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Classifications

Harrison's Chapter

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Inheritance

2

Autosomal Dominant HP:0000006

Most reported ACTN2 cardiomyopathy families show autosomal dominant transmission of a heterozygous missense or truncating variant, with incomplete penetrance and marked intrafamilial variability in the resulting cardiac phenotype.

Autosomal dominant inheritance

Show evidence (1 reference)

CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z SUPPORT Other

ClinGen Hereditary Cardiovascular Disease GCEP records autosomal dominant inheritance for the ACTN2 gene-disease relationship, with Definitive clinical validity.

Autosomal Recessive (Biallelic Truncating) HP:0000007

Rare biallelic ACTN2 protein-truncating genotypes cause cardiomyopathy through a mechanism distinct from the heterozygous state; a homozygous stop-gain variant was functionally validated by CRISPR-Cas9 editing in patient-derived iPSC-cardiomyocytes.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:34802252 SUPPORT In Vitro

"Together, these data advance our understanding of the role of ACTN2 in the human heart and establish recessive inheritance of ACTN2 truncation as causative of disease."

Directly establishes a recessive (biallelic truncating) mode of inheritance for ACTN2 cardiomyopathy alongside the dominant form. Classified IN_VITRO because causality was demonstrated in patient-derived iPSC-cardiomyocytes with CRISPR-Cas9 validation.

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Mechanistic Hypotheses

2

Z-disc force-transmission and myofilament-regulation model

actn2_zdisc_force_transmission_model CANONICAL

Evidence balance 1 support

The canonical model holds that ACTN2 variants degrade the mechanical and regulatory function of the Z-disc: cross-linking of antiparallel actin filaments and anchoring of Z-disc titin are perturbed, altering both thin-filament calcium sensitivity and thick-filament activation, so force generation and relaxation become abnormal and the myocardium remodels.

Pathograph links

Alpha-Actinin-2 Z-Disc Dysfunction -> Impaired Z-Disc Force Transmission and Myofilament Regulation DIRECT

Impaired Z-Disc Force Transmission and Myofilament Regulation -> Sarcomeric Disarray and Cardiomyocyte Hypertrophy DIRECT

Show evidence (1 reference)

PMID:37834023 SUPPORT In Vitro

"Our results can be explained by two Z-disc mediated communication pathways"

The study of explanted human myocardium carrying an ACTN2 variant states the two-pathway (actin/thin-filament and titin/thick-filament) Z-disc communication model that underlies this hypothesis group. The quote stops before the clause naming the two pathways because the source text spells them with a Greek alpha; the quantitative findings are quoted on the corresponding pathophysiology node.

Variant-specific alpha-actinin-2 destabilization and proteostatic stress

actn2_variant_specific_proteotoxicity EMERGING

Evidence balance 1 support 1 partial

An additional, variant-specific arm proposes that some mutant alpha-actinin-2 proteins are destabilized, misfold, and aggregate, triggering ubiquitin-proteasome and autophagy-lysosome activation and depleting sarcomere-associated proteins — a proteopathy superimposed on the mechanical defect. Human isogenic hiPSC-cardiomyocytes and an Actn2 knock-in mouse both show proteasomal activation, but whether this arm operates in the dilated (as opposed to hypertrophic or myopathic) presentations, and in patient myocardium rather than engineered tissue, is unresolved; ClinGen notes that the ACTN2 disease mechanism remains unclear and may be variant-specific.

Pathograph links

Alpha-Actinin-2 Z-Disc Dysfunction -> Mutant Alpha-Actinin-2 Destabilization and Proteostatic Stress DIRECT Variant-specific arm: only some mutant alpha-actinin-2 proteins are destabilized and aggregate.

Mutant Alpha-Actinin-2 Destabilization and Proteostatic Stress -> Sarcomeric Disarray and Cardiomyocyte Hypertrophy DIRECT

Show evidence (2 references)

PMID:36078153 SUPPORT In Vitro

"our study highlights the activation of proteolytic systems in ACTN2mut hiPSC-CMs likely to cope with ACTN2 aggregation and therefore directs towards proteopathy as an additional cellular pathology caused by this ACTN2 variant"

Provides the primary in vitro basis for the proteotoxicity arm, and its authors frame it as an additional (not established) cellular mechanism.

CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z PARTIAL Other

"The disease mechanism is currently unclear and may be variant-specific since some variants have been shown to result in protein aggregation while others do not have this effect"

ClinGen explicitly records that aggregation is variant-specific and that the overall mechanism is unresolved, which is why this hypothesis group is EMERGING rather than canonical.

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Discussions and Knowledge Gaps

3

Should dismech keep phenotype-specific ACTN2 entities (CMD1AA, CMH23, restrictive and arrhythmogenic forms, ACTN2 myopathy) as separate entries, or follow ClinGen in lumping them into a single ACTN2-related cardiac and skeletal myopathy entity?

INTERPRETATION OPEN actn2_lumping_vs_mondo_splitting

Attached to

pathophysiology#Alpha-Actinin-2 Z-Disc Dysfunction

ClinGen's Hereditary Cardiovascular Disease GCEP explicitly applied the Lumping and Splitting framework and concluded there is insufficient evidence to split ACTN2 presentations by inheritance, phenotype, or mechanism, whereas MONDO retains the phenotype-specific nodes that dismech uses as disease_term. This entry is scoped to the dilated node (MONDO:0012808) and records the hypertrophic and noncompaction expressions as spectrum context; if the field converges on the lumped entity, the dismech representation should be revisited rather than duplicated across sibling entries.

Show evidence (2 references)

CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z SUPPORT Other

"Per criteria outlined by the ClinGen Lumping and Splitting Working Group, all disease entities have been lumped into one inclusive disease entity, which is now being called ACTN2-related cardiac and skeletal myopathy."

Documents the lumping decision that is in tension with the MONDO phenotype-specific nodes.

PMID:36116040 SUPPORT Other

"Previously reported variants are in varying locations across the gene, but the potential clustering effect of pathogenic locations is not clearly understood."

Absence of a domain-to-phenotype mapping is part of why the phenotype split is hard to defend on mechanistic grounds.

Which molecular mechanism — dominant-negative incorporation of mutant alpha-actinin-2 into the Z-disc, altered myofilament calcium sensitivity, protein destabilization with proteostatic stress, or loss of sarcolemmal ACTN1/GJA1 coupling — actually drives the dilated (as opposed to hypertrophic or arrhythmic) presentation, and what determines which phenotype a given carrier develops?

KNOWLEDGE GAP OPEN actn2_dcm_mechanism_gap

Attached to

pathophysiology#Impaired Z-Disc Force Transmission and Myofilament Regulation pathophysiology#Mutant Alpha-Actinin-2 Destabilization and Proteostatic Stress

The same ACTN2 variant can produce dilation in one relative and hypertrophy, noncompaction, arrhythmia, or nothing in another, and the available mechanistic studies each characterize a different single variant in a different system (explanted myocardium, patient iPSC-cardiomyocytes, isogenic hiPSC lines, knock-in mouse, purified protein). Without a variant-to-mechanism map the pathograph cannot state which arm is rate-limiting for the dilated phenotype, and variant interpretation stays unanchored to mechanism.

Proposed experiments

Allelic-panel isogenic hiPSC-cardiomyocyte comparison of ACTN2 variants

exp_actn2_allelic_panel_isogenic_hipsc_cm

Systematically phenotype an allelic panel of dilated-, hypertrophic-, and noncompaction-associated ACTN2 variants in isogenic hiPSC-cardiomyocytes and engineered heart tissue with matched readouts (Z-disc incorporation, protein stability and aggregation, myofilament calcium sensitivity, connexin-43 localization, force), so that phenotype-specific mechanisms can be compared directly rather than inferred across heterogeneous studies.

Show evidence (2 references)

CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z SUPPORT Other

"The disease mechanism is currently unclear and may be variant-specific since some variants have been shown to result in protein aggregation while others do not have this effect"

ClinGen states the mechanism gap directly, including its variant-specific character.

PMID:34802252 SUPPORT Other

"The mechanisms linking ACTN2 mutations to myocardial disease phenotypes are unknown."

Independent statement of the same gap from the study that separated the monoallelic and biallelic mechanisms.

Why does a heterozygous Actn2 missense knock-in mouse remain phenotypically normal while heterozygous human carriers of comparable ACTN2 missense variants develop cardiomyopathy, and can such mice be used to model dominant ACTN2 disease at all?

HUMAN MODEL MISMATCH OPEN actn2_mouse_heterozygote_model_mismatch

Attached to

pathophysiology#Mutant Alpha-Actinin-2 Destabilization and Proteostatic Stress pathophysiology#Sarcomeric Disarray and Cardiomyocyte Hypertrophy

The only published Actn2 missense knock-in mouse shows no overt cardiac phenotype in heterozygotes (only molecular changes, and only in mature males), while homozygosity is embryonically lethal — a dosage profile that does not reproduce autosomal dominant human ACTN2 cardiomyopathy. Mechanistic inferences drawn from that model (proteasomal activation, mitochondrial and cell-cycle defects) therefore rest on either subclinical heterozygote molecular readouts or a lethal homozygous state with no human counterpart, and their translational weight for the human dilated phenotype is uncertain.

Proposed experiments

Stress- and age-challenged Actn2 heterozygote phenotyping with human comparison

exp_actn2_mouse_stress_and_aging_challenge

Phenotype Actn2 missense heterozygous mice under hemodynamic, exercise, and aging challenge with sex stratification, and compare the resulting molecular signatures against human ACTN2-variant myocardium and hiPSC-cardiomyocytes, to determine whether the silent heterozygote reflects a genuine species difference or an unstressed baseline.

Show evidence (2 references)

PMID:36899856 SUPPORT Model Organism

"Heterozygous Actn2 p.Met228Thr mice have no overt phenotype. Only mature males show molecular parameters indicative of cardiomyopathy."

Documents the absent heterozygous phenotype that constitutes the human-model mismatch.

PMID:36899856 SUPPORT Model Organism

"By contrast, the variant is embryonically lethal in the homozygous setting and E15.5 hearts show multiple morphological abnormalities."

The homozygous state is embryonically lethal, so the mechanistic readouts come from a genotype without a human dominant-disease counterpart.

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Pathophysiology

10

Alpha-Actinin-2 Z-Disc Dysfunction

ACTN2 encodes alpha-actinin-2, the only alpha-actinin isoform expressed in cardiac muscle. As an antiparallel homodimer it cross-links thin filaments from adjacent sarcomeres at the Z-disc, anchors the N-terminal (Z-disc) region of titin, and provides a docking platform for Z-disc partners including muscle LIM protein (MLP/CSRP3). Disease-associated variants are distributed across the actin-binding calponin-homology domains, the spectrin-repeat rod, and the C-terminal EF-hand/calmodulin-like region; they perturb actin binding, titin interaction, Z-disc incorporation, protein stability, or partner binding rather than abolishing the protein, and haploinsufficiency is not an established mechanism.

Variant-specific alpha-actinin-2 destabilization and proteostatic stress Z-disc force-transmission and myofilament-regulation model

Cardiomyocyte CL:0000746

ACTN2 hgnc:164

Sarcomere organization GO:0045214 ⚠ ABNORMAL

actin filament binding GO:0051015 ⚠ ABNORMAL structural constituent of muscle GO:0008307 ⚠ ABNORMAL

Myocardium UBERON:0002349

Downstream

Impaired Z-Disc Force Transmission and Myofilament Regulation

Mutant Alpha-Actinin-2 Destabilization and Proteostatic Stress Variant-specific arm: only some mutant alpha-actinin-2 proteins are destabilized and aggregate.

Loss of Sarcolemmal Partner Coupling and Arrhythmogenesis

Failed Trabecular Compaction ACTN2 truncating variants are among the few lesions specifically associated with a noncompaction phenotype, but the developmental path from Z-disc dysfunction to failed trabecular compaction is not established.

Show evidence (5 references)

PMID:36116040 SUPPORT Other

"ACTN2 encodes alpha-actinin-2, a protein expressed in human cardiac and skeletal muscle. The protein, located in the sarcomere Z-disk, functions as a link between the anti-parallel actin filaments. This important structural protein also binds N-terminal titins, and thus contributes to sarcomere..."

Establishes the normal Z-disc function of alpha-actinin-2 (actin cross-linking and titin anchoring) whose perturbation is the primary lesion of this disorder. Evidence source is OTHER because this is a mutation-update review.

PMID:34802252 SUPPORT Other

"ACTN2 (alpha-actinin 2) anchors actin within cardiac sarcomeres. The mechanisms linking ACTN2 mutations to myocardial disease phenotypes are unknown."

Confirms the actin-anchoring role of ACTN2 in cardiac sarcomeres and that the genotype-to-phenotype mechanism was still open when this study was designed. Evidence source is OTHER because the quote is the paper's background framing rather than its experimental result.

PMID:14567970 SUPPORT Human Clinical

"In another patient with DCM, a Q9R mutation was identified in alpha-actinin-2."

The founding CMD1AA observation: an ACTN2 missense variant identified in a patient with dilated cardiomyopathy.

+ 2 more references

Impaired Z-Disc Force Transmission and Myofilament Regulation

Because the Z-disc both transmits force between sarcomeres and relays regulatory information to the thin and thick filaments, an abnormal alpha-actinin-2 degrades contraction and relaxation simultaneously. Explanted myocardium carrying an ACTN2 EF-hand variant shows increased myofilament calcium sensitivity, reduced sinusoidal stiffness, faster tension redevelopment, and increased thick-to-thin filament separation, while patient-derived iPSC-cardiomyocytes show impaired contractility and aberrant calcium handling. Truncated alpha-actinin-2 that is still incorporated into the sarcomere distorts Z-disc ultrastructure, a dominant-negative pattern.

Z-disc force-transmission and myofilament-regulation model

Cardiomyocyte CL:0000746

Muscle contraction GO:0006936 ⚠ ABNORMAL Intracellular calcium ion homeostasis GO:0006874 ⚠ ABNORMAL

Experimental models

Patient-derived ACTN2 truncating-variant iPSC-cardiomyocytes IPSC DERIVED MODEL Contractility and electron-microscopy readouts measure Z-disc ultrastructure and force generation in the variant background.

Downstream

Sarcomeric Disarray and Cardiomyocyte Hypertrophy

Show evidence (4 references)

PMID:37834023 SUPPORT In Vitro

"However, contractile mechanics of permeabilized ACTN2 A868T variant cardiac tissue displayed higher myofilament Ca2+ sensitivity of isometric force, reduced sinusoidal stiffness, and faster rates of tension redevelopment at all Ca2+ levels."

Direct mechanical measurement in human myocardium carrying an ACTN2 variant demonstrates altered myofilament calcium sensitivity and passive stiffness. Evidence source is IN_VITRO because the measurements were made on permeabilized explanted tissue.

PMID:37834023 SUPPORT In Vitro

"Small-angle X-ray diffraction indicated increased separation between thick and thin filaments, possibly contributing to changes in muscle kinetics."

Structural correlate of the mechanical defect: Z-disc dysfunction translates into altered interfilament spacing within the sarcomere.

PMID:34802252 SUPPORT In Vitro

"In heterozygous indel cells, the truncated protein incorporates into cardiac sarcomeres, leading to aberrant Z-disc ultrastructure."

Shows that a truncated ACTN2 product is incorporated into the sarcomere and distorts Z-disc ultrastructure, the dominant-negative version of this node.

+ 1 more reference

Mutant Alpha-Actinin-2 Destabilization and Proteostatic Stress

For a subset of variants, mutant alpha-actinin-2 is destabilized, misfolds, and aggregates within the cardiomyocyte. In isogenic hiPSC-cardiomyocyte models the mutant allele produces protein aggregation, multinucleation, hypertrophy, and myofibrillar disarray with activation of both the ubiquitin-proteasome system and the autophagy-lysosome pathway, loss of sarcomere-associated proteins, and reduced force in engineered heart tissue; an Actn2 missense knock-in mouse independently shows a destabilized protein with increased ubiquitin-proteasome activity. This proteopathy arm is variant-specific and has not been demonstrated in patient myocardium.

Variant-specific alpha-actinin-2 destabilization and proteostatic stress

Cardiomyocyte CL:0000746

Inclusion body assembly GO:0070841 ↑ INCREASED Proteasome-mediated ubiquitin-dependent protein catabolic process GO:0043161 ↑ INCREASED Autophagy GO:0006914 ↑ INCREASED

Experimental models

Isogenic ACTN2 missense hiPSC-cardiomyocytes and engineered heart tissue IPSC DERIVED MODEL The isogenic pair isolates variant-specific protein aggregation and proteolytic-system activation from genetic background effects.

Downstream

Sarcomeric Disarray and Cardiomyocyte Hypertrophy

Show evidence (3 references)

PMID:36078153 SUPPORT In Vitro

"This study showed that ACTN2mut presents a higher percentage of multinucleation, protein aggregation, hypertrophy, myofibrillar disarray, and activation of both the ubiquitin-proteasome system and the autophagy-lysosomal pathway as compared to ACTN2wt in 2D-cultured hiPSC-CMs."

Primary experimental basis for the aggregation/proteostatic-stress node in an isogenic human cardiomyocyte model.

PMID:36078153 SUPPORT In Vitro

"Furthermore, the expression of ACTN2mut was associated with a marked reduction of sarcomere-associated protein levels in 2D-cultured hiPSC-CMs and force impairment in engineered heart tissues."

Links the proteotoxic arm to loss of sarcomeric proteins and measurable contractile impairment, connecting it to the shared remodeling pathway.

PMID:36899856 SUPPORT Model Organism

"The mutant alpha-actinin protein is found to be destabilised, associated with increased activity of the ubiquitin-proteasomal system."

An Actn2 p.Met228Thr knock-in mouse provides in vivo support for protein destabilization with proteasomal activation. The variant modeled is hypertrophic-cardiomyopathy-associated, so this corroborates the mechanism rather than the dilated phenotype.

Loss of Sarcolemmal Partner Coupling and Arrhythmogenesis

Beyond the sarcomere, the C-terminus of alpha-actinin-2 interacts with sarcolemma-associated proteins including alpha-actinin-1 (ACTN1) and connexin-43 (GJA1). C-terminal truncation disrupts these interactions, providing a mechanistic route from a Z-disc protein defect to impaired electrical coupling, arrhythmia, and abnormal relaxation. Clinically, ACTN2 carriers show atrial and ventricular arrhythmias, conduction abnormalities, and idiopathic ventricular fibrillation, which can precede or occur without overt ventricular dilation.

Cardiomyocyte CL:0000746

Cell communication by electrical coupling involved in cardiac conduction GO:0086064 ⚠ ABNORMAL

Experimental models

Patient-derived ACTN2 truncating-variant iPSC-cardiomyocytes IPSC DERIVED MODEL Affinity-purification mass spectrometry identified the loss of ACTN1 and GJA1 interactions on C-terminal truncation.

Downstream

Ventricular Arrhythmia

Sudden Cardiac Death

Show evidence (2 references)

PMID:34802252 SUPPORT In Vitro

"Loss of the C-terminus of ACTN2 disrupts interaction with ACTN1 (alpha-actinin 1) and GJA1 (gap junction protein alpha 1), 2 sarcolemma-associated proteins, which may contribute to the clinical arrhythmic and relaxation defects."

Supplies the molecular link between ACTN2 truncation and the arrhythmic and relaxation phenotype via loss of connexin-43 and ACTN1 coupling. The authors frame the clinical contribution as a possibility ("may contribute"), so this node is modeled as a mechanistic amplifier rather than a proven clinical driver.

CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z SUPPORT Other

"A study found that patients with ACTN2 presented with varying degrees and types of arrhythmias, including left bundle branch block, atypical flutter, paroxysmal atrial fibrillation or supraventricular tachycardia, as well as atrial, ventricular, or supraventricular premature beats"

Documents the clinical arrhythmia burden in ACTN2 variant carriers that this node accounts for.

Sarcomeric Disarray and Cardiomyocyte Hypertrophy

The converging consequence of impaired Z-disc mechanics and (for some variants) mutant protein destabilization is disorganized myofibrillar architecture with hypertrophic growth of the cardiomyocyte. Patient-derived iPSC-cardiomyocytes carrying ACTN2 truncating variants are hypertrophic and show sarcomeric structural disarray, impaired contractility, and aberrant calcium signaling.

Cardiomyocyte CL:0000746

Myofibril assembly GO:0030239 ⚠ ABNORMAL Cardiac muscle hypertrophy GO:0003300 ↑ INCREASED

Experimental models

Patient-derived ACTN2 truncating-variant iPSC-cardiomyocytes IPSC DERIVED MODEL Immunohistochemistry quantifies cellular hypertrophy and myofibrillar disarray.

Downstream

Neurohormonal Activation

Adverse Ventricular Remodeling

Show evidence (1 reference)

PMID:34802252 SUPPORT In Vitro

"Patient-derived iPSC-cardiomyocytes were hypertrophic, displayed sarcomeric structural disarray, impaired contractility, and aberrant Ca2+-signaling."

Directly documents the cellular phenotype of this node in human cardiomyocytes derived from ACTN2 variant carriers.

Neurohormonal Activation

As in other cardiomyopathies, the fall in contractile performance activates the renin-angiotensin-aldosterone and sympathetic systems. Initially compensatory, chronic activation drives cardiomyocyte hypertrophy, apoptosis, and fibrosis, converting the primary Z-disc lesion into progressive structural remodeling; this axis is what standard heart-failure pharmacotherapy targets in ACTN2 disease as in DCM generally.

Response to angiotensin GO:1990776 ↑ INCREASED

Downstream

Adverse Ventricular Remodeling

Show evidence (1 reference)

PMID:25445411 SUPPORT Other

"The systemic as well as the tissue RAAS are also dedicated to promote tissue remodeling, particularly relevant after damage, when chronic activation may configure as a maladaptive response, leading to fibrosis, hypertrophy and apoptosis, and organ dysfunction."

Shared module evidence that chronic renin-angiotensin-aldosterone activation is the maladaptive amplifier between a cardiomyocyte insult and structural remodeling. Evidence source is OTHER because this is a review.

Adverse Ventricular Remodeling

Cardiomyocyte hypertrophy and loss, cardiac fibroblast activation, and interstitial matrix deposition remodel the ventricle. In ACTN2 disease the net geometry is variable — the same gene, and sometimes the same variant, can yield a dilated, hypertrophic, restrictive, or noncompacted ventricle, and the dominant pattern can differ between relatives — but the remodeling machinery itself is the conserved cardiomyopathy step.

Cardiac fibroblast CL:0002548 Cardiomyocyte CL:0000746

Extracellular matrix organization GO:0030198 ↑ INCREASED Cardiac muscle cell apoptotic process GO:0010659 ↑ INCREASED

Heart left ventricle UBERON:0002084

Downstream

Left Ventricular Dilation and Systolic Dysfunction

Show evidence (2 references)

CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z SUPPORT Other

"Cardiac phenotypes are associated with both gain and loss of function ACTN2 variants and do not always fit well into classical cardiomyopathy diagnosis."

Supports modeling remodeling geometry as variable in ACTN2 disease rather than fixed to the dilated pattern.

PMID:22752727 SUPPORT Other

"The pathophysiological basis of heart failure is cardiac remodeling, a process that comprises structural and functional changes including cardiomyocyte proliferation, hypertrophy, necrosis, apoptosis, autophagy, interstitial fibrosis, contractile dysfunction and ventricular dilatation."

Shared module evidence enumerating the components of adverse remodeling that this node represents. Evidence source is OTHER because this is a mechanistic review.

Failed Trabecular Compaction

A subset of ACTN2 carriers show left ventricular noncompaction — prominent trabeculae with deep intertrabecular recesses over a thin compacted layer — either isolated or together with ventricular dilation, which is why the OMIM entity is designated "with or without LVNC". In a large rare-variant association analysis, ACTN2 truncating variants were among the few lesions associated specifically with noncompaction rather than shared with DCM/HCM, suggesting a partly distinct developmental route, plausibly through impaired cardiomyocyte maturation.

Heart left ventricle UBERON:0002084

Downstream

Left Ventricular Dilation and Systolic Dysfunction

Show evidence (3 references)

PMID:33500567 SUPPORT Human Clinical

"In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC etiology."

Case-control rare-variant evidence that ACTN2 truncating variants are specifically associated with a noncompaction phenotype.

PMID:25224718 SUPPORT Human Clinical

"While some individuals were asymptomatic, other presentations included left ventricular non-compaction, a resuscitated cardiac arrest due to idiopathic ventricular fibrillation, dilated cardiomyopathy, and sudden unexplained death."

Family segregation study showing noncompaction and dilated cardiomyopathy co-occurring within one ACTN2 kindred.

PMID:37374362 PARTIAL Human Clinical

"This report presents a rare case of DCM with myocardial non-compaction, probably resulting from allelic collapse of both the ACTN2 and RYR2 genes."

Pediatric case of dilated cardiomyopathy with noncompaction attributed to a 1q43 deletion, framed by the authors as impaired cardiomyocyte maturation. Support is PARTIAL because the deletion removes RYR2 as well as ACTN2, so the ACTN2 contribution cannot be isolated.

Left Ventricular Dilation and Systolic Dysfunction

The remodeled ventricle dilates and loses systolic shortening, producing the defining CMD1AA phenotype: left ventricular enlargement with reduced ejection fraction in the absence of loading conditions or coronary disease sufficient to explain it. Penetrance is incomplete and expression is heterogeneous, so affected relatives may be asymptomatic, dilated, hypertrophic, or arrhythmic; population data on DCM-gene carriers show that arrhythmia without substantial ventricular dilation is a common early expression.

Cardiomyocyte CL:0000746

Heart contraction GO:0060047 ↓ DECREASED

Heart left ventricle UBERON:0002084

Downstream

Heart Failure and Sudden Cardiac Death

Dilated Cardiomyopathy

Show evidence (3 references)

PMID:25224718 SUPPORT Human Clinical

"Mutations in the ACTN2 gene can be responsible for marked cardiac phenotype heterogeneity in families. The diverse mechanistic roles of ACTN2 in the cardiac Z-disc may explain this heterogeneous clinical presentation."

Supports both the dilated endpoint and the marked intrafamilial heterogeneity of expression in ACTN2 disease.

PMID:14567970 SUPPORT In Vitro

"This mutation also disrupted the interaction with MLP and appeared to inhibit alpha-actinin function in cultured cells, in respect to the nuclear localization of actinin and the initiation of cellular differentiation."

Functional characterization of the original DCM-associated ACTN2 Q9R variant, linking it to loss of the alpha-actinin-2/MLP interaction. Evidence source is IN_VITRO because the assays were done in cultured cells.

PMID:35708014 PARTIAL Human Clinical

"most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction"

UK Biobank data on carriers of putative pathogenic variants in 44 DCM genes (ACTN2 among them) show low penetrance of frank dilation and arrhythmia as the commonest early expression. Support is PARTIAL because the analysis is gene-panel-wide rather than ACTN2-specific.

Heart Failure and Sudden Cardiac Death

The clinical endpoint is structural and functional cardiac impairment: symptomatic heart failure that may progress to end-stage disease requiring transplantation, and — because the arrhythmic arm can act independently of pump failure — syncope, ventricular fibrillation, and sudden cardiac death, sometimes as the presenting event in an otherwise well relative.

Heart contraction GO:0060047 ⚠ ABNORMAL

Show evidence (2 references)

PMID:20022194 SUPPORT Human Clinical

"Affected family members showed marked clinical diversity, ranging from asymptomatic individuals to those with syncope, heart failure, and premature sudden death."

Documents the clinical endpoints (heart failure, syncope, premature sudden death) in an ACTN2 kindred. The index family was hypertrophic, so this supports the endpoint spectrum of ACTN2 disease rather than the dilated phenotype specifically.

PMID:31073128 SUPPORT Other

"As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM."

Shared module evidence that the dilated cardiomyopathy process culminates in impaired contractility managed as heart failure. Evidence source is OTHER because this is a review.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

9

Cardiovascular 6

Dilated Cardiomyopathy Dilated cardiomyopathy HP:0001644

Show evidence (2 references)

PMID:14567970 SUPPORT Human Clinical

"In another patient with DCM, a Q9R mutation was identified in alpha-actinin-2."

Original report of dilated cardiomyopathy in a patient with an ACTN2 variant.

CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z SUPPORT Other

"dilated cardiomyopathy in 2010 (Zimmerman et al, 2010, PMID 20474083)"

ClinGen's curated evidence summary lists dilated cardiomyopathy among the established ACTN2-associated cardiac phenotypes.

Ventricular Arrhythmia Ventricular arrhythmia HP:0004308

Show evidence (2 references)

PMID:25224718 SUPPORT Human Clinical

"a resuscitated cardiac arrest due to idiopathic ventricular fibrillation"

Documents a life-threatening ventricular arrhythmia in an ACTN2 variant carrier.

CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z SUPPORT Other

"as well as atrial, ventricular, or supraventricular premature beats"

ClinGen's evidence summary records ventricular ectopy among the arrhythmia types seen in ACTN2 patients.

Atrial Fibrillation Atrial fibrillation HP:0005110

Temporal: RECURRENT

Show evidence (1 reference)

CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z SUPPORT Other

"patients with ACTN2 presented with varying degrees and types of arrhythmias, including left bundle branch block, atypical flutter, paroxysmal atrial fibrillation or supraventricular tachycardia"

ClinGen's curated summary of the arrhythmia spectrum in ACTN2 variant carriers.

Sudden Cardiac Death Sudden cardiac death HP:0001645

Show evidence (2 references)

PMID:25224718 SUPPORT Human Clinical

"dilated cardiomyopathy, and sudden unexplained death"

Sudden unexplained death occurred among the phenotypes segregating with ACTN2 Ala119Thr.

PMID:20022194 SUPPORT Human Clinical

"those with syncope, heart failure, and premature sudden death"

Premature sudden death reported in an ACTN2-linked cardiomyopathy family.

Congestive Heart Failure Congestive heart failure HP:0001635

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:20022194 SUPPORT Human Clinical

"ranging from asymptomatic individuals to those with syncope, heart failure, and premature sudden death"

Heart failure documented among clinical outcomes in an ACTN2 cardiomyopathy family.

Hypertrophic Cardiomyopathy Hypertrophic cardiomyopathy HP:0001639

Curated as spectrum context. The ACTN2 hypertrophic presentation has its own MONDO representation; dismech records it here only to keep the intrafamilial heterogeneity of CMD1AA visible.

Show evidence (2 references)

PMID:20022194 SUPPORT Human Clinical

"This is the first genome-wide linkage analysis that shows mutations in ACTN2 cause HCM."

Establishes the hypertrophic arm of the ACTN2 allelic series.

CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z SUPPORT Other

"Individuals can show variable combinations of hypertrophy, dilatation, hyper/hypo contractility, and arrhythmias"

ClinGen records that hypertrophic and dilated features can combine within the same ACTN2 phenotype, including within one family.

Other 3

Left Ventricular Noncompaction Left ventricular noncompaction HP:0030682

Show evidence (2 references)

PMID:33500567 SUPPORT Human Clinical

"In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC etiology."

Rare-variant association analysis of 840 LVNC cases supports a specific ACTN2-noncompaction association.

PMID:25224718 SUPPORT Human Clinical

"other presentations included left ventricular non-compaction"

Noncompaction observed among the phenotypes segregating with ACTN2 Ala119Thr in a single family.

Restrictive Cardiomyopathy Restrictive cardiomyopathy HP:0001723

Curated as allelic-spectrum context for the same reason hypertrophic cardiomyopathy is: the entry curates the genotype (biallelic truncation) that produces it, so omitting the phenotype would leave the recessive inheritance block without its clinical counterpart. The p.Gln860Ter patient's detailed restrictive physiology is reported in the body of PMID:34802252 rather than its abstract, so the quotable evidence here is the ClinGen curation and the restrictive-cohort study.

Show evidence (2 references)

CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z SUPPORT Other

"restrictive cardiomyopathy in 2016 (Kostareva et al, 2016, PMID 27662471)"

ClinGen's curated evidence summary lists restrictive cardiomyopathy among the established ACTN2-associated cardiac phenotypes, citing the primary report.

PMID:27662471 SUPPORT Human Clinical

"in genes encoding structural and cytoskeletal proteins (BAG3, JUP, ACTN2, DES)"

In a next-generation-sequencing cohort of idiopathic restrictive cardiomyopathy, ACTN2 was among the cytoskeletal genes carrying pathogenic or likely-pathogenic variants.

Myocardial Fibrosis Myocardial fibrosis HP:0001685

The prognostic evidence is DCM-wide rather than ACTN2-specific; no ACTN2 cohort has reported LGE burden. Severe interstitial fibrosis in explanted ACTN2 p.Gln860Ter myocardium is described in the body (not the abstract) of PMID:34802252 and is therefore not quotable here.

Show evidence (1 reference)

PMID:39298146 PARTIAL Human Clinical

"The presence and extent of LGE were associated with various adverse clinical outcomes, whereas LVEF was not significantly associated with mortality and arrhythmic end points in NIDCM."

Meta-analysis of 103 studies establishes fibrosis (LGE) as the dominant prognostic marker in nonischemic DCM. Support is PARTIAL because the analysis is DCM-wide and not ACTN2-specific.

🧬

Genetic Associations

1

ACTN2 Pathogenic Variants (Pathogenic Variants)

Gene: ACTN2 hgnc:164 relationship_type: CAUSATIVE

Autosomal Dominant

Show evidence (4 references)

CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z SUPPORT Other

"In summary, there is definitive evidence to support the relationship between ACTN2 and ACTN2-related cardiac and skeletal myopathy."

ClinGen Hereditary Cardiovascular Disease GCEP classifies the ACTN2 gene-disease relationship as Definitive (upgraded from moderate in 2023).

PMID:33947203 SUPPORT Human Clinical

"Seven genes (14%; ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including 2 additional ontologies were classified as moderate evidence"

The DCM-specific ClinGen curation places ACTN2 in the moderate-evidence tier for the dilated phenotype, a narrower claim than the Definitive classification for the whole ACTN2 cardiac and skeletal spectrum.

PMID:25224718 SUPPORT Human Clinical

"Whole exome sequencing identified an Ala119Thr mutation in the alpha-actinin-2 (ACTN2) gene that segregated with disease."

Segregation evidence for an ACTN2 missense variant in a family with mixed dilated, noncompaction, and arrhythmic phenotypes.

+ 1 more reference

💊

Medical Actions

4

Guideline-Directed Heart Failure Pharmacotherapy

Action: Pharmacotherapy NCIT:C15986

Agent: angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan) NCIT:C190796 ACE inhibitor (alternative to ARNI) NCIT:C247 beta-blocker NCIT:C29576 mineralocorticoid receptor antagonist (spironolactone as the class exemplar) NCIT:C840 SGLT2 inhibitor NCIT:C98083

Standard heart-failure therapy for left ventricular systolic dysfunction — the four contemporary HFrEF pillars: an angiotensin receptor-neprilysin inhibitor (or an ACE inhibitor / angiotensin receptor blocker where ARNI is not tolerated), a beta-blocker, a mineralocorticoid receptor antagonist, and an SGLT2 inhibitor — which together target the neurohormonal amplifier of adverse remodeling. There is no ACTN2-specific disease-modifying therapy, so management is the generic DCM regimen.

Mechanism Target:

INHIBITS Neurohormonal Activation — Neurohormonal blockade interrupts the maladaptive amplifier between the primary Z-disc lesion and adverse ventricular remodeling.

Show evidence (1 reference)

PMID:31073128 SUPPORT Other

"As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM."

Establishes standard heart-failure therapy as first-line management for dilated cardiomyopathy, of which CMD1AA is a genetic form.

Implantable Cardioverter Defibrillator

Action: implantable cardioverter-defibrillator placement Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435

Device therapy for primary or secondary prevention of sudden cardiac death in carriers with high arrhythmic risk — relevant here because ventricular fibrillation and sudden death can occur in ACTN2 carriers with limited or no ventricular dilation.

Show evidence (1 reference)

PMID:31073128 SUPPORT Other

"Cardiac resynchronization therapy and implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias."

Establishes device therapy for arrhythmic protection as part of standard DCM management, the framework applied to ACTN2 carriers. Evidence source is OTHER because this is a Nature Reviews Disease Primers review.

Cascade Genetic Testing and Counseling

Action: Genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Predictive ACTN2 testing and cardiac surveillance of first-degree relatives, with counseling that addresses incomplete penetrance and the marked intrafamilial variability of expression (dilated, hypertrophic, noncompacted, or purely arrhythmic).

Show evidence (2 references)

PMID:25224718 SUPPORT Human Clinical

"Exome sequencing is a useful adjunct to cardiac genetic testing in families with mixed clinical presentations."

Supports genetic testing as the tool that resolves the diagnosis in ACTN2 families whose clinical presentations do not fit one cardiomyopathy label.

PMID:20301486 SUPPORT Other

"Provide a basic view of genetic risk assessment of at-risk asymptomatic relatives of a proband with DCM to inform cardiac surveillance and allow early detection and treatment of DCM to improve long-term outcome."

The GeneReviews DCM overview frames genetic risk assessment of at-risk asymptomatic relatives, with cardiac surveillance for early detection, as the purpose of cascade evaluation — precisely this treatment. Evidence source is OTHER because GeneReviews is an expert-authored review resource.

Heart Transplantation

Action: Organ transplantation Ontology label: Organ Transplantation NCIT:C15289

Advanced therapy for end-stage heart failure; explanted ACTN2-variant myocardium obtained at transplantation has been the source of the human mechanical studies of this disease.

Show evidence (1 reference)

PMID:37834023 PARTIAL Human Clinical

"Left ventricular free wall samples were obtained at the time of cardiac transplantation from a heart failure patient with the ACTN2 A868T heterozygous variant."

Documents that an ACTN2 variant carrier progressed to transplantation; this is incidental evidence of transplant use in this disease rather than an efficacy study, hence PARTIAL.

🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from Dilated Cardiomyopathy 1AA:

Ischemic and other acquired dilated cardiomyopathy

Overlapping Features Coronary artery disease, hypertension, valvular disease, tachyarrhythmia, alcohol and other cardiotoxins, and endocrine or autoimmune disease all produce a dilated, hypocontractile ventricle and must be excluded before a genetic diagnosis is made.

Distinguishing Features

Regional (coronary-territory) wall-motion abnormality, ischemic LGE pattern, or obstructive disease on angiography favors ischemic cardiomyopathy.
Absent family history plus an identified exposure or loading condition, with recovery after its removal, favors an acquired cause.

Show evidence (1 reference)

PMID:31073128 SUPPORT Other

"Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases."

Enumerates the acquired etiologies that constitute this differential. Evidence source is OTHER because this is a review.

Viral myocarditis Not Yet Curated MONDO:0023161

Overlapping Features Acute or chronic myocarditis can present with ventricular dilation and systolic dysfunction, and inflammatory presentations also occur in genetic arrhythmogenic cardiomyopathy, so the distinction is not always clean.

Distinguishing Features

Recent viral prodrome, troponin release, and inflammatory LGE with recovery of function favor myocarditis.
Endomyocardial biopsy showing inflammatory infiltrate is indicated when inflammation or infection is suspected.

Show evidence (1 reference)

PMID:31073128 SUPPORT Other

"immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected"

Supports biopsy as the discriminator when a myocarditic cause is suspected.

Alcoholic cardiomyopathy Not Yet Curated MONDO:0006643

Overlapping Features Chronic heavy alcohol exposure produces a dilated cardiomyopathy that is clinically indistinguishable on imaging alone and can coexist with (and unmask) a genetic predisposition.

Distinguishing Features

Documented sustained heavy alcohol intake with improvement on abstinence favors a toxic cause.
A pathogenic ACTN2 genotype or an affected first-degree relative argues for the genetic diagnosis even when exposure is present.

Peripartum cardiomyopathy MONDO:0018920

Overlapping Features De novo systolic heart failure in late pregnancy or the postpartum period overlaps clinically with a first presentation of genetic DCM unmasked by the hemodynamic load of pregnancy.

Distinguishing Features

Onset confined to late pregnancy or the first months postpartum, in a woman without previous heart disease, defines the peripartum entity.
Persistent dysfunction outside the peripartum window, or an affected relative, favors an underlying genetic cardiomyopathy.

Isolated left ventricular noncompaction MONDO:0018901

Overlapping Features Noncompaction is part of the CMD1AA phenotype rather than a separate disease in ACTN2 carriers, but isolated noncompaction (and physiological hypertrabeculation in athletes or pregnancy) is the differential when trabeculation is the dominant finding and dilation is mild.

Distinguishing Features

Noncompaction plus dilation with a pathogenic ACTN2 genotype is CMD1AA, not isolated LVNC.
Truncating variants in MYH7, ACTN2, and PRDM16 are the lesions specifically enriched in noncompaction cohorts, so genotype partly resolves the boundary.

Show evidence (1 reference)

PMID:33500567 SUPPORT Human Clinical

"We observed substantial genetic overlap indicating that LVNC often represents a phenotypic variation of DCM or HCM."

Establishes that noncompaction frequently is a phenotypic variant of DCM or HCM rather than a separate entity, which is exactly the boundary problem in an ACTN2 carrier.

Sarcomeric and cytoskeletal dilated cardiomyopathy of other genotype

Overlapping Features TTN truncations, LMNA, FLNC, DSP, RBM20, BAG3, PLN, DES, and SCN5A account for far more genotyped familial DCM than ACTN2 does; on phenotype alone they are indistinguishable, so the differential is resolved by the panel result rather than by imaging.

Distinguishing Features

LMNA and FLNC genotypes carry distinct arrhythmic risk and ICD thresholds, so the specific gene, not the DCM label, drives management.
ACTN2 sits in the moderate-evidence tier for DCM, so a variant there should be weighed more cautiously than one in a definitive-evidence gene.

Show evidence (1 reference)

PMID:33947203 SUPPORT Human Clinical

"Twelve genes (23%) from 8 gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence."

Names the definitive/strong DCM genes that constitute the genotypic differential and against which an ACTN2 finding must be weighed.

🧫

Experimental Models

2

Patient-derived ACTN2 truncating-variant iPSC-cardiomyocytes IPSC_DERIVED_MODEL

Induced pluripotent stem cell-derived cardiomyocytes generated from carriers of monoallelic and biallelic ACTN2 protein-truncating variants, characterized by RNA sequencing, video-based edge detection of contraction, immunohistochemistry, electron microscopy, and affinity-purification mass spectrometry, with CRISPR-Cas9 verification of the stop-gain variant. The reference human model for the ACTN2 contractile and Z-disc-ultrastructure phenotype.

Organism

human NCBITaxon:9606

Cell source

Patient-derived iPSC lines from ACTN2 protein-truncating variant carriers

Publication

PMID:34802252

Pathograph links

Impaired Z-Disc Force Transmission and Myofilament Regulation Contractility and electron-microscopy readouts measure Z-disc ultrastructure and force generation in the variant background.

Sarcomeric Disarray and Cardiomyocyte Hypertrophy Immunohistochemistry quantifies cellular hypertrophy and myofibrillar disarray.

Loss of Sarcolemmal Partner Coupling and Arrhythmogenesis Affinity-purification mass spectrometry identified the loss of ACTN1 and GJA1 interactions on C-terminal truncation.

Show evidence (1 reference)

PMID:34802252 SUPPORT In Vitro

"In patient-derived iPSC-cardiomyocytes, we investigated transcriptional profiles using RNA sequencing, contractile properties using video-based edge detection, and cellular hypertrophy using immunohistochemistry."

Describes the model system and its readouts as used to characterize ACTN2 cardiomyopathy.

Isogenic ACTN2 missense hiPSC-cardiomyocytes and engineered heart tissue IPSC_DERIVED_MODEL

CRISPR/Cas9-generated heterozygous functional knock-out hiPSC lines carrying either a wild-type or a missense ACTN2 allele, differentiated to cardiomyocytes and assembled into engineered heart tissue, and profiled by immunofluorescence, live-cell imaging, RNA sequencing, and mass spectrometry. Provides the isogenic comparison underlying the proteopathy arm.

Organism

human NCBITaxon:9606

Cell source

CRISPR/Cas9-edited human iPSC lines (isogenic ACTN2 wild-type versus missense)

Culture

2D monolayer hiPSC-cardiomyocytes and 3D engineered heart tissue

Publication

PMID:36078153

Pathograph links

Mutant Alpha-Actinin-2 Destabilization and Proteostatic Stress The isogenic pair isolates variant-specific protein aggregation and proteolytic-system activation from genetic background effects.

Show evidence (1 reference)

PMID:36078153 SUPPORT In Vitro

"Here, we created with CRISPR/Cas9 genetic tools two heterozygous functional knock-out hiPSC lines with a second wild-type (ACTN2wt) and missense ACTN2 (ACTN2mut) allele, respectively."

Documents the isogenic design of the model used to isolate the variant-specific proteostatic phenotype.

{ }

Source YAML

click to show

name: Dilated Cardiomyopathy 1AA
creation_date: "2026-08-01T00:00:00Z"
synonyms:
- CMD1AA
- ACTN2 familial isolated dilated cardiomyopathy
- dilated cardiomyopathy type 1AA
- cardiomyopathy, dilated, 1AA, with or without LVNC
description: >-
  Dilated cardiomyopathy 1AA (CMD1AA) is the ACTN2-related form of familial
  isolated dilated cardiomyopathy. ACTN2 encodes alpha-actinin-2, the only
  alpha-actinin isoform expressed in cardiac muscle and the principal
  cross-linker of antiparallel actin thin filaments at the sarcomeric Z-disc,
  where it also anchors the N-terminal region of titin and scaffolds Z-disc
  partners such as muscle LIM protein (MLP/CSRP3). Variants in ACTN2 destabilize
  Z-disc force transmission and myofilament regulation, producing sarcomeric
  disarray, cardiomyocyte hypertrophy, adverse ventricular remodeling, left
  ventricular dilation with systolic dysfunction, and heart failure. The clinical
  picture is notably heterogeneous even within a single family: dilated
  cardiomyopathy may occur alone or together with left ventricular noncompaction
  (hence the OMIM designation "with or without LVNC"), and atrial and ventricular
  arrhythmias, idiopathic ventricular fibrillation, and sudden cardiac death are
  part of the spectrum. CMD1AA is one node of a broader ACTN2 allelic series that
  also includes hypertrophic (CMH23), restrictive, and left-dominant
  arrhythmogenic cardiomyopathy plus ACTN2-related skeletal myopathy; ClinGen has
  lumped that whole spectrum into a single "ACTN2-related cardiac and skeletal
  myopathy" entity with Definitive gene-disease validity, while MONDO keeps the
  phenotype-specific nodes (including MONDO:0012808) separate. Inheritance is
  predominantly autosomal dominant, with rare biallelic protein-truncating
  disease.
category: Genetic
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
disease_term:
  preferred_term: dilated cardiomyopathy 1AA
  term:
    id: MONDO:0012808
    label: dilated cardiomyopathy 1AA
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    No population-based prevalence estimate exists for the ACTN2-specific form of
    dilated cardiomyopathy. ACTN2 is a minority cause of DCM: the ClinGen DCM
    gene-curation panel placed it in the "moderate evidence" tier (7 of 51
    curated genes), below the definitive/strong genes such as TTN, LMNA, and MYH7
    that account for most genotyped familial DCM.
  evidence:
  - reference: PMID:33947203
    reference_title: Evidence-Based Assessment of Genes in Dilated Cardiomyopathy.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven genes (14%; ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including 2
      additional ontologies were classified as moderate evidence; these genes are
      likely to emerge as strong or definitive with additional evidence.
    explanation: >-
      Establishes ACTN2 as a moderate-evidence (i.e., minority, not
      high-frequency) monogenic cause of DCM in the ClinGen curation of 51 DCM
      genes. Supports the rarity statement but does not itself provide a
      population prevalence, hence PARTIAL.
inheritance:
- name: Autosomal Dominant
  description: >-
    Most reported ACTN2 cardiomyopathy families show autosomal dominant
    transmission of a heterozygous missense or truncating variant, with
    incomplete penetrance and marked intrafamilial variability in the resulting
    cardiac phenotype.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ACTN2 | HGNC:164 | ACTN2-related cardiac and skeletal myopathy |
      MONDO:0700349 | AD | Definitive
    explanation: >-
      ClinGen Hereditary Cardiovascular Disease GCEP records autosomal dominant
      inheritance for the ACTN2 gene-disease relationship, with Definitive
      clinical validity.
- name: Autosomal Recessive (Biallelic Truncating)
  description: >-
    Rare biallelic ACTN2 protein-truncating genotypes cause cardiomyopathy
    through a mechanism distinct from the heterozygous state; a homozygous
    stop-gain variant was functionally validated by CRISPR-Cas9 editing in
    patient-derived iPSC-cardiomyocytes.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:34802252
    reference_title: Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Together, these data advance our understanding of the role of ACTN2 in the
      human heart and establish recessive inheritance of ACTN2 truncation as
      causative of disease.
    explanation: >-
      Directly establishes a recessive (biallelic truncating) mode of inheritance
      for ACTN2 cardiomyopathy alongside the dominant form. Classified IN_VITRO
      because causality was demonstrated in patient-derived iPSC-cardiomyocytes
      with CRISPR-Cas9 validation.
mechanistic_hypotheses:
- hypothesis_group_id: actn2_zdisc_force_transmission_model
  hypothesis_label: Z-disc force-transmission and myofilament-regulation model
  status: CANONICAL
  description: >-
    The canonical model holds that ACTN2 variants degrade the mechanical and
    regulatory function of the Z-disc: cross-linking of antiparallel actin
    filaments and anchoring of Z-disc titin are perturbed, altering both
    thin-filament calcium sensitivity and thick-filament activation, so force
    generation and relaxation become abnormal and the myocardium remodels.
  evidence:
  - reference: PMID:37834023
    reference_title: "Disruption of Z-Disc Function Promotes Mechanical Dysfunction in Human Myocardium: Evidence for a Dual Myofilament Modulatory Role by Alpha-Actinin 2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our results can be explained by two Z-disc mediated communication pathways
    explanation: >-
      The study of explanted human myocardium carrying an ACTN2 variant states
      the two-pathway (actin/thin-filament and titin/thick-filament) Z-disc
      communication model that underlies this hypothesis group. The quote stops
      before the clause naming the two pathways because the source text spells
      them with a Greek alpha; the quantitative findings are quoted on the
      corresponding pathophysiology node.
- hypothesis_group_id: actn2_variant_specific_proteotoxicity
  hypothesis_label: Variant-specific alpha-actinin-2 destabilization and proteostatic stress
  status: EMERGING
  description: >-
    An additional, variant-specific arm proposes that some mutant alpha-actinin-2
    proteins are destabilized, misfold, and aggregate, triggering
    ubiquitin-proteasome and autophagy-lysosome activation and depleting
    sarcomere-associated proteins — a proteopathy superimposed on the mechanical
    defect. Human isogenic hiPSC-cardiomyocytes and an Actn2 knock-in mouse both
    show proteasomal activation, but whether this arm operates in the dilated (as
    opposed to hypertrophic or myopathic) presentations, and in patient
    myocardium rather than engineered tissue, is unresolved; ClinGen notes that
    the ACTN2 disease mechanism remains unclear and may be variant-specific.
  evidence:
  - reference: PMID:36078153
    reference_title: ACTN2 Mutant Causes Proteopathy in Human iPSC-Derived Cardiomyocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      our study highlights the activation of proteolytic systems in ACTN2mut
      hiPSC-CMs likely to cope with ACTN2 aggregation and therefore directs
      towards proteopathy as an additional cellular pathology caused by this
      ACTN2 variant
    explanation: >-
      Provides the primary in vitro basis for the proteotoxicity arm, and its
      authors frame it as an additional (not established) cellular mechanism.
  - reference: CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      The disease mechanism is currently unclear and may be variant-specific
      since some variants have been shown to result in protein aggregation while
      others do not have this effect
    explanation: >-
      ClinGen explicitly records that aggregation is variant-specific and that
      the overall mechanism is unresolved, which is why this hypothesis group is
      EMERGING rather than canonical.
pathophysiology:
- name: Alpha-Actinin-2 Z-Disc Dysfunction
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Primary Cardiomyocyte Insult"
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    ACTN2 encodes alpha-actinin-2, the only alpha-actinin isoform expressed in
    cardiac muscle. As an antiparallel homodimer it cross-links thin filaments
    from adjacent sarcomeres at the Z-disc, anchors the N-terminal (Z-disc)
    region of titin, and provides a docking platform for Z-disc partners
    including muscle LIM protein (MLP/CSRP3). Disease-associated variants are
    distributed across the actin-binding calponin-homology domains, the
    spectrin-repeat rod, and the C-terminal EF-hand/calmodulin-like region; they
    perturb actin binding, titin interaction, Z-disc incorporation, protein
    stability, or partner binding rather than abolishing the protein, and
    haploinsufficiency is not an established mechanism.
  genes:
  - preferred_term: ACTN2
    term:
      id: hgnc:164
      label: ACTN2
  molecular_functions:
  - preferred_term: actin filament binding
    term:
      id: GO:0051015
      label: actin filament binding
    modifier: ABNORMAL
  - preferred_term: structural constituent of muscle
    term:
      id: GO:0008307
      label: structural constituent of muscle
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: Myocardium
    term:
      id: UBERON:0002349
      label: myocardium
  biological_processes:
  - preferred_term: Sarcomere organization
    term:
      id: GO:0045214
      label: sarcomere organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:36116040
    reference_title: Mutation update for the ACTN2 gene.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ACTN2 encodes alpha-actinin-2, a protein expressed in human cardiac and
      skeletal muscle. The protein, located in the sarcomere Z-disk, functions as
      a link between the anti-parallel actin filaments. This important structural
      protein also binds N-terminal titins, and thus contributes to sarcomere
      stability.
    explanation: >-
      Establishes the normal Z-disc function of alpha-actinin-2 (actin
      cross-linking and titin anchoring) whose perturbation is the primary lesion
      of this disorder. Evidence source is OTHER because this is a
      mutation-update review.
  - reference: PMID:34802252
    reference_title: Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ACTN2 (alpha-actinin 2) anchors actin within cardiac sarcomeres. The
      mechanisms linking ACTN2 mutations to myocardial disease phenotypes are
      unknown.
    explanation: >-
      Confirms the actin-anchoring role of ACTN2 in cardiac sarcomeres and that
      the genotype-to-phenotype mechanism was still open when this study was
      designed. Evidence source is OTHER because the quote is the paper's
      background framing rather than its experimental result.
  - reference: PMID:14567970
    reference_title: Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In another patient with DCM, a Q9R mutation was identified in
      alpha-actinin-2.
    explanation: >-
      The founding CMD1AA observation: an ACTN2 missense variant identified in a
      patient with dilated cardiomyopathy.
  - reference: CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      gain of function or dominant-negative effects are most likely;
      haploinsufficiency is not an established mechanism
    explanation: >-
      ClinGen's mechanism statement supports modeling the trigger as a
      qualitative perturbation of alpha-actinin-2 function (dominant-negative or
      gain of function) rather than simple loss of one allele.
  - reference: PMID:33802723
    reference_title: The Role of Z-disc Proteins in Myopathy and Cardiomyopathy.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Numerous proteins interact in the Z-disc to facilitate force transduction
      and intracellular signalling in both cardiac and skeletal muscle.
    explanation: >-
      Frames the Z-disc as both a force-transducing and a signalling structure,
      which is why an alpha-actinin-2 defect produces mechanical and signalling
      consequences rather than a purely structural one. Evidence source is OTHER
      because this is a review of Z-disc protein biology.
  downstream:
  - target: Impaired Z-Disc Force Transmission and Myofilament Regulation
    causal_link_type: DIRECT
    hypothesis_groups:
    - actn2_zdisc_force_transmission_model
  - target: Mutant Alpha-Actinin-2 Destabilization and Proteostatic Stress
    causal_link_type: DIRECT
    hypothesis_groups:
    - actn2_variant_specific_proteotoxicity
    description: >-
      Variant-specific arm: only some mutant alpha-actinin-2 proteins are
      destabilized and aggregate.
  - target: Loss of Sarcolemmal Partner Coupling and Arrhythmogenesis
    causal_link_type: DIRECT
  - target: Failed Trabecular Compaction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      ACTN2 truncating variants are among the few lesions specifically associated
      with a noncompaction phenotype, but the developmental path from Z-disc
      dysfunction to failed trabecular compaction is not established.

- name: Impaired Z-Disc Force Transmission and Myofilament Regulation
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    Because the Z-disc both transmits force between sarcomeres and relays
    regulatory information to the thin and thick filaments, an abnormal
    alpha-actinin-2 degrades contraction and relaxation simultaneously.
    Explanted myocardium carrying an ACTN2 EF-hand variant shows increased
    myofilament calcium sensitivity, reduced sinusoidal stiffness, faster tension
    redevelopment, and increased thick-to-thin filament separation, while
    patient-derived iPSC-cardiomyocytes show impaired contractility and aberrant
    calcium handling. Truncated alpha-actinin-2 that is still incorporated into
    the sarcomere distorts Z-disc ultrastructure, a dominant-negative pattern.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Muscle contraction
    term:
      id: GO:0006936
      label: muscle contraction
    modifier: ABNORMAL
  - preferred_term: Intracellular calcium ion homeostasis
    term:
      id: GO:0006874
      label: intracellular calcium ion homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37834023
    reference_title: "Disruption of Z-Disc Function Promotes Mechanical Dysfunction in Human Myocardium: Evidence for a Dual Myofilament Modulatory Role by Alpha-Actinin 2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      However, contractile mechanics of permeabilized ACTN2 A868T variant cardiac
      tissue displayed higher myofilament Ca2+ sensitivity of isometric force,
      reduced sinusoidal stiffness, and faster rates of tension redevelopment at
      all Ca2+ levels.
    explanation: >-
      Direct mechanical measurement in human myocardium carrying an ACTN2 variant
      demonstrates altered myofilament calcium sensitivity and passive stiffness.
      Evidence source is IN_VITRO because the measurements were made on
      permeabilized explanted tissue.
  - reference: PMID:37834023
    reference_title: "Disruption of Z-Disc Function Promotes Mechanical Dysfunction in Human Myocardium: Evidence for a Dual Myofilament Modulatory Role by Alpha-Actinin 2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Small-angle X-ray diffraction indicated increased separation between thick
      and thin filaments, possibly contributing to changes in muscle kinetics.
    explanation: >-
      Structural correlate of the mechanical defect: Z-disc dysfunction
      translates into altered interfilament spacing within the sarcomere.
  - reference: PMID:34802252
    reference_title: Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In heterozygous indel cells, the truncated protein incorporates into
      cardiac sarcomeres, leading to aberrant Z-disc ultrastructure.
    explanation: >-
      Shows that a truncated ACTN2 product is incorporated into the sarcomere and
      distorts Z-disc ultrastructure, the dominant-negative version of this node.
  - reference: PMID:27287556
    reference_title: Hypertrophic cardiomyopathy mutations in the calponin-homology domain of ACTN2 affect actin binding and cardiomyocyte Z-disc incorporation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The full length mEos2 tagged protein expressed in adult cardiomyocytes
      shows that both mutations additionally affect Z-disc localization and
      dynamic behaviour.
    explanation: >-
      Demonstrates that actin-binding-domain variants (including A119T, later
      found segregating with DCM/LVNC/ventricular fibrillation) disturb Z-disc
      localization and turnover in cardiomyocytes. The cohort studied was
      hypertrophic, so this supports the molecular step rather than the dilated
      phenotype itself.
  downstream:
  - target: Sarcomeric Disarray and Cardiomyocyte Hypertrophy
    causal_link_type: DIRECT
    hypothesis_groups:
    - actn2_zdisc_force_transmission_model

- name: Mutant Alpha-Actinin-2 Destabilization and Proteostatic Stress
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    For a subset of variants, mutant alpha-actinin-2 is destabilized, misfolds,
    and aggregates within the cardiomyocyte. In isogenic hiPSC-cardiomyocyte
    models the mutant allele produces protein aggregation, multinucleation,
    hypertrophy, and myofibrillar disarray with activation of both the
    ubiquitin-proteasome system and the autophagy-lysosome pathway, loss of
    sarcomere-associated proteins, and reduced force in engineered heart tissue;
    an Actn2 missense knock-in mouse independently shows a destabilized protein
    with increased ubiquitin-proteasome activity. This proteopathy arm is
    variant-specific and has not been demonstrated in patient myocardium.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Inclusion body assembly
    term:
      id: GO:0070841
      label: inclusion body assembly
    modifier: INCREASED
  - preferred_term: Proteasome-mediated ubiquitin-dependent protein catabolic process
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    modifier: INCREASED
  - preferred_term: Autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: INCREASED
  evidence:
  - reference: PMID:36078153
    reference_title: ACTN2 Mutant Causes Proteopathy in Human iPSC-Derived Cardiomyocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This study showed that ACTN2mut presents a higher percentage of
      multinucleation, protein aggregation, hypertrophy, myofibrillar disarray,
      and activation of both the ubiquitin-proteasome system and the
      autophagy-lysosomal pathway as compared to ACTN2wt in 2D-cultured
      hiPSC-CMs.
    explanation: >-
      Primary experimental basis for the aggregation/proteostatic-stress node in
      an isogenic human cardiomyocyte model.
  - reference: PMID:36078153
    reference_title: ACTN2 Mutant Causes Proteopathy in Human iPSC-Derived Cardiomyocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Furthermore, the expression of ACTN2mut was associated with a marked
      reduction of sarcomere-associated protein levels in 2D-cultured hiPSC-CMs
      and force impairment in engineered heart tissues.
    explanation: >-
      Links the proteotoxic arm to loss of sarcomeric proteins and measurable
      contractile impairment, connecting it to the shared remodeling pathway.
  - reference: PMID:36899856
    reference_title: Insights into the Role of a Cardiomyopathy-Causing Genetic Variant in ACTN2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The mutant alpha-actinin protein is found to be destabilised, associated
      with increased activity of the ubiquitin-proteasomal system.
    explanation: >-
      An Actn2 p.Met228Thr knock-in mouse provides in vivo support for protein
      destabilization with proteasomal activation. The variant modeled is
      hypertrophic-cardiomyopathy-associated, so this corroborates the mechanism
      rather than the dilated phenotype.
  downstream:
  - target: Sarcomeric Disarray and Cardiomyocyte Hypertrophy
    causal_link_type: DIRECT
    hypothesis_groups:
    - actn2_variant_specific_proteotoxicity

- name: Loss of Sarcolemmal Partner Coupling and Arrhythmogenesis
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    Beyond the sarcomere, the C-terminus of alpha-actinin-2 interacts with
    sarcolemma-associated proteins including alpha-actinin-1 (ACTN1) and
    connexin-43 (GJA1). C-terminal truncation disrupts these interactions,
    providing a mechanistic route from a Z-disc protein defect to impaired
    electrical coupling, arrhythmia, and abnormal relaxation. Clinically, ACTN2
    carriers show atrial and ventricular arrhythmias, conduction abnormalities,
    and idiopathic ventricular fibrillation, which can precede or occur without
    overt ventricular dilation.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Cell communication by electrical coupling involved in cardiac conduction
    term:
      id: GO:0086064
      label: cell communication by electrical coupling involved in cardiac conduction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:34802252
    reference_title: Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Loss of the C-terminus of ACTN2 disrupts interaction with ACTN1
      (alpha-actinin 1) and GJA1 (gap junction protein alpha 1), 2
      sarcolemma-associated proteins, which may contribute to the clinical
      arrhythmic and relaxation defects.
    explanation: >-
      Supplies the molecular link between ACTN2 truncation and the arrhythmic and
      relaxation phenotype via loss of connexin-43 and ACTN1 coupling. The
      authors frame the clinical contribution as a possibility ("may
      contribute"), so this node is modeled as a mechanistic amplifier rather
      than a proven clinical driver.
  - reference: CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A study found that patients with ACTN2 presented with varying degrees and
      types of arrhythmias, including left bundle branch block, atypical flutter,
      paroxysmal atrial fibrillation or supraventricular tachycardia, as well as
      atrial, ventricular, or supraventricular premature beats
    explanation: >-
      Documents the clinical arrhythmia burden in ACTN2 variant carriers that
      this node accounts for.
  downstream:
  - target: Ventricular Arrhythmia
    causal_link_type: DIRECT
  - target: Sudden Cardiac Death
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES

- name: Sarcomeric Disarray and Cardiomyocyte Hypertrophy
  biological_scale: CELLULAR
  role: effector
  description: >-
    The converging consequence of impaired Z-disc mechanics and (for some
    variants) mutant protein destabilization is disorganized myofibrillar
    architecture with hypertrophic growth of the cardiomyocyte. Patient-derived
    iPSC-cardiomyocytes carrying ACTN2 truncating variants are hypertrophic and
    show sarcomeric structural disarray, impaired contractility, and aberrant
    calcium signaling.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Myofibril assembly
    term:
      id: GO:0030239
      label: myofibril assembly
    modifier: ABNORMAL
  - preferred_term: Cardiac muscle hypertrophy
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
    modifier: INCREASED
  evidence:
  - reference: PMID:34802252
    reference_title: Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Patient-derived iPSC-cardiomyocytes were hypertrophic, displayed sarcomeric
      structural disarray, impaired contractility, and aberrant Ca2+-signaling.
    explanation: >-
      Directly documents the cellular phenotype of this node in human
      cardiomyocytes derived from ACTN2 variant carriers.
  downstream:
  - target: Neurohormonal Activation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Adverse Ventricular Remodeling
    causal_link_type: DIRECT

- name: Neurohormonal Activation
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Neurohormonal Activation"
  biological_scale: ORGANISM
  role: amplifier
  description: >-
    As in other cardiomyopathies, the fall in contractile performance activates
    the renin-angiotensin-aldosterone and sympathetic systems. Initially
    compensatory, chronic activation drives cardiomyocyte hypertrophy, apoptosis,
    and fibrosis, converting the primary Z-disc lesion into progressive
    structural remodeling; this axis is what standard heart-failure
    pharmacotherapy targets in ACTN2 disease as in DCM generally.
  biological_processes:
  - preferred_term: Response to angiotensin
    term:
      id: GO:1990776
      label: response to angiotensin
    modifier: INCREASED
  evidence:
  - reference: PMID:25445411
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The systemic as well as the tissue RAAS are also dedicated to promote
      tissue remodeling, particularly relevant after damage, when chronic
      activation may configure as a maladaptive response, leading to fibrosis,
      hypertrophy and apoptosis, and organ dysfunction.
    explanation: >-
      Shared module evidence that chronic renin-angiotensin-aldosterone
      activation is the maladaptive amplifier between a cardiomyocyte insult and
      structural remodeling. Evidence source is OTHER because this is a review.
  downstream:
  - target: Adverse Ventricular Remodeling
    causal_link_type: DIRECT

- name: Adverse Ventricular Remodeling
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  biological_scale: TISSUE
  role: central_effector
  description: >-
    Cardiomyocyte hypertrophy and loss, cardiac fibroblast activation, and
    interstitial matrix deposition remodel the ventricle. In ACTN2 disease the
    net geometry is variable — the same gene, and sometimes the same variant, can
    yield a dilated, hypertrophic, restrictive, or noncompacted ventricle, and
    the dominant pattern can differ between relatives — but the remodeling
    machinery itself is the conserved cardiomyopathy step.
  cell_types:
  - preferred_term: Cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: Heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  biological_processes:
  - preferred_term: Extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  - preferred_term: Cardiac muscle cell apoptotic process
    term:
      id: GO:0010659
      label: cardiac muscle cell apoptotic process
    modifier: INCREASED
  evidence:
  - reference: CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cardiac phenotypes are associated with both gain and loss of function ACTN2
      variants and do not always fit well into classical cardiomyopathy diagnosis.
    explanation: >-
      Supports modeling remodeling geometry as variable in ACTN2 disease rather
      than fixed to the dilated pattern.
  - reference: PMID:22752727
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The pathophysiological basis of heart failure is cardiac remodeling, a
      process that comprises structural and functional changes including
      cardiomyocyte proliferation, hypertrophy, necrosis, apoptosis, autophagy,
      interstitial fibrosis, contractile dysfunction and ventricular dilatation.
    explanation: >-
      Shared module evidence enumerating the components of adverse remodeling
      that this node represents. Evidence source is OTHER because this is a
      mechanistic review.
  downstream:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    causal_link_type: DIRECT

- name: Failed Trabecular Compaction
  biological_scale: TISSUE
  role: effector
  description: >-
    A subset of ACTN2 carriers show left ventricular noncompaction — prominent
    trabeculae with deep intertrabecular recesses over a thin compacted layer —
    either isolated or together with ventricular dilation, which is why the OMIM
    entity is designated "with or without LVNC". In a large rare-variant
    association analysis, ACTN2 truncating variants were among the few lesions
    associated specifically with noncompaction rather than shared with DCM/HCM,
    suggesting a partly distinct developmental route, plausibly through impaired
    cardiomyocyte maturation.
  locations:
  - preferred_term: Heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:33500567
    reference_title: Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely
      associated with LVNC and may reflect a distinct LVNC etiology.
    explanation: >-
      Case-control rare-variant evidence that ACTN2 truncating variants are
      specifically associated with a noncompaction phenotype.
  - reference: PMID:25224718
    reference_title: Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While some individuals were asymptomatic, other presentations included left
      ventricular non-compaction, a resuscitated cardiac arrest due to idiopathic
      ventricular fibrillation, dilated cardiomyopathy, and sudden unexplained
      death.
    explanation: >-
      Family segregation study showing noncompaction and dilated cardiomyopathy
      co-occurring within one ACTN2 kindred.
  - reference: PMID:37374362
    reference_title: "Impaired Cardiomyocyte Maturation Leading to DCM: A Case Report and Literature Review."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This report presents a rare case of DCM with myocardial non-compaction,
      probably resulting from allelic collapse of both the ACTN2 and RYR2 genes.
    explanation: >-
      Pediatric case of dilated cardiomyopathy with noncompaction attributed to a
      1q43 deletion, framed by the authors as impaired cardiomyocyte maturation.
      Support is PARTIAL because the deletion removes RYR2 as well as ACTN2, so
      the ACTN2 contribution cannot be isolated.
  downstream:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

- name: Left Ventricular Dilation and Systolic Dysfunction
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Progressive Contractile Dysfunction"
  biological_scale: ORGANISM
  role: effector
  description: >-
    The remodeled ventricle dilates and loses systolic shortening, producing the
    defining CMD1AA phenotype: left ventricular enlargement with reduced ejection
    fraction in the absence of loading conditions or coronary disease sufficient
    to explain it. Penetrance is incomplete and expression is heterogeneous, so
    affected relatives may be asymptomatic, dilated, hypertrophic, or arrhythmic;
    population data on DCM-gene carriers show that arrhythmia without substantial
    ventricular dilation is a common early expression.
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: Heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  biological_processes:
  - preferred_term: Heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: DECREASED
  evidence:
  - reference: PMID:25224718
    reference_title: Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in the ACTN2 gene can be responsible for marked cardiac phenotype
      heterogeneity in families. The diverse mechanistic roles of ACTN2 in the
      cardiac Z-disc may explain this heterogeneous clinical presentation.
    explanation: >-
      Supports both the dilated endpoint and the marked intrafamilial
      heterogeneity of expression in ACTN2 disease.
  - reference: PMID:14567970
    reference_title: Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This mutation also disrupted the interaction with MLP and appeared to
      inhibit alpha-actinin function in cultured cells, in respect to the nuclear
      localization of actinin and the initiation of cellular differentiation.
    explanation: >-
      Functional characterization of the original DCM-associated ACTN2 Q9R
      variant, linking it to loss of the alpha-actinin-2/MLP interaction.
      Evidence source is IN_VITRO because the assays were done in cultured cells.
  - reference: PMID:35708014
    reference_title: Frequency, Penetrance, and Variable Expressivity of Dilated Cardiomyopathy-Associated Putative Pathogenic Gene Variants in UK Biobank Participants.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      most commonly manifesting with arrhythmias in the absence of substantial
      ventricular dilation or dysfunction
    explanation: >-
      UK Biobank data on carriers of putative pathogenic variants in 44 DCM genes
      (ACTN2 among them) show low penetrance of frank dilation and arrhythmia as
      the commonest early expression. Support is PARTIAL because the analysis is
      gene-panel-wide rather than ACTN2-specific.
  downstream:
  - target: Heart Failure and Sudden Cardiac Death
    causal_link_type: DIRECT
  - target: Dilated Cardiomyopathy
    causal_link_type: DIRECT

- name: Heart Failure and Sudden Cardiac Death
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The clinical endpoint is structural and functional cardiac impairment:
    symptomatic heart failure that may progress to end-stage disease requiring
    transplantation, and — because the arrhythmic arm can act independently of
    pump failure — syncope, ventricular fibrillation, and sudden cardiac death,
    sometimes as the presenting event in an otherwise well relative.
  biological_processes:
  - preferred_term: Heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: ABNORMAL
  evidence:
  - reference: PMID:20022194
    reference_title: "Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Affected family members showed marked clinical diversity, ranging from
      asymptomatic individuals to those with syncope, heart failure, and
      premature sudden death.
    explanation: >-
      Documents the clinical endpoints (heart failure, syncope, premature sudden
      death) in an ACTN2 kindred. The index family was hypertrophic, so this
      supports the endpoint spectrum of ACTN2 disease rather than the dilated
      phenotype specifically.
  - reference: PMID:31073128
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      As DCM eventually leads to impaired contractility, standard approaches to
      prevent or treat heart failure are the first-line treatment for patients
      with DCM.
    explanation: >-
      Shared module evidence that the dilated cardiomyopathy process culminates
      in impaired contractility managed as heart failure. Evidence source is
      OTHER because this is a review.
phenotypes:
- category: Cardiovascular
  name: Dilated Cardiomyopathy
  description: >-
    Left ventricular dilation with systolic dysfunction, the defining feature of
    CMD1AA. It may be the sole cardiac manifestation or coexist with
    noncompaction, hypertrophy, or arrhythmia in the same family.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:14567970
    reference_title: Mutations in the muscle LIM protein and alpha-actinin-2 genes in dilated cardiomyopathy and endocardial fibroelastosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In another patient with DCM, a Q9R mutation was identified in
      alpha-actinin-2.
    explanation: >-
      Original report of dilated cardiomyopathy in a patient with an ACTN2
      variant.
  - reference: CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      dilated cardiomyopathy in 2010 (Zimmerman et al, 2010, PMID 20474083)
    explanation: >-
      ClinGen's curated evidence summary lists dilated cardiomyopathy among the
      established ACTN2-associated cardiac phenotypes.
- category: Cardiovascular
  name: Left Ventricular Noncompaction
  description: >-
    Prominent left ventricular trabeculae with deep intertrabecular recesses,
    reported both in isolation and together with dilation in ACTN2 families;
    ACTN2 truncating variants are enriched specifically in noncompaction cohorts.
  phenotype_term:
    preferred_term: Left ventricular noncompaction
    term:
      id: HP:0030682
      label: Left ventricular noncompaction
  evidence:
  - reference: PMID:33500567
    reference_title: Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely
      associated with LVNC and may reflect a distinct LVNC etiology.
    explanation: >-
      Rare-variant association analysis of 840 LVNC cases supports a specific
      ACTN2-noncompaction association.
  - reference: PMID:25224718
    reference_title: Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      other presentations included left ventricular non-compaction
    explanation: >-
      Noncompaction observed among the phenotypes segregating with ACTN2
      Ala119Thr in a single family.
- category: Cardiovascular
  name: Ventricular Arrhythmia
  description: >-
    Ventricular arrhythmia — including premature ventricular beats and idiopathic
    ventricular fibrillation causing resuscitated cardiac arrest — occurs in
    ACTN2 carriers, at times without overt ventricular dilation.
  phenotype_term:
    preferred_term: Ventricular arrhythmia
    term:
      id: HP:0004308
      label: Ventricular arrhythmia
  evidence:
  - reference: PMID:25224718
    reference_title: Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a resuscitated cardiac arrest due to idiopathic ventricular fibrillation
    explanation: >-
      Documents a life-threatening ventricular arrhythmia in an ACTN2 variant
      carrier.
  - reference: CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      as well as atrial, ventricular, or supraventricular premature beats
    explanation: >-
      ClinGen's evidence summary records ventricular ectopy among the arrhythmia
      types seen in ACTN2 patients.
- category: Cardiovascular
  name: Atrial Fibrillation
  description: >-
    Atrial arrhythmias, including paroxysmal atrial fibrillation, atypical
    flutter, and supraventricular tachycardia, are part of the ACTN2 cardiac
    phenotype and may reflect impaired intercellular electrical coupling.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
    temporality: RECURRENT
  evidence:
  - reference: CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      patients with ACTN2 presented with varying degrees and types of
      arrhythmias, including left bundle branch block, atypical flutter,
      paroxysmal atrial fibrillation or supraventricular tachycardia
    explanation: >-
      ClinGen's curated summary of the arrhythmia spectrum in ACTN2 variant
      carriers.
- category: Cardiovascular
  name: Sudden Cardiac Death
  description: >-
    Sudden unexplained death, including in young and previously asymptomatic
    relatives, has been reported in ACTN2 kindreds and can be the sentinel event
    that brings a family to genetic evaluation.
  phenotype_term:
    preferred_term: Sudden cardiac death
    term:
      id: HP:0001645
      label: Sudden cardiac death
  evidence:
  - reference: PMID:25224718
    reference_title: Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      dilated cardiomyopathy, and sudden unexplained death
    explanation: >-
      Sudden unexplained death occurred among the phenotypes segregating with
      ACTN2 Ala119Thr.
  - reference: PMID:20022194
    reference_title: "Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      those with syncope, heart failure, and premature sudden death
    explanation: >-
      Premature sudden death reported in an ACTN2-linked cardiomyopathy family.
- category: Cardiovascular
  name: Congestive Heart Failure
  description: >-
    Symptomatic heart failure from progressive systolic dysfunction, managed with
    standard heart-failure therapy and, in end-stage disease, transplantation.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20022194
    reference_title: "Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ranging from asymptomatic individuals to those with syncope, heart failure,
      and premature sudden death
    explanation: >-
      Heart failure documented among clinical outcomes in an ACTN2 cardiomyopathy
      family.
- category: Cardiovascular
  name: Hypertrophic Cardiomyopathy
  description: >-
    Left ventricular hypertrophy is the alternative cardiac expression of ACTN2
    variation (OMIM lists CMH23 at the same locus), and hypertrophic and dilated
    patterns can appear in relatives sharing one variant. It is listed here as
    part of the allelic spectrum, not as a feature of the dilated phenotype
    itself.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  notes: >-
    Curated as spectrum context. The ACTN2 hypertrophic presentation has its own
    MONDO representation; dismech records it here only to keep the intrafamilial
    heterogeneity of CMD1AA visible.
  evidence:
  - reference: PMID:20022194
    reference_title: "Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is the first genome-wide linkage analysis that shows mutations in
      ACTN2 cause HCM.
    explanation: >-
      Establishes the hypertrophic arm of the ACTN2 allelic series.
  - reference: CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals can show variable combinations of hypertrophy, dilatation,
      hyper/hypo contractility, and arrhythmias
    explanation: >-
      ClinGen records that hypertrophic and dilated features can combine within
      the same ACTN2 phenotype, including within one family.
- category: Cardiovascular
  name: Restrictive Cardiomyopathy
  description: >-
    Restrictive physiology — impaired ventricular filling with near-normal cavity
    size and wall thickness — is the third structural expression of ACTN2
    variation, and is the phenotype reported for the homozygous protein-truncating
    genotype that anchors the recessive inheritance block in this entry (the
    p.Gln860Ter patient who progressed to transplantation in early adulthood).
    ACTN2 was also recovered as one of the pathogenic cytoskeletal-gene findings
    in a next-generation-sequencing cohort of idiopathic restrictive
    cardiomyopathy.
  phenotype_term:
    preferred_term: Restrictive cardiomyopathy
    term:
      id: HP:0001723
      label: Restrictive cardiomyopathy
  notes: >-
    Curated as allelic-spectrum context for the same reason hypertrophic
    cardiomyopathy is: the entry curates the genotype (biallelic truncation) that
    produces it, so omitting the phenotype would leave the recessive inheritance
    block without its clinical counterpart. The p.Gln860Ter patient's detailed
    restrictive physiology is reported in the body of PMID:34802252 rather than
    its abstract, so the quotable evidence here is the ClinGen curation and the
    restrictive-cohort study.
  evidence:
  - reference: CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      restrictive cardiomyopathy in 2016 (Kostareva et al, 2016, PMID 27662471)
    explanation: >-
      ClinGen's curated evidence summary lists restrictive cardiomyopathy among
      the established ACTN2-associated cardiac phenotypes, citing the primary
      report.
  - reference: PMID:27662471
    reference_title: Genetic Spectrum of Idiopathic Restrictive Cardiomyopathy Uncovered by Next-Generation Sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in genes encoding structural and cytoskeletal proteins (BAG3, JUP, ACTN2,
      DES)
    explanation: >-
      In a next-generation-sequencing cohort of idiopathic restrictive
      cardiomyopathy, ACTN2 was among the cytoskeletal genes carrying pathogenic
      or likely-pathogenic variants.
- category: Cardiovascular
  name: Myocardial Fibrosis
  description: >-
    Interstitial myocardial fibrosis accompanies the remodeling myocardium and is
    detectable in vivo as late gadolinium enhancement on cardiac MRI. In
    nonischemic dilated cardiomyopathy generally, LGE presence and extent — not
    ejection fraction — carry the dominant prognostic signal for mortality and
    arrhythmic events, which is why fibrosis imaging is part of the workup for an
    ACTN2 carrier rather than a purely descriptive finding.
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  notes: >-
    The prognostic evidence is DCM-wide rather than ACTN2-specific; no ACTN2
    cohort has reported LGE burden. Severe interstitial fibrosis in explanted
    ACTN2 p.Gln860Ter myocardium is described in the body (not the abstract) of
    PMID:34802252 and is therefore not quotable here.
  evidence:
  - reference: PMID:39298146
    reference_title: "Risk Stratification in Nonischemic Dilated Cardiomyopathy Using CMR Imaging: A Systematic Review and Meta-Analysis."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presence and extent of LGE were associated with various adverse
      clinical outcomes, whereas LVEF was not significantly associated with
      mortality and arrhythmic end points in NIDCM.
    explanation: >-
      Meta-analysis of 103 studies establishes fibrosis (LGE) as the dominant
      prognostic marker in nonischemic DCM. Support is PARTIAL because the
      analysis is DCM-wide and not ACTN2-specific.
genetic:
- name: ACTN2 Pathogenic Variants
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: ACTN2
    term:
      id: hgnc:164
      label: ACTN2
  inheritance:
  - name: Autosomal Dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  features: >-
    Reported ACTN2 variants are distributed across the gene rather than clustered
    in one domain: missense changes in the N-terminal actin-binding
    calponin-homology domains (Q9R, G111V, A119T), the spectrin-repeat rod
    (T495M, E583A, E628G), and the C-terminal EF-hand/calmodulin-like region
    (A868T), plus protein-truncating and splice variants. Heterozygous truncated
    protein can still be incorporated into the sarcomere (dominant-negative),
    while rare biallelic stop-gain genotypes act through a distinct, recessive
    mechanism; haploinsufficiency is not an established mechanism. Segregation
    and functional data are limited for many reported missense variants, so
    variant interpretation in this gene requires caution.
  variants:
  - name: ACTN2 Q9R
    description: >-
      Missense variant in the N-terminal region identified in a patient with
      dilated cardiomyopathy; abolishes the alpha-actinin-2 interaction with
      muscle LIM protein in cell-based assays. The founding CMD1AA variant.
    gene:
      preferred_term: ACTN2
      term:
        id: hgnc:164
        label: ACTN2
  - name: ACTN2 Ala119Thr
    description: >-
      Actin-binding-domain missense variant segregating with a strikingly
      heterogeneous cardiac phenotype (left ventricular noncompaction, dilated
      cardiomyopathy, idiopathic ventricular fibrillation, sudden unexplained
      death) in two families sharing a common ancestral haplotype; also reported
      in hypertrophic cardiomyopathy, and shown to perturb Z-disc localization
      and dynamics in cardiomyocytes.
    gene:
      preferred_term: ACTN2
      term:
        id: hgnc:164
        label: ACTN2
  - name: ACTN2 A868T
    description: >-
      Variant in the EF 3-4 region that interacts with titin, studied in
      explanted myocardium from a heart-failure patient; associated with
      increased myofilament calcium sensitivity and reduced sinusoidal stiffness.
    gene:
      preferred_term: ACTN2
      term:
        id: hgnc:164
        label: ACTN2
  evidence:
  - reference: CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In summary, there is definitive evidence to support the relationship
      between ACTN2 and ACTN2-related cardiac and skeletal myopathy.
    explanation: >-
      ClinGen Hereditary Cardiovascular Disease GCEP classifies the ACTN2
      gene-disease relationship as Definitive (upgraded from moderate in 2023).
  - reference: PMID:33947203
    reference_title: Evidence-Based Assessment of Genes in Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seven genes (14%; ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including 2
      additional ontologies were classified as moderate evidence
    explanation: >-
      The DCM-specific ClinGen curation places ACTN2 in the moderate-evidence
      tier for the dilated phenotype, a narrower claim than the Definitive
      classification for the whole ACTN2 cardiac and skeletal spectrum.
  - reference: PMID:25224718
    reference_title: Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing identified an Ala119Thr mutation in the
      alpha-actinin-2 (ACTN2) gene that segregated with disease.
    explanation: >-
      Segregation evidence for an ACTN2 missense variant in a family with mixed
      dilated, noncompaction, and arrhythmic phenotypes.
  - reference: PMID:36116040
    reference_title: Mutation update for the ACTN2 gene.
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      However, limited segregation and functional data are available to support
      the pathogenicity of most previously reported missense variants and
      clear-cut genotype-phenotype correlations are currently only demonstrated
      for some ACTN2-related myopathies.
    explanation: >-
      Documents the interpretive caveat that much of the reported ACTN2 missense
      variation lacks robust segregation or functional support.
diagnosis:
- name: Echocardiography
  description: >-
    First-line imaging: left ventricular dimensions and ejection fraction
    establish the dilated phenotype, and the same study detects the prominent
    trabeculae and deep intertrabecular recesses of noncompaction and the
    near-normal cavity with impaired filling of the restrictive variant.
    Echocardiography is also the surveillance modality for genotype-positive,
    phenotype-negative relatives identified by cascade testing.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:31073128
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Echocardiography and other imaging techniques are required to assess
      ventricular dysfunction and adverse myocardial remodelling, and
      immunological and histological analyses of an endomyocardial biopsy sample
      are indicated when inflammation or infection is suspected.
    explanation: >-
      Establishes echocardiography as the required modality for assessing
      ventricular dysfunction and remodeling in DCM, with biopsy reserved for
      suspected inflammation. Evidence source is OTHER because this is a review.
  - reference: PMID:37374362
    reference_title: "Impaired Cardiomyocyte Maturation Leading to DCM: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Echocardiography showed an enlarged left ventricle and marked myocardial
      non-compaction.
    explanation: >-
      Worked example in an ACTN2-containing deletion: echocardiography
      simultaneously established the dilation and the noncompaction.
- name: Cardiac Magnetic Resonance Imaging with Late Gadolinium Enhancement
  description: >-
    CMR resolves trabecular architecture better than echocardiography (confirming
    or refuting noncompaction) and, with late gadolinium enhancement, quantifies
    myocardial fibrosis. In nonischemic DCM, LGE presence and extent — rather than
    ejection fraction — carry the dominant prognostic signal for mortality and
    arrhythmic events, so CMR informs risk stratification and ICD discussion as
    well as diagnosis.
  diagnosis_term:
    preferred_term: cardiac magnetic resonance imaging with late gadolinium enhancement
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:37374362
    reference_title: "Impaired Cardiomyocyte Maturation Leading to DCM: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac magnetic resonance imaging revealed increased left ventricular
      trabeculae, an enlarged left ventricle, and a reduced ejection fraction.
    explanation: >-
      Demonstrates the three CMR findings that matter in this disorder —
      trabeculation, chamber enlargement, and reduced ejection fraction — in a
      patient with an ACTN2-containing deletion.
  - reference: PMID:39298146
    reference_title: "Risk Stratification in Nonischemic Dilated Cardiomyopathy Using CMR Imaging: A Systematic Review and Meta-Analysis."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Late gadolinium enhancement (LGE) presence and extent (per 1%) were
      associated with higher all-cause mortality
    explanation: >-
      Supports LGE as the prognostically load-bearing CMR measurement in
      nonischemic DCM. Support is PARTIAL because the meta-analysis is DCM-wide
      rather than ACTN2-specific.
- name: Electrocardiography and Ambulatory Rhythm Monitoring
  description: >-
    Resting ECG plus ambulatory (Holter or extended) rhythm monitoring is
    disproportionately important in this disorder because the arrhythmic arm can
    precede or occur without ventricular dilation: conduction disease, atrial
    fibrillation or flutter, ventricular ectopy, and idiopathic ventricular
    fibrillation are all part of the ACTN2 spectrum. In population data on DCM
    gene carriers, arrhythmia or conduction disease is the commonest early
    expression, which makes rhythm assessment the highest-yield test in an
    otherwise phenotype-negative carrier.
  diagnosis_term:
    preferred_term: electrocardiography and ambulatory rhythm monitoring
    term:
      id: NCIT:C38053
      label: Electrocardiography
  evidence:
  - reference: PMID:35708014
    reference_title: Frequency, Penetrance, and Variable Expressivity of Dilated Cardiomyopathy-Associated Putative Pathogenic Gene Variants in UK Biobank Participants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Arrhythmias or conduction disease (15.2%) were the most common early DCM
      features
    explanation: >-
      Establishes rhythm and conduction abnormality as the commonest early
      expression in carriers of DCM-gene variants, justifying ECG plus ambulatory
      monitoring as the front-line test in phenotype-negative carriers.
  - reference: PMID:25224718
    reference_title: Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical evaluation of family members was performed, including physical
      examination, electrocardiography, 2D transthoracic echocardiography and
      review of autopsy records.
    explanation: >-
      Documents the actual evaluation protocol applied to an ACTN2 family:
      examination, ECG, and echocardiography.
- name: Natriuretic Peptide Measurement
  description: >-
    NT-proBNP (or BNP) supports detection and staging of heart failure in a
    carrier with symptoms or borderline imaging, and is the practical serum
    biomarker for longitudinal follow-up. It is neither diagnostic of DCM nor
    ACTN2-specific.
  diagnosis_term:
    preferred_term: NT-proBNP measurement
    term:
      id: NCIT:C96610
      label: N-Terminal ProB-type Natriuretic Peptide Measurement
  evidence:
  - reference: PMID:31073128
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      new diagnostic tools, such as serum biomarkers, that enable early diagnosis
      and treatment
    explanation: >-
      The DCM primer identifies serum biomarkers as enabling early diagnosis, but
      does not name NT-proBNP or give thresholds, so support for this specific
      analyte is PARTIAL.
- name: Cardiomyopathy Multigene Panel Sequencing with Copy-Number Analysis
  description: >-
    The confirmatory test is molecular: a clinically curated cardiomyopathy panel
    that includes ACTN2, interpreted against the caveat that many reported ACTN2
    missense variants lack segregation or functional support. Copy-number analysis
    matters specifically here — two of the informative ACTN2 genotypes are
    structural rather than single-nucleotide (a heterozygous multi-exon deletion,
    and the 1q43 deletion removing ACTN2 with RYR2) — so a sequencing-only panel
    without CNV calling can return a false negative. Exome or genome sequencing is
    a useful adjunct when a family's presentations do not fit one cardiomyopathy
    label.
  diagnosis_term:
    preferred_term: cardiomyopathy multigene panel sequencing with copy-number analysis
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:25224718
    reference_title: Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing is a useful adjunct to cardiac genetic testing in families
      with mixed clinical presentations.
    explanation: >-
      Supports broader sequencing beyond a targeted panel when the family
      phenotype is heterogeneous, exactly the ACTN2 situation.
  - reference: PMID:37374362
    reference_title: "Impaired Cardiomyocyte Maturation Leading to DCM: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing revealed a restricted genomic depletion in the 1q43
      region
    explanation: >-
      Concrete evidence that a copy-number lesion at the ACTN2 locus can be the
      causal finding, which is why copy-number analysis must accompany sequencing.
  - reference: PMID:36116040
    reference_title: Mutation update for the ACTN2 gene.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, limited segregation and functional data are available to support
      the pathogenicity of most previously reported missense variants and
      clear-cut genotype-phenotype correlations are currently only demonstrated
      for some ACTN2-related myopathies.
    explanation: >-
      The interpretive caveat that must accompany a panel result: an ACTN2
      missense variant of uncertain significance should not by itself be read as
      a CMD1AA diagnosis.
- name: Exclusion of Loading Conditions and Coronary Disease
  description: >-
    DCM is definitionally a diagnosis of exclusion: the dilation and systolic
    impairment must not be explained by hypertension, valvular disease, or
    coronary artery disease, and the acquired causes (myocarditis, alcohol and
    other toxins, the peripartum state, endocrine and autoimmune disease) must be
    considered before a genetic label is applied. A pathogenic ACTN2 genotype does
    not remove this step, because carriers can also acquire an unrelated
    cardiomyopathy and because penetrance is incomplete.
  evidence:
  - reference: PMID:31073128
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left
      ventricular or biventricular dilation and impaired contraction that is not
      explained by abnormal loading conditions (for example, hypertension and
      valvular heart disease) or coronary artery disease.
    explanation: >-
      States the exclusion criteria that define the DCM diagnosis. Evidence source
      is OTHER because this is a review.
  - reference: PMID:20301486
    reference_title: Dilated Cardiomyopathy Overview.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Provide the evaluation strategy of a proband with nonsyndromic DCM
    explanation: >-
      The GeneReviews DCM overview exists to supply this proband evaluation
      strategy, of which categorization and exclusion of non-genetic causes is
      the first step. Evidence source is OTHER because GeneReviews is an
      expert-authored review resource.
differential_diagnoses:
- name: Ischemic and other acquired dilated cardiomyopathy
  description: >-
    Coronary artery disease, hypertension, valvular disease, tachyarrhythmia,
    alcohol and other cardiotoxins, and endocrine or autoimmune disease all
    produce a dilated, hypocontractile ventricle and must be excluded before a
    genetic diagnosis is made.
  distinguishing_features:
  - Regional (coronary-territory) wall-motion abnormality, ischemic LGE pattern, or obstructive disease on angiography favors ischemic cardiomyopathy.
  - Absent family history plus an identified exposure or loading condition, with recovery after its removal, favors an acquired cause.
  evidence:
  - reference: PMID:31073128
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Nongenetic forms of DCM can result from different aetiologies, including
      inflammation of the myocardium due to an infection (mostly viral); exposure
      to drugs, toxins or allergens; and systemic endocrine or autoimmune
      diseases.
    explanation: >-
      Enumerates the acquired etiologies that constitute this differential.
      Evidence source is OTHER because this is a review.
- name: Viral myocarditis
  description: >-
    Acute or chronic myocarditis can present with ventricular dilation and
    systolic dysfunction, and inflammatory presentations also occur in genetic
    arrhythmogenic cardiomyopathy, so the distinction is not always clean.
  distinguishing_features:
  - Recent viral prodrome, troponin release, and inflammatory LGE with recovery of function favor myocarditis.
  - Endomyocardial biopsy showing inflammatory infiltrate is indicated when inflammation or infection is suspected.
  disease_term:
    preferred_term: viral myocarditis
    term:
      id: MONDO:0023161
      label: viral myocarditis
  evidence:
  - reference: PMID:31073128
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      immunological and histological analyses of an endomyocardial biopsy sample
      are indicated when inflammation or infection is suspected
    explanation: >-
      Supports biopsy as the discriminator when a myocarditic cause is suspected.
- name: Alcoholic cardiomyopathy
  description: >-
    Chronic heavy alcohol exposure produces a dilated cardiomyopathy that is
    clinically indistinguishable on imaging alone and can coexist with (and
    unmask) a genetic predisposition.
  distinguishing_features:
  - Documented sustained heavy alcohol intake with improvement on abstinence favors a toxic cause.
  - A pathogenic ACTN2 genotype or an affected first-degree relative argues for the genetic diagnosis even when exposure is present.
  disease_term:
    preferred_term: alcoholic cardiomyopathy
    term:
      id: MONDO:0006643
      label: alcoholic cardiomyopathy
- name: Peripartum cardiomyopathy
  description: >-
    De novo systolic heart failure in late pregnancy or the postpartum period
    overlaps clinically with a first presentation of genetic DCM unmasked by the
    hemodynamic load of pregnancy.
  distinguishing_features:
  - Onset confined to late pregnancy or the first months postpartum, in a woman without previous heart disease, defines the peripartum entity.
  - Persistent dysfunction outside the peripartum window, or an affected relative, favors an underlying genetic cardiomyopathy.
  disease_term:
    preferred_term: peripartum cardiomyopathy
    term:
      id: MONDO:0018920
      label: peripartum cardiomyopathy
- name: Isolated left ventricular noncompaction
  description: >-
    Noncompaction is part of the CMD1AA phenotype rather than a separate disease
    in ACTN2 carriers, but isolated noncompaction (and physiological
    hypertrabeculation in athletes or pregnancy) is the differential when
    trabeculation is the dominant finding and dilation is mild.
  distinguishing_features:
  - Noncompaction plus dilation with a pathogenic ACTN2 genotype is CMD1AA, not isolated LVNC.
  - Truncating variants in MYH7, ACTN2, and PRDM16 are the lesions specifically enriched in noncompaction cohorts, so genotype partly resolves the boundary.
  disease_term:
    preferred_term: left ventricular noncompaction
    term:
      id: MONDO:0018901
      label: left ventricular noncompaction
  evidence:
  - reference: PMID:33500567
    reference_title: Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We observed substantial genetic overlap indicating that LVNC often
      represents a phenotypic variation of DCM or HCM.
    explanation: >-
      Establishes that noncompaction frequently is a phenotypic variant of DCM or
      HCM rather than a separate entity, which is exactly the boundary problem in
      an ACTN2 carrier.
- name: Sarcomeric and cytoskeletal dilated cardiomyopathy of other genotype
  description: >-
    TTN truncations, LMNA, FLNC, DSP, RBM20, BAG3, PLN, DES, and SCN5A account for
    far more genotyped familial DCM than ACTN2 does; on phenotype alone they are
    indistinguishable, so the differential is resolved by the panel result rather
    than by imaging.
  distinguishing_features:
  - LMNA and FLNC genotypes carry distinct arrhythmic risk and ICD thresholds, so the specific gene, not the DCM label, drives management.
  - ACTN2 sits in the moderate-evidence tier for DCM, so a variant there should be weighed more cautiously than one in a definitive-evidence gene.
  evidence:
  - reference: PMID:33947203
    reference_title: Evidence-Based Assessment of Genes in Dilated Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Twelve genes (23%) from 8 gene ontologies were classified as having
      definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2,
      TTN) or strong (DSP) evidence.
    explanation: >-
      Names the definitive/strong DCM genes that constitute the genotypic
      differential and against which an ACTN2 finding must be weighed.
progression:
- phase: Genotype-positive, phenotype-negative
  notes: >-
    A relative identified by cascade testing may carry the ACTN2 variant with
    normal echocardiography, ECG, and function. Penetrance is incomplete —
    population data on DCM-gene carriers put combined clinical plus subclinical
    penetrance at no more than about 30% — so surveillance rather than treatment
    is the correct posture at this stage.
  evidence:
  - reference: PMID:35708014
    reference_title: Frequency, Penetrance, and Variable Expressivity of Dilated Cardiomyopathy-Associated Putative Pathogenic Gene Variants in UK Biobank Participants.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The combined clinical/subclinical penetrance was ≤30% with all 3 variant
      filtering strategies.
    explanation: >-
      Quantifies incomplete penetrance across DCM genes; PARTIAL because the
      figure is gene-panel-wide rather than ACTN2-specific.
- phase: Early or subclinical expression
  notes: >-
    First expression is often electrical or subtle-structural rather than frankly
    dilated: conduction disease, atrial or ventricular ectopy, hypokinetic
    non-dilated cardiomyopathy, or isolated trabecular abnormality. In ACTN2
    families this stage includes resuscitated ventricular fibrillation in
    individuals without overt dilation, which is why rhythm surveillance is not
    optional.
  evidence:
  - reference: PMID:35708014
    reference_title: Frequency, Penetrance, and Variable Expressivity of Dilated Cardiomyopathy-Associated Putative Pathogenic Gene Variants in UK Biobank Participants.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ECG and cardiovascular magnetic resonance analysis revealed evidence of
      subclinical DCM in an additional 1.6% and early DCM features in an
      additional 15.9% of individuals with putative pathogenic variants.
    explanation: >-
      Documents a substantial subclinical and early-feature stage detectable by
      ECG and CMR before clinical DCM; PARTIAL because it is gene-panel-wide.
  - reference: PMID:25224718
    reference_title: Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While some individuals were asymptomatic, other presentations included left
      ventricular non-compaction, a resuscitated cardiac arrest due to idiopathic
      ventricular fibrillation, dilated cardiomyopathy, and sudden unexplained
      death.
    explanation: >-
      Shows the full range within one ACTN2 kindred, including arrhythmic
      presentation without overt dilation.
- phase: Overt cardiomyopathy
  notes: >-
    Established structural disease: left ventricular dilation with reduced
    ejection fraction (or the hypertrophic, restrictive, or noncompacted variant
    of the same allelic series), symptomatic heart failure, and cumulative
    arrhythmic risk. Guideline-directed heart-failure therapy and ICD
    consideration belong to this stage.
  evidence:
  - reference: CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Individuals can show variable combinations of hypertrophy, dilatation,
      hyper/hypo contractility, and arrhythmias
    explanation: >-
      ClinGen records the variable structural expression that characterizes overt
      ACTN2 cardiomyopathy.
- phase: Advanced and end-stage disease
  notes: >-
    Progressive pump failure culminating in transplantation, or sudden cardiac
    death from the arrhythmic arm. The biallelic protein-truncating genotype is
    the most severe reported course, with transplantation in early adulthood;
    heterozygous carriers have also progressed to transplantation.
  evidence:
  - reference: PMID:37834023
    reference_title: "Disruption of Z-Disc Function Promotes Mechanical Dysfunction in Human Myocardium: Evidence for a Dual Myofilament Modulatory Role by Alpha-Actinin 2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Left ventricular free wall samples were obtained at the time of cardiac
      transplantation from a heart failure patient with the ACTN2 A868T
      heterozygous variant.
    explanation: >-
      Documents progression to transplantation in a heterozygous ACTN2 carrier.
  - reference: PMID:20022194
    reference_title: "Mutations in alpha-actinin-2 cause hypertrophic cardiomyopathy: a genome-wide analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      those with syncope, heart failure, and premature sudden death
    explanation: >-
      Documents the two end-stage outcomes, pump failure and premature sudden
      death, in an ACTN2 kindred.
treatments:
- name: Guideline-Directed Heart Failure Pharmacotherapy
  description: >-
    Standard heart-failure therapy for left ventricular systolic dysfunction —
    the four contemporary HFrEF pillars: an angiotensin receptor-neprilysin
    inhibitor (or an ACE inhibitor / angiotensin receptor blocker where ARNI is
    not tolerated), a beta-blocker, a mineralocorticoid receptor antagonist, and
    an SGLT2 inhibitor — which together target the neurohormonal amplifier of
    adverse remodeling. There is no ACTN2-specific disease-modifying therapy, so
    management is the generic DCM regimen.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan)
      term:
        id: NCIT:C190796
        label: Angiotensin Receptor-Neprilysin Inhibitor
    - preferred_term: ACE inhibitor (alternative to ARNI)
      term:
        id: NCIT:C247
        label: ACE Inhibitor
    - preferred_term: beta-blocker
      term:
        id: NCIT:C29576
        label: Beta-Adrenergic Antagonist
    - preferred_term: mineralocorticoid receptor antagonist (spironolactone as the class exemplar)
      term:
        id: NCIT:C840
        label: Spironolactone
    - preferred_term: SGLT2 inhibitor
      term:
        id: NCIT:C98083
        label: SGLT2 Inhibitor
  target_mechanisms:
  - target: Neurohormonal Activation
    treatment_effect: INHIBITS
    description: >-
      Neurohormonal blockade interrupts the maladaptive amplifier between the
      primary Z-disc lesion and adverse ventricular remodeling.
  evidence:
  - reference: PMID:31073128
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      As DCM eventually leads to impaired contractility, standard approaches to
      prevent or treat heart failure are the first-line treatment for patients
      with DCM.
    explanation: >-
      Establishes standard heart-failure therapy as first-line management for
      dilated cardiomyopathy, of which CMD1AA is a genetic form.
- name: Implantable Cardioverter Defibrillator
  description: >-
    Device therapy for primary or secondary prevention of sudden cardiac death in
    carriers with high arrhythmic risk — relevant here because ventricular
    fibrillation and sudden death can occur in ACTN2 carriers with limited or no
    ventricular dilation.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  notes: >-
    Indication follows general cardiomyopathy and arrhythmia guidelines; no
    ACTN2-specific risk-stratification rule has been validated.
  evidence:
  - reference: PMID:31073128
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Cardiac resynchronization therapy and implantable cardioverter-defibrillators
      may be required to prevent life-threatening arrhythmias.
    explanation: >-
      Establishes device therapy for arrhythmic protection as part of standard DCM
      management, the framework applied to ACTN2 carriers. Evidence source is
      OTHER because this is a Nature Reviews Disease Primers review.
- name: Cascade Genetic Testing and Counseling
  description: >-
    Predictive ACTN2 testing and cardiac surveillance of first-degree relatives,
    with counseling that addresses incomplete penetrance and the marked
    intrafamilial variability of expression (dilated, hypertrophic, noncompacted,
    or purely arrhythmic).
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:25224718
    reference_title: Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing is a useful adjunct to cardiac genetic testing in families
      with mixed clinical presentations.
    explanation: >-
      Supports genetic testing as the tool that resolves the diagnosis in ACTN2
      families whose clinical presentations do not fit one cardiomyopathy label.
  - reference: PMID:20301486
    reference_title: Dilated Cardiomyopathy Overview.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Provide a basic view of genetic risk assessment of at-risk asymptomatic
      relatives of a proband with DCM to inform cardiac surveillance and allow
      early detection and treatment of DCM to improve long-term outcome.
    explanation: >-
      The GeneReviews DCM overview frames genetic risk assessment of at-risk
      asymptomatic relatives, with cardiac surveillance for early detection, as
      the purpose of cascade evaluation — precisely this treatment. Evidence
      source is OTHER because GeneReviews is an expert-authored review resource.
- name: Heart Transplantation
  description: >-
    Advanced therapy for end-stage heart failure; explanted ACTN2-variant
    myocardium obtained at transplantation has been the source of the human
    mechanical studies of this disease.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Organ transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation
  evidence:
  - reference: PMID:37834023
    reference_title: "Disruption of Z-Disc Function Promotes Mechanical Dysfunction in Human Myocardium: Evidence for a Dual Myofilament Modulatory Role by Alpha-Actinin 2."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Left ventricular free wall samples were obtained at the time of cardiac
      transplantation from a heart failure patient with the ACTN2 A868T
      heterozygous variant.
    explanation: >-
      Documents that an ACTN2 variant carrier progressed to transplantation; this
      is incidental evidence of transplant use in this disease rather than an
      efficacy study, hence PARTIAL.
experimental_models:
- name: Patient-derived ACTN2 truncating-variant iPSC-cardiomyocytes
  description: >-
    Induced pluripotent stem cell-derived cardiomyocytes generated from carriers
    of monoallelic and biallelic ACTN2 protein-truncating variants, characterized
    by RNA sequencing, video-based edge detection of contraction,
    immunohistochemistry, electron microscopy, and affinity-purification mass
    spectrometry, with CRISPR-Cas9 verification of the stop-gain variant. The
    reference human model for the ACTN2 contractile and Z-disc-ultrastructure
    phenotype.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cell_source: Patient-derived iPSC lines from ACTN2 protein-truncating variant carriers
  publication: PMID:34802252
  modeled_mechanisms:
  - target: Impaired Z-Disc Force Transmission and Myofilament Regulation
    description: >-
      Contractility and electron-microscopy readouts measure Z-disc
      ultrastructure and force generation in the variant background.
  - target: Sarcomeric Disarray and Cardiomyocyte Hypertrophy
    description: >-
      Immunohistochemistry quantifies cellular hypertrophy and myofibrillar
      disarray.
  - target: Loss of Sarcolemmal Partner Coupling and Arrhythmogenesis
    description: >-
      Affinity-purification mass spectrometry identified the loss of ACTN1 and
      GJA1 interactions on C-terminal truncation.
  evidence:
  - reference: PMID:34802252
    reference_title: Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In patient-derived iPSC-cardiomyocytes, we investigated transcriptional
      profiles using RNA sequencing, contractile properties using video-based
      edge detection, and cellular hypertrophy using immunohistochemistry.
    explanation: >-
      Describes the model system and its readouts as used to characterize ACTN2
      cardiomyopathy.
- name: Isogenic ACTN2 missense hiPSC-cardiomyocytes and engineered heart tissue
  description: >-
    CRISPR/Cas9-generated heterozygous functional knock-out hiPSC lines carrying
    either a wild-type or a missense ACTN2 allele, differentiated to
    cardiomyocytes and assembled into engineered heart tissue, and profiled by
    immunofluorescence, live-cell imaging, RNA sequencing, and mass spectrometry.
    Provides the isogenic comparison underlying the proteopathy arm.
  experimental_model_type: IPSC_DERIVED_MODEL
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: Cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cell_source: CRISPR/Cas9-edited human iPSC lines (isogenic ACTN2 wild-type versus missense)
  culture_system: 2D monolayer hiPSC-cardiomyocytes and 3D engineered heart tissue
  publication: PMID:36078153
  modeled_mechanisms:
  - target: Mutant Alpha-Actinin-2 Destabilization and Proteostatic Stress
    description: >-
      The isogenic pair isolates variant-specific protein aggregation and
      proteolytic-system activation from genetic background effects.
  evidence:
  - reference: PMID:36078153
    reference_title: ACTN2 Mutant Causes Proteopathy in Human iPSC-Derived Cardiomyocytes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we created with CRISPR/Cas9 genetic tools two heterozygous functional
      knock-out hiPSC lines with a second wild-type (ACTN2wt) and missense ACTN2
      (ACTN2mut) allele, respectively.
    explanation: >-
      Documents the isogenic design of the model used to isolate the
      variant-specific proteostatic phenotype.
discussions:
- discussion_id: actn2_lumping_vs_mondo_splitting
  prompt: >-
    Should dismech keep phenotype-specific ACTN2 entities (CMD1AA, CMH23,
    restrictive and arrhythmogenic forms, ACTN2 myopathy) as separate entries, or
    follow ClinGen in lumping them into a single ACTN2-related cardiac and
    skeletal myopathy entity?
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - pathophysiology#Alpha-Actinin-2 Z-Disc Dysfunction
  rationale: >-
    ClinGen's Hereditary Cardiovascular Disease GCEP explicitly applied the
    Lumping and Splitting framework and concluded there is insufficient evidence
    to split ACTN2 presentations by inheritance, phenotype, or mechanism, whereas
    MONDO retains the phenotype-specific nodes that dismech uses as disease_term.
    This entry is scoped to the dilated node (MONDO:0012808) and records the
    hypertrophic and noncompaction expressions as spectrum context; if the field
    converges on the lumped entity, the dismech representation should be revisited
    rather than duplicated across sibling entries.
  evidence:
  - reference: CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Per criteria outlined by the ClinGen Lumping and Splitting Working Group,
      all disease entities have been lumped into one inclusive disease entity,
      which is now being called ACTN2-related cardiac and skeletal myopathy.
    explanation: >-
      Documents the lumping decision that is in tension with the MONDO
      phenotype-specific nodes.
  - reference: PMID:36116040
    reference_title: Mutation update for the ACTN2 gene.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Previously reported variants are in varying locations across the gene, but
      the potential clustering effect of pathogenic locations is not clearly
      understood.
    explanation: >-
      Absence of a domain-to-phenotype mapping is part of why the phenotype split
      is hard to defend on mechanistic grounds.
- discussion_id: actn2_dcm_mechanism_gap
  prompt: >-
    Which molecular mechanism — dominant-negative incorporation of mutant
    alpha-actinin-2 into the Z-disc, altered myofilament calcium sensitivity,
    protein destabilization with proteostatic stress, or loss of sarcolemmal
    ACTN1/GJA1 coupling — actually drives the dilated (as opposed to hypertrophic
    or arrhythmic) presentation, and what determines which phenotype a given
    carrier develops?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Z-Disc Force Transmission and Myofilament Regulation
  - pathophysiology#Mutant Alpha-Actinin-2 Destabilization and Proteostatic Stress
  rationale: >-
    The same ACTN2 variant can produce dilation in one relative and hypertrophy,
    noncompaction, arrhythmia, or nothing in another, and the available
    mechanistic studies each characterize a different single variant in a
    different system (explanted myocardium, patient iPSC-cardiomyocytes, isogenic
    hiPSC lines, knock-in mouse, purified protein). Without a
    variant-to-mechanism map the pathograph cannot state which arm is
    rate-limiting for the dilated phenotype, and variant interpretation stays
    unanchored to mechanism.
  proposed_experiments:
  - experiment_id: exp_actn2_allelic_panel_isogenic_hipsc_cm
    name: Allelic-panel isogenic hiPSC-cardiomyocyte comparison of ACTN2 variants
    description: >-
      Systematically phenotype an allelic panel of dilated-, hypertrophic-, and
      noncompaction-associated ACTN2 variants in isogenic hiPSC-cardiomyocytes
      and engineered heart tissue with matched readouts (Z-disc incorporation,
      protein stability and aggregation, myofilament calcium sensitivity,
      connexin-43 localization, force), so that phenotype-specific mechanisms can
      be compared directly rather than inferred across heterogeneous studies.
  evidence:
  - reference: CGGV:assertion_6710e329-d391-4355-85a5-02d03f8791a3-2025-07-23T040000.000Z
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The disease mechanism is currently unclear and may be variant-specific
      since some variants have been shown to result in protein aggregation while
      others do not have this effect
    explanation: >-
      ClinGen states the mechanism gap directly, including its variant-specific
      character.
  - reference: PMID:34802252
    reference_title: Mono- and Biallelic Protein-Truncating Variants in Alpha-Actinin 2 Cause Cardiomyopathy Through Distinct Mechanisms.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The mechanisms linking ACTN2 mutations to myocardial disease phenotypes are
      unknown.
    explanation: >-
      Independent statement of the same gap from the study that separated the
      monoallelic and biallelic mechanisms.
- discussion_id: actn2_mouse_heterozygote_model_mismatch
  prompt: >-
    Why does a heterozygous Actn2 missense knock-in mouse remain phenotypically
    normal while heterozygous human carriers of comparable ACTN2 missense
    variants develop cardiomyopathy, and can such mice be used to model dominant
    ACTN2 disease at all?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Mutant Alpha-Actinin-2 Destabilization and Proteostatic Stress
  - pathophysiology#Sarcomeric Disarray and Cardiomyocyte Hypertrophy
  rationale: >-
    The only published Actn2 missense knock-in mouse shows no overt cardiac
    phenotype in heterozygotes (only molecular changes, and only in mature males),
    while homozygosity is embryonically lethal — a dosage profile that does not
    reproduce autosomal dominant human ACTN2 cardiomyopathy. Mechanistic
    inferences drawn from that model (proteasomal activation, mitochondrial and
    cell-cycle defects) therefore rest on either subclinical heterozygote
    molecular readouts or a lethal homozygous state with no human counterpart, and
    their translational weight for the human dilated phenotype is uncertain.
  proposed_experiments:
  - experiment_id: exp_actn2_mouse_stress_and_aging_challenge
    name: Stress- and age-challenged Actn2 heterozygote phenotyping with human comparison
    description: >-
      Phenotype Actn2 missense heterozygous mice under hemodynamic, exercise, and
      aging challenge with sex stratification, and compare the resulting molecular
      signatures against human ACTN2-variant myocardium and hiPSC-cardiomyocytes,
      to determine whether the silent heterozygote reflects a genuine species
      difference or an unstressed baseline.
  evidence:
  - reference: PMID:36899856
    reference_title: Insights into the Role of a Cardiomyopathy-Causing Genetic Variant in ACTN2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Heterozygous Actn2 p.Met228Thr mice have no overt phenotype. Only mature
      males show molecular parameters indicative of cardiomyopathy.
    explanation: >-
      Documents the absent heterozygous phenotype that constitutes the
      human-model mismatch.
  - reference: PMID:36899856
    reference_title: Insights into the Role of a Cardiomyopathy-Causing Genetic Variant in ACTN2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      By contrast, the variant is embryonically lethal in the homozygous setting
      and E15.5 hearts show multiple morphological abnormalities.
    explanation: >-
      The homozygous state is embryonically lethal, so the mechanistic readouts
      come from a genotype without a human dominant-disease counterpart.
references:
- reference: PMID:20301486
  title: Dilated Cardiomyopathy Overview.
  tags:
  - GeneReviews
- reference: PMID:33802723
  title: The Role of Z-disc Proteins in Myopathy and Cardiomyopathy.
notes: >-
  Scope: this entry models MONDO:0012808 (dilated cardiomyopathy 1AA), the
  ACTN2-related dilated node of the ACTN2 allelic series, and conforms to the
  cardiomyopathy_maladaptive_remodeling module. The hypertrophic (CMH23),
  restrictive, left-dominant arrhythmogenic, and skeletal-myopathy expressions of
  ACTN2 variation appear here only as spectrum context and in the
  lumping/splitting discussion; ClinGen curates them as one lumped entity
  (MONDO:0700349, the MONDO parent of this term).

  Named Entity Confusion preflight (per CLAUDE.md): MONDO:0012808 was verified
  with OAK before curation — the definition names ACTN2 as the causal gene, the
  OMIM xref is OMIM:612158, and synonyms include CMD1AA and "cardiomyopathy,
  dilated, 1AA, with or without LVNC". All curated evidence concerns ACTN2, and
  the OMIM entry's inclusion of "cardiomyopathy, hypertrophic, 23" as a synonym
  of the same locus is handled explicitly rather than silently mixed into the
  dilated phenotype.

  Several mechanistic evidence items come from ACTN2 variants first reported in
  hypertrophic cardiomyopathy (A119T, p.Met228Thr) or from explanted myocardium of
  a single heart-failure patient (A868T). These are retained because they
  characterize the shared Z-disc mechanism, and each explanation states the
  phenotype caveat explicitly rather than implying dilated-specific evidence.

  GeneReviews scope: there is no ACTN2-specific GeneReviews chapter, so the
  applicable resource is the disease-level "Dilated Cardiomyopathy Overview"
  (PMID:20301486), tagged accordingly in `references`. The indexed record carries
  a four-clause purpose statement rather than the full chapter text, so
  section-by-section GeneReviews mining (Clinical Characteristics, Management,
  Genetic Counseling) is not possible from the cache; the two clauses that are
  verbatim-quotable are cited — the proband-evaluation clause on the
  diagnosis-by-exclusion entry, and the at-risk-relative risk-assessment clause
  on cascade testing. The Z-disc protein review (PMID:33802723) is now cited on
  the trigger node for the force-transduction/signalling framing.

  Diagnostics are modeled DCM-wide where no ACTN2-specific study exists (CMR-LGE
  prognosis, natriuretic peptides, penetrance) and those items are marked PARTIAL
  with the reason stated. The one ACTN2-specific diagnostic point is copy-number
  analysis: two informative genotypes in this gene are structural (a heterozygous
  multi-exon deletion and the 1q43 deletion that also removes RYR2), so a
  sequencing-only panel can miss the diagnosis.

📚

References & Deep Research

References

2

PMID:20301486

Dilated Cardiomyopathy Overview.

No top-level findings curated for this source.

PMID:33802723

The Role of Z-disc Proteins in Myopathy and Cardiomyopathy.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 27 citations 2026-08-01T12:02:44.245271

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Dilated Cardiomyopathy 1AA
MONDO ID: (if available)
Category: Genetic

Research Objectives

Please provide a comprehensive research report on Dilated Cardiomyopathy 1AA covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Dilated Cardiomyopathy 1AA (ACTN2-related cardiomyopathy): comprehensive disease-characteristics report

Executive summary and scope

Dilated cardiomyopathy 1AA (DCM1AA) is a legacy subtype designation for rare, usually familial cardiomyopathy attributed to pathogenic variation in ACTN2, which encodes the Z-disc protein α-actinin-2. Modern evidence supports viewing it as part of an ACTN2-related intrinsic cardiomyopathy spectrum, rather than as a uniformly dilated phenotype: reported manifestations include dilated cardiomyopathy (DCM), left-ventricular noncompaction (LVNC), arrhythmogenic presentations, hypertrophic cardiomyopathy (HCM), and—particularly with biallelic truncation—restrictive cardiomyopathy (RCM). Open Targets links ACTN2 to general DCM (MONDO:0005021), familial DCM (MONDO:0016333), and familial isolated DCM (MONDO:0700335), but the retrieved current resources did not expose a reliable distinct MONDO record specifically labelled “DCM1AA.” Therefore, database ingestion should retain the legacy name while mapping primarily to ACTN2-related cardiomyopathy/familial DCM, with the phenotype recorded separately. (OpenTargets Search: dilated cardiomyopathy-ACTN2, lindholm2021monoandbiallelic pages 1-3)

The evidence base is small and variant-specific. The first ACTN2 missense variant in a DCM patient was reported in 2003 (Mohapatra et al.; PMID 14567970). Later studies provided segregation and functional evidence for dominant disease and demonstrated recessive disease from a homozygous C-terminal truncation. Accordingly, epidemiologic, penetrance, prognosis, and treatment estimates for general DCM must not be misrepresented as DCM1AA-specific. (lindholm2021monoandbiallelic pages 1-3, lindholm2021monoandbiallelic pages 3-4)

domain	best-supported finding	evidence type	key quantitative detail or variant	source/year
Identity / causal gene	Dilated Cardiomyopathy 1AA is best interpreted as rare ACTN2-related familial/intrinsic dilated cardiomyopathy within a broader ACTN2 cardiomyopathy spectrum; modern resources strongly support ACTN2 as a DCM-associated target, but a distinct current MONDO record for the legacy subtype label is not clearly exposed	Curated disease-target association + review + primary human genetics	ACTN2 association score present for dilated cardiomyopathy/familial DCM; first DCM ACTN2 report noted in 2003	Open Targets / literature synthesis 2024-2025 (OpenTargets Search: dilated cardiomyopathy-ACTN2, lindholm2021monoandbiallelic pages 1-3)
Inheritance	ACTN2 cardiomyopathy can be autosomal dominant or recessive depending on variant class; dominant disease is supported for heterozygous indel/missense variants, while recessive severe disease is supported for homozygous truncation	Human clinical genetics + family segregation + functional validation	Heterozygous exon 8-10 deletion family; homozygous p.Gln860Ter (Q860X) restrictive/end-stage phenotype; recessive causality established	Lindholm et al. 2021 (lindholm2021monoandbiallelic pages 1-3, lindholm2021monoandbiallelic pages 3-4, lindholm2021monoandbiallelic pages 4-6)
Phenotypic spectrum	ACTN2 variants cause a mixed cardiomyopathy spectrum including DCM, arrhythmic phenotypes, LV noncompaction, restrictive cardiomyopathy, heart failure, and sudden death in some families	Human clinical + review	Family 2 had ventricular tachyarrhythmias, atrial fibrillation, LV noncompaction, symptomatic HF, and 2 early sudden cardiac deaths; Q860X patient required transplant at 23 years	Lindholm et al. 2021; review synthesis 2024 (lindholm2021monoandbiallelic pages 3-4, micolonghi2024unveilingthespectrum pages 29-30)
Core mechanism	Disease mechanisms converge on Z-disc/sarcomere dysfunction with impaired contractility, structural disarray, abnormal Ca2+ handling, and disrupted protein interactions; mechanism differs by zygosity	iPSC-CM, EM, RNA-seq, AP-MS, CRISPR	Heterozygous indel protein incorporates into sarcomeres with aberrant Z-disc ultrastructure; C-terminal truncation disrupts ACTN1 and GJA1 interactions	Lindholm et al. 2021 (lindholm2021monoandbiallelic pages 1-3, lindholm2021monoandbiallelic pages 8-9, lindholm2021monoandbiallelic pages 4-6)
Recent 2023 mouse study	A CRISPR knock-in Actn2 p.Met228Thr mouse provided recent in vivo evidence that ACTN2 dysfunction can drive cardiomyopathy-related biology via protein instability, mitochondrial dysfunction, and cell-cycle abnormalities	Mouse model + proteomics	Heterozygotes had no overt phenotype except molecular changes in mature males; homozygotes were embryonic lethal at/after E15.5 analysis	Broadway-Stringer et al. 2023 (broadwaystringer2023insightsintothe pages 1-2, broadwaystringer2023insightsintothe pages 2-4)
2023 human deletion case	A pediatric case with 1q43 deletion involving ACTN2 and RYR2 linked ACTN2 loss to severe early-onset DCM with LV noncompaction and reduced EF	Human case report	chr1:236,686,454-237,833,988 (hg38) deletion; enlarged LV with LVIDd 48 mm, Z-score 3.81; follow-up LVEF 41%; transplant recommended	Zhou et al. 2023 (zhou2023impairedcardiomyocytematuration pages 3-7, zhou2023impairedcardiomyocytematuration pages 7-8)
Molecular profiling	ACTN2 disease models show transcriptional and proteomic abnormalities consistent with fibrosis, hypertrophy, metabolic remodeling, and altered interaction networks	RNA-seq + GSEA + proteomics	Elevated MYL2; enriched extracellular matrix remodeling/collagen biosynthesis in Q860X tissue; induced respiratory electron transport and gluconeogenesis in hiPSC-CMs	Lindholm et al. 2021 (lindholm2021monoandbiallelic pages 3-4, lindholm2021monoandbiallelic pages 4-6)
Developmental / model evidence	Loss of ACTN2 perturbs cardiomyocyte maturation and cardiac development; zebrafish and mammalian models support reduced chamber/cell size and structural defects	Zebrafish LOF + mouse + human case synthesis	Zebrafish ACTN2 depletion reduced end-diastolic diameter, cardiomyocyte size/number, and ventricular chamber size; ACTN3 could not rescue LOF phenotype	Wadmore 2021; Lindholm 2021; Zhou 2023 (lindholm2021monoandbiallelic pages 8-9, wadmore2021theroleof pages 2-4, zhou2023impairedcardiomyocytematuration pages 7-8)
Diagnosis / prognosis	For DCM generally, diagnosis relies on multimodal imaging and genetics; prognosis is informed by genotype and CMR fibrosis burden more than EF alone in some contexts	Guideline review + population study + meta-analysis	DCM true prevalence estimated about 1:250 and 1:220 by UK Biobank CMR; in NIDCM, LGE HR 1.81 for all-cause mortality and 2.69 for arrhythmic events; Q860X patient progressed to transplant	Newman 2024; Eichhorn 2024; Lindholm 2021 (newman2024dilatedcardiomyopathya pages 1-2, eichhorn2024riskstratificationin pages 1-2, lindholm2021monoandbiallelic pages 3-4)
Current treatment status	No ACTN2-specific approved therapy or ACTN2-directed clinical trial was found; management follows standard DCM/HFrEF care, arrhythmia surveillance, family screening, devices, and advanced HF therapies when indicated	Guideline review + trial landscape + case report	Standard “quadruple” HFrEF drug classes apply broadly; pediatric deletion case received digoxin, captopril, metoprolol, levocarnitine/creatine phosphate, but remained severe; no ACTN2-specific interventional trial identified	Badger 2023 / MacDonald 2023 summaries, trial search, Zhou 2023 (zhou2023impairedcardiomyocytematuration pages 3-7)
Major evidence gaps	Evidence remains sparse, mostly case-based, with limited penetrance data, no subtype-specific epidemiology, and no validated preventive or genotype-specific treatment pathway for ACTN2-DCM	Evidence-gap synthesis	Do not overstate prevalence for DCM1AA specifically; available epidemiology/penetrance figures are for broader DCM gene sets or general DCM, not ACTN2 subtype alone	Shah 2022; Newman 2024; review synthesis 2024 (shah2022frequencypenetranceand pages 10-12, newman2024dilatedcardiomyopathya pages 1-2, micolonghi2024unveilingthespectrum pages 29-30)

Table: This table summarizes the strongest currently available evidence for Dilated Cardiomyopathy 1AA as ACTN2-related cardiomyopathy, separating subtype-specific findings from broader DCM context. It is useful for quickly identifying what is well supported, what remains generic to DCM, and where major evidence gaps remain.

1. Disease information

Definition

DCM is a myocardial disorder characterized by ventricular systolic dysfunction and chamber dilation not explained solely by abnormal loading or coronary disease. In DCM1AA, the initiating lesion is germline ACTN2 dysfunction, affecting the sarcomeric Z-disc, force transmission, mechanosignaling, calcium handling, and cardiomyocyte maturation. ACTN2 is highly expressed in cardiac and skeletal muscle and cross-links actin and titin at the Z-disc. (lindholm2021monoandbiallelic pages 1-3, broadwaystringer2023insightsintothe pages 1-2)

Identifiers and nomenclature

Preferred knowledge-base label: ACTN2-related dilated cardiomyopathy / ACTN2-related intrinsic cardiomyopathy.
Legacy synonym: Dilated cardiomyopathy 1AA; DCM1AA; familial dilated cardiomyopathy due to ACTN2.
Gene: ACTN2, actinin alpha 2; Ensembl ENSG00000077522; chromosome 1q42–q43.
MONDO mappings supported by retrieved curation: DCM MONDO:0005021; familial DCM MONDO:0016333; familial isolated DCM MONDO:0700335. A unique DCM1AA MONDO identifier was not verified. (OpenTargets Search: dilated cardiomyopathy-ACTN2)
Broad clinical coding: ICD-10-CM I42.0 (dilated cardiomyopathy); ICD-11 generally classifies it under dilated cardiomyopathy. These phenotype codes do not encode ACTN2 etiology.
MeSH: Dilated Cardiomyopathy.
OMIM: ACTN2 is the implicated locus; because legacy numbered DCM labels have changed across resources, the exact DCM1AA OMIM number should be verified directly in the live OMIM record before ingestion rather than inferred from secondary sources.

The present report is based on aggregated disease-level resources, published families, individual case reports, and experimental models, not longitudinal EHR-derived patient data.

2. Etiology, risk, protection, and gene–environment interaction

Causal factors

The primary cause is a germline ACTN2 variant that disrupts α-actinin-2 structure, abundance, localization, or interactions. Both monoallelic and biallelic mechanisms occur:

Dominant-negative or altered-function disease: a truncated or missense protein remains expressed and may incorporate into the Z-disc, disrupting sarcomeric architecture.
Loss-of-function/haploinsufficiency: large deletions or destabilizing variants reduce functional α-actinin-2.
Recessive truncation: homozygous p.Gln860Ter causes loss of the C-terminal interaction region and severe early disease. Lindholm et al. concluded that their data “establish recessive inheritance of ACTN2 truncation as causative of disease.” (lindholm2021monoandbiallelic pages 1-3, lindholm2021monoandbiallelic pages 8-9)

Genetic risk factors and modifiers

The strongest disease-level risk factor is a pathogenic/likely pathogenic ACTN2 variant plus a compatible phenotype and segregation pattern. Variant interpretation must be conservative: in 2021, ClinVar contained 14 pathogenic/likely pathogenic ACTN2 variants—eight missense, one splice-acceptor, and three nonsense variants—but 390 laboratory-reported VUS; ACTN2 was strongly loss-of-function constrained (pLI 1.0). These historical counts are not current and should be refreshed from ClinVar/gnomAD at ingestion. (lindholm2021monoandbiallelic pages 4-6)

Common regulatory variation also modifies heart-failure susceptibility. A large GWAS identified a chromosome-1 regulatory locus interacting with ACTN2; deletion of the enhancer in human embryonic-stem-cell-derived cardiomyocytes reduced ACTN2 expression. The discovery involved 10,976 cases and 437,573 controls, followed by replication in 24,829 cases and 1,614,513 controls; the ACTN2-region Hi-C interaction had P=0.00002. This is susceptibility evidence for heart failure, not proof that the common variant causes monogenic DCM1AA. (arvanitis2020genomewideassociationand pages 1-2)

Possible modifiers include other sarcomeric/calcium-handling variants. A 2023 child with a 1q43 deletion affecting ACTN2, RYR2, and MTR had severe DCM/LVNC, but the blended deletion prevents attribution to ACTN2 alone. No validated DCM1AA-specific modifier gene, protective allele, founder mutation, or polygenic score is established. (zhou2023impairedcardiomyocytematuration pages 3-7, zhou2023impairedcardiomyocytematuration pages 7-8)

Environmental and acquired risk factors

No ACTN2-specific exposure interaction has been quantified. By analogy with genetic DCM, pregnancy/peripartum stress, cardiotoxic chemotherapy, heavy alcohol exposure, myocarditis, tachyarrhythmia, hypertension, obesity, and sustained high hemodynamic load may reveal latent disease. These should be recorded as potential second hits, not ACTN2-specific causes. Population studies show that expression of DCM-gene variants depends on family history, genomic context, polygenic background, and environment. (shah2022frequencypenetranceand pages 10-12)

Protective factors

No reproducible genetic protective factor is known. Environmental risk reduction is prudent: avoid cardiotoxins and binge/heavy alcohol, treat hypertension and arrhythmia, maintain vaccination and infection prevention, and use individualized exercise advice. These measures prevent additional myocardial injury but have not been shown to prevent ACTN2 penetrance.

3. Phenotypes

ACTN2 disease exhibits marked variable expressivity. Frequencies cannot be estimated reliably because reports comprise a few families and cases.

Ventricular dilation and systolic dysfunction: central DCM phenotype; suggest HP:0001644 Dilated cardiomyopathy, HP:0001722 Decreased cardiac output, and HP:0012664 Reduced left ventricular ejection fraction. In the 2023 deletion case, LV internal diameter in diastole was 48 mm (Z=3.81) and follow-up LVEF remained 41%. Severity ranges from subclinical to transplant-level heart failure. (zhou2023impairedcardiomyocytematuration pages 3-7)
Heart failure symptoms: exertional intolerance, dyspnea/tachypnea, fatigue, diaphoresis, poor feeding in children, and edema in advanced disease; suggest HP:0001635 Congestive heart failure, HP:0002094 Dyspnea, HP:0002878 Respiratory distress, and HP:0003073 Hypohidrosis/diaphoresis only if clinically appropriate. The p.Gln860Ter patient presented in infancy with tachypnea and reduced EF and progressed to transplantation at 23. (lindholm2021monoandbiallelic pages 3-4)
Arrhythmias and conduction/repolarization abnormalities: atrial fibrillation, nonsustained or sustained ventricular tachyarrhythmia, T-wave inversion, conduction delay, syncope, and sudden death. Suggested HPO: HP:0005110 Atrial fibrillation, HP:0004756 Ventricular tachycardia, HP:0001279 Syncope, HP:0001645 Sudden cardiac death, and HP:0011714 Abnormality of cardiac conduction. In one deletion family, the proband had exertional syncope at 16; relatives had atrial arrhythmia, ventricular tachyarrhythmia, conduction delay, and two early sudden deaths. (lindholm2021monoandbiallelic pages 3-4)
LV noncompaction/hypertrabeculation: suggested HP:0030682 Left ventricular noncompaction. This occurred in the dominant deletion family and in the 2023 multigene deletion case. (zhou2023impairedcardiomyocytematuration pages 3-7, lindholm2021monoandbiallelic pages 3-4)
Restrictive physiology and biatrial enlargement: especially with biallelic p.Gln860Ter; suggest HP:0001723 Restrictive cardiomyopathy, HP:0005114 Atrial enlargement, and HP:0001639 Abnormality of the pericardium only when present. The reported patient developed severe biatrial enlargement, moderate biventricular dysfunction, diastolic dysfunction, equalized filling pressures, atrial fibrillation, and severe fibrosis. (lindholm2021monoandbiallelic pages 9-11, lindholm2021monoandbiallelic pages 3-4)
Myocardial fibrosis/hypertrophy: biopsy or CMR phenotype; suggest HP:0030858 Myocardial fibrosis and HP:0001639 Hypertrophic cardiomyopathy only when the actual phenotype is hypertrophic. Explanted p.Gln860Ter myocardium had severe interstitial fibrosis. (lindholm2021monoandbiallelic pages 3-4)
Skeletal-muscle phenotype: ACTN2 is expressed in skeletal muscle and dominant ACTN2 myopathy has been reported, but skeletal weakness is not established as a defining DCM1AA phenotype. Record separately when present.

Quality-of-life burden follows heart-failure severity: reduced exercise capacity, school/work limitations, recurrent monitoring and hospitalization, anxiety regarding sudden death, device shocks, and transplant burden. No ACTN2-specific EQ-5D, SF-36, or PROMIS study was found.

4. Genetic and molecular information

Gene and protein

ACTN2 encodes the 894-amino-acid α-actinin-2 homodimer. Each monomer contains an N-terminal actin-binding domain with CH1/CH2 calponin-homology domains, four spectrin-like repeats forming the rod/dimer interface, and a C-terminal calmodulin-like region with EF hands that participates in titin and partner interactions. The protein cross-links antiparallel actin filaments, anchors titin, organizes Z-disc architecture, regulates ion-channel complexes, and participates in mechanosensitive transcription. (lindholm2021monoandbiallelic pages 1-3, broadwaystringer2023insightsintothe pages 1-2)

Suggested annotations include GO:0055003 cardiac myofibril assembly, GO:0030239 myofibril assembly, GO:0007015 actin filament organization, GO:0030049 muscle filament sliding, GO:0006936 muscle contraction, GO:0007512 adult heart development, GO:0005925 focal adhesion, and cellular components GO:0030018 Z disc, GO:0030017 sarcomere, and GO:0015629 actin cytoskeleton.

Illustrative variants

p.Gln860Ter (Q860X): homozygous, absent from gnomAD in the report; C-terminal truncation causing infantile-onset progressive RCM/heart failure and transplant at 23. Protein persisted at near-normal abundance but lost selected interactions. (lindholm2021monoandbiallelic pages 8-9, lindholm2021monoandbiallelic pages 3-4)
NC_000001.10:g.236898807_236903093del, deleting exons 8–10 with a 41-bp intronic insertion: heterozygous in-frame alteration producing a 771-aa protein versus 894 aa; segregated with arrhythmia, LVNC, and early heart-failure manifestations in seven family members. Truncated transcript represented about 20–30% of full-length transcript in patient cells. (lindholm2021monoandbiallelic pages 3-4, lindholm2021monoandbiallelic pages 4-6)
p.Lys? / original 2003 DCM variant: the retrieved evidence confirms an ACTN2 missense DCM report (PMID 14567970), but exact HGVS should be taken from the primary record before database entry.
p.Leu320Arg: reported in a Chinese family with DCM and ventricular tachycardia. (micolonghi2024unveilingthespectrum pages 29-30)
p.Gly111Val, p.Ala119Thr, p.Met228Thr, p.Thr247Met: primarily HCM-associated actin-binding-domain variants; useful for mechanism and phenotypic spectrum but should not automatically be annotated as DCM1AA variants. (broadwaystringer2023insightsintothe pages 1-2, broadwaystringer2023insightsintothe pages 2-4)
Large 1q43 deletion: chr1:236,686,454–237,833,988 (hg38), affecting ACTN2, RYR2, and MTR; germline heterozygous CNV with DCM/LVNC. Its pathogenic contribution is multigenic. (zhou2023impairedcardiomyocytematuration pages 3-7)

All documented disease variants are germline. No somatic ACTN2 mechanism is established. Population frequencies must be variant-specific and taken from current gnomAD; absence or rarity alone is insufficient for ACMG/AMP pathogenicity. Segregation, phenotype specificity, functional evidence, predicted molecular consequence, and gene-level disease validity are required. CMA/WGS is important for exon-level or multigene deletions that sequencing-only panels may miss.

Epigenetic and chromosomal findings

No reproducible DCM1AA-specific DNA-methylation or histone signature is established. A cardiomyocyte-specific enhancer regulating ACTN2 is supported by chromatin conformation, developmental activation, and genome editing, providing a regulatory-genomic—not classical epigenetic-disease—mechanism. (arvanitis2020genomewideassociationand pages 1-2)

5. Environmental information

ACTN2-related disease is not infectious, toxic, or zoonotic. Viral myocarditis and toxins are differential or superimposed injuries rather than primary causes. No pathogen, pollutant, radiation exposure, occupational agent, smoking pattern, diet, or alcohol threshold has been demonstrated specifically to cause DCM1AA. Clinically, avoid excessive alcohol, cocaine/amphetamines, anabolic agents, and unnecessary cardiotoxic drugs; manage metabolic and vascular risk factors. Exercise prescriptions should be individualized because arrhythmia and sudden death occur in some ACTN2 families, but evidence is insufficient to impose an ACTN2-specific universal exercise ban.

6. Mechanism and pathophysiology

Causal chain

Upstream: pathogenic ACTN2 variant or regulatory loss → altered α-actinin-2 folding, stability, abundance, domain architecture, or partner binding.

Intermediate: abnormal actin/titin cross-linking and Z-disc assembly → sarcomeric disarray and defective force transmission; altered interaction with ion-channel and sarcolemmal proteins; impaired calcium handling; abnormal mechanosensitive transcription and cardiomyocyte maturation; mitochondrial energetic stress and proteostasis activation.

Downstream: reduced contractile velocity and compensatory hypertrophy → chamber dilation or restrictive remodeling, fibrosis, systolic/diastolic dysfunction, conduction abnormalities and arrhythmia → heart failure, sudden death, mechanical support, or transplantation. (lindholm2021monoandbiallelic pages 1-3, lindholm2021monoandbiallelic pages 8-9, lindholm2021monoandbiallelic pages 4-6, lindholm2021monoandbiallelic pages 3-4)

Variant-dependent mechanisms

In heterozygous exon 8–10 indel cells, the truncated protein entered sarcomeres and distorted Z-disc ultrastructure—a dominant-negative mechanism. Patient hiPSC cardiomyocytes were hypertrophic, structurally disarrayed, had impaired contractility and abnormal calcium signaling. (lindholm2021monoandbiallelic pages 1-3)

In homozygous p.Gln860Ter cells, loss of the C-terminal region disrupted interactions with ACTN1 and GJA1/connexin-43, potentially linking the variant to relaxation and electrical phenotypes. CRISPR introduction of the truncation into control cells reproduced the direction of contractile abnormalities, although the contractile-velocity result was borderline (P=0.058), an important limitation. (lindholm2021monoandbiallelic pages 8-9, lindholm2021monoandbiallelic pages 4-6)

RNA sequencing of p.Gln860Ter myocardium showed extracellular-matrix remodeling, collagen biosynthesis, and mRNA-splicing enrichment; COL1A1, COL1A2, COL4A1, fibronectin, TGF-β, NPPA and NPPB were elevated. Patient hiPSC cardiomyocytes had marked MYL2 induction (log fold change 5.23 for Q860X and 4.90 for deletion cells) and enrichment of respiratory electron transport and gluconeogenesis, indicating metabolic remodeling. (lindholm2021monoandbiallelic pages 3-4, lindholm2021monoandbiallelic pages 4-6)

The 2023 Actn2 p.Met228Thr mouse study found a destabilized mutant protein, increased ubiquitin–proteasome activity, sarcomeric quantitative abnormalities, mitochondrial dysfunction and cell-cycle defects. Its abstract states: “This missense variant in alpha-actinin renders the protein less stable.” These data support proteostasis and bioenergetic mechanisms, but the model represents an HCM-associated allele and should not be assumed to reproduce DCM1AA. (broadwaystringer2023insightsintothe pages 1-2)

Cells, anatomy, and ontology

Primary cell: cardiac muscle cell/cardiomyocyte — CL:0000746. Secondary cells implicated by fibrosis and remodeling include cardiac fibroblasts; direct ACTN2 pathology in fibroblasts is not established. Primary tissue is ventricular myocardium, particularly left ventricle; both ventricles and atria may become involved secondarily. Suggested anatomy: UBERON:0000948 heart, UBERON:0002084 heart left ventricle, UBERON:0002080 heart right ventricle, and myocardium/ventricular myocardium terms where supported. Disease is bilateral/nonlateralized at organ level; “left” reflects the dominant phenotype, not body lateralization.

Relevant processes include sarcomere organization, actin binding, calcium-ion homeostasis, mitochondrial ATP generation, ubiquitin-dependent proteolysis, cell-cycle regulation, hypertrophic signaling, extracellular-matrix organization, and fibrosis. No ACTN2-specific single-cell or spatial-transcriptomic atlas was found.

7. Anatomical structures affected

The heart is primary, particularly ventricular myocardium and cardiomyocyte Z-discs. Left-ventricular dilation, hypertrabeculation/noncompaction and systolic dysfunction predominate in DCM presentations. Right-ventricular dysfunction, biatrial enlargement, conduction tissue dysfunction and diffuse interstitial fibrosis can develop in severe disease. Secondary structures affected by heart failure include lungs (pulmonary congestion), liver and kidneys (venous congestion/hypoperfusion), and skeletal muscle through deconditioning; these are complications, not primary ACTN2 lesions.

Subcellular compartments include the Z-disc, sarcomere, actin thin filaments, titin-anchoring complex, sarcolemma/gap junction neighborhood, mitochondria, and ubiquitin–proteasome system. (lindholm2021monoandbiallelic pages 1-3, lindholm2021monoandbiallelic pages 8-9, broadwaystringer2023insightsintothe pages 1-2)

8. Temporal development

Onset ranges from infancy to adulthood and may be insidious or arrhythmia-first. The homozygous p.Gln860Ter patient presented in infancy, developed progressive heart failure and atrial fibrillation in her twenties, and underwent transplantation at 23. The dominant-deletion proband presented at 16 with exertional syncope; relatives showed variable arrhythmic, LVNC, and heart-failure phenotypes. (lindholm2021monoandbiallelic pages 3-4)

A practical course model is:

Genotype-positive/phenotype-negative: no imaging or electrical abnormality.
Early electrical or structural expression: T-wave changes, conduction delay, atrial/ventricular ectopy, mild dilation, noncompaction, or reduced strain.
Overt cardiomyopathy: dilation and reduced EF, or restrictive/noncompaction phenotype.
Advanced disease: recurrent arrhythmia, fibrosis, decompensated HF, device therapy, VAD, or transplantation.

The course is chronic and variably progressive. Reverse remodeling may occur with contemporary therapy in DCM generally, but ACTN2-specific remission rates are unavailable. Critical opportunities are presymptomatic family identification and initiation of therapy at the first evidence of dysfunction or arrhythmia.

9. Inheritance and population

Inheritance

Most reported ACTN2 cardiomyopathy is autosomal dominant, with variable expressivity and likely age-dependent, incomplete penetrance. Biallelic truncating variants can cause autosomal-recessive severe disease. Germline mosaicism is biologically possible but not documented as a characteristic. No genetic anticipation, sex-linked transmission, mitochondrial inheritance, established founder effect, or consanguinity-specific burden was identified. (lindholm2021monoandbiallelic pages 1-3, lindholm2021monoandbiallelic pages 8-9, broadwaystringer2023insightsintothe pages 2-4)

Epidemiology

No credible ACTN2/DCM1AA-specific prevalence, incidence, carrier frequency, sex ratio, geographic distribution, or ethnic enrichment is available. General DCM prevalence is estimated near 1:250, with UK Biobank CMR suggesting 1:220 among more than 39,000 participants; these figures must not be assigned to DCM1AA. Definitive DCM genes collectively explain up to about 40% of cases, while ACTN2 represents a rare minor-gene cause. (newman2024dilatedcardiomyopathya pages 1-2)

General-population penetrance studies likewise are not ACTN2-specific. In 18,665 UK Biobank participants, 7.8% carried at least one “putative pathogenic” variant under a broad 44-gene strategy, but combined penetrance remained ≤30%; broad filtering likely included variants that would not meet modern clinical pathogenicity standards. Another study found pathogenic/likely pathogenic DCM variants in approximately 1:251, with phenotype penetrance only 1.2–3.1% in the population setting. These observations reinforce the need for variant-level interpretation, family history, and serial phenotyping. (shah2022frequencypenetranceand pages 10-12)

10. Diagnostics

Clinical evaluation

Diagnosis requires demonstration of a compatible cardiac phenotype and exclusion of more common causes. Recommended assessment includes:

Three-generation pedigree, sudden-death history and extracardiac myopathy review.
Physical examination, ECG, ambulatory rhythm monitoring and exercise testing where appropriate.
Echocardiography for chamber dimensions, EF, diastolic function and trabeculation.
Cardiac MRI for volumes, function, noncompaction morphology, edema and fibrosis/LGE.
BNP/NT-proBNP and high-sensitivity troponin; CBC, electrolytes, renal/liver/thyroid indices, iron studies and CK according to presentation.
Coronary evaluation when ischemia is plausible; viral/immune testing only when clinically indicated.
Endomyocardial biopsy for selected rapidly progressive, inflammatory, infiltrative or unexplained presentations—not routine confirmation of ACTN2 disease.

Genetic testing

Use a clinically curated cardiomyopathy panel including ACTN2 and established DCM genes, with copy-number analysis. WES/WGS is appropriate when the panel is negative, disease is early/severe, or blended/syndromic disease is suspected. WGS offers improved noncoding and structural-variant detection. RNA sequencing can clarify splice effects but remains adjunctive. CMA is useful for large deletions such as the 1q43 ACTN2–RYR2 deletion; karyotype/FISH are not routine unless a chromosomal rearrangement is suspected. Mitochondrial DNA or repeat-expansion testing is phenotype-directed, not standard for isolated ACTN2 disease. (zhou2023impairedcardiomyocytematuration pages 3-7, lindholm2021monoandbiallelic pages 3-4)

A VUS must not establish diagnosis or direct predictive testing. Confirm pathogenic/likely pathogenic variants by an orthogonal method where required, test segregation, and periodically reanalyze. Once a causal familial variant is established, offer targeted cascade testing with genetic counseling.

Screening

First-degree relatives should receive ECG and cardiac imaging, with periodic reassessment guided by age, genotype, family onset and symptoms. Genotype-positive relatives require longitudinal surveillance even when initially normal. Newborn population screening is not established. Prenatal diagnosis and preimplantation genetic testing are possible when a familial pathogenic variant and inheritance model are known.

Differential diagnosis

Exclude ischemic, hypertensive, valvular, congenital, tachycardia-induced, alcohol/toxin/chemotherapy-related, peripartum, inflammatory/myocarditic, endocrine/metabolic, infiltrative and neuromuscular cardiomyopathy. Genetically, distinguish TTN-, LMNA-, FLNC-, DSP-, RBM20-, BAG3-, PLN-, DES-, SCN5A-, sarcoglycan-, dystrophin- and mitochondrial disease. HCM, RCM, LVNC and arrhythmogenic cardiomyopathy are not merely differentials: they may be alternate ACTN2 phenotypes.

11. Outcome and prognosis

ACTN2-specific survival curves do not exist. Documented outcomes range from asymptomatic carriers to sudden death and transplantation. The homozygous p.Gln860Ter case demonstrates severe progression and transplant at 23, while a dominant deletion family included two early sudden deaths. The 2023 multigene-deletion child remained dilated with LVEF 41% and was referred for transplantation. (zhou2023impairedcardiomyocytematuration pages 3-7, lindholm2021monoandbiallelic pages 3-4)

For broader nonischemic DCM, a 2024 meta-analysis of 103 studies and 29,687 patients found that CMR LGE predicted all-cause mortality (HR 1.81), cardiovascular mortality (HR 2.43), arrhythmic events (HR 2.69) and HF events (HR 1.98). Each 1% increase in LGE extent was associated with HRs of 1.07, 1.15, 1.07 and 1.06, respectively. LVEF was not significantly associated with mortality or arrhythmic outcomes in that analysis. These are general NIDCM prognostic data, not ACTN2-specific estimates. (eichhorn2024riskstratificationin pages 1-2)

Adverse prognostic factors likely include earlier onset, biallelic or severe truncating variants, progressive EF decline, ventricular arrhythmia, syncope, fibrosis/LGE, biventricular dysfunction, elevated natriuretic peptides, recurrent hospitalization and failure to reverse-remodel. No validated ACTN2-specific prognostic biomarker exists.

12. Treatment

Current standard care

There is no approved ACTN2-directed therapy. Treat the expressed phenotype according to heart-failure and arrhythmia guidelines.

For HFrEF, foundational therapy comprises:

ARNI—or ACE inhibitor/ARB if ARNI unsuitable.
Evidence-based β-blocker.
Mineralocorticoid-receptor antagonist.
SGLT2 inhibitor.

Add loop diuretics for congestion; consider ivabradine, hydralazine/isosorbide dinitrate, vericiguat, digoxin, iron replacement and anticoagulation according to standard indications. Continue therapy after EF improvement because genetic substrate persists. Relevant NCIT intervention concepts include angiotensin-receptor/neprilysin inhibitor therapy, beta-blocker therapy, mineralocorticoid-receptor antagonist therapy, SGLT2-inhibitor therapy, diuretic therapy and anticoagulation therapy.

Arrhythmia management includes ambulatory surveillance, β-blockade, antiarrhythmic drugs or catheter ablation when indicated. ICD decisions should integrate EF, symptoms, fibrosis, syncope, ventricular arrhythmia and family history; there is no validated ACTN2-specific threshold. CRT follows conventional QRS/LBBB and EF criteria. Advanced disease may require LVAD or heart transplantation.

The 2023 child with the ACTN2–RYR2 deletion received creatine phosphate, levocarnitine, digoxin, captopril and metoprolol, but remained severely affected and was referred for transplant; this is a case history, not evidence for genotype-specific efficacy. (zhou2023impairedcardiomyocytematuration pages 3-7)

A p.Thr247Met hiPSC model showed reduced L-type calcium-channel interaction and QT prolongation, with reported benefit from diltiazem in that individual. This is precision-treatment proof of concept for an ACTN2 electrophysiologic/HCM phenotype, not established DCM1AA treatment. (wadmore2021theroleof pages 2-4)

Experimental therapy and real-world implementation

Searches found no ACTN2-specific gene therapy, RNA therapy, cell therapy or interventional clinical trial. Contemporary trials target other genetic DCM forms, including BAG3 AAV replacement, and cannot be extrapolated directly. ACTN2 replacement/editing faces challenges including cardiac delivery, dominant-negative alleles, isoform dosage, immunity and off-target effects.

Real-world HFrEF implementation remains incomplete: a 2024 retrospective study of 73 hospitalized patients reported that only about one-third left hospital receiving all four recommended drug classes. This was not an ACTN2 cohort but illustrates the implementation gap.

13. Prevention

Primary prevention: germline occurrence cannot generally be prevented. Genetic counseling can support reproductive planning, including prenatal or preimplantation testing. Avoid additional myocardial insults and control blood pressure, alcohol exposure, obesity, diabetes, sleep apnea and arrhythmia.

Secondary prevention: targeted cascade testing plus serial ECG, rhythm monitoring and imaging offer the strongest opportunity to detect presymptomatic disease. Begin standard therapy promptly when ventricular dysfunction emerges. No population newborn or adult ACTN2 screening program is recommended.

Tertiary prevention: optimize guideline-directed therapy, vaccination and infection management, monitor renal function/electrolytes, treat congestion and arrhythmia, assess sudden-death risk, and refer early to inherited-cardiomyopathy and advanced-HF centers. There is no disease-specific vaccine or chemoprophylaxis.

14. Other species and naturally occurring disease

ACTN2 is evolutionarily conserved across vertebrates. Suggested taxa for comparative annotation include Homo sapiens (NCBI Taxon 9606), Mus musculus (10090) and Danio rerio (7955). Ortholog identifiers should be obtained from the current NCBI Gene/Alliance records during database loading.

No well-validated naturally occurring veterinary disorder specifically equivalent to human ACTN2-related DCM was identified. Cardiomyopathy is common in dogs and cats, and feline studies have explored ACTN2 variation, but this does not establish a naturally occurring DCM1AA ortholog or breed-specific VBO entity. There is no transmission or zoonotic potential.

15. Model organisms and experimental systems

Human iPSC cardiomyocytes

Patient-derived hiPSC cardiomyocytes reproduce hypertrophy, sarcomeric disarray, reduced contractile velocity and aberrant calcium signaling. RNA-seq, electron microscopy, immunostaining and interactome mass spectrometry have connected genotype to cellular phenotype. CRISPR introduction of p.Gln860Ter into an isogenic control supported causality. Advantages are human genetic context and suitability for drug screening; limitations include fetal-like maturation, absence of whole-heart loading and incomplete multicellular architecture. (lindholm2021monoandbiallelic pages 4-6, lindholm2021monoandbiallelic pages 1-3)

Mouse

The 2023 CRISPR knock-in Actn2 p.Met228Thr mouse was viable as a heterozygote; only mature males developed molecular cardiomyopathy markers without an overt phenotype. Homozygotes were embryonically lethal and E15.5 hearts showed morphological abnormalities, sarcomeric changes, cell-cycle defects, mitochondrial dysfunction and proteasome activation. It is valuable for developmental/proteostasis mechanisms but models an HCM-associated allele and has limited fidelity to adult human DCM. (broadwaystringer2023insightsintothe pages 1-2, broadwaystringer2023insightsintothe pages 2-4)

Zebrafish

Morpholino depletion of actn2 impaired lateral Z-disc alignment, reduced cardiac function, cardiomyocyte number and size, end-diastolic dimension and ventricular chamber size. Other reported loss models showed dilated hearts, thickened Z-discs, weakness and immobility; ACTN3 did not rescue the phenotype. Zebrafish are useful for rapid developmental and modifier screens, but morpholino artifacts, cardiac anatomy and dosage differences limit direct clinical translation. (lindholm2021monoandbiallelic pages 8-9, wadmore2021theroleof pages 2-4)

In vitro structural/biochemical models

Crystal and binding studies of actin-binding-domain variants show reduced thermal stability, altered tertiary structure, weaker actin binding, defective Z-disc incorporation and aggregation. These clarify molecular consequences but cannot establish penetrance or clinical pathogenicity alone. (wadmore2021theroleof pages 2-4)

Recent developments, expert interpretation, and evidence gaps

Important 2023–2024 developments include the 2023 Actn2 knock-in mouse/proteomics study, a 2023 human ACTN2–RYR2 deletion case linking cardiomyocyte maturation to severe pediatric DCM/LVNC, 2024 reviews emphasizing cautious interpretation of minor cardiomyopathy genes, and a 2024 CMR meta-analysis strengthening fibrosis-based risk assessment. (zhou2023impairedcardiomyocytematuration pages 3-7, broadwaystringer2023insightsintothe pages 1-2, eichhorn2024riskstratificationin pages 1-2)

The most defensible expert interpretation is that ACTN2 is a biologically compelling but rare and phenotypically pleiotropic cardiomyopathy gene. A clinical diagnosis should not be based on the “DCM1AA” label or an ACTN2 VUS alone. Strong evidence requires a compatible phenotype, a very rare variant with an appropriate molecular consequence, segregation or de novo evidence, and preferably functional support. Current major gaps are subtype-specific epidemiology, penetrance by variant class, prospective natural history, standardized sudden-death prediction, single-cell/spatial profiling, and ACTN2-directed therapy.

Selected primary-source quotations

Lindholm et al. 2021: “Patient-derived iPSC-cardiomyocytes were hypertrophic, displayed sarcomeric structural disarray, impaired contractility, and aberrant Ca2+-signaling.” DOI: https://doi.org/10.1161/CIRCGEN.121.003419; published December 2021. (lindholm2021monoandbiallelic pages 1-3)
Broadway-Stringer et al. 2023: “Heterozygous Actn2 p.Met228Thr mice have no overt phenotype. Only mature males show molecular parameters indicative of cardiomyopathy.” DOI: https://doi.org/10.3390/cells12050721; published 24 February 2023. (broadwaystringer2023insightsintothe pages 1-2)
Arvanitis et al. 2020: “Genome-editing in human embryonic stem cell-derived cardiomyocytes confirms the influence of the identified regulatory region in the expression of ACTN2.” DOI: https://doi.org/10.1038/s41467-020-14843-7; published February 2020. (arvanitis2020genomewideassociationand pages 1-2)

Overall evidence grade: moderate for ACTN2 as a cause of an intrinsic cardiomyopathy spectrum; lower for DCM1AA as a sharply bounded disease entity; high for the general DCM diagnostic and heart-failure treatment framework; insufficient for ACTN2-specific prevalence, penetrance, prognosis, prevention, or targeted therapy.

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(shah2022frequencypenetranceand pages 10-12): Ravi A. Shah, Babken Asatryan, Ghaith Sharaf Dabbagh, Nay Aung, Mohammed Y. Khanji, Luis R. Lopes, Stefan van Duijvenboden, Anthony Holmes, Daniele Muser, Andrew P. Landstrom, Aaron Mark Lee, Pankaj Arora, Christopher Semsarian, Virend K. Somers, Anjali T. Owens, Patricia B. Munroe, Steffen E. Petersen, and C. Anwar A. Chahal. Frequency, penetrance, and variable expressivity of dilated cardiomyopathy–associated putative pathogenic gene variants in uk biobank participants. Circulation, 146:110-124, Jul 2022. URL: https://doi.org/10.1161/circulationaha.121.058143, doi:10.1161/circulationaha.121.058143. This article has 104 citations and is from a highest quality peer-reviewed journal.
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OpenScientist Report

Classifications

Inheritance

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Differential Diagnoses

Experimental Models

Source YAML

References & Deep Research

References

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

Dilated Cardiomyopathy 1AA (ACTN2-related cardiomyopathy): comprehensive disease-characteristics report

Executive summary and scope

1. Disease information

Definition

Identifiers and nomenclature

2. Etiology, risk, protection, and gene–environment interaction

Causal factors

Genetic risk factors and modifiers

Environmental and acquired risk factors

Protective factors

3. Phenotypes

4. Genetic and molecular information

Gene and protein

Illustrative variants

Epigenetic and chromosomal findings

5. Environmental information

6. Mechanism and pathophysiology

Causal chain

Variant-dependent mechanisms

Cells, anatomy, and ontology

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

Inheritance

Epidemiology

10. Diagnostics

Clinical evaluation

Genetic testing

Screening

Differential diagnosis

11. Outcome and prognosis

12. Treatment

Current standard care

Experimental therapy and real-world implementation

13. Prevention

14. Other species and naturally occurring disease

15. Model organisms and experimental systems

Human iPSC cardiomyocytes

Mouse

Zebrafish

In vitro structural/biochemical models

Recent developments, expert interpretation, and evidence gaps

Selected primary-source quotations