| 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**. (pqac-00000000, pqac-00000001) | 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. (pqac-00000002, pqac-00000011) | 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. (pqac-00000000, pqac-00000013) | 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)**. (pqac-00000007) | 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. (pqac-00000002, pqac-00000011) | 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. (pqac-00000010, pqac-00000014) | 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. (pqac-00000004, pqac-00000005, pqac-00000006) | 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. (pqac-00000004) |
| 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. (pqac-00000005, pqac-00000006) | 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. (pqac-00000002, pqac-00000011) | 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.*