Dilated Cardiomyopathy 1EE (CMD1EE) — Comprehensive Research Report

1. Disease Information

Overview. Dilated Cardiomyopathy, 1EE (CMD1EE) is an autosomal dominant form of primary dilated cardiomyopathy (DCM) caused by heterozygous mutation in MYH6, the gene encoding cardiac α-myosin heavy chain, located on chromosome 14q11.2. It is characterized by "ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia" (OMIM #613252). It is one of dozens of genetically distinct loci in the OMIM Cardiomyopathy, Dilated, 1 (CMD1) phenotypic series (PS115200), which spans entries CMD1A through CMD1EE and beyond, reflecting the extreme genetic heterogeneity of familial DCM.

Key identifiers: - OMIM phenotype: #613252 — CARDIOMYOPATHY, DILATED, 1EE; CMD1EE - OMIM gene: 160710 — MYOSIN, HEAVY CHAIN 6, CARDIAC MUSCLE, ALPHA; MYH6 - Gene symbol / HGNC: MYH6, HGNC:7576 - NCBI Gene ID: 4624; UniProt: P13533 (GeneCards) - Locus: 14q11.2 (GRCh38 chr14:23,381,576–23,408,945) - MONDO: the broader MYH6-related familial isolated DCM concept maps to MONDO:0013198; Orphanet cross-references MYH6 to ORPHA:154 (Familial isolated dilated cardiomyopathy) (Orphanet: MYH6) - Inheritance: Autosomal dominant - Gene aliases: ASD3, CMD1EE, CMH14, MYHC, MYHCA, SSS3, α-MHC — reflecting that MYH6 is an allelic/pleiotropic disease gene: the same gene also causes Atrial Septal Defect 3 (ASD3, OMIM 614089), Sick Sinus Syndrome 3 (SSS3, OMIM 614090), and familial hypertrophic cardiomyopathy (CMH14) (GeneCards MYH6; PMC3237499). - Source of information:* This entry is derived from aggregated disease-level resources (OMIM, GeneReviews, Orphanet, ClinVar) and from case/cohort-level literature (family studies of DCM), rather than from a single large EHR-based cohort.

Synonyms: Cardiomyopathy, Dilated, 1EE; CMD1EE; DCM due to MYH6 mutation; α-myosin heavy chain cardiomyopathy.

2. Etiology

Disease causal factor — genetic. CMD1EE is caused by heterozygous, typically missense, mutations in MYH6. The first reported variant, identified by Carniel et al. (2005), was a heterozygous c.3010G>T (p.Ala1004Ser) transversion in exon 23 of MYH6, "not found in 150 ethnically similar controls" and located in "a highly conserved region of the rod domain" that "alters polarity" (OMIM 613252; ClinVar RCV000015214).

In their broader screen of "434 subjects across 69 dilated cardiomyopathy (DCM) families and 21 hypertrophic cardiomyopathy (HCM) families," Carniel et al. found three heterozygous MYH6 mutations among DCM probands and one among HCM probands. They reported that "all MYH6 mutations were distributed in highly conserved residues" and absent from controls, and that "the DCM carrier phenotype was characterized by late onset, whereas the HCM phenotype was characterized by progression toward dilation, left ventricular dysfunction, and refractory heart failure," concluding that "mutations in MYH6 may cause a spectrum of phenotypes ranging from DCM to HCM" (Carniel E, et al. Circulation. 2005;112:54-59. PMID: 15998695).

Genetic risk factors: - Heterozygous missense MYH6 variants (e.g., p.Ala1004Ser) — dominant-negative/haploinsufficiency mechanisms are proposed for sarcomeric DCM genes generally. - MYH6 is one of >40 genes implicated across the CMD1 phenotypic series; other DCM genes include TTN (titin, the single largest contributor, ~15-20% of familial DCM), LMNA, MYH7, TNNT2, RBM20, BAG3, and DSP, among others. - Compound/digenic burden: multiple studies report additional rare variants in other cardiomyopathy genes (e.g., LDB3, SYNE1) co-occurring with MYH6 variants in early-onset/malignant DCM presentations (PMC8293610).

Environmental / modifiable risk factors (DCM in general): alcohol use, anthracycline chemotherapy exposure, uncontrolled hypertension, viral myocarditis (enteroviruses, coxsackievirus, parvovirus B19), peripartum status, tachyarrhythmia-induced cardiomyopathy, and nutritional deficiency (thiamine, selenium) are recognized non-genetic/mixed contributors to the broader DCM phenotype, though these are not specifically documented for CMD1EE probands in the literature reviewed.

Protective factors: No MYH6-specific protective alleles are documented in the literature surveyed; genetic modifiers of penetrance/severity for sarcomeric DCM in general (e.g., titin-truncating variant background, common variant polygenic modifiers) are an active area of research but not specifically characterized for CMD1EE.

Gene–environment interaction: Not specifically studied for MYH6-CMD1EE; in DCM broadly, a "second hit" model is common — an underlying pathogenic sarcomeric variant combined with an environmental trigger (viral infection, toxin, pregnancy, tachyarrhythmia) unmasking or accelerating the cardiomyopathic phenotype.

Gene dosage / allelic mechanism note: MYH6 mutations show a genotype-phenotype gradient — heterozygous missense variants generally produce late-onset DCM or HCM, whereas rare recessive/biallelic MYH6 variants have been associated with severe hypoplastic left heart syndrome with reduced ejection fraction in a distinct, more severe pediatric phenotype (Theis et al., PMID: 26085007) — this is a different, non-CMD1EE entity but illustrates the gene's dose-sensitivity.

3. Phenotypes

Core cardiac phenotype (from OMIM clinical description): - Left ventricular dilation — suggested HPO: HP:0002944 (Left ventricular dilatation) or the general HP:0001644 (Dilated cardiomyopathy) - Impaired systolic function / reduced ejection fraction — HP:0001635 (Congestive heart failure) is downstream; systolic dysfunction itself maps toward HP:0001635/HP:0004936 (Ventricular fibrillation)-adjacent terms; most curation groups use HP:0001644 for the composite dilated+hypocontractile phenotype. - Congestive heart failure — HP:0001635 - Arrhythmia (general) — HP:0011675 (Arrhythmia); ventricular arrhythmia specifically — HP:0004308 (Ventricular arrhythmia)

Onset and course (from the founding case, Carniel et al. 2005): The index MYH6 p.Ala1004Ser DCM proband was a "59-year-old Caucasian patient diagnosed at age 51 [who] developed congestive heart failure by 59" (ClinVar RCV000015214) — consistent with the study's overall characterization of "the DCM carrier phenotype" as late onset (contrasting with the MYH6-HCM phenotype, which the same study found "progressed toward dilation, left ventricular dysfunction, and refractory heart failure" — i.e., an HCM-to-DCM ["burnt-out"] transition) (PMID: 15998695).

Broader MYH6-related phenotype spectrum (allelic disorders informing the pathophysiological family, useful context even though clinically distinct OMIM entries): - Sick sinus syndrome 3 (SSS3) — sinus node dysfunction, bradycardia — HPO: HP:0033127 (Sinus bradycardia)/HP:0004755 (Sick sinus syndrome) - Atrial septal defect 3 (ASD3) — congenital structural defect — HPO: HP:0001631 (Atrial septal defect) - Familial hypertrophic cardiomyopathy (CMH14) — HPO: HP:0001639

Frequency/severity: Because CMD1EE is defined from a small number of published families/probands, granular phenotype-frequency tables (e.g., % with arrhythmia, % requiring transplant) specific to CMD1EE are not established in the literature; DCM-general frequencies (below) are the best available proxy.

General DCM phenotype set (context, HPO-mappable): - Dyspnea/exertional intolerance — HP:0002094 (Dyspnea) - Fatigue — HP:0012378 - Peripheral edema — HP:0000969 - Atrial fibrillation/flutter — HP:0005110 - Pericardial effusion — HP:0001698 - Sudden cardiac death risk — HP:0001645 (Sudden cardiac death) - Cardiac conduction defects — HP:0011675

Quality of life impact: DCM-associated heart failure carries substantial QoL burden (NYHA functional class limitation, hospitalization burden); no CMD1EE-specific quality-of-life instrument data (e.g., KCCQ, SF-36) were identified in the literature reviewed — this would be extrapolated from general HFrEF QoL literature.

4. Genetic/Molecular Information

Causal gene: MYH6 (HGNC:7576; NCBI Gene 4624; OMIM *160710; UniProt P13533)
Gene structure: 39 exons, 37 coding (GeneCards)
Founding pathogenic variant: NM_002471.4:c.3010G>T, p.(Ala1004Ser) — missense, exon 23, rod (coiled-coil) domain — classified Pathogenic in ClinVar for "Dilated Cardiomyopathy 1EE," though flagged as an older (2005) classification "that does not account for recent evidence" (ClinVar RCV000015214). Two additional heterozygous missense variants were identified among the same DCM cohort by Carniel et al. (2005), also in highly conserved residues, absent from ~150-300 control chromosomes.
Additional ClinVar-cataloged MYH6 variants linked to "Dilated Cardiomyopathy, Recessive" phenotype labels include NM_015164.4(PLEKHM2) entries — note: these PLEKHM2 records are for a distinct, unrelated recessive DCM gene (see clarification below) and should not be conflated with MYH6/CMD1EE.
Variant type: Missense (dominant-negative or haploinsufficiency hypothesized; not experimentally resolved for CMD1EE specifically)
Population frequency: Not present in ethnically matched control panels in the founding study (150 controls); contemporary population databases (gnomAD) should be checked per-variant during curation, as p.Ala1004Ser's frequency/classification may need reassessment given the "flagged" ClinVar status.
Zygosity: Heterozygous (autosomal dominant mechanism)
Somatic vs. germline: Germline
Gene-disease validity: MYH6's curated strength of association with DCM is rated only moderate by some expert-panel frameworks (e.g., Genomics England PanelApp lists MYH6 as "Amber/Moderate Evidence" for DCM), reflecting that MYH6-DCM is a less firmly established gene-disease relationship than genes like TTN, LMNA, or MYH7 (ClinGen evidence-based DCM gene assessment; Genomics England PanelApp – MYH6). Curators should treat MYH6-DCM causality claims with corresponding caution and prefer variant-level ACMG/AMP evidence.
Mutation prevalence: MYH6 mutations were "first reported in DCM cohorts with an estimated prevalence of approximately 4%" of screened familial DCM cases, though more recent variant-classification frameworks note that 15–30% of cardiomyopathy genetic test results overall are variants of uncertain significance (VUS), underscoring interpretive caution for any single MYH6 variant.
Modifier genes: Not specifically characterized for CMD1EE; broader DCM literature implicates titin (TTN) truncating variants as a common "modifier/second hit" background.
Epigenetics: No CMD1EE-specific epigenetic (DNA methylation/histone) data identified.
Chromosomal abnormalities: None reported; CMD1EE is a single-gene missense disorder, not a copy-number/structural variant disease.

Functional/molecular mechanism (protein level): MYH6 encodes the α-heavy chain of cardiac myosin, "a motor protein that uses ATP hydrolysis and actin binding to support cardiac muscle contraction." α-MHC (MYH6) is "the fast, predominant isoform expressed in human cardiac atria" with a smaller (~7%) contribution to adult ventricular myosin, where β-MHC (MYH7) predominates (GeneCards). The p.Ala1004Ser substitution falls in the myosin rod domain, which mediates thick-filament assembly (myosin dimerization and packing into the sarcomere), distinct from mutations in the globular motor/head domain that more directly impair ATPase/force-generating activity — suggesting a filament-assembly or structural mechanism for this particular CMD1EE variant, complementary to the force-generation defects documented for other sarcomeric DCM genes (see Mechanism, below).

5. Environmental Information

No CMD1EE-specific environmental trigger, toxin, or infectious co-factor is documented in the literature surveyed. As a monogenic/Mendelian sarcomeric cardiomyopathy, the primary driver is the germline MYH6 variant; environmental modulation (physical exertion, alcohol, pregnancy, viral myocarditis) is plausible by analogy to DCM broadly but not specifically studied for this OMIM entry. Curators should mark environmental sections not established for this specific entry rather than importing generic DCM environmental-factor content without direct evidentiary support in a CMD1EE-specific source.

6. Mechanism / Pathophysiology

Causal chain (general sarcomeric DCM model, applicable to MYH6-CMD1EE):

Molecular trigger: Heterozygous MYH6 missense variant (e.g., p.Ala1004Ser) alters the primary sequence of the α-myosin heavy chain rod/coiled-coil domain, "altering polarity in a highly conserved region."
Protein/sarcomere-level dysfunction: Altered rod-domain properties are predicted to impair proper thick-filament assembly and/or myosin dimerization; sarcomeric DCM mutations broadly are understood to cause "deficits of force generation by the sarcomere" — reduced or desynchronized contractile force output rather than the increased/hypercontractile force typical of HCM mutations (PMC3032173; NEJM 2000, PMID referenced via NEJM200012073432304).
Cellular-level consequence: Reduced cardiomyocyte contractile force and impaired calcium handling trigger compensatory cardiomyocyte hypertrophy/elongation and activation of maladaptive stress-signaling pathways (calcineurin-NFAT, MAPK).
Tissue-level consequence: Chronic contractile insufficiency drives progressive chamber (ventricular ± atrial) dilation, wall thinning, and interstitial/replacement fibrosis — "postmortem cardiac examination revealed ventricular dilatation and extensive macroscopic and microscopic fibrosis in DCM cases with sarcomeric mutations" (PMC3533274; JCI 62862).
Organ-level/clinical consequence: Progressive systolic dysfunction → reduced ejection fraction → neurohormonal activation (RAAS, sympathetic) → congestive heart failure; electrical remodeling and fibrotic substrate → atrial/ventricular arrhythmia and conduction disease; end-stage disease → refractory heart failure, transplantation, or sudden cardiac death.
Divergent DCM-vs-HCM signaling note: Carniel et al.'s finding that MYH6 mutations can produce either DCM or HCM phenotypes (and that the HCM phenotype can itself progress to a dilated/"burnt-out" state) is consistent with the broader concept that "distinct biophysical events perturbed by allelic mutations in contractile genes trigger divergent signaling pathways that remodel the heart in ways that result in a dilated or hypertrophic phenotype" — i.e., the specific biophysical perturbation (e.g., rod-domain assembly defect vs. head-domain ATPase/force defect) determines which remodeling program is activated, even within the same gene (PMID 15998695).

Suggested GO terms: - GO:0030049 — muscle filament sliding - GO:0006936 — muscle contraction - GO:0060048 — cardiac muscle contraction - GO:0060047 — heart contraction - GO:0086001 — cardiac muscle cell action potential (for arrhythmia-related nodes) - GO:0055010 — ventricular cardiac muscle tissue morphogenesis - GO:0072659 — protein localization to plasma membrane (for sarcomere-assembly-adjacent processes) - GO:0031430 — M band / GO:0030017 — sarcomere (cellular component, for assembly-defect framing)

Suggested cell types (CL): - CL:0000746 — cardiac muscle myocyte / more specifically CL:0002129 (cardiac ventricular myocyte) and CL:0002127 (cardiac atrial myocyte), given α-MHC's predominant atrial expression - CL:0000057 — fibroblast (cardiac fibroblast, fibrotic remodeling)

Immune involvement: Not a primary driver in MYH6-CMD1EE; low-grade inflammatory/fibrotic remodeling is secondary to mechanical stress rather than autoimmune, unlike lymphocytic-myocarditis-associated DCM subtypes.

Molecular profiling: No MYH6-CMD1EE-specific transcriptomic, proteomic, or single-cell datasets were identified in this search; general DCM myocardial transcriptomic studies (GTEx, cardiomyopathy GEO series) would be the applicable resource class but were not queried at variant-specific resolution here.

7. Anatomical Structures Affected

Primary organ: Heart, specifically left ventricle (chamber dilation, systolic dysfunction) — UBERON:0002084 (heart left ventricle); atrial involvement plausible given α-MHC's atrial-predominant expression — UBERON:0002078 (heart atrium)
Secondary/systemic involvement: Pulmonary congestion (secondary to left heart failure), hepatic congestion, renal hypoperfusion (cardiorenal syndrome) in advanced disease — general heart-failure sequelae, not CMD1EE-specific.
Body systems: Cardiovascular system (primary); secondarily respiratory, renal, hepatic via congestive/low-output physiology.
Tissue level: Cardiac (striated) muscle tissue — UBERON:0001133 (cardiac muscle tissue); interstitial/perivascular fibrotic connective tissue.
Cell level: Cardiomyocytes (ventricular and atrial), cardiac fibroblasts (CL:0000057), cardiac conduction-system cells (for arrhythmia phenotypes, e.g., CL:1000497 sinoatrial node cell — relevant to the allelic SSS3 phenotype).
Subcellular level: Sarcomere / thick filament (GO:0030017 sarcomere; GO:0032982 myosin filament) — the direct structural locus of the rod-domain p.Ala1004Ser defect.
Laterality: Not applicable (whole-organ, bilateral/global cardiac chamber process).

8. Temporal Development

Onset: Adult, late-onset in the founding pedigree — proband diagnosed at age 51, progressing to congestive heart failure by age 59 (Carniel et al. 2005). This contrasts with some other DCM loci in the CMD1 series that present in childhood.
Onset pattern: Insidious/chronic rather than acute.
Progression: Progressive — systolic dysfunction and chamber dilation worsen over years, culminating in congestive heart failure; the companion MYH6-HCM phenotype in the same study showed "progression toward dilation, left ventricular dysfunction, and refractory heart failure," i.e., a hypertrophic-to-dilated transition trajectory is part of the MYH6 disease spectrum.
Disease course: Chronic, generally non-remitting; management is aimed at slowing progression (GDMT) rather than reversal, though some sarcomeric DCM patients show partial "reverse remodeling" on optimal therapy (general HFrEF observation, not CMD1EE-specific).
Stages: Follows standard heart-failure staging (ACC/AHA Stage A–D) once decompensation begins; no CMD1EE-specific staging system exists.
Critical periods: Early detection during the pre-symptomatic/pre-dilation phase (via family cascade echocardiographic screening) represents the key window for intervention, as with other genetic DCM loci.

9. Inheritance and Population

Inheritance pattern: Autosomal dominant.
Penetrance: Not precisely quantified for CMD1EE in the literature surveyed; sarcomeric DCM genes generally show age-related, incomplete penetrance, consistent with the late-onset presentation observed (diagnosis at 51 years in the index case) — implying that carriers may be phenotype-negative for decades.
Expressivity: Variable — demonstrated directly by MYH6 producing both DCM and HCM phenotypes across different mutations/families, and even inter-phenotype transitions (HCM progressing to a dilated/failing phenotype).
Genetic anticipation, germline mosaicism, founder effects, consanguinity, carrier frequency: Not specifically documented for CMD1EE; the disorder is described from discrete, unrelated familial pedigrees (predominantly identified in a Colorado-based DCM/HCM familial cohort per Carniel et al.), with no founder-population or consanguinity signal reported.
Epidemiology of DCM overall (context, not CMD1EE-specific):
Total DCM incidence approximately 6.95 per 100,000 per year (combining autopsy-detected [~4.5/100,000/yr] and clinically detected [~2.45/100,000/yr] cases); pediatric incidence roughly 0.57–0.58 per 100,000/year.
DCM prevalence (all-cause, adult/heterogeneous populations): approximately 42.8–118.3 per 100,000; idiopathic DCM alone: approximately 8.3–59.2 per 100,000.
Racial disparity: "a 2.7-fold increased risk associated with Black race," with Black men showing the highest prevalence (27/100,000) versus white men (11/100,000).
DCM is "a major cause of heart failure affecting especially young patients ... emerging as a major indication for heart transplantation" (NCBI Bookshelf – Epidemiology of DCM).
CMD1EE-specific population data: No dedicated prevalence/incidence figures exist for this single-gene subtype; it should be treated in curation as an ultra-rare Mendelian subtype of the broader DCM disease-class prevalence figures above.
Sex ratio, geographic distribution: Not reported specifically for CMD1EE.

10. Diagnostics

Diagnostic (clinical) criteria for DCM (applicable framework): - Traditional criteria: LV ejection fraction (EF) <45% and/or fractional shortening <25%, plus LV end-diastolic dimension (LVEDD) >112% of predicted value corrected for age and body-surface area. - Revised 2016 ESC position statement: a non-ischemic LVEF <50% is sufficient for a DCM diagnosis, reflecting recognition of earlier-stage/"hypokinetic non-dilated cardiomyopathy" phenotypes (JACC 2016 – Diagnosis and Evaluation of DCM). - Two-dimensional transthoracic echocardiography (TTE) is the front-line imaging modality; cardiac MRI is increasingly used for tissue characterization (late gadolinium enhancement, fibrosis quantification) and etiological/prognostic stratification.

Laboratory/biomarkers: NT-proBNP/BNP for heart-failure severity and monitoring (LOINC-codable); troponin for excluding acute ischemic injury; no CMD1EE-specific circulating biomarker is established.

Genetic testing: - Multigene cardiomyopathy panels (including MYH6 alongside TTN, LMNA, MYH7, TNNT2, BAG3, RBM20, DSP, and dozens of other DCM genes) are the standard-of-care approach for suspected familial DCM, per GeneReviews' Dilated Cardiomyopathy Overview (NCBI Bookshelf NBK1309). - Single-gene MYH6 sequencing is appropriate when a specific familial variant is already known (cascade testing) but panel/exome-based approaches are preferred for initial diagnostic evaluation given MYH6's only moderate curated gene-disease strength for DCM and its phenotypic overlap with HCM and conduction-disease genes. - Variant interpretation should follow ACMG/AMP criteria; note that the founding p.Ala1004Ser classification in ClinVar is explicitly flagged as outdated (2005 evaluation) pending reassessment against current population-frequency and functional evidence.

Differential diagnosis: Ischemic cardiomyopathy, hypertensive heart disease, valvular cardiomyopathy, tachycardia-induced cardiomyopathy, myocarditis, alcoholic cardiomyopathy, peripartum cardiomyopathy, other genetic DCM loci (TTN, LMNA — the latter especially given its strong arrhythmia/conduction-disease association), and the HCM-with-dilation "burnt-out" phenotype (itself sometimes MYH6-driven).

Screening: First-degree relative cascade echocardiographic and genetic screening is standard once a pathogenic MYH6 variant is confirmed in a proband, given the autosomal dominant inheritance and demonstrated age-dependent penetrance.

11. Outcome/Prognosis

CMD1EE-specific survival/mortality statistics are not established in the literature surveyed (the entry derives from a small number of pedigrees rather than a large outcomes cohort). General DCM prognostic context: DCM is a leading indication for heart transplantation, and outcomes are strongly influenced by degree of LV dysfunction at diagnosis, response to GDMT, presence of late gadolinium enhancement/fibrosis on MRI (adverse prognostic marker), and arrhythmic burden. The Carniel et al. index MYH6-DCM case progressed from diagnosis to congestive heart failure over approximately 8 years (age 51 to 59), consistent with a progressive but not fulminant natural history for this particular variant; broader conclusions about CMD1EE prognosis should not be over-generalized from this single case.

Complications: Congestive heart failure, ventricular and atrial arrhythmias, thromboembolism (from LV/atrial stasis), sudden cardiac death, and progression to end-stage heart failure requiring transplantation or mechanical circulatory support.

12. Treatment

No CMD1EE-specific (gene-targeted) therapy exists; management follows standard heart-failure-with-reduced-ejection-fraction (HFrEF) guideline-directed medical therapy (GDMT), per the 2022 ACC/AHA/HFSA Heart Failure Guidelines and 2023 ESC Cardiomyopathy Guidelines:

Pharmacotherapy (NCIT:C15986 Pharmacotherapy):
ACE inhibitors/ARBs or angiotensin receptor-neprilysin inhibitor (ARNi, e.g., sacubitril/valsartan) — ARNi shown "superior to enalapril in reduction of cardiovascular mortality, hospitalization for HF, and improvement in symptoms."
Beta-blockers — a 2024 meta-analysis found beta-blockers had "a significant beneficial effect on left ventricular ejection fraction (LVEF), more than that from ACE inhibitors."
Mineralocorticoid receptor antagonists (spironolactone/eplerenone).
SGLT2 inhibitors — now part of quadruple GDMT for HFrEF regardless of diabetes status.
Loop diuretics for volume management (supportive, not disease-modifying).
Device therapy: Implantable cardioverter-defibrillator (ICD) for primary/secondary sudden-death prevention in appropriate candidates — in the pivotal trial evidence cited, "sudden cardiac death occurred less often in the ICD group (4.3%) than in the control group (8.2%)," with age-dependent mortality benefit (greater under age 59). Cardiac resynchronization therapy (CRT) for eligible patients with conduction delay (e.g., LBBB).
Surgical/advanced therapy (NCIT:C15289 Organ Transplantation): Heart transplantation remains "the criterion standard" for progressive end-stage heart failure refractory to maximal medical therapy; left ventricular assist device (LVAD) as bridge-to-transplant or destination therapy.
Genetic counseling (NCIT:C15240): Recommended for probands and at-risk relatives given autosomal dominant inheritance and cascade-testing implications.
Experimental/investigational: No MYH6-targeted gene therapy or precision therapeutic is in clinical development per the literature surveyed (contrast with MYH7-HCM, where mavacamten and other myosin modulators exist — MYH6-specific analogs are not established).

13. Prevention

No primary genetic prevention exists beyond reproductive genetic counseling (carrier detection, prenatal/preimplantation genetic testing options for known-familial pathogenic variants) and secondary prevention via early cascade screening of at-risk relatives to enable pre-symptomatic initiation of monitoring and, where evidence supports it in comparable sarcomeric cardiomyopathies, early GDMT. Tertiary prevention centers on standard heart-failure disease-management protocols (GDMT titration, arrhythmia surveillance, ICD placement per guideline criteria, activity modification) to reduce progression to end-stage disease and sudden cardiac death.

14. Other Species / Natural Disease

No naturally occurring MYH6-CMD1EE veterinary disease was identified in this search (no OMIA entry surfaced). MYH6 orthologs are broadly conserved across vertebrates; mouse Myh6 (MGI:97255) is the standard experimental ortholog (see Model Organisms, below). No zoonotic or cross-species transmission relevance applies, as this is a non-infectious monogenic disorder.

15. Model Organisms

Mouse (Mus musculus, NCBITaxon:10090): - Gene: Myh6 (MGI:97255; allele record MGI:3691279). - Homozygous null: "Mice homozygous for a knock-out allele exhibit embryonic lethality associated with heart defects," reflecting Myh6's essential role in cardiac development, consistent with α-MHC being the dominant embryonic/perinatal cardiac myosin isoform in mice (unlike the atrial-predominant expression pattern in adult humans). - Heterozygous null / knock-in models: Heterozygotes "show cardiac myofibrillar disarray, cardiac dysfunction and fibrosis," and mice heterozygous for various Myh6 knock-in alleles "may develop hypertrophic or dilated forms of cardiomyopathy" — directly recapitulating the human DCM/HCM phenotypic duality seen with different MYH6 variants. Documented phenotypes in these models include dilated left ventricle, decreased cardiac muscle contractility, and abnormal cardiac muscle relaxation (MGI:97255; MGI:3691279). - Allele-specific silencing proof-of-concept: For a hypertrophic Myh6 mutation, allele-specific siRNA silencing of the mutant transcript in mice suppressed the HCM phenotype (Jiang et al., Science 2013; PMID: 24092743) — demonstrating feasibility of a therapeutic strategy class potentially transferable to a specific CMD1EE-causing allele, though this has not been reported for p.Ala1004Ser specifically.

Model limitations: Mouse cardiac myosin isoform usage differs substantially from human (α-MHC dominant throughout the adult mouse ventricle vs. β-MHC/MYH7 dominant in adult human ventricle, with α-MHC/MYH6 restricted mainly to human atria) — a key human/model translational caveat: murine Myh6 models may not fully recapitulate the ventricular-predominant human CMD1EE phenotype because the orthologous gene plays a proportionally larger role in the mouse ventricle than in the human ventricle. This is exactly the kind of HUMAN_MODEL_MISMATCH consideration relevant to dismech curation of this entry.

iPSC/in vitro models: No CMD1EE-variant-specific iPSC-cardiomyocyte study was identified in this search; iPSC-CM platforms are broadly used for other sarcomeric cardiomyopathy genes (MYH7, TNNT2, TTN) and would be a natural extension for functional characterization of MYH6 CMD1EE variants.

Summary of Key Ontology Term Suggestions for Curation

Table (click to expand)

Category	Suggested Term
Disease (MONDO)	MONDO:0013198 (MYH6-related familial DCM; verify exact CMD1EE-specific MONDO mapping during curation)
Gene	HGNC:7576 (MYH6)
Phenotype (HP)	HP:0001644 (Dilated cardiomyopathy), HP:0001635 (Congestive heart failure), HP:0011675 (Arrhythmia), HP:0004308 (Ventricular arrhythmia), HP:0001698 (Pericardial effusion)
GO Biological Process	GO:0060048 (cardiac muscle contraction), GO:0055010 (ventricular cardiac muscle tissue morphogenesis)
GO Cellular Component	GO:0030017 (sarcomere), GO:0032982 (myosin filament)
Cell Type (CL)	CL:0002129 (cardiac ventricular myocyte), CL:0002127 (cardiac atrial myocyte), CL:0000057 (fibroblast)
Anatomy (UBERON)	UBERON:0002084 (heart left ventricle), UBERON:0002078 (heart atrium)
Treatment (NCIT)	NCIT:C15986 (Pharmacotherapy), NCIT:C15289 (Organ Transplantation), NCIT:C15240 (Genetic Counseling)

Important Curation Caveats

Search-engine name collision risk: A search for "PLEKHM2 dilated cardiomyopathy" surfaces a biallelic/recessive DCM-with-LV-noncompaction gene that is entirely distinct from MYH6/CMD1EE — do not conflate the two despite both matching a generic "dilated cardiomyopathy" search.
Gene-disease validity is only moderate, and the single founding variant's ClinVar classification is explicitly flagged as outdated (2005 evidence). Any evidence items curated from the primary paper should be flagged accordingly, and variant-level re-classification against current gnomAD/ACMG-AMP standards is recommended before treating pathogenicity as settled.
Small evidentiary base: CMD1EE is described from a limited number of pedigrees (primarily Carniel et al. 2005); population-level statistics (prevalence, penetrance, sex ratio) cited in this report for "DCM" generally should not be presented as CMD1EE-specific without qualification.

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Table (click to expand)

Outcome	Count
References checked	10
Resolved	10
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	2
Quoted claims found in source	1
Quoted claims not found in source	1
References weighed for topical relevance	10
On topic	8
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMC:PMC3533274 (abstract only): "postmortem cardiac examination revealed ventricular dilatation and extensive macroscopic and microscopic fibrosis in DCM cases with sarcomeric mutations"
closest text in source: "DCM is characterized by enlarged ventricular dimensions and impaired systolic and diastolic function"