Dilated Cardiomyopathy 2A (DCM2A): Disease Characteristics Report

Executive summary and evidence boundary

Dilated cardiomyopathy 2A (DCM2A; also written CMD2A) is an exceptionally rare, usually neonatal or infantile, autosomal-recessive cardiomyopathy caused by biallelic loss-of-function variants in TNNI3, which encodes cardiac troponin I (cTnI). It should not be conflated with dominant hypertrophic, restrictive, or dilated cardiomyopathies caused by heterozygous TNNI3 alleles, or with disease involving the separate kinase gene TNNI3K. The strongest disease-specific synthesis available in the retrieved literature is Sorrentino et al., published March 2023, DOI 10.3390/genes14030748. It summarized only 20 individuals with biallelic TNNI3 variants; 16 had DCM, sometimes overlapping left-ventricular noncompaction (LVNC). Consequently, most frequencies and prognosis estimates remain imprecise, and treatment recommendations are necessarily extrapolated from pediatric/genetic DCM practice. (sorrentino2023homozygoustnni3mutations pages 8-9, sorrentino2023homozygoustnni3mutations pages 1-2)

Table: This table compacts the highest-yield knowledge-base facts for Dilated Cardiomyopathy 2A, separating subtype-specific evidence from broader dilated cardiomyopathy context. It is useful for rapid curation of identifiers, phenotype, mechanism, diagnosis, and current evidence gaps.

1. Disease information

Definition

DCM2A is a primary genetic myocardial disease characterized by ventricular—usually left-ventricular—dilation, severe systolic dysfunction, and rapidly progressive heart failure after biallelic TNNI3 loss of function. Cardiac troponin I is the inhibitory subunit of the thin-filament troponin complex and is essential for calcium-regulated cardiac contraction and relaxation. (sorrentino2023homozygoustnni3mutations pages 5-8, sorrentino2023homozygoustnni3mutations pages 2-4)

Identifiers and synonyms

• OMIM: 611880, Cardiomyopathy, dilated, 2A.
• Common names: DCM2A, CMD2A, cardiomyopathy dilated 2A, autosomal-recessive TNNI3-related dilated cardiomyopathy, recessive cardiac troponin-I cardiomyopathy.
• MONDO: a unique DCM2A-specific MONDO identifier was not confidently recoverable; map provisionally to the relevant MONDO dilated-cardiomyopathy concept while retaining OMIM:611880 as the subtype identifier.
• Orphanet: no confidently verified subtype-specific identifier was found.
• ICD-10-CM: I42.0, dilated cardiomyopathy; no gene-specific code.
• ICD-11: use the dilated-cardiomyopathy category with genetic etiology annotation; no dedicated DCM2A code was verified.
• MeSH: Cardiomyopathy, Dilated.

The evidence is mainly aggregated disease-level literature assembled from individual case reports and small families, not population EHR cohorts. The 2023 report combined two new patients with previously published cases. (sorrentino2023homozygoustnni3mutations pages 8-9, sorrentino2023homozygoustnni3mutations pages 4-5, sorrentino2023homozygoustnni3mutations pages 2-4)

2. Etiology, risk, protective factors, and gene–environment interaction

Primary causal factor

The established cause is a germline biallelic pathogenic TNNI3 genotype, especially nonsense, frameshift, or splice-disrupting alleles that abolish cTnI expression. Autosomal-recessive segregation was first supported by affected siblings of consanguineous parents; subsequent unrelated families consolidated the association. (sorrentino2023homozygoustnni3mutations pages 5-8, sorrentino2023homozygoustnni3mutations pages 2-4)

Genetic risk factors

• Having two pathogenic TNNI3 alleles is the principal risk factor.
• Parental consanguinity increases the chance that a rare allele is inherited homozygously, but DCM2A also occurs in nonconsanguineous families.
• Recurrent alleles include p.Arg69Alafs8 and p.Arg98. In the 2023 synthesis, p.Arg69Alafs* occurred in 9 of 16 families; estimated carrier frequencies were approximately 1/26,222 and 1/17,750, respectively. Aggregate healthy heterozygous carriage was estimated at 48/100,000. These are carrier—not disease-prevalence—figures. (sorrentino2023homozygoustnni3mutations pages 8-9, sorrentino2023homozygoustnni3mutations pages 4-5)
• No validated modifier gene or polygenic score specific to DCM2A has been established.

Environmental and protective factors

No environmental exposure is known to cause DCM2A, and no genetic protective allele has been validated. Avoiding alcohol excess, cocaine/amphetamines, cardiotoxic chemotherapy, smoking, obesity, and uncontrolled hypertension is prudent in genetic DCM generally, but evidence is not TNNI3-null-specific. Pregnancy, viral myocarditis, alcohol, and anthracyclines can interact with susceptibility alleles in broader DCM; equivalent gene–environment interaction data for DCM2A are absent. (arnautu2024riskassessmentand pages 21-23, mestroni2014geneticcausesof pages 6-8, bondue2018complexroadsfrom pages 19-22)

3. Phenotypes

Core disease-specific phenotype

The reviewed homozygous null genotypes showed relatively little variability and generally severe outcomes. Missense alleles with residual activity may have slower or atypical courses, including restrictive phenotypes; they should not automatically be grouped with null-allele DCM2A. (sorrentino2023homozygoustnni3mutations pages 8-9, sorrentino2023homozygoustnni3mutations pages 4-5)

Illustrative human cases

A seven-month-old child had dyspnea, LV dilation, and LVEF 25%, then required ECMO and ventricular assistance; an ischemic stroke complicated support, followed by transplantation and post-transplant LVEF 61%. A second child presented at six months with feeding difficulty, dyspnea, severe left-sided dilation, LVEF 25%, and mitral/tricuspid insufficiency; transplantation at eight months produced a favorable early outcome. Both reports involved homozygous c.292C>T (p.Arg98*). (sorrentino2023homozygoustnni3mutations pages 4-5)

Quality of life

No DCM2A-specific EQ-5D, SF-36, PedsQL, or PROMIS study exists. Severe heart failure is expected to impair feeding, growth, activity, sleep, and caregiver/family functioning, while hospitalization, mechanical support, and transplantation impose major burdens. These effects are clinically evident but have not been quantified in this subtype.

4. Genetic and molecular information

Causal gene

• Gene: TNNI3, troponin I3, cardiac type.
• Protein: cardiac troponin I, the inhibitory component of the troponin complex.
• Disease mechanism: biallelic loss of function.
• Origin: constitutional/germline, not somatic.

Pathogenic variants

The strongest DCM2A variants are rare biallelic null alleles: nonsense, frameshift, and splice-altering variants. In affected myocardium, premature-termination variants can undergo nonsense-mediated decay, producing markedly reduced TNNI3 RNA and complete absence of cTnI protein. The fetal slow-skeletal isoform TNNI1 may be compensatorily increased but does not prevent severe disease. (sorrentino2023homozygoustnni3mutations pages 8-9, sorrentino2023homozygoustnni3mutations pages 5-8)

Important reported alleles include:

• c.292C>T, p.Arg98*: nonsense; homozygous in severe infantile DCM. It was present heterozygously in gnomAD at approximately 1/9,187 among non-Finnish Europeans in the cited analysis; heterozygosity alone is insufficient to establish DCM2A. (sorrentino2023homozygoustnni3mutations pages 4-5)
• p.Arg69Alafs*8: recurrent frameshift/null allele; approximate allele/carrier frequency 1/26,222 in the 2023 synthesis. (sorrentino2023homozygoustnni3mutations pages 8-9, sorrentino2023homozygoustnni3mutations pages 5-8)
• p.Ala2Val: homozygous in the first reported recessive family, although the precise residual function and classification require variant-level reassessment under current ACMG/AMP criteria. (sorrentino2023homozygoustnni3mutations pages 5-8)

A variant should be classified with ACMG/AMP criteria using segregation, phenotype specificity, population frequency, predicted transcript effect, myocardial/RNA functional evidence, and ClinVar expert assertions where available. A VUS must not be used for predictive testing or reproductive decision-making as though pathogenic.

Other molecular categories

No recurrent DCM2A-specific chromosomal rearrangement, aneuploidy, somatic mechanism, DNA-methylation signature, or validated modifier gene has been demonstrated. Copy-number analysis remains relevant if sequencing detects only one pathogenic allele. Large deletions affecting TNNI3 would be biologically plausible but were not established as a common mechanism in the retrieved evidence.

5. Environmental and lifestyle information

DCM2A is genetic rather than infectious, toxic, occupational, or radiation-induced. No pathogen is causally implicated. Standard management should nevertheless exclude potentially reversible contributors such as myocarditis, endocrine/metabolic disease, nutritional deficiency, tachyarrhythmia, and toxic exposure. For genetically susceptible DCM generally, limiting alcohol and avoiding cocaine, amphetamines, and unnecessary cardiotoxic drugs is recommended; moderate, clinician-directed physical activity is preferable to inactivity, but exercise must be individualized in advanced pediatric heart failure. (arnautu2024riskassessmentand pages 21-23, mestroni2014geneticcausesof pages 6-8)

6. Mechanism and pathophysiology

Causal chain

1. Upstream genetic lesion: two damaging TNNI3 alleles.
2. Transcript/protein defect: nonsense-mediated decay or unstable/truncated transcript causes absent or markedly reduced cTnI.
3. Sarcomeric defect: the troponin complex loses normal inhibition of actin–myosin interaction at low cytosolic calcium and normal modulation of thin-filament activation.
4. Cellular dysfunction: abnormal calcium–myofilament coupling, impaired relaxation/contractile reserve, inefficient force production, and cardiomyocyte stress.
5. Tissue remodeling: chamber dilation, reduced systolic performance, neurohormonal activation, secondary valvular regurgitation, and potentially fibrosis/arrhythmia.
6. Clinical endpoint: severe infantile heart failure, cardiogenic shock, mechanical-support dependence, transplantation, or death. (sorrentino2023homozygoustnni3mutations pages 8-9, sorrentino2023homozygoustnni3mutations pages 5-8, sorrentino2023homozygoustnni3mutations pages 2-4)

The first two steps are directly supported in DCM2A myocardium; detailed calcium, metabolic, immune, and fibrosis pathways are largely inferred from troponin biology and general DCM. It would be inappropriate to assign a specific Wnt, MAPK, mTOR, or PI3K–AKT driver to human DCM2A without direct evidence.

Cells, tissues, and ontology suggestions

• Primary cell: cardiac muscle cell/cardiomyocyte, CL:0000746 (cardiac muscle cell; ontology releases may also expose more specific ventricular cardiomyocyte descendants).
• GO biological processes: cardiac muscle contraction GO:0060048; regulation of cardiac muscle contraction GO:0055117; sarcomere organization GO:0045214; muscle filament sliding GO:0030049; calcium-mediated signaling GO:0019722; regulation of heart contraction GO:0008016.
• GO cellular components: sarcomere GO:0030017; myofibril GO:0030016; troponin complex GO:0005861; thin filament GO:0005865.

Molecular profiling and advanced technologies

Disease-specific single-cell, spatial-transcriptomic, proteomic, metabolomic, lipidomic, or integrated multi-omic studies were not found. Direct myocardial assays showing absent TNNI3 and increased TNNI1 are the most relevant expression/protein observations. RNA sequencing can be diagnostically valuable for suspected splice variants, but it is not a routine validated biomarker. No DCM2A-specific CRISPR screen was identified. (sorrentino2023homozygoustnni3mutations pages 8-9, sorrentino2023homozygoustnni3mutations pages 5-8)

7. Anatomical structures affected

• Primary organ: heart, UBERON:0000948.
• Primary chamber: left ventricle, UBERON:0002084; biventricular disease can develop.
• Tissue: myocardium UBERON:0002349, particularly ventricular myocardium.
• Cell: ventricular cardiomyocyte/cardiac muscle cell.
• Subcellular site: sarcomere, myofibril, thin filament, troponin complex.
• Secondary organs: lungs through pulmonary congestion/hypertension; liver, kidneys, and brain through advanced low-output failure or treatment complications. The reported ischemic stroke occurred during advanced support and is not necessarily a primary DCM2A phenotype. (sorrentino2023homozygoustnni3mutations pages 4-5)
• Lateralization: not applicable; myocardial disease is not unilateral, although LV dysfunction predominates.

8. Temporal development

Onset is usually congenital, neonatal, or in the first year of life; six- and seven-month presentations are documented. The course is chronic but often rapidly progressive rather than episodic. A useful clinical staging model is: genotype-positive/presymptomatic → subtle chamber or functional abnormality → overt DCM with reduced EF → advanced/refractory heart failure → VAD/transplantation or death. Homozygous null cases commonly reach advanced stages shortly after recognition. Durable spontaneous remission has not been demonstrated; improvement after transplantation reflects organ replacement rather than correction of the genotype. (sorrentino2023homozygoustnni3mutations pages 8-9, sorrentino2023homozygoustnni3mutations pages 4-5, sorrentino2023homozygoustnni3mutations pages 1-2)

The critical intervention window is therefore before or at the earliest sign of ventricular dysfunction in an at-risk sibling. Serial surveillance should not wait for symptoms.

9. Inheritance and population

Inheritance

DCM2A is autosomal recessive. For two confirmed heterozygous parents, each pregnancy has a 25% probability of an affected child, 50% probability of a heterozygous carrier, and 25% probability of inheriting neither familial allele. Penetrance appears high for biallelic null genotypes but cannot be quantified reliably from the small, ascertainment-biased literature. Expressivity is severe and relatively consistent for null alleles, but residual-function alleles can produce variable DCM, LVNC, or restrictive phenotypes. Anticipation is not expected. Germline mosaicism has not been established but cannot be excluded after an apparently de novo result. Consanguinity is relevant but not necessary. (sorrentino2023homozygoustnni3mutations pages 8-9, sorrentino2023homozygoustnni3mutations pages 4-5, sorrentino2023homozygoustnni3mutations pages 5-8)

Epidemiology

No population prevalence or incidence is available for DCM2A. Only approximately 20 biallelic cases had been summarized by 2023, so it qualifies as ultra-rare. Variant carrier frequencies must not be converted into disease prevalence without accounting for allelic heterogeneity and penetrance. (sorrentino2023homozygoustnni3mutations pages 8-9)

For context only, general DCM prevalence estimates range widely, from 36.5 per 100,000 in older epidemiology to over 0.4% in newer imaging-based estimates; incidence near 7 per 100,000/year has been cited. These figures do not describe DCM2A. General pediatric DCM has a higher incidence in infancy, and one 2024 genetics review reported a molecular diagnosis in 54% of pediatric versus 27% of adult DCM. (newman2024dilatedcardiomyopathya pages 1-2, mestroni2014geneticcausesof pages 1-3, eldemire2024geneticsofdilated pages 1-3)

No reproducible ethnic, geographic, or sex enrichment has been established for DCM2A. Reported families include European and North African ancestry, reflecting case ascertainment rather than prevalence.

10. Diagnostics

Clinical evaluation

1. Echocardiography: chamber dimensions, fractional shortening/LVEF, valvular regurgitation, RV function, and LVNC morphology.
2. ECG and ambulatory monitoring: conduction disease, atrial/ventricular arrhythmia, and repolarization abnormalities.
3. Cardiac MRI: ventricular volumes/function, LVNC, edema, and late-gadolinium enhancement when feasible and safe.
4. Laboratory assessment: BNP/NT-proBNP and troponin for severity/injury; CBC, electrolytes, renal/liver/thyroid testing, creatine kinase, lactate, acylcarnitines, and other metabolic testing guided by age and presentation. No laboratory biomarker is specific to DCM2A.
5. Endomyocardial biopsy: not required for routine genetic diagnosis; consider only when myocarditis, storage disease, infiltrative disease, or an actionable histological diagnosis remains plausible.

Genetic testing algorithm

A comprehensive cardiomyopathy panel including TNNI3 is generally the first-line molecular test. Ensure reliable coverage of coding exons, splice boundaries, and copy-number changes. Trio WES is especially useful in severe infantile disease; WGS can detect deep-intronic and structural variants missed by panels/WES. If one allele or a suspected splice variant remains unresolved, RNA analysis from an informative tissue may help. Karyotype, FISH, chromosomal microarray, mitochondrial sequencing, and repeat-expansion testing are not first-line for isolated DCM2A but may be appropriate for syndromic presentations. A negative test does not exclude hereditary DCM. (eldemire2024geneticsofdilated pages 1-3, arnautu2024riskassessmentand pages 11-12)

The most affected individual should be tested first, followed by targeted parental segregation and cascade testing. In a national pediatric DCM cohort, 38/107 tested children (36%) had a pathogenic/likely pathogenic variant, and variant-positive children had a higher death/transplant risk (HR 2.8, 95% CI 1.3–5.8); these are general pediatric DCM data supporting routine genetic evaluation, not TNNI3-specific estimates. (eldemire2024geneticsofdilated pages 1-3)

Differential diagnosis

Exclude myocarditis; anomalous coronary origin; congenital structural disease; tachycardia-induced cardiomyopathy; metabolic/mitochondrial disorders; Barth syndrome; carnitine deficiency; neuromuscular disease; sepsis; endocrine disease; toxic cardiomyopathy; and other monogenic DCM. Dominant TNNI3-associated hypertrophic/restrictive cardiomyopathy differs by genotype, ventricular morphology, and inheritance.

Screening

There is no newborn biochemical screen. Siblings and other at-risk relatives require genetic counseling, targeted testing for known familial alleles, and phenotype screening with history, examination, ECG, and echocardiography. Prenatal diagnosis and preimplantation genetic testing are technically possible once both familial pathogenic variants are established.

11. Outcome and prognosis

Disease-specific prognosis is unfavorable for biallelic null genotypes. Early onset, severely depressed EF, escalation to inotropes/ECMO/VAD, and inability to recover ventricular function indicate high transplant/death risk. In the two 2023 patients, transplantation produced favorable early cardiac outcomes, but no DCM2A-specific five- or ten-year survival estimate exists. (sorrentino2023homozygoustnni3mutations pages 8-9, sorrentino2023homozygoustnni3mutations pages 4-5)

General pediatric DCM should not substitute for subtype-specific prognosis, although it provides context: a 2024 review cited 94% five-year survival but a 38% transplantation rate in genetically characterized pediatric disease. Broader nonischemic DCM cohorts have reported major cardiac events in about 50% over 12 years and death/transplant/VAD in 17% over eight years. (newman2024dilatedcardiomyopathya pages 1-2, eldemire2024geneticsofdilated pages 1-3)

Major morbidities include recurrent hospitalization, growth and feeding impairment, arrhythmia, thromboembolism, secondary valve regurgitation, pulmonary hypertension, end-organ dysfunction, and complications of mechanical support/transplantation. No validated DCM2A-specific prognostic biomarker exists; phenotype severity and trajectory currently dominate risk assessment.

12. Treatment

Current treatment

There is no approved therapy that restores TNNI3 in DCM2A. Management should occur in a pediatric advanced-heart-failure and inherited-cardiomyopathy center.

• Congestion: loop diuretics; NCIT concept suggestion: Diuretic Therapy.
• Chronic systolic failure: age-appropriate ACE inhibitor/ARB or ARNI, evidence-based beta-blocker, mineralocorticoid-receptor antagonist, and—in selected older pediatric patients under specialist protocols—an SGLT2 inhibitor. The four-class regimen is established principally in adult HFrEF; pediatric dosing and evidence differ. (arnautu2024riskassessmentand pages 21-23, mestroni2014geneticcausesof pages 6-8)
• Acute decompensation: oxygen/ventilation, inotropes, vasopressors, and intensive monitoring as indicated.
• Mechanical support: ECMO and ventricular-assist devices as rescue or bridge to transplant; both were clinically relevant in reported DCM2A. Suggested NCIT terms: Extracorporeal Membrane Oxygenation; Ventricular Assist Device. (sorrentino2023homozygoustnni3mutations pages 4-5)
• Transplantation: definitive therapy for refractory end-stage disease; suggested NCIT term: Heart Transplantation.
• Arrhythmia/device therapy: individualized Holter surveillance, antiarrhythmics, pacing, or ICD based on phenotype. Unlike LMNA/FLNC/PLN disease, no TNNI3-specific threshold supports prophylactic ICD implantation. (arnautu2024riskassessmentand pages 21-23)
• Supportive care: nutrition, vaccination, psychosocial support, physical/occupational therapy for deconditioning, and transplant rehabilitation.

Experimental and precision therapy

No DCM2A-specific interventional clinical trial was found. AAV-mediated TNNI3 replacement, transcript rescue, and genome editing are biologically plausible but remain preclinical concepts. The principal challenges are cardiac delivery, dose control, immune responses, developmental timing, and avoiding abnormal troponin stoichiometry. Genotype currently informs diagnosis, recurrence risk, family screening, and urgency—not selection of an approved TNNI3-targeted drug.

Pharmacogenomic associations involving ADRB1, GRK5, ACE, and AGTR1 have been described in broader DCM/HFrEF, but routine use to guide DCM2A therapy lacks clinical validity. (arnautu2024riskassessmentand pages 21-23)

13. Prevention

• Primary prevention: the genotype cannot be prevented after conception. Preconception counseling, carrier testing of partners in relevant families, IVF with preimplantation genetic testing, donor gametes, prenatal diagnosis, or natural conception with informed testing are reproductive options.
• Secondary prevention: early cascade testing and scheduled ECG/echocardiography can detect presymptomatic disease and permit earlier therapy. This is the most actionable prevention strategy. (arnautu2024riskassessmentand pages 11-12)
• Tertiary prevention: guideline-directed heart-failure care, vaccination, nutrition, arrhythmia/thromboembolism assessment, avoidance of cardiotoxins, and timely referral for mechanical support/transplantation.
• Immunization: no disease-specific vaccine; routine respiratory vaccination is valuable in medically fragile heart-failure patients.
• Public health: no population-wide newborn or carrier-screening program is justified by current evidence. Real-world genetic testing remains underused: only 827/101,919 newly diagnosed DCM patients (0.8%) in a large US EHR/claims study had documented testing within six months, underscoring an implementation gap, though the cohort was not DCM2A-specific. (arnautu2024riskassessmentand pages 11-12)

14. Other species and natural disease

No convincing naturally occurring TNNI3-biallelic DCM2A counterpart was identified in dogs, cats, livestock, or wildlife, and there is no zoonotic or transmissible component. Orthologs are present across vertebrates, reflecting conservation of cardiac thin-filament regulation, but orthology alone does not establish a natural veterinary disease.

A major curation warning is that TNNI3K encodes cardiac troponin-I-interacting kinase, not cardiac troponin I. Cardiac-specific Tnni3k-knockout mice develop age-progressive dysfunction, dilation, hypertrophy, fibrosis, and apoptosis involving p38 MAPK, but this is not a DCM2A model and should not be annotated as TNNI3 evidence. (qu2022knockoutofcardiac pages 7-7)

15. Model organisms and experimental systems

No well-validated model reproducing human biallelic TNNI3-null DCM2A was identified in the retrieved literature. Relevant platforms for future work include:

• Knock-in/knockout mice: suitable for chamber remodeling, hemodynamics, arrhythmia, and AAV replacement, but complete loss may cause developmental lethality and murine calcium/heart-rate physiology limits translation.
• Zebrafish: rapid CRISPR modeling and live cardiac imaging are advantages; duplicated genes and two-chamber physiology are limitations.
• Patient-derived or isogenic hiPSC cardiomyocytes: appropriate for sarcomere assembly, calcium transients, contractility, transcript rescue, and drug screening. Immaturity and fetal TNNI1 expression can obscure a disease whose biology depends on the developmental TNNI1-to-TNNI3 switch.
• Engineered heart tissue/organoids: can quantify force and test gene replacement in a three-dimensional context, but do not reproduce whole-organ loading, immunity, conduction, or systemic failure.

Models of heterozygous TNNI3 missense cardiomyopathy can clarify troponin biology but cannot be assumed to model biallelic null disease. Likewise, TNNI3K models are non-equivalent. (sorrentino2023homozygoustnni3mutations pages 5-8, qu2022knockoutofcardiac pages 7-7)

Recent developments and authoritative interpretation

The key 2023 advance was consolidation of the claim that biallelic TNNI3 null variants cause a severe neonatal/infantile DCM, supported by two additional unrelated patients and a systematic review. The authors’ abstract states that “an increasing amount of evidence has validated the hypothesis that biallelic TNNI3 null mutations cause a severe form of neonatal dilated cardiomyopathy.” (sorrentino2023homozygoustnni3mutations pages 1-2)

Current 2024 genetic-DCM reviews emphasize that genetic testing is now integral to pediatric diagnosis, prognosis, and cascade screening, while warning that more than 200 genes have been associated with DCM but evidence is limited for many. For DCM2A, the causal claim is strongest when the phenotype is severe and early, variants are genuinely biallelic and loss-of-function, segregation is compatible, and population frequency is sufficiently low. (newman2024dilatedcardiomyopathya pages 1-2, eldemire2024geneticsofdilated pages 1-3, arnautu2024riskassessmentand pages 11-12)

The expert interpretation is therefore conservative: DCM2A is a credible but ultra-rare recessive troponinopathy with a compelling loss-of-function mechanism and severe natural history. Its immediate real-world applications are molecular diagnosis, rapid family testing, reproductive counseling, intensive presymptomatic surveillance, and early advanced-heart-failure referral. Disease-specific epidemiology, longitudinal quality-of-life data, multi-omics, validated models, and targeted therapy remain major unmet needs.

References

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