Dilated Cardiomyopathy 2G

Genetic MONDO:0030887 Pathograph 6 Show in embeddings browser Dilated Cardiomyopathy Genetic Disorder

Dilated cardiomyopathy 2G (CMD2G) is the LMOD2-related form of dilated cardiomyopathy, and the most severe member of the series curated here: a recessive, neonatal-onset disease that is frequently lethal in the first weeks to months of life. LMOD2 encodes leiomodin-2, an actin-binding protein that sets the length of the sarcomeric thin filament by nucleating and elongating actin from the pointed end. Thin-filament length is a determinant of the overlap between thin and thick filaments and therefore of how much force the sarcomere can generate at a given sarcomere length, so a leiomodin-2 defect degrades contraction by mis-specifying the geometry of the contractile apparatus rather than by damaging the motor, its regulation, or its scaffold. Disease is caused by homozygous biallelic variants; the first reported allele was the nonsense change p.Trp398Ter. Patient-derived iPSC-cardiomyocytes and a matched mouse model show dysregulated actin-thin filament lengths together with altered contractility and calcium handling. ClinGen classifies the LMOD2-dilated cardiomyopathy relationship as Definitive with autosomal recessive inheritance.

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1
Inheritance
5
Pathophys.
2
Phenotypes
6
Pathograph
1
Genes
2
Medical Actions
1
References
🏷

Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal recessive HP:0000007
CMD2G is inherited as an autosomal recessive trait, caused by homozygous biallelic LMOD2 variants. This distinguishes it from the dominant numbered CMD entities and accounts for the severity: both alleles are lost, so the neonatal heart has no functional leiomodin-2.
Autosomal recessive inheritance
Show evidence (2 references)
CGGV:assertion_d19140d6-8200-4fce-9906-fdda527a4f7e-2024-10-04T160000.000Z SUPPORT Other
"LMOD2 | HGNC:6648 | dilated cardiomyopathy | MONDO:0005021 | AR | Definitive"
ClinGen's gene curation classifies the LMOD2-dilated cardiomyopathy relationship as Definitive with autosomal recessive inheritance.
PMID:39285234 SUPPORT In Vitro
"Several homozygous biallelic variants in LMOD2, the gene encoding the actin-binding protein Leiomodin 2, have been identified to result in severe DCM."
Documents the homozygous biallelic (recessive) genotype that causes this entity.
⚙

Pathophysiology

5
Biallelic LMOD2 Loss-of-Function Variant
The initiating lesion in CMD2G is a homozygous loss-of-function variant in LMOD2, encoding the actin-binding protein leiomodin-2. The first reported allele was the nonsense change c.1193G>A (p.Trp398Ter). Because inheritance is recessive, affected neonates have no functional leiomodin-2 at all, which is why the phenotype is present from birth rather than developing over decades as in the dominant members of this series.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
LMOD2 hgnc:6648 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves LMOD2 (hgnc:6648). hgnc:6648 is a gene from the HUGO Gene Nomenclature Committee.
Actin binding GO:0003779 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased Actin binding (GO:0003779). GO:0003779 is a molecular function from the Gene Ontology. ↓ DECREASED
Downstream
Dysregulated Thin-Filament Length Loss of the actin pointed-end nucleator/elongator mis-specifies sarcomeric thin-filament length.
Show evidence (2 references)
PMID:39285234 SUPPORT In Vitro
"This study aimed to understand the underlying pathophysiology and signaling pathways related to the first reported LMOD2 variant (c.1193 G > A, p.Trp398*)."
Names the founding LMOD2 allele whose pathophysiology this entry models.
PMID:39285234 SUPPORT In Vitro
"Thus, it is evident that Lmod2 is essential to normal human cardiac muscle function."
States the essentiality of leiomodin-2 to human cardiac function that makes its biallelic loss a severe disease.
Dysregulated Thin-Filament Length
Leiomodin-2 nucleates and elongates actin at the pointed end of the sarcomeric thin filament, setting its length. Losing it dysregulates thin-filament length, which changes the extent of thin-thick filament overlap available for cross-bridge formation. This is a geometric lesion unique within the series: the motor, its calcium regulation, its scaffold and its quality-control machinery are all intact, but the filament they act on is built to the wrong specification. Patient-derived iPSC-cardiomyocytes and a mouse model carrying the homologous mutation both show this dysregulation.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Sarcomere Organization GO:0045214 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Sarcomere Organization (GO:0045214). GO:0045214 is a biological process from the Gene Ontology. ⚠ ABNORMAL Actin Filament Organization GO:0007015 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Actin Filament Organization (GO:0007015). GO:0007015 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Actin thin filament GO:0005884 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Actin thin filament, annotated with actin filament (GO:0005884). GO:0005884 is a cellular component from the Gene Ontology.
Downstream
Impaired Cardiomyocyte Contractility Mis-specified filament geometry, with altered calcium handling, degrades contractile performance.
Show evidence (2 references)
PMID:39285234 SUPPORT In Vitro
"we discovered dysregulated actin-thin filament lengths, altered contractility and calcium handling properties"
Demonstrates dysregulated thin-filament lengths together with altered contractility and calcium handling, in patient-derived iPSC-cardiomyocytes and a matched mouse model.
PMID:39285234 SUPPORT In Vitro
"Using patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and a mouse model harboring the homologous mutation to the patient"
Establishes the two independent systems - patient-derived human cardiomyocytes and a matched mouse model - in which the lesion was characterized.
Impaired Cardiomyocyte Contractility
The consequence at cell level is decreased contractility together with altered calcium handling. Transcriptional consequences accompany the structural ones: the same work found altered actin gene signatures and changes in serum response factor (SRF)-dependent signaling, a pathway that responds to the state of the actin cytoskeleton - so the mis-built thin filament also feeds back on the cell's transcriptional programme.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Cardiac Muscle Cell Contraction GO:0086003 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Cardiac Muscle Cell Contraction (GO:0086003). GO:0086003 is a biological process from the Gene Ontology. ↓ DECREASED Regulation of Cardiac Muscle Contraction by Calcium GO:0010882 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Regulation of Cardiac Muscle Contraction by Calcium, annotated with regulation of cardiac muscle contraction by calcium ion signaling (GO:0010882). GO:0010882 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Neonatal Ventricular Dilation and Decreased Contractility
Show evidence (1 reference)
PMID:39285234 SUPPORT In Vitro
"we discovered dysregulated actin-thin filament lengths, altered contractility and calcium handling properties, as well as alterations in the serum response factor (SRF)-dependent signaling pathway"
Documents the contractile and calcium-handling impairment plus the SRF-dependent transcriptional response that constitute this node.
Neonatal Ventricular Dilation and Decreased Contractility
At tissue level the disease presents as cardiac dilation with decreased heart contractility, present in the neonatal period rather than developing over decades. This compressed timescale is the clinical signature of the entity and follows from the recessive genotype: the heart never has functional leiomodin-2, so there is no long compensated phase.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Heart Contraction GO:0060047 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Heart Contraction (GO:0060047). GO:0060047 is a biological process from the Gene Ontology. ↓ DECREASED
Left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Left ventricle, annotated with heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Neonatal Heart Failure and Death
Show evidence (1 reference)
PMID:39285234 SUPPORT In Vitro
"Collectively, LMOD2-related cardiomyopathies present with cardiac dilation and decreased heart contractility, often resulting in neonatal death."
States the tissue-level presentation - cardiac dilation with decreased contractility - and its neonatal timing.
Neonatal Heart Failure and Death
The clinical endpoint is severe neonatal heart failure that often results in neonatal death. CMD2G is accordingly the most severe entity in this series; management is supportive heart-failure care with transplantation as the only definitive option for survivors.
Cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Heart Contraction GO:0060047 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Heart Contraction (GO:0060047). GO:0060047 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (1 reference)
PMID:39285234 SUPPORT In Vitro
"Collectively, LMOD2-related cardiomyopathies present with cardiac dilation and decreased heart contractility, often resulting in neonatal death."
Documents neonatal death as the frequent outcome, the endpoint of this entity.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Dilated Cardiomyopathy 2G Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

2
Dilated Cardiomyopathy OBLIGATE Cardiovascular HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39285234 SUPPORT In Vitro
"Collectively, LMOD2-related cardiomyopathies present with cardiac dilation and decreased heart contractility, often resulting in neonatal death."
Establishes cardiac dilation with decreased contractility as the phenotype of LMOD2-related cardiomyopathy.
Neonatal Heart Failure FREQUENT Cardiovascular HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39285234 SUPPORT In Vitro
"Collectively, LMOD2-related cardiomyopathies present with cardiac dilation and decreased heart contractility, often resulting in neonatal death."
Documents the frequent progression to neonatal death from heart failure.
🧬

Genetic Associations

1
LMOD2
Gene: LMOD2 hgnc:6648 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is LMOD2 (hgnc:6648). hgnc:6648 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
CGGV:assertion_d19140d6-8200-4fce-9906-fdda527a4f7e-2024-10-04T160000.000Z SUPPORT Other
"LMOD2 | HGNC:6648 | dilated cardiomyopathy | MONDO:0005021 | AR | Definitive"
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.
PMID:39285234 SUPPORT In Vitro
"Several homozygous biallelic variants in LMOD2, the gene encoding the actin-binding protein Leiomodin 2, have been identified to result in severe DCM."
Establishes the biallelic LMOD2 genotype as the cause of severe dilated cardiomyopathy, and by describing it as several identified families rather than a cohort fraction is also the basis for recording no case fraction.
💊

Medical Actions

2
Supportive Heart Failure Care
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Management of neonatal heart failure is supportive; there is no disease-modifying therapy for the underlying thin-filament defect.
Heart Transplantation
Action: organ transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is organ transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. Ontology label: Organ Transplantation NCIT:C15289
Transplantation is the only definitive option for infants who survive the initial presentation.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
CMD2G is an ultra-rare entity known from a small number of reported homozygous families; no population rate is established.
Show evidence (1 reference)
PMID:39285234 SUPPORT In Vitro
"Several homozygous biallelic variants in LMOD2, the gene encoding the actin-binding protein Leiomodin 2, have been identified to result in severe DCM."
Indicates that the entity is known from a small number of reported biallelic variants rather than from population-scale data.
{ }

Source YAML

click to show 
name: Dilated Cardiomyopathy 2G
creation_date: "2026-08-23T00:00:00Z"
synonyms:
- CMD2G
- LMOD2 dilated cardiomyopathy
- cardiomyopathy, dilated, 2G
- leiomodin-2-related dilated cardiomyopathy
- LMOD2 neonatal dilated cardiomyopathy
description: >-
  Dilated cardiomyopathy 2G (CMD2G) is the LMOD2-related form of dilated
  cardiomyopathy, and the most severe member of the series curated here: a
  recessive, neonatal-onset disease that is frequently lethal in the first weeks to
  months of life. LMOD2 encodes leiomodin-2, an actin-binding protein that sets
  the length of the sarcomeric thin filament by nucleating and elongating actin
  from the pointed end. Thin-filament length is a determinant of the overlap
  between thin and thick filaments and therefore of how much force the sarcomere
  can generate at a given sarcomere length, so a leiomodin-2 defect degrades
  contraction by mis-specifying the geometry of the contractile apparatus rather
  than by damaging the motor, its regulation, or its scaffold. Disease is caused by
  homozygous biallelic variants; the first reported allele was the nonsense change
  p.Trp398Ter. Patient-derived iPSC-cardiomyocytes and a matched mouse model show
  dysregulated actin-thin filament lengths together with altered contractility and
  calcium handling. ClinGen classifies the LMOD2-dilated cardiomyopathy
  relationship as Definitive with autosomal recessive inheritance.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: cardiomyopathy, dilated, 2G
  term:
    id: MONDO:0030887
    label: cardiomyopathy, dilated, 2G
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
inheritance:
- name: Autosomal recessive
  description: >-
    CMD2G is inherited as an autosomal recessive trait, caused by homozygous
    biallelic LMOD2 variants. This distinguishes it from the dominant numbered CMD
    entities and accounts for the severity: both alleles are lost, so the neonatal
    heart has no functional leiomodin-2.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: CGGV:assertion_d19140d6-8200-4fce-9906-fdda527a4f7e-2024-10-04T160000.000Z
    reference_title: "LMOD2 / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "LMOD2 | HGNC:6648 | dilated cardiomyopathy | MONDO:0005021 | AR | Definitive"
    explanation: >-
      ClinGen's gene curation classifies the LMOD2-dilated cardiomyopathy
      relationship as Definitive with autosomal recessive inheritance.
  - reference: PMID:39285234
    reference_title: "Leiomodin 2 neonatal dilated cardiomyopathy mutation results in altered actin gene signatures and cardiomyocyte dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Several homozygous biallelic variants in LMOD2, the gene encoding the
      actin-binding protein Leiomodin 2, have been identified to result in severe
      DCM.
    explanation: >-
      Documents the homozygous biallelic (recessive) genotype that causes this
      entity.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    CMD2G is an ultra-rare entity known from a small number of reported homozygous
    families; no population rate is established.
  evidence:
  - reference: PMID:39285234
    reference_title: "Leiomodin 2 neonatal dilated cardiomyopathy mutation results in altered actin gene signatures and cardiomyocyte dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Several homozygous biallelic variants in LMOD2, the gene encoding the
      actin-binding protein Leiomodin 2, have been identified to result in severe
      DCM.
    explanation: >-
      Indicates that the entity is known from a small number of reported biallelic
      variants rather than from population-scale data.
pathophysiology:
- name: Biallelic LMOD2 Loss-of-Function Variant
  biological_scale: MOLECULAR
  role: trigger
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  description: >-
    The initiating lesion in CMD2G is a homozygous loss-of-function variant in
    LMOD2, encoding the actin-binding protein leiomodin-2. The first reported allele
    was the nonsense change c.1193G>A (p.Trp398Ter). Because inheritance is
    recessive, affected neonates have no functional leiomodin-2 at all, which is why
    the phenotype is present from birth rather than developing over decades as in
    the dominant members of this series.
  genes:
  - preferred_term: LMOD2
    term:
      id: hgnc:6648
      label: LMOD2
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  molecular_functions:
  - preferred_term: Actin binding
    term:
      id: GO:0003779
      label: actin binding
    modifier: DECREASED
  evidence:
  - reference: PMID:39285234
    reference_title: "Leiomodin 2 neonatal dilated cardiomyopathy mutation results in altered actin gene signatures and cardiomyocyte dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This study aimed to understand the underlying pathophysiology and signaling
      pathways related to the first reported LMOD2 variant (c.1193 G > A, p.Trp398*).
    explanation: >-
      Names the founding LMOD2 allele whose pathophysiology this entry models.
  - reference: PMID:39285234
    reference_title: "Leiomodin 2 neonatal dilated cardiomyopathy mutation results in altered actin gene signatures and cardiomyocyte dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Thus, it is evident that Lmod2 is essential to normal human cardiac muscle
      function.
    explanation: >-
      States the essentiality of leiomodin-2 to human cardiac function that makes
      its biallelic loss a severe disease.
  downstream:
  - target: Dysregulated Thin-Filament Length
    causal_link_type: DIRECT
    description: >-
      Loss of the actin pointed-end nucleator/elongator mis-specifies sarcomeric
      thin-filament length.
- name: Dysregulated Thin-Filament Length
  biological_scale: MOLECULAR
  role: effector
  description: >-
    Leiomodin-2 nucleates and elongates actin at the pointed end of the sarcomeric
    thin filament, setting its length. Losing it dysregulates thin-filament length,
    which changes the extent of thin-thick filament overlap available for
    cross-bridge formation. This is a geometric lesion unique within the series: the
    motor, its calcium regulation, its scaffold and its quality-control machinery
    are all intact, but the filament they act on is built to the wrong specification.
    Patient-derived iPSC-cardiomyocytes and a mouse model carrying the homologous
    mutation both show this dysregulation.
  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
  - preferred_term: Actin Filament Organization
    term:
      id: GO:0007015
      label: actin filament organization
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: Actin thin filament
    term:
      id: GO:0005884
      label: actin filament
  evidence:
  - reference: PMID:39285234
    reference_title: "Leiomodin 2 neonatal dilated cardiomyopathy mutation results in altered actin gene signatures and cardiomyocyte dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we discovered dysregulated actin-thin filament lengths, altered contractility
      and calcium handling properties
    explanation: >-
      Demonstrates dysregulated thin-filament lengths together with altered
      contractility and calcium handling, in patient-derived iPSC-cardiomyocytes and
      a matched mouse model.
  - reference: PMID:39285234
    reference_title: "Leiomodin 2 neonatal dilated cardiomyopathy mutation results in altered actin gene signatures and cardiomyocyte dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Using patient-specific human induced pluripotent stem cell-derived
      cardiomyocytes (hiPSC-CMs) and a mouse model harboring the homologous mutation
      to the patient
    explanation: >-
      Establishes the two independent systems - patient-derived human
      cardiomyocytes and a matched mouse model - in which the lesion was
      characterized.
  downstream:
  - target: Impaired Cardiomyocyte Contractility
    causal_link_type: DIRECT
    description: >-
      Mis-specified filament geometry, with altered calcium handling, degrades
      contractile performance.
- name: Impaired Cardiomyocyte Contractility
  biological_scale: CELLULAR
  role: effector
  description: >-
    The consequence at cell level is decreased contractility together with altered
    calcium handling. Transcriptional consequences accompany the structural ones:
    the same work found altered actin gene signatures and changes in serum response
    factor (SRF)-dependent signaling, a pathway that responds to the state of the
    actin cytoskeleton - so the mis-built thin filament also feeds back on the
    cell's transcriptional programme.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cardiac Muscle Cell Contraction
    term:
      id: GO:0086003
      label: cardiac muscle cell contraction
    modifier: DECREASED
  - preferred_term: Regulation of Cardiac Muscle Contraction by Calcium
    term:
      id: GO:0010882
      label: regulation of cardiac muscle contraction by calcium ion signaling
    modifier: ABNORMAL
  evidence:
  - reference: PMID:39285234
    reference_title: "Leiomodin 2 neonatal dilated cardiomyopathy mutation results in altered actin gene signatures and cardiomyocyte dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we discovered dysregulated actin-thin filament lengths, altered contractility
      and calcium handling properties, as well as alterations in the serum response
      factor (SRF)-dependent signaling pathway
    explanation: >-
      Documents the contractile and calcium-handling impairment plus the
      SRF-dependent transcriptional response that constitute this node.
  downstream:
  - target: Neonatal Ventricular Dilation and Decreased Contractility
    causal_link_type: DIRECT
- name: Neonatal Ventricular Dilation and Decreased Contractility
  biological_scale: TISSUE
  role: central_effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    At tissue level the disease presents as cardiac dilation with decreased heart
    contractility, present in the neonatal period rather than developing over
    decades. This compressed timescale is the clinical signature of the entity and
    follows from the recessive genotype: the heart never has functional
    leiomodin-2, so there is no long compensated phase.
  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: DECREASED
  locations:
  - preferred_term: Left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:39285234
    reference_title: "Leiomodin 2 neonatal dilated cardiomyopathy mutation results in altered actin gene signatures and cardiomyocyte dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Collectively, LMOD2-related cardiomyopathies present with cardiac dilation and
      decreased heart contractility, often resulting in neonatal death.
    explanation: >-
      States the tissue-level presentation - cardiac dilation with decreased
      contractility - and its neonatal timing.
  downstream:
  - target: Neonatal Heart Failure and Death
    causal_link_type: DIRECT
- name: Neonatal Heart Failure and Death
  biological_scale: ORGANISM
  role: consequence
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >-
    The clinical endpoint is severe neonatal heart failure that often results in
    neonatal death. CMD2G is accordingly the most severe entity in this series;
    management is supportive heart-failure care with transplantation as the only
    definitive option for survivors.
  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:39285234
    reference_title: "Leiomodin 2 neonatal dilated cardiomyopathy mutation results in altered actin gene signatures and cardiomyocyte dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Collectively, LMOD2-related cardiomyopathies present with cardiac dilation and
      decreased heart contractility, often resulting in neonatal death.
    explanation: >-
      Documents neonatal death as the frequent outcome, the endpoint of this entity.
phenotypes:
- name: Dilated Cardiomyopathy
  category: Cardiovascular
  description: >-
    Cardiac dilation with decreased contractility, present in the neonatal period,
    is the defining feature of CMD2G.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  frequency: OBLIGATE
  evidence:
  - reference: PMID:39285234
    reference_title: "Leiomodin 2 neonatal dilated cardiomyopathy mutation results in altered actin gene signatures and cardiomyocyte dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Collectively, LMOD2-related cardiomyopathies present with cardiac dilation and
      decreased heart contractility, often resulting in neonatal death.
    explanation: >-
      Establishes cardiac dilation with decreased contractility as the phenotype of
      LMOD2-related cardiomyopathy.
- name: Neonatal Heart Failure
  category: Cardiovascular
  description: >-
    Severe heart failure presents in the neonatal period and frequently causes
    death.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  frequency: FREQUENT
  evidence:
  - reference: PMID:39285234
    reference_title: "Leiomodin 2 neonatal dilated cardiomyopathy mutation results in altered actin gene signatures and cardiomyocyte dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Collectively, LMOD2-related cardiomyopathies present with cardiac dilation and
      decreased heart contractility, often resulting in neonatal death.
    explanation: >-
      Documents the frequent progression to neonatal death from heart failure.
genetic:
- name: LMOD2
  gene_term:
    preferred_term: LMOD2
    term:
      id: hgnc:6648
      label: LMOD2
  relationship_type: CAUSATIVE
  frequency: >-
    Ultra-rare. Known from a small number of reported biallelic families; no
    case-fraction estimate in any dilated cardiomyopathy cohort has been
    published.
  evidence:
  - reference: CGGV:assertion_d19140d6-8200-4fce-9906-fdda527a4f7e-2024-10-04T160000.000Z
    reference_title: "LMOD2 / dilated cardiomyopathy (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      LMOD2 | HGNC:6648 | dilated cardiomyopathy | MONDO:0005021 | AR |
      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:39285234
    reference_title: "Leiomodin 2 neonatal dilated cardiomyopathy mutation results in altered actin gene signatures and cardiomyocyte dysfunction."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Several homozygous biallelic variants in LMOD2, the gene encoding the
      actin-binding protein Leiomodin 2, have been identified to result in
      severe DCM.
    explanation: >-
      Establishes the biallelic LMOD2 genotype as the cause of severe dilated
      cardiomyopathy, and by describing it as several identified families
      rather than a cohort fraction is also the basis for recording no case
      fraction.
  notes: >-
    No case_fractions record is curated because no denominator exists: the
    reported literature is a handful of consanguineous or
    compound-heterozygous families rather than a screened dilated
    cardiomyopathy cohort.
treatments:
- name: Supportive Heart Failure Care
  description: >-
    Management of neonatal heart failure is supportive; there is no
    disease-modifying therapy for the underlying thin-filament defect.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Heart Transplantation
  description: >-
    Transplantation is the only definitive option for infants who survive the
    initial presentation.
  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: >-
  CMD2G is the LMOD2 member of the dilated cardiomyopathy series and carries
  ClinGen Definitive gene-disease validity. It conforms to the shared
  cardiomyopathy_maladaptive_remodeling module.

  It is distinctive on two axes. Mechanistically, it is a *geometric* lesion: the
  motor, its calcium regulation, its Z-disc scaffold and its quality-control
  machinery are all intact, but leiomodin-2 sets sarcomeric thin-filament length,
  so its loss builds the filament to the wrong specification and degrades the
  thin-thick overlap available for force generation. Clinically, it is the severe
  recessive pole of the series - biallelic loss means the neonatal heart never has
  functional leiomodin-2, so there is no compensated phase and presentation is at
  birth, frequently lethal, in contrast to the adult-onset dominant members.

  Evidence-scope caveat: the mechanism nodes rest on patient-derived
  iPSC-cardiomyocytes plus a mouse model carrying the homologous mutation, both
  from a single study of the first reported allele (p.Trp398Ter). The evidence is
  strong for that allele in two systems including human cells, but the entity is
  ultra-rare and cohort-scale human data do not exist; the SRF-signaling arm in
  particular is curated as an observed accompaniment rather than an established
  causal step.

  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 LMOD2 cohort and pedigree literature
  cited throughout, principally PMID:39285234.
📚

References & Deep Research

References

1
PMID:20301486
Dilated Cardiomyopathy Overview.
No top-level findings curated for this source.