Dilated cardiomyopathy 1G (CMD1G) is the TTN-related form of familial isolated dilated cardiomyopathy and the single commonest genetic cause of the disease. TTN encodes titin, the largest protein in the human proteome: a single molecule spans half the sarcomere from Z-disc to M-band, acting as a molecular ruler for sarcomere assembly, as the elastic spring that sets passive myocardial stiffness, and as a mechanosensing scaffold. The disease alleles are titin truncating variants (TTNtv) - nonsense, frameshift, splice-disrupting, and copy-number changes predicted to truncate the full-length polypeptide - which Herman and colleagues established in 2012 as a common cause of dilated cardiomyopathy, present in roughly a quarter of familial and a fifth of sporadic cases. Position within the gene is the critical determinant of pathogenicity: truncations in the inextensible A-band, the region that binds myosin and myosin-binding protein C, are the disease-associated class, whereas TTNtv elsewhere - and TTNtv found at appreciable frequency in the general population - are largely benign, so a truncating variant is not by itself a diagnosis. Inheritance is autosomal dominant with high penetrance in clinically ascertained families but substantially lower penetrance among population carriers. TTNtv-positive DCM is clinically distinctive for an appreciable burden of atrial and ventricular arrhythmia alongside the ventricular dilation and systolic dysfunction.
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name: Dilated Cardiomyopathy 1G
creation_date: "2026-08-22T00:00:00Z"
synonyms:
- CMD1G
- TTN familial isolated dilated cardiomyopathy
- dilated cardiomyopathy type 1G
- cardiomyopathy, dilated, 1G
- titin-related dilated cardiomyopathy
- TTNtv dilated cardiomyopathy
description: >-
Dilated cardiomyopathy 1G (CMD1G) is the TTN-related form of familial isolated
dilated cardiomyopathy and the single commonest genetic cause of the disease.
TTN encodes titin, the largest protein in the human proteome: a single molecule
spans half the sarcomere from Z-disc to M-band, acting as a molecular ruler for
sarcomere assembly, as the elastic spring that sets passive myocardial
stiffness, and as a mechanosensing scaffold. The disease alleles are titin
truncating variants (TTNtv) - nonsense, frameshift, splice-disrupting, and
copy-number changes predicted to truncate the full-length polypeptide - which
Herman and colleagues established in 2012 as a common cause of dilated
cardiomyopathy, present in roughly a quarter of familial and a fifth of sporadic
cases. Position within the gene is the critical determinant of pathogenicity:
truncations in the inextensible A-band, the region that binds myosin and
myosin-binding protein C, are the disease-associated class, whereas TTNtv
elsewhere - and TTNtv found at appreciable frequency in the general population -
are largely benign, so a truncating variant is not by itself a diagnosis.
Inheritance is autosomal dominant with high penetrance in clinically ascertained
families but substantially lower penetrance among population carriers.
TTNtv-positive DCM is clinically distinctive for an appreciable burden of
atrial and ventricular arrhythmia alongside the ventricular dilation and systolic
dysfunction.
category: Genetic
classifications:
harrisons_chapter:
- classification_value: CARDIOVASCULAR
- classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
preferred_term: dilated cardiomyopathy 1G
term:
id: MONDO:0011400
label: dilated cardiomyopathy 1G
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
inheritance:
- name: Autosomal dominant
description: >-
CMD1G is inherited as an autosomal dominant trait; a single TTN truncating
allele causes disease. Penetrance is high in clinically ascertained families -
exceeding 95% among family members over 40 years of age in the founding study -
but is substantially lower among TTNtv carriers ascertained from the general
population, so a family-based penetrance figure must not be quoted to an
incidentally genotyped individual.
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
penetrance: INCOMPLETE
evidence:
- reference: CGGV:assertion_1ec53217-814e-44b3-a7b7-0f18311c20f3-2025-05-30T160000.000Z
reference_title: "TTN / dilated cardiomyopathy (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "TTN | HGNC:12403 | dilated cardiomyopathy | MONDO:0005021 | AD | Definitive"
explanation: >-
ClinGen's Dilated Cardiomyopathy Gene Curation Expert Panel classifies the
TTN-dilated cardiomyopathy relationship as Definitive with autosomal
dominant inheritance.
- reference: PMID:22335739
reference_title: "Truncations of titin causing dilated cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the penetrance of TTN truncating mutations was more than 95%"
explanation: >-
Quantifies penetrance among family members over 40 years of age in the
founding TTN dilated cardiomyopathy study - the clinically ascertained
figure, higher than in population carriers.
prevalence:
- population: Familial idiopathic dilated cardiomyopathy
measure_type: UNKNOWN
prevalence_class: UNKNOWN
notes: >-
TTN truncating variants account for approximately 25% of familial and 18% of
sporadic idiopathic dilated cardiomyopathy - a share-of-cases figure, not a
population rate. This makes TTN the largest single genetic contributor to DCM.
evidence:
- reference: PMID:22335739
reference_title: "Truncations of titin causing dilated cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
TTN truncating mutations are a common cause of dilated cardiomyopathy,
occurring in approximately 25% of familial cases of idiopathic dilated
cardiomyopathy and in 18% of sporadic cases.
explanation: >-
Gives the familial and sporadic share of dilated cardiomyopathy attributable
to TTN truncating variants.
pathophysiology:
- name: TTN Truncating Variant in the A-Band
biological_scale: MOLECULAR
role: trigger
conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
description: >-
The initiating lesion in CMD1G is a titin truncating variant (TTNtv) -
a nonsense, frameshift, splice-disrupting, or copy-number change predicted to
substantially alter the full-length titin polypeptide. Position is the critical
determinant of pathogenicity: disease-associated TTNtv are located
predominantly in the inextensible A-band, the segment that binds myosin and
myosin-binding protein C and is thought to be critical for biomechanical
sensing and signaling. This positional dependence is what separates pathogenic
from benign truncations, since TTNtv also occur in the general population.
genes:
- preferred_term: TTN
term:
id: hgnc:12403
label: TTN
cell_types:
- preferred_term: Cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
biological_processes:
- preferred_term: Sarcomere Organization
term:
id: GO:0045214
label: sarcomere organization
modifier: ABNORMAL
cellular_components:
- preferred_term: Sarcomeric A band
term:
id: GO:0031672
label: A band
evidence:
- reference: PMID:22335739
reference_title: "Truncations of titin causing dilated cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We prioritized for analysis four types of variants - i.e., nonsense,
frameshift, splicing, and copynumber - that (unlike most missense variants)
are predicted to have a profound effect on the structure of full-length titin
polypeptides
explanation: >-
Defines the TTN truncating variant class that constitutes the disease allele
in this entity.
- reference: PMID:25589632
reference_title: "Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The inextensible A-band binds myosin and myosin-binding protein and is
thought to be critical for biomechanical sensing and signaling.
explanation: >-
Establishes the functional significance of the A-band, the region in which
pathogenic truncations are concentrated.
- reference: PMID:25589632
reference_title: "Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our previous study of severe and familial DCM identified TTNtv that were located predominantly in the A-band"
explanation: >-
Documents the A-band concentration of disease-associated TTNtv, the
positional rule this node encodes.
downstream:
- target: Sarcomere Insufficiency and Impaired Mechanosensing
causal_link_type: DIRECT
description: >-
Loss of full-length titin from the sarcomere degrades assembly, elastic
recoil, and mechanosensing.
- name: Sarcomere Insufficiency and Impaired Mechanosensing
biological_scale: MOLECULAR
role: effector
description: >-
Titin is the molecular ruler and elastic backbone of the sarcomere: it
templates myofibril assembly, provides the passive restoring force of diastole,
and transduces mechanical strain into signalling at the Z-disc and M-band. A
truncating allele removes full-length titin from half the molecular pool, and
the truncated product does not substitute for it. The consequence is a
sarcomere that assembles and transmits force imperfectly and that senses
mechanical load abnormally - a contractile and mechanosensing deficit rather
than the hypercontractility of the hypertrophic sarcomeropathies. Human heart
tissue analyses integrating RNA and protein data underpin the discrimination
of pathogenic from benign truncations on this basis.
cell_types:
- preferred_term: Cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
biological_processes:
- preferred_term: Cardiac Myofibril Assembly
term:
id: GO:0055003
label: cardiac myofibril assembly
modifier: ABNORMAL
- preferred_term: Muscle Contraction
term:
id: GO:0006936
label: muscle contraction
modifier: DECREASED
evidence:
- reference: PMID:25589632
reference_title: "Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we coupled TTN gene sequencing with cardiac phenotyping in 5267 individuals
across the spectrum of cardiac physiology and integrated these data with RNA
and protein analyses of human heart tissues
explanation: >-
Describes the integrated human tissue RNA/protein analysis on which the
molecular consequences of TTN truncation in this node rest.
- reference: PMID:25589632
reference_title: "Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A-band are excluded by alternate splicing, or whether the pathogenesis of TTN
DCM is determined either by critical functional elements located in the
A-band, or by the length of a truncated TTN protein product.
explanation: >-
Records the open question this node deliberately does not over-resolve -
whether pathogenicity follows from A-band functional elements or from
truncated-product length. PARTIAL because the mechanism is stated as
alternatives rather than settled.
downstream:
- target: Ventricular Dilation and Systolic Dysfunction
causal_link_type: DIRECT
description: >-
A sarcomere that generates and transmits force poorly dilates and loses
systolic performance under load.
- name: Ventricular Dilation and Systolic Dysfunction
biological_scale: TISSUE
role: central_effector
conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
description: >-
Chronic sarcomeric insufficiency produces the defining structural remodeling of
dilated cardiomyopathy: progressive left ventricular chamber enlargement with
wall thinning, myocyte loss, and interstitial fibrosis, accompanied by falling
ejection fraction. Unlike the hypertrophic sarcomeropathies, the geometric
response is dilation rather than wall thickening, and neurohormonal activation
drives the remodeling forward.
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:25589632
reference_title: "Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
TTNtv is the most common genetic cause of DCM in ambulant patients in the
community, identify clinically important manifestations of TTNtv-positive
DCM, and define the penetrance and outcomes of TTNtv in the general
population.
explanation: >-
Establishes TTNtv as the leading genetic cause of the dilated cardiomyopathy
phenotype this node represents, in a community-ascertained cohort.
downstream:
- target: Heart Failure and Arrhythmic Risk
causal_link_type: DIRECT
- name: Heart Failure and Arrhythmic Risk
biological_scale: ORGANISM
role: consequence
conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
description: >-
The dilated, poorly contracting, fibrotic ventricle produces the clinical
endpoints of CMD1G: progressive systolic heart failure requiring standard
heart-failure therapy and, in advanced disease, mechanical support or
transplantation. TTNtv-positive DCM additionally carries a clinically important
burden of atrial and ventricular arrhythmia, so rhythm surveillance is part of
management rather than an incidental concern.
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:25589632
reference_title: "Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
identify clinically important manifestations of TTNtv-positive DCM, and
define the penetrance and outcomes of TTNtv in the general population.
explanation: >-
Anchors the clinically important manifestations and outcomes of TTNtv-positive
dilated cardiomyopathy that constitute this endpoint node.
phenotypes:
- name: Dilated Cardiomyopathy
category: Cardiovascular
description: >-
Left ventricular dilation with systolic dysfunction, not explained by loading
conditions or coronary disease, is the defining feature of CMD1G.
phenotype_term:
preferred_term: Dilated cardiomyopathy
term:
id: HP:0001644
label: Dilated cardiomyopathy
frequency: OBLIGATE
evidence:
- reference: PMID:22335739
reference_title: "Truncations of titin causing dilated cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
TTN truncating mutations are a common cause of dilated cardiomyopathy,
occurring in approximately 25% of familial cases of idiopathic dilated
cardiomyopathy and in 18% of sporadic cases.
explanation: >-
Establishes dilated cardiomyopathy as the phenotype caused by TTN truncating
variants.
- name: Congestive Heart Failure
category: Cardiovascular
description: >-
Progressive systolic dysfunction produces heart failure; dilated cardiomyopathy
is the commonest precipitating cause of heart transplantation.
phenotype_term:
preferred_term: Congestive heart failure
term:
id: HP:0001635
label: Congestive heart failure
evidence:
- reference: PMID:21353195
reference_title: "Genome-wide studies of copy number variation and exome sequencing identify rare variants in BAG3 as a cause of dilated cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Dilated cardiomyopathy commonly causes heart failure and is the most frequent
precipitating cause of heart transplantation.
explanation: >-
States the heart-failure and transplantation burden of dilated cardiomyopathy,
the endpoint this phenotype records. Cited from a DCM gene-discovery paper
that states the general clinical burden.
- name: Ventricular Arrhythmia
category: Cardiovascular
description: >-
TTNtv-positive dilated cardiomyopathy carries a clinically important burden of
ventricular arrhythmia on the dilated, fibrotic substrate.
phenotype_term:
preferred_term: Ventricular arrhythmia
term:
id: HP:0004308
label: Ventricular arrhythmia
evidence:
- reference: PMID:25589632
reference_title: "Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
identify clinically important manifestations of TTNtv-positive DCM, and
define the penetrance and outcomes of TTNtv in the general population.
explanation: >-
The community cohort defining the clinically important manifestations of
TTNtv-positive DCM, among which arrhythmia is prominent; PARTIAL because the
quoted sentence names the manifestations collectively rather than arrhythmia
specifically.
genetic:
- name: TTN
gene_term:
preferred_term: TTN
term:
id: hgnc:12403
label: TTN
relationship_type: CAUSATIVE
frequency: >-
The largest single genetic contributor to dilated cardiomyopathy:
truncating variants account for roughly a quarter of familial and a fifth
of sporadic idiopathic cases.
case_fractions:
- population: Familial idiopathic dilated cardiomyopathy
case_fraction_percent: 25.0
notes: >-
Share of familial idiopathic dilated cardiomyopathy attributable to
titin truncating variants in the founding study. Pathogenicity is
position-dependent, so this figure applies to TTNtv as ascertained there
and not to any truncating variant found incidentally.
evidence:
- reference: PMID:22335739
reference_title: "Truncations of titin causing dilated cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
TTN truncating mutations are a common cause of dilated cardiomyopathy,
occurring in approximately 25% of familial cases of idiopathic dilated
cardiomyopathy and in 18% of sporadic cases.
explanation: >-
Directly states the familial share of cases attributable to TTN
truncating variants.
- population: Sporadic idiopathic dilated cardiomyopathy
case_fraction_percent: 18.0
notes: >-
Share of sporadic idiopathic dilated cardiomyopathy attributable to
titin truncating variants in the same study; recorded separately from
the familial figure because the two denominators are different
populations.
evidence:
- reference: PMID:22335739
reference_title: "Truncations of titin causing dilated cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
TTN truncating mutations are a common cause of dilated cardiomyopathy,
occurring in approximately 25% of familial cases of idiopathic dilated
cardiomyopathy and in 18% of sporadic cases.
explanation: >-
Directly states the sporadic share of cases attributable to TTN
truncating variants.
evidence:
- reference: CGGV:assertion_1ec53217-814e-44b3-a7b7-0f18311c20f3-2025-05-30T160000.000Z
reference_title: "TTN / dilated cardiomyopathy (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: >-
TTN | HGNC:12403 | 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:22335739
reference_title: "Truncations of titin causing dilated cardiomyopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the penetrance of TTN truncating mutations was more than 95%
explanation: >-
Gene-level penetrance, quoted with the caveat that matters clinically:
this is the figure among family members over 40 in clinically
ascertained families, and penetrance among TTNtv carriers ascertained
from the general population is substantially lower. PARTIAL because the
number cannot be transferred to an incidentally genotyped individual.
treatments:
- name: Heart Failure Pharmacotherapy
description: >-
Standard guideline-directed heart-failure therapy (renin-angiotensin-aldosterone
system inhibition, beta-blockade, mineralocorticoid receptor antagonism)
targets the neurohormonal drive of adverse remodeling.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: renin-angiotensin-aldosterone system inhibitor
term:
id: NCIT:C247
label: ACE Inhibitor
- preferred_term: beta-blocker
term:
id: NCIT:C29576
label: Beta-Adrenergic Antagonist
- preferred_term: mineralocorticoid receptor antagonist
term:
id: NCIT:C101255
label: Aldosterone Receptor Antagonist
- name: Implantable Cardioverter-Defibrillator
description: >-
Considered for prevention of sudden cardiac death given the arrhythmic burden
of TTNtv-positive dilated cardiomyopathy.
therapeutic_modality: DEVICE
treatment_term:
preferred_term: implantable cardioverter-defibrillator placement
term:
id: NCIT:C80435
label: Implantable Cardioverter-Defibrillator Placement
- name: Heart Transplantation
description: >-
Advanced, refractory disease is an indication for transplantation; dilated
cardiomyopathy is the most frequent precipitating cause of heart transplant.
therapeutic_modality: SURGERY
treatment_term:
preferred_term: organ transplantation
term:
id: NCIT:C15289
label: Organ Transplantation
references:
- reference: PMID:20301486
title: Dilated Cardiomyopathy Overview.
tags:
- GeneReviews
notes: >-
CMD1G is curated as the TTN member of the numbered dilated cardiomyopathy series
and is the highest-value DCM gene entry: TTN truncating variants are the single
commonest genetic cause of the disease (~25% familial, ~18% sporadic), and TTN
carries ClinGen Definitive gene-disease validity for DCM. It conforms to the
shared cardiomyopathy_maladaptive_remodeling module.
Positional caveat preserved on the pathograph, deliberately. TTNtv occur in the
general population, so a truncating variant is not by itself a diagnosis;
pathogenicity tracks with A-band location. The entry also records the unresolved
question (PMID:25589632) of whether pathogenicity follows from critical
functional elements in the A-band or from the length of the truncated product,
rather than asserting a single settled mechanism. Penetrance is curated with the
ascertainment caveat: >95% in clinically ascertained families over 40, but
substantially lower among population-ascertained carriers.
Note the contrast with Hypertrophic Cardiomyopathy 9 (also TTN): TTN truncating
variants are established in dilated, not hypertrophic, cardiomyopathy, and the
TTN-HCM association rests on rare missense reports - a caveat already recorded on
that entry and in the Familial Hypertrophic Cardiomyopathy grouping.
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 TTN cohort and pedigree literature
cited throughout, principally PMID:22335739, PMID:21353195, PMID:25589632.