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Review

The Genetic Architecture of Sudden Cardiac Death: A State-of-the-Art Review

by
Sabrina Montuoro
1,†,
Emanuele Monda
2,*,†,
Gaetano Diana
2,
Emanuele Bobbio
2,
Vera Fico
2,
Marta Rubino
2,
Martina Caiazza
2,
Adelaide Fusco
2,
Annapaola Cirillo
2,
Federica Verrillo
2,
Francesca Dongiglio
2,
Giuseppe Palmiero
2,
Federica Barra
2,
Giulia Frisso
3,
Maria Giovanna Russo
2,
Paolo Calabrò
2 and
Giuseppe Limongelli
2
1
Health Science Interdisciplinary Center, Scuola Superiore Sant’Anna, Piazza Martiri della Libertà 33, 56127 Pisa, Italy
2
Inherited and Rare Cardiovascular Diseases, Department of Translational Medical Sciences, University of Campania ‘Luigi Vanvitelli’, Monaldi Hospital, Via Leonardo Bianchi 1, c/o Monaldi Hospital, AORN Colli, 80131 Naples, Italy
3
Department of Advanced Biomedical Sciences, Università degli Studi di Napoli Federico II, Via Pansini, 80131 Naples, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cardiogenetics 2026, 16(1), 6; https://doi.org/10.3390/cardiogenetics16010006
Submission received: 26 January 2026 / Revised: 10 March 2026 / Accepted: 12 March 2026 / Published: 19 March 2026
(This article belongs to the Special Issue Genetic Insights into Sudden Cardiac Death: From Risk Stratification to Precision Prevention)
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Abstract

Sudden cardiac death (SCD) is a major global health issue, defined as sudden natural death presumed to be of cardiac cause. While in the elderly SCD is commonly associated with coronary artery disease, in the younger population it is linked to inherited cardiomyopathies or channelopathies, even though SCD can remain unexplained even after a comprehensive autopsy in a substantial proportion of cases. In this context, genetic testing has gained importance, supported by the widespread availability of techniques such as next-generation and whole-exome/genome sequencing and their reduced costs. This state-of-the-art review summarizes the genetic bases of sudden cardiac death among cardiomyopathies, channelopathies and in sudden unexplained death presumed to be of arrhythmic cause. Among the structural causes, inherited cardiomyopathies such as hypertrophic, dilated, non-dilated left ventricular, arrhythmogenic right ventricular and restrictive ones represent major substrates for malignant ventricular arrhythmias mostly arising from variants in sarcomeric or desmosomal genes. Channelopathies (long or short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia) are caused by variants in genes encoding cardiac ion channels and/or regulatory proteins, which equally predispose to high risk of life-threatening ventricular arrhythmias. In sudden arrhythmic death syndrome, with a structurally normal heart, post-mortem genetic testing (molecular autopsy) can uncover an underlying inherited condition. However, variants of uncertain significance are detected in more than half of the cases, underscoring the need for a multidisciplinary approach. Genetic testing also plays a key role in cascade screening of first-degree relatives. While monogenic variants drive risk in inherited cardiac disorders, emerging evidence suggests that polygenic contributions may modulate SCD susceptibility, highlighting future roles for polygenic risk scores in risk stratification.

1. Introduction

Sudden cardiac death (SCD) is defined as a sudden natural death presumed to be of cardiac cause, occurring within 1 h of symptom onset in witnessed cases and within 24 h of last being seen alive in unwitnessed cases [1]. In older individuals, SCD is predominantly caused by coronary artery disease (CAD), whereas in younger populations it is more frequently associated with cardiomyopathies or channelopathies [2].
For this reason and owing to the increased availability of clinical data and reduced costs, the 2022 European Society of Cardiology (ESC) guidelines on SCD and ventricular arrhythmias expanded the role of genetic testing compared with the 2015 guidelines. Previously, genetic testing was considered only during the initial diagnostic work-up of patients with suspected inherited arrhythmogenic disease or when the proband had a first-degree relative who experienced SCD. In contrast, in the latest guidelines, genetic testing is considered a priority in SCD prevention, made possible by the introduction of extensive gene panel sequencing and improved methodologies, such as next-generation sequencing (NGS) or the whole-exome sequencing (WES).
Genetic testing should be performed in conditions predisposing to VA or when SCD is suspected to have a genetic basis, both in living and deceased individuals. This includes patients with cardiomyopathies such as hypertrophic (HCM, OMIM phenotypic series number: 192600), dilated (DCM, OMIM phenotypic series number: 115200), non-dilated left ventricular (NDLVC, OMIM phenotypic series number: 604169), arrhythmogenic right ventricular (ARVC, OMIM phenotypic series number: 107970) and restrictive cardiomyopathy (RCM, OMIM phenotypic series number: 115210) [1]. Genetic testing is equally recommended in patients with channelopathies, such as long QT syndrome (LQTS, OMIM phenotypic series number: 192500), Brugada syndrome (BrS, OMIM phenotypic series number: 601144), catecholaminergic polymorphic ventricular tachycardia (CPVT, OMIM phenotypic series number: 604772), and short QT syndrome (SQTS, OMIM phenotypic series number: 609620) [1]. Additionally, the role of post-mortem genetic testing (i.e., molecular autopsy) has been underscored, given its ability to identify underlying inherited cardiac conditions in deceased people with negative autopsy, therefore enabling relatives to undergo complete cascade screening and appropriate risk stratification.
This state-of-the-art review addresses the clinical relevance of genetic variants in SCD, highlighting the role of genetics in cardiomyopathies, channelopathies, and unexplained death. It also explores the clinical implications of a positive genetic test and discusses future perspectives in this rapidly evolving field.

2. Epidemiology and Mechanisms of Sudden Cardiac Death

SCD represents a major global health issue, accounting for approximately 15–20% of all deaths and 50% of deaths attributable to cardiovascular disease [3,4]. Despite substantial advances in both preventive strategies and therapeutic interventions, SCD remains a leading cause of mortality, with survival rates after cardiac arrest still below 5% [3].
The incidence of SCD increases markedly with advancing age, independently of sex or race. However, the proportion of deaths classified as sudden is greater among younger populations [4]. At any age, females have a lower incidence of SCD than males, although most events occur in structurally normal hearts in the female population [5]. Racial differences have also been reported, although not fully understood, with a higher prevalence in Black populations [6].
Sudden cardiac arrest, the clinical event underlying most SCDs, typically occurs without warning and presents with abrupt loss of consciousness, collapse, and absence of breathing due to cerebral hypoperfusion [7]. Following sudden death, a comprehensive premorbid evaluation and autopsy (including macroscopic, histological, and toxicological analyses) are essential to determine whether the cause is non-cardiac, cardiac, or unexplained [8]. In the latter scenario, or when a genetic etiology is suspected, molecular autopsy and subsequent cascade genetic testing in first-degree relatives are recommended (Figure 1) [8].
Undetected cardiovascular diseases may predispose to SCD: most cases indeed result from arrhythmic events, such as ventricular fibrillation (VF) or ventricular tachycardia [9]. The causes of SCD can be broadly categorized into structural and arrhythmogenic etiologies. In individuals under 35 years, SCD is most often due to congenital or inherited cardiac conditions, whereas CAD accounts for approximately 80% of SCD cases in those over 35 years [7].
Among the structural causes in young individuals, HCM remains the most common, followed by DCM, ARVC and NDLVC [10]. In cardiomyopathies, post-mortem examination typically identifies a clear pathological substrate. In contrast, this is not the case for inherited arrhythmogenic disorders, such as LQTS, SQTS, BrS, and CPVT. These disorders result from pathogenic variants affecting cardiac ion channel genes, predisposing individuals to ventricular arrhythmias and VF [11]. Because these conditions rarely produce structural cardiac abnormalities, post-mortem examinations are often unremarkable (“negative autopsy”), with normal histology and toxicology. These unexplained sudden deaths, which may account for up to 40% of SCD cases in the young (1–40 years), are referred to as sudden arrhythmic death syndrome (SADS) [10].
In this context, genetic testing has become a key diagnostic and preventive tool, particularly in SADS among children and young adults. As many of these disorders follow an autosomal dominant inheritance pattern, identifying a pathogenic variant enables post-mortem diagnosis, family risk stratification, and implementation of targeted preventive measures.

3. Genetic Basis of Sudden Cardiac Death in Cardiomyopathies

The main group of inherited arrhythmogenic syndromes responsible for SCD in the young are cardiomyopathies, characterized by progressive structural abnormalities that predispose to malignant arrhythmias. Although structural changes can be detected at forensic autopsy, the major arrhythmic event may eventually occur before overt structural changes become apparent in the heart [12]. This is the so-called “concealed cardiomyopathy” [13].
A wide range of genes have been implied in inherited cardiomyopathies, reflecting the marked genetic heterogeneity underlying these disorders (Table 1) [14]. Most of them encode sarcomere proteins, which are responsible for force generation in the myocardium [15]. Other genes implied are desmosomal ones, whose variation leads to impaired cell-cell adhesion and myocardial fibrofatty replacement, and cytoskeletal and Z-disc genes, which play structural and signaling roles [16]. Finally, genes related to calcium handling and various metabolic or storage disorders can also be involved.

3.1. Hypertrophic Cardiomyopathy

HCM is a genetically heterogenous disease with variable expressivity and incomplete penetrance, characterized by left ventricle hypertrophy not entirely explained by cardiac overload [60].
The most recent American Heart Association (AHA) classification subdivides HCM into primary HCM, caused by variants in sarcomeric genes, and secondary HCM, due to non-sarcomeric mutation (e.g., metabolic disorders, neuromuscular diseases, malformative syndromes or mitochondrial disorders) [80]. Pathogenic variants in sarcomere genes can be detected in 40% of sporadic and 60% of familial HCM cases [81]. The most commonly involved genes encode cardiac myosin-binding protein C (MYBPC3, accounting for approximately 30–40% of cases), β-myosin heavy chain (MYH7, accounting for approximately 10–30%) and cardiac troponin T and I (TNNT2 and TNNI3, each accounting for 3–10%) [82,83].
In pediatric patients and young athletes [84], HCM is associated with an increased arrhythmic risk due to myocyte disarray, cardiac fibrosis and small-vessel disease, resulting in higher SCD risk. Currently, both pediatric and adult SCD risk scores do not include genetic testing as a predictive factor [85,86,87,88], because its prognostic role remains uncertain and therefore not clinically useful [12]. Nevertheless, in patients with a family history of HCM, identifying a pathogenic variant may identify patients at risk of developing HCM during follow-up and potentially introduce personalized management [89,90].

3.2. Dilated Cardiomyopathy

DCM is defined as the presence of LV dilatation and global or regional systolic dysfunction unexplained solely by abnormal loading conditions or CAD [91]. Despite improvements in DCM management, the incidence of SCD remains approximately 0.15% per year, mainly due to ventricular arrhythmias and electromechanical dissociation [92].
In pediatric patients, an inherited cause is the most common etiology, with genetic variants accounting for up to 50% of idiopathic DCM cases [93]. Genetic testing is recommended in patients with idiopathic DCM, particularly in young individuals and in those with conduction delay or a positive family history [94]. As an inherited cardiomyopathy, DCM is usually transmitted in an autosomal dominant pattern, with more than 40 implicated genes, mostly encoding sarcomeric or structural proteins. Among these, TTN truncating variants are the most frequent, accounting for more than 25% of hereditary DCM [95]. The association between TTN variants and SCD is not limited to a higher burden of high-risk non-sustained ventricular tachycardia; rather, it appears to be primarily driven by severe left ventricular dysfunction and myocardial fibrosis [44].
Recent studies indicate that pathogenic variants in PLN [52], DSP [49], LMNA [45], FLNC [96], DES [46,47], and RBM20 [53] confer significantly higher arrhythmic risk than other causes of DCM, independent of systolic function [92]. In LMNA pathogenic variant carriers, the arrhythmic substrate for ventricular arrhythmias coexists with an elevated risk of brady-arrhythmias due to atrioventricular block, together predisposing to SCD and supporting ICD-based preventive strategies [97]. In the DES gene, the coil 1 domain is a mutational hotspot. The p.L136P and p.A120D variants impair filament assembly: the former is associated with DCM, whereas the latter disrupts desmin localization at the intercalated disc, increasing arrhythmic risk [46,47].
The growing evidence linking specific phenotypes with variants in genes encoding nuclear envelope proteins (LMNA, EMD, and TMEM43), desmosomal proteins (DSP, DSG2, DSC2 and PKP2), and certain cytoskeleton proteins has led to the development of risk-estimation scores to identify individuals with an increased risk for SCD [98]. Particularly, specific risk scores for PLN R14del [99], FLNC truncating variant [100], LMNA [98] and DSP [101] variants are available.

3.3. Arrhythmogenic Right Ventricular Cardiomyopathy

ARVC is a genetically determined heart muscle disorder characterized by fibrofatty replacement of the myocardium [60]. This pathological remodeling creates an anatomical substrate for electrical instability, which predisposes affected individuals (particularly young patients and athletes) to SCD, with an incidence of approximately 7% per year as shown in a meta-analysis of 5845 ARVC patients without ICD [102].
ARVC is typically inherited in an autosomal dominant pattern with incomplete penetrance, or it may arise from de novo pathogenic variants. The involved genes include desmosomal genes, such as PKP2 (plakophilin-2), DSP (desmoplakin), DSG2 (desmoglein-2), DSC2 (desmocollin-2), and JUP (plakoglobin) [103]. Carriers of multiple pathogenic variants often exhibit an earlier onset of sustained ventricular arrhythmias. Although most desmosomal variants confer comparable risk, DSP variants are particularly associated with increased susceptibility to SCD [104], while PKP2 variants have been linked to earlier arrhythmic onset [105]. Non-desmosomal genes such as TMEM43, LMNA, and PLN also contribute to arrhythmogenic phenotypes, increasing SCD risk [106].

3.4. Non-Dilated Left Ventricular Cardiomyopathy

According to the latest ESC guidelines, NDLVC is a recently defined entity characterized by left ventricular non-ischemic scarring, with or without global or regional systolic dysfunction, without evidence of left ventricular dilation [60]. Among the diagnostic criteria, global isolated hypokinesia without scarring not explained by loading conditions is included [60]. It shares a genetic continuum with DCM and ARVC, and SCD risk and ICD indications largely mirror those of DCM, with myocardial fibrosis representing an additional arrhythmic substrate.
Although the etiology is heterogenous, a recent study involving 42 NDLVC patients displayed positive genetic testing in more than one-third of them. Particularly, a genetic cause was more frequent in patients with LV fibrosis at CMR [107]. As with other cardiomyopathies, genetic predisposition is a key determinant of SCD risk [60]. Among high-risk genotypes, LMNA pathogenic variants are notable for their high penetrance, often leading to early-onset ventricular arrhythmias or advanced atrioventricular blocks [108]. Similarly, the DSP [104], RBM20 and PLN pathogenic variants are associated with a higher incidence risk of life-threatening arrhythmias. The genetic overlap among DCM, NDLVC, and ARVC, particularly involving desmosomal genes (DSP, DSG2, DSC2, PKP2), emphasizes the need for etiology-based diagnosis to guide management [14].
High-risk genotypes, myocardial inflammation, male sex, non-sustained VTs, left ventricular ejection fraction <45%, and septal or ring-like late gadolinium enhancement have been recently identified as independent predictors of a first major arrhythmic event within 60 months, leading to the development of a validated risk prediction score [108].

3.5. Restrictive Cardiomyopathy

RMC is the least common form of cardiomyopathy and is characterized by restrictive left or right ventricular pathophysiology due to myocardial dysfunction, interstitial fibrosis or endomyocardial disorders. The disease often progresses rapidly, leading to heart failure and frequently requiring heart transplantation. Both metabolic (i.e., Anderson–Fabry disease) and infiltrative disorders, such as cardiac amyloidosis, may present with a restrictive phenotype [92].
Evidence regarding SCD risk stratification in RCM is limited for most etiologies. Nevertheless, arrhythmias are highly prevalent, with a great incidence of atrial fibrillation and approximately 10% of VTs, contributing to an increase risk of intracardiac thrombosis and death [109].
From a genetic perspective, variants encoding for cardiac troponin I (TNNI3) represent the major identified genetic cause of primary RCM. Particularly, in a large Chinese pediatric RCM cohort (n = 185), TNNI3 variants were identified in 61% of patients, followed by MYH7 and TTNT2 [110]. In a pediatric RCM case, a pathogenic variant in encoded cardiac troponin T (TNNT2-R94C) was shown to cause dysfunction of calcium-dependent regulation of myocardial contraction, probably leading to malignant arrhythmias [74]. However, the genetic RCM background partially overlaps with other cardiomyopathies, including variants in DES or FLNC genes [111]. Given the short event-free survival, often less than two years, management strategies such as low thresholds for ICD or early referral for heart transplant should be considered to reduce SCD risk.

4. Genetic Basis of Sudden Cardiac Death in Channelopathies

Approximately 5% of SCD occur in patients without structural heart disease or CAD and are therefore attributed to primary electric disorders [112]. Cardiac channelopathies alter the cardiac action potential and the electrical conduction system and are predominantly caused by pathogenic variants in ion channel genes (Figure 2). Variants affecting sodium channels (SCN5A), potassium channels (KCNQ1, KCNH2, KCNJ2), and calcium channels or calcium-regulating proteins (CACNA1C, CALM1, CALM2, CALM3), as well as genes involved in calcium release from the sarcoplasmic reticulum (RYR2, CASQ2, TRDN, TECRL), have been implicated in these disorders [113].
Genetic testing plays a key role in diagnosis and risk stratification. Early identification of affected individuals through recognition of specific electrocardiographic abnormalities at rest or arrhythmogenic responses during exercise or pharmacological testing is essential for timely management [95].

4.1. Long QT Syndrome

LQTS is an inherited channelopathy characterized by a delayed ventricular repolarization, manifesting as a prolonged correct QT interval (>450 ms in men and >470 ms in women) [1]. It represents the most frequent genetic channelopathy, with an estimated prevalence of 1 in 2000/2500 individuals in the general population. The disorder most commonly results from loss-of-function variants in the voltage-gated potassium channel, leading to a prolonged action potential duration [114].
According to the gene variant implied, we can distinguish three main genotypes, accounting 75–90% of diagnosed cases [115]. LQT1 is caused by pathogenic variants in the KCNQ1 gene, encoding the alpha-subunit of the slow delayed rectifier potassium current. LQT2 is associated with KCNH2 variants, affecting the rapid delayed rectifier current, while LQT3 is caused by gain-of-function variants in SCN5A, which enhance the late sodium current [116,117]. LQTS exhibits incomplete penetrance and variable expressivity, even within the same family [118]. The presence of modifier genes partially explains this variability. For instance, NOS1AP or KCHN2 polymorphism can modulate arrhythmic risk [118].
A prolonged QTc reflects an increased action potential duration and increased cardiomyocyte refractoriness, responsible for an electrical substrate that can result in frequent early afterdepolarizations [106]. This electrical heterogeneity can generate the substrate for polymorphic ventricular arrhythmias, particularly torsades de pointes, and consequently to SCD [117]. Nevertheless, the arrhythmic risk is highly heterogeneous and depends on the interplay of clinical, electrophysiological and genetic factors. Genotype-specific triggers have been described: arrhythmias typically occur during sport in LQT1 patients; during emotional or auditory stress in LQT2 patients; and during sleep or at rest in LQT3 individuals [119].
In LQTS, lifestyle modification is essential, including avoidance of QT-prolonging drugs, correction of electrolyte imbalances, and prevention of genotype-specific triggers [120]. From a pharmacological standpoint, non-selective β-blockers, such as nadolol or propranolol, are the most effective in reducing arrhythmic risk and are recommended even for genotype-positive, phenotype-negative individuals [121]. Genotype-specific therapies, such as mexiletine for LQT3, may be beneficial [122]. ICD implantation is indicated in symptomatic or high-risk patients [1], while left cardiac sympathetic denervation can be considered for recurrent or refractory ventricular arrhythmias [123].

4.2. Short QT Syndrome

SQTS is a rare inherited channelopathy characterized by an abnormally short QT interval on the ECG (<350 ms) and an increased susceptibility to supraventricular and ventricular arrhythmias, including SCD [106]. Despite its severity, SQTS remains poorly understood and underdiagnosed.
From a genetic standpoint, pathogenic variants in potassium channel genes, most commonly KCNH2, KCNQ1, and KCNJ2, account for a proportion of cases. Interestingly, although these are the same genes implicated in LQTS, the variants in SQTS are gain-of-function, leading to accelerated cardiac repolarization rather than its delay. In addition, variants in genes encoding the CaV1.2 L-type calcium channel subunits (CACNA1C and CACNB2) have been described. These variants abbreviate the ventricular action potential and may produce an overlapping Brugada ECG phenotype.
The arrhythmogenic mechanism of SQTS remains incompletely defined, even if it is thought to involve an increased transmural dispersion of repolarization, resulting from heterogeneity in the action potential duration across the ventricular wall. Notably, despite the presence of a positive family history in approximately half of patients, only a minority (≈14%) of clinically diagnosed cases have an identifiable genetic variant, underscoring the genetic heterogeneity and current limitations of molecular diagnosis [124]. SQTS is considered a highly lethal condition, emphasizing the need for early recognition and tailored management.

4.3. Brugada Syndrome

BrS, first described as an inherited arrhythmia syndrome by Pedro and Josep Brugada, is a polygenic cardiac channelopathy characterized by a predisposition to syncope, ventricular arrhythmias, and SCD, most commonly occurring during sleep [125]. The global prevalence is estimated at approximately 0.5 per 1000 individuals, with a male predominance [125]. However, its true prevalence is likely underestimated, as many affected individuals remain asymptomatic or may present with SCD as the first manifestation.
BrS reflects abnormalities in ion channel function, particularly involving the right ventricular outflow tract, leading to both repolarization and depolarization disturbances. These electrical alterations manifest as the characteristic “coved-type” ST-segment elevation in the right precordial ECG leads (i.e., V1–V3), known as the Brugada type 1 pattern. In certain cases, the ECG abnormalities are latent and require pharmacological provocation (e.g., with ajmaline or flecainide) to unmask the diagnostic pattern [1].
BrS accounts for up to 28% of SCD cases in individuals with structurally normal hearts, most often due to VF, triggered by premature ventricular complexes with a short coupling interval [126,127]. Two main hypotheses have been proposed to explain its arrhythmogenic mechanism: the repolarization and the depolarization ones [120]. The repolarization hypothesis suggests that accentuated transmural gradients in repolarization, driven by enhanced outward potassium currents, produce both the ECG features and the propensity for re-entry [128]. The depolarization hypothesis posits that conduction slowing, particularly in the RVOT, leads to delayed activation and truncation of the action potential upstroke, facilitating re-entrant arrhythmias [129].
Only variants in the SCN5A gene are currently recognized as definitively disease-causing for BrS, although the majority of cases are not attributable to a single pathogenic variant [130]. SCN5A encodes the α-subunit of the cardiac sodium channel Nav1.5, and loss-of-function variants lead to impaired sodium current due to delayed channel activation and premature inactivation, ultimately resulting in abbreviation of the cardiac action potential [131]. Beyond SCN5A, more than 20 additional genes have been proposed to contribute to BrS pathogenesis. However, using an evidence-based semiquantitative scoring system integrating genetic and experimental data, independent curation teams demonstrated that, to date, only SCN5A shows definitive evidence for disease causation, while the causal role of the other genes remains disputed [130]. These include genes encoding other sodium channel subunits (SCN1B, SCN2B, SCN3B, SCN10A), potassium channel components (KCNAB2, KCNE3, KCND3, SEMA3A), and L-type calcium channel subunits (CACNA1C, CACNB2b) [127]. Moreover, variants in non-channel proteins, such as GPD1L (which regulates Nav1.5 phosphorylation) [132] and PKP2 (a desmosomal protein) [133], have also been implicated.
The current evidence supports a polygenic or multifactorial inheritance model, with multiple variants and modifier genes contributing to disease expression, as demonstrated from genome-wide association studies [134]. Notably, three single-nucleotide polymorphisms (SNPs, rs11708996 in SCN5A, rs10428132 in SCN10A, and rs9388451 near HEY2) were identified to be associated with increased BrS risk, leading to the development of a BrS polygenic risk score. While SCN5A remains a key genetic determinant for BrS SCD risk stratification as demonstrated by a recent meta-analysis [135], polygenic and electrophysiological studies support a multifactorial risk model [136].
ICD implantation represents the cornerstone of BrS management and remains the most effective method for SCD prevention [125]. Given that BrS diagnosis is mostly done in young individuals, accurate risk stratification is crucial [94]. In patients at high risk for SCD but also at increased risk of device-related infection, a subcutaneous ICD may represent an effective alternative. Conversely, in lower-risk patients, such as asymptomatic patients with a drug-provoked type 1 ECG pattern, the use of an implantable loop recorder should be preferred for long-term rhythm monitoring [137].

4.4. Catecholaminergic Polymorphic Ventricular Tachycardia

CPVT is a rare inherited arrhythmia with an estimated prevalence of approximately 1 in 10,000 individuals. It typically manifests in childhood, between 4 and 12 years, with exercise- or emotion-induced syncope or cardiac arrest [138]. The baseline ECG is usually normal, and diagnosis relies on exercise testing, after the exclusion of structural heart disease. During exertion, premature ventricular contractions usually appears at heart rates over 100 beats per minute and may progress to polymorphic VT or to the pathognomonic “bidirectional VT” [139]. Although many patients remain asymptomatic, symptomatic individuals usually experience stress-induced syncope, making athletes a particularly vulnerable population [140]. Despite being less frequent than LQTS, CPVT accounts for a significant proportion of SADS, with an untreated mortality rate approaching 30% before the age of 40 years [141].
Pathogenic variants in RYR2 (encoding the cardiac ryanodine receptor) cause approximately 60% of cases and are inherited in an autosomal dominant manner, whereas CASQ2 (encoding calsequestrin-2) variants account for about 5% and follow an autosomal recessive pattern [142]. Rare variants in other calcium-handling genes, such as CALM1 and TRDN, have also been described [139]. CPVT results from an abnormal calcium release from the sarcoplasmic reticulum, leading to cytosolic Ca2+ overload and activation of the Na+/Ca2+ exchanger. The consequent transient inward current produces delayed afterdepolarizations that can trigger ventricular arrhythmias [106].
The role of genetic testing in CPVT is evolving, as benign variants in RYR2 are a relatively common finding in these patients. Nevertheless, RYR2 variants affecting the C-terminal region are associated with a high risk of life-threatening arrhythmias [143,144], while CASQ2 variants are linked to a more severe phenotype [145]. The overall diagnostic yield of genetic testing remains modest, with approximately 40% of clinically diagnosed cases testing negative [119].
Management focuses on reducing adrenergic stimulation through lifestyle modification (avoidance of emotional stress and competitive sports), and non-selective β-blockers, which represent first-line therapy and are also recommended for asymptomatic carriers [146]. Flecainide may be added in symptomatic or refractory patients. In high-risk individuals, left cardiac sympathetic denervation or ICD implantation can be considered, although ICD use remains controversial due to the risk of catecholamine-mediated electrical storms [147].

5. Genetic Basis of Sudden Unexplained Death

While autopsy may identify a structural cardiac abnormality, up to 40% of sudden deaths remain unexplained even after comprehensive pathological and toxicological assessment, warranting a more in-depth search for underlying genetic causes [148]. This scenario is particularly common in the young, where a fatal arrhythmia is often presumed. In such cases, post-mortem genetic testing enhances diagnostic accuracy, as cardiomyopathies and channelopathies [149] represent major inherited causes of SCD in the absence of structural heart disease [150].
The so-called “molecular autopsy” is typically performed on fresh-frozen tissue or EDTA-preserved blood, and the current guidelines recommend retaining formalin-fixed, paraffin-embedded samples to enable subsequent DNA analysis [151]. Over the past two decades, molecular autopsy has evolved from Sanger sequencing of selected candidate genes to NGS and WES [152], expanding analysis to both channelopathy- and cardiomyopathy-related genes.
Traditional genetic testing targeted only four major genes (KCNQ1, KCNH2, SCN5A, and RYR2), yielding putatively pathogenic variants in ≤30% of autopsy-negative SUD cases. The use of WES increases this yield, reaching up to 44% in a study of 32 SUDY cases [153], although results across large cohorts remain heterogeneous (13–44%) [149,154]. The diagnostic utility of molecular autopsy alone is significantly improved when combined with clinical and genetic evaluation of relatives (cascade screening), achieving an overall diagnostic yield up to 39% [149].
The diagnostic utility of molecular autopsy alone (≈13–22%) is significantly enhanced when combined with comprehensive clinical and genetic evaluation of surviving relatives (cascade screening), reaching an overall diagnostic yield of up to 39% [149]. Genetic contributors to sudden unexplained death are mainly variants in channelopathy genes [155] (such as SCN5A, KCNQ1, KCNH2, and RYR2) and in cardiomyopathy genes (e.g., MYBPC3, MYH7, PKP2, DSP, TTN), supporting the concept of concealed cardiomyopathy [150]. An extended approach using WES, a broadened virtual gene panel, and multidisciplinary variant prioritization has achieved a 69% diagnostic yield, including 80% in structurally normal hearts, outperforming standard genetic strategies in a cohort of 39 cases [156].
Beside the identification of putative or causative pathogenic or likely pathogenic variants, variants of uncertain significance (VUS) are identified in up to 50–80% of cases, underscoring the need for a multidisciplinary approach to classify their probability of being pathogenic or benign [156]. When the heart appears structurally normal, a broader genomic approach, extending beyond targeted panels and incorporating polygenic risk assessment, may further enhance diagnostic yield [157].

6. Genetics for Prediction of Sudden Cardiac Death

In addition to demographic and environmental determinants, familial aggregation and heritable factors substantially contribute to the overall risk of SCD [2]. Furthermore, familial predisposition plays a significant role in the susceptibility to SCD. A family history of SCD in a first-degree relative has been shown to be independently associated with an increased risk of SCD [4]. The risk is further amplified within the framework of parental early-onset SCD, particularly when both parents are affected [2]. Nevertheless, especially in DCM patients, a negative family history does not exclude familial disease [158].
For Mendelian cardiovascular disorders, the role of genetic testing is well established, enabling the identification of pathogenic variants and the implementation of gene-specific preventive and therapeutic strategies, as well as a cascade screening of relatives [159]. Conversely, the contribution of genetic testing to the prediction of CAD-associated SCD remains scarce, with the notable exception of familiar hypercholesterolemia [160].
It has been hypothesized that SCD in the setting of common and complex disease does not result from a single mutation but rather from the cumulative effect of multiple SNPs [9], each conferring a modest increase in risk. GWASs have therefore compared the genomes of individuals who experienced sudden cardiac arrest to those of healthy controls, identifying common variants associated with SCD risk [161], some of them overlapping with loci influencing established risk factors such as QT interval duration [162].
In parallel, polygenic risk scores, which aggregate the effects of numerous SNPs into a single estimate of genetic susceptibility, are emerging as a potential tool for identifying individuals at high risk of SCD [9], especially CAD-associated SCD [163]. However, their clinical translation remains limited, largely due to challenges in demonstrating strong and specific associations between genetic profiles and SCD occurrence.
Importantly, the traditional dichotomy between monogenic and polygenic diseases is increasingly being reconsidered. Evidence suggests that, in classical monogenic disorders, such as BrS and inherited cardiomyopathies, common genetic variants may act as modifiers of disease penetrance and severity, thereby blurring the boundary between monogenic and polygenic inheritance [9].

7. Clinical Consequences of Positive Genetic Testing

The risk of SCD is dynamic and influenced by multifactorial drivers and may vary over time, requiring continuous and individualized monitoring. Genotype-positive individuals should undergo periodic assessment through ECG, Holter monitoring, imaging and stress testing, and other non-invasive tools [1,60]. While genetic analysis cannot replace clinical assessment due to its variable yield, it complements it by identifying pathogenic or sporadic variants that direct the targeted evaluation of relatives.
In families with a proband carrying pathogenic variants associated with cardiomyopathies or channelopathies, first-degree relatives should initially undergo ECG and echocardiography [89], as up to 60% may show latent phenotypes [2]. Early detection allows timely preventive measures such as ICD implantation, pharmacologic therapy, or lifestyle adjustments [92].
Genetic counselling is crucial to ensure accurate interpretation of results and informed decision-making [164], also because up to 50% of first-degree relatives display a positive genetic testing for genes associated with SCD [13]. Variant misclassification can lead to inappropriate management and significant psychological distress; thus, evaluation should occur within expert multidisciplinary teams [156]. National registries, such as ToRSADE, are instrumental for harmonizing diagnostic criteria and improving genotype–phenotype correlations [165].
Given that disease expression and arrhythmic risk evolve, periodic re-evaluation is essential, reflecting the shift toward precision medicine. Moreover, comprehensive post-cardiac arrest care, including psychological support and rehabilitation, is fundamental for survivors and their families to restore quality of life [166].

8. Future Perspectives

Advances in NGS technologies have made large-scale genetic testing increasingly accessible and affordable. WES and whole-genome sequencing (WGS) now represent key tools for identifying novel variants and expanding the spectrum of genes associated with SCD [136,167]. When clinical testing fails to reveal a causative variant in patients with a strong suspicion of inherited disease, genomic research focused on novel gene discovery should be prioritized [9].
Although genetic testing has proven effective in monogenic conditions, our understanding remains incomplete [151]. A comprehensive view of SCD susceptibility will emerge only by integrating genetic, epigenetic, and environmental determinants. Artificial intelligence and machine learning will be pivotal in managing the expanding volume of genomic and clinical data, refining variant classification, and improving diagnostic accuracy through large, publicly available genotype–phenotype databases [94].
Emerging therapeutic strategies, including gene therapy, hold promise for directly correcting pathogenic variants and restoring normal protein function [95]. In CPVT, for instance, adeno-associated viral vectors expressing the CASQ2 gene have shown antiarrhythmic effects in preclinical models, proportional to protein restoration levels [168].
Finally, ensuring equitable access to genetic testing, counselling, and post-mortem molecular analysis remains a global priority. The implementation of standardized and widely available genetic screening is essential to translate genomic advances into effective prevention and care.

9. Conclusions

SCD remains a major global health challenge, particularly in such cases that remain unexplained. While in older people established cardiovascular diseases are the most frequent causes of SCD, inherited cardiomyopathies and channelopathies are the predominant etiology in the young. Pathogenic or likely pathogenic variants in sarcomeric and ion channel genes are the most common findings, with each cardiomyopathy or channelopathy associated with specific gene variants and molecular mechanisms.
In this setting, the increased accessibility to low-cost NGS and the new multidisciplinary genetic approach have substantially improved diagnostic accuracy and familiar risk assessment. Therefore, genetic testing has become part of the clinical practice and post-mortem examination as well, enabling precision in diagnosis, prevention, and patient-tailored therapy. Nevertheless, the full translation of genetic discoveries into clinical benefit requires continuous refinement of variant interpretation, integration with other “omics” approaches, and incorporation of artificial intelligence tools. Moving forward, equitable access to genetic testing and expert interpretation will be essential to ensure that genomic medicine effectively contributes to reducing the burden of sudden cardiac death worldwide.

Author Contributions

Conceptualization, S.M., E.M. and G.L.; writing—original draft preparation, S.M., E.M., G.D., E.B., V.F., M.R., M.C., A.F., A.C., F.V., F.D., G.P. and F.B.; writing—review and editing, G.F., M.G.R., P.C. and G.L.; visualization, S.M.; supervision, G.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were generated or analyzed in this study.

Conflicts of Interest

The authors declare no conflicts of interest.

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Figure 1. Post-mortem diagnostic pathway and familial evaluation after sudden arrhythmic death. This figure illustrates the diagnostic pathway following sudden cardiac death, integrating medico-legal autopsy findings with molecular autopsy, genetic analysis, and subsequent cascade screening of first-degree relatives.
Figure 1. Post-mortem diagnostic pathway and familial evaluation after sudden arrhythmic death. This figure illustrates the diagnostic pathway following sudden cardiac death, integrating medico-legal autopsy findings with molecular autopsy, genetic analysis, and subsequent cascade screening of first-degree relatives.
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Figure 2. Channelopathies: Main pathophysiological mechanisms and main genes variants. Schematic overview of the key pathophysiological mechanisms and major gene variants associated with the main cardiac channelopathies. For LQTS, prolonged repolarization is caused by reduced outward K+ currents or increased inward Na+/Ca2+ currents. SQTS results from accelerated repolarization due to increased K+ currents or, in some cases, Ca2+-channel loss of function. Brugada syndrome is characterized by early repolarization abnormalities mainly due to reduced Na+ current or increased Ito. CPVT arises from abnormal sarcoplasmic reticulum Ca2+ handling leading to delayed after depolarizations (DADs) and triggered activity. Genes shown in bold are those with definitive or strong evidence for pathogenic involvement. Dotted lines illustrate the modifications of the cardiac action potential associated with each channelopathy. Red crosses indicate ion currents that are abolished, while thicker arrows represent enhancement of the corresponding currents.
Figure 2. Channelopathies: Main pathophysiological mechanisms and main genes variants. Schematic overview of the key pathophysiological mechanisms and major gene variants associated with the main cardiac channelopathies. For LQTS, prolonged repolarization is caused by reduced outward K+ currents or increased inward Na+/Ca2+ currents. SQTS results from accelerated repolarization due to increased K+ currents or, in some cases, Ca2+-channel loss of function. Brugada syndrome is characterized by early repolarization abnormalities mainly due to reduced Na+ current or increased Ito. CPVT arises from abnormal sarcoplasmic reticulum Ca2+ handling leading to delayed after depolarizations (DADs) and triggered activity. Genes shown in bold are those with definitive or strong evidence for pathogenic involvement. Dotted lines illustrate the modifications of the cardiac action potential associated with each channelopathy. Red crosses indicate ion currents that are abolished, while thicker arrows represent enhancement of the corresponding currents.
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Table 1. Genes associated with major monogenic cardiomyopathies, inheritance patterns, and characteristic ECG/CMR features.
Table 1. Genes associated with major monogenic cardiomyopathies, inheritance patterns, and characteristic ECG/CMR features.
CardiomyopathyCommon Associated Genes InheritanceOther: Typical ECG/CMR Patterns (When Relevant)
HCMSarcomeric: ACTC1 [17], MYBPC3 [18], MYH7 [19], MYL2 [20], MYL3 [21], TNNI3 [22], TNNT2 [22]

Others: ABCC9 [23], ALPK3 [24], BAG3 [25], CACNA1C [26], CAV3 [26], COX15 [27], CRYAB [28], DES [29], FHL1 [30], FLNC [31], FXN [32], GAA [33], GLA [34], LAMP2 [35], LDB3 [36], PLN [36], PRKAG2 [37], PTPN11 [38], RAF1 [39], RIT1 [40], SLC25A4 [41], TPM1 [42], TTR [43] 		AD: Predominantly sarcomeric, RASopathy

X-linked: Anderson–Fabry (GLA), Danon disease (LAMP2)

AR: Friedreich’s ataxia (FXN)		ECG: Low-voltage QRS, Q waves/pseudo-infarct pattern (amyloidosis).

CMR: Patchy mid-wall LGE in hypertrophied segments (sarcomeric HCM).
DCMTitin: TTN [44]

Nuclear envelope: LMNA [45]

Others: BAG3 [45], DES [46,47], DMD [48], DSP [49], FLNC [50], MYH7 [51], PLN [52], RBM20 [53], SCN5A [54], TNNC1 [55], TNNT2 [56]		AD: LMNA, RBM20, sarcomeric

X-linked: Dystrophinopathy (DMD),
Emery–Dreifuss disease (emerin)

AR: DES		ECG: AV block/conduction disease (LMNA, DES). Low peripheral QRS voltages (PLN). Pseudo-infarct posterolateral pattern (DMD).

CMR: Mid-wall septal LGE (LMNA). Extensive inferolateral LGE (dystrophinopathies). Ring-like/subepicardial LGE (DSP, truncating FLNC).
NDLVCFrequent:
DSP [57], FLNC [57], LMNA [58], PLN [14], RBM20 [59], TMEM43 [14]

Others [60]:
ACTC1, ACTN2, DES, DMD, DMPK, GATA4, ILK, LDB3, MIB1, MYBPC3, MYH7, MYL2, MYL3, NKX2-5, NNT, NONO, OBSCN, PRDM16, SCN5A, TAZ, TBX5, TBX20, TCAP, TNNT2, TPM1, TTN		AD: LMNA, DES, FLNC, PLN, TMEM43, RBM20

AR: DES		ECG: AV block/conduction disease (LMNA, DES). Low QRS voltages (DSP, PLN).

CMR: Presence of non-ischemic scar (LGE) or fatty replacement, often essential for diagnosis.
Ring-like/subepicardial pattern (DSP, FLNC, PLN, TMEM43). Mid-wall septal fibrosis (LMNA).
ARVCDesmosomal: PKP2 [61], DSP [62], DSG2 [63], DSC2 [63], JUP [64]

Others: DES [65], PLN [66], TMEM43 [67]		AD: PLN, Desmosomal, TMEM43

AR: Desmosomal 		ECG: T-wave inversion in V1–V3; terminal activation delay.

CMR: Structural/functional RV abnormalities; fibrofatty replacement, often biventricular. CMR is recommended as a first-line imaging modality for RV assessment.
RCMSarcomeric: TNNI3 [68], MYBPC3 [69], MYH7 [70], MYL2 [71], MYL3 [72], MYPN [73], TNNT2 [74], TMP1 [42], TTN [75]

Other: ACTN2 [76], BAG3 [77], DES [78], FHL1 [30], FLNC [79] 		AD: Sarcomeric, DES, FLNC, BAG3, RASopathy

AR: DES		ECG: AV block (desminopathy, amyloidosis).

CMR: Partial LV or RV apical obliteration + LGE at endocardial level.
AD = autosomal dominant; AR = autosomal recessive; ARVC = arrhythmogenic right ventricular cardiomyopathy; AV = atrioventricular; CMR = cardiac magnetic resonance; DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy; LGE = late gadolinium enhancement; NDLVC = non-dilated left ventricular cardiomyopathy; RCM = restrictive cardiomyopathy; RV = right ventricular.
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Montuoro, S.; Monda, E.; Diana, G.; Bobbio, E.; Fico, V.; Rubino, M.; Caiazza, M.; Fusco, A.; Cirillo, A.; Verrillo, F.; et al. The Genetic Architecture of Sudden Cardiac Death: A State-of-the-Art Review. Cardiogenetics 2026, 16, 6. https://doi.org/10.3390/cardiogenetics16010006

AMA Style

Montuoro S, Monda E, Diana G, Bobbio E, Fico V, Rubino M, Caiazza M, Fusco A, Cirillo A, Verrillo F, et al. The Genetic Architecture of Sudden Cardiac Death: A State-of-the-Art Review. Cardiogenetics. 2026; 16(1):6. https://doi.org/10.3390/cardiogenetics16010006

Chicago/Turabian Style

Montuoro, Sabrina, Emanuele Monda, Gaetano Diana, Emanuele Bobbio, Vera Fico, Marta Rubino, Martina Caiazza, Adelaide Fusco, Annapaola Cirillo, Federica Verrillo, and et al. 2026. "The Genetic Architecture of Sudden Cardiac Death: A State-of-the-Art Review" Cardiogenetics 16, no. 1: 6. https://doi.org/10.3390/cardiogenetics16010006

APA Style

Montuoro, S., Monda, E., Diana, G., Bobbio, E., Fico, V., Rubino, M., Caiazza, M., Fusco, A., Cirillo, A., Verrillo, F., Dongiglio, F., Palmiero, G., Barra, F., Frisso, G., Russo, M. G., Calabrò, P., & Limongelli, G. (2026). The Genetic Architecture of Sudden Cardiac Death: A State-of-the-Art Review. Cardiogenetics, 16(1), 6. https://doi.org/10.3390/cardiogenetics16010006

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