A late-onset autosomal dominant dilated cardiomyopathy attributed to heterozygous missense variants in MYH6, the gene for cardiac alpha-myosin heavy chain. It is one entry in the long numbered OMIM series of dilated cardiomyopathy loci, and it is curated here with an explicit qualification that most entries in that series do not carry. The gene-disease relationship is weakly supported. ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classified MYH6 for dilated cardiomyopathy as **Limited** in March 2025 - the lowest tier above disputed, meaning the accumulated genetic and experimental evidence does not establish the relationship. That assessment is curated on the gene entry with its own evidence item rather than buried, because a reader deciding what to do with a MYH6 variant in a patient needs it more than they need anything else in this entry. What is well documented is narrower than a disease claim. Three heterozygous MYH6 missense variants were found in 4.3% of dilated cardiomyopathy probands in the founding screen, in conserved residues and absent from controls, with a late-onset carrier phenotype. A later functional study took two of those variants into cardiomyocytes and found something genuinely informative: they alter contractility in opposite ways, and neither disturbs the calcium transient. So whatever MYH6 variants do, they do it at the contractile apparatus rather than through calcium handling - and they do not do one uniform thing. Read alongside the ClinGen classification, that heterogeneity is part of the problem. Alleles in one gene producing divergent cellular phenotypes and a late, incompletely penetrant clinical phenotype is exactly the pattern that makes a gene-disease relationship hard to establish. MYH6 is more securely associated with two other cardiac phenotypes - sick sinus syndrome and left-sided congenital heart defects. Those are separate entities and are curated as differential diagnoses.
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Conditions with similar clinical presentations that must be differentiated from Dilated Cardiomyopathy 1EE:
name: Dilated Cardiomyopathy 1EE
creation_date: "2026-08-26T16:00:00Z"
category: Mendelian
disease_term:
preferred_term: dilated cardiomyopathy 1EE
term:
id: MONDO:0013198
label: dilated cardiomyopathy 1EE
synonyms:
- CMD1EE
- cardiomyopathy, dilated, 1EE
- MYH6-related dilated cardiomyopathy
description: >-
A late-onset autosomal dominant dilated cardiomyopathy attributed to heterozygous
missense variants in MYH6, the gene for cardiac alpha-myosin heavy chain. It is one entry
in the long numbered OMIM series of dilated cardiomyopathy loci, and it is curated here
with an explicit qualification that most entries in that series do not carry.
The gene-disease relationship is weakly supported. ClinGen's Dilated Cardiomyopathy Gene
Curation Expert Panel classified MYH6 for dilated cardiomyopathy as **Limited** in March
2025 - the lowest tier above disputed, meaning the accumulated genetic and experimental
evidence does not establish the relationship. That assessment is curated on the gene entry
with its own evidence item rather than buried, because a reader deciding what to do with a
MYH6 variant in a patient needs it more than they need anything else in this entry.
What is well documented is narrower than a disease claim. Three heterozygous MYH6 missense
variants were found in 4.3% of dilated cardiomyopathy probands in the founding screen, in
conserved residues and absent from controls, with a late-onset carrier phenotype. A later
functional study took two of those variants into cardiomyocytes and found something
genuinely informative: they alter contractility in opposite ways, and neither disturbs the
calcium transient. So whatever MYH6 variants do, they do it at the contractile apparatus
rather than through calcium handling - and they do not do one uniform thing.
Read alongside the ClinGen classification, that heterogeneity is part of the problem.
Alleles in one gene producing divergent cellular phenotypes and a late, incompletely
penetrant clinical phenotype is exactly the pattern that makes a gene-disease relationship
hard to establish.
MYH6 is more securely associated with two other cardiac phenotypes - sick sinus syndrome
and left-sided congenital heart defects. Those are separate entities and are curated as
differential diagnoses.
parents:
- Familial Dilated Cardiomyopathy
- Sarcomeric Cardiomyopathy
prevalence:
- population: Familial dilated cardiomyopathy probands
measure_type: CASES_IN_LITERATURE
prevalence_class: NOT_YET_DOCUMENTED
notes: >-
No population prevalence exists for this locus. The only frequency figure is the yield
within a screened cohort: 3 of 69 dilated cardiomyopathy probands, reported as 4.3%.
That is a mutation-detection rate in a selected familial cohort, not a disease
prevalence, and it should not be used as one.
evidence:
- reference: PMID:15998695
reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Three heterozygous MYH6 missense mutations were identified in DCM probands (P830L,
A1004S, and E1457K; 4.3% of probands).
explanation: >-
PARTIAL because it gives a detection rate among screened familial probands rather than
an occurrence measure in any population.
pathophysiology:
- name: Heterozygous MYH6 Missense Variant
role: trigger
biological_scale: MOLECULAR
description: >-
A single MYH6 allele carries a missense substitution. The founding screen reported
P830L, A1004S and E1457K in dilated cardiomyopathy probands, all in highly conserved
residues, predicted to alter the structure or chemical bonding of the protein, and
absent from at least 300 control chromosomes.
Those are the classical arguments for pathogenicity, and they are also exactly the
arguments that expert-panel curation has since found insufficient on their own. This
node states what was observed; the gene entry states how much weight it currently bears.
genetic_context:
gene:
preferred_term: MYH6
term:
id: hgnc:7576
label: MYH6
variant_origin: GERMLINE
zygosity: HETEROZYGOUS
description: >-
Heterozygous missense alleles. No `functional_impact_category` is asserted: the
functional work below shows two of these variants behaving differently from one
another, so no single consequence term describes the class.
downstream:
- target: Altered Sarcomere Contractile Output
causal_link_type: DIRECT
description: >-
The substituted residues sit in alpha-myosin heavy chain, and the measured
consequence is a change in how the sarcomere shortens.
evidence:
- reference: PMID:15998695
reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Three heterozygous MYH6 missense mutations were identified in DCM probands (P830L,
A1004S, and E1457K; 4.3% of probands).
explanation: >-
The founding variants, in the probands they were found in.
- reference: PMID:15998695
reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
All MYH6 mutations were distributed in highly conserved residues, were predicted to
change the structure or chemical bonds of alphaMyHC, and were absent in at least 300
control chromosomes from an ethnically similar population.
explanation: >-
The conservation, predicted structural effect and control absence that constituted the
original pathogenicity argument.
- name: Altered Sarcomere Contractile Output
role: central_effector
biological_scale: CELLULAR
mechanism_confidence: PROVISIONAL
description: >-
The one place MYH6 dilated-cardiomyopathy variants have been studied functionally. Two
of the founding alleles were expressed in adult rat ventricular myocytes and their
contractile behaviour measured directly.
The result is more interesting than a simple deficit. A1004S reduced peak sarcomere
shortening; P830L shortened almost normally at baseline. Under beta-adrenergic
stimulation the two diverged again, in opposite directions relative to the alpha and
beta myosin controls. The authors' conclusion is that the two alleles alter myocyte
contractility in completely different ways despite a shared clinical association.
So there is no single "MYH6 contractile defect" to curate. There is a gene in which
different disease-associated alleles perturb contraction differently - which is a
substantive finding, and one reason the gene-level disease claim has been hard to
establish.
PROVISIONAL: adenoviral expression of human mutant protein in rat myocytes is a
heterologous system, and no measurement has been made in human cardiac tissue or in
patient-derived cardiomyocytes.
cell_types:
- preferred_term: regular ventricular cardiac myocyte
term:
id: CL:0002131
label: regular ventricular cardiac myocyte
cellular_components:
- preferred_term: sarcomere
term:
id: GO:0030017
label: sarcomere
- preferred_term: myosin filament
term:
id: GO:0032982
label: myosin filament
biological_processes:
- preferred_term: muscle filament sliding
term:
id: GO:0030049
label: muscle filament sliding
modifier: ABNORMAL
- preferred_term: cardiac muscle contraction
term:
id: GO:0060048
label: cardiac muscle contraction
modifier: ABNORMAL
downstream:
- target: Preserved Calcium Handling
causal_link_type: DIRECT
description: >-
Drawn as an explicit edge because the negative result is part of the finding: the
contractile change occurs without a change in the calcium transient, which localises
the defect to the myofilament.
- target: Progressive Left Ventricular Dilatation and Systolic Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The step from an altered single-myocyte contractile phenotype to a dilated, failing
ventricle decades later has not been demonstrated for these alleles. Typed with
unknown intermediates for that reason; it is the weakest link in this entry's chain
and is the subject of a knowledge gap below.
evidence:
- reference: PMID:28088328
reference_title: "Altered myocyte contractility and calcium homeostasis in alpha-myosin heavy chain point mutations linked to familial dilated cardiomyopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The A1004S mutation resulted in decreased peak sarcomere shortening while P830L
demonstrated near normal shortening kinetics at baseline.
explanation: >-
The divergent baseline contractile phenotypes of the two alleles, measured directly.
- reference: PMID:28088328
reference_title: "Altered myocyte contractility and calcium homeostasis in alpha-myosin heavy chain point mutations linked to familial dilated cardiomyopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Despite a shared association with DCM, the P830L and A1004S αMHC mutations alter
myocyte contractility in completely different ways while at the same preserving peak
intracellular calcium.
explanation: >-
The authors' summary: same disease association, different contractile mechanism,
calcium spared. This is the sentence the node is built on.
- name: Preserved Calcium Handling
role: modifier
biological_scale: CELLULAR
description: >-
A curated negative. Calcium transients were identical across mutant, wild-type and
uninfected myocytes, so the contractile abnormality is not secondary to altered calcium
delivery.
Recorded as its own node because it is discriminating: many cardiomyopathy mechanisms
run through calcium handling, and for these alleles that route is excluded rather than
merely unexamined. It also means calcium-directed therapies have no mechanistic
rationale here.
cell_types:
- preferred_term: regular ventricular cardiac myocyte
term:
id: CL:0002131
label: regular ventricular cardiac myocyte
evidence:
- reference: PMID:28088328
reference_title: "Altered myocyte contractility and calcium homeostasis in alpha-myosin heavy chain point mutations linked to familial dilated cardiomyopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
All experimental groups had identical calcium transients.
explanation: >-
The negative result itself, stated without qualification by the source.
- name: Progressive Left Ventricular Dilatation and Systolic Dysfunction
role: outcome
biological_scale: ORGANISM
description: >-
The clinical phenotype: a dilated, hypocontractile left ventricle presenting late.
In the founding cohort the dilated-cardiomyopathy carrier phenotype was characterised
specifically by late onset, in contrast with the hypertrophic phenotype seen with a
different MYH6 allele in the same study, which progressed towards dilatation and
refractory heart failure.
Late onset matters for interpretation as much as for the clinic: a phenotype that
appears in the sixth decade in some carriers and not at all in others is difficult to
segregate convincingly in a pedigree, and thin segregation evidence is part of why the
gene-disease relationship remains weakly supported.
locations:
- preferred_term: heart left ventricle
term:
id: UBERON:0002084
label: heart left ventricle
cell_types:
- preferred_term: cardiac muscle cell
term:
id: CL:0000746
label: cardiac muscle cell
downstream:
- target: Congestive Heart Failure
causal_link_type: DIRECT
description: >-
Progressive systolic dysfunction reduces cardiac output until it is symptomatic.
evidence:
- reference: PMID:15998695
reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
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.
explanation: >-
The late-onset dilated phenotype and the contrasting hypertrophic one, which together
define the reported MYH6 spectrum.
- name: Congestive Heart Failure
role: outcome
biological_scale: ORGANISM
description: >-
The endpoint of the dilated phenotype. In the index carrier the interval from diagnosis
to congestive failure was several years, consistent with a progressive but not fulminant
course.
locations:
- preferred_term: heart
term:
id: UBERON:0000948
label: heart
evidence:
- reference: PMID:15998695
reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
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.
explanation: >-
PARTIAL against this node: the refractory heart failure named in the quoted sentence
belongs to the hypertrophic arm of the MYH6 spectrum, not to the dilated one. Cited
here to place the endpoint within the gene's reported range while making clear the
source does not attribute it to the dilated phenotype.
phenotypes:
- category: Cardiovascular
name: Dilated Cardiomyopathy
frequency: OBLIGATE
description: >-
A dilated, hypocontractile left ventricle - the defining feature of the entity.
Onset is in adulthood and characterised by the founding study as late, which
distinguishes this locus from several other entries in the dilated cardiomyopathy
series that present in childhood. No onset_category is asserted: the source gives no
age, and HPO's LATE band means onset after sixty, which is a more specific claim than
"late onset" relative to the CMD1 series supports.
phenotype_term:
preferred_term: Dilated cardiomyopathy
term:
id: HP:0001644
label: Dilated cardiomyopathy
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:15998695
reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Three heterozygous MYH6 missense mutations were identified in DCM probands (P830L,
A1004S, and E1457K; 4.3% of probands).
explanation: >-
Establishes that the variants were ascertained in probands with dilated
cardiomyopathy, which is the phenotype this record names.
- reference: PMID:15998695
reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The DCM carrier phenotype was characterized by late onset
explanation: >-
States late onset as the characterising feature of the dilated-cardiomyopathy carrier
phenotype. Carried on this record rather than on a separate onset record, since a
second record reusing HP:0001644 would duplicate the phenotype.
- category: Cardiovascular
name: Left Ventricular Systolic Dysfunction
phenotype_term:
preferred_term: Left ventricular systolic dysfunction
term:
id: HP:0025169
label: Left ventricular systolic dysfunction
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:15998695
reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In failing human hearts, downregulation of alphaMyHC mRNA or protein has been
correlated with systolic dysfunction.
explanation: >-
PARTIAL, and the shortfall is worth stating precisely. This sentence is from the
paper's background - the rationale for screening the gene - and it concerns unselected
failing hearts, not MYH6 missense carriers. It also describes a correlation with
reduced alphaMyHC expression, which is a different mechanism from the heterozygous
missense alleles this entry curates and deliberately declines to assign a
functional_impact_category. It supports systolic dysfunction as a phenomenon connected
to alpha-myosin heavy chain, not as a documented feature of this genotype.
No frequency is asserted for the same reason: nothing cited reports one, and the
founding cohort is three probands.
- category: Cardiovascular
name: Congestive Heart Failure
description: >-
The clinical syndrome the ventricular dysfunction produces, and the terminal node of
this entry's pathophysiology chain. Recorded as a phenotype as well as a node because
asserting it in one place and not the other is internally inconsistent.
phenotype_term:
preferred_term: Congestive heart failure
term:
id: HP:0001635
label: Congestive heart failure
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:15998695
reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the HCM phenotype was characterized by progression toward dilation, left ventricular
dysfunction, and refractory heart failure
explanation: >-
PARTIAL because the quoted progression to refractory heart failure is stated for the
hypertrophic carrier phenotype in this cohort, not the dilated one. It is cited here
as the only direct statement about heart failure in the MYH6 carrier literature; the
dilated-phenotype claim rests on the pathophysiology of dilated cardiomyopathy
generally rather than on a measurement in these carriers.
genetic:
- name: MYH6
relationship_type: CAUSATIVE
variant_origin: GERMLINE
gene_term:
preferred_term: MYH6
term:
id: hgnc:7576
label: MYH6
association: >-
MYH6 encodes cardiac alpha-myosin heavy chain, the faster and less abundant of the two
adult ventricular myosin isoforms. Heterozygous missense variants in it were proposed as
a cause of dilated cardiomyopathy on the strength of a 2005 screen: three variants in
4.3% of dilated cardiomyopathy probands, in conserved residues, absent from controls,
with a late-onset carrier phenotype.
That claim has not strengthened with time. In March 2025 ClinGen's Dilated
Cardiomyopathy Gene Curation Expert Panel classified the MYH6 - dilated cardiomyopathy
relationship as **Limited** under SOP10. Limited is the lowest classification above
Disputed: it means some genetic evidence exists but is insufficient to establish the
gene as a cause of the disease. A MYH6 variant found in a patient with dilated
cardiomyopathy should be interpreted against that, and this entry types the relationship
CAUSATIVE only because the OMIM-defined entity it curates makes that assertion - not
because the evidence is settled.
The same gene has better support for two other cardiac phenotypes: a common Icelandic
variant confers a large increase in sick sinus syndrome risk, and MYH6 variants are
recurrent in left-sided congenital heart defects. Both are curated as differential
diagnoses. That MYH6 is genuinely a cardiac disease gene is not in question; what is in
question is whether dilated cardiomyopathy is one of the things it causes.
evidence:
- reference: CGGV:assertion_6d55ac7b-e9d8-4a97-bb20-92beeffaed96-2025-03-07T170000.000Z
reference_title: "MYH6 / dilated cardiomyopathy (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
MYH6 | HGNC:7576 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited | SOP10 |
Dilated Cardiomyopathy Gene Curation Expert Panel
explanation: >-
The current expert-panel classification of this gene-disease relationship. Typed
PARTIAL because it qualifies the causal claim rather than supporting it - it is the
single most important thing in this entry for anyone interpreting a MYH6 variant.
- reference: PMID:15998695
reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A cohort of 434 subjects, 374 (134 affected, 214 unaffected, 26 unknown) belonging to
69 DCM families and 60 (29 affected, 30 unaffected, 1 unknown) in 21 HCM families,
was screened for alphaMyHC gene (MYH6) mutations.
explanation: >-
The size and structure of the screen that produced the original gene-disease claim.
- reference: PMID:15998695
reference_title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This study suggests that mutations in MYH6 may cause a spectrum of phenotypes ranging
from DCM to HCM.
explanation: >-
PARTIAL because it is the founding study stating its own conclusion in hedged terms -
"suggests" and "may cause" - which is closer to the current expert-panel view than the
OMIM entity's framing is.
inheritance:
- name: Autosomal dominant
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Heterozygous variants transmitted dominantly, with age-dependent and probably incomplete
penetrance given the late onset. Incomplete penetrance is not merely a counselling
caveat here: it weakens pedigree segregation evidence, and thin segregation evidence is
a principal reason the gene-disease relationship is classified Limited.
evidence:
- reference: CGGV:assertion_6d55ac7b-e9d8-4a97-bb20-92beeffaed96-2025-03-07T170000.000Z
reference_title: "MYH6 / dilated cardiomyopathy (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
MYH6 | HGNC:7576 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited | SOP10 |
Dilated Cardiomyopathy Gene Curation Expert Panel
explanation: >-
Records the mode of inheritance the expert panel curated the relationship under, AD,
alongside the classification.
diagnosis:
- name: Echocardiographic Evaluation of the Proband
description: >-
Dilated cardiomyopathy is diagnosed on imaging - a dilated left ventricle with impaired
systolic function and no ischaemic or load-related explanation - before any genetic
question arises. GeneReviews frames the evaluation of a proband with nonsyndromic
dilated cardiomyopathy as one of the purposes of its overview of the disease.
evidence:
- reference: PMID:20301486
reference_title: "Dilated Cardiomyopathy Overview."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
Provide the evaluation strategy of a proband with nonsyndromic DCM
explanation: >-
The GeneReviews overview's statement that it defines the proband evaluation strategy
for this disease class.
- name: Multigene Cardiomyopathy Panel Testing
description: >-
Genetic testing is by panel or exome rather than single-gene sequencing. For MYH6 that
is not merely a matter of efficiency: with the gene-disease relationship classified
Limited, a MYH6 variant found in isolation carries little interpretive weight, and the
main value of testing is to find a variant in a gene with stronger support.
A MYH6 variant in a dilated-cardiomyopathy proband should not be treated as a molecular
diagnosis without further evidence, and cascade testing of relatives on the strength of
one is difficult to justify.
evidence:
- reference: CGGV:assertion_6d55ac7b-e9d8-4a97-bb20-92beeffaed96-2025-03-07T170000.000Z
reference_title: "MYH6 / dilated cardiomyopathy (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
MYH6 | HGNC:7576 | dilated cardiomyopathy | MONDO:0005021 | AD | Limited | SOP10 |
Dilated Cardiomyopathy Gene Curation Expert Panel
explanation: >-
The classification that governs how much weight a MYH6 result should carry in this
setting.
treatments:
- name: Cardiac Surveillance of At-Risk Relatives
therapeutic_modality: OTHER
description: >-
Serial cardiac assessment of first-degree relatives, which for a late-onset
cardiomyopathy is the intervention with the clearest rationale: it detects dilatation
before symptoms, when guideline heart-failure therapy can be started early. GeneReviews
frames genetic risk assessment of at-risk asymptomatic relatives as serving exactly
this purpose.
Whether surveillance should be triggered by a MYH6 variant specifically is a different
question, and one this entry cannot answer affirmatively given the Limited
classification. Clinical surveillance of relatives of an affected proband stands on the
family history regardless of genotype.
treatment_term:
preferred_term: serial cardiac surveillance
term:
id: NCIT:C15747
label: Supportive Care
target_mechanisms:
- target: Progressive Left Ventricular Dilatation and Systolic Dysfunction
description: >-
Detects the phenotype early rather than modifying the mechanism; the benefit comes
from starting treatment before decompensation.
evidence:
- reference: PMID:20301486
reference_title: "Dilated Cardiomyopathy Overview."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
relatives of a proband with DCM to inform cardiac surveillance and allow early
detection and treatment of DCM to improve long-term outcome
explanation: >-
The GeneReviews statement of purpose for risk assessment of relatives: surveillance,
early detection, and improved long-term outcome.
- name: Guideline-Directed Heart Failure Therapy
therapeutic_modality: SMALL_MOLECULE
description: >-
Standard pharmacological treatment of reduced-ejection-fraction heart failure, with
device therapy and transplantation as the disease advances. It is not specific to this
locus, and no MYH6-directed therapy exists.
Recorded without an evidence item: the cited MYH6 literature reports no treatment
outcomes, and quoting a general heart-failure trial would attach evidence about a
different population to a claim about this entity.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
target_mechanisms:
- target: Congestive Heart Failure
description: >-
Acts on the clinical endpoint, not on the sarcomeric lesion upstream.
notes: >-
Deliberately unevidenced. Nothing in the MYH6 dilated-cardiomyopathy literature reports
a treatment result.
- name: Implantable Cardioverter-Defibrillator
therapeutic_modality: DEVICE
description: >-
Device implantation for prevention of sudden cardiac death once ejection fraction and
arrhythmic risk meet guideline thresholds. Indicated by the severity of ventricular
dysfunction rather than by genotype, which is why it is described here without any
MYH6-specific claim.
treatment_term:
preferred_term: implantable cardioverter-defibrillator placement
term:
id: NCIT:C80435
label: Implantable Cardioverter-Defibrillator Placement
target_mechanisms:
- target: Congestive Heart Failure
description: >-
Addresses the arrhythmic mortality that accompanies the failing dilated ventricle
rather than the pump failure itself.
notes: >-
Deliberately unevidenced, for the same reason as the pharmacotherapy record: the MYH6
literature reports no device outcomes, and quoting a general heart-failure device trial
would attach evidence about a different population to a claim about this entity.
- name: Cardiac Resynchronization Therapy
therapeutic_modality: DEVICE
description: >-
Biventricular pacing for patients with heart failure and conduction delay. Like
defibrillator implantation, it is selected on physiology rather than on genotype.
treatment_term:
preferred_term: cardiac resynchronization therapy
term:
id: NCIT:C80436
label: Cardiac Resynchronization Therapy
target_mechanisms:
- target: Congestive Heart Failure
description: >-
Improves the mechanical efficiency of the dilated, dyssynchronous ventricle.
notes: >-
Deliberately unevidenced; no MYH6-specific device outcomes are reported.
- name: Heart Transplantation
therapeutic_modality: SURGERY
description: >-
The endpoint of escalation for refractory disease, with mechanical circulatory support
as a bridge where transplantation is not immediately available. Recorded because this
entry's terminal pathophysiology node is congestive heart failure, and an entry that
recommends surveillance so heart-failure therapy can start early should say what that
therapy escalates to.
treatment_term:
preferred_term: heart transplantation
term:
id: NCIT:C15246
label: Heart Transplantation
target_mechanisms:
- target: Congestive Heart Failure
description: >-
Replaces the failing organ; the only intervention here that removes the diseased
myocardium rather than compensating for it.
notes: >-
Deliberately unevidenced; no MYH6-specific transplantation outcomes are reported.
differential_diagnoses:
- name: MYH6-related sick sinus syndrome
description: >-
The allelic phenotype with much stronger genetic support. A missense variant,
c.2161C>T (p.Arg721Trp), present in 0.38% of Icelanders, raises the lifetime risk of
sick sinus syndrome from about 6% in non-carriers to roughly 50% in carriers, with an
odds ratio above 12 in a population-scale study.
The contrast is instructive rather than incidental: the same gene supports a
population-scale, high-penetrance association for a conduction phenotype while its
dilated-cardiomyopathy relationship is classified Limited.
distinguishing_features:
- Sinus node dysfunction and bradycardia rather than ventricular dilatation
- A common population variant with a measured lifetime risk, rather than private familial missense alleles
evidence:
- reference: PMID:21378987
reference_title: "A rare variant in MYH6 is associated with high risk of sick sinus syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We show that the lifetime risk of being diagnosed with sick sinus syndrome is around
6% for non-carriers of c.2161C>T but is approximately 50% for carriers of the
c.2161C>T variant.
explanation: >-
The penetrance figures that make this the best-supported MYH6 cardiac phenotype.
- reference: PMID:21378987
reference_title: "A rare variant in MYH6 is associated with high risk of sick sinus syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we have discovered a previously unidentified sick sinus syndrome susceptibility gene,
MYH6, encoding the alpha heavy chain subunit of cardiac myosin
explanation: >-
Establishes MYH6 as a sick sinus syndrome gene, the entity distinguished here.
- name: MYH6-related left-sided congenital heart defects
description: >-
MYH6 variants are recurrent in congenital heart disease, and the phenotype is
predominantly left-sided: in a French cohort of 29 individuals with congenital heart
defects and a MYH6 variant, about two thirds had a left heart defect, most commonly
hypoplastic left heart syndrome.
Relevant to this entry because a MYH6 variant reported in a patient may have been
ascertained through a congenital rather than a cardiomyopathy phenotype.
distinguishing_features:
- Structural congenital malformation present from birth rather than acquired ventricular dilatation in adulthood
- Left-sided obstructive lesions, particularly hypoplastic left heart syndrome
evidence:
- reference: PMID:41165794
reference_title: "MYH6 in Congenital Heart Defects: A Genotype-Phenotype Characterization in a French Cohort."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Of the 29 individuals included, 20 (68.9%) had a principal phenotype of left heart
defect: hypoplastic left heart syndrome
explanation: >-
The proportion with left heart defects and the commonest lesion among them.
experimental_models:
- name: Adenoviral expression of mutant human alpha-MyHC in adult rat ventricular myocytes
experimental_model_type: PRIMARY_CELL_CULTURE
description: >-
Ventricular myocytes isolated from adult Sprague Dawley rats, infected with recombinant
adenovirus carrying the P830L or A1004S mutant human alpha-myosin heavy chain, with
sarcomere shortening and calcium transients recorded with and without isoproterenol.
This is the single functional pillar of the entry. Its result is also the entry's
headline caveat, which is why it is curated as a model with declared fidelity rather
than described in prose inside a node.
modeled_mechanisms:
- target: Altered Sarcomere Contractile Output
relationship: PARTIALLY_RECAPITULATES
fidelity: LOW
description: >-
Measures the contractile consequence of two of the founding alleles directly, and
finds them diverging rather than converging - the observation the pathophysiology
node is built on.
limitations: >-
The isoform context is wrong in a way that matters for this gene specifically. The
adult rat ventricle is alpha-MyHC dominant while the adult human ventricle is
beta-MyHC dominant, so a mutant alpha-MyHC is being expressed into a myocyte where
the wild-type protein is the major ventricular isoform rather than the minor one.
Expression is also adenoviral and supraphysiological rather than from the native
locus, and nothing here was measured in human cardiac tissue or in patient-derived
cardiomyocytes.
readouts:
- name: Peak sarcomere shortening (A1004S)
target: Altered Sarcomere Contractile Output
direction: DECREASED
interpretation: >-
A1004S reduced peak shortening; P830L shortened near-normally at baseline, so the
two alleles do not share a contractile phenotype.
evidence:
- reference: PMID:28088328
reference_title: "Altered myocyte contractility and calcium homeostasis in alpha-myosin heavy chain point mutations linked to familial dilated cardiomyopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The A1004S mutation resulted in decreased peak sarcomere shortening while P830L
demonstrated near normal shortening kinetics at baseline.
explanation: >-
The divergence between the two alleles, measured directly.
evidence:
- reference: PMID:28088328
reference_title: "Altered myocyte contractility and calcium homeostasis in alpha-myosin heavy chain point mutations linked to familial dilated cardiomyopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Despite a shared association with DCM, the P830L and A1004S αMHC mutations alter
myocyte contractility in completely different ways while at the same preserving peak
intracellular calcium.
explanation: >-
The authors' own conclusion, and the reason this entry declines to curate a single
MYH6 contractile defect.
- target: Preserved Calcium Handling
relationship: MEASURES
fidelity: LOW
description: >-
The same preparation measured calcium transients alongside shortening, which is what
makes the preserved-calcium claim a measurement rather than an assumption. Curated as
its own link because a model measures different things for different nodes, and the
calcium result speaks to this node rather than to the contractile one.
limitations: >-
Same isoform and expression caveats as the contractile link, and with the added point
that a preserved calcium transient in rat myocytes does not exclude a calcium-handling
difference in human ventricle, where the isoform balance and the handling machinery
are not identical. This is a negative in one system, not a demonstration of normality
in patients.
readouts:
- name: Intracellular calcium transient
target: Preserved Calcium Handling
direction: UNCHANGED
interpretation: >-
A real negative result: peak intracellular calcium was preserved across all groups,
which is what locates the defect at the contractile apparatus rather than in calcium
handling.
evidence:
- reference: PMID:28088328
reference_title: "Altered myocyte contractility and calcium homeostasis in alpha-myosin heavy chain point mutations linked to familial dilated cardiomyopathy."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
All experimental groups had identical calcium transients.
explanation: >-
Supports this node as a measured negative rather than an absence of data.
discussions:
- discussion_id: mismatch_myosin_isoform_context
kind: HUMAN_MODEL_MISMATCH
status: OPEN
attaches_to:
- experimental_models#Adenoviral expression of mutant human alpha-MyHC in adult rat ventricular myocytes
- pathophysiology#Altered Sarcomere Contractile Output
prompt: >-
Does a mutant alpha-MyHC behave the same way in an alpha-MyHC-dominant rat ventricular
myocyte as it would in the beta-MyHC-dominant human ventricle it is supposed to model?
rationale: >-
This is not an absence of evidence. The measurement was made, it is careful, and it is
the only functional data these alleles have. The question is what it transfers to.
Adult rat ventricle is alpha-MyHC dominant; adult human ventricle is beta-MyHC dominant.
So the model expresses a mutant version of what is, in that species, the major
ventricular motor protein - while in the patient the same protein is a minor component
of the ventricle. For a gene whose disease association ClinGen rates Limited, and whose
two studied alleles already behave differently from one another, the isoform context is
not a detail: it could plausibly determine both the size and the direction of the
contractile effect.
The study's own isoproterenol result sharpens this rather than settling it. Under
beta-adrenergic stimulation A1004S shortening became identical to the beta-MyHC control
and P830L identical to the alpha-MyHC control - the two alleles landing on opposite
reference isoforms, in a cell whose isoform balance is not the human one.
proposed_experiments:
- experiment_id: express_mutant_myh6_human_ipsc_cardiomyocytes
name: Contractility of MYH6 variants in human iPSC-derived ventricular cardiomyocytes
description: >-
Introduce P830L and A1004S at the native locus in human iPSC-derived ventricular
cardiomyocytes, which carry a human isoform balance, and repeat the sarcomere
shortening and calcium transient measurements with and without beta-adrenergic
stimulation.
would_support:
- pathophysiology#Altered Sarcomere Contractile Output
supporting_outcome:
- >-
The divergent, allele-specific contractile phenotypes reproduce in a human isoform
context, supporting the rat-myocyte result as informative for the human mechanism.
refuting_outcome:
- >-
The contractile effects are absent or substantially attenuated in human cardiomyocytes,
indicating the rat result is an artefact of expressing a mutant major isoform in a cell
where it is the dominant motor, and leaving these alleles without functional support.
- discussion_id: gap_gene_disease_validity
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- genetic#MYH6
- disease#Dilated Cardiomyopathy 1EE
prompt: >-
Is MYH6 a cause of dilated cardiomyopathy at all, or is CMD1EE an OMIM entity built on
evidence that has not held up?
rationale: >-
This entry exists because OMIM defines CMD1EE and MONDO carries the concept. But
ClinGen's disease-specific expert panel, applying a structured framework in 2025,
classified MYH6 for dilated cardiomyopathy as Limited - some evidence, not enough to
establish the relationship.
Both statements are curated here because both are true of the current record, and the
tension between them is the honest state of the field rather than an error in either
source. Numbered OMIM loci were assigned when a candidate-gene screen with controls was
the standard of evidence; expert-panel curation applies a framework those screens were
not designed for.
What would resolve it is not more of the same. Additional probands with private missense
variants and late-onset disease will not move a Limited classification, because that is
precisely the evidence type already weighed and found insufficient. Segregation in large
pedigrees, or functional evidence tied to a variant rather than to the gene, would.
The practical stake is immediate. If the relationship is genuine, cascade testing of
relatives of MYH6 variant carriers is warranted. If it is not, families are being
offered surveillance and carrying a genetic diagnosis on the strength of a variant that
does not explain their disease.
proposed_experiments:
- experiment_id: myh6_dcm_segregation_and_burden
name: Case-control burden and multi-pedigree segregation for MYH6 in dilated cardiomyopathy
description: >-
Test rare MYH6 missense burden in large dilated-cardiomyopathy cohorts against ancestry
matched controls, and assemble segregation data across all reported pedigrees, scoring
the result under the same framework the expert panel applies.
would_support:
- genetic#MYH6
supporting_outcome:
- >-
Significant excess of rare MYH6 missense variants in cases over controls with
supportive segregation, which would move the classification above Limited and justify
cascade testing.
refuting_outcome:
- >-
No case-control burden excess and no informative segregation, which would support
reclassifying the relationship as Disputed and retiring CMD1EE as a distinct entity.
- discussion_id: gap_allele_specific_contractile_divergence
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Altered Sarcomere Contractile Output
prompt: >-
If two MYH6 alleles associated with the same clinical phenotype alter contractility in
opposite directions, what do they actually share?
rationale: >-
A1004S reduces peak sarcomere shortening; P830L does not, at baseline. Under
beta-adrenergic stimulation they diverge again. Neither disturbs the calcium transient.
The authors state plainly that the two alter contractility in completely different ways
despite a shared association with dilated cardiomyopathy.
That is a problem for any single mechanistic account. Either the shared clinical
association is real and the two alleles converge on something the contractility assay
does not measure - thick-filament assembly, myosin content, or long-term mechanical
signalling - or the shared association is not real, which returns to the validity
question above.
Notably, the measurement was made in adult rat ventricular myocytes expressing human
protein by adenovirus. Rat ventricle is alpha-myosin dominant while human ventricle is
beta-myosin dominant, so the isoform context in which these variants were tested is not
the one in which patients express them.
proposed_experiments:
- experiment_id: myh6_isogenic_ipsc_contractility
name: Contractile and assembly phenotyping of MYH6 variants in isogenic human cardiomyocytes
description: >-
Introduce P830L, A1004S and E1457K individually into an isogenic human iPSC background,
differentiate to ventricular cardiomyocytes, and measure contractility, thick-filament
assembly and myosin content on engineered tissue alongside calcium handling.
would_support:
- pathophysiology#Altered Sarcomere Contractile Output
supporting_outcome:
- >-
The alleles converge on a shared defect in thick-filament assembly or myosin content
in human cells even where contractility diverges, giving the shared clinical
association a mechanism.
refuting_outcome:
- >-
The alleles remain divergent on every measure in a human ventricular context and some
are indistinguishable from wild type, which would argue that not all three are
pathogenic and would feed back into the validity question.
notes: >-
Gene-disease validity is the headline. ClinGen classified MYH6 for dilated cardiomyopathy
as Limited in March 2025. This entry curates the OMIM-defined entity CMD1EE because MONDO
carries it, and simultaneously curates the classification that qualifies it. Anyone using
this entry to interpret a patient's MYH6 variant should read the genetic section before
anything else.
GeneReviews. The applicable chapter is the Dilated Cardiomyopathy Overview (PMID:20301486),
tagged below. It is an overview of the disease class rather than a gene-specific chapter,
and it does not mention MYH6. Its PubMed record is a four-point statement of the chapter's
purpose and carries no Clinical Characteristics, Diagnosis, Management or Genetic
Counseling sections of the kind a gene-specific GeneReviews abstract has. Two of its four
purpose statements support real claims here - proband evaluation strategy, and risk
assessment of at-risk relatives for surveillance - and both are cited. The remaining
sections are not mined because they are not present in the source, not because they were
skipped.
Allelic phenotypes. MYH6 is associated with sick sinus syndrome, hypertrophic
cardiomyopathy and left-sided congenital heart defects as well as dilated cardiomyopathy.
Two are curated as differential diagnoses. Evidence about them is deliberately not used to
support claims about this entity, since a gene being a genuine cardiac disease gene is not
evidence that it causes this particular disease - the distinction the ClinGen
classification turns on.
Model context. The functional data come from adult rat ventricular myocytes expressing
human mutant protein. Rat ventricular myosin is alpha-dominant and human ventricular
myosin is beta-dominant, so the variants were characterised in an isoform environment
unlike the human ventricle. That caveat is recorded on the relevant node.
references:
- reference: PMID:20301486
title: "Dilated Cardiomyopathy Overview."
tags:
- GeneReviews
- reference: PMID:15998695
title: "Alpha-myosin heavy chain: a sarcomeric gene associated with dilated and hypertrophic phenotypes of cardiomyopathy."
- reference: PMID:28088328
title: "Altered myocyte contractility and calcium homeostasis in alpha-myosin heavy chain point mutations linked to familial dilated cardiomyopathy."
- reference: PMID:21378987
title: "A rare variant in MYH6 is associated with high risk of sick sinus syndrome."
- reference: PMID:41165794
title: "MYH6 in Congenital Heart Defects: A Genotype-Phenotype Characterization in a French Cohort."
- reference: CGGV:assertion_6d55ac7b-e9d8-4a97-bb20-92beeffaed96-2025-03-07T170000.000Z
title: "MYH6 / dilated cardiomyopathy (Limited)"
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.
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.
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.
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).
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.
Causal chain (general sarcomeric DCM model, applicable to MYH6-CMD1EE):
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.
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.
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.
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:
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.
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.
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.
| 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) |
Checked with linkml-reference-validator 0.2.1.
| 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 |
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"