Dilated cardiomyopathy 1I (CMD1I) is the DES-related form of familial isolated dilated cardiomyopathy. DES encodes desmin, the muscle-specific type III intermediate filament protein that forms the cytoskeletal network linking successive Z-discs to each other, to the sarcolemma and costameres, to mitochondria and to the nuclear envelope - the scaffold that keeps the contractile apparatus mechanically registered and transmits force laterally across the myocyte. CMD1I is therefore a cytoskeletal rather than a sarcomeric disease: the lesion is loss or disorganization of the filament network that holds the sarcomeres in place, not a defect of the motor or its regulation. Desmin disease is a spectrum - desminopathies are clinically heterogeneous, manifesting with myopathy and/or cardiomyopathy and with intra-sarcoplasmic desmin-positive deposits - and CMD1I is the cardiac-predominant pole of that spectrum, with the skeletal-muscle-predominant, aggregate-centred pole curated separately in this knowledge base as myofibrillar myopathy. Both dominant (typically missense, acting on filament assembly) and recessive (truncating, abolishing desmin) genotypes occur. ClinGen classifies the DES-dilated cardiomyopathy relationship as Definitive with autosomal dominant inheritance.
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name: Dilated Cardiomyopathy 1I
creation_date: "2026-08-23T00:00:00Z"
synonyms:
- CMD1I
- DES familial isolated dilated cardiomyopathy
- dilated cardiomyopathy type 1I
- cardiomyopathy, dilated, 1I
- desmin-related dilated cardiomyopathy
description: >-
Dilated cardiomyopathy 1I (CMD1I) is the DES-related form of familial isolated
dilated cardiomyopathy. DES encodes desmin, the muscle-specific type III
intermediate filament protein that forms the cytoskeletal network linking
successive Z-discs to each other, to the sarcolemma and costameres, to
mitochondria and to the nuclear envelope - the scaffold that keeps the
contractile apparatus mechanically registered and transmits force laterally
across the myocyte. CMD1I is therefore a cytoskeletal rather than a sarcomeric
disease: the lesion is loss or disorganization of the filament network that holds
the sarcomeres in place, not a defect of the motor or its regulation. Desmin
disease is a spectrum - desminopathies are clinically heterogeneous, manifesting
with myopathy and/or cardiomyopathy and with intra-sarcoplasmic desmin-positive
deposits - and CMD1I is the cardiac-predominant pole of that spectrum, with the
skeletal-muscle-predominant, aggregate-centred pole curated separately in this
knowledge base as myofibrillar myopathy. Both dominant (typically missense,
acting on filament assembly) and recessive (truncating, abolishing desmin)
genotypes occur. ClinGen classifies the DES-dilated cardiomyopathy relationship
as Definitive with autosomal dominant inheritance.
category: Genetic
classifications:
harrisons_chapter:
- classification_value: CARDIOVASCULAR
- classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
preferred_term: dilated cardiomyopathy 1I
term:
id: MONDO:0011482
label: dilated cardiomyopathy 1I
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
inheritance:
- name: Autosomal dominant
description: >-
The common form is autosomal dominant, typically caused by missense variants
that are incorporated into the filament and disrupt its assembly, so a single
allele suffices to disorganize the network.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
penetrance: INCOMPLETE
evidence:
- reference: CGGV:assertion_91b2595a-5eb9-4ac3-aa3d-d5f99cacad84-2025-05-30T160000.000Z
reference_title: "DES / dilated cardiomyopathy (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "DES | HGNC:2770 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
explanation: >-
ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies the
DES-dilated cardiomyopathy relationship as Definitive with autosomal dominant
inheritance.
- reference: PMID:34106405
reference_title: "A Novel L1 Linker Mutation in DES Resulted in Total Absence of Protein."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
They have either an autosomal dominant (AD) or recessive (AR) pattern of
inheritance.
explanation: >-
Documents that desminopathies segregate in both dominant and recessive
patterns, the basis for curating two inheritance modes on this entity.
- name: Autosomal recessive (biallelic loss of function)
description: >-
A recessive form results from biallelic truncating DES alleles that abolish
desmin entirely. In the reported consanguineous case a homozygous nonsense
variant (p.Arg150Ter) produced complete absence of desmin protein, with dilated
cardiomyopathy alongside respiratory insufficiency and distal weakness; the
heterozygous parents were carriers.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:34106405
reference_title: "A Novel L1 Linker Mutation in DES Resulted in Total Absence of Protein."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Next-generation sequencing revealed a novel homozygous nonsense mutation
c.448C>T, p.R150X in the patient, while the parents were heterozygous
carriers.
explanation: >-
Documents the biallelic (recessive) genotype with unaffected heterozygous
parents in a consanguineous kindred.
prevalence:
- population: Dilated cardiomyopathy cohorts
measure_type: UNKNOWN
prevalence_class: UNKNOWN
notes: >-
DES is a definitive but numerically minor dilated cardiomyopathy gene; no
population-based rate is established for the DES-specific entity.
pathophysiology:
- name: DES Variant in the Desmin Intermediate Filament
biological_scale: MOLECULAR
role: trigger
conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
description: >-
The initiating lesion in CMD1I is a variant in DES, encoding desmin - the
muscle-specific intermediate filament protein that regulates various cellular
functions in muscle cells and forms the cytoskeletal network of the myocyte.
Two allele classes operate: dominant missense variants that are incorporated
into the filament and disrupt its assembly, and recessive truncating variants
that abolish the protein outright, as in the reported homozygous p.Arg150Ter
case where immunostaining showed complete lack of desmin expression. Unlike the
sarcomeric members of this series, the affected protein is not part of the
contractile machinery but of the scaffold that holds it in register.
genes:
- preferred_term: DES
term:
id: hgnc:2770
label: DES
cell_types:
- preferred_term: Cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
cellular_components:
- preferred_term: Intermediate filament
term:
id: GO:0005882
label: intermediate filament
evidence:
- reference: PMID:34106405
reference_title: "A Novel L1 Linker Mutation in DES Resulted in Total Absence of Protein."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Desmin is a crucial intermediate filament protein regulating various cellular
functions in muscle cells.
explanation: >-
Establishes desmin's role as the muscle intermediate filament protein whose
loss constitutes the trigger lesion.
- reference: PMID:34106405
reference_title: "A Novel L1 Linker Mutation in DES Resulted in Total Absence of Protein."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Immunostaining showed complete lack of desmin expression, further confirmed by
western blot analysis.
explanation: >-
Documents complete absence of desmin protein in patient muscle for the
truncating allele class, confirming loss of function at the protein level.
downstream:
- target: Intermediate Filament Network Disorganization and Desmin Aggregation
causal_link_type: DIRECT
description: >-
The variant filament fails to assemble or is absent, disorganizing the
cytoskeletal network and, for aggregating alleles, depositing desmin-positive
inclusions.
- name: Intermediate Filament Network Disorganization and Desmin Aggregation
biological_scale: CELLULAR
role: effector
description: >-
The desmin network normally interconnects Z-discs and links them to the
sarcolemma, mitochondria and nucleus. When desmin is absent or misassembled the
network is lost and, for the aggregating allele class, desmin-positive deposits
accumulate in the sarcoplasm - the histological hallmark of desminopathy.
Ultrastructurally this manifests as subsarcolemmal granular material, expanded
Z-band aggregation, distortion of myofilaments and focal Z-band streaming: the
contractile apparatus loses its mechanical registration. This is the point at
which CMD1I and myofibrillar myopathy share a lesion; they differ in which
tissue bears the burden.
cell_types:
- preferred_term: Cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
biological_processes:
- preferred_term: Intermediate Filament Organization
term:
id: GO:0045109
label: intermediate filament organization
modifier: ABNORMAL
- preferred_term: Sarcomere Organization
term:
id: GO:0045214
label: sarcomere organization
modifier: ABNORMAL
cellular_components:
- preferred_term: Z disc
term:
id: GO:0030018
label: Z disc
evidence:
- reference: PMID:34106405
reference_title: "A Novel L1 Linker Mutation in DES Resulted in Total Absence of Protein."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Ultrastructurally, subsarcolemmal granular material, expanded Z-band
aggregation, distortion of myofilaments, focal Z-band streaming, lobed and
clustered myonuclei were observed.
explanation: >-
Documents the ultrastructural disorganization of the contractile apparatus and
Z-band that follows loss of the desmin network, in patient muscle.
- reference: PMID:34106405
reference_title: "A Novel L1 Linker Mutation in DES Resulted in Total Absence of Protein."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Desminopathies (MIM*601419) are clinically heterogeneous, manifesting with
myopathy and/or cardiomyopathy and with intra-sarcoplasmic desmin-positive
deposits.
explanation: >-
Names the desmin-positive sarcoplasmic deposits that define the aggregating
arm of this node, and the myopathy/cardiomyopathy heterogeneity that places
CMD1I at the cardiac pole.
downstream:
- target: Ventricular Dilation and Systolic Dysfunction
causal_link_type: DIRECT
description: >-
A myocyte whose contractile apparatus is mechanically unregistered transmits
force poorly, driving chamber dilation.
- name: Ventricular Dilation and Systolic Dysfunction
biological_scale: TISSUE
role: central_effector
conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
description: >-
Loss of lateral force transmission and mechanical registration produces the
defining structural remodeling of dilated cardiomyopathy: left ventricular
chamber enlargement with wall thinning, myocyte loss and interstitial fibrosis,
with falling ejection fraction. Cardiac conduction disease is a characteristic
accompaniment of desminopathy, reflecting involvement of the conduction tissue
by the same cytoskeletal lesion.
cell_types:
- preferred_term: Cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
- preferred_term: Cardiac Fibroblast
term:
id: CL:0002548
label: fibroblast of cardiac tissue
biological_processes:
- preferred_term: Heart Contraction
term:
id: GO:0060047
label: heart contraction
modifier: DECREASED
- preferred_term: Extracellular Matrix Organization
term:
id: GO:0030198
label: extracellular matrix organization
modifier: INCREASED
locations:
- preferred_term: Left ventricle
term:
id: UBERON:0002084
label: heart left ventricle
evidence:
- reference: PMID:34106405
reference_title: "A Novel L1 Linker Mutation in DES Resulted in Total Absence of Protein."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
who presented with dilated cardiomyopathy, respiratory insufficiency and
predominant distal upper limb weakness.
explanation: >-
Documents dilated cardiomyopathy as the cardiac presentation in a
desmin-null patient, alongside the skeletal and respiratory involvement that
marks the spectrum.
downstream:
- target: Heart Failure
causal_link_type: DIRECT
- name: Heart Failure
biological_scale: ORGANISM
role: consequence
conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
description: >-
The dilated, poorly contracting ventricle produces progressive systolic heart
failure. Because desminopathy commonly involves conduction tissue and skeletal
and respiratory muscle as well, management of the cardiac endpoint sits within
broader neuromuscular care.
cell_types:
- preferred_term: Cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
biological_processes:
- preferred_term: Heart Contraction
term:
id: GO:0060047
label: heart contraction
modifier: ABNORMAL
evidence:
- reference: PMID:34106405
reference_title: "A Novel L1 Linker Mutation in DES Resulted in Total Absence of Protein."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Desminopathies (MIM*601419) are clinically heterogeneous, manifesting with
myopathy and/or cardiomyopathy and with intra-sarcoplasmic desmin-positive
deposits.
explanation: >-
Establishes cardiomyopathy as a core manifestation of desminopathy, the
endpoint this node represents.
phenotypes:
- name: Dilated Cardiomyopathy
category: Cardiovascular
description: >-
Left ventricular dilation with systolic dysfunction is the defining cardiac
feature of CMD1I.
phenotype_term:
preferred_term: Dilated cardiomyopathy
term:
id: HP:0001644
label: Dilated cardiomyopathy
frequency: OBLIGATE
evidence:
- reference: PMID:34106405
reference_title: "A Novel L1 Linker Mutation in DES Resulted in Total Absence of Protein."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
who presented with dilated cardiomyopathy, respiratory insufficiency and
predominant distal upper limb weakness.
explanation: >-
Documents dilated cardiomyopathy as the presenting cardiac phenotype in a
desmin-null patient.
- name: Cardiac Conduction Abnormality
category: Cardiovascular
description: >-
Conduction disease is a characteristic accompaniment of desmin-related
cardiomyopathy, reflecting involvement of conduction tissue by the same
cytoskeletal lesion.
phenotype_term:
preferred_term: Cardiac conduction abnormality
term:
id: HP:0031546
label: Cardiac conduction abnormality
evidence:
- reference: PMID:34106405
reference_title: "A Novel L1 Linker Mutation in DES Resulted in Total Absence of Protein."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Desminopathies (MIM*601419) are clinically heterogeneous, manifesting with
myopathy and/or cardiomyopathy and with intra-sarcoplasmic desmin-positive
deposits.
explanation: >-
Establishes the clinical heterogeneity of desminopathy within which conduction
disease occurs; PARTIAL because the quoted sentence names cardiomyopathy
generally rather than conduction disease specifically.
- name: Skeletal Muscle Weakness
category: Musculoskeletal
description: >-
Distal-predominant skeletal muscle weakness and respiratory involvement occur
across the desminopathy spectrum and may accompany the cardiomyopathy.
phenotype_term:
preferred_term: Distal muscle weakness
term:
id: HP:0002460
label: Distal muscle weakness
evidence:
- reference: PMID:34106405
reference_title: "A Novel L1 Linker Mutation in DES Resulted in Total Absence of Protein."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
who presented with dilated cardiomyopathy, respiratory insufficiency and
predominant distal upper limb weakness.
explanation: >-
Documents distal weakness and respiratory insufficiency accompanying the
cardiomyopathy in a desmin-null patient.
genetic:
- name: DES
gene_term:
preferred_term: DES
term:
id: hgnc:2770
label: DES
relationship_type: CAUSATIVE
frequency: >-
Definitive but numerically minor cause of familial dilated cardiomyopathy;
no case fraction has been reported in a screened cohort.
evidence:
- reference: CGGV:assertion_91b2595a-5eb9-4ac3-aa3d-d5f99cacad84-2025-05-30T160000.000Z
reference_title: "DES / dilated cardiomyopathy (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
DES | HGNC:2770 | dilated cardiomyopathy | MONDO:0005021 | AD |
Definitive
explanation: >-
ClinGen's Gene Curation Expert Panel classifies this gene-disease
relationship as Definitive, which is the authority for curating the gene
as CAUSATIVE rather than a candidate.
- reference: PMID:34106405
reference_title: "A Novel L1 Linker Mutation in DES Resulted in Total Absence of Protein."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
They have either an autosomal dominant (AD) or recessive (AR) pattern of
inheritance.
explanation: >-
Records that desmin-related disease segregates in both dominant and
recessive patterns, which is why this entry carries two inheritance
blocks for one gene.
- reference: PMID:34106405
reference_title: "A Novel L1 Linker Mutation in DES Resulted in Total Absence of Protein."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Next-generation sequencing revealed a novel homozygous nonsense mutation
c.448C>T, p.R150X in the patient, while the parents were heterozygous
carriers.
explanation: >-
The biallelic p.R150X genotype with heterozygous unaffected parents is
the allele class behind the recessive arm; the same gene is therefore
causative under two different allele doses rather than being two
gene-disease relationships.
notes: >-
Both allele classes are curated on this one gene record rather than split,
because the gene-disease relationship is single and it is the dose that
differs. Truncating alleles have been reported to act recessively while
missense alleles more commonly act dominantly through a filament-assembly
dominant-negative mechanism.
treatments:
- name: Heart Failure Pharmacotherapy
description: >-
Standard guideline-directed heart-failure therapy targeting the neurohormonal
drive of adverse remodeling.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
- name: Device Therapy for Conduction Disease and Arrhythmia
description: >-
Pacing for conduction disease, and defibrillator therapy where arrhythmic risk
warrants it, address the rhythm arm that characteristically accompanies
desmin-related cardiomyopathy.
therapeutic_modality: DEVICE
treatment_term:
preferred_term: pacemaker placement
term:
id: NCIT:C80434
label: Pacemaker Placement
references:
- reference: PMID:20301486
title: Dilated Cardiomyopathy Overview.
tags:
- GeneReviews
notes: >-
CMD1I is the DES member of the numbered dilated cardiomyopathy series and carries
ClinGen Definitive gene-disease validity. It conforms to the shared
cardiomyopathy_maladaptive_remodeling module.
Scope relative to the existing Myofibrillar Myopathy entry, which also covers DES.
Desminopathy is a spectrum running from cardiac-predominant to
skeletal-predominant disease, and the two entries take different poles of it:
CMD1I is the familial isolated dilated cardiomyopathy entity (MONDO:0011482),
curated around loss of the cardiomyocyte intermediate filament network, while
Myofibrillar Myopathy is the morphologically defined protein-aggregation myopathy
in which DES is one of many Z-disc and quality-control genes. They meet at the
aggregation/Z-disc-disorganization node, which is curated here as the shared
lesion rather than duplicated as a separate mechanism.
Two allele classes are curated as separate inheritance blocks because they act
differently: dominant missense variants incorporate into the filament and disrupt
assembly, while recessive truncating variants abolish desmin entirely (evidenced
here by a homozygous p.Arg150Ter case with complete absence of desmin protein and
unaffected heterozygous parents).
Evidence-scope caveat: the mechanism and phenotype nodes rest substantially on a
single well-characterized desmin-null case report plus the general desminopathy
framing from the same source. Broader cohort evidence for the dominant missense
arm, and direct evidence for the conduction-disease association, are the natural
augmentations; the conduction phenotype is accordingly marked PARTIAL.
GeneReviews scope. The GeneReviews resource applicable to this entry is the
disease-level "Dilated Cardiomyopathy Overview" (PMID:20301486), tagged
accordingly in `references`. Its indexed PubMed record is content_type
abstract_only and carries only the chapter's purpose statement, not the
Clinical Characteristics, Management, or Genetic Counseling sections, so
section-by-section GeneReviews mining is not possible from the cache and no
snippet is quoted from it. The clinical-characteristics baseline for this
entry is therefore built from the primary DES cohort and pedigree literature
cited throughout, principally PMID:34106405.