Alternative titles; symbols
HGNC Approved Gene Symbol: SCN5A
SNOMEDCT: 283645003, 51178009, 60423000, 698249005; ICD10CM: I49.8; ICD9CM: 427.81, 798.0;
Cytogenetic location: 3p22.2 Genomic coordinates (GRCh38): 3:38,548,062-38,649,687 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p22.2 | {Sudden infant death syndrome, susceptibility to} | 272120 | Autosomal recessive | 3 |
| Atrial fibrillation, familial, 10 | 614022 | Autosomal dominant | 3 | |
| Brugada syndrome 1 | 601144 | Autosomal dominant | 3 | |
| Cardiomyopathy, dilated, 1E | 601154 | Autosomal dominant | 3 | |
| Heart block, nonprogressive | 113900 | Autosomal dominant | 3 | |
| Heart block, progressive, type IA | 113900 | Autosomal dominant | 3 | |
| Long QT syndrome 3 | 603830 | Autosomal dominant | 3 | |
| Sick sinus syndrome 1 | 608567 | Autosomal recessive | 3 | |
| Ventricular fibrillation, familial, 1 | 603829 | 3 |
Gellens et al. (1992) cloned and characterized the cardiac sodium channel gene SCN5A. The deduced 2,016-amino acid protein has a structure similar to that of previously characterized sodium channels (see 182392) and contains 4 homologous domains, each of which has 6 putative membrane-spanning regions.
Freyermuth et al. (2016) stated that alternative splicing creates fetal and adult isoforms of SCN5A that differ in inclusion of alternative exons 6a or 6b, respectively. Both exons 6 have 92 bp, but encode 7 different amino acids in the voltage-sensor region of SCN5A domain I.
Wang et al. (1996) found that SCN5A consists of 28 exons spanning approximately 80 kb. They described the sequences of all intron/exon boundaries and a dinucleotide repeat polymorphism in intron 16.
George et al. (1995) mapped the SCN5A gene to chromosome 3p21 by fluorescence in situ hybridization, thus making it an important candidate gene for long QT syndrome-3 (LQT3; 603830).
Gross (2019) mapped the SCN5A gene to chromosome 3p22.2 based on an alignment of the SCN5A sequence (GenBank BC051374) with the genomic sequence (GRCh38).
By immunoprecipitation and nano-liquid chromatography-mass spectroscopy/mass spectroscopy of transgenic mouse bone marrow macrophages expressing the human macrophage splice variant of SCN5A, followed by Western blot analysis, Jones et al. (2014) identified interaction of SCN5A with activating transcription factor-2 (ATF2; 123811). Microarray analysis of SCN5A-positive macrophages revealed increased expression of Sp100 (604585), an Atf2-regulated gene. Knockdown of Adcy8 (103070), the calcium-dependent isoform of adenylate cyclase, inhibited channel agonist-induced expression of Sp100-related genes. Activation of SCN5A increased expression of cAMP in macrophages. Treatment of macrophages with poly(I:C), a mimic of viral double-stranded RNA, activated the Adcy8 signaling pathway to regulate expression of Sp100-related genes and Ifnb (147640). Electrophysiologic analysis showed that the SCN5A variant mediated nonselective outward currents, as well as a small yet detectable inward current. Jones et al. (2014) proposed that human macrophage SCN5A initiates signaling in an innate immune pathway relevant to antiviral host defense, and that SCN5A is a pathogen sensor.
Myotonic dystrophy (see DM1, 160900) is caused by expression of mutant RNAs containing expanded CUG repeats. These repeats sequester muscleblind-like (MBNL; see MBNL1, 606516) splicing factors in nuclear RNA foci, resulting in changes in pre-mRNA splicing. Freyermuth et al. (2016) showed that MBNL1 specifically promoted inclusion of exon 6b in SCN5A pre-mRNA and expression of the adult SCN5A isoform. Freyermuth et al. (2016) found that left ventricle samples of 3 adult DM1 patients showed alternative splicing in a number of genes, including SCN5A. A portion of the SCN5A mRNA in these samples was the fetal isoform. When expressed in Xenopus oocytes, the fetal isoform of SCN5A showed reduced excitability compared with the adult SCN5A isoform. In mice, expression of fetal Scn5a promoted heart arrhythmia and cardiac-conduction delay, which are 2 predominant features of myotonic dystrophy.
Missense mutations in the skeletal muscle sodium channel gene, SCN4A (603967), cause myotonia. Physiologic data show that these mutations affect sodium channel inactivation and lead to repetitive depolarizations, consistent with the myotonic phenotype. By analogy, similar mutations in the cardiac sodium channel gene might be expected to cause a phenotype like LQT. Indeed, Wang et al. (1995) found a mutation in the SCN5A gene in families with chromosome 3-linked LQT (see 600163.0001).
Bennett et al. (1995) determined the functional defect resulting from the 3-amino acid (KPQ) deletion (600163.0001) in the SCN5A protein. By expression of recombinant human heart sodium channels in Xenopus laevis oocytes, mutant channels showed a sustained inward current during membrane depolarization. Single-channel recordings indicated that mutant channels fluctuate between normal and noninactivating gating modes. Persistent inward sodium current explains prolongation of cardiac action potentials and provides a molecular mechanism for the chromosome 3-linked form of long QT syndrome.
Wang et al. (1995) identified SCN5A mutations in affected members of 4 additional families with chromosome 3-linked LQT. Two of the families had the same 9-bp deletion found earlier; the other families were found to have missense mutations affecting highly conserved amino acid residues (600163.0002 and 600163.0003). The location and character of the mutation suggested to the authors that this form of LQT results from a delay in cardiac sodium channel fast inactivation or altered voltage-dependence of inactivation.
Wang et al. (1996) determined the biophysical and functional characteristics of each of the 3 distinct mutations that had been identified in the cardiac sodium channel gene in patients with LQT3 to that time. For this they used heterologous expression of a recombinant human heart sodium channel in a mammalian cell line. Each mutation caused a sustained, noninactivating sodium current amounting to a few percent of the peak inward sodium current, observable during long (more than 50 msec) depolarizations. The voltage dependence and rate of inactivation were altered and the rate of recovery from inactivation was changed compared with wildtype channels. These mutations in diverse regions of the ion channel protein all produced a common defect in channel gating that can cause the long QT phenotype. The sustained inward current caused by these mutations would prolong the action potential. Furthermore, they might create conditions that promote arrhythmias due to prolonged depolarization and the altered recovery from inactivation.
Wang et al. (1997) explored the potential for targeted suppression of the defect in LQT3 by heterologous expression of mutant channels in cultured human cells. Channel behavior and inhibition by mexiletine were investigated by whole-cell patch-clamp methods. The investigators showed that late-opening LQT3 mutant channels were much more sensitive to inhibition by mexiletine than were wildtype sodium channels. The defective late openings were selectively suppressed more than the peak sodium current and these late openings could be suppressed by concentrations at the lower end of the therapeutic range.
Using a candidate gene approach, Chen et al. (1998) studied 6 small families and 2 sporadic patients with idiopathic ventricular fibrillation (IVF; 603829) using SSCP and DNA sequence analyses to identify mutations in known ion channel genes, including the cardiac sodium channel gene SCN5A. They identified several mutations in families with a distinct form of IVF known as Brugada syndrome (BRGDA1; 601144). In 1 family all affected members had 2 mutations: an arg1232-to-trp mutation in exon 21 of the gene in the extracellular loop between transmembrane segments S1 and S2 of domain III of the protein, and a thr1620-to-met mutation in exon 28 of the gene in the extracellular loop between S3 and S4 of domain IV of the protein (600163.0004). Additional SCN5A mutations were found in 2 IVF families: insertion of 2 nucleotides (AA) in the splice-donor sequence of intron 7 (600163.0005); and deletion of a single nucleotide (A) at codon 1397, resulting in an in-frame stop codon (600163.0006). The frameshift mutation caused the sodium channel to be nonfunctional.
Schott et al. (1999) reported a mutation in the SCN5A gene that segregated with progressive familial heart block (PFHB1A; 113900) in an autosomal dominant manner in a large French family. In a smaller Dutch family, another SCN5A mutation cosegregated with familial nonprogressive conduction defect (see 113900). The French family with PFHB1A was identified through a member with right bundle branch block (RBBB) and syncope; a brother had RBBB, and a sister had complete atrioventricular (AV) block and syncope. Clinical and electrocardiographic abnormalities were found in 15 members of the family; mean QRS duration was 135 +/- 7 ms. RBBB was present in 5, left bundle branch block (LBBB) in 2, left anterior or posterior hemiblock in 3, and long PR interval (more than 210 ms) in 8. None had a structural heart disease. Four members of earlier generations had received a pacemaker implantation because of syncope or complete AV block. Long-term follow-up of several affected members demonstrated that their conduction defect increased in severity with age. In the Dutch family, the proband presented after birth with an asymptomatic first-degree AV block associated with RBBB (PR interval and QRS duration, 200 and 120 ms, respectively). In the French family, Schott et al. (1999) excluded the chromosome 19 locus for this disorder (604559) by linkage studies, as well as other loci for inherited cardiac disorders associated with conduction defects. SCN5A was considered a candidate locus, and using markers flanking SCN5A, the authors demonstrated segregation of the disease with D3S1260 in every affected individual (maximum lod score of 6.03 at theta of 0.0). A donor splice site mutation in SCN5A was found in the French family (600163.0009), and a frameshift mutation was identified in the Dutch family (600163.0010). Clinical data and family histories indicated that none of the affected individuals in these 2 families had LQT3 or idiopathic ventricular fibrillation (Brugada syndrome). Therefore, PFHB1 represents a third cardiac disease linked to SCN5A.
Splawski et al. (2000) screened 262 unrelated individuals with LQT syndrome for mutations in the 5 defined genes (KCNQ1, 607542; KCNH2, 152427; SCN5A; KCNE1, 176261; and KCNE2, 603796) and identified mutations in 177 individuals (68%). KCNQ1 and KCNH2 accounted for 87% of mutations (42% and 45%, respectively), and SCN5A, KCNE1, and KCNE2 for the remaining 13% (8%, 3%, and 2%, respectively).
Tan et al. (2002) demonstrated that calmodulin (114180) binds to the carboxy terminal 'IQ' domain of the SCN5A in a calcium-dependent manner. This binding interaction significantly enhances slow inactivation, a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. Mutations targeted to the IQ domain disrupted calmodulin binding and eliminated calcium/calmodulin-dependent slow inactivation, whereas the gating effects of calcium/calmodulin were restored by intracellular application of a peptide modeled after the IQ domain. A naturally occurring mutation (A1924T; 600163.0012) in the IQ domain altered SCN5A function in a manner characteristic of the Brugada syndrome, but at the same time inhibited slow inactivation induced by calcium/calmodulin, yielding a clinically benign (arrhythmia-free) phenotype.
Splawski et al. (2002) identified a common variant of the SCN5A gene, ser1103 to tyr (S1103Y; 600163.0024), which is present in 13.2% of African Americans and is associated with accelerated channel activation, increasing the likelihood of abnormal cardiac repolarization and arrhythmia. Splawski et al. (2002) suggested that the S1103Y mutation in the African American population may be a useful molecular marker for the prediction of arrhythmia susceptibility in the context of additional acquired risk factors such as the use of certain medications or the presence of hypokalemia.
Rivolta et al. (2001) identified 2 mutations at the same codon of the SCN5A gene: a tyr1795-to-cys mutation (Y1795C; 600163.0029) in a patient with LQT3, and a Y1795H (600163.0030) mutation in a patient with Brugada syndrome. Functional analysis revealed marked and opposing effects on channel gating consistent with activity associated with the cellular basis of each clinical disorder: Y1795H accelerated and Y1795C slowed the onset of activation; Y1795H, but not Y1795C, caused a marked negative shift in the voltage dependence of inactivation; and neither affected the kinetics of the recovery from inactivation. However, both mutations increased the expression of sustained Na(+) channel activity compared with wildtype channels, although this effect was most pronounced for the Y1795C mutation, and both promoted entrance into an intermediate or slowly developing inactivated state. Rivolta et al. (2001) concluded that these data confirmed the key role of the C-terminal tail of the cardiac Na(+) channel in the control of channel gating and provided further evidence of the close interrelationship between Brugada syndrome and LQT3 at the molecular level.
Clancy et al. (2002) performed detailed kinetic analyses of the Y1795C mutant described by Rivolta et al. (2001). Theoretical entry and exit rates from the bursting mode of gating were derived from single channels. Computational analysis suggested that the amount of time mutant channels spend bursting (burst mode dwell time) is primarily responsible for rate-dependent changes in single-channel bursting and macroscopic inward sodium channel (I-sus), hence delaying repolarization and prolonging the QT interval. This prediction was experimentally confirmed by analysis of delta-KPQ mutant channels (600163.0001) for which the burst mode exit rate (determined by the burst mode dwell time) was found to be very similar to the derived rate for Y1795C channels. These results provided an explanation of the molecular mechanism for bradycardia-induced QT prolongation in patients carrying LQT3 mutations.
Veldkamp et al. (2003) studied the effect of the 1795insD SCN5A mutation (600163.0013), which causes LQT3 or Brugada syndrome, on sinoatrial (SA) pacemaking. Activity of 1795insD channels during SA node pacemaking was confirmed by action potential (AP) clamp experiments, and the previously characterized persistent inward current (I-pst) and negative shift were implemented into SA node (AP) models. The -10 mV shift decreased the sinus rate by decreasing the diastolic depolarization rate, whereas the I-pst decreased the sinus rate by AP prolongation, despite a concomitant increase in the diastolic depolarization rate. In combination, a moderate I-pst (1 to 2%) and the shift reduced the sinus rate by about 10%. Veldkamp et al. (2003) concluded that sodium channel mutations displaying an I-pst or a negative shift in inactivation may account for the bradycardia seen in LQT3 patients, whereas SA node pauses or arrest may result from failure of SA node cells to repolarize under conditions of extra net inward current.
Based on prior associations with disorders of cardiac rhythm and conduction, Benson et al. (2003) screened the SCN5A gene as a candidate gene in 10 pediatric patients from 7 families who were diagnosed with autosomal recessive congenital sick sinus syndrome (SSS1; 608567) during the first decade of life. Probands from 3 kindreds exhibited compound heterozygosity for 6 distinct SCN5A alleles (e.g., 600163.0025), 2 of which had previously been associated with dominant disorders of cardiac excitability. Biophysical characterization of the mutants using heterologously expressed recombinant human heart sodium channels demonstrated loss of function or significant impairment in channel gating that predicted reduced myocardial excitability. Thus Benson et al. (2003) provided a molecular basis for some forms of congenital SSS and defined a recessive disorder of a human heart voltage-gated sodium channel.
In a patient with Brugada syndrome, Mohler et al. (2004) identified an E1053K mutation (600163.0033) in the ankyrin-binding motif of Na(v)1.5. The mutation abolished binding of Na(v)1.5 to ankyrin-G (ANK3; 600465), and also prevented accumulation of Na(v)1.5 at cell surface sites in ventricular cardiomyocytes. Both ankyrin-G and Na(v)1.5 localized at intercalated disc and T-tubule membranes in cardiomyocytes, and Na(v)1.5 coimmunoprecipitated with the 190-kD ankyrin-G isoform from detergent-soluble lysates from rat heart. These data suggested that Na(v)1.5 associates with ankyrin-G and that ankyrin-G is required for Na(v)1.5 localization at excitable membranes in cardiomyocytes.
Miller et al. (2004) reported a case of repeated germline transmission of a severe form of LQT syndrome from an asymptomatic mother with somatic mosaicism for a mutation in the SCN5A gene (600163.0007).
Maekawa et al. (2005) sequenced the SCN5A gene in 166 Japanese patients with arrhythmia who were not diagnosed with LQT or Brugada syndrome and in 232 healthy controls, identifying 69 genetic variations including 66 SNPs. The frequency of a 703+130G-A SNP was significantly higher in patients than in controls (OR, 1.70), suggesting an association with an unknown risk factor for arrhythmia. Haplotype analysis revealed that the so-called GG haplotype with both the leu1988-to-arg and his558-to-arg (600163.0031) SNPs was significantly less frequent in patients than in controls (p = 0.018), suggesting a possible protective effect.
Tester et al. (2005) analyzed 5 LQTS-associated cardiac channel genes in 541 consecutive unrelated patients with LQT syndrome (average QTc, 482 ms). In 272 (50%) patients, they identified 211 different pathogenic mutations, including 88 in KCNQ1, 89 in KCNH2, 32 in SCN5A, and 1 each in KCNE1 and KCNE2. Mutations considered pathogenic were absent in more than 1,400 reference alleles. Among the mutation-positive patients, 29 (11%) had 2 LQTS-causing mutations, of which 16 (8%) were in 2 different LQTS genes (biallelic digenic). Tester et al. (2005) noted that patients with multiple mutations were younger at diagnosis, but they did not discern any genotype/phenotype correlations associated with location or type of mutation.
In 44 unrelated patients with LQT syndrome, Millat et al. (2006) used DHLP chromatography to analyze the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes for mutations and SNPs. Most of the patients (84%) showed a complex molecular pattern, with an identified mutation associated with 1 or more SNPs located in several LQTS genes; 4 of the patients also had a second mutation in a different LQTS gene (biallelic digenic inheritance; see, e.g., 600163.0007 and 603796.0005).
In affected members of the family reported by Greenlee et al. (1986) with a form of dilated cardiomyopathy (CMD1E; 601154), McNair et al. (2004) identified heterozygosity for a missense mutation (D1765N; 600163.0001) in the SCN5A gene. In affected members of a family with atrial standstill (ATRST1; 108770), Groenewegen et al. (2003) had identified coinheritance of the D1275N mutation in the SCN5A gene with polymorphisms in the atria-specific junction channel protein connexin-40 (GJA5; 121013). None of the patients with atrial standstill had dilated cardiomyopathy, leading Groenewegen and Wilde (2005) to question the relationship of the SCN5A mutation to dilated cardiomyopathy in the family reported by McNair et al. (2004). McNair et al. (2005) responded that the younger age of the affected members studied by Groenewegen et al. (2003) as well as additional or genetic environmental factors may account for the difference between the 2 families.
In a Japanese family in which an 11-year-old boy had sick sinus syndrome that progressed to atrial standstill, Makita et al. (2005) analyzed 3 cardiac ion channel genes previously associated with atrial standstill, atrial fibrillation, or sick sinus syndrome: SCN5A, HCN4 (605206), and GJA5. No mutations were found in HCN4, but the proband and his asymptomatic father were heterozygous for a missense mutation in SCN5A (L212P; 600163.0048). In addition, the proband and his unaffected mother and maternal grandmother were all heterozygous for the same 2 rare GJA5 polymorphisms identified by Groenewegen et al. (2003) in atrial standstill patients, -44A/+71G. Functional analysis with the L212P mutant channels demonstrated large hyperpolarizing shifts in both the voltage dependence of activation and inactivation and delayed recovery from inactivation compared to wildtype. Makita et al. (2005) suggested that defects in SCN5A underlie atrial standstill, and that coinheritance of GJA5 polymorphisms represents a possible genetic modifier of the clinical manifestations.
Olson et al. (2005) analyzed the SCN5A gene in 156 unrelated patients with dilated cardiomyopathy who were negative for mutations in the known CMD genes encoding cardiac actin (102540), alpha-tropomyosin (191010), and metavinculin (see 193065), and identified 5 heterozygous mutations in 5 probands, respectively (see, e.g., 600163.0027, 600163.0038-600163.0039). All of the mutations altered highly conserved residues in the transmembrane domains of SCN5A.
Albert et al. (2008) analyzed 5 cardiac ion channel genes, SCN5A, KCNQ1, KCNH2, KCNE1, and KCNE2, in 113 cases of sudden cardiac death. No mutations or rare variants were identified in any of the 53 male subjects, but in 6 (10%) of 60 female subjects, 5 rare missense variants in SCN5A were identified, 2 previously associated with long QT syndrome, 1 with sudden infant death syndrome, and 2 not previously reported in control populations. Functional studies showed that all of the variants resulted in significantly shorter recovery times from inactivation. Albert et al. (2008) concluded that functionally significant mutations and rare variants in the SCN5A gene may contribute to the risk of sudden cardiac death in women.
Makita et al. (2008) genotyped 66 members of 44 LQT3 families of multiple ethnicities and identified the E1784K mutation (600163.0008) in 41 individuals from 15 (34%) of the kindreds; the diagnoses in these individuals included LQT3 syndrome, Brugada syndrome, and/or sinus node dysfunction (see 608567). In vitro functional characterization of E1784K channels compared to properties reported for other LQT3 variants suggested that a negative shift of steady-state Na channel inactivation and enhanced tonic block in response to Na channel blockers confer an additional Brugada syndrome/sinus node dysfunction phenotype, and further indicated that class IC drugs should be avoided in patients with Na channels displaying these behaviors.
In a large Finnish family with atrial fibrillation (AF) and conduction defects (ATFB10; 614022), Laitinen-Forsblom et al. (2006) analyzed the SCN5A gene and identified a heterozygous missense mutation (600163.0034) that segregated with disease and was not found in more than 370 control chromosomes.
Ellinor et al. (2008) analyzed the SCN5A gene in 57 probands with a familial history of isolated or 'lone' atrial fibrillation and identified heterozygosity for a missense mutation (600163.0041) in a 45-year-old male proband and his affected father. The authors concluded that SCN5A gene was not a major cause of familial AF.
Darbar et al. (2008) analyzed the SCN5A gene in 375 probands with AF, including 118 with lone AF, which was defined as AF occurring in individuals less than 65 years of age who did not have hypertension, overt structural heart disease, or thyroid dysfunction. The authors identified 8 heterozygous variants in 10 probands that were not found in 360 age-, sex-, and ethnicity-matched controls (see, e.g., 600163.0042-600163.0045). In addition, 11 previously reported rare nonsynonymous coding region variants were identified in 12 probands (see, e.g., 600163.0033), and 3 known common nonsynonymous SCN5A polymorphisms were also identified in the AF cohort (see, e.g., 600163.0024 and 600163.0031). Darbar et al. (2008) stated that in their study, nearly 6% of AF probands carried heterozygous mutations or rare variants in the SCN5A gene.
In affected members of 2 unrelated families with CMD and conduction system disease, Hershberger et al. (2008) identified heterozygosity for 2 different missense mutations in the SCN5A gene, R222Q (600163.0046) and I1835T (600163.0047), respectively. Cheng et al. (2010) restudied the 2 families, noting that all affected individuals were also either homozygous or heterozygous for the SCN5A common polymorphism, H558R (600163.0031). Whole-cell voltage clamp studies in HEK293 cells using the Q1077del background, which is the more abundant alternatively spliced SCN5A transcript present in human hearts (65%), showed that sodium current densities of the R222Q and I1835T mutants were not different from wildtype, but the combined variants R222Q/H558R and I1835T/H558R caused approximately 35% and 30% reduction, respectively, and each showed slower recovery from inactivation than wildtype. With the Q1077del background, R222Q and R222Q/H558R variants also exhibited a significant negative shift in both activation and inactivation, whereas I1835T/H558R showed a significant negative shift in inactivation that tended to decrease window current. In contrast, expression in the Q1077 background showed no changes in peak sodium current densities, decay, or recovery from inactivation for R222Q/H558R or I1835T/H558R. Cheng et al. (2010) concluded that CMD-associated SCN5A rare variants perturb the SCN5A biophysical phenotype that is modulated by SCN5A common variants.
In 3 unrelated families with multifocal ectopic Purkinje-related premature contractions and dilated cardiomyopathy, Laurent et al. (2012) identified heterozygosity for the R222Q mutation in the SCN5A gene, which was fully penetrant and strictly segregated with the cardiac phenotype in each family. Laurent et al. (2012) stated that the R222Q effects that they observed on channel parameters were similar to those measured by Cheng et al. (2010); in addition, they noted that the effects were intermediate in the heterozygous state and also impaired the window current, which is crucial during the plateau phase of the action potential. In vitro studies recapitulated the normalization of the ventricular action potentials in the presence of quinidine.
In affected members of a 3-generation Canadian family with CMD and junctional escape ventricular capture bigeminy, Nair et al. (2012) identified the R222Q mutation in the SCN5A gene. Heterologous expression studies revealed a unique biophysical phenotype of R222Q channels in which an approximately 10-mV leftward shift in the sodium current steady-state activation curve occurs without corresponding shifts in steady-state inactivation at cardiomyocyte resting membrane-potential voltages. Nair et al. (2012) noted that the absence of H558R in these patients established that the H558R polymorphism is not required for the induction of cardiomyopathy in patients carrying the R222Q mutation.
In 16 affected members over 3 generations of a large kindred with CMD and multiple arrhythmias, including premature ventricular complexes (PVCs) of variable morphologies, Mann et al. (2012) identified heterozygosity for the R222Q mutation in the SCN5A gene. The mutation was also identified in 1 clinically unaffected family member, a 56-year-old man with a normal EKG and echocardiogram. None of the R222Q carriers had the common SCN5A variant, H558R.
O'Neill et al. (2022) studied the effects of 50 previously published, functionally characterized missense variants in the SCN5A gene. Based on their effects on peak currents, variants were divided into loss-of-function (less than 10% of wildtype peak current, 35 variants) and partial loss-of-function (10-50% of wildtype peak current, 15 variants). Using cell lines created to study the effects of the variants in heterozygous coexpression with wildtype SCN5A, the authors found that 32 of 35 loss-of-function variants and 6 of 15 partial loss-of-function variants showed a reduction to less than 75% of wildtype-alone peak current, demonstrating evidence of dominant-negative effects. Using data from a published consortia and gnomAD, they found that patients with dominant-negative variants were 2.7 times more likely to present with Brugada syndrome than individuals with putative haploinsufficient variants (p = 0.019).
Associations Pending Confirmation
For discussion of a possible association between variants in the SCN5A, SCN10A (604427), and HEY2 (604674) genes and Brugada syndrome, see 601144.
Westenskow et al. (2004) analyzed the KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 genes in 252 probands with long QT syndrome and identified 19 with biallelic mutations in LQTS genes, of whom 18 were either compound (monogenic) or double (digenic) heterozygotes and 1 was a homozygote. They also identified 1 patient who had triallelic digenic mutations (see 152427.0021). Compared with probands who had 1 or no identified mutation, probands with 2 mutations had longer QTc intervals (p less than 0.001) and were 3.5-fold more likely to undergo cardiac arrest (p less than 0.01). All 20 probands with 2 mutations had experienced cardiac events. Westenskow et al. (2004) concluded that biallelic mono- or digenic mutations (which the authors termed 'compound mutations') cause a severe phenotype and are relatively common in long QT syndrome. The authors noted that these findings support the concept of arrhythmia risk as a multi-hit process and suggested that genotype can be used to predict risk.
Niu et al. (2006) analyzed the SCN5A gene in 17 members of a 4-generation Han Chinese family with apparent autosomal dominant inheritance of cardiac arrhythmias and sudden death. All affected individuals were heterozygous for a nonsense mutation in the SCN5A gene (W1421X; 600163.0036), and 1 unaffected individual was compound heterozygous for the W1421X mutation and R1193Q (600163.0023). Niu et al. (2006) suggested that the R1193Q mutation, which results in a gain of sodium channel function, may compensate for the deleterious effects of W1421X.
Nuyens et al. (2001) reported that mice heterozygous for a knockin KPQ deletion (600163.0001) of the Scn5a gene showed the essential features of LQT3 and spontaneously developed life-threatening polymorphous ventricular arrhythmias. Sudden accelerations in heart rate or premature beats caused lengthening of the action potential with early after-depolarization and triggered arrhythmias in mice heterozygous for the deletion. Adrenergic agonists normalized the response to rate acceleration in vitro and suppressed arrhythmias upon premature stimulation in vivo. These results showed the possible risk of sudden heart rate accelerations. The heterozygous knockin mouse with its predisposition for pacing-induced arrhythmia might be a useful model for the development of new treatments for the LQT3 syndrome.
Papadatos et al. (2002) showed that disruption of the mouse Scn5a gene caused intrauterine lethality in homozygotes with severe defects in ventricular morphogenesis, whereas heterozygotes showed normal survival. Whole-cell patch-clamp analyses of isolated ventricular myocytes from adult Scn5a +/- mice demonstrated a reduction of approximately 50% in sodium conductance. Scn5a +/- hearts had several defects, including impaired atrioventricular conduction, delayed intramyocardial conduction, increased ventricular refractoriness, and ventricular tachycardia with characteristics of reentrant excitation. These findings reconciled reduced activity of the cardiac sodium channel leading to slowed conduction with several apparently diverse clinical phenotypes, providing a model for the detailed analysis of the pathophysiology of arrhythmias. Noble (2002) commented that detailed understanding of the mechanisms of cardiac arrhythmia at all relevant levels is important to the design of therapeutic programs, and cited the work of Papadatos et al. (2002) as an important step.
In 2 apparently unrelated kindreds with chromosome 3-linked LQT syndrome (LQT3; 603830), Wang et al. (1995) found deletion of 9 basepairs beginning at nucleotide 4661 of their cDNA for SCN5A. The deletion, which was detected by sequencing an aberrant SSCP conformer, resulted in deletion of lys-pro-gln (KPQ), which are 3 conserved amino acids in the cytoplasmic linker between domains III and IV of the channel protein. The 3 amino acids involved in the in-frame deletion are lys1505, pro1506, and gln1507. The effect of this mutation on membrane depolarization was studied by Bennett et al. (1995).
Clancy and Rudy (1999) developed a model representative of the behavior of the sodium channel in heart muscle cells using a single-channel-based Markov model approach. They showed that the delta-KPQ mutant form of the sodium channel stays open for too long, causing an overlarge inward current of sodium which gives rise to arrhythmia. This model view was corroborated by experiments recording actual sodium currents in cardiac muscle cells.
In a mother and son with the long QT syndrome (LQT3; 603830), Wang et al. (1995) demonstrated a CGC-to-CAC mutation in codon 1644, resulting in the substitution of a highly conserved arginine residue by histidine.
In a family in which members of 4 generations had been affected by the long QT syndrome (LQT3; 603830), Wang et al. (1995) found an AAT-to-AGT transition in codon 1325, predicted to cause substitution of a highly conserved asparagine residue by a serine residue.
In affected members of a family with Brugada syndrome (BRGDA1; 601144), a distinct form of idiopathic ventricular fibrillation, Chen et al. (1998) found an arg1232-to-trp (R1232W) and a thr1620-to-met (T1620M) mutation on the same chromosome with no mutation in the other chromosome, suggesting to them that IVF in this family was inherited as an autosomal dominant trait. The presence of both normal and mutated sodium channels in the same tissue would promote heterogeneity of the refractory period, a well established mechanism in arrhythmogenesis, and therefore may be the underlying molecular defect that causes re-entrant arrhythmia in this family. The potential contribution of R1232W and T1620M mutations to the mechanism of IVF was determined by heterologous expression in Xenopus oocytes. They found that sodium channels with the missense mutation recovered from inactivation more rapidly than normal, indicating that IVF with right bundle branch block (RBBB) and ST segment elevation is a defect distinct from long QT syndrome. When studied alone, the R1232W mutant behaved most like normal channels, whereas the T1620M mutant closely followed the kinetic pattern of the double mutant. This indicated that T1620M is the mutation probably responsible for the IVF phenotype in this kindred and that R1232W could be a rare polymorphism. In summary, biophysical analysis of the 2 missense mutations in SCN5A showed a shift in the voltage dependence of steady-state inactivation toward more positive potentials associated with a 25 to 30% acceleration in recovery time from inactivation at potentials near -80mV.
Commenting that studies of the thr1620-to-met mutant by Chen et al. (1998) revealed an abnormal electrophysiologic profile at room temperature that did not adequately explain the ECG signature of Brugada syndrome, Dumaine et al. (1999) undertook a more detailed electrophysiologic study of the thr1620-to-met mutant protein. Dumaine et al. (1999) expressed the mutant protein in a mammalian cell line and employed a patch-clamp technique to study current kinetics at 32 degrees C. The results indicated that current decay kinetics were faster in mutant than in wildtype channels at this temperature and that recovery from inactivation was slower, with a significant shift in steady-state activation. These findings provided an explanation for the ECG features of Brugada syndrome and represented the first illustration of a cardiac sodium channel mutation in which arrhythmogenicity is revealed only at temperatures approaching the physiologic range.
Voltage-gated sodium channels are multimeric structures consisting of a large, heavily glycosylated alpha subunit and 1 or 2 smaller beta subunits. The beta subunits are thought necessary for normal gating function. In brain and skeletal muscle, the beta-1 subunit (600235) accelerates sodium channel inactivation. Makita et al. (2000) characterized the functional roles of the auxiliary beta subunit by coexpression of the beta subunit with either wildtype SCN5A or SCN5A carrying the heterologously expressed T1620M mutation in Xenopus oocytes. The midpoint of steady-state inactivation was significantly shifted to positive potentials in the T1620M alpha/beta-1 channel, with an acceleration in recovery from inactivation when compared to other channels. Makita et al. (2000) therefore suggested that coexpression of T1620M alpha/beta-1 subunits exposed a significant electrophysiologic deficit that may predispose to ventricular fibrillation. Expression of both normal and mutant channels, as in the hearts of patients with Brugada syndrome, would promote heterogeneity of the refractory period in their myocardium, which serves as an ideal electrical substrate for reentrant arrhythmia.
In affected members of a family with idiopathic ventricular fibrillation with right bundle branch block (RBBB) and elevated ST segments, a disorder known as Brugada syndrome (BRGDA1; 601144), Chen et al. (1998) found an insertion of 2 nucleotides, AA, after the first 4 nucleotides (gtaa) in the splice donor sequence of intron 7 of the SCN5A gene. The functional consequences of this splicing mutation were not established.
In affected members of a family with idiopathic ventricular fibrillation characterized by RBBB and elevated ST segments, a disorder known as Brugada syndrome (BRGDA1; 601144), Chen et al. (1998) found a deletion of a single nucleotide (A) from codon 1397 of the SCN5A gene. This deletion resulted in an in-frame stop at codon 1398 (normally val). The resulting truncation eliminated DIII/S6, DIV/S1-S6, and the C-terminal portion of the cardiac sodium channel.
In an infant Japanese girl with a severe form of long QT syndrome (LQT3; 603830), Makita et al. (1998) identified a de novo missense mutation, arg1623 to gln (R1623Q), in the S4 segment of domain 4 of the SCN5A gene. When expressed in oocytes, mutant sodium channels exhibited only minor abnormalities in channel activation, but in contrast to 3 previously characterized LQT3 mutations, had significantly delayed macroscopic inactivation. Single channel analysis revealed that R1623Q channels had significantly prolonged open times with bursting behavior, suggesting a novel mechanism of pathophysiology in Na(+) channel-linked long QT syndrome.
Kambouris et al. (2000) reported that the R1623Q mutation imparts unusual lidocaine sensitivity to the sodium channel that is attributable to its altered functional behavior. Studies of lidocaine on individual R1623Q single-channel openings indicated that the open-time distribution was not changed, indicating the drug does not block the open pore as proposed previously. Rather, the mutant channels have a propensity to inactivate without ever opening ('closed-state inactivation'), and lidocaine augments this gating behavior. An allosteric gating model incorporating closed-state inactivation recapitulated the effects of lidocaine on the pathologic sodium current. These findings explained the unusual drug sensitivity of R1623Q and provided a general and unanticipated mechanism for understanding how sodium channel-blocking agents may suppress the pathologic, sustained sodium current induced by LQT3 mutations.
In a male infant diagnosed with ventricular arrhythmias and cardiac decompensation in utero at 28 weeks' gestation and with long QT syndrome at birth, Miller et al. (2004) identified heterozygosity for the R1623Q mutation. The mother had no ECG abnormalities, but a previous and a subsequent pregnancy both ended in stillbirth at 7 months. Initial studies detected no genetic abnormality, but a sensitive restriction enzyme-based assay revealed a small percentage (8 to 10%) of cells harboring the mutation in the mother's blood, skin, and buccal mucosa; R1623Q was also identified in cord blood from the third fetus. Miller et al. (2004) concluded that recurrent late-term fetal loss or sudden infant death can result from unsuspected parental mosaicism for LQT-associated mutations.
In a 1-month-old male infant who had syncope, torsade de pointes, cardiac arrest, and a QTc of 460 ms, Millat et al. (2006) identified biallelic digenic mutations: a 4868G-A transition in exon 28 of the SCN5A gene resulting in the R1623Q substitution; and a missense mutation in the KCNE2 gene (F60L; 603796.0005).
Wei et al. (1999) described a family in which the 13-year-old proband died suddenly at rest with no antecedent illness and no significant findings at postmortem. Her father had sinus bradycardia with occasional sinus pauses and ventricular ectopy together with profound prolongation of his QT interval (QTc = 527 ms) (see LQT3; 603830). He experienced only occasional light-headedness. Other family members experienced occasional syncope and had sinus bradycardia and prolonged QT intervals on their ECGs. In those individuals with prolonged QT intervals, SSCP analysis detected an aberrant conformer in the coding region of the SCN5A gene corresponding to the C terminus. Nucleotide sequencing revealed a G-to-A transition at codon 1784, resulting in a glu-to-lys substitution. This mutation occurs at a highly conserved residue in most voltage-gated sodium channels in most animals, including invertebrates. When the mutation was expressed in Xenopus oocytes, a defect in channel inactivation was demonstrated in the form of a small residual steady state current throughout prolonged depolarization. Wei et al. (1999) explored this further by engineering SCN5A constructs with amino acid substitutions at other positions in the C terminus. All exhibited similar electrophysiologic phenotypes, suggesting that heterozygous charge-neutralizing amino acid substitution at this site causes an allosteric effect on sodium channel gating, resulting in delayed myocardial repolarization. This provided a novel mechanism for LQT3.
Makita et al. (2008) genotyped 66 members of 44 LQT3 families of multiple ethnicities and identified the E1784K mutation in 41 individuals from 15 (34%) of the kindreds, including the family previously reported by Wei et al. (1999); the diagnoses in these individuals included LQT3 syndrome, Brugada syndrome (BRGDA1; 601144), and/or sinus node disease (see 608567). Heterologously expressed E1784K channels showed a 15.0-mV negative shift in the voltage dependence of Na channel inactivation and a 7.5-fold increase in flecainide affinity for resting-state channels, properties also seen with other LQT3 mutations associated with a mixed clinical phenotype. Furthermore, these properties were absent in Na channels harboring the T1304M mutation, which is associated with LQT3 without a mixed clinical phenotype. Makita et al. (2008) suggested that a negative shift of steady-state Na channel inactivation and enhanced tonic block by class IC drugs represent common biophysical mechanisms underlying the phenotypic overlap of LQT3 and Brugada syndromes, and further indicated that class IC drugs should be avoided in patients with Na channels displaying these behaviors.
In a large French family with progressive heart block (PFHB1A; 113900), Schott et al. (1999) identified a T-to-C transition in the highly conserved +2 donor splice site of intron 22 of the SCN5A gene. The abnormal transcript predicted in-frame skipping of exon 22 and an impaired gene product lacking the voltage-sensitive DIIIS4 segment.
In a Dutch family with asymptomatic first-degree atrioventricular block associated with right bundle branch block from birth, without apparent progression (see 113900), Schott et al. (1999) identified a 1-bp deletion (G) at nucleotide 5280 of the SCN5A gene, resulting in a frameshift predicted to cause a premature stop codon.
In the screening of SCN5A in 6 individuals with Brugada syndrome (BRGDA1; 601144), Rook et al. (1999) found missense mutations in the coding region of the gene in 2: arg1512 to trp (R1512W) in the DIII-DIV cytoplasmic linker, and ala1924 to thr (A1924T; 600163.0012) in the C-terminal cytoplasmic domain. In 2 other patients mutations were detected near intron/exon junctions. To assess the functional consequences of the R1512W and A1924T mutations, wildtype and mutant sodium channel proteins were expressed in Xenopus oocytes. Both missense mutations affected channel function and seemed to be associated with an increase in inward sodium current during the action potential upstroke.
For discussion of the ala1924-to-thr (A1924T) substitution in the SCN5A gene that was found in compound heterozygous state in 2 patients with Brugada syndrome (BRGDA1; 601144) by Rook et al. (1999), see 600163.0011.
In a large Dutch family with electrocardiographic features both of long QT syndrome (LQT3; 603830) and Brugada syndrome (BRGDA1; 601144), Bezzina et al. (1999) demonstrated a 3-bp insertion at nucleotide position 5537 of the SCN5A gene, predicted to cause insertion of an aspartic acid residue at amino acid position 1795 (1795insD) in the C-terminal domain of the protein. Expression of this mutant channel protein in Xenopus oocytes permitted characterization of defects in channel activation and inactivation when compared to a wildtype control. These defects were predicted to cause a reduction in sodium flux during the upstroke of the cardiac action potential.
The co-occurrence of Brugada syndrome and long QT syndrome in this family was paradoxical, since LQT3 is associated with activating SCN5A mutations and Brugada syndrome with inactivating mutations. Clancy and Rudy (2002) modeled the cellular effects of the 1795insD mutation in a virtual transgenic cell. Since ion channel proteins are expressed nonuniformly throughout the myocardium, there is an intrinsic electrophysiologic heterogeneity. The authors demonstrated that the interplay between this underlying myocardial electrophysiologic heterogeneity and the mutation-induced changes in cardiac sodium channel function provided the substrate for both ST segment elevation (in Brugada syndrome) and QT prolongation (LQT3) in a rate-dependent manner.
Akai et al. (2000) screened 25 Japanese patients with idiopathic ventricular fibrillation (VF1; 603829). The diagnosis was based on the occurrence of at least one episode of syncope and/or cardiac arrest and documentation of ventricular fibrillation. Structural heart disorders were excluded. Eighteen patients were diagnosed as Brugada syndrome. The authors identified a heterozygous ser1710-to-leu missense mutation of the SCN5A gene in a 39-year-old man who was admitted to the hospital for recurrent syncope and suffered an episode of spontaneous ventricular fibrillation while hospitalized. An implanted cardiac defibrillator was successful in preventing further attacks of palpitation or syncope. Brugada syndrome was not present. The paternal grandfather and a paternal uncle had died suddenly in their sixth decade of unknown cause; the parents and sibs were asymptomatic.
Schwartz et al. (2000) described an infant who nearly died of SIDS (272120), whose parents had normal QT intervals and in whom the long QT syndrome (LQT3; 603830) was diagnosed with identification of a spontaneous mutation of the SCN5A gene: a change of codon 941 from TCC (serine) to AAC (asparagine). The patient had all the classic features of near-SIDS. Before the episode, the infant appeared to be in perfect health. His age at the time of the episode (7 weeks) was within the age range of 5 to 12 weeks during which the incidence of SIDS peaks. The parents found him cyanotic, apneic, and pulseless. Ventricular fibrillation was documented in an emergency room; this point is important given the frequent statements that ventricular arrhythmias have not been recorded in infants at risk for SIDS. Had the infant died--an outcome that was almost a certainty in the absence of cardioversion--the absence of an electrocardiogram and the normal QT intervals of both parents would have eliminated suspicion of the long QT syndrome and would have prompted a diagnosis of SIDS.
Tan et al. (2001) studied a family who came to medical attention when the proband, a 3-year-old girl, experienced episodes of fainting during a febrile illness. Her 12-lead ECG showed characteristics of slow conduction throughout the atria and ventricles, including broad P waves, PR interval prolongation, and a wide QRS complex (see 113900). Continuous monitoring revealed episodes of severe bradycardia (25 beats/minute). During these slow periods the cardiac rhythm was maintained by infrequent atrioventricular nodal 'escape' impulses. Conduction disturbance persisted after the febrile illness, but there was no evidence of structural heart disease or systemic diseases associated with conduction defects in children. Therapeutic intervention with a dual-chamber pacemaker was initially limited by inability to pace the atrium (maximal stimulus: 10 V, 1 ms); however, this difficulty resolved with 1 week of empiric steroid treatment. During the 4 years following diagnosis, the patient continuously required dual-chamber pacing. The proband's 6-year-old sister was similarly affected and required pacemaker implantation, with episodes of noncapture that reproducibly resolved with corticosteroid therapy. Three other family members with no structural heart disease had ECG evidence of conduction slowing (prolonged PR and QRS intervals), but did not experience bradycardia or require pacemaker implantation. All affected family members had a G-to-T transition in the first nucleotide of codon 514 in exon 12 of the SCN5A gene resulting in the replacement of glycine by cysteine (G514C). Biophysical characterization of the mutant channel showed that there were abnormalities in voltage-dependent gating behavior that could be partially corrected by dexamethasone, consistent with the salutary effects of glucocorticoids on the clinical phenotype. Computational analysis predicts that the gating defects of G514C selectively slow myocardial conduction, but do not provoke the rapid cardiac arrhythmias associated previously with SCN5A mutations.
Wang et al. (2002) reported a family in which the proband had presented with first-degree atrioventricular block at the age of 9, progressing to complete AV block by the age of 20 (PFHB1A; 113900). The proband's sister and father had electrocardiographic evidence of right bundle branch block and left axis deviation with normal PR intervals. The corrected QT interval was normal (less than 420 ms) in all 3 individuals. Sequencing of the coding region of SCN5A revealed a G-to-A mutation at nucleotide position 4783, which replaced an aspartic acid residue at amino acid position 1595 with asparagine (D1595N). The G4783A mutation was engineered into a recombinant human heart sodium channel and transiently coexpressed with human sodium channel beta-1 subunit (600760) in a cultured mammalian cell line (tsA201). Functional characterization using a patch-clamp technique revealed a significant defect in the kinetics of fast-channel inactivation distinct from those of SCN5A mutations reported in LQT3 (603830). The authors considered this a plausible mechanism for the observed conduction system disease in this family.
Wang et al. (2002) reported a child in whom second-degree atrioventricular block had been diagnosed at the age of 6, progressing to complete atrioventricular block by the age of 12 (PFHB1A; 113900). The child's mother had a normal electrocardiogram and the father declined testing. There was no family history of sudden death. Sequencing of the coding region of SCN5A revealed a G-to-A mutation at nucleotide position 892 that replaced a glycine residue at amino acid position 298 with serine (G298S). The G892A mutation was engineered into a recombinant human heart sodium channel and transiently coexpressed with human sodium channel beta-1 subunit (600760) in a cultured mammalian cell line (tsA201). Functional characterization using a patch-clamp technique revealed a significant defect in the kinetics of fast-channel inactivation distinct from those of SCN5A mutations reported in LQT3 (603830). The authors considered this a plausible mechanism for the observed conduction system disease in this family.
In a 6-week-old male infant who died of SIDS (272120), Ackerman et al. (2001) identified a heterozygous G-to-T transversion in the SCN5A gene, resulting in an ala997-to-ser substitution. The mutation was not detected in 800 control alleles. Ackerman et al. (2001) determined that amino acid 997 is located in the cytoplasmic connector between the second and third domains of the sodium channel and is highly conserved across species. They demonstrated that the mutant SCN5A channel expressed a sodium current characterized by slower decay and a 2- to 3-fold increase in late sodium current.
In a 42-day-old male infant who died of possible SIDS (272120), Ackerman et al. (2001) identified a heterozygous G-to-A replacement in the SCN5A gene, resulting in an arg1826-to-his substitution. The mutation was not detected in 800 control alleles. Ackerman et al. (2001) determined that amino acid 1826 is located in the cytoplasmic C-terminal region of the sodium channel and is highly conserved. They demonstrated that the SCN5A mutant channel expressed a sodium current characterized by slower decay and a 2- to 3-fold increase in late sodium current.
Sudden unexplained nocturnal death syndrome (SUNDS), a disorder found in southeast Asia, is characterized by an abnormal electrocardiogram with ST segment elevation in leads V1 to V3 and sudden death due to ventricular fibrillation, identical to that seen in Brugada syndrome (BRGDA1; 601144). Vatta et al. (2002) found mutations in the SCN5A gene in 3 of 10 Asian SUNDS patients. In a sporadic Asian SUNDS patient, the authors identified a 1100G-A transition in SCN5A. The mutation is predicted to result in an arg367-to-his (R367H) substitution, which lies in the first P segment of the pore-lining region between the DIS5 and DIS6 transmembrane segments. In transfected Xenopus oocytes, the R367H mutant channel did not express any current. The authors hypothesized that the likely effect of this mutation is to depress peak current due to the loss of one functional allele.
In a family with SUNDS, a disorder identical to Brugada syndrome (BRGDA1; 601144), that exhibited autosomal dominant inheritance, Vatta et al. (2002) identified among affected members a 2204C-T transition, which is predicted to result in an ala735-to-val (A735V) substitution. The mutation lies in the first transmembrane segment of domain II, (DIIS1), close to the first extracellular loop between DIIS1 and DIIS2. In transfected Xenopus oocytes, the A735V mutant expressed currents with steady-state activation voltage shifted to more positive potentials and exhibited reduced sodium channel current at the end of phase I of the action potential.
In a pair of Japanese dizygotic twins, one of whom died at 4 months of SUNDS, a disorder identical to Brugada syndrome (BRGDA1; 601144), Vatta et al. (2002) identified a 3575G-A transition in exon 20 of the SCN5A gene, predicted to result in an arg1192-to-gln (R1192Q) substitution in Domain III. In transfected Xenopus oocytes, the mutation accelerated the inactivation of the sodium channel current and exhibited reduced sodium channel current at the end of phase I of the action potential. Wang (2005) stated that this variant was mislabeled in the Vatta et al. (2002) report and should be designated R1993Q.
In an 82-year-old Caucasian male who developed long QT syndrome after the administration of D-sotolol or quinidine (see LQT3, 603830), Wang et al. (2004) identified heterozygosity for the R1993Q mutation in the SCN5A gene. The mutation was found in 4 of 2,087 predominantly Caucasian controls (0.2%). Electrophysiologic studies showed that mutant R1193Q channels destabilize inactivation gating and generate a persistent, nonactivating current that is expected to prolong the cardiac action potential duration, leading to LQT syndrome; single channel recording revealed the molecular mechanism to be frequent, dispersed reopening of the channels. The patient also carried the H558R SCN5A variant (600163.0031), but due to a lack of family members, it could not be determined whether H558R was in cis or trans with R1993Q.
Hwang et al. (2005) found the R1993Q mutation in 11 of 94 (12%) randomly selected Han Chinese individuals and concluded that the variant is a common polymorphism in this population. None of the carriers had electrocardiographic signs of Brugada syndrome, although 1 had a prolonged QTc interval (472 ms) and another, who was homozygous for the mutation, had a borderline long QTc (437 ms).
In an asymptomatic 73-year-old male member of a 4-generation Han Chinese family with autosomal dominant cardiac arrhythmias and sudden death, Niu et al. (2006) identified compound heterozygosity for R1193Q and a nonsense mutation in the SCN5A gene (W1421X; 600163.0036). Niu et al. (2006) suggested that the R1193Q mutation, which results in a gain of sodium channel function, may compensate for the deleterious effects of W1421X. Haplotype analysis of an asymptomatic daughter-in-law and 2 asymptomatic grandchildren who also carried the R1193Q mutation revealed that the children inherited the mutation from their mother rather than their grandfather.
Splawski et al. (2002) screened DNA samples from individuals with nonfamilial cardiac arrhythmias and identified a C-to-A transversion in the SCN5A gene leading to a ser1103-to-tyr (S1103Y) substitution 1 patient. Ackerman et al. (2004) noted that the variant was originally published as SER1102TYR from numbering based on the 2,015 amino acid alternatively spliced transcript. Subsequently, numbering was revised to account for the full-length 2,016 amino acid transcript. Serine-1103 is a conserved residue located in the intracellular sequences that link domains II and III of the channel. The proband had idiopathic dilated cardiomyopathy and hypokalemia and developed prolonged QT and torsade de pointes ventricular tachycardia while on amiodarone. Splawski et al. (2002) determined that the Y1103 allele is present in 19.2% of West Africans and Caribbeans and in 13.2% of African Americans. The Y1103 allele was not found in 511 Caucasians or 578 Asians. Splawski et al. (2002) studied 22 African Americans with acquired arrhythmia and 100 population-matched controls. The Y1103 allele was overrepresented among arrhythmia patients, being found in 56.5% of cases and among 13% of controls. The likelihood of displaying signs of arrhythmia in a Y1103 carrier heterozygote or homozygote yielded an odds ratio of 8.7 (95% CI 3.2 to 23.9). The odds ratio was not significantly altered after controlling for age or gender. To determine whether this mutation is an inherited risk factor for arrhythmias, Splawski et al. (2002) examined the extended family of 1 proband. They ascertained and phenotypically characterized 23 members of this kindred. Phenotypic analysis revealed that 11 members of the family had prolonged QT and/or a history of syncope. All 11 phenotypically affected members of this family carried the Y1103 allele (6 were homozygotes and 5 were heterozygotes). Physiologic analysis of the effect of this mutation recorded a small but significant negative shift in the voltage dependence of activation. Splawski et al. (2002) concluded that the Y1103 allele is a common SCN5A variant in Africans and African Americans and causes a small but inherent chronic risk of acquired arrhythmia. In the setting of additional acquired risk factors, including medications, hypokalemia, or structural heart disease, individuals carrying this allele are at increased risk of arrhythmia.
In 3 white sisters and their father, Chen et al. (2002) identified the S1103Y mutation, thus demonstrating that this mutation does exist in the white population. The mutation was associated with a considerable risk of syncope, ventricular arrhythmia, ventricular fibrillation, and sudden death, Each of the 3 sibs was genotyped for 31 'ancestry informative markers' to provide an estimation of biogeographic ancestry on 3 axes: Native American, West African, and European. The maximum likelihood point estimates for each of the sibs were 100% European, 0.0% African, and 0.0% Native American. The proband had a baseline QTc of 520 ms, and developed 2 episodes of syncope at age 49 years. The first episode was triggered by emotion and excitement. The second episode occurred in the setting of amiodarone and low serum potassium, and progressed to ventricular fibrillation and cardiac arrest. She was resuscitated by cardioversion. The second sister had a QTc of 431 ms, and died suddenly at age 44 years when awakening from sleep. The third sister had a QTc of 452 ms, developed 1 episode of syncope at the age of 33 years, and had complained of palpitations all her life. The father died suddenly in his sleep at age 50 years. Family members without S1103Y had a normal QTc.
Plant et al. (2006) screened DNA samples from 133 African American autopsy-confirmed cases of sudden infant death syndrome (SIDS; 272120) and identified 3 that were homozygous for the S1103Y variant. Among 1,056 African American controls, 120 were carriers of the heterozygous genotype, suggesting that infants with 2 copies of S1103Y have a 24-fold increased risk for SIDS. Variant Y1103 channels were found to operate normally under baseline conditions in vitro. Because risk factors for SIDS include apnea and respiratory acidosis, Y1103 and wildtype channels were subjected to lowered intracellular pH; only Y1103 channels developed abnormal function, with late reopenings suppressible by the drug mexiletine. Plant et al. (2006) suggested that the Y1103 variant confers susceptibility to acidosis-induced arrhythmia, a gene-environment interaction.
Darbar et al. (2008) stated that the S1103Y variant was a known common nonsynonymous polymorphism in the SCN5A gene; they detected S1103Y in 1 patient with lone atrial fibrillation and in 5 patients with atrial fibrillation associated with other heart disease, as well as in 15 of 720 control chromosomes, for a minor allele frequency of 0.7%.
In 3 sibs with congenital sick sinus syndrome (SSS1; 608567), Benson et al. (2003) identified compound heterozygosity for 2 mutations in the SCN5A gene. The maternal allele carried a 3893C-T transition, resulting in a pro1298-to-leu (P1298L) change; the paternal allele carried a gly1408-to-arg substitution (600163.0026).
In 3 sibs with congenital sick sinus syndrome (SSS1; 608567) with compound heterozygosity for mutation in the SCN5A gene, Benson et al. (2003) found on the paternal allele a 4222G-A transition, resulting in a gly1408-to-arg substitution (G1408R). The maternal allele carried a pro1298-to-leu substitution (600163.0025).
Kyndt et al. (2001) reported the G1408R mutation, which they designated GLY1406ARG, in heterozygous state in a large French family segregating both isolated cardiac conduction defect (see 601144) and Brugada syndrome (BRGDA1; 601144).
In a child with congenital sick sinus syndrome (SSS1; 608567), Benson et al. (2003) identified compound heterozygosity for 2 mutations in the SCN5A gene: the paternal allele carried a 659C-T transition, resulting in a thr220-to-ile (T220I) mutation, and the maternal allele carried a 4867C-T transition, resulting in an arg1623-to-ter mutation (R1623X; 600163.0028). The authors noted that an R1623Q mutation (600163.0007) resulting in congenital long QT syndrome-3 (603830) had previously been described.
In a 54-year-old man with dilated cardiomyopathy (CMD1E; 601154), atrial fibrillation, and heart block, Olson et al. (2005) identified heterozygosity for a 659C-T transition in exon 6 of the SCN5A gene, resulting in a thr220-to-ile (T220I) substitution at a highly conserved residue in the transmembrane domain. Coronary artery disease was excluded by angiography; cardiac biopsy showed moderate myocyte hypertrophy and marked interstitial fibrosis. He died 13 years later in severe congestive heart failure. A female first cousin once removed who also carried the mutation was diagnosed at 55 years of age with dilated cardiomyopathy (ejection fraction, 10%) and incomplete bundle branch block; she died 2 years later, also in severe congestive heart failure. Other relatives were reported to have enlarged hearts, but were unavailable for evaluation.
For discussion of the arg1623-to-ter (R1623X) mutation that was found in compound heterozygous state in a child with congenital sick sinus syndrome (SSS1; 608567) by Benson et al. (2003), see 600163.0027.
In a patient with long QT syndrome-3 (LQT3; 603830), Rivolta et al. (2001) identified a tyr1795-to-cys (Y1795C) mutation in the SCN5A gene. The mutation slowed the onset of activation, but did not cause a marked negative shift in the voltage dependence of inactivation or affect the kinetics of the recovery from inactivation. The mutation increased the expression of sustained Na(+) channel activity compared with wildtype channels and promoted entrance into an intermediate or slowly developing inactivated state.
In a patient with Brugada syndrome (BRGDA1; 601144), Rivolta et al. (2001) identified a tyr1795-to-his (Y1795H) mutation in the SCN5A gene. The mutation accelerated the onset of activation and caused a marked negative shift in the voltage dependence of inactivation. It did not affect the kinetics of the recovery from inactivation. The mutation increased the expression of sustained Na(+) channel activity compared with wildtype channels and promoted entrance into an intermediate or slowly developing inactivated state.
In a 2-year-old boy with second-degree atrioventricular conduction block (PFHB1A; 113900) necessitating a pacemaker, Viswanathan et al. (2003) identified a heterozygous 1535C-T transition in the SCN5A gene, resulting in a thr512-to-ile (T512I) substitution. In addition, there was a homozygous 1673A-G transition, resulting in a his558-to-arg (H558R) substitution. H558R (rs1805124) is a polymorphism present in 20% of the population (Yang et al., 2002). One of the patient's alleles contained both T512I and H558R. The patient's father was heterozygous for the H558R substitution, the asymptomatic mother was compound heterozygous for the T512I and H558R substitutions, and 2 sibs were heterozygous for the H558R substitution. Functional expression studies showed that activation and inactivation of wildtype and H558R channels were similar. By contrast, voltage-dependent activation and inactivation of the T512I channel was shifted negatively by 8 to 9 mV and had enhanced slow activation and slower recovery from inactivation compared to the wildtype channel. Studies of the double H558R/T512I channel showed that H558R eliminated the negative shift induced by T512I, but only partially restored the kinetic abnormalities. Viswanathan et al. (2003) suggested that enhanced slow inactivation disproportionately affected Purkinje cells, which have a longer action potential duration and smaller diastolic interval, resulting in slowed atrioventricular conduction.
Darbar et al. (2008) stated that the H558R variant was a known common nonsynonymous polymorphism in the SCN5A gene; they detected H558R in 59 patients with lone atrial fibrillation and in 130 patients with atrial fibrillation associated with other heart disease, as well as in 128 of 720 control chromosomes, for a minor allele frequency of approximately 25%.
Shin et al. (2004) studied a family with 9 members as well as 12 unrelated sporadic cases, all Koreans, diagnosed with Brugada syndrome (BRGDA1; 601144). They identified a novel missense mutation associated with Brugada syndrome in the family: a single-nucleotide substitution of G to A at nucleotide position 3934 in exon 21 of the SCN5A gene that changed glycine-1262 to serine (G1262S) in segment 2 of domain III of the SCN5A protein. Four individuals in the family carried the identical mutation, but none of the 12 sporadic patients did. The mutation was not found in 150 unrelated normal individuals.
In a patient with Brugada syndrome (BRGDA1; 601144), Mohler et al. (2004) identified a 3157G-A transition in the SCN5A gene resulting in a glu1053-to-lys (E1053K) mutation in the ankyrin-binding motif of the cardiac sodium channel. The mutation abolished binding of Na(v)1.5 to ankyrin-G (600465) and also prevented accumulation of Na(v)1.5 at cell surface sites in ventricular cardiomyocytes.
In a patient with lone atrial fibrillation (ATFB10; 614022), Darbar et al. (2008) identified heterozygosity for the E1053K mutation in the SCN5A gene. The mutation was not found in 720 control alleles.
In a large family reported by Greenlee et al. (1986) with dilated cardiomyopathy with conduction disorder and arrhythmia (CMD1E; 601154), McNair et al. (2004) identified heterozygosity for a 3823G-A mutation in exon 21 of the SCN5A gene, resulting in an asp1275-to-asn (D1275N) substitution and predicting a change of charge within the S2 segment of domain III. The mutation was present in 22 affected family members and was not found in 300 control chromosomes.
Groenewegen et al. (2003) reported the D1275N mutation, coinherited with polymorphisms in the atrial-specific gap junction channel protein connexin-40 (GJA5; 121013), in affected members of a family with atrial standstill (ATRST1; 108770). No member of this family had dilated cardiomyopathy, leading Groenewegen and Wilde (2005) to question whether the D1275N mutation was the primary cause of dilated cardiomyopathy as reported by McNair et al. (2004).
In affected members of a large Finnish family with atrial fibrillation and conduction defects (ATFB10; 614022), Laitinen-Forsblom et al. (2006) identified heterozygosity for the D1275N mutation in the SCN5A gene. The mutation was not found in more than 370 control chromosomes. Echocardiography revealed an enlarged left ventricle with an increased end-diastolic left ventricular diameter in 1 affected individual, and the right ventricle was slightly enlarged in 3 other affected individuals.
In a 41-year-old female who had cardiac arrest due to torsade de pointes triggered by exercise and leading to ventricular fibrillation, and a QTc of 520 ms (see 603830), Millat et al. (2006) identified biallelic digenic mutations: a 5455G-A transition in exon 28 of the SCN5A gene, resulting in an asp1819-to-asn (D1819N) substitution; and a missense mutation in the KCNH2 gene (R100G; 152427.0023).
In affected members of a 4-generation Han Chinese family with autosomal dominant cardiac arrhythmias and sudden death (BRGDA1; 601144), Niu et al. (2006) identified heterozygosity for a G-A transition in exon 24 of the SCN5A gene, resulting in a trp1421-to-ter (W1421X) substitution. The mutation was not found in 95 control subjects. An asymptomatic 73-year-old male family member was found to be compound heterozygous for W1421X and the R1993Q mutation (600163.0023). Niu et al. (2006) suggested that R1193Q, which results in a gain of sodium channel function, may compensate for the deleterious effects of W1421X.
In a man with dilated cardiomyopathy (CMD1E; 601154) and monomorphic ventricular tachycardia who later developed third-degree heart block requiring pacemaker implantation, Olson et al. (2005) identified heterozygosity for a 2-bp insertion (2550insTG) in exon 17 of the SCN5A gene, resulting in a premature stop codon and a truncated protein. Cardiac biopsy was normal. His father, who carried the mutation, was diagnosed with CMD (ejection fraction, 30%), left bundle branch block, and monomorphic ventricular tachycardia at age 67 years. The mutation was also present in a paternal uncle who had sinus bradycardia, first-degree heart block, and complete left bundle branch block; his paternal grandfather developed congestive heart failure at 50 years of age and died 6 years later, but DNA was unavailable for evaluation.
In a 7-year-old boy with early manifestations of dilated cardiomyopathy (CMD1E; 601154) including sinus bradycardia, left ventricular dilation, and normal contractile function, Olson et al. (2005) identified heterozygosity for a 4783G-C transversion in exon 27 of the SCN5A gene, resulting in an asp1595-to-his (D1595H) substitution at a highly conserved residue in the transmembrane domain. The mutation was found in DNA from postmortem tissue of a brother who died at 34 years of age with an autopsy diagnosis of cardiomyopathy and only mild coronary artery disease. The mutation was also identified in 2 sibs and a paternal uncle, all of whom had sinus bradycardia, and a paternal aunt with borderline left atrial enlargement. His father, an obligate mutation carrier, had atrial fibrillation and died at 49 years of age from pulmonary embolism; his paternal grandfather, a presumed mutation carrier, developed congestive heart failure at 70 years of age.
In a 45-year-old black man with no history of cardiac disease who developed monomorphic wide-complex ventricular tachycardia with right precordial ST segment elevation consistent with Brugada syndrome (BRGDA1; 601144) after the administration of lidocaine, Barajas-Martinez et al. (2008) identified 2 mutations in the SCN5A gene, a G-to-A transition in exon 6 of the SCN5A gene, resulting in a val232-to-ile (V232I) substitution in the C terminus of the transmembrane segment S4 of domain I, and a C-to-T transition in exon 22, resulting in a leu1308-to-phe (L1308F) substitution, in the C terminus of transmembrane segment S4 of domain III. Although L1308F had previously been identified as a polymorphism found mostly in Americans of African descent (Ackerman et al., 2004), Barajas-Martinez et al. (2008) did not find either mutation in over 400 alleles from 200 ethnically matched controls. The patient's parents were unavailable for study, but given the severity of his clinical manifestations, the authors strongly suspected that both mutations were on the same allele (Dumaine, 2009). Using patch-clamp techniques in mammalian TSA201 cells, Barajas-Martinez et al. (2008) observed use-dependent inhibition of I(Na) by lidocaine that was more pronounced in double-mutant channels than in wildtype; the individual mutations produced a much less accentuated effect. The authors concluded that the double mutation in SCN5A alters the affinity of the cardiac sodium channel for lidocaine such that the drug assumes class IC characteristics with potent use-dependent block of the sodium channel.
In a father and son with atrial fibrillation (ATFB10; 614022), Ellinor et al. (2008) identified heterozygosity for a 5958C-A transversion in the SCN5A gene, resulting in an asn1986-to-lys (N1986K) substitution in the C-terminal region of the protein. The mutation was not found in more than 600 ethnically and racially matched control chromosomes. Expression of the N1986K mutant in Xenopus oocytes revealed a hyperpolarizing shift in channel steady-state inactivation.
In white male proband who was diagnosed with paroxysmal lone atrial fibrillation (ATFB10; 614022) at 39 years of age, Darbar et al. (2008) identified heterozygosity for a G-to-C transversion in the SCN5A gene, resulting in a his445-to-asp (H445D) substitution at a highly conserved residue that was predicted to perturb cardiac sodium channel function. The proband had left atrial enlargement and an ejection fraction of 60% by transthoracic echocardiography. The mutation was also detected in his affected father and brother, but was not found in an unaffected sister or in 720 control alleles.
In a black male proband who was diagnosed with paroxysmal lone atrial fibrillation (ATFB10; 614022) at 17 years of age, Darbar et al. (2008) identified heterozygosity for a G-to-C transversion in the SCN5A gene, resulting in an asn470-to-lys (N470K) substitution at a highly conserved residue and predicted to perturb cardiac sodium channel function. The proband had left atrial enlargement with an ejection fraction of 60% by transthoracic echocardiography. The mutation was also detected in his affected mother and maternal grandmother, but was not found in an unaffected maternal aunt or in 720 control alleles.
In a white male proband who was diagnosed with paroxysmal lone atrial fibrillation (ATFB10; 614022) at 52 years of age, Darbar et al. (2008) identified heterozygosity for a A-to-G transition in the SCN5A gene, resulting in an glu428-to-lys (E428K) substitution at a highly conserved residue and predicted to perturb cardiac sodium channel function. The proband had left atrial enlargement with an ejection fraction of 58% by transthoracic echocardiography. The mutation was also detected in his affected daughter and granddaughter, but was not found in an unaffected daughter and granddaughter or in 720 control alleles.
In a white female proband who was diagnosed with paroxysmal lone atrial fibrillation (ATFB10; 614022) at 37 years of age, Darbar et al. (2008) identified heterozygosity for an A-to-G transition in the SCN5A gene, resulting in a glu655-to-lys (E655K) substitution at a highly conserved residue that was predicted to perturb cardiac sodium channel function. The proband had a normal-sized left atrium and ventricle with an ejection fraction of 55% by transthoracic echocardiography. The mutation was also detected in her affected daughter and maternal grandmother, but was not found in 720 control alleles.
In 6 affected members over 3 generations of a non-Hispanic white family with cardiomyopathy and conduction system disease (CMD1E; 601154), Hershberger et al. (2008) identified heterozygosity for a 36683G-A (numbering per SeattleSNP) transition in exon 6 of the SCN5A gene, resulting in an arg222-to-gln (R222Q) substitution at a conserved residue. The mutation was not found in unaffected family members or in 253 controls.
In 19 affected individuals from 3 unrelated 3-generation families with multifocal ectopic Purkinje-related premature contractions and dilated cardiomyopathy, Laurent et al. (2012) identified heterozygosity for the 665G-A (R222Q) mutation in the SCN5A gene, located in the voltage-sensing S4 segment of domain I. The mutation, which was fully penetrant and strictly segregated with the cardiac phenotype in each family, was not found in 600 control chromosomes; haplotype analysis showed that a founder effect for these 3 families was very unlikely. In vitro studies recapitulated the normalization of the ventricular action potentials in the presence of quinidine. Because only 6 of the 19 patients carrying the R222Q mutation had CMD, and the cardiomyopathy recovered at least partially with antiarrhythmia treatment and a reduction in the number of premature ventricular contractions, Laurent et al. (2012) suggested that CMD might be a consequence of the arrhythmia and not directly linked to the mutation.
In affected members of a 3-generation Canadian family with CMD and junctional escape ventricular capture bigeminy, Nair et al. (2012) identified the R222Q mutation in the SCN5A gene. Heterologous expression studies in Chinese hamster ovary K1 cells revealed a unique biophysical phenotype of R222Q channels in which an approximately 10-mV leftward shift in the sodium current steady-state activation curve occurs without corresponding shifts in steady-state inactivation at cardiomyocyte resting membrane-potential voltages. The activation and inactivation of cells expressing equimolar combinations of wildtype and R222Q channels showed properties intermediate between those seen in cells expressing either wildtype or mutant channels alone. The changes in mutant channel properties were predicted to produce hyperexcitability of R222Q sodium channels.
In 16 affected members over 3 generations of a large kindred with CMD and multiple arrhythmias, including premature ventricular complexes (PVCs) of variable morphology, Mann et al. (2012) identified heterozygosity for the R222Q mutation in the SCN5A gene. The mutation was also identified in 1 clinically unaffected family member, a 56-year-old man with a normal EKG and echocardiogram, but was not found in 200 control chromosomes. Patch-clamp studies showed that the R222Q mutation did not alter sodium channel current density, but did shift steady-state parameters of activation and inactivation to the left. Using a voltage ramp protocol, normalized current responses of mutant channels were of earlier onset and greater magnitude than wildtype. Action potential modeling using Purkinje fiber and ventricular cell models suggested that rate-dependent ectopy of Purkinje fiber origin is the predominant ventricular effect of the R222Q variant; this was supported by the clinical observation that PVC frequency increased during periods of low heart rate at rest and at night, and was reduced by high heart rates during exercise. Patients responded to sodium-channel blocking drugs with early and substantial reductions in PVCs followed by normalization of CMD over time.
In 3 affected members over 2 generations of an African American family with cardiomyopathy and conduction system disease (CMD1E; 601154), Hershberger et al. (2008) identified heterozygosity for a 99599T-C transition (numbering per SeattleSNP) in exon 28 of the SCN5A gene, resulting in an ile1835-to-thr (I1835T) substitution at a conserved residue. The mutation was not found in unaffected family members or in 253 controls.
In a Japanese boy with atrial standstill (ATRST1; 108770), Makita et al. (2005) identified coinheritance of a heterozygous c.635C-T transition in exon 6 of the SCN5A gene, resulting in a leu212-to-pro (L212P) substitution in the extracellular loop connecting transmembrane segments 3 and 4 of domain 1 of the Nav1.5 cardiac sodium channel, and heterozygous rare polymorphisms in the GJA5 gene (121013). The L212P mutation, which was also present in the proband's asymptomatic father, was not found in 400 control chromosomes. Functional analysis with the L212P mutant channels demonstrated large hyperpolarizing shifts in both the voltage dependence of activation and inactivation and delayed recovery from inactivation compared to wildtype. The asymptomatic father did not carry the rare polymorphisms in the GJA5 gene; the GJA5 polymorphisms were, however, present in heterozygosity in the proband's unaffected mother and maternal grandmother, who did not carry the L212P mutation.
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