Dilated Cardiomyopathy 2G

Genetic MONDO:0030887 Pathograph 32 Show in embeddings browser Dilated Cardiomyopathy Genetic Disorder

Dilated cardiomyopathy 2G (CMD2G) is an early-onset, predominantly cardiac disorder caused by biallelic LMOD2 variants. Homozygous and compound-heterozygous nonsense, frameshift, and splice-site variants impair leiomodin-2, a regulator of sarcomeric actin pointed-end elongation. Severe thin-filament shortening and reduced contractile force have been demonstrated in patient myocardium. Presentation ranges from fetal or neonatal cardiac dysfunction to symptomatic disease later in infancy; neonatal lethality is not universal, and several children have undergone heart transplantation. Transcript loss, residual mutant protein, calcium dysregulation, and actin-dependent transcriptional changes vary by allele and model. ClinGen classifies the autosomal recessive LMOD2-CMD2G relationship as Definitive.

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1
Inheritance
11
Pathophys.
2
Histopath.
6
Phenotypes
1
Hypotheses
2
Gaps
32
Pathograph
1
Genes
12
Medical Actions
1
Datasets
7
Models
15
References
🏷

Classifications

Harrison's Part
CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal recessive HP:0000007
Homozygous or compound-heterozygous pathogenic LMOD2 variants cause CMD2G. Confirm parental segregation before recurrence-risk counseling. Clinically unaffected heterozygous relatives have been reported, but adult biobank associations mean that lifelong absence of cardiac risk should not be assumed.
Autosomal recessive inheritance
Show evidence (2 references)
CGGV:assertion_d19140d6-8200-4fce-9906-fdda527a4f7e-2026-03-04T170000.000Z SUPPORT Other
"LMOD2 | HGNC:6648 | cardiomyopathy, dilated, 2G | MONDO:0030887 | AR | Definitive"
The March 2026 ClinGen assertion is specific to CMD2G and supports definitive recessive gene-disease validity.
PMID:34888509 SUPPORT Human Clinical
"We report a family with 2 neonatal deaths related to dilated cardiomyopathy (DCM) and compound heterozygous loss-of-function variants (c.1243_1244del, p.Leu415Valfs*108 and c.1537C > T, p.Arg513*) in Leiomodin 2 (LMOD2), a recently documented cause of early DCM."
Two genetically confirmed siblings establish that disease is not restricted to homozygous variants.
◈

Mechanistic Hypotheses

1
Actin-dependent MRTFB-SRF transcriptional feedback
actin_mrtfb_srf EMERGING
Evidence balance 1 support
Loss of normal LMOD2-mediated actin assembly may increase G-actin, reduce MRTFB nuclear localization, and suppress SRF target genes. Molecular and transcriptional observations support this model, but the causal sequence and contribution to human disease need intervention experiments.
Pathograph links
Reduced Functional Leiomodin-2 -> Increased Monomeric Cardiac Actin INDIRECT KNOWN INTERMEDIATES Impaired actin assembly is proposed to increase the soluble actin pool.
Increased Monomeric Cardiac Actin -> Reduced MRTFB Nuclear Localization INDIRECT UNKNOWN INTERMEDIATES G-actin association may limit MRTFB nuclear entry.
Reduced MRTFB Nuclear Localization -> Reduced SRF-Dependent Transcription INDIRECT KNOWN INTERMEDIATES Reduced nuclear availability of the SRF cofactor may lower its target-gene program.
Reduced SRF-Dependent Transcription -> Impaired Cardiomyocyte Contractility INDIRECT UNKNOWN INTERMEDIATES Altered expression of muscle and calcium-regulatory genes may compound the primary structural defect.
Show evidence (1 reference)
PMID:39285234 SUPPORT Computational
"These findings reveal that LMOD2 may be regulating SRF activity in an actin-dependent manner"
The authors frame SRF regulation as a potential mechanism rather than an established clinical pathway.
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Discussions and Knowledge Gaps

2
What cardiac risk do heterozygous LMOD2 truncating variants confer across the lifespan?
KNOWLEDGE GAP OPEN heterozygous_lmod2_risk
Attached to
inheritance#Autosomal recessive genetic#LMOD2
Pediatric pedigrees include asymptomatic carriers with incomplete cardiac evaluation, whereas biobank analyses suggest an adult monoallelic association. These observations do not establish high-penetrance dominant CMD2G or a uniform surveillance interval.
Show evidence (2 references)
PMID:38666070 SUPPORT Human Clinical
"Several of these genes have monoallelic association with disease outcomes and cardiac traits in the UK Biobank, including LMOD2 and ALPK3 with dilated and hypertrophic CM, respectively."
The association study warrants caution about assuming that every carrier is unaffected for life.
PMID:35188328 SUPPORT Human Clinical
"Evaluation by ECG and echocardiogram have not been performed on parents or carrier siblings."
Absence of reported symptoms in this family does not establish normal cardiac testing.
Why does the homologous W405Ter mouse retain more protein and develop a milder course than severe human W398Ter cardiomyopathy?
HUMAN MODEL MISMATCH OPEN lmod2_model_severity
Attached to
pathophysiology#Reduced Functional Leiomodin-2 animal_models#Mouse
Allele-matched mice, patient-derived cells, and explanted human myocardium differ in residual protein and disease timing. Differences in RNA surveillance, maturation, loading, and terminal disease remodeling may affect translation of rescue experiments.
Show evidence (2 references)
PMID:39285234 SUPPORT Model Organism
"Immunoblot analysis of LV tissue at P70 showed that mutant mice express truncated Lmod2 protein at approximately 45% of wild-type (full-length) Lmod2 levels"
The in vivo mouse allele retains substantial protein.
PMID:31517052 SUPPORT Human Clinical
"Full-length or truncated Lmod2 was not detected in the LV of the proband’s explanted heart via Western blot analysis"
The W398Ter proband had undetectable protein in the explanted ventricle.
⚙

Pathophysiology

11
Biallelic LMOD2 Loss-of-Function Variant
Biallelic LMOD2 nonsense, frameshift, or splice-site variants initiate the disease. Alleles differ in transcript processing, residual protein abundance, and retained function; recessive inheritance alone does not prove complete protein absence.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves 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.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
actin binding GO:0003779 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves actin binding (GO:0003779). GO:0003779 is a molecular function from the Gene Ontology.
Downstream
Nonsense-Mediated LMOD2 Transcript Decay W398Ter and Arg513Ter introduce premature termination codons that can trigger transcript surveillance.
Reduced Functional Leiomodin-2 Splice-site disruption and other loss-of-function alleles impair functional protein through allele-dependent routes.
Show evidence (2 references)
PMID:34888509 SUPPORT Human Clinical
"We report a family with 2 neonatal deaths related to dilated cardiomyopathy (DCM) and compound heterozygous loss-of-function variants (c.1243_1244del, p.Leu415Valfs*108 and c.1537C > T, p.Arg513*) in Leiomodin 2 (LMOD2), a recently documented cause of early DCM."
Two genetically confirmed siblings establish that disease is not restricted to homozygous variants.
PMID:35082396 SUPPORT Human Clinical
"Exome sequencing identified a homozygous LMOD2 variant in both siblings, (GRCh38)chr7:g.123656237G > A; NM_207163.2:c.273 + 1G > A, ablating the donor 5' splice-site of intron-1."
A donor splice-site variant is an additional established allelic mechanism.
Nonsense-Mediated LMOD2 Transcript Decay
Nonsense-mediated decay lowers mature LMOD2 mRNA carrying W398Ter or Arg513Ter in intron-containing human constructs. Mature RNA falls while pre-mRNA is preserved, and translation inhibition or exon-junction-complex blockade increases mutant RNA/protein. This mechanism is experimentally established for these nonsense alleles; it is not a blanket explanation for all CMD2G variants.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
nuclear-transcribed mRNA catabolic process, nonsense-mediated decay GO:0000184 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:0000184). GO:0000184 is a biological process from the Gene Ontology.
Experimental models
LMOD2 minigene and steric-blocking oligonucleotide assays CELL LINE The W398Ter and Arg513Ter constructs reproduce intron-dependent transcript loss.
LMOD2 minigene and steric-blocking oligonucleotide assays CELL LINE Steric blockade suppresses abnormal decay and restores mutant expression in the construct assay.
Downstream
Reduced Functional Leiomodin-2 Depletion of mature mutant transcript reduces protein production.
Show evidence (1 reference)
PMID:38748723 SUPPORT INDIRECT In Vitro
"The addition of W398* and R513* mutations result in a decrease of LMOD2 MG mature mRNA levels but have no effect on LMOD2 CDS mature mRNA levels, when compared to their respective WT constructs"
Intron-containing minigenes demonstrate transcript loss for these two nonsense alleles; the result is not generalized to every frameshift or splice variant.
Reduced Functional Leiomodin-2
Functional leiomodin-2 is markedly reduced. W398Ter patient myocardium had undetectable protein, while patient-derived cardiomyocytes and the homologous W405Ter mouse retained truncated protein. In minigene assays, Leu415ValfsTer108 did not significantly lower mutant protein abundance; this distinguishes loss of normal function from an invariant null state.
Actin-dependent MRTFB-SRF transcriptional feedback
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
actin binding GO:0003779 ↓ DECREASED 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.
Downstream
Dysregulated Thin-Filament Length Loss of normal pointed-end elongation impairs thin-filament length regulation.
Altered Cardiomyocyte Calcium Handling Calcium transients are perturbed after loss of normal LMOD2; intermediate steps are unresolved.
Increased Monomeric Cardiac Actin Impaired actin assembly is proposed to increase the soluble actin pool. Actin-dependent MRTFB-SRF transcriptional feedback
Show evidence (3 references)
PMID:31517052 SUPPORT Human Clinical
"Full-length or truncated Lmod2 was not detected in the LV of the proband’s explanted heart via Western blot analysis"
The W398Ter proband had undetectable protein in the explanted ventricle.
PMID:39285234 SUPPORT In Vitro
"Immunoblot analysis confirmed LMOD2 W398* hiPSC-CMs express truncated LMOD2 protein"
The corresponding patient-derived cellular model retains truncated protein, so complete absence cannot be assumed in every system.
PMID:38748723 SUPPORT In Vitro
"while another unstudied mutation (p.V415fs*108) does not significantly decrease mutant protein levels."
The source uses this abbreviated spelling for the Leu415ValfsTer108 frameshift discussed in the same paragraph. Its abundance differs from the nonsense alleles.
Dysregulated Thin-Filament Length
Sarcomeric actin thin filaments are shortened in affected myocardium and experimental models. The W398Ter truncation impairs the rate and processivity of pointed-end elongation in single-filament assays. Shortening reduces available thin-thick filament overlap, although the full contractile defect can also involve calcium handling and remodeling.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
actin filament polymerization GO:0030041 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased actin filament polymerization (GO:0030041). GO:0030041 is a biological process from the Gene Ontology. sarcomere organization GO:0045214 ⚠ ABNORMAL 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.
actin filament GO:0005884 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves actin filament (GO:0005884). GO:0005884 is a cellular component from the Gene Ontology.
Experimental models
W398Ter patient-derived cardiomyocytes with isogenic controls IPSC DERIVED MODEL The patient allele shortens actin thin filaments relative to isogenic controls.
Purified LMOD2 single-filament elongation assay OTHER The disease-associated truncation reduces polymerization rate and processivity.
Animal models
Constitutive Lmod2 knockout mouse Mouse partially recapitulates Knockout reproduces abnormal filament shortening.
Lmod2 W405Ter knock-in mouse Mouse partially recapitulates The homologous allele produces short thin filaments.
AAV-Lmod2 rescue of knockout mice Mouse rescues Replacement elongates abnormally short thin filaments.
Downstream
Impaired Cardiomyocyte Contractility Abnormal thin-filament geometry reduces effective actomyosin force generation.
Show evidence (2 references)
PMID:31517052 SUPPORT Human Clinical
"Mean thin filament length was significantly reduced in the patient’s heart (by ~70%)"
Direct patient-tissue evidence of severe shortening; the magnitude is specific to this explant.
PMID:42477321 SUPPORT In Vitro
"Removal of the C-terminal WH2-containing region in this disease-associated variant results in a substantial reduction in elongation rate and processivity"
Single-filament experiments support impaired pointed-end polymerization for the W398Ter-related truncation.
Altered Cardiomyocyte Calcium Handling
W398Ter patient-derived cardiomyocytes have reduced calcium-transient amplitude and faster release/reuptake kinetics. Re-expression of full-length Lmod2 improves transient amplitude. Unchanged abundance of several major calcium-handling proteins does not establish normal calcium regulation; the initiating signaling defect remains uncertain.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
regulation of cardiac muscle contraction by calcium ion signaling GO:0010882 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of cardiac muscle contraction by calcium ion signaling (GO:0010882). GO:0010882 is a biological process from the Gene Ontology.
Experimental models
W398Ter patient-derived cardiomyocytes with isogenic controls IPSC DERIVED MODEL Calcium release and reuptake kinetics are altered in electrically paced cells.
Downstream
Impaired Cardiomyocyte Contractility Reduced calcium availability and altered kinetics can contribute to abnormal contraction.
Show evidence (1 reference)
PMID:39285234 SUPPORT In Vitro
"Overall, the faster calcium release and reuptake kinetics of LMOD2 W398* cardiomyocytes provide a potential explanation for the decreased contraction time observed in these cells."
Calcium handling is altered in mutant cultured cardiomyocytes; the upstream molecular cause remains unresolved.
Impaired Cardiomyocyte Contractility
Patient myocardial cells and patient-derived engineered heart tissue generate less contractile force. Thin-filament shortening and altered calcium dynamics contribute, with the magnitude depending on the allele and experimental system.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
cardiac muscle cell contraction GO:0086003 ↓ DECREASED 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.
Experimental models
W398Ter engineered heart tissue IPSC DERIVED MODEL The constructs generate less force and have shorter contraction times.
Downstream
Ventricular Dilation Sustained contractile impairment is associated with ventricular remodeling and dilation.
Heart Failure Severe loss of myocardial force leads to inadequate cardiac output.
Show evidence (2 references)
PMID:31517052 SUPPORT In Vitro
"The infant’s explanted heart showed extraordinarily short thin filaments with isolated cardiomyocytes displaying a large reduction in maximum calcium-activated force production."
Ex vivo myocytes from the affected human heart directly demonstrate reduced force.
PMID:39285234 SUPPORT In Vitro
"Overall, EHT analysis demonstrated a decrease in force production and a decrease in contraction time, similar to our reported findings in monolayer hiPSC-CM cultures."
Patient-derived engineered heart tissues show a contractile deficit.
Ventricular Dilation
Ventricular chamber dilation accompanies severe systolic dysfunction. Presentation may be neonatal or later in infancy; some early presentations have marked dysfunction before clear dilation.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
heart left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Constitutive Lmod2 knockout mouse Mouse partially recapitulates Ventricular enlargement accompanies contractile dysfunction.
AAV-Lmod2 rescue of knockout mice Mouse rescues Replacement rescues structural ventricular defects.
Downstream
Dilated Cardiomyopathy Ventricular dilation together with systolic impairment defines the clinical cardiomyopathy.
Show evidence (1 reference)
PMID:35188328 SUPPORT Human Clinical
"The initial echocardiogram demonstrated dilated cardiomyopathy (LV diastolic dimension of 3.82 cm, Z-score 5.06) with severely depressed LV systolic function (ejection fraction or EF of 15%)."
Human imaging establishes dilation and systolic dysfunction in later infancy.
Heart Failure
Severe systolic dysfunction can cause neonatal cardiogenic shock or decompensated heart failure in infancy. Death and transplantation are alternative observed outcomes, not an obligatory combined endpoint.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Downstream
Congestive Heart Failure Pump dysfunction produces the clinical heart-failure syndrome.
Show evidence (2 references)
PMID:35082396 SUPPORT Human Clinical
"Here, we describe two siblings with DCM who died shortly after birth due to heart failure."
Heart failure can be rapidly lethal in affected neonates.
PMID:37296576 SUPPORT Human Clinical
"The proband is a 4-month male infant of Hispanic descent with advanced heart failure."
Advanced failure also occurs after the neonatal period.
Increased Monomeric Cardiac Actin
An increased monomeric actin pool was measured in Lmod2 knockout and W405Ter mouse hearts. It is proposed to retain MRTFB outside the nucleus; the same causal sequence has not been established in patients.
Actin-dependent MRTFB-SRF transcriptional feedback
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Animal models
Lmod2 W405Ter knock-in mouse Mouse partially recapitulates Fractionation shows increased monomeric cardiac actin.
Downstream
Reduced MRTFB Nuclear Localization G-actin association may limit MRTFB nuclear entry. Actin-dependent MRTFB-SRF transcriptional feedback
Show evidence (1 reference)
PMID:39285234 SUPPORT Model Organism
"Our studies demonstrated that Lmod2 W405* mice and Lmod2-KO mice had significant increases in cardiac G-actin."
Cardiac tissue fractionation supports the increased monomeric actin pool in these mouse models.
Reduced MRTFB Nuclear Localization
MRTFB nuclear localization is reduced in W398Ter patient-derived cardiomyocytes. Mouse tissue also shows increased MRTFB association with the G-actin fraction. These results support, but do not fully prove, an actin-dependent transcriptional feedback mechanism.
Actin-dependent MRTFB-SRF transcriptional feedback
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
MRTFB hgnc:29819 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MRTFB (hgnc:29819). hgnc:29819 is a gene from the HUGO Gene Nomenclature Committee.
Experimental models
W398Ter patient-derived cardiomyocytes with isogenic controls IPSC DERIVED MODEL Nuclear MRTFB localization is reduced.
Downstream
Reduced SRF-Dependent Transcription Reduced nuclear availability of the SRF cofactor may lower its target-gene program. Actin-dependent MRTFB-SRF transcriptional feedback
Show evidence (1 reference)
PMID:39285234 SUPPORT In Vitro
"demonstrated significantly reduced MRTFB nuclear localization (~25%) in LMOD2 W398* hiPSC-CMs"
Immunocytochemistry supports altered localization of the SRF cofactor in patient-derived cells.
Reduced SRF-Dependent Transcription
SRF-associated transcriptional pathways are downregulated in mutant cardiomyocytes and mouse hearts. Whether this is a causal driver, a compensatory response, or both remains unresolved; SRF-targeted treatment is a research hypothesis.
Actin-dependent MRTFB-SRF transcriptional feedback
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
SRF hgnc:11291 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SRF (hgnc:11291). hgnc:11291 is a gene from the HUGO Gene Nomenclature Committee.
positive regulation of transcription by RNA polymerase II GO:0045944 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased positive regulation of transcription by RNA polymerase II (GO:0045944). GO:0045944 is a biological process from the Gene Ontology.
Downstream
Impaired Cardiomyocyte Contractility Altered expression of muscle and calcium-regulatory genes may compound the primary structural defect. Actin-dependent MRTFB-SRF transcriptional feedback
Show evidence (1 reference)
PMID:39285234 SUPPORT Computational
"Of the transcriptionally downregulated pathways, the serum response factor (SRF) pathway was identified in both mutant hiPSC-CMs and mouse heart tissue RNA sequencing analysis."
RNA-sequencing pathway analysis identifies reduced SRF-associated transcription; the causal feedback model remains emerging.
✶

Histopathology

2
Myofibrillar disarray and Z-disc abnormalities
Patient myocardium can show disorganized myofibrils and widened or streamed Z-discs. Findings differ between cases and do not establish a generalized skeletal myopathy.
Show evidence (1 reference)
PMID:31517052 SUPPORT Human Clinical
"Deconvolution immunofluorescence microscopy of LV cryosections from the patient’s heart revealed myofibrillar disarray and wide Z-discs"
Human myocardial ultrastructure supports sarcomeric architectural disturbance.
Myocardial fibrosis
Interstitial and subendocardial fibrosis occur in some severely affected hearts; the later-infantile frameshift case had only mild interstitial fibrosis and no significant endocardial fibrosis or myocardial disarray.
Show evidence (2 references)
PMID:31517052 SUPPORT Human Clinical
"Marked fibrosis (blue) is present throughout the subendocardium of both ventricles with patchy interstitial nonreplacement-type perimyocyte fibrosis"
Histological evidence from the founding patient.
PMID:35188328 SUPPORT Human Clinical
"Microscopic examination with H&E staining of both ventricles showed moderately hypertrophied myocytes with focal areas of mild interstitial fibrosis but no significant endocardial fibrosis or myocardial disarray."
The later-infantile case establishes histological variability.
⬡

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

6
Dilated Cardiomyopathy 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 (3 references)
PMID:35188328 SUPPORT Human Clinical
"The initial echocardiogram demonstrated dilated cardiomyopathy (LV diastolic dimension of 3.82 cm, Z-score 5.06) with severely depressed LV systolic function (ejection fraction or EF of 15%)."
Human imaging establishes dilation and systolic dysfunction in later infancy.
PMID:35188328 SUPPORT Human Clinical
"Here, we describe a third family with a child harboring a previously described homozygous frameshift variant, c.1243_1244delCT (p.L415Vfs*108) with DCM, presenting later in infancy at 9 months of age."
The documented nine-month presentation contradicts an obligately neonatal onset.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Because of rapid growth in children, expert cardiovascular assessment is recommended to assess left ventricular enlargement in the pediatric population."
General DCM clinical baseline, not LMOD2-specific frequency evidence.
Congestive Heart Failure 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 (2 references)
PMID:35082396 SUPPORT Human Clinical
"Here, we describe two siblings with DCM who died shortly after birth due to heart failure."
Heart failure can be rapidly lethal in affected neonates.
PMID:37296576 SUPPORT Human Clinical
"The proband is a 4-month male infant of Hispanic descent with advanced heart failure."
Advanced failure also occurs after the neonatal period.
Ventricular Tachycardia Cardiovascular HP:0004756 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventricular tachycardia (HP:0004756). HP:0004756 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31517052 SUPPORT Human Clinical
"While waiting, she had intermittent episodes of ventricular tachycardia and ectopy"
Observed before transplant in the founding proband receiving mechanical support.
Supraventricular Tachycardia Cardiovascular HP:0004755 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Supraventricular tachycardia (HP:0004755). HP:0004755 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35188328 SUPPORT Human Clinical
"His clinical course during the hospitalization was complicated by supraventricular tachycardia for which he was started on amiodarone."
A genetically confirmed patient had supraventricular tachycardia.
Mitral Regurgitation Cardiovascular HP:0001653 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Mitral regurgitation (HP:0001653). HP:0001653 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35188328 SUPPORT Human Clinical
"He also had moderate mitral valve regurgitation, moderate tricuspid valve regurgitation, and a mildly dilated RV with severely depressed RV systolic function"
Clinical imaging documents regurgitation in the nine-month presentation.
Tricuspid Regurgitation Cardiovascular HP:0005180 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tricuspid regurgitation (HP:0005180). HP:0005180 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34888509 SUPPORT Human Clinical
"However, at 37 weeks’ gestational age, the right atrium and right ventricle were qualitatively dilated, and there was mildly reduced right ventricular systolic function and severe tricuspid regurgitation."
Prenatal cardiac abnormalities in an affected sibling preclude a universal claim of normal fetal function.
🧬

Genetic Associations

1
LMOD2
Gene: LMOD2 hgnc:6648 gene page 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 variant_origin: GERMLINE
Show evidence (4 references)
CGGV:assertion_d19140d6-8200-4fce-9906-fdda527a4f7e-2026-03-04T170000.000Z SUPPORT Other
"LMOD2 | HGNC:6648 | cardiomyopathy, dilated, 2G | MONDO:0030887 | AR | Definitive"
The March 2026 ClinGen assertion is specific to CMD2G and supports definitive recessive gene-disease validity.
PMID:34888509 SUPPORT Human Clinical
"We report a family with 2 neonatal deaths related to dilated cardiomyopathy (DCM) and compound heterozygous loss-of-function variants (c.1243_1244del, p.Leu415Valfs*108 and c.1537C > T, p.Arg513*) in Leiomodin 2 (LMOD2), a recently documented cause of early DCM."
Two genetically confirmed siblings establish that disease is not restricted to homozygous variants.
PMID:31517052 SUPPORT Human Clinical
"Exome sequencing identified a biallelic homozygous nonsense variant (c.1193G > A, p.Trp398*) in a candidate gene LMOD2, which encodes Lmod2."
Founding nonsense allele identified by exome sequencing.
+ 1 more reference
💊

Medical Actions

12
Diuretic therapy
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
Agent: Diuretic NCIT:C448 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Diuretic (NCIT:C448). NCIT:C448 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Relieve congestion in children with fluid retention and ventricular dysfunction; individualize therapy and monitor volume status and electrolytes. This is general pediatric guidance; suitability in neonates and infants requires specialist assessment.
Mechanism Target:
Congestive Heart Failure — Treats downstream heart failure; it does not restore leiomodin-2.
Show evidence (1 reference)
url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"In children with fluid retention and ventricular dysfunction (HF stage C), diuretic therapy is recommended to achieve a euvolemic state"
ISHLT pediatric heart-failure guidance extrapolated to CMD2G; this is not evidence of a genotype-specific trial.
ACE inhibition or ARB therapy
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
Agent: ACE Inhibitor NCIT:C247 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses ACE Inhibitor (NCIT:C247). NCIT:C247 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
ACE inhibitors are recommended for pediatric left ventricular systolic dysfunction unless contraindicated; an ARB is a reasonable alternative when ACE inhibitors are not tolerated. This is general pediatric guidance; suitability in neonates and infants requires specialist assessment.
Mechanism Target:
Congestive Heart Failure — Treats downstream heart failure; it does not restore leiomodin-2.
Show evidence (1 reference)
url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"In children with left ventricular systolic dysfunction, ACE inhibitors should be routinely used unless there is a specific contraindication"
ISHLT pediatric heart-failure guidance extrapolated to CMD2G; this is not evidence of a genotype-specific trial.
Beta-blocker therapy
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
Agent: Beta-Adrenergic Antagonist NCIT:C29576 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Beta-Adrenergic Antagonist (NCIT:C29576). NCIT:C29576 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Beta-blockade is reasonable for pediatric systemic LV systolic dysfunction under specialist care. This is general pediatric guidance; suitability in neonates and infants requires specialist assessment.
Mechanism Target:
Congestive Heart Failure — Treats downstream heart failure; it does not restore leiomodin-2.
Show evidence (1 reference)
url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"In children with systemic LV systolic dysfunction, use of β-blockers is reasonable"
ISHLT pediatric heart-failure guidance extrapolated to CMD2G; this is not evidence of a genotype-specific trial.
Aldosterone antagonist therapy
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
Agent: Aldosterone Receptor Antagonist NCIT:C101255 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Aldosterone Receptor Antagonist (NCIT:C101255). NCIT:C101255 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
An aldosterone antagonist is reasonable for symptomatic systemic LV dysfunction, with renal function and electrolyte monitoring. This is general pediatric guidance; suitability in neonates and infants requires specialist assessment.
Mechanism Target:
Congestive Heart Failure — Treats downstream heart failure; it does not restore leiomodin-2.
Show evidence (1 reference)
url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"In children with symptomatic systemic left ventricular dysfunction, treatment with aldosterone antagonists is reasonable"
ISHLT pediatric heart-failure guidance extrapolated to CMD2G; this is not evidence of a genotype-specific trial.
Angiotensin receptor-neprilysin inhibition
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
Agent: Sacubitril Valsartan NCIT:C222078 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Sacubitril Valsartan (NCIT:C222078). NCIT:C222078 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Sacubitril-valsartan can replace an ACE inhibitor or ARB in appropriate children with symptomatic systemic LV systolic dysfunction. Pediatric treatment selection depends on age and clinical circumstances; it is not a LMOD2-specific therapy. This is general pediatric guidance; suitability in neonates and infants requires specialist assessment.
Mechanism Target:
Congestive Heart Failure — Treats downstream heart failure; it does not restore leiomodin-2.
Show evidence (1 reference)
url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"In children with symptomatic systemic left ventricular systolic dysfunction, ARNI in the place of an ACE inhibitor or ARB is reasonable"
ISHLT pediatric heart-failure guidance extrapolated to CMD2G; this is not evidence of a genotype-specific trial.
Ivabradine
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
Agent: Ivabradine NCIT:C65995 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Ivabradine (NCIT:C65995). NCIT:C65995 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Consider in selected children with stable heart failure when heart-rate reduction is desirable; this is general pediatric guidance, not a LMOD2-specific effect. This is general pediatric guidance; suitability in neonates and infants requires specialist assessment.
Mechanism Target:
Congestive Heart Failure — Treats downstream heart failure; it does not restore leiomodin-2.
Show evidence (1 reference)
url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"In children with stable HF, ivabradine is reasonable when heart rate reduction is desirable"
ISHLT pediatric heart-failure guidance extrapolated to CMD2G; this is not evidence of a genotype-specific trial.
SGLT2 inhibitors
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
Agent: SGLT2 Inhibitor NCIT:C98083 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses SGLT2 Inhibitor (NCIT:C98083). NCIT:C98083 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
May be considered for symptomatic pediatric HFrEF by specialists. Pediatric safety and effectiveness have not been systematically established, and adult outcome benefits cannot be assumed for CMD2G. This is general pediatric guidance; suitability in neonates and infants requires specialist assessment.
Mechanism Target:
Congestive Heart Failure — Treats downstream heart failure; it does not restore leiomodin-2.
Show evidence (1 reference)
url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"In children with symptomatic HFrEF, SGLT2 inhibitors may be considered, although their safety and effectiveness in children have not been systematically studied"
ISHLT pediatric heart-failure guidance extrapolated to CMD2G; this is not evidence of a genotype-specific trial.
Heart transplantation
Action: Heart TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Heart Transplantation (NCIT:C15246). NCIT:C15246 is a clinical intervention from the NCI Thesaurus. NCIT:C15246
Platform: Surgery
Transplantation has been performed for refractory heart failure in neonatal and later-infantile CMD2G. It replaces the failing heart without correcting the germline genotype.
Mechanism Target:
Impaired Cardiomyocyte Contractility — Replaces the myocardium with impaired force generation.
Show evidence (2 references)
PMID:37296576 SUPPORT Human Clinical
"Eventually, the infant received an ABO-compatible orthotopic heart transplant (OHT) at 7 months of age."
Directly documented transplant in the four-month-onset patient.
PMID:35188328 SUPPORT Human Clinical
"He underwent orthotopic heart transplantation (OHT) at 14 months of age."
Transplantation also occurred after a later-infantile presentation.
Mechanical circulatory support
Action: Mechanical Circulatory SupportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Mechanical Circulatory Support (NCIT:C99540). NCIT:C99540 is a clinical intervention from the NCI Thesaurus. NCIT:C99540
Platform: Device
ECMO and ventricular assist devices have been used during severe decompensation and as a bridge to transplantation. These are supportive interventions with substantial risks, not correction of the thin-filament defect.
Mechanism Target:
Heart Failure — Supports circulation when cardiac output is inadequate.
Show evidence (1 reference)
PMID:31517052 SUPPORT Human Clinical
"She required mechanical circulatory support with either extracorporeal membrane oxygenation or a Berlin Heart left ventricular assist device (LVAD) for the majority of her early life"
Observed support in the founding patient.
Genetic counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Other
Explain recessive segregation and offer family testing. For confirmed heterozygous parents, Mendelian segregation predicts a 25% chance of inheriting both pathogenic alleles, 50% chance of inheriting one, and 25% chance of neither in each pregnancy. These are genotype probabilities, not measured age-specific penetrance. Discuss reproductive options and individualized cardiac follow-up.
Show evidence (2 references)
PMID:35188328 SUPPORT INDIRECT Human Clinical
"Each parent was found to be heterozygous for the variant by Sanger sequencing with no known cardiac dysfunction"
Parental segregation supplies the premise for the stated Mendelian calculation.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"It is appropriate to clarify the clinical and genetic status of asymptomatic family members at risk for DCM prior to the onset of manifestations"
General GeneReviews baseline for family risk assessment.
Experimental LMOD2 replacement
Action: Gene TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Gene Therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. NCIT:C15238
Platform: Gene therapy
AAV delivery of full-length Lmod2 rescued structural and functional abnormalities in mouse models. This is preclinical evidence; efficacy, dosing, delivery safety, and durability in children have not been established by these experiments.
Mechanism Target:
Reduced Functional Leiomodin-2 — Restores leiomodin-2 in the experimental system.
Show evidence (1 reference)
PMID:26487682 SUPPORT Model Organism
"Introduction of GFP-Lmod2 via adeno-associated viral transduction elongates thin filaments and rescues structural and functional defects observed in Lmod2-KO mice, extending their lifespan to adulthood."
Mouse rescue supports therapeutic research, not established patient care.
Experimental steric blockade of LMOD2 nonsense-mediated decay
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
Platform: Antisense oligonucleotide Steric blockade Chemistry: 2′-MOE
RNA target: LMOD2 hgnc:6648 HUGO Gene Nomenclature Committee (hgnc) Relation: this treatment base-pairs with the transcript of this gene This treatment base-pairs with the transcript of LMOD2 (hgnc:6648). hgnc:6648 is a gene from the HUGO Gene Nomenclature Committee. LMOD2 exon-junction-complex binding region upstream of the exon 2-exon 3 junction
LMOD2-directed steric-blocking oligonucleotides restored mutant transcript/protein in engineered HEK293-derived cells by blocking exon-junction-complex deposition. Rescue of cardiac function in patients or patient-derived cardiomyocytes was not shown. Restored truncated protein need not be fully functional.
Mechanism Target:
Nonsense-Mediated LMOD2 Transcript Decay — Prevents recognition of selected premature-termination transcripts by the exon-junction-complex-dependent decay pathway.
Show evidence (1 reference)
PMID:38748723 SUPPORT In Vitro
"Furthermore, we generated steric-blocking oligonucleotides that obstruct deposition of the exon junction complex, preventing nonsense-mediated mRNA decay of mutant LMOD2 transcripts, thereby restoring mutant protein expression."
Cell-based proof of concept for allele-selective transcript rescue.
🔬

Diagnosis

3
Cardiac imaging and rhythm assessment
Pediatric echocardiography assesses chamber dimensions, systolic function, and valve regurgitation; ECG and rhythm monitoring evaluate accompanying arrhythmias.
Echocardiography Test NCIT:C16525 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:35188328 SUPPORT Human Clinical
"The initial echocardiogram demonstrated dilated cardiomyopathy (LV diastolic dimension of 3.82 cm, Z-score 5.06) with severely depressed LV systolic function (ejection fraction or EF of 15%)."
Human imaging establishes dilation and systolic dysfunction in later infancy.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"The left ventricular ejection fraction is the most commonly used clinical measure of systolic function, and is usually estimated from a two-dimensional echocardiogram or from cardiac MRI."
General DCM imaging guidance applicable to specialist evaluation.
LMOD2-inclusive molecular testing
Use a cardiomyopathy panel that includes LMOD2 or exome/genome sequencing, with parental segregation. Reassess older negative panels when the phenotype remains unexplained because historical panels omitted LMOD2.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"A cardiomyopathy multigene panel that includes the genes with a ClinGen classification of definitive, strong, or moderate"
GeneReviews supports panels restricted to genes with established validity; current ClinGen includes LMOD2.
PMID:34888509 SUPPORT Human Clinical
"The recurrence of disease in a family with an initially comprehensive but uninformative genetic evaluation emphasizes the importance of reviewing previously negative results in a timely manner"
The authors explicitly recommend reassessing previously negative genetic evaluations as new disease genes are identified.
Cascade testing and family cardiac assessment
Clarify familial genotypes and obtain individualized cardiac evaluation of at-risk relatives. Published pediatric pedigrees include clinically unaffected carriers, but adult association data do not justify assuming lifelong zero risk for all heterozygotes.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf SUPPORT REVIEW SYNTHESIS Human Clinical
"Molecular genetic testing is recommended for parents, sibs, offspring, and other at-risk family members in order to clarify their genetic status."
General DCM family-testing guidance; the JPH2/TNNI3-specific paragraphs in this overview are not treated as LMOD2-specific guidance.
📊

Prevalence

1
📊

Related Datasets

1
A leiomodin 2 neonatal dilated cardiomyopathy causing mutation results inaltered actin-regulatory gene signatures andcardiomyocyte dysfunction geo:GSE271871
Bulk RNA sequencing of human LMOD2-mutant and isogenic iPSC-derived cardiomyocytes and mouse Lmod2-mutant/knockout and control cardiac tissue. The mixed-species series is relevant to actin-regulatory and SRF-associated transcriptional changes; it is not a patient prevalence cohort.
BULK RNA SEQ
PMID:39285234
GEO lists Homo sapiens and Mus musculus. Both species are retained in the description because the organism slot accepts one descriptor. RNA-sequencing changes support model biology, not clinical phenotype frequencies.
🧫

Experimental Models

4
W398Ter patient-derived cardiomyocytes with isogenic controls IPSC_DERIVED_MODEL
Cultured cardiomyocytes from the founding patient model shortened thin filaments, altered calcium transients, reduced contraction amplitude, and altered MRTFB localization. Re-expression of full-length Lmod2 improves selected readouts.
Organism
Homo sapiens NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Patient-derived iPSCs and CRISPR-corrected isogenic controls
Publication
PMID:39285234
Pathograph links
Dysregulated Thin-Filament Length partially recapitulates fidelity: moderate observes: molecular The patient allele shortens actin thin filaments relative to isogenic controls.
Limitations: One patient-derived genotype in immature cultured cells does not establish the magnitude of shortening across alleles or intact human myocardium.
Divergences from the human mechanism
population mismatch qualifying
One patient-derived genotype in immature cultured cells does not establish the magnitude of shortening across alleles or intact human myocardium.
Show evidence (1 reference)
PMID:39285234 SUPPORT In Vitro
"This correlated to a ~5% decrease in actin-thin filament lengths in mutant hiPSC-CMs."
Measured structural readout in cultured patient-derived cardiomyocytes.
Altered Cardiomyocyte Calcium Handling partially recapitulates fidelity: moderate observes: cellular Calcium release and reuptake kinetics are altered in electrically paced cells.
Limitations: The cell system lacks whole-heart loading and neurohumoral context; the upstream calcium-regulatory lesion is unresolved.
Divergences from the human mechanism
boundary omission qualifying
The cell system lacks whole-heart loading and neurohumoral context; the upstream calcium-regulatory lesion is unresolved.
Show evidence (1 reference)
PMID:39285234 SUPPORT In Vitro
"Overall, the faster calcium release and reuptake kinetics of LMOD2 W398* cardiomyocytes provide a potential explanation for the decreased contraction time observed in these cells."
Calcium handling is altered in mutant cultured cardiomyocytes; the upstream molecular cause remains unresolved.
Reduced MRTFB Nuclear Localization partially recapitulates fidelity: moderate observes: cellular Nuclear MRTFB localization is reduced.
Limitations: Localization in a single patient-derived genotype does not demonstrate a causal contribution to clinical heart failure.
Divergences from the human mechanism
population mismatch qualifying
Localization in a single patient-derived genotype does not demonstrate a causal contribution to clinical heart failure.
Show evidence (1 reference)
PMID:39285234 SUPPORT In Vitro
"demonstrated significantly reduced MRTFB nuclear localization (~25%) in LMOD2 W398* hiPSC-CMs"
Immunocytochemistry supports altered localization of the SRF cofactor in patient-derived cells.
W398Ter engineered heart tissue IPSC_DERIVED_MODEL
Engineered tissues quantify force under increasing pacing frequency, extending the monolayer observations to a multicellular contractile preparation.
Organism
Homo sapiens NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
Patient-derived and isogenic control iPSC cardiomyocytes
Culture
Three-dimensional constructs with PDMS force-sensing posts
Publication
PMID:39285234
Pathograph links
Impaired Cardiomyocyte Contractility partially recapitulates fidelity: moderate observes: tissue The constructs generate less force and have shorter contraction times.
Limitations: Engineered tissue lacks mature whole-heart anatomy, circulation, and the full nonmyocyte environment.
Divergences from the human mechanism
boundary omission qualifying
Engineered tissue lacks mature whole-heart anatomy, circulation, and the full nonmyocyte environment.
Show evidence (1 reference)
PMID:39285234 SUPPORT In Vitro
"Overall, EHT analysis demonstrated a decrease in force production and a decrease in contraction time, similar to our reported findings in monolayer hiPSC-CM cultures."
Patient-derived engineered heart tissues show a contractile deficit.
LMOD2 minigene and steric-blocking oligonucleotide assays CELL_LINE
Intron-containing constructs distinguish nonsense-mediated decay from protein instability. LMOD2-directed oligonucleotides reduce exon-junction-complex association and recover selected mutant transcripts/proteins.
Organism
Homo sapiens NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Cell source
AD-293 and FT-293 human embryonic kidney-derived cell lines
Publication
PMID:38748723
Pathograph links
Nonsense-Mediated LMOD2 Transcript Decay partially recapitulates fidelity: moderate observes: molecular The W398Ter and Arg513Ter constructs reproduce intron-dependent transcript loss.
Limitations: Engineered kidney-derived cell lines do not establish decay efficiency in cardiomyocytes or clinical severity.
Divergences from the human mechanism
boundary omission qualifying
Engineered kidney-derived cell lines do not establish decay efficiency in cardiomyocytes or clinical severity.
Show evidence (1 reference)
PMID:38748723 SUPPORT In Vitro
"The addition of W398* and R513* mutations result in a decrease of LMOD2 MG mature mRNA levels but have no effect on LMOD2 CDS mature mRNA levels, when compared to their respective WT constructs"
Intron-containing minigenes demonstrate transcript loss for these two nonsense alleles; the result is not generalized to every frameshift or splice variant.
Nonsense-Mediated LMOD2 Transcript Decay rescues fidelity: moderate observes: molecular Steric blockade suppresses abnormal decay and restores mutant expression in the construct assay.
Limitations: This rescues an RNA/protein endpoint in engineered cells; it has not demonstrated patient cardiac recovery.
Divergences from the human mechanism
boundary omission qualifying
This rescues an RNA/protein endpoint in engineered cells; it has not demonstrated patient cardiac recovery.
Show evidence (1 reference)
PMID:38748723 SUPPORT In Vitro
"Furthermore, we generated steric-blocking oligonucleotides that obstruct deposition of the exon junction complex, preventing nonsense-mediated mRNA decay of mutant LMOD2 transcripts, thereby restoring mutant protein expression."
The rescue is at the transcript/protein-expression level.
Purified LMOD2 single-filament elongation assay OTHER
Single-molecule and single-filament microscopy compares full-length and truncated LMOD2 pointed-end elongation and processivity in a reconstituted actin system.
Publication
PMID:42477321
Pathograph links
Dysregulated Thin-Filament Length perturbs fidelity: moderate observes: molecular The disease-associated truncation reduces polymerization rate and processivity.
Limitations: Purified actin and LMOD2 lack sarcomeric load, RNA surveillance, and intact-cell regulation.
Divergences from the human mechanism
boundary omission qualifying
Purified actin and LMOD2 lack sarcomeric load, RNA surveillance, and intact-cell regulation.
Show evidence (1 reference)
PMID:42477321 SUPPORT In Vitro
"Removal of the C-terminal WH2-containing region in this disease-associated variant results in a substantial reduction in elongation rate and processivity"
Single-filament experiments support impaired pointed-end polymerization for the W398Ter-related truncation.
🐁

Animal Models

3
Constitutive Lmod2 knockout mouse
Knockout mice develop shortened thin filaments, ventricular dilation, and juvenile lethality.
Species
Mouse
Genotype
Biallelic Lmod2 knockout
Publication
PMID:26487682
Pathograph links
Dysregulated Thin-Filament Length partially recapitulates fidelity: moderate observes: molecular Knockout reproduces abnormal filament shortening.
Limitations: A complete mouse knockout differs from human alleles that preserve truncated protein.
Divergences from the human mechanism
species mismatch qualifying
A complete mouse knockout differs from human alleles that preserve truncated protein.
Show evidence (1 reference)
PMID:26487682 SUPPORT Model Organism
"We found that knockout of Lmod2 in mice results in abnormally short thin filaments in the heart."
Loss of Lmod2 produces the structural lesion in vivo.
Ventricular Dilation partially recapitulates fidelity: moderate observes: tissue Ventricular enlargement accompanies contractile dysfunction.
Limitations: Mouse postnatal maturation and disease timing differ from those of human infants.
Divergences from the human mechanism
species mismatch qualifying
Mouse postnatal maturation and disease timing differ from those of human infants.
Show evidence (1 reference)
PMID:26487682 SUPPORT Model Organism
"Lmod2-KO mice die as juveniles with hearts displaying contractile dysfunction and ventricular chamber enlargement consistent with dilated cardiomyopathy."
In vivo remodeling phenotype.
Lmod2 W405Ter knock-in mouse
Knock-in mice develop thin-filament shortening and DCM while retaining truncated protein and surviving substantially longer than knockout mice.
Species
Mouse
Genotype
Homozygous Lmod2 p.Trp405Ter, homologous to human p.Trp398Ter
Publication
PMID:39285234
Pathograph links
Dysregulated Thin-Filament Length partially recapitulates fidelity: moderate observes: molecular The homologous allele produces short thin filaments.
Limitations: The mouse retains substantially more truncated protein than the patient-derived cardiomyocytes and does not reproduce the severe neonatal time course.
Divergences from the human mechanism
species mismatch qualifying
The mouse retains substantially more truncated protein than the patient-derived cardiomyocytes and does not reproduce the severe neonatal time course.
Show evidence (1 reference)
PMID:39285234 SUPPORT Model Organism
"Thin filament lengths were reduced at both P21 (0.74 ± 0.02 μm vs 0.84 ± 0.02 μm) and P70 (0.78 ± 0.03 μm vs 0.86 ± 0.03 μm) in the LVs of Lmod2 W405* compared to wild-type mice, respectively"
The knock-in model reproduces shortening, with a less severe clinical course than neonatal human presentations.
Increased Monomeric Cardiac Actin partially recapitulates fidelity: moderate observes: molecular Fractionation shows increased monomeric cardiac actin.
Limitations: The tissue observation is from mice; the corresponding pool has not been measured directly in affected human myocardium.
Divergences from the human mechanism
species mismatch qualifying
The tissue observation is from mice; the corresponding pool has not been measured directly in affected human myocardium.
Show evidence (1 reference)
PMID:39285234 SUPPORT Model Organism
"Our studies demonstrated that Lmod2 W405* mice and Lmod2-KO mice had significant increases in cardiac G-actin."
Cardiac tissue fractionation supports the increased monomeric actin pool in these mouse models.
Show evidence (1 reference)
PMID:39285234 SUPPORT Model Organism
"The Lmod2 W405* mice begin to die at ~6 months of age with a median survival of 186 days"
The model has a substantially different survival time course from severe neonatal human disease.
AAV-Lmod2 rescue of knockout mice
Postnatal delivery of full-length Lmod2 rescues filament length and cardiac function in the knockout setting.
Species
Mouse
Genotype
Lmod2 knockout treated with AAV expressing GFP-Lmod2
Publication
PMID:26487682
Pathograph links
Dysregulated Thin-Filament Length rescues fidelity: moderate observes: molecular Replacement elongates abnormally short thin filaments.
Limitations: Early postnatal murine gene delivery does not establish safe or effective treatment of critically ill human infants.
Divergences from the human mechanism
species mismatch qualifying
Early postnatal murine gene delivery does not establish safe or effective treatment of critically ill human infants.
Show evidence (1 reference)
PMID:26487682 SUPPORT Model Organism
"Introduction of GFP-Lmod2 via adeno-associated viral transduction elongates thin filaments and rescues structural and functional defects observed in Lmod2-KO mice, extending their lifespan to adulthood."
Full-length replacement rescues the knockout phenotype in mice.
Ventricular Dilation rescues fidelity: moderate observes: tissue Replacement rescues structural ventricular defects.
Limitations: Preventive treatment in a mouse knockout does not prove reversal of established human cardiac remodeling.
Divergences from the human mechanism
species mismatch qualifying
Preventive treatment in a mouse knockout does not prove reversal of established human cardiac remodeling.
Show evidence (1 reference)
PMID:26487682 SUPPORT Model Organism
"Introduction of GFP-Lmod2 via adeno-associated viral transduction elongates thin filaments and rescues structural and functional defects observed in Lmod2-KO mice, extending their lifespan to adulthood."
Full-length replacement rescues the knockout phenotype in mice.
{ }

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
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
description: Dilated cardiomyopathy 2G (CMD2G) is an early-onset, predominantly cardiac disorder caused by biallelic LMOD2 variants. Homozygous and compound-heterozygous nonsense, frameshift, and splice-site variants impair leiomodin-2, a regulator of sarcomeric actin pointed-end elongation. Severe thin-filament shortening and reduced contractile force have been demonstrated in patient myocardium. Presentation ranges from fetal or neonatal cardiac dysfunction to symptomatic disease later in infancy; neonatal lethality is not universal, and several children have undergone heart transplantation. Transcript loss, residual mutant protein, calcium dysregulation, and actin-dependent transcriptional changes vary by allele and model. ClinGen classifies the autosomal recessive LMOD2-CMD2G relationship as Definitive.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: Homozygous or compound-heterozygous pathogenic LMOD2 variants cause CMD2G. Confirm parental segregation before recurrence-risk counseling. Clinically unaffected heterozygous relatives have been reported, but adult biobank associations mean that lifelong absence of cardiac risk should not be assumed.
  evidence:
  - reference: CGGV:assertion_d19140d6-8200-4fce-9906-fdda527a4f7e-2026-03-04T170000.000Z
    reference_title: LMOD2 / cardiomyopathy, dilated, 2G (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: LMOD2 | HGNC:6648 | cardiomyopathy, dilated, 2G | MONDO:0030887 | AR | Definitive
    explanation: The March 2026 ClinGen assertion is specific to CMD2G and supports definitive recessive gene-disease validity.
  - reference: PMID:34888509
    reference_title: Early Death of 2 Siblings Related to Mutations in LMOD2, a Recently Discovered Cause of Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report a family with 2 neonatal deaths related to dilated cardiomyopathy (DCM) and compound heterozygous loss-of-function variants (c.1243_1244del, p.Leu415Valfs*108 and c.1537C > T, p.Arg513*) in Leiomodin 2 (LMOD2), a recently documented cause of early DCM.
    explanation: Two genetically confirmed siblings establish that disease is not restricted to homozygous variants.
prevalence:
- population: Published LMOD2-related cardiomyopathy cases through the 2023 report
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: The 2023 report described the seventh published patient. This is a dated literature count, not a population prevalence estimate or a current exhaustive census.
  evidence:
  - reference: PMID:37296576
    reference_title: Whole-Exome Sequencing Identifies Homozygote Nonsense Variants in LMOD2 Gene Causing Infantile Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The present case of infantile cardiomyopathy is the second report of p.W398* LMOD2, the fifth report in the homozygous loss of leiomodin 2 protein expression, and the seventh patient of LMOD2-related DCM.
    explanation: The explicit patient count supports rarity without inventing a population denominator.
pathophysiology:
- name: Biallelic LMOD2 Loss-of-Function Variant
  biological_scale: MOLECULAR
  description: Biallelic LMOD2 nonsense, frameshift, or splice-site variants initiate the disease. Alleles differ in transcript processing, residual protein abundance, and retained function; recessive inheritance alone does not prove complete protein absence.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:34888509
    reference_title: Early Death of 2 Siblings Related to Mutations in LMOD2, a Recently Discovered Cause of Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report a family with 2 neonatal deaths related to dilated cardiomyopathy (DCM) and compound heterozygous loss-of-function variants (c.1243_1244del, p.Leu415Valfs*108 and c.1537C > T, p.Arg513*) in Leiomodin 2 (LMOD2), a recently documented cause of early DCM.
    explanation: Two genetically confirmed siblings establish that disease is not restricted to homozygous variants.
  - reference: PMID:35082396
    reference_title: Neonatal-lethal dilated cardiomyopathy due to a homozygous LMOD2 donor splice-site variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Exome sequencing identified a homozygous LMOD2 variant in both siblings, (GRCh38)chr7:g.123656237G > A; NM_207163.2:c.273 + 1G > A, ablating the donor 5' splice-site of intron-1.
    explanation: A donor splice-site variant is an additional established allelic mechanism.
  role: trigger
  genes:
  - preferred_term: LMOD2
    term:
      id: hgnc:6648
      label: LMOD2
  conforms_to: cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Nonsense-Mediated LMOD2 Transcript Decay
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: W398Ter and Arg513Ter introduce premature termination codons that can trigger transcript surveillance.
    evidence:
    - reference: PMID:38748723
      reference_title: Human disease-causing mutations result in loss of leiomodin 2 through nonsense-mediated mRNA decay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The addition of W398* and R513* mutations result in a decrease of LMOD2 MG mature mRNA levels but have no effect on LMOD2 CDS mature mRNA levels, when compared to their respective WT constructs
      explanation: Intron-containing minigenes demonstrate transcript loss for these two nonsense alleles; the result is not generalized to every frameshift or splice variant.
      directness: INDIRECT
  - target: Reduced Functional Leiomodin-2
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Splice-site disruption and other loss-of-function alleles impair functional protein through allele-dependent routes.
    evidence:
    - reference: PMID:35082396
      reference_title: Neonatal-lethal dilated cardiomyopathy due to a homozygous LMOD2 donor splice-site variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Consistent with the RT-PCR results, LMOD2 c.273 + 1G > A was associated with loss of full-length LMOD2 protein in cardiac tissue and MyoD-fibroblasts from the affected proband
      explanation: Patient tissue and myogenic cells demonstrate loss of full-length protein; the splice-site study did not resolve every transcript-loss mechanism.
  molecular_functions:
  - preferred_term: actin binding
    term:
      id: GO:0003779
      label: actin binding
- name: Nonsense-Mediated LMOD2 Transcript Decay
  biological_scale: MOLECULAR
  description: Nonsense-mediated decay lowers mature LMOD2 mRNA carrying W398Ter or Arg513Ter in intron-containing human constructs. Mature RNA falls while pre-mRNA is preserved, and translation inhibition or exon-junction-complex blockade increases mutant RNA/protein. This mechanism is experimentally established for these nonsense alleles; it is not a blanket explanation for all CMD2G variants.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:38748723
    reference_title: Human disease-causing mutations result in loss of leiomodin 2 through nonsense-mediated mRNA decay.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The addition of W398* and R513* mutations result in a decrease of LMOD2 MG mature mRNA levels but have no effect on LMOD2 CDS mature mRNA levels, when compared to their respective WT constructs
    explanation: Intron-containing minigenes demonstrate transcript loss for these two nonsense alleles; the result is not generalized to every frameshift or splice variant.
    directness: INDIRECT
  biological_processes:
  - preferred_term: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    term:
      id: GO:0000184
      label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    modifier: INCREASED
  downstream:
  - target: Reduced Functional Leiomodin-2
    causal_link_type: DIRECT
    description: Depletion of mature mutant transcript reduces protein production.
    evidence:
    - reference: PMID:38748723
      reference_title: Human disease-causing mutations result in loss of leiomodin 2 through nonsense-mediated mRNA decay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The addition of W398* and R513* mutations result in a decrease of LMOD2 MG mature mRNA levels but have no effect on LMOD2 CDS mature mRNA levels, when compared to their respective WT constructs
      explanation: Intron-containing minigenes demonstrate transcript loss for these two nonsense alleles; the result is not generalized to every frameshift or splice variant.
      directness: INDIRECT
- name: Reduced Functional Leiomodin-2
  biological_scale: MOLECULAR
  description: Functional leiomodin-2 is markedly reduced. W398Ter patient myocardium had undetectable protein, while patient-derived cardiomyocytes and the homologous W405Ter mouse retained truncated protein. In minigene assays, Leu415ValfsTer108 did not significantly lower mutant protein abundance; this distinguishes loss of normal function from an invariant null state.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:31517052
    reference_title: 'Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Full-length or truncated Lmod2 was not detected in the LV of the proband’s explanted heart via Western blot analysis
    explanation: The W398Ter proband had undetectable protein in the explanted ventricle.
  - 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: Immunoblot analysis confirmed LMOD2 W398* hiPSC-CMs express truncated LMOD2 protein
    explanation: The corresponding patient-derived cellular model retains truncated protein, so complete absence cannot be assumed in every system.
  - reference: PMID:38748723
    reference_title: Human disease-causing mutations result in loss of leiomodin 2 through nonsense-mediated mRNA decay.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: while another unstudied mutation (p.V415fs*108) does not significantly decrease mutant protein levels.
    explanation: The source uses this abbreviated spelling for the Leu415ValfsTer108 frameshift discussed in the same paragraph. Its abundance differs from the nonsense alleles.
  molecular_functions:
  - preferred_term: actin binding
    term:
      id: GO:0003779
      label: actin binding
    modifier: DECREASED
  downstream:
  - target: Dysregulated Thin-Filament Length
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Loss of normal pointed-end elongation impairs thin-filament length regulation.
    evidence:
    - reference: PMID:31517052
      reference_title: 'Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Mean thin filament length was significantly reduced in the patient’s heart (by ~70%)
      explanation: Direct patient-tissue evidence of severe shortening; the magnitude is specific to this explant.
    - reference: PMID:42477321
      reference_title: Leiomodin 2 is a processive pointed-end elongator of actin filaments.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Removal of the C-terminal WH2-containing region in this disease-associated variant results in a substantial reduction in elongation rate and processivity
      explanation: Single-filament experiments support impaired pointed-end polymerization for the W398Ter-related truncation.
  - target: Altered Cardiomyocyte Calcium Handling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Calcium transients are perturbed after loss of normal LMOD2; intermediate steps are unresolved.
    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: Overall, the faster calcium release and reuptake kinetics of LMOD2 W398* cardiomyocytes provide a potential explanation for the decreased contraction time observed in these cells.
      explanation: Calcium handling is altered in mutant cultured cardiomyocytes; the upstream molecular cause remains unresolved.
  - target: Increased Monomeric Cardiac Actin
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Impaired actin assembly is proposed to increase the soluble actin pool.
    hypothesis_groups:
    - actin_mrtfb_srf
    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: MODEL_ORGANISM
      snippet: Our studies demonstrated that Lmod2 W405* mice and Lmod2-KO mice had significant increases in cardiac G-actin.
      explanation: Cardiac tissue fractionation supports the increased monomeric actin pool in these mouse models.
- name: Dysregulated Thin-Filament Length
  biological_scale: MOLECULAR
  description: Sarcomeric actin thin filaments are shortened in affected myocardium and experimental models. The W398Ter truncation impairs the rate and processivity of pointed-end elongation in single-filament assays. Shortening reduces available thin-thick filament overlap, although the full contractile defect can also involve calcium handling and remodeling.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:31517052
    reference_title: 'Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Mean thin filament length was significantly reduced in the patient’s heart (by ~70%)
    explanation: Direct patient-tissue evidence of severe shortening; the magnitude is specific to this explant.
  - reference: PMID:42477321
    reference_title: Leiomodin 2 is a processive pointed-end elongator of actin filaments.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Removal of the C-terminal WH2-containing region in this disease-associated variant results in a substantial reduction in elongation rate and processivity
    explanation: Single-filament experiments support impaired pointed-end polymerization for the W398Ter-related truncation.
  biological_processes:
  - preferred_term: actin filament polymerization
    term:
      id: GO:0030041
      label: actin filament polymerization
    modifier: DECREASED
  - preferred_term: sarcomere organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: actin filament
    term:
      id: GO:0005884
      label: actin filament
  downstream:
  - target: Impaired Cardiomyocyte Contractility
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Abnormal thin-filament geometry reduces effective actomyosin force generation.
    evidence:
    - reference: PMID:31517052
      reference_title: 'Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The infant’s explanted heart showed extraordinarily short thin filaments with isolated cardiomyocytes displaying a large reduction in maximum calcium-activated force production.
      explanation: Ex vivo myocytes from the affected human heart directly demonstrate reduced force.
    - 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: Overall, EHT analysis demonstrated a decrease in force production and a decrease in contraction time, similar to our reported findings in monolayer hiPSC-CM cultures.
      explanation: Patient-derived engineered heart tissues show a contractile deficit.
- name: Altered Cardiomyocyte Calcium Handling
  biological_scale: CELLULAR
  description: W398Ter patient-derived cardiomyocytes have reduced calcium-transient amplitude and faster release/reuptake kinetics. Re-expression of full-length Lmod2 improves transient amplitude. Unchanged abundance of several major calcium-handling proteins does not establish normal calcium regulation; the initiating signaling defect remains uncertain.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  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: Overall, the faster calcium release and reuptake kinetics of LMOD2 W398* cardiomyocytes provide a potential explanation for the decreased contraction time observed in these cells.
    explanation: Calcium handling is altered in mutant cultured cardiomyocytes; the upstream molecular cause remains unresolved.
  biological_processes:
  - preferred_term: regulation of cardiac muscle contraction by calcium ion signaling
    term:
      id: GO:0010882
      label: regulation of cardiac muscle contraction by calcium ion signaling
    modifier: ABNORMAL
  downstream:
  - target: Impaired Cardiomyocyte Contractility
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Reduced calcium availability and altered kinetics can contribute to abnormal contraction.
    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: Overall, the faster calcium release and reuptake kinetics of LMOD2 W398* cardiomyocytes provide a potential explanation for the decreased contraction time observed in these cells.
      explanation: Calcium handling is altered in mutant cultured cardiomyocytes; the upstream molecular cause remains unresolved.
- name: Impaired Cardiomyocyte Contractility
  biological_scale: CELLULAR
  description: Patient myocardial cells and patient-derived engineered heart tissue generate less contractile force. Thin-filament shortening and altered calcium dynamics contribute, with the magnitude depending on the allele and experimental system.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:31517052
    reference_title: 'Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The infant’s explanted heart showed extraordinarily short thin filaments with isolated cardiomyocytes displaying a large reduction in maximum calcium-activated force production.
    explanation: Ex vivo myocytes from the affected human heart directly demonstrate reduced force.
  - 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: Overall, EHT analysis demonstrated a decrease in force production and a decrease in contraction time, similar to our reported findings in monolayer hiPSC-CM cultures.
    explanation: Patient-derived engineered heart tissues show a contractile deficit.
  biological_processes:
  - preferred_term: cardiac muscle cell contraction
    term:
      id: GO:0086003
      label: cardiac muscle cell contraction
    modifier: DECREASED
  downstream:
  - target: Ventricular Dilation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Sustained contractile impairment is associated with ventricular remodeling and dilation.
    evidence:
    - reference: PMID:35188328
      reference_title: LMOD2-related dilated cardiomyopathy presenting in late infancy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The initial echocardiogram demonstrated dilated cardiomyopathy (LV diastolic dimension of 3.82 cm, Z-score 5.06) with severely depressed LV systolic function (ejection fraction or EF of 15%).
      explanation: Human imaging establishes dilation and systolic dysfunction in later infancy.
  - target: Heart Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Severe loss of myocardial force leads to inadequate cardiac output.
    evidence:
    - reference: PMID:35082396
      reference_title: Neonatal-lethal dilated cardiomyopathy due to a homozygous LMOD2 donor splice-site variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Here, we describe two siblings with DCM who died shortly after birth due to heart failure.
      explanation: Heart failure can be rapidly lethal in affected neonates.
    - reference: PMID:37296576
      reference_title: Whole-Exome Sequencing Identifies Homozygote Nonsense Variants in LMOD2 Gene Causing Infantile Dilated Cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The proband is a 4-month male infant of Hispanic descent with advanced heart failure.
      explanation: Advanced failure also occurs after the neonatal period.
- name: Ventricular Dilation
  biological_scale: TISSUE
  description: Ventricular chamber dilation accompanies severe systolic dysfunction. Presentation may be neonatal or later in infancy; some early presentations have marked dysfunction before clear dilation.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:35188328
    reference_title: LMOD2-related dilated cardiomyopathy presenting in late infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The initial echocardiogram demonstrated dilated cardiomyopathy (LV diastolic dimension of 3.82 cm, Z-score 5.06) with severely depressed LV systolic function (ejection fraction or EF of 15%).
    explanation: Human imaging establishes dilation and systolic dysfunction in later infancy.
  locations:
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  conforms_to: cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling
  downstream:
  - target: Dilated Cardiomyopathy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Ventricular dilation together with systolic impairment defines the clinical cardiomyopathy.
    evidence:
    - reference: PMID:35188328
      reference_title: LMOD2-related dilated cardiomyopathy presenting in late infancy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The initial echocardiogram demonstrated dilated cardiomyopathy (LV diastolic dimension of 3.82 cm, Z-score 5.06) with severely depressed LV systolic function (ejection fraction or EF of 15%).
      explanation: Human imaging establishes dilation and systolic dysfunction in later infancy.
- name: Heart Failure
  biological_scale: ORGANISM
  description: Severe systolic dysfunction can cause neonatal cardiogenic shock or decompensated heart failure in infancy. Death and transplantation are alternative observed outcomes, not an obligatory combined endpoint.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:35082396
    reference_title: Neonatal-lethal dilated cardiomyopathy due to a homozygous LMOD2 donor splice-site variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we describe two siblings with DCM who died shortly after birth due to heart failure.
    explanation: Heart failure can be rapidly lethal in affected neonates.
  - reference: PMID:37296576
    reference_title: Whole-Exome Sequencing Identifies Homozygote Nonsense Variants in LMOD2 Gene Causing Infantile Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The proband is a 4-month male infant of Hispanic descent with advanced heart failure.
    explanation: Advanced failure also occurs after the neonatal period.
  conforms_to: cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure
  downstream:
  - target: Congestive Heart Failure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Pump dysfunction produces the clinical heart-failure syndrome.
    evidence:
    - reference: PMID:35082396
      reference_title: Neonatal-lethal dilated cardiomyopathy due to a homozygous LMOD2 donor splice-site variant.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Here, we describe two siblings with DCM who died shortly after birth due to heart failure.
      explanation: Heart failure can be rapidly lethal in affected neonates.
    - reference: PMID:37296576
      reference_title: Whole-Exome Sequencing Identifies Homozygote Nonsense Variants in LMOD2 Gene Causing Infantile Dilated Cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The proband is a 4-month male infant of Hispanic descent with advanced heart failure.
      explanation: Advanced failure also occurs after the neonatal period.
- name: Increased Monomeric Cardiac Actin
  biological_scale: MOLECULAR
  description: An increased monomeric actin pool was measured in Lmod2 knockout and W405Ter mouse hearts. It is proposed to retain MRTFB outside the nucleus; the same causal sequence has not been established in patients.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  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: MODEL_ORGANISM
    snippet: Our studies demonstrated that Lmod2 W405* mice and Lmod2-KO mice had significant increases in cardiac G-actin.
    explanation: Cardiac tissue fractionation supports the increased monomeric actin pool in these mouse models.
  downstream:
  - target: Reduced MRTFB Nuclear Localization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: G-actin association may limit MRTFB nuclear entry.
    hypothesis_groups:
    - actin_mrtfb_srf
    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: MODEL_ORGANISM
      snippet: These findings suggest a significant proportion of MRTFB is associated with the G-actin pool and is therefore unavailable to activate SRF
      explanation: Mouse left-ventricular fractionation associates MRTFB with the increased G-actin pool, supporting the proposed sequestration mechanism without establishing the complete causal sequence in patients.
      directness: INDIRECT
- name: Reduced MRTFB Nuclear Localization
  genes:
  - preferred_term: MRTFB
    term:
      id: hgnc:29819
      label: MRTFB
  biological_scale: CELLULAR
  description: MRTFB nuclear localization is reduced in W398Ter patient-derived cardiomyocytes. Mouse tissue also shows increased MRTFB association with the G-actin fraction. These results support, but do not fully prove, an actin-dependent transcriptional feedback mechanism.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  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: demonstrated significantly reduced MRTFB nuclear localization (~25%) in LMOD2 W398* hiPSC-CMs
    explanation: Immunocytochemistry supports altered localization of the SRF cofactor in patient-derived cells.
  downstream:
  - target: Reduced SRF-Dependent Transcription
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Reduced nuclear availability of the SRF cofactor may lower its target-gene program.
    hypothesis_groups:
    - actin_mrtfb_srf
    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: COMPUTATIONAL
      snippet: Of the transcriptionally downregulated pathways, the serum response factor (SRF) pathway was identified in both mutant hiPSC-CMs and mouse heart tissue RNA sequencing analysis.
      explanation: RNA-sequencing pathway analysis identifies reduced SRF-associated transcription; the causal feedback model remains emerging.
- name: Reduced SRF-Dependent Transcription
  genes:
  - preferred_term: SRF
    term:
      id: hgnc:11291
      label: SRF
  biological_scale: CELLULAR
  description: SRF-associated transcriptional pathways are downregulated in mutant cardiomyocytes and mouse hearts. Whether this is a causal driver, a compensatory response, or both remains unresolved; SRF-targeted treatment is a research hypothesis.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  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: COMPUTATIONAL
    snippet: Of the transcriptionally downregulated pathways, the serum response factor (SRF) pathway was identified in both mutant hiPSC-CMs and mouse heart tissue RNA sequencing analysis.
    explanation: RNA-sequencing pathway analysis identifies reduced SRF-associated transcription; the causal feedback model remains emerging.
  biological_processes:
  - preferred_term: positive regulation of transcription by RNA polymerase II
    term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
    modifier: DECREASED
  downstream:
  - target: Impaired Cardiomyocyte Contractility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Altered expression of muscle and calcium-regulatory genes may compound the primary structural defect.
    hypothesis_groups:
    - actin_mrtfb_srf
    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: COMPUTATIONAL
      snippet: Of the transcriptionally downregulated pathways, the serum response factor (SRF) pathway was identified in both mutant hiPSC-CMs and mouse heart tissue RNA sequencing analysis.
      explanation: RNA-sequencing pathway analysis identifies reduced SRF-associated transcription; the causal feedback model remains emerging.
mechanistic_hypotheses:
- hypothesis_group_id: actin_mrtfb_srf
  hypothesis_label: Actin-dependent MRTFB-SRF transcriptional feedback
  status: EMERGING
  description: Loss of normal LMOD2-mediated actin assembly may increase G-actin, reduce MRTFB nuclear localization, and suppress SRF target genes. Molecular and transcriptional observations support this model, but the causal sequence and contribution to human disease need intervention experiments.
  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: COMPUTATIONAL
    snippet: These findings reveal that LMOD2 may be regulating SRF activity in an actin-dependent manner
    explanation: The authors frame SRF regulation as a potential mechanism rather than an established clinical pathway.
phenotypes:
- name: Dilated Cardiomyopathy
  category: Cardiovascular
  description: Severe ventricular dilation and systolic dysfunction, usually early in life but not restricted to birth.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:35188328
    reference_title: LMOD2-related dilated cardiomyopathy presenting in late infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The initial echocardiogram demonstrated dilated cardiomyopathy (LV diastolic dimension of 3.82 cm, Z-score 5.06) with severely depressed LV systolic function (ejection fraction or EF of 15%).
    explanation: Human imaging establishes dilation and systolic dysfunction in later infancy.
  - reference: PMID:35188328
    reference_title: LMOD2-related dilated cardiomyopathy presenting in late infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we describe a third family with a child harboring a previously described homozygous frameshift variant, c.1243_1244delCT (p.L415Vfs*108) with DCM, presenting later in infancy at 9 months of age.
    explanation: The documented nine-month presentation contradicts an obligately neonatal onset.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Because of rapid growth in children, expert cardiovascular assessment is recommended to assess left ventricular enlargement in the pediatric population.
    explanation: General DCM clinical baseline, not LMOD2-specific frequency evidence.
    quote_role: REVIEW_SYNTHESIS
- name: Congestive Heart Failure
  category: Cardiovascular
  description: Heart failure can present in the neonatal period or later infancy and may progress to shock, death, or transplantation.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:35082396
    reference_title: Neonatal-lethal dilated cardiomyopathy due to a homozygous LMOD2 donor splice-site variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here, we describe two siblings with DCM who died shortly after birth due to heart failure.
    explanation: Heart failure can be rapidly lethal in affected neonates.
  - reference: PMID:37296576
    reference_title: Whole-Exome Sequencing Identifies Homozygote Nonsense Variants in LMOD2 Gene Causing Infantile Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The proband is a 4-month male infant of Hispanic descent with advanced heart failure.
    explanation: Advanced failure also occurs after the neonatal period.
- name: Ventricular Tachycardia
  category: Cardiovascular
  description: Ventricular tachycardia and ectopy were observed during severe cardiac disease; no syndrome-wide frequency is established.
  phenotype_term:
    preferred_term: Ventricular tachycardia
    term:
      id: HP:0004756
      label: Ventricular tachycardia
  evidence:
  - reference: PMID:31517052
    reference_title: 'Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: While waiting, she had intermittent episodes of ventricular tachycardia and ectopy
    explanation: Observed before transplant in the founding proband receiving mechanical support.
- name: Supraventricular Tachycardia
  category: Cardiovascular
  description: Supraventricular tachyarrhythmias have complicated the course in several reports.
  phenotype_term:
    preferred_term: Supraventricular tachycardia
    term:
      id: HP:0004755
      label: Supraventricular tachycardia
  evidence:
  - reference: PMID:35188328
    reference_title: LMOD2-related dilated cardiomyopathy presenting in late infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His clinical course during the hospitalization was complicated by supraventricular tachycardia for which he was started on amiodarone.
    explanation: A genetically confirmed patient had supraventricular tachycardia.
- name: Mitral Regurgitation
  category: Cardiovascular
  description: Mitral regurgitation accompanies ventricular dysfunction in some reported patients.
  phenotype_term:
    preferred_term: Mitral regurgitation
    term:
      id: HP:0001653
      label: Mitral regurgitation
  evidence:
  - reference: PMID:35188328
    reference_title: LMOD2-related dilated cardiomyopathy presenting in late infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He also had moderate mitral valve regurgitation, moderate tricuspid valve regurgitation, and a mildly dilated RV with severely depressed RV systolic function
    explanation: Clinical imaging documents regurgitation in the nine-month presentation.
- name: Tricuspid Regurgitation
  category: Cardiovascular
  description: Tricuspid regurgitation can occur with biventricular dysfunction, including a reported late-fetal presentation.
  phenotype_term:
    preferred_term: Tricuspid regurgitation
    term:
      id: HP:0005180
      label: Tricuspid regurgitation
  evidence:
  - reference: PMID:34888509
    reference_title: Early Death of 2 Siblings Related to Mutations in LMOD2, a Recently Discovered Cause of Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: However, at 37 weeks’ gestational age, the right atrium and right ventricle were qualitatively dilated, and there was mildly reduced right ventricular systolic function and severe tricuspid regurgitation.
    explanation: Prenatal cardiac abnormalities in an affected sibling preclude a universal claim of normal fetal function.
genetic:
- name: LMOD2
  gene_term:
    preferred_term: LMOD2
    term:
      id: hgnc:6648
      label: LMOD2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: CGGV:assertion_d19140d6-8200-4fce-9906-fdda527a4f7e-2026-03-04T170000.000Z
    reference_title: LMOD2 / cardiomyopathy, dilated, 2G (Definitive)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: LMOD2 | HGNC:6648 | cardiomyopathy, dilated, 2G | MONDO:0030887 | AR | Definitive
    explanation: The March 2026 ClinGen assertion is specific to CMD2G and supports definitive recessive gene-disease validity.
  - reference: PMID:34888509
    reference_title: Early Death of 2 Siblings Related to Mutations in LMOD2, a Recently Discovered Cause of Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report a family with 2 neonatal deaths related to dilated cardiomyopathy (DCM) and compound heterozygous loss-of-function variants (c.1243_1244del, p.Leu415Valfs*108 and c.1537C > T, p.Arg513*) in Leiomodin 2 (LMOD2), a recently documented cause of early DCM.
    explanation: Two genetically confirmed siblings establish that disease is not restricted to homozygous variants.
  - reference: PMID:31517052
    reference_title: 'Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Exome sequencing identified a biallelic homozygous nonsense variant (c.1193G > A, p.Trp398*) in a candidate gene LMOD2, which encodes Lmod2.
    explanation: Founding nonsense allele identified by exome sequencing.
  - reference: PMID:35082396
    reference_title: Neonatal-lethal dilated cardiomyopathy due to a homozygous LMOD2 donor splice-site variant.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Exome sequencing identified a homozygous LMOD2 variant in both siblings, (GRCh38)chr7:g.123656237G > A; NM_207163.2:c.273 + 1G > A, ablating the donor 5' splice-site of intron-1.
    explanation: The donor splice-site allele extends the loss-of-function spectrum.
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_d19140d6-8200-4fce-9906-fdda527a4f7e-2026-03-04T170000.000Z
    evidence:
    - reference: CGGV:assertion_d19140d6-8200-4fce-9906-fdda527a4f7e-2026-03-04T170000.000Z
      reference_title: LMOD2 / cardiomyopathy, dilated, 2G (Definitive)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: LMOD2 | HGNC:6648 | cardiomyopathy, dilated, 2G | MONDO:0030887 | AR | Definitive
      explanation: The March 2026 ClinGen assertion is specific to CMD2G and supports definitive recessive gene-disease validity.
  notes: Established alleles include c.1193G>A (p.Trp398Ter), c.1537C>T (p.Arg513Ter), c.1243_1244delCT (p.Leu415ValfsTer108), and c.273+1G>A. Homozygosity and compound heterozygosity are both documented. The Leu415 frameshift preserves more mutant protein in minigene assays than the two studied nonsense alleles. The same Trp398Ter allele has neonatal and four-month presentations, so onset cannot be inferred from genotype alone. No population penetrance estimate is established.
diagnosis:
- name: Cardiac imaging and rhythm assessment
  description: Pediatric echocardiography assesses chamber dimensions, systolic function, and valve regurgitation; ECG and rhythm monitoring evaluate accompanying arrhythmias.
  diagnosis_term:
    preferred_term: Echocardiography Test
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:35188328
    reference_title: LMOD2-related dilated cardiomyopathy presenting in late infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The initial echocardiogram demonstrated dilated cardiomyopathy (LV diastolic dimension of 3.82 cm, Z-score 5.06) with severely depressed LV systolic function (ejection fraction or EF of 15%).
    explanation: Human imaging establishes dilation and systolic dysfunction in later infancy.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The left ventricular ejection fraction is the most commonly used clinical measure of systolic function, and is usually estimated from a two-dimensional echocardiogram or from cardiac MRI.
    explanation: General DCM imaging guidance applicable to specialist evaluation.
    quote_role: REVIEW_SYNTHESIS
- name: LMOD2-inclusive molecular testing
  description: Use a cardiomyopathy panel that includes LMOD2 or exome/genome sequencing, with parental segregation. Reassess older negative panels when the phenotype remains unexplained because historical panels omitted LMOD2.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A cardiomyopathy multigene panel that includes the genes with a ClinGen classification of definitive, strong, or moderate
    explanation: GeneReviews supports panels restricted to genes with established validity; current ClinGen includes LMOD2.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:34888509
    reference_title: Early Death of 2 Siblings Related to Mutations in LMOD2, a Recently Discovered Cause of Neonatal Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The recurrence of disease in a family with an initially comprehensive but uninformative genetic evaluation emphasizes the importance of reviewing previously negative results in a timely manner
    explanation: The authors explicitly recommend reassessing previously negative genetic evaluations as new disease genes are identified.
- name: Cascade testing and family cardiac assessment
  description: Clarify familial genotypes and obtain individualized cardiac evaluation of at-risk relatives. Published pediatric pedigrees include clinically unaffected carriers, but adult association data do not justify assuming lifelong zero risk for all heterozygotes.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Molecular genetic testing is recommended for parents, sibs, offspring, and other at-risk family members in order to clarify their genetic status.
    explanation: General DCM family-testing guidance; the JPH2/TNNI3-specific paragraphs in this overview are not treated as LMOD2-specific guidance.
    quote_role: REVIEW_SYNTHESIS
treatments:
- name: Diuretic therapy
  description: Relieve congestion in children with fluid retention and ventricular dysfunction; individualize therapy and monitor volume status and electrolytes. This is general pediatric guidance; suitability in neonates and infants requires specialist assessment.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Congestive Heart Failure
    description: Treats downstream heart failure; it does not restore leiomodin-2.
  evidence:
  - reference: url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    reference_title: https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In children with fluid retention and ventricular dysfunction (HF stage C), diuretic therapy is recommended to achieve a euvolemic state
    explanation: ISHLT pediatric heart-failure guidance extrapolated to CMD2G; this is not evidence of a genotype-specific trial.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Diuretic
      term:
        id: NCIT:C448
        label: Diuretic
- name: ACE inhibition or ARB therapy
  description: ACE inhibitors are recommended for pediatric left ventricular systolic dysfunction unless contraindicated; an ARB is a reasonable alternative when ACE inhibitors are not tolerated. This is general pediatric guidance; suitability in neonates and infants requires specialist assessment.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Congestive Heart Failure
    description: Treats downstream heart failure; it does not restore leiomodin-2.
  evidence:
  - reference: url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    reference_title: https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In children with left ventricular systolic dysfunction, ACE inhibitors should be routinely used unless there is a specific contraindication
    explanation: ISHLT pediatric heart-failure guidance extrapolated to CMD2G; this is not evidence of a genotype-specific trial.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ACE Inhibitor
      term:
        id: NCIT:C247
        label: ACE Inhibitor
- name: Beta-blocker therapy
  description: Beta-blockade is reasonable for pediatric systemic LV systolic dysfunction under specialist care. This is general pediatric guidance; suitability in neonates and infants requires specialist assessment.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Congestive Heart Failure
    description: Treats downstream heart failure; it does not restore leiomodin-2.
  evidence:
  - reference: url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    reference_title: https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In children with systemic LV systolic dysfunction, use of β-blockers is reasonable
    explanation: ISHLT pediatric heart-failure guidance extrapolated to CMD2G; this is not evidence of a genotype-specific trial.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Beta-Adrenergic Antagonist
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
- name: Aldosterone antagonist therapy
  description: An aldosterone antagonist is reasonable for symptomatic systemic LV dysfunction, with renal function and electrolyte monitoring. This is general pediatric guidance; suitability in neonates and infants requires specialist assessment.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Congestive Heart Failure
    description: Treats downstream heart failure; it does not restore leiomodin-2.
  evidence:
  - reference: url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    reference_title: https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In children with symptomatic systemic left ventricular dysfunction, treatment with aldosterone antagonists is reasonable
    explanation: ISHLT pediatric heart-failure guidance extrapolated to CMD2G; this is not evidence of a genotype-specific trial.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Aldosterone Receptor Antagonist
      term:
        id: NCIT:C101255
        label: Aldosterone Receptor Antagonist
- name: Angiotensin receptor-neprilysin inhibition
  description: Sacubitril-valsartan can replace an ACE inhibitor or ARB in appropriate children with symptomatic systemic LV systolic dysfunction. Pediatric treatment selection depends on age and clinical circumstances; it is not a LMOD2-specific therapy. This is general pediatric guidance; suitability in neonates and infants requires specialist assessment.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Congestive Heart Failure
    description: Treats downstream heart failure; it does not restore leiomodin-2.
  evidence:
  - reference: url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    reference_title: https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In children with symptomatic systemic left ventricular systolic dysfunction, ARNI in the place of an ACE inhibitor or ARB is reasonable
    explanation: ISHLT pediatric heart-failure guidance extrapolated to CMD2G; this is not evidence of a genotype-specific trial.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Sacubitril Valsartan
      term:
        id: NCIT:C222078
        label: Sacubitril Valsartan
- name: Ivabradine
  description: Consider in selected children with stable heart failure when heart-rate reduction is desirable; this is general pediatric guidance, not a LMOD2-specific effect. This is general pediatric guidance; suitability in neonates and infants requires specialist assessment.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Congestive Heart Failure
    description: Treats downstream heart failure; it does not restore leiomodin-2.
  evidence:
  - reference: url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    reference_title: https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In children with stable HF, ivabradine is reasonable when heart rate reduction is desirable
    explanation: ISHLT pediatric heart-failure guidance extrapolated to CMD2G; this is not evidence of a genotype-specific trial.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: Ivabradine
      term:
        id: NCIT:C65995
        label: Ivabradine
- name: SGLT2 inhibitors
  description: May be considered for symptomatic pediatric HFrEF by specialists. Pediatric safety and effectiveness have not been systematically established, and adult outcome benefits cannot be assumed for CMD2G. This is general pediatric guidance; suitability in neonates and infants requires specialist assessment.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Congestive Heart Failure
    description: Treats downstream heart failure; it does not restore leiomodin-2.
  evidence:
  - reference: url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    reference_title: https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In children with symptomatic HFrEF, SGLT2 inhibitors may be considered, although their safety and effectiveness in children have not been systematically studied
    explanation: ISHLT pediatric heart-failure guidance extrapolated to CMD2G; this is not evidence of a genotype-specific trial.
    quote_role: REVIEW_SYNTHESIS
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: SGLT2 Inhibitor
      term:
        id: NCIT:C98083
        label: SGLT2 Inhibitor
- name: Heart transplantation
  description: Transplantation has been performed for refractory heart failure in neonatal and later-infantile CMD2G. It replaces the failing heart without correcting the germline genotype.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Heart Transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_mechanisms:
  - target: Impaired Cardiomyocyte Contractility
    description: Replaces the myocardium with impaired force generation.
  evidence:
  - reference: PMID:37296576
    reference_title: Whole-Exome Sequencing Identifies Homozygote Nonsense Variants in LMOD2 Gene Causing Infantile Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Eventually, the infant received an ABO-compatible orthotopic heart transplant (OHT) at 7 months of age.
    explanation: Directly documented transplant in the four-month-onset patient.
  - reference: PMID:35188328
    reference_title: LMOD2-related dilated cardiomyopathy presenting in late infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He underwent orthotopic heart transplantation (OHT) at 14 months of age.
    explanation: Transplantation also occurred after a later-infantile presentation.
- name: Mechanical circulatory support
  description: ECMO and ventricular assist devices have been used during severe decompensation and as a bridge to transplantation. These are supportive interventions with substantial risks, not correction of the thin-filament defect.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Mechanical Circulatory Support
    term:
      id: NCIT:C99540
      label: Mechanical Circulatory Support
  target_mechanisms:
  - target: Heart Failure
    description: Supports circulation when cardiac output is inadequate.
  evidence:
  - reference: PMID:31517052
    reference_title: 'Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She required mechanical circulatory support with either extracorporeal membrane oxygenation or a Berlin Heart left ventricular assist device (LVAD) for the majority of her early life
    explanation: Observed support in the founding patient.
- name: Genetic counseling
  description: Explain recessive segregation and offer family testing. For confirmed heterozygous parents, Mendelian segregation predicts a 25% chance of inheriting both pathogenic alleles, 50% chance of inheriting one, and 25% chance of neither in each pregnancy. These are genotype probabilities, not measured age-specific penetrance. Discuss reproductive options and individualized cardiac follow-up.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:35188328
    reference_title: LMOD2-related dilated cardiomyopathy presenting in late infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Each parent was found to be heterozygous for the variant by Sanger sequencing with no known cardiac dysfunction
    explanation: Parental segregation supplies the premise for the stated Mendelian calculation.
    directness: INDIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
    reference_title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: It is appropriate to clarify the clinical and genetic status of asymptomatic family members at risk for DCM prior to the onset of manifestations
    explanation: General GeneReviews baseline for family risk assessment.
    quote_role: REVIEW_SYNTHESIS
- name: Experimental LMOD2 replacement
  description: AAV delivery of full-length Lmod2 rescued structural and functional abnormalities in mouse models. This is preclinical evidence; efficacy, dosing, delivery safety, and durability in children have not been established by these experiments.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: Gene Therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Reduced Functional Leiomodin-2
    description: Restores leiomodin-2 in the experimental system.
  evidence:
  - reference: PMID:26487682
    reference_title: Knockout of Lmod2 results in shorter thin filaments followed by dilated cardiomyopathy and juvenile lethality.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Introduction of GFP-Lmod2 via adeno-associated viral transduction elongates thin filaments and rescues structural and functional defects observed in Lmod2-KO mice, extending their lifespan to adulthood.
    explanation: Mouse rescue supports therapeutic research, not established patient care.
- name: Experimental steric blockade of LMOD2 nonsense-mediated decay
  description: LMOD2-directed steric-blocking oligonucleotides restored mutant transcript/protein in engineered HEK293-derived cells by blocking exon-junction-complex deposition. Rescue of cardiac function in patients or patient-derived cardiomyocytes was not shown. Restored truncated protein need not be fully functional.
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  oligonucleotide_details:
    oligonucleotide_mechanism: STERIC_BLOCKADE
    target_gene:
      preferred_term: LMOD2
      term:
        id: hgnc:6648
        label: LMOD2
    target_transcript: LMOD2 exon-junction-complex binding region upstream of the exon 2-exon 3 junction
    oligonucleotide_chemistry: TWO_PRIME_O_METHOXYETHYL
  target_mechanisms:
  - target: Nonsense-Mediated LMOD2 Transcript Decay
    description: Prevents recognition of selected premature-termination transcripts by the exon-junction-complex-dependent decay pathway.
  evidence:
  - reference: PMID:38748723
    reference_title: Human disease-causing mutations result in loss of leiomodin 2 through nonsense-mediated mRNA decay.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Furthermore, we generated steric-blocking oligonucleotides that obstruct deposition of the exon junction complex, preventing nonsense-mediated mRNA decay of mutant LMOD2 transcripts, thereby restoring mutant protein expression.
    explanation: Cell-based proof of concept for allele-selective transcript rescue.
datasets:
- accession: geo:GSE271871
  title: A leiomodin 2 neonatal dilated cardiomyopathy causing mutation results inaltered actin-regulatory gene signatures andcardiomyocyte dysfunction
  description: Bulk RNA sequencing of human LMOD2-mutant and isogenic iPSC-derived cardiomyocytes and mouse Lmod2-mutant/knockout and control cardiac tissue. The mixed-species series is relevant to actin-regulatory and SRF-associated transcriptional changes; it is not a patient prevalence cohort.
  data_type: BULK_RNA_SEQ
  publication: PMID:39285234
  notes: GEO lists Homo sapiens and Mus musculus. Both species are retained in the description because the organism slot accepts one descriptor. RNA-sequencing changes support model biology, not clinical phenotype frequencies.
discussions:
- discussion_id: heterozygous_lmod2_risk
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: What cardiac risk do heterozygous LMOD2 truncating variants confer across the lifespan?
  attaches_to:
  - inheritance#Autosomal recessive
  - genetic#LMOD2
  rationale: Pediatric pedigrees include asymptomatic carriers with incomplete cardiac evaluation, whereas biobank analyses suggest an adult monoallelic association. These observations do not establish high-penetrance dominant CMD2G or a uniform surveillance interval.
  evidence:
  - reference: PMID:38666070
    reference_title: Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Several of these genes have monoallelic association with disease outcomes and cardiac traits in the UK Biobank, including LMOD2 and ALPK3 with dilated and hypertrophic CM, respectively.
    explanation: The association study warrants caution about assuming that every carrier is unaffected for life.
  - reference: PMID:35188328
    reference_title: LMOD2-related dilated cardiomyopathy presenting in late infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Evaluation by ECG and echocardiogram have not been performed on parents or carrier siblings.
    explanation: Absence of reported symptoms in this family does not establish normal cardiac testing.
- discussion_id: lmod2_model_severity
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: Why does the homologous W405Ter mouse retain more protein and develop a milder course than severe human W398Ter cardiomyopathy?
  attaches_to:
  - pathophysiology#Reduced Functional Leiomodin-2
  - animal_models#Mouse
  rationale: Allele-matched mice, patient-derived cells, and explanted human myocardium differ in residual protein and disease timing. Differences in RNA surveillance, maturation, loading, and terminal disease remodeling may affect translation of rescue experiments.
  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: MODEL_ORGANISM
    snippet: Immunoblot analysis of LV tissue at P70 showed that mutant mice express truncated Lmod2 protein at approximately 45% of wild-type (full-length) Lmod2 levels
    explanation: The in vivo mouse allele retains substantial protein.
  - reference: PMID:31517052
    reference_title: 'Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Full-length or truncated Lmod2 was not detected in the LV of the proband’s explanted heart via Western blot analysis
    explanation: The W398Ter proband had undetectable protein in the explanted ventricle.
references:
- reference: PMID:31517052
  title: 'Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy.'
- reference: PMID:34888509
  title: Early Death of 2 Siblings Related to Mutations in LMOD2, a Recently Discovered Cause of Neonatal Dilated Cardiomyopathy.
- reference: PMID:35082396
  title: Neonatal-lethal dilated cardiomyopathy due to a homozygous LMOD2 donor splice-site variant.
- reference: PMID:35188328
  title: LMOD2-related dilated cardiomyopathy presenting in late infancy.
- reference: PMID:37296576
  title: Whole-Exome Sequencing Identifies Homozygote Nonsense Variants in LMOD2 Gene Causing Infantile Dilated Cardiomyopathy.
- reference: PMID:38748723
  title: Human disease-causing mutations result in loss of leiomodin 2 through nonsense-mediated mRNA decay.
- reference: PMID:39285234
  title: Leiomodin 2 neonatal dilated cardiomyopathy mutation results in altered actin gene signatures and cardiomyocyte dysfunction.
- reference: PMID:42477321
  title: Leiomodin 2 is a processive pointed-end elongator of actin filaments.
- reference: PMID:26487682
  title: Knockout of Lmod2 results in shorter thin filaments followed by dilated cardiomyopathy and juvenile lethality.
- reference: PMID:38666070
  title: Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies.
- reference: CGGV:assertion_d19140d6-8200-4fce-9906-fdda527a4f7e-2026-03-04T170000.000Z
  title: LMOD2 / cardiomyopathy, dilated, 2G (Definitive)
- reference: PMID:20301486
  title: Dilated Cardiomyopathy Overview.
  tags:
  - GeneReviews
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
  title: https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
  tags:
  - GeneReviews
- reference: url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
  title: https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
- reference: DOI:10.1016/j.healun.2025.06.003
  title: The International Society for Heart and Lung Transplantation Guidelines for the Management of Pediatric Heart Failure (Update From 2014)
notes: LMOD2-related CMD2G is distinct from LMOD1 visceral myopathy and LMOD3 nemaline myopathy. Clinical reports support predominantly cardiac disease; isolated intestinal malrotation, infections, treatment complications, and untested deceased relatives do not establish additional core manifestations. Human phenotype frequencies and survival probabilities cannot be inferred from the small published families. The GeneReviews DCM Overview supplies general diagnosis and family-evaluation guidance, while LMOD2-specific phenotypes and segregation are taken from primary reports. The NBK1309 PDF is the full text of Dilated Cardiomyopathy Overview (PMID:20301486). The ISHLT 2025 PDF is the full text of the pediatric heart-failure guideline identified by DOI:10.1016/j.healun.2025.06.003; its URL-based reference preserves the cached full-text quotations.
experimental_models:
- name: W398Ter patient-derived cardiomyocytes with isogenic controls
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Patient-derived iPSCs and CRISPR-corrected isogenic controls
  description: Cultured cardiomyocytes from the founding patient model shortened thin filaments, altered calcium transients, reduced contraction amplitude, and altered MRTFB localization. Re-expression of full-length Lmod2 improves selected readouts.
  publication: PMID:39285234
  modeled_mechanisms:
  - target: Dysregulated Thin-Filament Length
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: The patient allele shortens actin thin filaments relative to isogenic controls.
    limitations: One patient-derived genotype in immature cultured cells does not establish the magnitude of shortening across alleles or intact human myocardium.
    divergences:
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: One patient-derived genotype in immature cultured cells does not establish the magnitude of shortening across alleles or intact human myocardium.
    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 correlated to a ~5% decrease in actin-thin filament lengths in mutant hiPSC-CMs.
      explanation: Measured structural readout in cultured patient-derived cardiomyocytes.
  - target: Altered Cardiomyocyte Calcium Handling
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Calcium release and reuptake kinetics are altered in electrically paced cells.
    limitations: The cell system lacks whole-heart loading and neurohumoral context; the upstream calcium-regulatory lesion is unresolved.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: The cell system lacks whole-heart loading and neurohumoral context; the upstream calcium-regulatory lesion is unresolved.
    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: Overall, the faster calcium release and reuptake kinetics of LMOD2 W398* cardiomyocytes provide a potential explanation for the decreased contraction time observed in these cells.
      explanation: Calcium handling is altered in mutant cultured cardiomyocytes; the upstream molecular cause remains unresolved.
  - target: Reduced MRTFB Nuclear Localization
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Nuclear MRTFB localization is reduced.
    limitations: Localization in a single patient-derived genotype does not demonstrate a causal contribution to clinical heart failure.
    divergences:
    - divergence_type: POPULATION_MISMATCH
      materiality: QUALIFYING
      description: Localization in a single patient-derived genotype does not demonstrate a causal contribution to clinical heart failure.
    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: demonstrated significantly reduced MRTFB nuclear localization (~25%) in LMOD2 W398* hiPSC-CMs
      explanation: Immunocytochemistry supports altered localization of the SRF cofactor in patient-derived cells.
- name: W398Ter engineered heart tissue
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: Patient-derived and isogenic control iPSC cardiomyocytes
  culture_system: Three-dimensional constructs with PDMS force-sensing posts
  description: Engineered tissues quantify force under increasing pacing frequency, extending the monolayer observations to a multicellular contractile preparation.
  publication: PMID:39285234
  modeled_mechanisms:
  - target: Impaired Cardiomyocyte Contractility
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: The constructs generate less force and have shorter contraction times.
    limitations: Engineered tissue lacks mature whole-heart anatomy, circulation, and the full nonmyocyte environment.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: Engineered tissue lacks mature whole-heart anatomy, circulation, and the full nonmyocyte environment.
    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: Overall, EHT analysis demonstrated a decrease in force production and a decrease in contraction time, similar to our reported findings in monolayer hiPSC-CM cultures.
      explanation: Patient-derived engineered heart tissues show a contractile deficit.
- name: LMOD2 minigene and steric-blocking oligonucleotide assays
  experimental_model_type: CELL_LINE
  organism:
    preferred_term: Homo sapiens
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_source: AD-293 and FT-293 human embryonic kidney-derived cell lines
  description: Intron-containing constructs distinguish nonsense-mediated decay from protein instability. LMOD2-directed oligonucleotides reduce exon-junction-complex association and recover selected mutant transcripts/proteins.
  publication: PMID:38748723
  modeled_mechanisms:
  - target: Nonsense-Mediated LMOD2 Transcript Decay
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: The W398Ter and Arg513Ter constructs reproduce intron-dependent transcript loss.
    limitations: Engineered kidney-derived cell lines do not establish decay efficiency in cardiomyocytes or clinical severity.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: Engineered kidney-derived cell lines do not establish decay efficiency in cardiomyocytes or clinical severity.
    evidence:
    - reference: PMID:38748723
      reference_title: Human disease-causing mutations result in loss of leiomodin 2 through nonsense-mediated mRNA decay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The addition of W398* and R513* mutations result in a decrease of LMOD2 MG mature mRNA levels but have no effect on LMOD2 CDS mature mRNA levels, when compared to their respective WT constructs
      explanation: Intron-containing minigenes demonstrate transcript loss for these two nonsense alleles; the result is not generalized to every frameshift or splice variant.
  - target: Nonsense-Mediated LMOD2 Transcript Decay
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Steric blockade suppresses abnormal decay and restores mutant expression in the construct assay.
    limitations: This rescues an RNA/protein endpoint in engineered cells; it has not demonstrated patient cardiac recovery.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: This rescues an RNA/protein endpoint in engineered cells; it has not demonstrated patient cardiac recovery.
    evidence:
    - reference: PMID:38748723
      reference_title: Human disease-causing mutations result in loss of leiomodin 2 through nonsense-mediated mRNA decay.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Furthermore, we generated steric-blocking oligonucleotides that obstruct deposition of the exon junction complex, preventing nonsense-mediated mRNA decay of mutant LMOD2 transcripts, thereby restoring mutant protein expression.
      explanation: The rescue is at the transcript/protein-expression level.
- name: Purified LMOD2 single-filament elongation assay
  experimental_model_type: OTHER
  description: Single-molecule and single-filament microscopy compares full-length and truncated LMOD2 pointed-end elongation and processivity in a reconstituted actin system.
  publication: PMID:42477321
  modeled_mechanisms:
  - target: Dysregulated Thin-Filament Length
    relationship: PERTURBS
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: The disease-associated truncation reduces polymerization rate and processivity.
    limitations: Purified actin and LMOD2 lack sarcomeric load, RNA surveillance, and intact-cell regulation.
    divergences:
    - divergence_type: BOUNDARY_OMISSION
      materiality: QUALIFYING
      description: Purified actin and LMOD2 lack sarcomeric load, RNA surveillance, and intact-cell regulation.
    evidence:
    - reference: PMID:42477321
      reference_title: Leiomodin 2 is a processive pointed-end elongator of actin filaments.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Removal of the C-terminal WH2-containing region in this disease-associated variant results in a substantial reduction in elongation rate and processivity
      explanation: Single-filament experiments support impaired pointed-end polymerization for the W398Ter-related truncation.
animal_models:
- name: Constitutive Lmod2 knockout mouse
  species: Mouse
  genotype: Biallelic Lmod2 knockout
  publication: PMID:26487682
  description: Knockout mice develop shortened thin filaments, ventricular dilation, and juvenile lethality.
  modeled_mechanisms:
  - target: Dysregulated Thin-Filament Length
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Knockout reproduces abnormal filament shortening.
    limitations: A complete mouse knockout differs from human alleles that preserve truncated protein.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: A complete mouse knockout differs from human alleles that preserve truncated protein.
    evidence:
    - reference: PMID:26487682
      reference_title: Knockout of Lmod2 results in shorter thin filaments followed by dilated cardiomyopathy and juvenile lethality.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: We found that knockout of Lmod2 in mice results in abnormally short thin filaments in the heart.
      explanation: Loss of Lmod2 produces the structural lesion in vivo.
  - target: Ventricular Dilation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Ventricular enlargement accompanies contractile dysfunction.
    limitations: Mouse postnatal maturation and disease timing differ from those of human infants.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Mouse postnatal maturation and disease timing differ from those of human infants.
    evidence:
    - reference: PMID:26487682
      reference_title: Knockout of Lmod2 results in shorter thin filaments followed by dilated cardiomyopathy and juvenile lethality.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Lmod2-KO mice die as juveniles with hearts displaying contractile dysfunction and ventricular chamber enlargement consistent with dilated cardiomyopathy.
      explanation: In vivo remodeling phenotype.
- name: Lmod2 W405Ter knock-in mouse
  species: Mouse
  genotype: Homozygous Lmod2 p.Trp405Ter, homologous to human p.Trp398Ter
  publication: PMID:39285234
  description: Knock-in mice develop thin-filament shortening and DCM while retaining truncated protein and surviving substantially longer than knockout mice.
  modeled_mechanisms:
  - target: Dysregulated Thin-Filament Length
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: The homologous allele produces short thin filaments.
    limitations: The mouse retains substantially more truncated protein than the patient-derived cardiomyocytes and does not reproduce the severe neonatal time course.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: The mouse retains substantially more truncated protein than the patient-derived cardiomyocytes and does not reproduce the severe neonatal time course.
    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: MODEL_ORGANISM
      snippet: Thin filament lengths were reduced at both P21 (0.74 ± 0.02 μm vs 0.84 ± 0.02 μm) and P70 (0.78 ± 0.03 μm vs 0.86 ± 0.03 μm) in the LVs of Lmod2 W405* compared to wild-type mice, respectively
      explanation: The knock-in model reproduces shortening, with a less severe clinical course than neonatal human presentations.
  - target: Increased Monomeric Cardiac Actin
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Fractionation shows increased monomeric cardiac actin.
    limitations: The tissue observation is from mice; the corresponding pool has not been measured directly in affected human myocardium.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: The tissue observation is from mice; the corresponding pool has not been measured directly in affected human myocardium.
    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: MODEL_ORGANISM
      snippet: Our studies demonstrated that Lmod2 W405* mice and Lmod2-KO mice had significant increases in cardiac G-actin.
      explanation: Cardiac tissue fractionation supports the increased monomeric actin pool in these mouse models.
  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: MODEL_ORGANISM
    snippet: The Lmod2 W405* mice begin to die at ~6 months of age with a median survival of 186 days
    explanation: The model has a substantially different survival time course from severe neonatal human disease.
- name: AAV-Lmod2 rescue of knockout mice
  species: Mouse
  genotype: Lmod2 knockout treated with AAV expressing GFP-Lmod2
  publication: PMID:26487682
  description: Postnatal delivery of full-length Lmod2 rescues filament length and cardiac function in the knockout setting.
  modeled_mechanisms:
  - target: Dysregulated Thin-Filament Length
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Replacement elongates abnormally short thin filaments.
    limitations: Early postnatal murine gene delivery does not establish safe or effective treatment of critically ill human infants.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Early postnatal murine gene delivery does not establish safe or effective treatment of critically ill human infants.
    evidence:
    - reference: PMID:26487682
      reference_title: Knockout of Lmod2 results in shorter thin filaments followed by dilated cardiomyopathy and juvenile lethality.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Introduction of GFP-Lmod2 via adeno-associated viral transduction elongates thin filaments and rescues structural and functional defects observed in Lmod2-KO mice, extending their lifespan to adulthood.
      explanation: Full-length replacement rescues the knockout phenotype in mice.
  - target: Ventricular Dilation
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: TISSUE
    description: Replacement rescues structural ventricular defects.
    limitations: Preventive treatment in a mouse knockout does not prove reversal of established human cardiac remodeling.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: Preventive treatment in a mouse knockout does not prove reversal of established human cardiac remodeling.
    evidence:
    - reference: PMID:26487682
      reference_title: Knockout of Lmod2 results in shorter thin filaments followed by dilated cardiomyopathy and juvenile lethality.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Introduction of GFP-Lmod2 via adeno-associated viral transduction elongates thin filaments and rescues structural and functional defects observed in Lmod2-KO mice, extending their lifespan to adulthood.
      explanation: Full-length replacement rescues the knockout phenotype in mice.
histopathology:
- name: Myofibrillar disarray and Z-disc abnormalities
  description: Patient myocardium can show disorganized myofibrils and widened or streamed Z-discs. Findings differ between cases and do not establish a generalized skeletal myopathy.
  evidence:
  - reference: PMID:31517052
    reference_title: 'Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Deconvolution immunofluorescence microscopy of LV cryosections from the patient’s heart revealed myofibrillar disarray and wide Z-discs
    explanation: Human myocardial ultrastructure supports sarcomeric architectural disturbance.
- name: Myocardial fibrosis
  description: Interstitial and subendocardial fibrosis occur in some severely affected hearts; the later-infantile frameshift case had only mild interstitial fibrosis and no significant endocardial fibrosis or myocardial disarray.
  evidence:
  - reference: PMID:31517052
    reference_title: 'Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Marked fibrosis (blue) is present throughout the subendocardium of both ventricles with patchy interstitial nonreplacement-type perimyocyte fibrosis
    explanation: Histological evidence from the founding patient.
  - reference: PMID:35188328
    reference_title: LMOD2-related dilated cardiomyopathy presenting in late infancy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Microscopic examination with H&E staining of both ventricles showed moderately hypertrophied myocytes with focal areas of mild interstitial fibrosis but no significant endocardial fibrosis or myocardial disarray.
    explanation: The later-infantile case establishes histological variability.
📚

References & Deep Research

References

15
PMID:31517052
Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy.
No top-level findings curated for this source.
PMID:34888509
Early Death of 2 Siblings Related to Mutations in LMOD2, a Recently Discovered Cause of Neonatal Dilated Cardiomyopathy.
No top-level findings curated for this source.
PMID:35082396
Neonatal-lethal dilated cardiomyopathy due to a homozygous LMOD2 donor splice-site variant.
No top-level findings curated for this source.
PMID:35188328
LMOD2-related dilated cardiomyopathy presenting in late infancy.
No top-level findings curated for this source.
PMID:37296576
Whole-Exome Sequencing Identifies Homozygote Nonsense Variants in LMOD2 Gene Causing Infantile Dilated Cardiomyopathy.
No top-level findings curated for this source.
PMID:38748723
Human disease-causing mutations result in loss of leiomodin 2 through nonsense-mediated mRNA decay.
No top-level findings curated for this source.
PMID:39285234
Leiomodin 2 neonatal dilated cardiomyopathy mutation results in altered actin gene signatures and cardiomyocyte dysfunction.
No top-level findings curated for this source.
PMID:42477321
Leiomodin 2 is a processive pointed-end elongator of actin filaments.
No top-level findings curated for this source.
PMID:26487682
Knockout of Lmod2 results in shorter thin filaments followed by dilated cardiomyopathy and juvenile lethality.
No top-level findings curated for this source.
PMID:38666070
Exploring the complex spectrum of dominance and recessiveness in genetic cardiomyopathies.
No top-level findings curated for this source.
CGGV:assertion_d19140d6-8200-4fce-9906-fdda527a4f7e-2026-03-04T170000.000Z
LMOD2 / cardiomyopathy, dilated, 2G (Definitive)
No top-level findings curated for this source.
PMID:20301486
Dilated Cardiomyopathy Overview.
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
https://www.ncbi.nlm.nih.gov/sites/books/NBK1309/pdf/Bookshelf_NBK1309.pdf
No top-level findings curated for this source.
url:https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
https://www.ishlt.org/docs/default-source/standards-guidelines/2025_guideline_ishlt_pedshfmanagement.pdf
No top-level findings curated for this source.
DOI:10.1016/j.healun.2025.06.003
The International Society for Heart and Lung Transplantation Guidelines for the Management of Pediatric Heart Failure (Update From 2014)
No top-level findings curated for this source.