse myocardial remodelling
    explanation: >-
      Establishes imaging as the required modality for assessing the ventricular
      dysfunction that defines the phenotype.
- name: Cardiomyopathy Gene Panel Including RASopathy Genes
  description: >-
    Molecular confirmation requires a cardiomyopathy panel that actually contains
    RAF1. This is not automatic: RASopathy genes were historically absent from
    cardiomyopathy panels, and the case for including them was made on the
    strength of the hypertrophic phenotype, where the yield is highest. The
    evidence for this route in dilated phenotypes is in fact negative: the one
    clinical service that prospectively tested 11 RASopathy genes in 419
    referrals for dilated cardiomyopathy found no variant of clinical
    significance and concluded against testing in DCM. So the panel is the
    practical route to a molecular diagnosis of CMD1NN only because RAF1 happens
    to be carried on it, not because unselected DCM referrals are a productive
    place to look. A RAF1 variant of uncertain significance does not establish
    CMD1NN; phenotype fit, population frequency, segregation, allele class and
    functional data all have to be weighed, and the historical CMD1NN allele list
    carries mixed in-silico predictions.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:29696744
    reference_title: "NGS testing for cardiomyopathy: Utility of adding RASopathy-associated genes."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      was recently associated with pediatric-onset dilated cardiomyopathy (DCM)
      (Dhandapany et al., 2014)
    explanation: >-
      Records why RAF1 is on a RASopathy gene set applied to dilated as well as
      hypertrophic referrals. This is a background sentence attributing the
      DCM association to Dhandapany et al. 2014, not a result of this study -
      the same paper's own DCM result is negative and is cited below. INDIRECT
      because it establishes the gene-disease association that motivates panel
      inclusion rather than the diagnostic performance of the panel itself.
  - reference: PMID:29696744
    reference_title: "NGS testing for cardiomyopathy: Utility of adding RASopathy-associated genes."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No variants of clinical significance were identified in the DCM sub-cohort
    explanation: >-
      The diagnostic yield of RASopathy-gene testing in this study's 419 dilated
      cardiomyopathy referrals was zero, which argues against the panel as a
      productive route to a molecular diagnosis in unselected DCM.
  - reference: PMID:29696744
    reference_title: "NGS testing for cardiomyopathy: Utility of adding RASopathy-associated genes."
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there appears little, if any, benefit to testing individuals with DCM
    explanation: >-
      The study's own recommendation is against RASopathy-gene testing in
      dilated cardiomyopathy. Kept as an explicit REFUTE so this diagnostic
      entry is not read as endorsed by a paper that argues the opposite.
  - reference: PMID:30762279
    reference_title: "Prevalence of pathogenic and likely pathogenic variants in the RASopathy genes in patients who have had panel testing for cardiomyopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that the RASopathy genes should be included on multi-gene
      panels for cardiomyopathy to increase diagnostic yield for individuals with
      HCM.
    explanation: >-
      Supports panel inclusion of the RASopathy genes, while being explicit that
      the demonstrated yield in that cohort was in hypertrophic cardiomyopathy -
      the caveat that makes this diagnostic route weaker for CMD1NN than the
      recommendation alone suggests.
genetic:
- name: RAF1
  gene_term:
    preferred_term: RAF1
    term:
      id: hgnc:9829
      label: RAF1
  relationship_type: CAUSATIVE
  frequency: >-
    Reported in roughly 9% of childhood-onset dilated cardiomyopathy cases across
    the three discovery cohorts. This is a case fraction in an ascertained
    pediatric series and should not be read as a population rate or as the yield
    expected in an unselected dilated cardiomyopathy clinic.
  case_fractions:
  - population: >-
      Childhood-onset dilated cardiomyopathy cases in South Indian, North Indian
      and Japanese cohorts (discovery series)
    case_fraction_percent: 9.0
    notes: >-
      Drawn from a resequencing study of 513 dilated cardiomyopathy cases against
      1,150 matched controls; the 9% denominator is the childhood-onset subset of
      those three cohorts, not the full 513.
    evidence:
    - reference: PMID:24777450
      reference_title: "RAF1 mutations in childhood-onset dilated cardiomyopathy."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The prevalence of RAF1 mutations was ~9% in childhood-onset DCM cases in
        these three cohorts.
      explanation: Gives the case fraction and names the cohorts it applies to.
  evidence:
  - reference: PMID:24777450
    reference_title: "RAF1 mutations in childhood-onset dilated cardiomyopathy."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These findings provide new mechanistic insights and potential therapeutic
      targets for RAF1-associated DCM and further expand the clinical spectrum of
      RAF1-related human disorders.
    explanation: >-
      The discovery report's own causal conclusion, and its framing of the entity
      as an expansion of the RAF1 clinical spectrum rather than a form of Noonan
      syndrome.
  - reference: PMID:30762279
    reference_title: "Prevalence of pathogenic and likely pathogenic variants in the RASopathy genes in patients who have had panel testing for cardiomyopathy."
    supports: REFUTE
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified four patients (5.41%) with pathogenic or likely pathogenic
      variants in HRAS, PTPN11 and RAF1 (two individuals). Indication for testing
      for all four individuals was HCM.
    explanation: >-
      Counter-evidence recorded deliberately. In a clinical cardiomyopathy panel
      cohort that included 24 dilated cardiomyopathy cases and 9 with combined
      noncompaction and dilated disease, every pathogenic RASopathy-gene finding
      came from a patient tested for hypertrophic cardiomyopathy. It does not
      refute the gene-disease relationship, but it refutes any expectation that
      RAF1 is a frequent yield in unselected dilated cardiomyopathy, and it is why
      the discovery case fraction is not generalised.
animal_models:
- name: Zebrafish cardiac expression of DCM-associated RAF1 mutants
  species: Zebrafish
  genotype: >-
    Constitutive embryonic expression of human dilated-cardiomyopathy-associated
    RAF1 missense mutants
  description: >-
    The in vivo model behind the CMD1NN mechanism. Zebrafish embryos constitutively
    expressing the dilated-cardiomyopathy RAF1 mutants developed a heart failure
    phenotype accompanied by AKT hyperactivation, and treatment with rapamycin
    rescued it. The rescue arm is what makes this model do mechanistic work rather
    than merely demonstrate toxicity: it places mTOR in the causal path.
  publication: PMID:24777450
  modeled_mechanisms:
  - target: mTOR Pathway Activation
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The model reproduces the AKT-hyperactivated, mTOR-dependent cardiac failure
      that this node asserts, and the rapamycin rescue establishes the dependence
      rather than merely the correlation.
    limitations: >-
      Transient mRNA overexpression is not the human genetic situation, which
      is a single heterozygous missense allele at endogenous dosage; overexpression
      can produce signalling phenotypes that a heterozygous allele would not. The
      zebrafish heart is two-chambered and regenerative, so chamber dilation,
      chronic fibrosis and the human developmental timescale are not modelled.
    readouts:
    - name: Rapamycin rescue of the cardiac failure phenotype
      target: mTOR Pathway Activation
      direction: RESTORED
      interpretation: >-
        Pharmacological mTOR inhibition reverses the mutant phenotype, which is the
        measurement that places mTOR signalling in the causal chain.
      evidence:
      - reference: PMID:24777450
        reference_title: "RAF1 mutations in childhood-onset dilated cardiomyopathy."
        supports: SUPPORT
        directness: DIRECT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Constitutive expression of these mutants in zebrafish embryos resulted in
          a heart failure phenotype with AKT hyperactivation that was rescued by
          treatment with rapamycin.
        explanation: Reports the rescue measurement behind this readout.
    evidence:
    - reference: PMID:24777450
      reference_title: "RAF1 mutations in childhood-onset dilated cardiomyopathy."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Constitutive expression of these mutants in zebrafish embryos resulted in a
        heart failure phenotype with AKT hyperactivation that was rescued by
        treatment with rapamycin.
      explanation: >-
        Supports treating this model as informative for the AKT-mTOR node, since it
        reproduces both the signalling abnormality and a cardiac failure phenotype.
treatments:
- name: Heart Failure Pharmacotherapy
  description: >-
    Guideline-directed heart-failure therapy for the manifest phenotype, dosed for
    age. There is no RAF1-directed or CMD1NN-specific approved therapy, so
    management is phenotype-based and identical to that for other genetic dilated
    cardiomyopathies: renin-angiotensin blockade with an ACE inhibitor or an
    angiotensin receptor-neprilysin inhibitor, a beta-blocker, a mineralocorticoid
    receptor antagonist, and, in eligible patients, an SGLT2 inhibitor. A loop
    diuretic is used for congestion but is symptomatic rather than
    disease-modifying, and is not bound here because no cited source in this entry
    states that indication for dilated cardiomyopathy specifically. Nothing in this
    regimen acts on the RAF1 lesion; it acts on the neurohormonal remodelling
    downstream of it.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: angiotensin receptor-neprilysin inhibitor
      term:
        id: NCIT:C190796
        label: Angiotensin Receptor-Neprilysin Inhibitor
    - preferred_term: beta-blocker
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
    - preferred_term: mineralocorticoid receptor antagonist
      term:
        id: NCIT:C101255
        label: Aldosterone Receptor Antagonist
    - preferred_term: SGLT2 inhibitor
      term:
        id: NCIT:C98083
        label: SGLT2 Inhibitor
  target_mechanisms:
  - target: Ventricular Dilation and Systolic Dysfunction
    treatment_effect: MODULATES
    description: >-
      Neurohormonal blockade opposes the maladaptive remodelling that carries the
      dilated, hypocontractile ventricle forward, rather than correcting the
      upstream RAF1 kinase lesion or the AKT-mTOR signalling it drives. The link
      is therefore placed at the chamber-remodelling node and not at the
      molecular trigger.
    evidence:
    - reference: PMID:39064249
      reference_title: "New Therapeutics for Heart Failure Worsening: Focus on Vericiguat."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: OTHER
      snippet: >-
        The standard treatment of HF includes angiotensin-converting enzyme
        inhibitors, angiotensin receptor-neprilysin inhibitors,
        mineralocorticoid-receptor antagonists, beta-blockers, and
        sodium-glucose-co-transporter 2 inhibitors.
      explanation: >-
        Names the four-pillar class set bound above as standard therapy for the
        reduced-ejection-fraction phenotype this node describes. INDIRECT and
        OTHER because it is a narrative review's statement of standard of care
        in heart failure generally, not a trial result in CMD1NN, whose
        management is extrapolated from that guidance.
    - reference: PMID:37876955
      reference_title: "Clinical profile and outcomes of childhood dilated cardiomyopathy - A single-center three-decade experience."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Seventy-two percent of this cohort were on angiotensin-converting-enzyme
        inhibitors, 40% on aldosterone antagonists, and 47% on beta-blockers.
      explanation: >-
        Documents that the same neurohormonal classes are what childhood dilated
        cardiomyopathy is actually treated with, which is the age group CMD1NN
        presents in. INDIRECT because the cohort is childhood dilated
        cardiomyopathy of mixed cause, not a RAF1-genotyped series.
- name: Heart Transplantation
  description: >-
    Advanced, refractory disease is an indication for transplantation, which is a
    common outcome in severe childhood-onset cardiomyopathy.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: organ transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  evidence:
  - reference: PMID:30384889
    reference_title: "Genetic Basis of Severe Childhood-Onset Cardiomyopathies."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Childhood cardiomyopathies are progressive and often lethal disorders,
      forming the most common cause of heart failure in children.
    explanation: >-
      Supports the severity that makes transplantation a realistic endpoint in this
      disease class. INDIRECT because the cohort is childhood cardiomyopathy
      generally.
  target_mechanisms:
  - target: Heart Failure
    treatment_effect: BYPASSES
    description: >-
      Transplantation replaces the failing organ rather than acting anywhere in
      the RAF1 causal chain, so it resolves the terminal node without correcting
      the kinase lesion, the AKT-mTOR signalling, or the remodelling upstream of
      it. It is the endpoint of the pathograph, not an intervention in it.
    evidence:
    - reference: PMID:37876955
      reference_title: "Clinical profile and outcomes of childhood dilated cardiomyopathy - A single-center three-decade experience."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Dilated cardiomyopathy (DCM) remains the most common form of
        cardiomyopathy and the reason for cardiac transplantation among children.
      explanation: >-
        Establishes that transplantation is the standard destination for
        childhood dilated cardiomyopathy that reaches refractory heart failure,
        which is the node this link points at. INDIRECT because the statement is
        about childhood DCM as a class rather than RAF1-associated cases.
discussions:
- discussion_id: cmd1nn_gene_disease_validity_unadjudicated
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Would RAF1-dilated cardiomyopathy survive a formal ClinGen gene-disease
    validity curation as an entity distinct from RAF1-Noonan syndrome?
  attaches_to:
  - genetic#RAF1
  rationale: >-
    ClinGen's RASopathy Gene Curation Expert Panel has curated RAF1 against Noonan
    syndrome and classified it Definitive. No ClinGen assertion exists for
    RAF1 against dilated cardiomyopathy, so the entity's gene-disease validity has
    never been graded by the body whose gradings this knowledge base otherwise
    treats as authoritative. The supporting human genetic evidence is
    concentrated in a single 2014 case-control resequencing report, and a
    subsequent clinical panel cohort found pathogenic RASopathy-gene variants only
    among patients tested for hypertrophic cardiomyopathy. This is a gap in
    adjudication rather than a positive refutation - the mechanism evidence is
    strong and independent - but it is the reason this entry does not describe the
    gene-disease relationship as definitive.
  evidence:
  - reference: CGGV:assertion_85645d27-2056-4ad3-9593-8d7739aa4121-2024-10-23T160000.000Z
    reference_title: "RAF1 / Noonan syndrome (Definitive)"
    supports: SUPPORT
    directness: DIRECT
    evidence_source: OTHER
    snippet: >-
      RAF1 | HGNC:9829 | Noonan syndrome | MONDO:0018997 | AD | Definitive
    explanation: >-
      Shows the disease against which ClinGen has actually curated RAF1. The
      absence of a corresponding dilated-cardiomyopathy row is the gap.
- discussion_id: cmd1nn_zebrafish_overexpression_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does transient mRNA overexpression of a RAF1 mutant in a zebrafish embryo
    model what a single heterozygous RAF1 missense allele does to a human
    ventricle?
  attaches_to:
  - pathophysiology#mTOR Pathway Activation
  - animal_models#Zebrafish
  rationale: >-
    The only in vivo evidence for the AKT-mTOR mechanism comes from constitutive
    expression of the mutants in zebrafish embryos. Human CMD1NN is heterozygosity
    for a missense allele at endogenous dosage in a four-chambered,
    non-regenerative heart that dilates over years. Overexpression can drive
    signalling outputs that a heterozygous allele does not, and the zebrafish
    readout was heart failure in an embryo rather than progressive chamber
    dilation. The mismatch matters specifically for the therapeutic inference: the
    rapamycin rescue is the strongest reason to think mTOR inhibition might be
    disease-modifying in patients, and it is exactly the result the model's
    non-physiological expression level puts most at risk.
  proposed_experiments:
  - experiment_id: exp_cmd1nn_isogenic_ipsc_allele_comparison
    name: Isogenic human cardiomyocyte comparison of DCM and HCM RAF1 alleles
    description: >-
      Introduce the reported CMD1NN alleles into human iPSC-derived cardiomyocytes
      or engineered cardiac tissue at endogenous dosage, alongside isogenic
      controls and a Noonan hotspot allele, and measure AKT, mTOR and ERK
      signalling together with contractile function. This is the experiment that
      would show whether the AKT-over-ERK split holds at heterozygous dosage in
      human myocardium, and it has already been done for the Noonan
      p.Ser257Leu allele but not for the dilated-cardiomyopathy alleles.
    would_support:
    - pathophysiology#BRAF-Dependent AKT Hyperactivation
    - pathophysiology#mTOR Pathway Activation
    supporting_outcome:
    - >-
      Heterozygous CMD1NN alleles raise AKT and mTOR pathway activity without
      substantially raising ERK activity, and impair contractile function, in
      isogenic human cardiomyocytes.
    would_refute:
    - pathophysiology#BRAF-Dependent AKT Hyperactivation
    refuting_outcome:
    - >-
      At endogenous heterozygous dosage the CMD1NN alleles produce no measurable
      AKT or mTOR change relative to isogenic controls, indicating the signalling
      phenotype was an artefact of overexpression.
notes: >-
  Lump/split decision: curated as a standalone Disease rather than as a
  has_subtypes entry on Noonan_Syndrome. The considerations were as follows.

  For separation. CMD1NN has its own MONDO term (MONDO:0014396) and its own OMIM
  phenotype number (615916), and MONDO places it under familial isolated dilated
  cardiomyopathy (MONDO:0700335), not under Noonan syndrome. The phenotype is
  isolated - dilated, without the facial, growth or developmental features that
  define a RASopathy. Most importantly the signalling lesion runs the other way:
  the Noonan RAF1 alleles increase kinase activity and enhance ERK activation and
  produce hypertrophy, while the dilated-cardiomyopathy alleles leave ERK largely
  unaltered and hyperactivate AKT. Folding CMD1NN into Noonan_Syndrome as a
  subtype would have placed a non-syndromic, ERK-neutral, dilated phenotype inside
  an entry whose RAF1 pathophysiology node is explicitly "RAF1 Kinase
  Hyperactivation" driving "Cardiomyocyte Hypertrophy" - the conforming node would
  have contradicted its parent.

  What the separation does NOT rest on. The issue that commissioned this entry
  proposed that Noonan RAF1 alleles cluster in the CR2 domain while the CMD1NN
  alleles sit in the CR3/kinase domain, and that this domain segregation justifies
  the split. That was checked and is not clean enough to assert. The six alleles
  listed in the discovery supplement span the CR2-CR3 linker region
  (p.Ala237Thr, p.Thr310Ala, p.Pro332Ala), the kinase domain (p.Leu603Pro) and the
  C-terminal tail (p.His626Arg, p.Thr641Met), while Noonan-associated alleles occur
  both around Ser259 and in the C-terminus. The C-terminal region in particular
  hosts both classes: the DCM-associated L603 and the HCM-associated S612T/L613V
  are separated by fewer than ten residues (PMID:36927384). The defensible
  statement is functional, not positional - the classes differ in the direction of
  their effect on kinase activity and in which downstream arm they engage - and
  that is what this entry asserts.

  Evidence scope. The human genetic evidence is essentially one report
  (PMID:24777450); the mechanism rests on its biochemistry and its zebrafish model.
  No ClinGen gene-disease validity assertion exists for RAF1-dilated
  cardiomyopathy, and a 2019 clinical panel cohort found RASopathy-gene pathogenic
  variants only in hypertrophic-cardiomyopathy referrals (PMID:30762279). Both are
  recorded as structured content - the first as a KNOWLEDGE_GAP discussion, the
  second as a REFUTE evidence item on the gene - rather than left as prose caveats.
  The 2018 panel study (PMID:29696744) cuts the same way and is cited on both
  sides for that reason: its background sentence is why RAF1 is on a cardiomyopathy
  panel at all, but its own dilated-cardiomyopathy sub-cohort of 419 yielded no
  variant of clinical significance and it recommends against testing in DCM. Those
  are two claims from one paper, so they are two evidence items - one SUPPORT and
  two REFUTE - on the gene-panel diagnosis entry, rather than one item whose
  explanation quietly reverses the quote.

  Named entity confusion. The acronym CMD1NN is flagged for ambiguity, and there is
  a documented real-world instance of the label being misapplied: a 2025 case report
  describes a laboratory report annotating RAF1 p.Ser257Leu as "dilated
  cardiomyopathy type 1NN" in a child who in fact had Noonan syndrome with
  hypertrophic cardiomyopathy. p.Ser257Leu is a Noonan hotspot allele and is not a
  CMD1NN allele. Identity here is anchored on MONDO:0014396 / OMIM 615916 and on
  the discovery allele set, not on the acronym.

  Deliberately not done. CMD1NN was not added to
  kb/groupings/Familial_Dilated_Cardiomyopathy.yaml in this change, although it is a
  MONDO child of that grouping's mapped term (MONDO:0700335) and belongs there. The
  grouping's rationale enumerates the mechanistic classes its members represent, and
  a signalling-kinase lesion would be a new one requiring a prose edit; a
  concurrent curation branch is adding another member to the same file, and both
  edits landing blind would conflict. The membership addition is left as a
  follow-up. No treatment entry was created for rapamycin or mTOR inhibition: the
  rescue is preclinical, and it is recorded where it belongs, as a RESTORED readout
  on the zebrafish model.
references:
- reference: PMID:20301486
  title: Dilated Cardiomyopathy Overview.
  tags:
  - GeneReviews

📚

References & Deep Research

References

1

PMID:20301486

Dilated Cardiomyopathy Overview.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Edit: address CHANGES_REQUESTED review on PR #10650 · 2026-09-03T03:48:58Z · View source

Addressed the three blocking evidence findings from the automated review of PR #10650. Item 1 - diagnosis 'Cardiomyopathy Gene Panel Including RASopathy Genes' cited PMID:29696744 as a single SUPPORT item, but that paper's own dilated-cardiomyopathy result is negative. Split into three evidence items per the CLAUDE.md rule that a source supporting one part of a claim and contradicting another becomes two items, each quoting the sentence that carries it. The SUPPORT item keeps the background sentence establishing why RAF1 sits on a cardiomyopathy panel, extended to include its '(Dhandapany et al., 2014)' attribution so the quote shows it is a citation and not a result, regraded to directness INDIRECT, with an explanation that no longer reads as an endorsement. Two new REFUTE items quote the study's null yield in its 419-patient DCM sub-cohort ('No variants of clinical significance were identified in the DCM sub-cohort') and its recommendation ('there appears little, if any, benefit to testing individuals with DCM'). The entry description was rewritten to state the negative result rather than only hedging that hypertrophic yield is highest. Item 2 - pathophysiology node 'RAF1 Missense Variant Altering Kinase Activity' described the same reference as an 'Independent restatement'. The source sentence ends '(Dhandapany et al., 2014)', citing the discovery paper already used on that node, so the claim of independence was wrong. Snippet extended to include that attribution, evidence_source changed HUMAN_CLINICAL -> IN_VITRO (the sentence restates kinase biochemistry, not a clinical result from this sequencing cohort), directness DIRECT -> INDIRECT, explanation rewritten to say the source is a citation of the discovery paper. Item 3 - treatment 'Heart Failure Pharmacotherapy' had a bare NCIT:C15986 with no therapeutic_agent and no evidence. Added five NCIT drug-class agents, each CURIE verified against NCIT via OLS rather than taken from the deep-research report: NCIT:C247 ACE Inhibitor, NCIT:C190796 Angiotensin Receptor-Neprilysin Inhibitor, NCIT:C29576 Beta-Adrenergic Antagonist, NCIT:C101255 Aldosterone Receptor Antagonist, NCIT:C98083 SGLT2 Inhibitor. The falcon report's suggested NCIT:C2478 for 'ACE inhibitor' resolves to Dinitrophenyl and was not used. Loop diuretic was deliberately left unbound because no source cited in this entry states that indication for dilated cardiomyopathy, and the omission is recorded in the treatment description. Two new references fetched with just fetch-reference: PMID:39064249 (names the four-pillar class set as standard HFrEF therapy) and PMID:37876955 (a 30-year childhood dilated-cardiomyopathy cohort documenting real ACE-inhibitor, aldosterone-antagonist and beta-blocker use). Non-blocking suggestions taken: PMID:36927384's 'The experimental data suggest...' snippet regraded COMPUTATIONAL -> IN_VITRO, since that sentence summarises the prior kinase measurements the paper sets out to explain rather than its own molecular-dynamics result, which is cited separately and stays COMPUTATIONAL. Both truncated snippets extended past the cache's run-together HTML-italics artifact so their subject or attribution is visible. Both treatments joined to the pathograph via target_mechanisms: pharmacotherapy MODULATES 'Ventricular Dilation and Systolic Dysfunction' (neurohormonal blockade acts on remodelling, not on the RAF1 lesion), heart transplantation BYPASSES 'Heart Failure'. Deliberately not done: CMD1NN still not added to kb/groupings/Familial_Dilated_Cardiomyopathy.yaml. PRs #10647 and #10649 are editing that file concurrently and the grouping rationale needs a prose edit to admit a signalling-kinase mechanistic class; the deferral is flagged for the maintainer in the entry notes. Validated: just validate (schema + terms + references, 33/33 snippets verified), validate-terms, count-verified-snippets, check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms, check-enum-values, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-source-defect-claims, validate-disorders. No cache/ churn: both new NCIT CURIEs were already present in cache/ncit/terms.csv and the chemicalentityterm enum cache with matching labels.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 25 citations 2026-09-02T17:50:14.383674

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

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

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

Disease Characteristics Research Template

Target Disease

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

Research Objectives

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

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

1. Disease Information

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

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

2. Etiology

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

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

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

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

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

4. Genetic/Molecular Information

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

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

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

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

5. Environmental Information

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

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

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

6. Mechanism / Pathophysiology

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

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

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

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

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

7. Anatomical Structures Affected

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

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

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

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

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

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

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

10. Diagnostics

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

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

11. Outcome/Prognosis

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

12. Treatment

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

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

13. Prevention

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

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

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

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

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

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

15. Model Organisms

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

Citation Requirements

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

Output Format

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

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

Dilated Cardiomyopathy 1NN (DCM1NN): comprehensive disease-characteristics report

Executive summary and evidence boundary

Dilated cardiomyopathy 1NN is an exceptionally rare, predominantly childhood-onset, autosomal-dominant cardiomyopathy attributed to heterozygous variants in RAF1, encoding RAF-1 serine/threonine kinase. The authoritative identifiers are OMIM 615916 for DCM1NN and OMIM 164760 for RAF1; the causal publication is Dhandapany et al., Nature Genetics (online 27 April 2014), PMID 24777450, DOI/URL: https://doi.org/10.1038/ng.2963. The 2025 neuromuscular gene table independently retains this disease–gene assignment. (benarroch2025the2025version pages 24-25, OpenTargets Search: dilated cardiomyopathy-RAF1)

The evidence base is unusually narrow: most subtype-specific claims derive from the 2014 discovery study and its experimental models. Consequently, population frequency, penetrance, natural history, sex ratio, prognosis, and treatment response have not been established specifically for DCM1NN. Findings from general DCM or from RAF1-associated Noonan syndrome/hypertrophic cardiomyopathy (HCM) are identified below as indirect and must not be imported into DCM1NN as proven facts.

Domain	DCM1NN-specific finding	Suggested ontology/identifier terms	Evidence level/caveat
Identity	Dilated cardiomyopathy 1NN (DCM1NN) is an inherited, predominantly childhood-onset dilated cardiomyopathy associated with heterozygous RAF1 variants; disease OMIM 615916, gene OMIM 164760. (benarroch2025the2025version pages 24-25, OpenTargets Search: dilated cardiomyopathy-RAF1)	OMIM:615916; RAF1; HGNC:9829; NCBI Gene:5894; Ensembl:ENSG00000132155; MONDO parent: MONDO:0005021 (dilated cardiomyopathy)	Disease identity is authoritative; a dedicated MONDO identifier for the 1NN subtype was not established in the retrieved evidence and should not be inferred from the parent term.
Core phenotype	Left-ventricular or biventricular dilation with impaired systolic/contractile function, presenting in childhood and potentially progressing to heart failure; RAF1 reportedly accounted for approximately 9% of childhood-onset DCM in the foundational study context. (mestroni2014geneticcausesof pages 6-8)	HP:0001644 (dilated cardiomyopathy); HP:0001635 (congestive heart failure); HP:0001732 (abnormality of the ventricular myocardium); HP:0012664 (reduced left-ventricular ejection fraction); HP:0011463 (childhood onset)	The ∼9% estimate derives from the original discovery setting and should not be treated as population prevalence. Subtype-specific phenotype frequencies, severity distribution, and longitudinal outcomes remain unquantified.
Inheritance	Autosomal dominant, germline RAF1-associated disease; familial segregation and de novo occurrence are possible. (benarroch2025the2025version pages 24-25, ma2025raf1mutationexpands pages 1-2)	HP:0000006 (autosomal dominant inheritance); GENO: germline allele; RAF1	Penetrance is insufficiently quantified and likely age-/context-dependent. A reported de novo RAF1 p.Ser257Leu case had Noonan syndrome with HCM, not demonstrated DCM1NN, so it supports inheritance/heterogeneity rather than the DCM phenotype.
Reported RAF1 variants	Six heterozygous missense substitutions listed in the foundational DCM1NN supplement: NM_002880.3:c.709G>A (p.Ala237Thr), c.928A>G (p.Thr310Ala), c.994C>G (p.Pro332Ala), c.1808T>C (p.Leu603Pro), c.1877A>G (p.His626Arg), and c.1922C>T (p.Thr641Met). (dhandapany2014raf1mutationsin pages 1-7)	SO:0001583 (missense variant); RAF1; ClinVar/gnomAD identifiers to be assigned only after transcript- and genome-build normalization	The supplement’s in-silico predictions were mixed: the first three were largely predicted benign/tolerated, whereas p.Leu603Pro and p.Thr641Met had stronger damaging predictions. Modern ACMG/AMP classification, current ClinVar status, segregation, functional evidence, and population frequencies must be checked variant by variant; the historical list alone does not establish present-day pathogenicity.
Molecular mechanism	DCM-associated RAF1 mutants produced AKT hyperactivation, leading to increased mTOR-pathway signaling and pathological cardiac remodeling; a mutant zebrafish cardiac phenotype was rescued by rapamycin-mediated AKT–mTOR inhibition. (mestroni2014geneticcausesof pages 6-8)	GO:0043491 (protein kinase B signaling); GO:0031929 (TOR signaling); GO:0007165 (signal transduction); GO:0007507 (heart development); CL:0000746 (cardiac muscle cell); CHEBI:9168 (rapamycin)	Strong mechanistic evidence from cellular/animal experiments, but the exact direction and consequences may vary by RAF1 variant. Rapamycin rescue is preclinical and does not demonstrate efficacy or safety in humans with DCM1NN.
Related RAF1 biology	RAF1 regulates RAS–MAPK/MEK, ERK5, calcineurin–NFAT, calcium handling, sarcomere organization, and cell-survival pathways. RAF1 p.Ser257Leu iPSC-derived cardiac tissues showed titin-isoform switching, altered sarcomeres and contractility, partly reversed by MEK inhibition. (nakhaeirad2023molecularandcellular pages 1-2, dhandapany2011cyclosporineattenuatescardiomyocyte pages 1-2)	GO:0000165 (MAPK cascade); GO:0048016 (inositol phosphate-mediated signaling); GO:0030049 (muscle filament sliding); GO:0030017 (sarcomere); CL:0000746 (cardiac muscle cell); NCIT:C125154 (MEK inhibitor)	Indirect evidence: these studies modeled RAF1-associated Noonan-syndrome hypertrophic cardiomyopathy, not DCM1NN. They support pathway plausibility and allelic heterogeneity but must not be used as direct proof of the DCM1NN mechanism or phenotype.
Diagnostics	Diagnose the DCM phenotype using history, three-generation pedigree, examination, ECG, ambulatory rhythm monitoring, echocardiography, laboratory evaluation, and cardiac MRI where indicated; confirm etiology with a curated cardiomyopathy panel including RAF1, followed by segregation/cascade testing. (stroeks2023diagnosticandprognostic pages 1-2, eldemire2024geneticsofdilated pages 1-3, grasso2024thenew2023 pages 1-2)	NCIT:C16543 (genetic testing); NCIT:C38054 (echocardiography); NCIT:C16809 (magnetic resonance imaging); NCIT:C38084 (electrocardiography); HP:0001644	General DCM guidance extrapolated to DCM1NN. In a 2023 cohort, expanding a negative 48-gene panel to 299 genes yielded only one additional clearly explanatory diagnosis and generated 186 VUSs in 127/225 patients, supporting curated robust-gene panels rather than indiscriminate expansion. (stroeks2023diagnosticandprognostic pages 1-2)
Treatment	No approved RAF1- or DCM1NN-specific treatment exists. Manage manifest systolic heart failure with age-appropriate guideline-directed therapy; consider diuretics for congestion and, according to standard indications, arrhythmia therapy, ICD/CRT, mechanical circulatory support, or transplantation. (eldemire2024geneticsofdilated pages 1-3, grasso2024thenew2023 pages 1-2)	NCIT:C101788 (heart-failure therapy); NCIT:C66885 (beta-adrenergic blocker); NCIT:C2478 (ACE inhibitor); NCIT:C804 (diuretic); NCIT:C16830 (implantable cardioverter-defibrillator); NCIT:C15289 (heart transplantation)	Clinical management is extrapolated from pediatric/adult DCM and HFrEF guidance. Rapamycin/mTOR inhibition and MEK or calcineurin inhibition remain experimental; no relevant RAF1/DCM1NN interventional clinical trial was identified.
Prognosis and surveillance	Serial echocardiography is important because progressive ventricular dilation and deteriorating contractility predict death or transplantation in pediatric DCM. In a general pediatric registry, 40/794 (5.0%) died and 117/794 (14.7%) underwent transplantation within one year.	HP:0001635 (heart failure); HP:0001695 (cardiac arrest); NCIT:C38054 (echocardiography); NCIT:C15289 (heart transplantation)	Indirect general pediatric DCM data, not DCM1NN-specific. RAF1-specific survival, transplant-free survival, arrhythmic risk, and reverse-remodeling rates are unavailable.
Evidence limitations	DCM1NN rests predominantly on one 2014 discovery report, limited reported families/variants, and experimental models. No reliable subtype-specific incidence, prevalence, sex ratio, penetrance, carrier frequency, founder effect, protective factor, epigenomic signature, metabolomic profile, natural veterinary disease, or treatment-response dataset was identified. (mestroni2014geneticcausesof pages 6-8)	ECO:0000218 (manual assertion); MONDO:0005021 parent term; evidence provenance fields: human clinical, in vitro, model organism, indirect/general DCM	Knowledge-base assertions should separate direct DCM1NN evidence from general DCM and RAF1-Noonan/HCM evidence. Historical variant pathogenicity should be re-evaluated under current ACMG/AMP and ClinGen standards before clinical use.

Table: Compact ontology-ready summary of RAF1-associated dilated cardiomyopathy 1NN, including identity, variants, mechanism, diagnostics, treatment, and evidence limitations. Direct subtype evidence is separated from indirect RAF1-Noonan HCM and general DCM findings.

1. Disease information

Definition

DCM1NN is a genetic form of dilated cardiomyopathy characterized by left-ventricular or biventricular enlargement and impaired systolic function not adequately explained by coronary disease, abnormal loading conditions, or another secondary cause. The contemporary ESC definition describes cardiomyopathies as myocardial disorders with structural and functional abnormality not sufficiently explained by coronary artery disease, hypertension, valvular disease, or congenital heart disease. (stroeks2023diagnosticandprognostic pages 1-2, grasso2024thenew2023 pages 1-2)

Identifiers and synonyms

Preferred name: Dilated cardiomyopathy 1NN
Synonyms: DCM1NN; CMD1NN; cardiomyopathy, dilated, 1NN; RAF1-related dilated cardiomyopathy; RAF1-associated childhood-onset DCM
OMIM: 615916
Causal gene: RAF1; OMIM 164760; HGNC:9829; NCBI Gene 5894; Ensembl ENSG00000132155
MONDO: a confidently retrieved dedicated DCM1NN identifier was not available. Use the parent MONDO:0005021, dilated cardiomyopathy, with OMIM:615916 and RAF1 qualifiers rather than inventing a subtype code. Open Targets also associates RAF1 with familial DCM and cites PMID 24777450. (benarroch2025the2025version pages 24-25, OpenTargets Search: dilated cardiomyopathy-RAF1)
Orphanet: no DCM1NN-specific ORPHA identifier was established in the retrieved evidence.
ICD-10-CM: I42.0, dilated cardiomyopathy; this is not genotype-specific.
ICD-11: use the applicable dilated-cardiomyopathy category; no RAF1-specific code was established.
MeSH: Cardiomyopathy, Dilated.

The report is based on aggregated disease-level resources and published cohorts/models, not individual EHR data. A 2025 case report noted that a laboratory report labeled RAF1 p.Ser257Leu with “dilated cardiomyopathy type 1NN,” but the patient actually had Noonan syndrome with HCM, septal defects, and LV outflow obstruction. This illustrates database-label carryover and RAF1 allelic heterogeneity rather than confirming DCM1NN in that child. (ma2025raf1mutationexpands pages 9-10, ma2025raf1mutationexpands pages 1-2)

2. Etiology

Primary cause and genetic risk

The accepted cause is a heterozygous germline RAF1 variant, with autosomal-dominant inheritance. Six missense changes appear in the discovery supplement: c.709G>A (p.Ala237Thr), c.928A>G (p.Thr310Ala), c.994C>G (p.Pro332Ala), c.1808T>C (p.Leu603Pro), c.1877A>G (p.His626Arg), and c.1922C>T (p.Thr641Met), using the transcript reported by that study. (dhandapany2014raf1mutationsin pages 1-7)

Historical inclusion does not automatically equal current pathogenic classification. In the original computational analysis, p.Ala237Thr and p.Thr310Ala were predicted benign/neutral/tolerated; p.Pro332Ala had mixed predictions; p.Leu603Pro and p.Thr641Met had stronger damaging predictions; and p.His626Arg was mixed. Each variant therefore requires present-day transcript normalization, ClinVar review, gnomAD frequency assessment, segregation, functional evidence, and ACMG/AMP classification before clinical reporting. (dhandapany2014raf1mutationsin pages 1-7)

Environmental and lifestyle risks

No exposure has been demonstrated specifically to cause or modify DCM1NN. For genetic DCM generally, myocarditis, alcohol, chemotherapy and other cardiotoxins, pregnancy/peripartum stress, hypertension, and metabolic stress can unmask or worsen disease. A 2024 review emphasizes gene–environment interaction rather than a purely Mendelian model for many DCM families. (eldemire2024geneticsofdilated pages 1-3)

The 2024 GWAS by Jurgens et al. used 9,365 cases and 946,368 controls, identified 70 significant loci, and used Mendelian randomization to nominate higher bodyweight and systolic blood pressure as potentially actionable DCM causes. These are general DCM modifiers, not proven RAF1-specific effects. (jurgens2024genomewideassociationstudy pages 1-2)

Protective factors

No genetic protective RAF1 allele is established. No diet, supplement, or exercise regimen has been shown to prevent DCM1NN. Plausible general protection consists of maintaining healthy blood pressure and bodyweight, avoiding tobacco, excess alcohol and cardiotoxic drugs, treating infections and metabolic disease, and obtaining surveillance during pregnancy. Competitive or high-intensity exercise should be individualized according to ventricular function and arrhythmic risk rather than universally prohibited.

Polygenic and modifier effects

Large 2024 studies show that common genetic background modifies DCM risk and penetrance. Zheng et al. analyzed 14,256 cases and 1,199,156 controls, identified 80 loci and 62 putative effector genes, and found that polygenic scores modified penetrance in carriers of rare DCM variants. Whether this applies quantitatively to RAF1 carriers remains unknown. (zheng2024genomewideassociationanalysis pages 1-2)

3. Phenotypes

The following are appropriate knowledge-base phenotypes, but frequencies are not available specifically for DCM1NN:

Dilated cardiomyopathy — HP:0001644: cardinal structural/functional phenotype; childhood onset was prominent in the discovery setting; severity is variable and may be progressive.
Left-ventricular dilatation — HP:0001711: imaging sign; generally progressive if remodeling is uncontrolled.
Reduced left-ventricular ejection fraction — HP:0012664: imaging/functional abnormality.
Systolic dysfunction — HP:0006670: functional sign.
Congestive heart failure — HP:0001635: fatigue, dyspnea, poor exercise tolerance, pulmonary/systemic congestion and, in children, feeding or growth difficulty.
Cardiomegaly — HP:0001640: physical/imaging manifestation.
Dyspnea — HP:0002094; fatigue — HP:0012378; exercise intolerance — HP:0003546: symptoms that impair school, work, play, sleep and daily activity.
Cardiac arrhythmia — HP:0011675; ventricular arrhythmia — HP:0004308; sudden cardiac death — HP:0001645: clinically important possibilities in DCM, although RAF1-specific frequencies are unavailable.
Mitral regurgitation — HP:0001653: may develop secondarily from annular dilation.
Peripheral edema — HP:0012398; hepatomegaly — HP:0002240: signs of advanced systemic congestion.

No behavioral phenotype is intrinsic to isolated DCM1NN. Syndromic RAF1 variants may produce Noonan features, but those should be coded under the appropriate RASopathy and not assumed in isolated DCM1NN. No DCM1NN-specific EQ-5D, SF-36, PROMIS, or pediatric quality-of-life dataset was identified.

4. Genetic and molecular information

Causal gene and protein

RAF1 is located at chromosome 3p25.2 and encodes a cytoplasmic serine/threonine kinase and signaling scaffold in receptor-tyrosine-kinase/RAS pathways. Disease-causing RAF1 alleles are highly phenotype- and domain-dependent: many activating variants cause Noonan-spectrum HCM, whereas the variants reported in DCM1NN were associated with AKT–mTOR hyperactivation and a dilated phenotype. Complete or severe biallelic RAF1 loss is a distinct developmental disorder; it should not be equated with DCM1NN.

Variant properties

Origin: germline; heterozygous.
Class: missense in the foundational report.
Inheritance: autosomal dominant; familial or de novo occurrence is biologically possible.
Mechanism: experimentally associated with aberrant signaling, especially AKT–mTOR activation; a single uniform gain-of-function/loss-of-function label is not justified for all listed alleles.
Allele frequencies: no reliable frequencies were captured in the retrieved source. Clinically causal alleles should generally be absent or exceptionally rare in ancestry-matched population data, but exact gnomAD values must be queried by normalized genomic coordinate.
Somatic versus germline: DCM1NN is germline. Somatic RAF1 alterations are relevant to cancer, not the inherited cardiomyopathy diagnosis.

No validated DCM1NN modifier gene, methylation signature, histone abnormality, pathogenic copy-number change, translocation, inversion, or aneuploidy was identified. General DCM can be oligogenic: a 2024 review estimates that 20–38% may have contributions from multiple rare variants with incomplete penetrance. (eldemire2024geneticsofdilated pages 1-3)

5. Environmental information

No toxin, radiation exposure, pollutant, occupational exposure, or infectious agent is a primary cause of genetically defined DCM1NN. Clinicians should nevertheless investigate common DCM phenocopies and co-triggers: viral/inflammatory myocarditis, Chagas disease where epidemiologically relevant, alcohol, cocaine/amphetamine exposure, anthracyclines, HER2-targeted therapy, some tyrosine-kinase inhibitors, nutritional deficiency, endocrine disease, tachyarrhythmia, and peripartum cardiomyopathy.

The practical gene–environment model is that a RAF1 allele establishes myocardial susceptibility, while hemodynamic, inflammatory, toxic, or metabolic stress may alter penetrance or timing. This is plausible from general DCM evidence but untested in RAF1 families. Pregnancy deserves prospective cardio-obstetric monitoring because familial DCM may first manifest or accelerate peripartum. (eldemire2024geneticsofdilated pages 1-3, mestroni2014geneticcausesof pages 6-8)

6. Mechanism and pathophysiology

Ordered causal chain

A heterozygous DCM-associated RAF1 missense variant leads to altered RAF1 signaling activity or scaffolding in cardiomyocytes.
Altered RAF1 leads to pathological AKT activation; this step was demonstrated in cellular assays and a zebrafish model. (mestroni2014geneticcausesof pages 6-8)
AKT hyperactivation leads to increased mTOR signaling, changing cardiomyocyte growth, protein synthesis and remodeling programs.
Dysregulated signaling leads to abnormal myocardial growth/remodeling and impaired contractile performance; the exact intermediate sarcomeric and metabolic lesions in DCM1NN are incompletely demonstrated.
Contractile impairment leads to increased end-systolic/end-diastolic volume and ventricular dilation, with compensatory neurohormonal activation.
Dilation and neurohormonal stress lead to wall stress, secondary mitral regurgitation, fibrosis and further systolic failure; these downstream steps are inferred from general DCM biology.
Progressive pump failure leads to dyspnea, fatigue, congestion and pediatric growth/feeding limitation.
Branch: electrical and fibrotic remodeling may lead to atrial/ventricular arrhythmia, syncope and sudden death; RAF1-specific arrhythmia incidence is unknown.
Experimental intervention branch: rapamycin inhibition of mTOR led to rescue of the RAF1-mutant zebrafish phenotype, but human efficacy has not been demonstrated. (mestroni2014geneticcausesof pages 6-8)

Pathways, processes and cells

Suggested terms include RAS protein signal transduction (GO:0007265), MAPK cascade (GO:0000165), protein kinase B signaling (GO:0043491), TOR signaling (GO:0031929), regulation of cardiac muscle-cell growth (GO:0055021), cardiac muscle contraction (GO:0060048), apoptotic process (GO:0006915), extracellular-matrix organization (GO:0030198) and response to oxidative stress (GO:0006979). The principal cell is the ventricular cardiomyocyte (CL:0000746); cardiac fibroblasts (CL:0002548), endothelial cells (CL:0000115) and immune cells are likely downstream participants in remodeling.

RAF1 also restrains pro-apoptotic ASK1/MST2 signaling, providing a mechanistic reason why profound RAF1 deficiency or pharmacologic pathway disruption can injure myocardium. A 2023 human RAF1-deficiency study found impaired MAPK activity and increased stress-induced apoptosis, but this is a separate recessive disorder and only supports RAF1’s cardiac-survival biology indirectly.

Molecular profiling and advanced technologies

No DCM1NN-specific single-cell, spatial, proteomic, metabolomic, lipidomic, or epigenomic atlas was identified. Important adjacent findings are:

RAF1-Noonan/HCM model, indirect: patient iPSC-derived cardiomyocytes and 3D bioartificial tissues carrying RAF1 p.Ser257Leu showed shortened sarcomeric I-bands, a titin N2BA-to-N2B shift, altered force/contractile tension, MAPK/p38/YAP abnormalities, and substantial reversal by gene correction or MEK inhibition. Publication: 19 June 2023, https://doi.org/10.1038/s42003-023-05013-8. These data prove RAF1 can directly remodel human cardiomyocyte contractile machinery, but they model HCM rather than DCM1NN. (nakhaeirad2023molecularandcellular pages 1-2)
General DCM: the 2024 Zheng study integrated single-nucleus transcriptomics and identified disease-associated cellular states, pathways and intracellular communication; cardiomyocytes and contractile machinery were strongly implicated across both major 2024 GWAS. (zheng2024genomewideassociationanalysis pages 1-2, jurgens2024genomewideassociationstudy pages 1-2)

7. Anatomical structures affected

Primary organ: heart, especially left-ventricular myocardium; biventricular disease can occur.
UBERON suggestions: heart (UBERON:0000948), myocardium (UBERON:0002349), left ventricle (UBERON:0002084), right ventricle (UBERON:0002080), interventricular septum (UBERON:0002094).
Tissues/cells: cardiac muscle tissue and ventricular cardiomyocytes (CL:0000746); secondary interstitial fibroblast and vascular involvement accompanies remodeling.
Subcellular structures: cytosol (GO:0005829), plasma membrane signaling complexes (GO:0005886), sarcomere (GO:0030017), Z disc (GO:0030018), mitochondrion (GO:0005739) and nucleus (GO:0005634).
Secondary organs: lungs from pulmonary venous congestion; liver, kidneys and peripheral tissues from low output/systemic congestion.
Lateralization: not applicable; cardiac involvement is midline/organ-wide, although regional fibrosis may be heterogeneous.

8. Temporal development

DCM1NN was discovered in a childhood-onset context, but neonatal, infantile, adult and late penetrance have not been quantified. Onset can be insidious, detected through family screening, or clinically acute after decompensation or an intercurrent stress.

A practical staging model is: (1) genotype-positive/phenotype-negative; (2) early electrical, strain or imaging abnormality; (3) overt ventricular dilation and systolic dysfunction; (4) symptomatic heart failure/arrhythmia; and (5) advanced disease requiring mechanical support or transplantation. The course is chronic and variable. Reverse remodeling may occur with therapy, but “recovered” function does not necessarily eliminate genetic relapse risk.

General pediatric DCM evidence supports serial imaging. In the Pediatric Cardiomyopathy Registry, 40/794 children (5.0%) died and 117/794 (14.7%) underwent transplantation within one year; improvement in fractional shortening reduced later death/transplant risk, while progressive dilation increased it. These figures are not DCM1NN-specific.

9. Inheritance and population

Inheritance

DCM1NN is autosomal dominant. A heterozygous affected individual generally presents a 50% transmission probability per pregnancy, but clinical penetrance and severity cannot be predicted reliably. Penetrance is likely incomplete and age-dependent, as in many DCM genes, but no RAF1-DCM1NN estimate is available. Expressivity is variable, and RAF1 variants can produce dilated, hypertrophic, syndromic, or developmental phenotypes. Anticipation has not been reported. Germline mosaicism is possible in principle after an apparently de novo case but is not quantified. No founder effect, consanguinity association, or carrier frequency has been established.

Epidemiology

Subtype-specific incidence and prevalence are unknown. The historical statement that RAF1 accounted for approximately 9% of childhood-onset DCM arose from the discovery setting and must not be used as population prevalence. (mestroni2014geneticcausesof pages 6-8)

For context only, a 2024 review reports that around 40% of familial DCM has an identifiable genetic cause and that pediatric diagnostic yield can be higher than adult yield, 54% versus 27% in cited cohorts. An older population estimate was 36.5 per 100,000, whereas a 2024 GWAS article cites approximately 1 in 250; ascertainment and definitions differ substantially. (eldemire2024geneticsofdilated pages 1-3, zheng2024genomewideassociationanalysis pages 1-2)

No DCM1NN-specific ethnicity, geographic distribution, age distribution, or sex ratio is established. General DCM is male-predominant clinically, but that observation cannot be assigned to RAF1 carriers without targeted data.

10. Diagnostics

Clinical and laboratory work-up

Diagnosis requires both the DCM phenotype and credible molecular attribution to RAF1. Recommended evaluation includes:

Detailed symptoms, medications, toxin/exposure and infection history; physical examination; three-generation pedigree.
ECG and ambulatory monitoring to detect conduction disease and atrial/ventricular arrhythmia.
Transthoracic echocardiography for chamber dimensions, ejection fraction, wall thickness, valvular regurgitation, right-heart function and serial remodeling.
Cardiac MRI for ventricular volumes/function, tissue characterization, edema and late-gadolinium-enhancement fibrosis.
BNP or NT-proBNP and high-sensitivity troponin; CBC, electrolytes, renal/liver function, thyroid studies, iron indices and age/context-directed metabolic testing.
Coronary evaluation when clinically indicated; infectious, inflammatory, toxic, endocrine and neuromuscular studies according to presentation.
Endomyocardial biopsy only when myocarditis, infiltrative/storage disease or another biopsy-actionable diagnosis is suspected; it is not routine for uncomplicated genetic DCM. The 2023 ESC framework prioritizes multimodal imaging, deep phenotyping and genetics. (eldemire2024geneticsofdilated pages 1-3, grasso2024thenew2023 pages 1-2)

Genetic testing

Use a curated cardiomyopathy panel containing robust DCM genes and RAF1, with deletion/duplication analysis where technically appropriate. WES or WGS is reasonable when panel testing is negative, the phenotype is syndromic, or structural/noncoding variation is suspected. RNA sequencing from blood or myocardial tissue may clarify splice variants, but it is not established as routine DCM1NN testing. CMA/karyotype/FISH are not first-line for isolated DCM unless congenital anomalies or developmental findings suggest a chromosomal disorder. mtDNA and repeat-expansion testing should be phenotype-directed.

A 2023 study provides a caution against indiscriminate panel expansion: among 225 DCM patients negative on a 48-gene panel, a 299-gene analysis found 13 P/LP calls, but five were reclassifications in already tested genes and only one of the remaining eight clearly explained the phenotype; 186 VUSs occurred in 127 patients. The authors’ abstract concludes that panels “should be limited to the robust DCM-associated genes.” Publication: 17 May 2023, https://doi.org/10.1038/s41431-023-01384-y. (stroeks2023diagnosticandprognostic pages 1-2)

A RAF1 VUS does not establish DCM1NN. Interpretation should assess phenotype fit, population frequency, segregation, de novo status, domain/mechanism, functional studies and ClinGen/ACMG evidence.

Differential diagnosis

Exclude ischemic cardiomyopathy; hypertensive or valvular remodeling; myocarditis; tachycardia-induced cardiomyopathy; alcohol/toxin/drug-induced disease; peripartum cardiomyopathy; congenital heart disease; neuromuscular or mitochondrial disease; iron overload; thyroid disease; nutritional deficiency; sarcoidosis; amyloidosis; arrhythmogenic cardiomyopathy; left-ventricular non-dilated cardiomyopathy; and physiologic athletic remodeling. Distinguish RAF1-Noonan HCM by wall hypertrophy, dysmorphism/developmental signs and often pulmonary-valve or other congenital disease.

Screening

Offer genetic counseling and cascade testing for a confirmed P/LP familial RAF1 variant. Variant-positive relatives require baseline ECG, echocardiography, clinical review and usually periodic follow-up even when asymptomatic. Variant-negative relatives in a family with a conclusively causal variant can usually be released from genotype-specific surveillance, while relatives in unresolved families need serial clinical screening.

11. Outcome and prognosis

No DCM1NN-specific 5- or 10-year survival, transplant rate, life expectancy, sudden-death rate or quality-of-life statistic exists. Prognosis should therefore be estimated from phenotype severity rather than the “1NN” label alone.

Adverse general DCM markers include severe or worsening LVEF, progressive ventricular dilation, NYHA III/IV symptoms, recurrent hospitalization, elevated BNP/NT-proBNP or troponin, extensive CMR fibrosis, ventricular arrhythmia, syncope, conduction disease, right-ventricular dysfunction, renal dysfunction and failure to reverse remodel. Pediatric registry evidence shows that serial deterioration in fractional shortening and dilation predicts death or transplantation.

A 2024 prospective nonischemic-DCM cohort of 1,152 adults found diabetes in 155 (13%); diabetes was associated with more fibrosis and a higher annual death/transplant event rate, 10.2% versus 5.7%, and adjusted HR 1.61. These are useful general modifiers but are not RAF1-specific.

Morbidity includes chronic exercise limitation, school/work absence, medication burden, anxiety over sudden death and inheritance, repeated imaging, hospitalization, device therapy and transplantation. Genetic diagnosis also affects relatives and reproductive decisions.

12. Treatment

Current clinical care

There is no approved RAF1- or DCM1NN-specific therapy. Treat the manifest phenotype according to pediatric or adult heart-failure guidance:

ACE inhibitor/ARB or ARNI to reduce maladaptive renin–angiotensin signaling and afterload.
Evidence-based beta blocker to blunt sympathetic activation.
Mineralocorticoid-receptor antagonist and SGLT2 inhibitor for eligible HFrEF patients, with age, renal function, potassium, blood pressure and local pediatric evidence considered.
Loop diuretic for congestion; it improves symptoms but is not a disease-modifying substitute.
Anticoagulation for standard indications such as atrial fibrillation or intracardiac thrombus, not solely because DCM is present.
ICD for guideline-defined sudden-death risk; CRT for persistent low LVEF with qualifying QRS morphology/duration after optimized therapy.
Mechanical circulatory support and heart transplantation for refractory advanced failure.
Cardiac rehabilitation and individualized activity prescription when stable.

Suggested NCIT concepts include Heart Failure Therapy; Angiotensin-Converting Enzyme Inhibitor; Angiotensin Receptor Blocker; Beta-Adrenergic Blocker; Mineralocorticoid Receptor Antagonist; Sodium-Glucose Cotransporter 2 Inhibitor; Diuretic; Implantable Cardioverter-Defibrillator; Cardiac Resynchronization Therapy; Ventricular Assist Device; and Heart Transplantation. Exact NCIT codes should be validated against the current thesaurus release.

Experimental pathway-directed treatment

RAF1-mutant cellular and zebrafish experiments support AKT–mTOR inhibition, and rapamycin rescued the fish cardiomyopathy phenotype. This is compelling target-validation evidence, not clinical efficacy. (mestroni2014geneticcausesof pages 6-8)

MEK inhibition, calcineurin inhibition and dual RAS/MAPK–PI3K/AKT inhibition are being studied in RAF1-related HCM/RASopathies, not established DCM1NN. In RAF1-mutant rat cardiomyocytes, cyclosporine suppressed hypertrophy through calcineurin–NFAT effects, but systemic cyclosporine is not justified for DCM1NN outside research because of nephrotoxicity, hypertension, immunosuppression and absent clinical benefit data. (dhandapany2011cyclosporineattenuatescardiomyocyte pages 1-2)

Searches found no interventional ClinicalTrials.gov study specifically for RAF1-associated DCM1NN. No gene replacement, CRISPR, ASO, siRNA, mRNA, or cell therapy is clinically available.

13. Prevention

Primary prevention

The inherited allele cannot currently be prevented after conception. Risk reduction includes avoidance of tobacco, cocaine/amphetamines, excess alcohol and unnecessary cardiotoxins; control of blood pressure, bodyweight, diabetes and sleep apnea; vaccination and prompt management of infection according to standard practice; and cardio-oncology surveillance when cardiotoxic therapy is unavoidable.

Secondary prevention

The strongest strategy is early identification: genetic counseling, cascade testing of a confirmed familial P/LP RAF1 variant, and periodic ECG/echo surveillance of carriers. Family screening can detect preclinical dysfunction when treatment and activity counseling may have greater benefit.

Tertiary prevention

Optimize HF therapy, monitor ventricular function and rhythm, manage pregnancy through a cardio-obstetric team, and use ICD/CRT or advanced-HF referral when indicated. Continue surveillance after apparent recovery because relapse can occur in genetic DCM.

Reproductive prevention and counseling

Discuss the 50% transmission risk, uncertainty in penetrance/severity, prenatal diagnosis, and preimplantation genetic testing for monogenic disease. A 2024 inherited-cardiac-disease PGT study proposed a severity/penetrance-based model; among 83 referred couples, the model reached a decision for 76 (92%) and agreed with multidisciplinary decisions in 95%. This is general inherited-cardiac-disease evidence, not RAF1-specific.

Population newborn or carrier screening is not recommended because the condition is ultra-rare, dominant, variably penetrant and not associated with a validated newborn intervention.

14. Other species and natural disease

No naturally occurring RAF1-defined DCM1NN was identified in companion animals, livestock or wildlife. Dogs and cats develop natural DCM from other genetic and nutritional causes, but those disorders should not be labeled DCM1NN.

RAF1 orthologs are highly conserved across vertebrates, supporting cross-species signaling studies. Relevant taxa include Homo sapiens (NCBI Taxon 9606), Mus musculus (10090), Danio rerio (7955), Drosophila melanogaster (7227) and Xenopus species. Exact orthologous NCBI Gene IDs and any VBO breed identifiers should be retrieved from the current organism databases before ingestion. There is no infectious transmission or zoonotic potential.

15. Model organisms and experimental systems

Zebrafish

Cardiomyocyte-directed expression of DCM-associated RAF1 mutants reproduced a cardiomyopathy phenotype with AKT hyperactivation; rapamycin rescue supports causal involvement of AKT–mTOR. Strengths are rapid cardiac phenotyping and in-vivo drug testing. Limitations include two-chambered anatomy, regenerative capacity, transgene dosage and uncertain equivalence to heterozygous human expression. (mestroni2014geneticcausesof pages 6-8)

Cellular models

RAF1 variants have been expressed in neonatal/adult rat cardiomyocytes to study MEK/ERK, calcineurin–NFAT, SERCA2a/calcium signaling and cellular hypertrophy. These models establish pathway competence but incompletely reproduce ventricular dilation, chronic fibrosis and human developmental timing. (dhandapany2011cyclosporineattenuatescardiomyocyte pages 1-2)

Human iPSC and engineered tissue

Patient-derived iPSC cardiomyocytes, isogenic CRISPR-corrected controls, cardiac bodies and bioartificial tissues provide human sarcomere, calcium-handling and contractility readouts. The best recent RAF1 study used p.Ser257Leu Noonan/HCM cells; correction and MEK inhibition reversed much of the phenotype. Its relevance to DCM1NN is mechanistic and comparative, not direct. (nakhaeirad2023molecularandcellular pages 1-2)

Mouse and other models

Cardiac RAF1 loss models support roles in cardiomyocyte survival and protection against ASK1/MST2-mediated apoptosis, whereas RAF1 RASopathy knock-in models generally reproduce HCM. These opposing phenotypes underscore variant-specific mechanisms and warn against treating all RAF1 alleles with the same pathway inhibitor.

Recent developments and expert interpretation

Three 2023–2024 developments materially change how DCM1NN should be curated:

Variant curation has become more conservative. The 2023 expanded-panel study showed minimal additional diagnostic yield but a large VUS burden, favoring robust gene–disease evidence and variant-level reassessment over historical disease labels. (stroeks2023diagnosticandprognostic pages 1-2)
DCM is now understood as rare-plus-common genetic architecture. Two independent November 2024 Nature Genetics studies identified 70–80 loci, highlighted cardiomyocytes and the contractile apparatus, and showed that polygenic background predicts risk and modifies penetrance. This may ultimately explain why carriers of the same rare allele differ clinically. (zheng2024genomewideassociationanalysis pages 1-2, jurgens2024genomewideassociationstudy pages 1-2)
Human engineered myocardium can resolve RAF1 mechanism. The 2023 RAF1 iPSC/3D-tissue study tied abnormal signaling to titin isoform switching and sarcomeric dysfunction and demonstrated reversal by gene correction/MEK inhibition. Applying similar isogenic models to the six historical DCM1NN variants is a major unmet need. (nakhaeirad2023molecularandcellular pages 1-2)

The appropriate expert conclusion is therefore cautious: RAF1 is an accepted DCM1NN gene–disease association, but pathogenicity and mechanism must be adjudicated at the individual-variant level. The strongest DCM1NN-specific therapeutic signal—AKT–mTOR inhibition—is preclinical. Clinical care should currently follow phenotype-based DCM/HFrEF guidance, combined with rigorous genetic counseling and family surveillance.

Key references

Dhandapany PS et al. “RAF1 mutations in childhood-onset dilated cardiomyopathy.” Nature Genetics. Published online 27 April 2014. PMID: 24777450. https://doi.org/10.1038/ng.2963. The key abstract-level finding is summarized as: RAF1 mutations were identified in childhood-onset DCM, mutant signaling activated AKT–mTOR, and rapamycin rescued the zebrafish phenotype. (OpenTargets Search: dilated cardiomyopathy-RAF1, mestroni2014geneticcausesof pages 6-8)
Stroeks SLVM et al. “Diagnostic and prognostic relevance of using large gene panels in the genetic testing of patients with dilated cardiomyopathy.” European Journal of Human Genetics. Published 17 May 2023. https://doi.org/10.1038/s41431-023-01384-y. Direct abstract quote: “Overall, the use of large gene panels for genetic testing in DCM does not increase the diagnostic yield.” (stroeks2023diagnosticandprognostic pages 1-2)
Nakhaei-Rad S et al. “Molecular and cellular evidence for the impact of a hypertrophic cardiomyopathy-associated RAF1 variant…” Communications Biology. Published 19 June 2023. https://doi.org/10.1038/s42003-023-05013-8. Direct abstract quote: the study “uncovered a direct link between a RASopathy gene variant and the abnormal sarcomere structure resulting in a cardiac dysfunction.” This is indirect HCM evidence. (nakhaeirad2023molecularandcellular pages 1-2)
Eldemire R, Mestroni L, Taylor MRG. “Genetics of Dilated Cardiomyopathy.” Annual Review of Medicine. Published 29 January 2024. https://doi.org/10.1146/annurev-med-052422-020535. Direct abstract quote: “An estimated 40% of cases of familial DCM have an identifiable genetic cause.” (eldemire2024geneticsofdilated pages 1-3)
Grasso M et al. “The new 2023 ESC guidelines for the management of cardiomyopathies.” European Heart Journal Supplements. April 2024. https://doi.org/10.1093/eurheartjsupp/suae002. (grasso2024thenew2023 pages 1-2)
Jurgens S et al. “Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience.” Nature Genetics. Published 21 November 2024. https://doi.org/10.1038/s41588-024-01975-5. Direct abstract result: 9,365 cases, 946,368 controls and 70 significant loci. (jurgens2024genomewideassociationstudy pages 1-2)
Zheng SL et al. “Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy.” Nature Genetics. Published 21 November 2024. https://doi.org/10.1038/s41588-024-01952-y. Direct abstract result: 14,256 cases, 80 risk loci and 62 putative effector genes, with polygenic modification of rare-variant penetrance. (zheng2024genomewideassociationanalysis pages 1-2)

References

(benarroch2025the2025version pages 24-25): Louise Benarroch, Gisèle Bonne, François Rivier, Vincent Procaccio, and Dalil Hamroun. The 2025 version of the gene table of neuromuscular disorders (nuclear genome). Jan 2025. URL: https://doi.org/10.1016/j.nmd.2024.105261, doi:10.1016/j.nmd.2024.105261. This article has 16 citations and is from a peer-reviewed journal.
(OpenTargets Search: dilated cardiomyopathy-RAF1): Open Targets Query (dilated cardiomyopathy-RAF1, 6 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(mestroni2014geneticcausesof pages 6-8): Luisa Mestroni, Francesca Brun, Anita Spezzacatene, Gianfranco Sinagra, and Matthew R.G. Taylor. Genetic causes of dilated cardiomyopathy. Progress in pediatric cardiology, 37 1-2:13-18, Dec 2014. URL: https://doi.org/10.1016/j.ppedcard.2014.10.003, doi:10.1016/j.ppedcard.2014.10.003. This article has 145 citations and is from a peer-reviewed journal.
(ma2025raf1mutationexpands pages 1-2): Nan Ma, Zhong-Wei Li, Jia-Jia Liu, Xing-Guang Liu, Xing Zhou, Bo-Wen Wang, Yan-Ling Li, Tian-Cheng Zhang, and Ping Xie. Raf1 mutation expands the cardiac phenotypic spectrum of noonan syndrome: a case report. World Journal of Cardiology, Jun 2025. URL: https://doi.org/10.4330/wjc.v17.i6.106525, doi:10.4330/wjc.v17.i6.106525. This article has 1 citations.
(dhandapany2014raf1mutationsin pages 1-7): Perundurai S Dhandapany, Md Abdur Razzaque, Uthiralingam Muthusami, Sreejith Kunnoth, Jonathan J Edwards, Sonia Mulero-Navarro, Ilan Riess, Sherly Pardo, Jipo Sheng, Deepa Selvi Rani, Bindu Rani, Periyasamy Govindaraj, Elisabetta Flex, Tomohiro Yokota, Michiko Furutani, Tsutomu Nishizawa, Toshio Nakanishi, Jeffrey Robbins, Giuseppe Limongelli, Roger J Hajjar, Djamel Lebeche, Ajay Bahl, Madhu Khullar, Andiappan Rathinavel, Kirsten C Sadler, Marco Tartaglia, Rumiko Matsuoka, Kumarasamy Thangaraj, and Bruce D Gelb. Raf1 mutations in childhood-onset dilated cardiomyopathy. Nature Genetics, 46:635-639, Apr 2014. URL: https://doi.org/10.1038/ng.2963, doi:10.1038/ng.2963. This article has 99 citations and is from a highest quality peer-reviewed journal.
(nakhaeirad2023molecularandcellular pages 1-2): Saeideh Nakhaei-Rad, Fereshteh Haghighi, Farhad Bazgir, Julia Dahlmann, Alexandra Viktoria Busley, Marcel Buchholzer, Karolin Kleemann, Anne Schänzer, Andrea Borchardt, Andreas Hahn, Sebastian Kötter, Denny Schanze, Ruchika Anand, Florian Funk, Annette Vera Kronenbitter, Jürgen Scheller, Roland P. Piekorz, Andreas S. Reichert, Marianne Volleth, Matthew J. Wolf, Ion Cristian Cirstea, Bruce D. Gelb, Marco Tartaglia, Joachim P. Schmitt, Martina Krüger, Ingo Kutschka, Lukas Cyganek, Martin Zenker, George Kensah, and Mohammad R. Ahmadian. Molecular and cellular evidence for the impact of a hypertrophic cardiomyopathy-associated raf1 variant on the structure and function of contractile machinery in bioartificial cardiac tissues. Jun 2023. URL: https://doi.org/10.1038/s42003-023-05013-8, doi:10.1038/s42003-023-05013-8. This article has 45 citations and is from a peer-reviewed journal.
(dhandapany2011cyclosporineattenuatescardiomyocyte pages 1-2): Perundurai S. Dhandapany, Frank Fabris, Rahul Tonk, Ardo Illaste, Ioannis Karakikes, Mehran Sorourian, Jipo Sheng, Roger J. Hajjar, Marco Tartaglia, Eric A. Sobie, Djamel Lebeche, and Bruce D. Gelb. Cyclosporine attenuates cardiomyocyte hypertrophy induced by raf1 mutants in noonan and leopard syndromes. Journal of molecular and cellular cardiology, 51 1:4-15, Jul 2011. URL: https://doi.org/10.1016/j.yjmcc.2011.03.001, doi:10.1016/j.yjmcc.2011.03.001. This article has 43 citations and is from a domain leading peer-reviewed journal.
(stroeks2023diagnosticandprognostic pages 1-2): Sophie L. V. M. Stroeks, Debby Hellebrekers, Godelieve R. F. Claes, Ingrid P. C. Krapels, Michiel H. T. M. Henkens, Maurits Sikking, Els K. Vanhoutte, Apollonia Helderman-van den Enden, Han G. Brunner, Arthur van den Wijngaard, and Job A. J. Verdonschot. Diagnostic and prognostic relevance of using large gene panels in the genetic testing of patients with dilated cardiomyopathy. European Journal of Human Genetics, 31:776-783, May 2023. URL: https://doi.org/10.1038/s41431-023-01384-y, doi:10.1038/s41431-023-01384-y. This article has 10 citations and is from a domain leading peer-reviewed journal.
(eldemire2024geneticsofdilated pages 1-3): Ramone Eldemire, Luisa Mestroni, and Matthew R.G. Taylor. Genetics of dilated cardiomyopathy. Jan 2024. URL: https://doi.org/10.1146/annurev-med-052422-020535, doi:10.1146/annurev-med-052422-020535. This article has 83 citations and is from a domain leading peer-reviewed journal.
(grasso2024thenew2023 pages 1-2): Maurizia Grasso, Davide Bondavalli, Viviana Vilardo, Claudia Cavaliere, Ilaria Gatti, Alessandro Di Toro, Lorenzo Giuliani, Mario Urtis, Michela Ferrari, Barbara Cattadori, Alessandra Serio, Carlo Pellegrini, and Eloisa Arbustini. The new 2023 esc guidelines for the management of cardiomyopathies: a guiding path for cardiologist decisions. European Heart Journal Supplements : Journal of the European Society of Cardiology, 26:i1-i5, Apr 2024. URL: https://doi.org/10.1093/eurheartjsupp/suae002, doi:10.1093/eurheartjsupp/suae002. This article has 18 citations.
(ma2025raf1mutationexpands pages 9-10): Nan Ma, Zhong-Wei Li, Jia-Jia Liu, Xing-Guang Liu, Xing Zhou, Bo-Wen Wang, Yan-Ling Li, Tian-Cheng Zhang, and Ping Xie. Raf1 mutation expands the cardiac phenotypic spectrum of noonan syndrome: a case report. World Journal of Cardiology, Jun 2025. URL: https://doi.org/10.4330/wjc.v17.i6.106525, doi:10.4330/wjc.v17.i6.106525. This article has 1 citations.
(jurgens2024genomewideassociationstudy pages 1-2): S. Jurgens, Joel T. Rämö, D. Kramarenko, L. Wijdeveld, Jan Haas, M. Chaffin, S. Garnier, L. Gaziano, L. Weng, Alex Lipov, S. Zheng, Albert Henry, J. Huffman, Saketh Challa, Frank Rühle, Carmen Diaz Verdugo, C. Krijger Juárez, Shinwan Kany, C. A. van Orsouw, K. Biddinger, Edwin Poel, Amanda L Elliott, Xin Wang, C. Francis, Richard Ruan, Satoshi Koyama, L. Beekman, Dominic S Zimmerman, J. Deleuze, E. Villard, D. Trégouët, Richard Isnard, Joel T. Amanda L. Juha Teemu Jari Aarno Mark Rämö Elliott Sinisalo Niiranen Laukkanen Palotie D, J. Sinisalo, T. Niiranen, J. Laukkanen, A. Palotie, Mark Daly, Jennifer E. Kyong-Mi Philip S. Krishna G. Huffman Chang Tsao Aragam, Kyong-Mi Chang, Phil Tsao, Krishna G. Aragam, Sean L. Albert Kiran James S. R. Thomas Patrick T. Kris Zheng Henry Biddinger Ware Lumbers Ellinor Aragam, James S. Ware, R. Lumbers, P. Ellinor, D. Boomsma, E. D. de Geus, R. Tadros, Y. Pinto, A. Wilde, J. Hottenga, Roddy Walsh, A. F. Schmidt, Seung Hoan Choi, P. Matthews, S. N. van der Crabben, Ahmad S. Amin, P. Charron, Benjamin Meder, and C. Bezzina. Genome-wide association study reveals mechanisms underlying dilated cardiomyopathy and myocardial resilience. Nature Genetics, 56:2636-2645, Nov 2024. URL: https://doi.org/10.1038/s41588-024-01975-5, doi:10.1038/s41588-024-01975-5. This article has 68 citations and is from a highest quality peer-reviewed journal.
(zheng2024genomewideassociationanalysis pages 1-2): Sean L. Zheng, Albert Henry, Douglas Cannie, Michael Lee, David Miller, Kathryn A. McGurk, Isabelle Bond, Xiao Xu, Hanane Issa, Catherine Francis, Antonio De Marvao, Pantazis I. Theotokis, Rachel J. Buchan, Doug Speed, Erik Abner, Lance Adams, Krishna G. Aragam, Johan Ärnlöv, Anna Axelsson Raja, Joshua D. Backman, John Baksi, Paul J. R. Barton, Kiran J. Biddinger, Eric Boersma, Jeffrey Brandimarto, Søren Brunak, Henning Bundgaard, David J. Carey, Philippe Charron, James P. Cook, Stuart A. Cook, Spiros Denaxas, Jean-François Deleuze, Alexander S. Doney, Perry Elliott, Christian Erikstrup, Tõnu Esko, Eric H. Farber-Eger, Chris Finan, Sophie Garnier, Jonas Ghouse, Vilmantas Giedraitis, Daniel F. Guðbjartsson, Christopher M. Haggerty, Brian P. Halliday, Anna Helgadottir, Harry Hemingway, Hans L. Hillege, Isabella Kardys, Lars Lind, Cecilia M. Lindgren, Brandon D. Lowery, Charlotte Manisty, Kenneth B. Margulies, James C. Moon, Ify R. Mordi, Michael P. Morley, Andrew D. Morris, Andrew P. Morris, Lori Morton, Mahdad Noursadeghi, Sisse R. Ostrowski, Anjali T. Owens, Colin N. A. Palmer, Antonis Pantazis, Ole B. V. Pedersen, Sanjay K. Prasad, Akshay Shekhar, Diane T. Smelser, Sundararajan Srinivasan, Kari Stefansson, Garðar Sveinbjörnsson, Petros Syrris, Mari-Liis Tammesoo, Upasana Tayal, Maris Teder-Laving, Guðmundur Thorgeirsson, Unnur Thorsteinsdottir, Vinicius Tragante, David-Alexandre Trégouët, Thomas A. Treibel, Henrik Ullum, Ana M. Valdes, Jessica van Setten, Marion van Vugt, Abirami Veluchamy, W. M. Monique Verschuren, Eric Villard, Yifan Yang, Mahdad Noursadeghi, Ole B. V. Pedersen, Kari Stefansson, Unnur Thorsteinsdottir, Henrik Ullum, Folkert W. Asselbergs, Antonio De Marvao, Marie-Pierre Dube, Michael E. Dunn, Patrick T. Ellinor, Sophie Garnier, Chim C. Lang, Andrew P. Morris, Lori Morton, Colin N. A. Palmer, Nilesh J. Samani, Svati H. Shah, Akshay Shekhar, J. Gustav Smith, Sundarajan Srinivasan, Guðmundur Thorgeirsson, Ramachandran S. Vasan, Jessica van Setten, Marion van Vugt, Abirami Veluchamy, W. M. Monique Verschuuren, Eric Villard, Quinn Wells, Folkert W. Asselbergs, Thomas P. Cappola, Marie-Pierre Dube, Michael E. Dunn, Patrick T. Ellinor, Aroon D. Hingorani, Chim C. Lang, Nilesh J. Samani, Svati H. Shah, J. Gustav Smith, Ramachandran S. Vasan, Declan P. O’Regan, Hilma Holm, Michela Noseda, Quinn Wells, James S. Ware, and R. Thomas Lumbers. Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy. Nature Genetics, 56:2646-2658, Nov 2024. URL: https://doi.org/10.1038/s41588-024-01952-y, doi:10.1038/s41588-024-01952-y. This article has 77 citations and is from a highest quality peer-reviewed journal.

Artifacts

Edison artifact artifact-00

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	7
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	64
Resolved	60
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	3
Terms whose name was checked	2
Terms named correctly	1
Terms named as a different term	0
Terms whose name is worth a second look	1

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0048016 (obsolete inositol phosphate-mediated signaling) (1 mention)

Terms whose name is worth a second look

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

SO:0001583 (1 mention) - the report calls it "missense variant"; SO calls it missense_variant

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: OMIM, Gene.

60 of 64 terms resolved to a current term; the rest could not be looked up either way.

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

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

Citation Requirements

Output Format

Dilated Cardiomyopathy 1NN (DCM1NN): comprehensive disease-characteristics report

Executive summary and evidence boundary

1. Disease information

Definition

Identifiers and synonyms

2. Etiology

Primary cause and genetic risk

Environmental and lifestyle risks

Protective factors

Polygenic and modifier effects

3. Phenotypes

4. Genetic and molecular information

Causal gene and protein

Variant properties

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Pathways, processes and cells

Molecular profiling and advanced technologies

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

Inheritance

Epidemiology

10. Diagnostics

Clinical and laboratory work-up

Genetic testing

Differential diagnosis

Screening

11. Outcome and prognosis

12. Treatment

Current clinical care

Experimental pathway-directed treatment

13. Prevention

Primary prevention

Secondary prevention

Tertiary prevention

Reproductive prevention and counseling

14. Other species and natural disease

15. Model organisms and experimental systems

Zebrafish

Cellular models

Human iPSC and engineered tissue