Exploring the Genetic Architecture of Myocarditis and Inherited Cardiomyopathies

Abstract

Myocarditis is a complex inflammatory myocardial disease. Although traditionally regarded as exclusively immune-mediated, recent evidence highlights the significant role of underlying genetics on susceptibility, phenotypic variability, and long-term prognosis. This narrative review examines the evolving genetic architecture of myocarditis and its relationship to inherited cardiomyopathies, integrating mechanistic insights from molecular, imaging, and clinical studies. Variants in desmosomal genes such as desmoplakin (DSP) and plakophilin-2 (PKP2) are increasingly linked to recurrent myocarditis that may evolve into arrhythmogenic cardiomyopathy, supporting the concept of a genetically predisposed myocardium in which inflammatory stressors can act as triggers. Truncating variants in titin (TTN) and Filamin C (FLNC) are associated with fulminant or dilated phenotypes. Conversely, mutations in Lamin A/C (LMNA), Desmin (DES), and BCL2-Associated Athanogene 3 (BAG3) contribute to inflammatory myocardial remodeling and other forms of inherited cardiomyopathies. These findings collectively have the potential to redefine myocarditis as an inflammatory disorder influenced by genetic factors. Furthermore, advancements in genetic testing and multi-omics approaches show promise in enhancing diagnostic accuracy and informing management strategies.

1. Introduction

Myocarditis encompasses a wide spectrum of inflammatory disorders of the myocardium, which may be triggered by infectious, immune-mediated, or toxic mechanisms. The clinical spectrum ranges from being asymptomatic to fulminant heart failure and sudden cardiac death (SCD). Despite extensive research, the etiology often remains unclear, requiring a comprehensive approach that includes clinical assessment, cardiovascular imaging, and, in select cases, histopathological confirmation through endomyocardial biopsy (EMB) for accurate diagnosis [1]. While estimates of prevalence vary according to geography and diagnostic methodology, myocarditis remains a leading cause of non-ischemic cardiomyopathy in young adults.

Traditionally viewed as an acquired illness, myocarditis has been increasingly recognized as a disorder where underlying genetic susceptibility has been implicated in determining vulnerability to myocardial injury and influencing long-term clinical outcomes. Several contemporary cohort studies have identified a subset of patients presenting with acute myocarditis who harbor pathogenic or likely pathogenic variants in genes associated with inherited cardiac conditions (ICC), an umbrella term that includes genetic dilated (DCM), arrhythmogenic (ACM), and related cardiomyopathy phenotypes that may be predisposed to inflammatory myocardial injury [2,3].

In parallel, imaging techniques such as cardiac magnetic resonance (CMR) employ tissue characterization methods, including T1/T2 mapping and late gadolinium enhancement (LGE), which have enhanced diagnostic accuracy for myocarditis, enabling recognition of distinct inflammatory phenotypes. Certain patterns on CMR, such as ring-like subepicardial enhancement or disproportionate tissue injury, are more commonly observed in patients with underlying genetic variants, supporting an association between genotype and inflammatory response. The 2025 European Society of Cardiology (ESC) Guidelines on Myocarditis and Pericarditis now clearly acknowledge this relationship and recommend the consideration of genetic testing [4].

Therefore, an increasing body of evidence supports a model in which myocarditis and inflammatory cardiomyopathy exist along a continuum influenced by genetic factors. This review examines the genetic architecture of myocarditis, integrating findings from observational and retrospective studies. Our focus is on presenting evidence for genetic associations with myocarditis, highlighting the pathways and gene variants involved, and their clinical implications for diagnosis, risk assessment, and management.

Framed in the context of recent large-scale observational studies, meta-analyses, and updated guideline recommendations, this review aims to synthesize the evolving evidence linking genetic susceptibility to inflammatory myocardial disease. Consolidating the “second hit” conceptual framework that integrates inherited myocardial vulnerability with acquired inflammatory triggers, it aims to place myocarditis within a broader inflammatory cardiomyopathy continuum. As a result, it defines the scope and rationale for a precision-oriented perspective on the diagnosis and management of myocarditis.

2. Methods

A comprehensive literature search was conducted in PubMed and Embase from database inception to 25 September 2025. The search combined terms related to myocardial inflammation and genetic susceptibility, including “myocarditis,” “inflammatory cardiomyopathy,” “genetics,” “genetic variants,” and “myocardial inflammation.” Studies were eligible if they involved human participants with clinically suspected, CMR-defined, or biopsy-proven myocarditis and reported genotype–phenotype associations or mechanistic insights linking genetic variation to myocardial inflammation, disease expression, or outcomes. Animal studies were excluded unless they provided pathophysiological insights directly relevant, as were non-English publications, conference abstracts, and editorials or commentaries, unless used solely for contextualization. Titles and abstracts were screened for relevance, followed by full-text review of potentially eligible articles; the reference lists of included studies and relevant reviews were manually cross-checked to identify additional publications; any uncertainties regarding eligibility were resolved by consensus discussion. For each included study, data were extracted on the implicated gene(s) and variant class, cohort size, study design, myocarditis phenotype, and associated cardiomyopathy phenotypes. In total, 72 studies met the eligibility criteria, with key genetic findings compiled into a table and synthesized narratively in the subsequent sections, summarizing convergent themes rather than quantitative pooling. Given the narrative scope of the review and the heterogeneity of study designs, no formal risk-of-bias assessment or quantitative synthesis was performed.

3. Results

3.1. Diagnosis of Myocarditis

The diagnosis of myocarditis relies on a multimodal approach that integrates clinical, laboratory, imaging, and histological data (

Table 1. Multimodality diagnostic framework for suspected myocarditis and implications for genetic disease.

Modality	Key Information	Strengths	Limitations	Genetic Clues/Implications
ECG	Atrial arrhythmias, conduction disturbances, ST-T wave changes	Rapid	Low specificity	Ventricular arrhythmias may suggest LMNA, DSG2, DSP, or SCN5A variants
High-sensitivity Troponin	Indicates myocardial injury	Very sensitive	Non-specific	Present in DSP/ACM
TTE	LV/RV function, wall motion	Accessible, repeatable	Poor tissue characterization	Dilatation/dysfunction and monitoring of systolic function relevant to variants in TTN, FLNC, or BAG3
CMR	T1/T2 mapping for edema/interstitial fibrosis/inflammation; LGE for replacement fibrosis	Reference standard	Limited availability & depends on expertise	Ring-like or inferolateral epicardial LGE is typical for DSP cardiomyopathy
18F-FDG PET	Detects active inflammation; useful in atypical cases	Complements CMR	Physiologic uptake confounds	Persistent focal FDG uptake may occur in FLNC, DSP, or LMNA inflammatory phenotypes
EMB	Histological subtype and viral PCR	Gold standard	Invasive, sampling error	Inflammation on EMB may reflect inflammatory cardiomyopathy in DSP, FLNC, and LMNA
Genetic Testing	Identifies P/LP variants	Enables diagnosis & risk stratification	VUS interpretation. Reported diagnostic yields vary by cohort and case definition	Allows identification of known/unknown pathogenic variants

CMR: cardiovascular magnetic resonance; LGE: late gadolinium enhancement; EMB: endomyocardial biopsy; TTE: transthoracic echocardiogram; ACM: arrhythmogenic cardiomyopathy; P/LP: pathogenic or likely pathogenic variant; DSP: desmoplakin; VUS: variant of uncertain significance. Diagnostic observations that are disproportionate to the degree of myocardial dysfunction (e.g., recurrent troponin rise, extensive LGE despite preserved LVEF, or malignant arrhythmias) should prompt consideration of an underlying ICM.

). Recent guidelines emphasize a precision-driven strategy based predominantly on cardiac imaging for tissue characterization, thereby sparing the need for an endomyocardial biopsy (EMB), unless in challenging scenarios [4]. Primarily, symptoms include chest pain, dyspnea, palpitations, or dizziness. Subsequent blood tests may indicate elevated cardiac troponin levels or increased N-terminal pro-B-type natriuretic peptide (NT-proBNP). However, these markers are non-specific [5]. Electrocardiographic (ECG) abnormalities include atrial arrhythmias, ST-T wave changes, and premature ventricular complexes [6,7].

The diagnostic algorithm typically includes transthoracic echocardiography (TTE), which provides a timely assessment of cardiac function and can detect pericardial effusion. However, CMR remains the gold standard for detecting myocardial edema and fibrosis through T1/T2 mapping, extracellular volume measurement, and late gadolinium enhancement (LGE) assessment [8,9]. Typically, patterns of myocarditis include subepicardial or mid-myocardial LGE in a non-ischemic distribution, often observed in the inferolateral segments. Parametric mapping offers additional insights. Importantly, patterns observed on CMR may also suggest an underlying genetic association; for instance, a ring-like distribution is commonly observed in patients with desmoplakin cardiomyopathies [10]. Important additional diagnostic tests include 18F-FDG positron emission tomography (PET), which evaluates metabolic activity [11,12,13]. Ultimately, EMB remains the reference standard for definitive diagnosis, based on direct histological evidence of inflammatory infiltrates and myocyte necrosis. Due to its invasive nature and sampling limitations, this technique is typically reserved for cases in which the diagnosis is in question or would significantly alter management [14].

3.2. Guideline Recommendations for Genetic Testing

Emerging evidence and the 2025 European Society of Cardiology (ESC) guidelines support a stratified risk-based approach to genetic evaluation in patients presenting with myocarditis, with genetic testing considered most informative in contexts that suggest an underlying genetic cardiomyopathy substrate or elevated arrhythmic risk rather than as indiscriminate routine testing for all patients with inflammatory cardiac injury. The 2025 ESC guidelines on myocarditis and pericarditis integrate holistic, phenotype-driven risk stratification and recommend multidisciplinary evaluation, including genetic input for complicated or recurrent inflammatory myopericardial syndromes, recognizing that genetic predisposition may underlie recurrent presentations and influence long-term outcomes [4]. Clinical contexts in which genetic testing is reasonable include recurrent myocarditis or repeated “myocarditis-like” episodes, particularly when such episodes are associated with repeated elevations in biomarkers or imaging abnormalities; presentation with malignant ventricular arrhythmias, high ectopic burden, or resuscitated cardiac arrest where electrical instability exceeds expectations for a purely inflammatory injury; advanced cardiovascular magnetic resonance features such as extensive late gadolinium enhancement, ring-like patterns, or fibrosis that seems disproportionate to the acute insult (Figure 1); persistent left ventricular dysfunction or failure to recover expected systolic function following resolution of acute inflammation; a family history of genetic cardiomyopathy, sudden cardiac death, or recurrent inflammatory cardiac syndromes; presentation in pediatric or young adult populations where genetic cardiomyopathy is more prevalent; and clinical phenotypes overlapping with inherited cardiomyopathies (for example, features of ACM or DCM). In these settings, genetic evaluation should be embedded within structured pre-test counselling to discuss potential outcomes, implications for prognosis, surveillance strategies, and family cascade testing, with the recognition that identification of a pathogenic or likely pathogenic variant informs both clinical management and family screening. Variants of uncertain significance should be interpreted cautiously; they are not, by themselves, an indication to alter management and should be reviewed in the context of phenotype, familial segregation, and evolving evidence [15].

3.3. Epidemiology of Myocarditis

The incidence of myocarditis ranges from 1–10 cases per 100,000 persons per year, with an increase noted during the pandemic. Precise estimates remain challenging due to diagnostic uncertainty, with a significant proportion of cases remaining unrecognized [5,16]. Variations by gender exist, with a higher reported prevalence among young males, attributed to hormonal and immunological factors, although definitive explanations remain limited [17]. Furthermore, ethnic variation has been documented, likely reflecting differences in viral exposure and underlying immunological factors [18]. Geographically, such fluctuations in incidence are secondary to discrepancies in exposure to infectious agents, vaccination patterns, and healthcare system infrastructure.

Viral myocarditis remains the most common, with enteroviruses, adenoviruses, and parvoviruses accounting for the majority of cases. Recently, COVID-19 and vaccinations have been supplemented to the recognized list of triggers [18]. Mortality rates vary substantially, with low rates of in-hospital mortality (<5%) [19]. Similarly, long-term outcomes remain heterogeneous, ranging from full recovery to persistent disability. Such disease trajectories are influenced by host factors, such as age, comorbidities, and immune response, as well as the underlying genetic susceptibility, which predisposes patients to specific long-term outcomes.

3.4. Pathogenesis

The pathogenesis of myocarditis is variable and often incompletely defined, reflecting variation in etiology and host immune responses [20]. Most are described secondary to an initial infection, predominantly viral. However, immune-mediated and iatrogenic forms are increasingly acknowledged, including immune-checkpoint inhibitor-associated myocarditis [21]. Viral-mediated myocarditis is characterized by viral entry and replication within cardiomyocytes, which trigger an immune response via pattern recognition receptors. Classic associations with polymorphisms in the TLR3 gene have been reported to increase susceptibility to enteroviral myocarditis and inflammatory DCM in animal studies [22,23]. Further downstream, interferon pathways and Nuclear Factor kappa B (NFκB) signaling prime chemokine-driven recruitment of leukocytes [24]. Several key players in the innate response have been identified, including the NLRP3 inflammasome and IL-1β [25]. Although this early phase is short-lived and aimed at restricting the spread of pathogens, a large, dysregulated response to the stimulus can amplify myocardial injury by driving excessive cytokine release and activating macrophages and dendritic cells, thereby establishing an inflammatory microenvironment. T-cell-mediated responses involving both cytotoxic and helper lineages may sustain the inflammation through interferon gamma, TNF-α, and interleukin-mediated signaling. Emerging evidence indicates that coordination between innate and adaptive immune responses is a determinant of progression to persistent cardiomyopathy [26]. Furthermore, insights from molecular studies suggest failure of immune resolution, driven by Th17-derived IL-17, sustained IFN-γ signaling, and genetically modulated immune responses, including HLA-DQA1*/B1* associated CD4+ T-cell activation, appear to underlie this transition from acute myocarditis to chronic cardiomyopathy [27,28,29]. In immune-mediated myocarditis, including immune checkpoint inhibitor-associated disease, a loss of peripheral tolerance is associated with activated T-cell responses and a heightened likelihood of cardiomyocyte cytotoxicity [21].

From a histopathological perspective, the hallmark of myocarditis is an inflammatory infiltrate with associated cardiomyocyte injury. The specific cellular composition varies by etiology, yet it has been shown to influence clinical phenotype and prognosis [20]. Lymphocytic myocarditis remains the most frequently described pattern and is commonly associated with a viral etiology, whereas eosinophilic myocarditis is associated with hypersensitivity and systemic inflammation. Of these patterns, giant cell myocarditis represents a fulminant, T-cell-mediated disorder characterized by extensive necrosis and multinucleated giant cells. This subtype is associated with significantly worse clinical outcomes as patients are at high risk of malignant arrhythmias and rapid hemodynamic collapse [30]. Sustained injury and changes to the ventricular myocardium are thought to arise from a combination of persistent antigenic stimulus with potential molecular mimicry and autoantibody formation against cardiac antigens, continuing myocardial inflammation after pathogen clearance. Across various subtypes and etiologies, the ongoing question is how environmental exposures influence immunological responses, how these exposures reveal a genetically susceptible myocardium consistent with cardiomyopathy patterns, and how host susceptibility is modulated by genetic factors that affect immune responses.

3.5. Conceptual Framework: The Genetically Vulnerable Myocardium and Second-Hit Model

Observational studies demonstrate a “genetically vulnerable myocardium” model in which clinically overt myocarditis reflects the interaction between an inherited substrate and an acquired inflammatory trigger. In this framework, rare pathogenic or likely pathogenic variants that affect myocardial architecture, electromechanical coupling, or inflammatory control lower the threshold for injury and remodel the host response to inflammatory stress [31].

The inherited substrate spans both conventional genes implicated in genetic cardiomyopathies and immune susceptibility pathways. For instance, genes include desmosomal, sarcomeric, cytoskeletal, and ion-channel genes [15]. On the immune aspect, variation in pathways governing viral sensing and antigen presentation has been linked to myocarditis susceptibility and severity, including signals from innate immune sensors and HLA-associated risk in selected contexts [32].

Environmental or acquired exposures then act as a second hit. Viral infection remains a dominant trigger, but immune dysregulation and drug-related immune activation can similarly precipitate inflammatory injury in predisposed individuals [20]. Clinical trajectories following this interaction are heterogeneous. While many recover following resolution of inflammation, others exhibit relapse-prone or persistent inflammatory phenotypes with progressive fibrosis. In a clinically important subset, inflammatory injury may unmask an underlying cardiomyopathy or accelerate transition to a genetic cardiomyopathy, with inherent ventricular arrhythmia risk. Collectively, this model provides a unifying framework for the myocarditis–cardiomyopathy continuum and supports emerging approaches that integrate genotype with phenotype to refine risk stratification and guide follow-up intensity and family evaluation [33].

3.6. Clinical Significance and Prognostic Implications of Myocarditis

The timely recognition of myocarditis remains critical due to its association with malignant ventricular arrhythmias and sudden cardiac death in young individuals and athletes [27]. Post-mortem studies have consistently identified myocarditis as a considerable cause of SCD. These fatal presentations may occur without a preceding diagnosis or prodrome, which reinforces the need for diagnostic vigilance and comprehensive assessment of those with a family history of genetic cardiomyopathy or myocarditis [28]. A range of markers has been associated with poor outcomes [4]. Extensive LGE is associated with an increased risk of life-threatening arrhythmic events [29]. Regardless, a significant unmet need remains for integrating genetic data into risk stratification [34].

3.7. Treatment of Myocarditis

Most cases involve supportive care [4]. However, a subset who present with catastrophic heart failure, ventricular arrhythmias, necessitate further and long-term treatment with careful ongoing surveillance. Hence, management of myocarditis is multifactorial, which includes pharmacotherapy for heart failure and arrhythmias, and in selected cases, mechanical circulatory support and even cardiac transplantation [35]. Importantly, routine immunosuppression in acute myocarditis has not been found to be beneficial [36]. However, it plays a role in immune-checkpoint inhibitor myocarditis as well as biopsy-proven immune-mediated, giant cell, and eosinophilic myocarditis [37]. Steroid-sparing agents such as mycophenolate mofetil and azathioprine have been used in refractory cases, although evidence is limited. In addition, guideline-directed medical therapy should be initiated in the presence of heart failure [4]. The management of arrhythmia remains a cornerstone of care for patients with myocarditis. Beyond anti-arrhythmic therapies, catheter ablation, an implantable cardiac defibrillator (ICD) may be considered in select cases with persistent atrial or ventricular arrhythmias, prior sudden cardiac arrest, or persistent left ventricular dysfunction [38,39].

When a pathogenic or likely pathogenic variant is identified in an individual presenting with myocarditis, genotyping may refine clinical decision-making alongside standard risk assessment. Certain DCM-associated genes overlapping with myocarditis, including LMNA, FLNC-truncating variants, DSP, and other high-risk arrhythmic genotypes [40], are consistently linked to elevated risk of malignant ventricular arrhythmias and sudden cardiac death irrespective of left ventricular ejection fraction. Contemporary cardiomyopathy guidelines [41] incorporate this evidence, supporting consideration of primary prevention ICD in selected genotype-positive individuals who demonstrate additional markers of arrhythmic risk, such as documented non-sustained ventricular tachycardia, conduction disease, or significant myocardial fibrosis on imaging, after multidisciplinary evaluation. In these contexts, rhythm surveillance with ambulatory monitoring and repeat cardiac magnetic resonance imaging to characterize scar may inform the timing and intensity of follow-up. Identification of certain variants also justifies cascade genetic testing and structured clinical surveillance of first-degree relatives within established workup pathways. Throughout this process, careful interpretation is essential; variants of uncertain significance should not be used in isolation to dictate therapeutic interventions or device implantation.

4. The Genetic Architecture

Large-scale cohort studies and case reports between pathogenic variants and patterns of inherited cardiomyopathy have supported the concept of genetic susceptibility in myocarditis [31]. Here, a substantial proportion of patients with biopsy or imaging-proven myocarditis harbor pathogenic or likely pathogenic variants in genes classically characteristic of inherited cardiomyopathies and channelopathies (

Table 2. Genetic architecture of myocarditis: chromosomal distribution of pathogenic variants and associated clinical phenotypes.

Chromosome	Genetic Variant/Locus	Features	Variant Class	ClinVar/Clinical Interpretation
1	LMNA [42,43,44] RYR2 [45,46] TNNT2 [47,48]	Myocarditis may unmask inherited cardiomyopathy or channelopathy; inflammatory stress has been associated with malignant ventricular arrhythmias; in children, myocarditis-labelled presentations may reflect genetically mediated DCM/HCM triggered by infection rather than primary inflammatory disease	LMNA: truncating/splice-site; RYR2: missense (channel); TNNT2: missense (sarcomeric)	Variant- and phenotype-dependent. Many LMNA truncating/splice-site variants are Pathogenic/Likely Pathogenic (P/LP); RYR2 and TNNT2 include P/LP variants and VUS depending on the specific variant and clinical context
2	DES A213V [49] DES p.Glu439Lys [50] TTN truncating variants [43,51,52,53] IFIH1 rs1990760/rs3747517 [54]	Inflammatory stress may accelerate progression to DCM with fibrosis and arrhythmias; fulminant myocarditis-like HF may mask inherited DCM; innate immune sensing variants may modify post-viral disease trajectory (association-level evidence)	DES: missense; TTN: truncating (loss-of-function); IFIH1: common immune-modifier SNPs	DES p.Ala213Val reported as Benign; DES p.Glu439Lys reported as VUS in ClinVar; TTN truncating interpretation is context-dependent (region, transcript, phenotype); IFIH1 SNPs are association loci and not ACMG-classified
3	SCN5A [44,52,55]	Channelopathy substrate interacting with inflammatory triggers; myocarditis has been associated with increased malignant ventricular arrhythmia risk in genetically susceptible individuals, with phenotypic overlap with inherited arrhythmogenic cardiomyopathy	SCN5A: missense (most common), less often truncating	Variant-dependent. Includes Pathogenic/Likely Pathogenic variants and VUS in ClinVar; interpretation requires disease-specific context
5	SDHA [47]	Metabolic–genetic vulnerability in pediatric myocarditis-labelled DCM; severe LV dysfunction may not be fully explained by inflammation alone	SDHA: missense or truncating (mitochondrial)	Variant-dependent. Pathogenic/Likely Pathogenic variants reported in mitochondrial disease contexts; interpretation requires phenotype correlation
6	DSP truncating variants [56,57,58,59] PKP2 [45,60,61] DSG2 [34,62] HLA-A*01:01–B*08:01–C*07:01 [63] HLA/MHC loci [64]	Myocarditis-like inflammatory “hot phases” may represent an early manifestation of inherited ACM; recurrent myocarditis-like episodes may precede overt cardiomyopathy; high arrhythmic burden may occur even with preserved early LVEF; HLA associations are subtype-specific	DSP: truncating; PKP2/DSG2: truncating or missense; HLA: haplotypes/association loci	DSP and PKP2 truncating variants are frequently P/LP in ACM contexts (variant-dependent); DSG2 interpretation is variant-dependent; HLA haplotypes are not ACMG-classified and should be interpreted only in defined myocarditis subtypes
7	FLNC [31,52,65,66] KCNH2/hERG [67]	Inflammation may modify an underlying arrhythmogenic or dilated cardiomyopathy substrate; viral myocarditis may exacerbate ion-channel dysfunction, increasing malignant arrhythmic risk	FLNC: truncating/splice-site; KCNH2: missense or truncating	FLNC truncating variants are frequently P/LP; KCNH2 interpretation is variant-dependent (P/LP and VUS both reported)
8	CTSB [68]	Inflammasome activation and pyroptosis contribute to viral myocarditis severity in experimental models; genetic deletion has been associated with improved survival and LV function in animal models	Functional/experimental	Not applicable. Mechanistic evidence; not a Mendelian clinical variant claim
9	TNC Tenascin-C [69,70,71]	ECM–immune coupling promotes myocardial inflammation and fibrosis and may facilitate transition from acute myocarditis to inflammatory cardiomyopathy	Functional/biomarker (ECM signalling)	Not applicable
10	BAG3 truncating variants [48,51,72,73] RBM20 [44,65]	Fulminant myocarditis-like acute HF may mask inherited DCM; inflammatory stress may precipitate cardiogenic shock with incomplete LV recovery and progression to chronic DCM	BAG3: truncating; RBM20: missense (splicing regulator)	BAG3 truncating variants are frequently P/LP; RBM20 interpretation is variant-dependent
11	MYBPC3 truncating variants [50,74] UNC93B1 [75] IRF7 [76] KCNQ1 [67]	Sarcomeric cardiomyopathy may display malignant phenotypes during infection; defects in antiviral innate immunity may worsen viral myocarditis; channelopathy–infection interactions may contribute to arrhythmias	MYBPC3: truncating; UNC93B1/IRF7: rare loss-of-function; KCNQ1: missense or truncating	MYBPC3 truncating variants are frequently P/LP; KCNQ1 interpretation is variant-dependent; immune-pathway genes are phenotype-specific and variant-dependent
12	PKP2 [45,60,61] CACNA1C [67] TBK1 [77] GABARAPL1 [77]	Myocarditis may trigger biventricular ACM; autophagy and innate immune pathways may modulate viral myocarditis severity; channelopathy–inflammation interaction may increase arrhythmic risk	PKP2: truncating/missense; CACNA1C: missense; TBK1: truncating; GABARAPL1: autophagy pathway	PKP2 variants are frequently P/LP (variant-dependent); CACNA1C and TBK1 are variant-dependent; GABARAPL1 is mechanistic and not ACMG-classified
14	MYH7 [42,47,48,78]	Pediatric and familial cardiomyopathy may present as myocarditis; myocarditis may act as a trigger or unmasker with adverse remodelling and arrhythmic risk	MYH7: missense (rarely truncating)	Variant-dependent. Many MYH7 variants are Pathogenic/Likely Pathogenic, but not all
15	TPM1 [47,79]	Sarcomeric disease may be misdiagnosed as myocarditis in children; severe LV dysfunction may occur during inflammatory stress	TPM1: missense (sarcomeric)	Variant-dependent (Pathogenic/Likely Pathogenic and VUS reported)
16	GABARAPL2 [77]	Autophagy–immune signalling may modify viral myocarditis severity	Mechanistic/autophagy pathway	Not applicable
17	MIR10A rs3809783 [68] ADORA2B [76] Non-MHC immune loci [80]	Altered antiviral immune signalling may increase myocarditis susceptibility; polygenic predisposition may contribute to chronic or autoimmune myocarditis	Common SNPs/association loci	Not ACMG-classified (risk-modifier associations)
18	DSG2 [62] DTNA [45]	Desmosomal and cytoskeletal substrates may drive myocarditis-like episodes with progression to ACM and high arrhythmic risk	DSG2: truncating/missense; DTNA: missense/truncating	Variant-dependent. DSG2 includes P/LP variants; DTNA interpretation requires phenotype context
19	GNA15 [81,82] TNNI3 [47,48]	Polygenic susceptibility may contribute to specific drug-induced myocarditis phenotypes (association-level evidence); sarcomeric variants may influence prognosis in myocarditis-labelled DCM	GNA15: association locus; TNNI3: missense	GNA15 is not ACMG-classified; TNNI3 interpretation is variant-dependent
21	CXADR [83]	Host–virus interaction may influence susceptibility and severity of myocarditis and DCM through viral entry pathways; strength of evidence varies across experimental and association studies	Host susceptibility locus	Not ACMG-classified unless a specific rare clinical variant is defined
X	DMD splice-site variants [84] Dystrophin/DGC remodeling [85]	X-linked DCM may present as myocarditis-like illness; viral infection may increase myocardial injury susceptibility even in the absence of skeletal myopathy	DMD: splice-site or truncating (loss-of-function)	DMD LoF/splice variants are frequently P/LP; cardiomyopathy interpretation remains phenotype-dependent
Viral genome	Coxsackievirus B3 lineages [86]	Viral genetic diversity may influence myocarditis phenotype and severity via host–virus genomic interaction	Viral lineage	Not applicable
Multiple	ACE2/TMPRSS2/IL6/FURIN/AGT/PAI-1 [87] Broad cardiomyopathy panels [43,88,89] Familial screening/autopsy yield [52,66,90,91]	Pathogenic variants are identified in a subset of acute myocarditis cases in some cohorts; genotype-positive myocarditis has been associated with recurrence, fibrosis, and arrhythmias; supports targeted genetic testing and family screening when red flags are present	Mixed: association loci and Mendelian cardiomyopathy genes	Association loci are not ACMG-classified; Mendelian genes are interpreted variant-by-variant using ACMG criteria and phenotype context

LMNA: Lamin A/C; RYR2: Ryanodine Receptor 2; TNNT2: Cardiac Troponin T; DES: Desmin; TTN: Titin; IFIH1: Interferon Induced with Helicase C Domain 1; SCN5A: Sodium Voltage-Gated Channel Alpha Subunit 5; SDHA: Succinate Dehydrogenase Complex Flavoprotein Subunit A; DSP: Desmoplakin; PKP2: Plakophilin-2; DSG2: Desmoglein-2; HLA: Human Leukocyte Antigen; MHC: Major Histocompatibility Complex; FLNC: Filamin C; KCNH2: Potassium Voltage-Gated Channel Subfamily H Member 2; hERG: Human Ether-à-go-go-Related Gene; CTSB: Cathepsin B; TNC: Tenascin-C; BAG3: BCL2-Associated Athanogene 3; RBM20: RNA Binding Motif Protein 20; MYBPC3: Myosin-Binding Protein C, Cardiac-Type; UNC93B1: Unc-93 Homolog B1; IRF7: Interferon Regulatory Factor 7; KCNQ1: Potassium Voltage-Gated Channel Subfamily Q Member 1; CACNA1C: Calcium Voltage-Gated Channel Subunit Alpha1 C; TBK1: TANK-Binding Kinase 1; GABARAPL1: GABA Type A Receptor-Associated Protein Like 1; MYH7: Beta-Myosin Heavy Chain; TPM1: Tropomyosin 1; GABARAPL2: GABA Type A Receptor-Associated Protein Like 2; MIR10A: MicroRNA 10A; ADORA2B: Adenosine A2B Receptor; DTNA: Dystrobrevin Alpha; GNA15: G Protein Subunit Alpha 15; TNNI3: Cardiac Troponin I; CXADR: Coxsackievirus and Adenovirus Receptor; DMD: Dystrophin; ACE2: Angiotensin-Converting Enzyme 2; TMPRSS2: Transmembrane Serine Protease 2; IL6: Interleukin-6; FURIN: Furin; AGT: Angiotensinogen; PAI-1: Plasminogen Activator Inhibitor-1; DCM: Dilated Cardiomyopathy; ACM: Arrhythmogenic Cardiomyopathy; LV: Left Ventricle; LVEF: Left Ventricular Ejection Fraction; ECM: Extracellular Matrix; rs: Reference Single-Nucleotide Polymorphism Identifier; DGC: Dystrophin–Glycoprotein Complex; Coxsackievirus B3: Coxsackievirus B3.

). These findings imply that acute myocardial inflammation exposes latent genetic disease rather than being a primary disease. This observation may be particularly relevant in younger patients with malignant ventricular arrhythmias or recurrent myocarditis-like episodes with an incomplete recovery of cardiac function.

4.1. Desmosomal Genes and ACM

Mutations in desmosomal genes, which encode proteins that serve as strong mechanical anchors in tissues under high mechanical stress (e.g., DSP, PKP2, DSG2, and DSC2), have been associated with fibrofatty ventricular muscle displacement, predisposing patients to arrhythmias in ACM. Notably, inflammation is now widely recognized as a key driver of disease progression in ACM, with loss of desmosome integrity triggering pro-inflammatory signaling pathways. JUS and PKP2 are the two most common genes associated with ACM, and studies using cardiomyocyte models show that PKP2 knockdown leads to upregulation of the NF-KB and STAT3 pathways, promoting inflammation. Similarly, mutant plakoglobin variants in JUP are implicated in myocyte apoptosis and trigger inflammatory pathways [92]. Additionally, autoimmune responses have also been implicated in ACM, with some individuals being found to harbor anti-intercalated disc antibodies, suggesting immune susceptibility [93].

Clinically, mutations in desmosomal genes often manifest with arrhythmic features out of proportion to LV dysfunction. CMR in these patients may demonstrate epicardial LGE in inferolateral segments of the left ventricle [94], as seen in left-dominant disease, or a “triangle of dysplasia” in the right ventricle [95,96]. Some cases labelled as myocarditis may in fact represent the inflammatory phase of an ACM and desmoplakin cardiomyopathy. Of these subtypes, desmoplakin (DSP) has emerged as a notable genetic culprit of a unique cardiomyopathy [16]. DSP mutations have been linked with a distinct fibrotic cardiomyopathy with recurring “hot-phase” myocarditis-mimicking episodes. In a cohort of 107 carriers, 15% experienced acute myocardial injury episodes, often labelled as myocarditis or sarcoidosis. During these episodes, subepicardial scars were observed in the LV on CMR and FDP-PET imaging [16]. Unlike traditional ACM, which predominantly affects the right ventricle, DSP cardiomyopathy tends to display left-dominant patterns and progressive worsening. The scars visible on imaging often precede systolic dysfunction and create arrhythmogenic vulnerability, predisposing DSP carriers to high rates of malignant ventricular arrhythmias. In the largest cohort study, DSP truncating variants were among the most well-established genetic risk factors, with 1.3% of cases carrying the mutation and 0% of the 1053 controls [31]. No other ACM gene reached individual significance, although collectively, the five major genes (DSC2, DSG2, DSP, PKP2, and JUP) showed enrichment for rare truncating variants (3.1% of cases versus 0.4% of controls; odds ratio, 8.2; p = 0.001). These carriers were often young males who displayed normal LV systolic function but an increased incidence of ventricular arrhythmias, similar to the ACM phenotype. Consistently, in pooled cohorts, patients with myocarditis and preserved ejection fraction, 64% of reported P/LP variants were in desmosomal genes [97,98]

4.2. Sarcomeres, Titin, and DCM

Sarcomeric gene variants such as TTN, MYH7, MYBPC3, and FLNC are classically associated with hypertrophic cardiomyopathy and DCM. Yet novel evidence suggests that these mutations may also contribute to myocardial inflammation through contractile instability and myofibril disarray, particularly in DCM-like myocarditis associated with severe systolic dysfunction. Of these associated variants, titin truncating variants (TTN-tv) have been explained in the literature. Titin acts as a spring-like protein, stabilizing the sarcomere and generating tension, and heterozygous TTN-tv variants are the most common cause of idiopathic DCM. In myocarditis, these variants appear to serve as a “weak link” unmasking underlying vulnerability to heart failure induced by the stress of inflammation. Classically, TTN-tv positive myocarditis correlates with severe acute presentations and a greater risk of progression to chronic DCM [3].

For TTN variants, Lota et al. found that these mutations were significantly enriched amongst patients with reduced LVEF. In their Maastricht cohort, 6.6% of myocarditis cases carried a TTN-tv compared to 0.9% of controls (odds ratio, 3.6; p = 0.0116) [31,97]. Several other studies support titin’s role in DCM-associated myocarditis, supporting similar associations with fulminant myocarditis and lower rates of LV function recovery [20,99,100]. Beyond titin, other sarcomeric associations, such as FLNC truncating mutations, have been implicated in aggressive forms of DCM/ACM with early fibrosis. Rare cases of FLNC-truncation cardiomyopathy have been noted to present with life-threatening features, including cardiogenic shock. In the analysis of FLNC truncation carriers, myocarditis-like episodes have been noted to precede the diagnosis of familial cardiomyopathies [101,102]. Even genes implicated in HCM, such as MYH7 and MYBPC3, have been linked to inflammation, as cardiomyocytes under chronic stress are predisposed to necrosis and fibrotic replacement. Whilst overt myocarditis is atypical, acute inflammatory flares have been described in HCM patients [103].

4.3. Nuclear Envelope Genes and Stress Pathways

The third category of genetic contributors to myocardial inflammation includes nuclear envelope proteins (e.g., LMNA, BAG3, EMD) and their cytoskeletal elements (e.g., SYNE1/2 and DES). Variants in these genes are increasingly recognized in myocardial inflammation, with certain mutations carrying the risk of cardiomyopathies with systemic neuromuscular dysfunction.

Lamin A and C are structural proteins that form the architecture surrounding the inner nuclear membrane, regulate gene expression, and provide mechanical support. Mutations in LMNA have been reported in laminopathies, leading to fragile nuclei that are susceptible to mechanical stress. Hence, cardiomyocytes with LMNA dysfunction undergo repeated nuclear membrane stress with each contraction, leading to leakage of nuclear DNA and the activation of intrinsic inflammatory pathways. Mouse model studies have shown that Lamin A/C-deficient mice exhibit nuclear envelope ruptures, which precede inflammation and trigger a pro-fibrotic inflammatory cascade via cytokines and growth factors [104]. Clinically, this correlates with high levels of LGE and inflammatory infiltrates on biopsy and presents as a form of DCM [105]. This represents a highly inheritable cardiomyopathy in which patients typically develop atrioventricular blocks and ventricular arrhythmias around the third decade of life with subsequent heart failure [106]. Other nuclear envelope proteins, such as emerin (EMD) and nesprins (SYNE1/SYNE2), connect the nuclear envelope to the cytoskeleton and form complexes with lamins. Mutations in these genes similarly disrupt the nuclear-cytoskeleton infrastructure, leading to cardiomyocyte death from shear stress and nuclear rupture. While fewer studies investigate the phenotypic burden of these mutations, it is plausible that similar rupture events occur in susceptible cardiomyocytes with contractile activity, leading to subsequent inflammatory signaling. Whilst mutations in these nuclear envelope genes are frequently associated with muscular dystrophies, associations with DCM have been studied, showing that EMD variant-carriers have a risk of progressive heart failure and ventricular arrhythmias comparable to that of LMNA variant-carriers [107]. Patients with nuclear envelope cardiomyopathies may present with systemic neuromuscular dysfunction and inflammatory patterns on medical imaging and biopsy. These require early intervention, including timely ICD implantation for those with LMNA mutations, and consideration of anti-inflammatory medications to prevent fibrosis and scarring [108]. In routine clinical practice, patients with underlying LMNA or EMD mutations should be carefully evaluated with non-specific symptoms mimicking myocarditis for prompt therapeutic assessment.

Furthermore, mutations in cytoskeletal genes such as BAG3, DES, and VCL may promote inflammation and cell death by impairing cellular cleanup and structural support. Among these, BAG3 is a cellular chaperone that mediates assisted autophagy of misfolded proteins, including sarcomeric proteins. Loss-of-function mutations in these genes result in the aggregation of damaged proteins, triggering stress pathways, inducing apoptosis, and local inflammation. Recent evidence has shown that BAG3 haploinsufficiency activates the cardiac NRLP3 inflammasome and alters cytokine signaling pathways [109,110]. Consequently, animal studies have shown that BAG-3-deficient mice display enhanced caspase activation with impaired mitochondrial function [111]. In clinical practice, patients with these mutations experience a variant of DCM that typically presents in young adulthood with rapid decompensation [112]. EMB findings include diffuse cytoplasmic inclusion bodies and inflammatory cells. Desmin (DES) is another intermediate filament linking sarcomeric Z-discs to the cellular membrane. These mutations support a model of a myopathy with misaligned myofibrils and rapid cell death. Mice with DES-null variants have shown acute stress responses with prominent inflammation during early stages of life, with a high expression of inflammatory cytokines within the first few weeks of life, preceding fibrosis and heart failure [113]. Whilst cytoskeletal defects are likely to have systemic consequences as discussed before, the extended fibrosis and DCM patterns observed in these cases can also be observed in cases of myocarditis. Finally, vinculin (VCL) mutations share a mechanism of causing cardiomyopathy by weakening adhesion to the extracellular matrix, although inflammation is not classically implicated in the pathophysiology. In the context of myocarditis, if patients are identified as having BAG3 or DES mutations, early escalation is necessary to mitigate the risk patterns associated with each phenotype. Whilst many targeted treatments described in the literature, such as colchicine or NLRP3 inhibitors, hold promise, they remain in their infancy.

4.4. Ion Channelopathies and Electrical Instability

Other genetic associations of myocarditis include ion channels and calcium-handling genes. These defects are classically associated with arrhythmic syndromes, although if identified in patients with myocarditis, they can significantly amplify the arrhythmogenic potential of the inflamed myocardium. It is well documented that myocardial inflammation profoundly alters the electrophysiology of the heart, with acute inflammation and cytokine signaling modulating ion channel expression and function, and chronic inflammation triggering fibrotic pathways promoting arrhythmias. One example from animal studies is the role of TNF-α and IL-1β in diastolic calcium leak from the sarcoplasmic reticulum by modulating RYR2 channels [114]. In individuals with RYR2 mutations, this calcium leak can predispose patients to afterdepolarizations and ventricular ectopic beats, further exacerbating existing predispositions to ventricular tachyarrhythmias [115,116]. Other mutations, such as SCN5A, which is widely associated with long QT and Brugada syndromes, affect sodium channels, which are functionally impaired in inflammatory states and have been documented to associate with cardiomyopathy [117]. Moreover, in patients with Brugada syndrome, high fevers have been associated with the emergence of characteristic ECG patterns and the triggering of ventricular arrhythmias [118,119]. There are documented cases in the literature of patients with SCN5A variants who have exhibited biopsy evidence of myocarditis, with diffuse or localized right ventricular inflammation and viral genomes detected by polymerase chain reaction, providing evidence that myocarditis may mimic such sodium-channelopathies [120]. Additionally, another calcium-handling regulator protein, phospholamban (PLN), is associated with a distinct cardiomyopathy that could present with myocarditis-like “hot phases”, much like desmosomal ACM [121]. In patients with such mutations, aggressive arrhythmia management would be appropriate. For example, fever control with anti-pyretic drugs in patients with SCN5A mutations and post-myocarditis risk stratification with monitoring for ACM and SCD [15].

5. Discussion

Although the clinical presentation of myocarditis is frequently considered self-limiting, a considerable proportion of individuals experience persistent LV dysfunction, heightened arrhythmogenic risk, and progression to a chronic cardiomyopathy [37]. The variability of its manifestations and long-term clinical outcomes highlights the importance of host susceptibility in modulating myocardial susceptibility and response to inflammatory insult [122]. Advances in genetic testing, including GWAS and NGS, have substantially improved the detection of pathogenic variants in patients presenting with imaging- or biopsy-proven myocarditis [31]. The evolution in genomic technologies further supports the incorporation of cascade screening for disease prevention and risk stratification informed by evidence-based strategies.

Once regarded as separate concepts entirely, inherited cardiomyopathy and inflammatory myocardial disorders have been increasingly intertwined in the literature [31]. Genetic data, as aforementioned in this review, support the hypothesis that myocarditis may overlap with, and may reveal, the progression into a genetic cardiomyopathy. Pathogenic variants in genes such as DSP, PKP2, LMNA, TTN, BAG3, MYH7, and MYBPC3 are frequently identified in patients with myocarditis and are particularly associated with poor clinical outcomes [97]. Several studies have documented phenotypic overlap between myocarditis and inherited cardiomyopathies [2]. In such cases, guideline-directed therapies should be prioritized, arrhythmias should be mitigated, and family screening should be performed.

Across genetic categories, the strength of evidence is heterogeneous and should be interpreted in light of study design and phenotype definition. Evidence is strongest for overlap with inherited cardiomyopathy genes, supported by population-based and multicentre observational cohorts demonstrating enrichment of rare pathogenic or likely pathogenic variants in acute myocarditis, alongside clinically relevant associations with recurrence, arrhythmic events, and incomplete recovery [31]. This is reinforced by a meta-analysis estimating a non-trivial prevalence of cardiomyopathy-gene pathogenic variants among acute myocarditis presentations, with desmosomal and selected sarcomeric or cytoskeletal genes contributing, although heterogeneity across cohorts and gene panels limits gene-level inference [97]. In contrast, evidence for immune susceptibility loci and channelopathy genes in myocarditis remains hypothesis-generating, with much of the literature relying on smaller series, candidate-gene associations, and mechanistic or experimental data that plausibly explain vulnerability but do not establish robustness. Despite this trend, contemporary guidelines have moved toward phenotype-driven genetic evaluation rather than universal testing, explicitly recommending consideration of genetic input in complicated, recurrent, or arrhythmic presentations and emphasising multidisciplinary interpretation [4].

6. Limitations

While this review brings together a broad and clinically relevant body of evidence, several limitations should be acknowledged. Its narrative design, although appropriate for integrating heterogeneous genetic and mechanistic evidence, carries an inherent risk of selection bias and does not permit weighting of evidence. Much of the literature linking genetic variation to myocarditis consists of observational studies and case-based reports, which limit causal inference and make it difficult to separate genetic predisposition from disease unmasking during inflammatory injury. In addition, diagnostic heterogeneity across studies, with myocarditis defined variably using clinical criteria, cardiovascular magnetic resonance, or endomyocardial biopsy, complicates direct comparison of genotype–phenotype associations. The predominance of European ancestry cohorts further limits generalizability, particularly given ethnic variation in cardiomyopathy genetics and immune responses. Finally, clinical implementation remains challenged by access and cost constraints, variability in genetic testing strategies, and the high frequency of variants of uncertain significance, which restricts immediate clinical actionability.

7. Future Directions

Looking ahead, translating genetic insights in myocarditis into clinically actionable strategies will require coordinated advances in study design, data integration, and health system infrastructure. Prospective registries with harmonized definitions represent a critical next step for advancing genetic research in myocarditis, as they reduce diagnostic misclassification and enable reproducible cross-center genotype–phenotype analyses. Large international initiatives, including the ESC-led international Cardiomyopathy and Myocarditis Registry [42], have demonstrated the feasibility of prospective enrolment and longitudinal follow-up, but further progress will depend on the consistent application of unified clinical, CMR, and EMB criteria, alongside systematic outcome capture [20]. Deliberate inclusion of ethnically diverse populations will also be essential to improve generalizability and address population-specific genetic and immune determinants of disease [8].

Beyond registry design, future advances are likely to be driven by multi-omics integration, particularly in patients undergoing EMB. Transcriptomic profiling of myocardial tissue has shown promise in distinguishing inflammatory cardiomyopathy subtypes and refining diagnostic classification beyond conventional histology [123,124]. More recent work using deeper RNA sequencing approaches continues to develop this concept for inflammatory cardiomyopathy and myocarditis-relevant phenotypes [125]. In parallel, early proteomic profiling of EMB specimens demonstrated the feasibility of identifying disease-associated protein patterns in myocardial tissue, providing a complementary layer that can link inflammation, extracellular matrix remodeling, and energy pathways to clinical course [126].

Equally, equitable access and interpretation infrastructure will determine whether these advances improve care or simply increase uncertainty. High-level cardiovascular genetics guidance increasingly emphasizes that precision medicine depends on fair access to testing and specialist services, and that disparities in availability, referral pathways, and insurance or reimbursement can widen existing outcome gaps if not addressed [127,128]. At the same time, the interpretive burden of widespread sequencing is well recognized. Authoritative standards explicitly state that variants of uncertain significance should not be used in clinical decision-making, reinforcing the need for periodic reappraisal of the evidence and for phenotype-anchored interpretation rather than immediate management changes [129]. This is where interpretation infrastructure becomes central, including curated variant knowledge bases and disease-specific expert panels, such as those developed through ClinGen, which aim to standardize and improve the consistency of variant classification across laboratories and health systems [130]. In practice, the most realistic implementation pathway is therefore one that couples targeted testing indications with equitable pathways to cardiogenetic expertise and formal variant curation processes, so that genetic information can be translated into reproducible surveillance and family evaluation strategies without over-interpretation. Collectively, these steps will be necessary to realize a clinically meaningful precision-medicine approach in myocarditis [4,131].

8. Conclusions

Myocarditis has traditionally been characterized as an acute, often post-viral, inflammatory myocardial disorder. However, emerging evidence indicates that myocarditis is a complex syndrome involving genetic susceptibility and may be associated with the development of inherited cardiomyopathies. The narrative review highlights numerous genetic variants that influence the clinical progression and phenotypic diversity of the disease. These findings emphasize the importance of clinicians considering familial and genetic factors when diagnosing myocarditis and advocate integrating genetic testing into risk assessment, family counseling, and treatment planning. Large-scale prospective registries will be crucial for validating current evidence and facilitating the transition to a precision medicine approach.