Mutations in the gene encoding voltage-gated sodium channels can disrupt sodium channels, cause abnormal sodium current flow and trigger ventricular arrhythmias, due to the significant role of voltage-gated sodium channels in action potentials (15). Alterations in sodium current can cause several types of cardiac disease, including LQTS, BrS, isolated (progressive) conduction defect, atrial fibrillation, sick sinus syndrome, dilated cardiomyopathy and multifocal ectopic premature Purkinje-related complexes (15). In ventricular arrhythmias without structural heart disease, enhanced sodium currents are usually associated with LQTS, whereas diminished sodium currents are associated with BrS (15, 83). Several sodium channel-related pathogenic genes have been identified in ventricular arrhythmias without structural heart disease, including SCN5A, SCN1B, SCN2B, SCN3B, SCN4B, GPD1L, RANGRF, SCN10A, among which SCN5A is the most reported (Table 2). SCN5A encodes Na_v1.5, which is the alpha subunit of voltage-gated sodium channels. As the main functional subunit of sodium ion channels, it provides activity for the channel. Na_v1.5 is responsible for the influx of sodium ions and plays a major role during membrane depolarization, as well as the sodium current in the repolarization and refractory period. SCN5A Mutation can be divided into gain-of-function and loss-of-function mutation, leading to an increase or decrease in sodium ion influx and an acceleration or delay in channel inactivation, responsible for about 5–10% of LQTS patients and ~30% of patients with BrS, respectively (15, 16).

In addition to Nav1.5 that directly affects sodium currents, some proteins can achieve indirect regulation of sodium currents by modulating Nv1.5, have been associated with BrS and LQTS. although their clinical relevance may be limited. SCN1B, SCN2B, and SCN3B encode voltage-gated sodium channel β subunits. Mutations can decrease Na_v1.5 cell surface expression and reduce sodium current, leading to BrS (38, 39, 41). SCN4B also encodes sodium channel β subunit, can cause LQTS in a minority of cases. Consistent with the molecular/electrophysiological phenotype previously displayed by LQTS, compared to wild type, the mutation L179F of SCN4B leads to an increase of late sodium current (42). GPD1L is SCN5A regulatory proteins, links redox state to cardiac excitability by PKC-dependent phosphorylation of the sodium channel (84). The GPD1L A280V mutation reduces SCN5A membrane expression, decreases inward Na⁺ current, leading to BrS (43). RANGRF (MOG1) is a co-factor of Na_v1.5, which plays a potential role in the regulation of Na_v1.5 expressions and trafficking. The dominant-negative mutations in RANGRF can disrupt the transport of Na_v1.5 to the membrane, resulting in a reduction of I_Na and causing clinical manifestations of BrS. Silencing RANGRF can reduce I_Na density, in addition, replacing E83D, D148Q, R150Q, and S151Q could disrupt the interaction of RANGRF with Na_v1.5 and significantly impair the trafficking of Na_v1.5 to the cell surface, indicating that RANGRF may play an important role in the expression of Na_v1.5 channel on the cell surface (44, 45). SCN10A encodes Na_v1.8, a voltage-gated sodium channel like Na_v1.5. Both SCN10A and SCN5A are located on chromosome 3p22.2. Co-expression of SCN10A-WT and SCN5A can increase sodium channel current, while SCN10A mutants (R14L and R1268Q) can cause loss of Na_v1.5 current function, which may be the genetic basis of BrS caused by SCN10A. However, most of the mutations associated with SCN10A are not rare variants, are relatively frequent in the population (46).

The potassium ion currents associated with ventricular arrhythmias include transient outward potassium current (I_to), delayed rectifier potassium current (I_K), inward rectifier K⁺ current (I_K1), and hyperpolarization-activated currents (I_h). Dysfunction of potassium ion channels can also cause changes in ion balance, causing arrhythmia (Table 2).

Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are responsible for pacing current in neurons and cardiomyocytes, in which HCN4 encode a member of the hyperpolarization-activated cyclic nucleotide–gated (HCN) channels showing slow activation and inactivation kinetics and is the highest expressed isotype in sinoatrial node (SAN) muscle cells, necessary for cardiac pacing (85). HCN4 gene mutation was detected in patients with idiopathic ventricular arrhythmias, which resulted in the decrease of pacemaker (I_f) current (85, 86).

The repolarization of the ventricles is spatially heterogeneous, largely dependent on the gradient of potassium current, especially I_to (87). Under normal circumstances, the density of I_to in the epicardium is higher than the endocardium and the initial repolarization of the epicardium is earlier than the endocardium, generating a transmural voltage gradient that plays an important role in synchronizing repolarization (87). Gain of function of I_to is related to BrS. I_to channel is composed of α subunit and β subunit, with the α subunit K_v4.3 encoded by KCND3, and the negatively regulated β-subunit MiRP2 encoded by KCNE3. It is a voltage-gated, calcium-independent potassium (K_v) current that can be quickly activated and inactivated, mainly responsible for the initial repolarization phase of the cardiac action potential (88), KCND3 mutations are known to cause BrS. The mutation KCND3 Arg431His (c.1292G>A) detected in BrS patients does not affect the mRNA and total protein expression level of K_v4.3, but increase the membrane protein expression of K_v4.3 and up-regulate the transient outward potassium current (48). Besides, at the same time, KCNE3 mutation may be the basis of the development of BrS. The co-transfection of the KCNE3 gain-of-function mutation R99H with KCND3 causes a significantly increased current intensity compared to WT KCNE3+KCND3 (49). Actually, the KCNE family encodes five isotypes in the human genome. In addition to KCNE3, KCND3 can be assembled with multiple KCNE subunits, of which KCNE5 can regulate I_to, showing a correlation with BrS and idiopathic ventricular fibrillation (50). KCNE5 is located on the X chromosome and when coexpressed with KCND3, the brugada-associated KCNE5 mutations upregulate I_to compared to the wild type (50).

There are two types of delayed rectifier K⁺ current, slowly activating delayed rectifier K⁺ current (I_Ks) and rapidly activating delayed rectifier K⁺ current (I_Kr). Its enhancement is related to SQTS, whereas weakening is related to LQTS (89). The outward K⁺ current of I_Ks channel is one of the main repolarizing potassium currents in the human heart, which helps to terminate cardiac action potential. The channel is composed of the pore-forming α subunit encoded by KCNQ1 (also known as K_v7.1 or K_vLQT1) and the β subunit encoded by KCNE1 (90, 91). Cardiac KCNQ1/KCNE1 channel mutations are the most common cause of inherited long-QT syndromes (92). Loss-of-function mutations of KCNQ1 decrease I_Ks current density, leading to LQTS, and there are also mutations that are gain-of-function mutations increase I_Ks, leading to SQTS (93, 94). Mutations in KCNE1 gene cause reduced I_Ks current density, manifested as loss of function, which can lead to LQTS (53). However, a recent study has indicated that QTc Interval Prolongation (>460 ms) was not observed in most people carrying KCNE1 loss-of-function mutations (95). The rapidly activating delayed rectifier potassium channel is encoded by KCNH2 and KCNE2, which produces only a small outward current during membrane depolarization, however, after the membrane is repolarized, the channel quickly recovers from the inactivation state to the open state, producing a recovery current before the slow channel deactivation. KCNH2 gene encodes the pore-forming α subunit of voltage-gated K⁺ channel K_v11.1, commonly referred to as Herg. Approximately 90% of LQT- associated KCNH2 mutations reduced I_Kr by reducing K_v11.1, responsible for 25–30% of LQTS cases channel synthesis or trafficking (54). Gain-of-function mutations are the genetic basis of SQTS, which increase the repolarization current activated in the early stages of AP, resulting in a shortening of the action potential and the QT interval (55). KCNE2 encodes MiRP1, an auxiliary beta-subunit. Compared with the wild-type channel, the mutant HERG/MiRP1 (V65M) channel detected in LQTS patients has a shorter current inactivation time, which may reduce the I_Kr current density of cardiomyocytes, weakening the cardiomyocytes' ability to repolarize sudden membrane depolarization (56). It has also been reported that overexpression of wild-type KCNE2 can rescue the phenotype caused by KCNH2 mutation, facilitating the transport of K_v11.1 channel protein and cell surface expression, significantly increasing the mutation current (96).

Inwardly rectifying potassium (Kir) channels allow potassium ions to move more easily into rather than out of the cell. The inwardly rectifying potassium channels gene associated with ventricular arrhythmia has KCNJ2, KCNJ5, KCNJ8, and ABCC9 (Table 2). I_K1 plays an important role in stabilizing the resting membrane potential, regulating excitability and causing the final repolarization of atrial and ventricular action potential. Like delayed rectifier potassium channel, its enhancement is related to SQTS and reduction is related to LQTS, while ATP-sensitive potassium channel current (I_K−ATP) enhancement will lead to BrS. One of the molecular basis is Kir2.1, which is coded by KCNJ2. Gain-of-function KCNJ2 mutations have been found in SQTS patients, resulting in increased I_K1, accelerated ventricular repolarization and shortened QT interval (57, 97). There are also reports in the literature that loss-of-function mutations can cause LQTS (58). Mutations in the Inwardly rectifying potassium channels Kir2.1 encoded by KCNJ2 causing loss of function are associated with a rare clinical phenotype called Andersen-Tawil syndrome (ATS), which contains pleomorphic ventricular tachycardia (98). KCNJ5 encodes Kir3.4, a subunit of the voltage-gated potassium channel, which is controlled by G proteins and combination with Kir3.1, responsible for acetylcholine-activated potassium channel current (I_KACh) (59). The KCNJ5 mutation results in defects in channel trafficking and a reduction in the I_KACh, which is considered to be the pathogenic gene of LQTS (59). ATP-sensitive potassium channel (K_ATP) is one kind of inwardly rectifying channel composed of the pore forming subunits and the regulatory subunits. Kir6.1 encoded by KCNJ8 and SUR2 encoded by ABCC9 are both subunits of ATP-sensitive potassium channels (99). KCNJ8 mutation can reduce the sensitivity of K_ATP channels to ATP, resulting in enhanced I_K−ATP function, which may lead to BrS (60, 100). Gain-of-function mutation of ABCC9 has also been reported as a possible pathogenic site for BrS, however, the relevance of pathogenic requires further confirmation (61).

Voltage-gated L-type calcium channel (LTCC) is the main channel mediating influx of calcium ions into cells in repolarization stage, and in addition, NCX, an ion transport protein, can mediate the exchange cycle of sodium ions and calcium ions with a coupling ratio of 3:1 (101). Calcium entering the cell through these two distinct mechanisms triggers the release of calcium from the sarcoplasmic reticulum. Voltage-gated L-type calcium channel consists of four subunits α1 subunit, auxiliary β subunit, α2δ subunit, and γ subunit. The four subunits of voltage-gated L-type calcium channels which are, respectively, coded by CACNA1C or CACNA1D, CACNB2, CACNA2D, and CACNG (102, 103). Among them, the mutant genes that have been reported to cause ventricular arrhythmia are CACNA1C, CACNB2, CACNA2D (Table 2). CACNA1C encodes Ca_v1.2 pore-forming α1 subunit. In general, the enhancement of I_{Ca, L} is related to LQTS, on the contrary causes BrS. Timothy syndrome (TS), which manifests as severe LQTS and multiorgan dysfunction, is mainly caused by gain-of-function mutations located in CACNA1C alternative splicing exon 8 which leads to almost complete loss of voltage-related channel inactivation, resulting in maintained inward Ca²⁺ current, and prolonged Ca²⁺ current that delay cardiomyocyte repolarization (104–106). A few cases are caused by mutations within exon 9 and exon 38 of CACNA1C (107, 108). Gain-of-function mutations in CACNA1C at positions other than exon 8 can cause LQTS with non-Timothy syndrome symptoms (62, 109). The phenotype caused by the loss-of-function mutations of the cardiac L-type calcium channel α1 and β2b subunits is similar to calcium channel blockers, leading to reduced I_{Ca, L}, resulting in BrS (63, 110, 111). Subsequent studies identified CACNA2D1 as a novel BrS/SQTS susceptibility gene (64, 112). In addition, it is also reported that KCNE2 can affect I_{Ca, L} by regulating Ca_v1.2 (113).

The main function of the sarcoplasmic reticulum (SR) is to store calcium in striated muscle. The genes involved in the release of calcium from the sarcoplasmic reticulum are RYR2, CASQ2, TRDN, CALM1, CALM2, and CALM3, which are pathogenic genes of CPVT (Table 2) (65, 114). Among them, TRDN, CALM1, CALM2, CALM3 mutations can also cause LQTS. RYR2 encodes ryanodine receptors (RyR2), responsible for the rapid release of calcium ions from the sarcoplasmic/endoplasmic reticulum (SR/ER) into the cytoplasm. RYR2 mutations may be either loss or gain of function and this may be related with different clinical phenotypes. Approximately 60% of patients with CPVT carry RYR2 mutations, and the main pathogenic mechanism of gain-of-function mutations is increased spontaneous RyR2 opening and pathological calcium release during diastole (17, 65, 115). The RyR2 mutation associated with idiopathic ventricular fibrillation confirmed as a loss-of-function mutation exhibiting Ca²⁺ release deficiency (66). However, a recent study identified a loss-of-function mutation D3291V, which markedly reduced luminal Ca²⁺ sensitivity, and blunted response to adrenergic stimulation, also exhibiting a CPVT phenotype (116). The relationship between gain-of-function or loss-of-function and the clinical phenotype still needs to be elucidated (117). The calsequestrin encoded by CASQ2 is a calcium-binding protein that regulates the amount of calcium released from the SR during excitation-contraction coupling by buffering the calcium in the SR (118, 119). Triadin (TRD) encoded by TRDN is located on the sarcoplasmic reticulum, forms a complex with ryanodine receptors, calsequestrin and junctin, regulating the storage and release of calcium ions (120). Triadn anchors calsequestrin to junctional SR membrane and stabilizes the structure of Ca 2+ release units (121). TRDN deficiency leads to significantly reduced protein levels of RyR2, calsequestrin, and junctin, impaired coupling efficiency between LTCC and RyR2, reduced SR calcium release and calcium-dependent inactivation of LTCC, resulting in defective cardiac excitation-contraction coupling (121, 122). Similarly, Triadin mutations are thought to result in reduced protein levels, which in turnincreased calcium currents and prolonged cardiac action potentials, and increased spontaneous calcium release events caused by cellular and SR calcium overload, which is the basis of TRDN mutation leading to CPVT and LQTS (69, 123). CALM1~3 encodes Calmodulin, which is Ca²⁺ sensor, signal-transducing protein. Calmodulin binds to RyR2 and LTCC, plays a key role in the calcium-dependent inactivation of the L-type calcium channel Ca_v1.2 and the timely closure of the myocardial sarcoplasmic reticulum calcium release channel RyR2. Calcium binding to calmodulin inactivates the LTCC channel, namely calcium-dependent inactivation (124). The mutations associated with LQTS are mainly due to weakening of the combination of calmodulin and calcium, completely eliminating the calcium-dependent inactivation. On the other hand, the binding of calmodulin to RyR2 can inhibit the release of calcium from SR during diastole. Mutations associated with CPVT mainly lead to dysregulation of RyR2 calcium release (70, 125).

The protein encoded by SNTA1 is a component of the Na_v1.5 channel macromolecular complex, interacting with the pore-forming α subunit (126). Gain-of-function SNTA1 mutations can affect Na_v1.5 gating kinetics, leading to the LQTS phenotype (71). SLMAP encodes the sarcolemmal associated protein located in T-tubules and sarcoplasmic reticulum. SLMAP mutation may cause BrS by regulating the intracellular transport of Na_v1.5 channel (72). PKP2 encodes Plakophilin-2, a desmosomal protein. Loss and/or changes in the Plakophlin-2 structure in the heart desmosomes can impair the interaction between myocardial cells and cause myocardial rupture, especially in response to mechanical stress (127). Mutations in PKP2 have been associated with BrS, and the deletion of PKP2 can lead to a decrease in sodium current and Na_v1.5 at the site of cell contact (73). Ankyrins bind to spectrins, connects the plasma membrane with the actin cytoskeleton, maintains mechanical strength and regulates the excitability of various cells. The ankyrin family contains three members: ankyrin-R, ankyrin-B and ankyrin-G, are encoded by ANK1, ANK2 and ANK3, respectively (128). Loss-of-function mutation (E1425G) in ankyrin-B (also known as ankyrin 2) can lead to dominant long QT arrhythmia (74, 129). CAV3 encodes a scaffold protein for the cavern in cardiomyocytes and participates in the separation of ion channels. CAV3 mutations are related to LQTS, which can prolong repolarization times by enhancing the late sodium current, enhancing the peak value of L-type calcium current, slowing down deactivation, reducing delayed rectifier potassium current and transient outward potassium current (75). TECRL (TERL) is an oxidoreductase enzyme localized to the endoplasmic reticulum. Patients with TECRL pathogenic variants manifest a specialized mixed phenotype of CPVT and LQTS, which is an autosomal recessive disease. Functional experiments have shown that homozygous pathogenic variants can lead to reduced levels of RYR2 and CASQ2 proteins, and reduced calcium storage of sarcoplasmic reticulum and aberrant calcium handling (76).

SLC4A3 (AE3) is an electroneutral Cl⁻/HCO3- exchanger (130). Studies have found that reducing intracellular pH (PHi) could prolong QT interval; the regulation of chloride ion conductance in cardiomyocytes can also change action potential duration. In zebrafish, SLC4A3 mutations can lead to transport defects, reduce Cl,HCO3-exchange over the cell membrane, increase pHi and reduce the QT duration, which may be another development mechanism of SQTS (77). The protein encoded by TRPM4 is a transmembrane N-glycosylated ion channel, a non-selective channel activated by intracellular calcium, permeable to monovalent cations. At present, Trpm4 mutations have been detected in both BrS and LQTS cohort. Miraculously, gain-and loss-of-function variants of TRPM4 channels can cause similar phenotypes (78).

Idiopathic ventricular fibrillation is an exclusive disease that requires excluding the presence of the ventricular fibrillation substrate and specific diseases, including structural heart disease and primary arrhythmia syndrome (131). At present, most genes related to idiopathic ventricular fibrillation overlap with the pathogenic genes of hereditary ventricular arrhythmias, such as CALM1~3, RYR2, TRDN, CACNA1C, SCN5A, KCNE5 (50, 125, 132–137). However, there are also specific causative genes in the idiopathic ventricular fibrillation (138). A single-pass type II membrane protein DPP6 can promote the cell surface expression of potassium channel KCND2 and regulate its activity and gating characteristics (139–141). Haplotype analysis in both familial and sporadic cases indicated the relevance of DPP6 with idiopathic ventricular fibrillation (133, 142). Furthermore, a DPP6 mutation was detected in idiopathic ventricular fibrillation patients, which disturbs the efflux of potassium ion (79). In addition, mutations of transcription factor IRX3, specifically expressed in His bundle, have also been reported to cause idiopathic ventricular fibrillation by down-regulating SCN5A and connexin-40 mRNA (80). Although several diagnostic approaches have been proposed and pathogenic mechanisms discussed, it is far from enough for studies of idiopathic ventricular fibrillation (143). This situation may change with the development of diagnostic techniques for structural heart disease and the discovery of potential pathogenic mechanisms.

Besides the above germline mutations, i.e., mutations carried by all cells, the effect of somatic mutations, i.e., mutations carried by only some somatic cells, on the occurrence of ventricular arrhythmias is also being investigated. Idiopathic right ventricular outflow tract ventricular tachycardia (RVOT-VT) is the most common form of ventricular arrhythmias in patients without structural heart disease. GNAI2 (f200l) and A1AR (R296C) mutations were detected in biopsy samples collected from the origin of ventricular tachycardia in patients with adenosine insensitive RVOT tachycardia, but not in remote myocardium (18, 81). GNAI2 (F200L) increases intracellular cAMP concentrations and inhibited the inhibition of cAMP by adenosine, the effect of another mutation is unclear (81). Another study identified a cardiac somatic mutation (W234R) in GNAS (Gs-alpha, stimulatory G protein alpha-subunit) in endomyocardial biopsy samples from the origin of tachycardia in RVOT-VT patient, which was not detected in right ventricular apex biopsy samples. The mutation impairs GTP hydrolysis and increased basal intracellular cAMP levels, increasing the basal inward calcium current, and silico modeling show delayed afterdepolarizations and triggered activity (82).