Alternative titles; symbols
HGNC Approved Gene Symbol: SCN4A
SNOMEDCT: 304737009, 41574007, 702355008, 715788001, 715789009; ICD10CM: G71.12, G71.19, G72.3;
Cytogenetic location: 17q23.3 Genomic coordinates (GRCh38) : 17:63,938,554-63,972,918 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q23.3 | Congenital myopathy 22A, classic | 620351 | Autosomal recessive | 3 |
| Congenital myopathy 22B, severe fetal | 620369 | Autosomal recessive | 3 | |
| Hyperkalemic periodic paralysis | 170500 | Autosomal dominant | 3 | |
| Hypokalemic periodic paralysis, type 2 | 613345 | Autosomal dominant | 3 | |
| Myasthenic syndrome, congenital, 16 | 614198 | Autosomal recessive | 3 | |
| Myotonia congenita, atypical, acetazolamide-responsive | 608390 | Autosomal dominant | 3 | |
| Paramyotonia congenita | 168300 | Autosomal dominant | 3 |
The SCN4A gene encodes the alpha subunit of the skeletal muscle voltage-gated sodium channel Na(v)1.4. This channel is essential for the generation and propagation of the muscle action potential needed for muscle contraction (summary by Zaharieva et al., 2016).
Wang et al. (1992) deduced the amino acid sequence of the SCN4A gene from adult human skeletal muscle by cross-species PCR-mediated cloning and sequencing of the cDNA. The protein consists of 1,836 residues and shows 93% sequence identity to the alpha subunit from rat adult skeletal muscle and 70% identity to the alpha subunit from other mammalian tissues. Similar results were reported by George et al. (1992).
Bergareche et al. (2015) found expression of the SCN4A gene in mouse skeletal muscle and brain, as well as in human cerebral cortex, suggesting that it has a role in neuronal tissues.
McClatchey et al. (1992) and George et al. (1993) determined that the SCN4A gene contains 24 exons.
Fontaine et al. (1990) cloned portions of the adult SCN4A gene and localized it to chromosome 17 using somatic cell hybrids. One of the probes used in this study showed hybridization also to chromosome 3, probably indicating cross-hybridization with the fetal gene. Using RFLPs, they found that the SCN4A gene was closely linked to the growth hormone gene (GH1; 139250) on 17q (maximum lod = 9.89 at theta = 0.00). Furthermore, with very high odds, the gene was placed between NGFR (162010) and TK1 (188300).
Using clones of the SCN4A gene, George et al. (1991) found a regional assignment of 17q23.1-q25.3 by study of somatic cell hybrids that retained various portions of human chromosome 17. The growth hormone gene cluster (139250), which spans 47 kb, was assigned to 17q22-q24. Bennani-Baiti et al. (1995) demonstrated that the GH gene cluster and the SCN4A gene colocalized to a single 525-kb YAC. Furthermore, restriction mapping and sequencing demonstrated that the SCN4A gene and the entire GH gene cluster are contained within 100 kb on chromosome 17 and are separated by only 21.5 kb. Remarkably, Bennani-Baiti et al. (1995) found that multiple elements critical to tissue-specific transcriptional activation of the GH gene lie within the SCN4A gene.
Heterozygous missense mutations in the SCN4A gene have been identified in a group of related muscular disorders, including hyperkalemic periodic paralysis (HYPP; 170500), paramyotonia congenita (PMC; 168300), a group of disorders classified as potassium-aggravated myotonia (608390), and hypokalemic periodic paralysis type 2 (HOKPP2; 613345). These mutations result in a gain-of-function effect via different mechanisms. Less commonly, biallelic loss-of-function or hypomorphic mutations in the SCN4A gene cause congenital myasthenic syndrome-16 (CMS16; 614198), classic congenital myopathy-22A (CMYO22A; 620351), and severe fetal congenital myopathy-22B (CMYO22B; 620369). The severity of the disorder seems to correlate with the detrimental effect of the mutation on SCN4A function (Cannon, 2016).
Ackerman and Clapham (1997) gave a comprehensive review of the role of ion channel defects in disease and provided figures illustrating the physiology and structure of ion channels and patch-clamp measurement of ion channel activity.
Hyperkalemic Periodic Paralysis
In 3 of 7 unrelated patients with HYPP (170500), Ptacek et al. (1991) identified the same mutation in the SCN4A gene (T704M; 603967.0001). In 9 of 12 families with HYPP, Feero et al. (1993) identified mutations in the SCN4A gene: 3 families had the M1592V mutation (603967.0002) and 6 had the T704M mutation. No mutation was identified in 3 families, 1 of whom did not show linkage to the SCN4A gene, suggesting genetic heterogeneity. Jurkat-Rott et al. (2000) stated that 5 mutations in the SCN4A gene had been reported in HYPP patients, none of which was directly located in the voltage sensors.
Paramyotonia Congenita
In patients with paramyotonia congenita (163800), McClatchey et al. (1992) identified 2 point mutations in the III-IV cytoplasmic loop region of the SCN4A gene (603967.0007-603967.0008), and suggested that these are the first known examples of molecular definition of temperature-sensitive mutations. The authors postulated that the mutations restrict the channel movement in response to transmembrane potential, and that even a minor drop in temperature may impede movement of the loop enough to allow an abnormal sodium flux.
Gay et al. (2008) reported a female infant with severe fatal neonatal nondystrophic myotonia in whom they identified a heterozygous mutation (N1297K; 603967.0027) in the SCN4A gene. The phenotype showed overlapping features of paramyotonia congenita and hyperkalemic periodic paralysis.
Myotonia, Potassium-Aggravated
Lerche et al. (1993) identified heterozygous mutations in the same codon of the SCN4A gene (G1306V, 603967.0007; G1306A, 603967.0012; and G1306E, 603967.0025) in patients with exercise and potassium-aggravated myotonia, myotonia fluctuans, and myotonia permanens, respectively (see 608390). Patch-clamp recordings on patient muscle samples showed slower sodium fast channel inactivation and an increase in late channel opening, resulting in a steady-state inward current, sustained muscle depolarization, and muscle fiber hyperexcitability. The findings indicated that SCN4A residue 1306 is important for sodium channel inactivation.
In a family with dominantly inherited potassium-aggravated myotonia (608390), Orrell et al. (1998) found a heterozygous mutation in the SCN4A gene (603967.0009). The myotonic phenotype was characterized by painful cramps, stiffness without weakness, fluctuation of symptoms, and cold sensitivity.
Hypokalemic Periodic Paralysis
In 4 affected individuals of family with hypokalemic periodic paralysis, Bulman et al. (1999) identified a heterozygous missense mutation in the SCN4A gene (603967.0015). In several families with HOKPP in which defects of the CACNL1A3 gene (CACNA1S; 114208) had been excluded, Jurkat-Rott et al. (2000) identified 2 heterozygous disease-causing missense mutations in the SCN4A gene (603967.0016-603967.0017). This form of HOKPP did not differ clinically from the form of the disorder due to mutations in the gene for CACNL1A3.
Sokolov et al. (2007) showed that, in contrast with the well-established paradigm in which alterations in control of ion conductance through the central pore of ion channels impair cell function, 3 mutations in gating charge-carrying arginine residues in an S4 segment that cause hypokalemic periodic paralysis (HOKPP) induce a hyperpolarization-activated cationic leak through the voltage sensor of the skeletal muscle Nav1.4 channel. This gating pore current is active at the resting membrane potential and closed by depolarizations that activate the voltage sensor. It has similar permeability to sodium, potassium, and cesium ions, but the organic monovalent cations tetraethylammonium and N-methyl-D-glucamine are much less permeant. The inorganic divalent cations barium, calcium, and zinc are not detectably permeant and block the gating pore at millimolar concentrations. Sokolov et al. (2007) concluded that their results revealed gating pore current in naturally occurring disease mutations of an ion channel and showed a clear correlation between mutations that cause gating pore current and hypokalemic periodic paralysis. This gain-of-function gating pore current would contribute in an important way to the dominantly inherited membrane depolarization, action potential failure, flaccid paralysis, and cytopathology that are characteristic of hypokalemic periodic paralysis. Sokolov et al. (2007) postulated that their observations might be generalizable to other ion channelopathies.
Matthews et al. (2009) identified mutations in the CACNA1S (114208) or SCN4A gene in 74 (almost 90%) of 83 patients with HOKPP. All of the mutations, including 3 novel mutations, affected arginine residues in the S4 voltage sensing region in 1 of the transmembrane domains of each gene. The most common CACNA1S mutations affected residues arg528 (25 cases) and arg1239 (39 cases) (see, e.g., R1239H; 114208.0001 and R528H; 114208.0003). The most common SCN4A mutations affected residues arg672 (see, e.g., 603967.0016) and arg1132. The findings supported the hypothesis that loss of positive charge in S4 voltage sensors is important to the pathogenesis of this disorder. (Sokolov et al., 2007).
Francis et al. (2011) demonstrated that an R1132Q mutation (603967.0030) in the domain III voltage sensor domain of SCN4A found in a family with HOKPP created an anomalous gating pore current similar to that observed by Sokolov et al. (2007). This current is sufficient to depolarize and render the muscle fiber inexcitable particularly during low external potassium. The findings suggested a mechanism for loss of sarcolemmal excitability during attacks of weakness in HOKPP. In contrast, the R1148C mutation (603967.0003) causing PMC does not result in gating pore abnormalities.
Congenital Myasthenic Syndrome 16
In a patient with congenital myasthenic syndrome-16 (CMS16; 614198) associated with fatigable generalized weakness and recurrent attacks of respiratory and bulbar paralysis since birth, Tsujino et al. (2003) identified compound heterozygous variants in the SCN4A gene (V1442E, 603967.0018 and S246L, 603967.0031).
In a 57-year-old woman, born of consanguineous parents, with CMS16, Arnold et al. (2015) identified a homozygous missense mutation in the SCN4A gene (R1457H; 603967.0032). In vitro electrophysiologic studies showed that the mutation caused a 25-mV hyperpolarizing shift in the voltage dependence of inactivation, resulting in enhanced fast inactivation as well as slowed recovery from fast inactivation. In addition, repetitive stimuli elicited markedly weaker current responses. These changes resulted in reduced channel availability, which could explain the patient's muscle weakness. The unaffected parents and sibs were heterozygous for the mutation.
In a 26-year-old Lebanese woman, born of consanguineous parents, with CMS16 and features of normokalemic periodic paralysis, Habbout et al. (2016) identified a homozygous missense mutation in the SCN4A gene (R1454W; 603967.0041). Each unaffected parent was heterozygous for the mutation. In vitro functional expression studies showed that the mutation resulted in a loss-of-function effect, with slowed current decay, slowed fast inactivation, and increased activation time compared to wildtype. Slowed inactivation was also disturbed. Current density was not affected, but there was a decrease in current amplitude in response to repetitive stimulation above 10 Hz. The findings thus showed a combination of gating behaviors that favor the inactivation state; defective inactivation may induce fatigable weakness during muscle firing.
Congenital Myopathy 22A, Classic
In 8 patients from 4 unrelated families (families 1-4) with classic congenital myopathy-22A (CMYO22A; 620351), Zaharieva et al. (2016) identified homozygous or compound heterozygous mutations in the SCN4A gene (see, e.g., 603967.0034-603967.0035). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. There were missense, nonsense, frameshift, and splice site mutations distributed throughout the gene. Electrophysiologic studies of the missense variants in HEK293 cells showed that they caused a loss-of-function effect of varying degrees. All patients carried 1 mutation that resulted in a completely nonfunctional channel in combination with a hypomorphic allele. None of the carrier parents was affected, indicating that loss of function in only 1 SCN4A allele is insufficient to cause a clinical phenotype.
In 2 brothers, born of unrelated parents of East Indian descent, with CMYO22A, Gonorazky et al. (2017) identified compound heterozygous missense mutations in the SCN4A gene (C375R, 603967.0039 and R1142Q, 603967.0040). The mutations, which were found by exome sequencing, segregated with the disorder in the family. In vitro electrophysiologic studies in HEK293 cells showed that the C375R mutation abolished sodium activity and caused a complete loss of SCN4A function, whereas the R1142Q mutation was hypomorphic with reduced peak current densities due to a 4-mV depolarizing shift of activation. Fast inactivation properties of the R1142Q mutant channel were also mildly affected.
In an 18-year-old girl, born of unrelated parents, with CMYO22A, Berghold et al. (2022) identified compound heterozygous missense mutations in the SCN4A gene (R1454W, 603967.0041 and N1205K, 603967.0042). The mutations, which were found by whole-exome sequencing, were inherited from the unaffected parents. R1454W, located in the voltage sensor of domain IV, had been demonstrated to be a loss-of-function variant by Habbout et al. (2016). The N1205K, located in a region forming the channel pore, was a novel variant. Functional studies of N1205K were not performed, but it was predicted to cause a loss of function based on studies of paralogous variants in other SCNA genes.
Congenital Myopathy 22B, Severe Fetal
In 6 patients from 2 unrelated families (families 5 and 6) with severe fetal congenital myopathy-22B (CMYO22B; 620369) resulting in death in utero or in the perinatal period, Zaharieva et al. (2016) identified homozygous or compound heterozygous mutations in the SCN4A gene. Three sibs in family 5 carried a homozygous missense mutation (P382T; 603967.0036) that was demonstrated to result in a complete loss of function with no detectable sodium current when expressed in HEK293 cells. Three sibs in family 6 were compound heterozygous for a missense mutation (M203K; 603967.0037) that was demonstrated to have a hypomorphic effect on channel function, and a nonsense mutation (Y1593X; 603967.0038) that was predicted to result in a complete loss of channel function. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. None of the carrier parents was affected, indicating that loss of function in only 1 SCN4A allele is insufficient to cause a clinical phenotype.
Associations Pending Confirmation
For discussion of a possible association between essential tremor (see, e.g., ETM1, 190300) and variation in the SCN4A gene, see 603967.0033.
Rudolph et al. (1992, 1992) identified a mutation in the SCN4A gene in Quarter horses with HYPP (see 170500).
Hayward et al. (2008) introduced a missense substitution corresponding to the human M1592V mutation into the mouse Scn4a gene and found that few homozygous mutant (m/m) mice survived and those that did showed fixed limb weakness, muscle atrophy, and abnormal muscle morphology. Heterozygous (+/m) mice showed only a mild myopathy at 4 months of age, but myopathic changes developed with age and included electrical myotonia, fiber type switching to a more oxidative type, size variation, and internalized nuclei, and +/m muscle developed less tetanic force and exhibited slower relaxation compared with muscle from wildtype controls. Rapid and sustained weakness of isolated mutant muscle was induced when the extracellular K+ concentration was increased to that observed in exercising human muscle interstitium, and weakness was exacerbated by lowering extracellular Ca(2+) and by partial inhibition of the Na+/K+ pump. Mutant muscle recovered from stimulation-induced fatigue more slowly than did control muscle, particularly in the presence of high extracellular K+. Hayward et al. (2008) concluded that this myotonia is consistent with persistent Na+ influx through the noninactivating mutant Na+ channel that mildly depolarizes the membrane and thereby increases excitability.
Wu et al. (2016) found that mice homozygous for a null Scn4a allele (exon 12 deletion) did not survive beyond postnatal day 2. Heterozygous mutant mice showed no gross motor deficits. Electrophysiologic studies in heterozygous mice showed that the sodium current amplitude was decreased about 2-fold and subtle myasthenic features were observed on repetitive stimulation at high frequencies. The myasthenic features were termed 'pseudo-myasthenic' because the defect resided in the intrinsic excitability of the muscle fiber rather than at the postsynaptic endplate potential. Heterozygosity for the loss-of-function allele was not sufficient to cause hypokalemic periodic paralysis.
In 3 of 7 unrelated patients with hyperkalemic periodic paralysis (HYPP; 170500), Ptacek et al. (1991) identified a heterozygous C-to-T change at a CpG dimer in the SCN4A gene, resulting in a thr704-to-met (T704M) substitution in S5 of domain II in the membrane-spanning segment of the sodium channel protein. All 3 patients had prominent fixed muscle weakness, whereas the remaining 4 did not. In 2 of the families, the mutation cosegregated with HYPP; in the third it appeared to be a de novo mutation. The authors noted that threonine-704 is absolutely conserved in sodium channel genes across highly divergent species.
Sillen et al. (1996) found the T704M mutation in 2 Swedish families with HYPP. The mutation was linked to different microsatellite alleles, suggesting that the mutation may have arisen independently in the 2 families.
In a family with features of both HYPP and paramyotonia congenita (PMC; 168300), which the authors termed 'paralysis periodica paramyotonica,' Kim et al. (2001) identified the T704M mutation. Both exercise sensitivity and temperature sensitivity were present, and the authors commented on the phenotypic variation resulting from this mutation.
In an Italian kindred in which 9 members were affected with a severe form of HYPP/PMC, Brancati et al. (2003) found the T704M mutation. Onset of the disorder was in the first months of life in all affected patients and the episodes of paralysis increased in severity and frequency, sometimes up to several times a day, with age.
Miller et al. (2004) identified the T704M mutation in affected members of 10 kindreds with HYPP. All patients had onset before 1 year of age and overall showed only a 50% chance of favorable response to acetazolamide.
Hisama (2005) described a 7-generation family in which multiple members were affected with a complicated neurologic phenotype including variable features of neuropathy, myotonia, and periodic paralysis. The same family had been described in the medical literature since 1934. The proband had late-onset demyelinating Charcot-Marie-Tooth disease (CMT1B; 118200), muscle cramping, and myotonia. His sister had HYPP, and his father had severe childhood-onset CMT and periodic paralysis. Multiple other relatives had similar features of 1 or both disorders. Molecular analysis identified a missense mutation in the MPZ gene (159440) in the proband and the SCN4A T704M mutation in the sister; the father was deceased. One other family member tested had the MPZ mutation, and 4 other family members had the SCN4A mutation. Hisama (2005) commented on the unusual occurrence of 2 genetically unlinked neurologic disorders in this family and emphasized the diagnostic difficulties.
In a patient with familial hyperkalemic periodic paralysis (HYPP; 170500), Rojas et al. (1991) identified a heterozygous A-to-G transition in the SCN4A gene, resulting in a met-to-val substitution in a highly conserved region of the alpha subunit, predicted to be in S6 of transmembrane domain IV. The same change was found as a new mutation in a sporadic case. Rojas (1992) stated that the transition occurred at nucleotide 4774 and changed met to val at residue 1592 (M1592V). Heine et al. (1993) found the M1592V mutation in 6 families with a myotonic, nondystrophic form of HYPP.
Kelly et al. (1997) described a large kindred in which affected members were phenotypically heterogeneous with episodic potassium-sensitive paralysis as well as stiffness and weakness induced by exercise and cold, suggesting a combined paramyotonia congenita (PMC; 168300)/HYPP phenotype. Affected members had a heterozygous M1592V mutation, and the authors commented on the phenotypic variation associated with this mutation.
In a family with paramyotonia congenita (PMC; 168300), Ptacek et al. (1992) identified a heterozygous mutation in the SCN4A gene, resulting in an arg1448-to-cys (R1448C) substitution. This codon is a highly conserved residue in the S4 helix of domain IV in the adult skeletal muscle sodium channel.
In 2 other families with PMC, Ptacek et al. (1992) found a heterozygous mutation in the same codon, resulting in an arg1448-to-his (R1448H) substitution (see 603967.0004).
In 2 families with paramyotonia congenita (PMC; 168300), Ptacek et al. (1992) found a heterozygous mutation in the SCN4A gene, resulting in an arg1448-to-his (R1448H) substitution.
Meyer-Kleine et al. (1994) found that the R1448H mutation is exceptionally frequent in the Ravensberger Land region of northwest Germany, where it exists on a specific SCN4A microsatellite haplotype, indicating a founder effect within this subpopulation.
In a family of Finnish extraction whose affected members displayed an unusual mixture of clinical features of both paramyotonia congenita (PMC; 168300) and hyperkalemic periodic paralysis (HYPP; 170500), McClatchey et al. (1992) identified a heterozygous c.3466G-A transition in the SCN4A gene, resulting in an ala1156-to-thr (A1156T) substitution.
In affected members of an Italian family with features of both paramyotonia congenita (PMC; 168300) and myotonia congenita (see 608390), McClatchey et al. (1992) identified a heterozygous c.2411C-T transition in the SCN4A gene, resulting in a ser804-to-phe (S804F) substitution predicted to be in the cytoplasmic face of the sixth transmembrane segment of domain II. A serine had been present at this position in all sodium channels sequenced to that date.
Ricker et al. (1994) found the S804F mutation in a family with the 'myotonia fluctuans' (608390) phenotype. See also 603967.0012.
In a Belgian family with paramyotonia congenita (PMC; 168300), McClatchey et al. (1992) identified a heterozygous c.3917G-T transversion in the SCN4A gene, resulting in a gly1306-to-val (G1306V) substitution. The mutation affected a highly conserved residue in the III-IV cytoplasmic loop, a portion of the sodium channel thought to pivot in response to membrane depolarization, thereby blocking and inactivating the channel. Muscle weakness was not reported. The authors suggested that this is a temperature-sensitive mutation.
Lerche et al. (1993) identified a heterozygous G1306V substitution in a mother and son with potassium-aggravated myotonia (608390). Muscle stiffness in these individuals was also aggravated by exercise, but not by cold. Muscle weakness was not reported. Patch-clamp recordings on patient muscle samples showed slower sodium fast channel inactivation and an increase in late channel opening, resulting in a steady-state inward current, sustained muscle depolarization, and muscle fiber hyperexcitability. Lerche et al. (1993) identified different pathogenic mutations in the same codon (G1306A; 603967.0012 and G1306E; 603967.0025) in other families with similar disorders, indicating that residue 1306 is important for sodium channel inactivation.
Dupre et al. (2009) reported French Canadian patients with myotonia associated with the G1306V mutation. They had moderate myotonia with mild muscle hypertrophy. They noted exacerbation of symptoms with cold temperatures but no paradoxical myotonia. Female patients showed dramatic symptom improvement after menopause.
In a family with paramyotonia congenita (PMC; 168300) living in North America, McClatchey et al. (1992) identified a heterozygous C-to-T transition in the SCN4A gene, resulting in a thr1313-to-met (T1313M) substitution. The mutation affected a highly conserved residue in the III-IV cytoplasmic loop of the protein.
Tahmoush et al. (1994) identified the T1313M mutation in a 3-generation paramyotonia congenita family with 5 affected individuals. Single-channel recordings of normal and abnormal sodium channels in myotubes in tissue-cultured muscles derived from the proband showed that abnormal sodium channels at 22 degrees centigrade exhibited long duration and late openings.
Yamada et al. (1995) found the same mutation in a Japanese woman and her son who had PMC manifested by difficulty in closure of eyelids or chewing, and stiffness and weakness in hands aggravated by cold beginning at about 7 years of age.
Matthews et al. (2011) reported a family with PMC due to the heterozygous T1313M mutation. Before correct diagnosis, the youngest affected individual presented with neonatal inspiratory stridor and poor feeding. Laryngoscopy showed findings consistent with laryngomalacia. He continued to have stridor for the first 6 months of life, and later motor milestones were mildly delayed. In early childhood, he was noted to have frequent episodic muscle weakness and stiffness associated with cold weather. At age 4 years, he continued to have episodes of inspiratory stridor exacerbated by viral illness, cold weather, and prolonged laughing or crying. His mother, grandfather, and great-uncle reported similar episodes of muscle stiffness and weakness exacerbated by cold and exercise.
In a father and daughter (family SCM8) with potassium-aggravated myotonia (608390) without muscle weakness, Heine et al. (1993) identified a heterozygous c.4765G-A transition in exon 24 of the SCN4A gene, predicted to result in a val1589-to-met (V1589M) substitution. The family had previously been reported by Iaizzo et al. (1991) as family MyC2. The myotonia in this family was aggravated by both cold and potassium loading, similar to paramyotonia congenita (PMC; 168300). The mutation is located within transmembrane segment S6 of channel repeat IV close to the cytoplasmic surface, a region thought to act as acceptor of the inactivation gate of the channel. An increase in the number of noninactivating sodium channels had been demonstrated in earlier electrophysiologic studies on excised muscle from the index patient. The nearby M1592V (603967.0002) mutation causes hyperkalemic periodic paralysis (170500) of the myotonic, nondystrophic form.
Orrell et al. (1998) identified the V1589M mutation in a family in which 9 members spanning 4 generations had cramps in the fingers, toes, and eyelids, consistent with potassium-aggravated myotonia. A reduction in amplitude of compound muscle action potential on cooling and administration of potassium was demonstrated. The authors noted that the phenotype in this family was milder than that in the family reported by Heine et al. (1993).
In a patient with acetazolamide-responsive myotonia congenita without periodic paralysis (see 608390), Ptacek et al. (1994) identified a heterozygous c.3555A-G transition in the SCN4A gene, predicted to result in an ile1160-to-val (I1160V) substitution. This isoleucine is a highly conserved residue, cosegregated with the disease phenotype in one studied kindred, and was not present in samples from 100 unrelated unaffected individuals.
Ptacek et al. (1993) reported that a heterozygous leu-to-arg (L1433R) change in the SCN4A gene results in the paramyotonia congenita (PMC; 168300) phenotype.
In affected members of 3 families with a muscle sodium channel disorder termed 'myotonia fluctuans' (see 608390), Ricker et al. (1994) identified a heterozygous c.3917G-C transversion in exon 22 of the SCN4A gene, resulting in a gly1306-to-ala (G1306A) substitution. The mutation resides in the region of the sodium channel protein containing the cytoplasmic loop between domains 3 and 4. The phenotype consists of fluctuating myotonia of varying severity, a warm-up phenomenon, worsening of myotonia after potassium loading, increased myotonia of delayed onset following exercise, and no significant increase of myotonia following exposure to cold. Muscle weakness did not occur. One other family with the same phenotype had a previously described mutation of the sodium channel (603967.0006).
Lerche et al. (1993) identified the G1306A mutation in a patient with myotonia fluctuans. Patch-clamp recordings on patient muscle samples showed slower sodium fast channel inactivation and an increase in late channel opening, resulting in a steady-state inward current, sustained muscle depolarization, and muscle fiber hyperexcitability. Lerche et al. (1993) identified different pathogenic mutations in the same codon (G1306V; 603967.0007 and G1306E; 603967.0025) in other families with similar disorders, indicating that residue 1306 is important for sodium channel inactivation.
In 3 unrelated 3-generation families segregating paramyotonia without cold paralysis (see 168300) as an autosomal dominant trait, Koch et al. (1995) identified a heterozygous c.3877G-A transition in exon 21 of the SCN4A gene, resulting in a val1293-to-ile (V1293I) substitution. The amino acid alteration was not found to be a mild polymorphism in their survey of 200 chromosomes from the German population. The predicted mutation was located at the intracellular phase of segment S6 in domain III of the channel protein. Val1293 is conserved in human, rat, and eel.
Rosenfeld et al. (1997) reported the first known mutation in the first repeat domain (D1) of the SCN4A gene. The previous conspicuous absence of mutations in this region fueled speculation that mutations in this domain were either inconsequential or possibly lethal. The heterozygous mutation, val445-to-met (V445M), was associated with an unusual form of painful congenital myotonia (see 608390). The distinctive phenotype suggested that the pattern of sodium channel dysfunction might also be unique.
Wang et al. (1999) characterized the V445M mutation using heterologous expression of recombinant mutant and wildtype skeletal muscle sodium channel alpha subunits. Their findings established that the mutation causes a defect in sodium channel gating that is compatible with a myotonia-producing lesion. The pattern of dysfunction was distinct from other muscle sodium channel mutations, supporting the notion that D1 sodium channel mutations may be associated with unusual phenotypes. They also demonstrated that flecainide effectively suppressed the abnormal channel behavior, consistent with the observed clinical efficacy of the drug in treating the unusual form of myotonia.
Dupre et al. (2009) reported French Canadian patients with the V445M mutation. The phenotype was characterized by severe and painful generalized myotonia and severe muscle hypertrophy. Ethanol or mexiletine significantly alleviated myotonia in 1 patient.
Bulman et al. (1999) found a heterozygous arg669-to-his (R669H) mutation in the SCN4A gene in a family in which 4 members had hypokalemic periodic paralysis type 2 (HOKPP2; 613345).
By in vitro studies, Kuzmenkin et al. (2002) showed that the R669H mutation caused enhanced fast and slow inactivation of the SCN4A sodium channel. The inactivation defect could be alleviated by decreased pH, which may explain why some patients have relief by some physical exercise.
In affected members of 3 unrelated families (HypoPP29, HypoPP18, and HypoPP105) with hypokalemic periodic paralysis type 2 (HOKPP2; 613345), Jurkat-Rott et al. (2000) identified a heterozygous c.2016G-A transition in exon 12 of the SCN4A gene, resulting in an arg672-to-his (R672H) substitution in the voltage sensor of domain-2.
By in vitro studies in HEK293 cells, Kuzmenkin et al. (2002) showed that the R672H mutation caused enhanced fast inactivation of the SCN4A sodium channel. The inactivation defect could be alleviated by decreased pH, which may explain why some patients have relief by some physical exercise.
In affected members of 2 multigenerational families (HypoPP106 and HypoPP6) with hypokalemic periodic paralysis type 2 (HOKPP2; 613345), Jurkat-Rott et al. (2000) identified a heterozygous c.2015C-G transversion in the SCN4A gene, resulting in an arg672-to-gly (R672G) substitution in the voltage sensor of domain-2. Excised skeletal muscle fibers from a patient heterozygous for R672G displayed depolarization and weakness in low-potassium extracellular solution. Slowing and smaller size of action potentials were suggestive of excitability of the wildtype channel population only. Alterations found were decisive for the pathogenesis of episodic muscle weakness by reducing the number of excitable sodium channels, particularly at sustained membrane depolarization. This form of the disease was caused by enhanced channel inactivation and current reduction, and showed no myotonia.
By in vitro studies in HEK293 cells, Kuzmenkin et al. (2002) showed that the R672G mutation caused enhanced slow and fast inactivation of the SCN4A sodium channel.
In a patient with a congenital myasthenic syndrome-16 (CMS16; 614198) associated with fatigable generalized weakness and recurrent attacks of respiratory and bulbar paralysis since birth, Tsujino et al. (2003) detected compound heterozygosity for 2 variants in the SCN4A gene involving conserved residues not present in 400 normal alleles: a c.4325T-A transversion, resulting in a val1442-to-glu (V1442E) substitution in the S3/S4 extracellular linker in domain IV, and a c.737C-T transition, resulting in a ser246-to-leu (S246L; 603967.0031) change in the S4/S5 cytoplasmic linker in domain I. The genetically engineered V1442E sodium channel expressed in cultured cells showed marked enhancement of fast inactivation close to the resting potential, and enhanced use-dependent inactivation on high-frequency stimulation. The proband's asymptomatic mother and sister were heterozygous for the S246L mutation. Paternal DNA was unavailable for analysis. The authors considered S246L likely to be a benign polymorphism, whereas the V1442E mutation defines a novel disease mechanism and a novel phenotype with myasthenic features. Tsujino et al. (2003) concluded that the inheritance pattern of this congenital myasthenic syndrome could not be unambiguously established. They suggested that the more severe V1442E mutation may be dominant, but it could not be proven because the mutation was observed only in combination with S246L on the other chromosome.
In a large Japanese family with paramyotonia congenita (PMC; 168300), Sasaki et al. (1999) identified a heterozygous c.4367G-A change in exon 24 of the SCN4A gene, resulting in a gly1456-to-glu (G1456E) substitution in S4 of domain IV of the channel. Only 3 of 9 affected members reported episodes of severe generalized weakness, which were always after cold exposure.
In a family with PMC without periodic paralysis, which the authors termed 'pure paramyotonia,' Davies et al. (2000) identified the G1456E mutation. The authors predicted that the mutation would impair voltage sensing or channel inactivation in a temperature-dependent fashion and concluded that exon 24 is a hotspot for paramyotonia mutations.
In the proband of a family with hypokalemic periodic paralysis type 2 (HOKPP2; 613345), Davies et al. (2001) identified a heterozygous c.2014C-A change in exon 12 of the SCN4A gene, resulting in an arg672-to-ser (R672S) substitution. The patient responded well to acetazolamide. The authors noted that 2 other mutations in the same codon had been reported in HOKPP (see 603967.0016 and 603967.0017).
Functional expression studies of the R672S sodium channel by Bendahhou et al. (2001) showed a small but significant hyperpolarizing shift in the steady-state fast inactivation, and a dramatic enhancement in channel slow inactivation. The defects are mainly due to a slow recovery of the mutant channels from inactivation. The authors noted that their patient with this mutation had shown a worsening of symptoms from acetazolamide.
Venance et al. (2004) reported a sporadic patient with HOKPP and the R672S mutation who responded well to acetazolamide. The authors noted the variability in response to the drug and suggested that carbonic anhydrase inhibitors should be considered in patients with HOKPP.
In a Japanese family with an unusual form of hypokalemic periodic paralysis type 2 (HOKPP2; 613345), Sugiura et al. (2000) identified a heterozygous c.3472C-T transition in exon 19 of the SCN4A gene, resulting in a pro1158-to-ser (P1158S) substitution between the fourth and fifth transmembrane segments of domain III. The phenotype in this family was unusual in that affected members showed heat-induced myotonia and cold-induced paralysis with hypokalemia. Myotonia lessened with exercise and was alleviated by cold, thus distinguishing the myotonia from paramyotonia congenita (PMC; 168300). Treatment with acetazolamide alleviated the myotonia, but slightly worsened the paralysis. Patients showed seasonal swings with myotonia in the summer and paralysis in the winter, with hypokalemia during the paralytic attacks.
By functional studies, Sugiura et al. (2003) showed that the P1158S mutation exhibited temperature-dependent negative shifts in the voltage dependence of activation and inactivation as well as a slower rate of inactivation compared to wildtype.
In 5 affected members of a family with potassium-sensitive normokalemic periodic paralysis (see HYPP, 170500), Vicart et al. (2004) identified a heterozygous C-to-G transversion in exon 13 of the SCN4A gene, resulting in an arg675-to-gly (R675G) substitution within the membrane-spanning segment S4 of domain II of the protein, which is known to be involved in the voltage sensing of the channel. Acetazolamide therapy was effective in almost all patients.
Vicart et al. (2004) noted that mutations affecting codon 672--R672H (603967.0016), R672G (603967.0017), and R672S (603967.0020)--and codon 669 (R669H; 603967.0015) affect 2 nearby arginines in segment S4 of domain II and lead to hypokalemic periodic paralysis type 2 (HOKPP2; 613345).
In affected members of a family with potassium-sensitive normokalemic periodic paralysis (see HYPP, 170500), Vicart et al. (2004) identified a heterozygous arg675-to-gln (R675Q) substitution in the SCN4A gene.
In affected members of a family with potassium-sensitive normokalemic periodic paralysis (see HYPP, 170500), Vicart et al. (2004) identified a heterozygous arg675-to-trp (R675W) mutation in the SCN4A gene.
In a woman with severe myotonia permanens (608390), Lerche et al. (1993) identified a heterozygous c.3917G-A transition in the SCN4A gene, resulting in a gly1306-to-glu (G1306E) substitution in the III-IV linker region of the protein. Patch-clamp recordings on patient muscle samples showed slower sodium fast channel inactivation and an increase in late channel opening, resulting in a steady-state inward current, sustained muscle depolarization, and muscle fiber hyperexcitability. Lerche et al. (1993) identified different pathogenic mutations in the same codon (G1306V; 603967.0007 and G1306A; 603967.0012) in other families with similar disorders, indicating that residue 1306 is important for sodium channel inactivation.
Colding-Jorgensen et al. (2006) identified a heterozygous G1306E substitution in a father and son with myotonia permanens. The authors noted that the mutation may interfere with the channel voltage sensor.
In 44 patients from 11 French Canadian families with a myotonia phenotype most consistent with paramyotonia congenita (PMC; 168300), Rossignol et al. (2007) identified a heterozygous 4428G-A transition in the SCN4A gene, resulting in a met1476-to-ile (M1476I) substitution in a highly conserved residue of the domain IV cytoplasmic loop, which is known to be involved in fast inactivation. The patients originated from the Saguenay-Lac-Saint-Jean region with notable clustering around Saint-Felicien. Haplotype analysis indicated a founder effect. The phenotype was quite variable, with age at onset ranging from 5 to 67 years (mean, 21 years) and mild to severe symptoms. Eleven (25%) patients were asymptomatic despite myotonic discharges on EMG. The most consistent features were cold-induced myotonia (41%) and painful myotonia (18%). Potassium challenge was not conducted.
In a female infant with severe fatal neonatal nondystrophic myotonia with overlapping features of paramyotonia congenita (PMC; 168300) and hyperkalemic periodic paralysis (HYPP; 170500), Gay et al. (2008) identified a de novo heterozygous 3891C-A transversion in exon 21 of the SCN4A gene, resulting in an asn1297-to-lys (N1297K) substitution in the interdomain loop III-IV. The mutation was not found in either parent or in 100 controls.
In 6 patients from 4 unrelated European families with paramyotonia congenita (PMC; 168300), Matthews et al. (2008) identified a heterozygous mutation in the SCN4A gene, resulting in an ile693-to-thr (I693T) substitution in the domain II S4-5 cytoplasmic loop. All the patients presented with transient neonatal hypotonia, in some cases requiring feeding or respiratory assistance, and later developed classic PMC by age 5 years. Earlier generations of 3 of the families reported a history of PMC without neonatal hypotonia. The findings expanded the phenotypic spectrum of PMC to include neonatal hypotonia.
In affected members of a family with a phenotype consistent with paramyotonia congenita (PMC; 168300), Petitprez et al. (2008) identified a heterozygous A-to-G transition in exon 4 of the SCN4A gene, resulting in an ile141-to-val (I141V) substitution in the first transmembrane segment of domain I. The patients had myotonia without muscle weakness. The mutation was not identified in unaffected family members and 100 control individuals. In vitro functional expression studies showed that the mutant protein resulted in a hyperpolarizing shift of the activation curve, with concomitant increase in window current amplitude, suggestive of a gain of function. The studies also showed enhanced slow inactivation, which may have prevented weakness.
In affected members of a 3-generation family with hypokalemic periodic paralysis type 2 (HOKPP2; 613345), Carle et al. (2006) identified a heterozygous 3395G-A transition in exon 18 of the SCN4A gene, resulting in an arg1132-to-gln (R1132Q) substitution in the voltage sensor S4 of domain III. The mutation, which segregated with the disorder in the family, was not found in 325 control individuals. In vitro functional expression studies in HEK cells showed that the mutation induced a depolarizing shift in the voltage dependence, as well as enhancement of both fast and slow inactivation. These results were consistent with a loss-of-function effect with reduced effectiveness of membrane excitability, resulting in muscle hypoexcitability. Sodium channel conductance was similar to wildtype.
In Xenopus oocytes, Francis et al. (2011) demonstrated that the R1132Q mutation caused an abnormal gating pore current with a sustained inward sodium flow, consistent with a leaky channel. This current is sufficient to depolarize and render the muscle fiber inexcitable particularly during low external potassium. The findings suggested a mechanism for loss of sarcolemmal excitability during attacks of weakness in HOKPP. In contrast, the R1148C mutation (603967.0003) causing paramyotonia congenita did not result in gating pore abnormalities.
For discussion of the ser246-to-leu (S246L) mutation in the SCN4A gene that was found in compound heterozygous state in a patient with congenital myasthenic syndrome-16 (CMS16; 614198) by Tsujino et al. (2003), see 603967.0018.
In a 57-year-old woman, born of consanguineous parents, with congenital myasthenic syndrome-16 (CMS16; 614198), Arnold et al. (2015) identified a homozygous c.4370G-A transition (c.4370G-A, NM_000334.4) in exon 24 of the SCN4A gene, resulting in an arg1457-to-his (R1457H) substitution at a conserved residue in the voltage-sensing D4/S4 transmembrane domain. In vitro electrophysiologic studies showed that the mutation caused a 25-mV hyperpolarizing shift in the voltage dependence of inactivation, resulting in enhanced fast inactivation as well as slowed recovery from fast inactivation. In addition, repetitive stimuli elicited markedly weaker current responses. These changes resulted in reduced channel availability, which could explain the patient's muscle weakness. The unaffected parents and sibs were heterozygous for the mutation.
This variant is classified as a variant of unknown significance because its contribution to essential tremor (see, e.g., ETM1, 190300) has not been confirmed.
In 5 individuals from a Spanish family with variable manifestations of essential tremor, Bergareche et al. (2015) identified a heterozygous c.4609G-A transition in the SCN4A gene, resulting in a gly1537-to-ser (G1537S) substitution at a highly conserved residue in the portion of the IVS5-S6 loop that dips into the membrane and forms the lining of the pore, which is important for ion selectivity. The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the phenotype and was not found in the dbSNP (build 137), 1000 Genomes Project, or Exome Variant Server databases, or in 188 ethnically matched control chromosomes. The authors noted that the variant was subsequently listed in the dbSNP database as rs571210585 and at a low frequency (6.6 x 10(-5)) in the ExAC database. Whole-cell patch-clamp studies indicated that the variant channel had a tendency toward faster activation and significantly faster inactivation at near-threshold potentials compared to wildtype, which may gradually decrease the amplitude in repetitive action potential firing and facilitate oscillations associated with tremor. Monovalent ion selectivity studies showed that the variant channel had increased conductivity for ammonium and potassium, consistent with a gain of function. The phenotype in this family was heterogeneous: the age at onset of postural and/or action tremor ranged from the early twenties to early sixties. Two patients had tremor occurring in the hands and head, 2 had tremor of both hands, which progressed to head tremor in 1 patient and voice tremor in the other, and 1 patient showed only head tremor. In addition, 2 patients had generalized epilepsy with onset at ages 10 and 20 years, respectively. Bergareche et al. (2015) concluded that the SCN4A variant contributed to tremor and increased the susceptibility to epilepsy in this family, and that essential tremor may result from a channelopathy in some cases. The G1537S variant was not detected in 76 sporadic and 25 familial Spanish patients with essential tremor, and other pathogenic SCN4A variants were not found in 22 additional cases with familial essential tremor.
In a 35-year-old Caucasian woman, born of unrelated parents (family 2), with classic congenital myopathy-22A (CMYO22A; 620351), Zaharieva et al. (2016) identified compound heterozygous mutations in the SCN4A gene: a c.673C-T transition, resulting in an arg225-to-trp (R225W) substitution, and a c.3628G-T transversion, resulting in a cys1209-to-phe (C1209F; 603967.0035) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither variant was present in the ExAC database. Electrophysiologic studies in HEK293 cells transfected with the mutations showed that R225W was a hypomorphic allele causing reduced current amplitude, whereas C1209F resulted in a complete loss of channel function. The patient showed moderate hypotonia at birth requiring early respiratory support, delayed motor milestones, and proximal muscle weakness, but she did not have limb contractures and was ambulatory with a slow waddling gait. Her motor skills improved during childhood, but began to deteriorate around age 30. Her carrier parents were clinically unaffected.
Zaharieva et al. (2016) noted that Lee et al. (2009) had identified a heterozygous R225W mutation in a 21-year-old Korean man (patient 3) with mild nonpainful paramyotonia congenita (PMC; 168300). R225W is located at the cytoplasmic side of transmembrane S3 segment of domain I.
For discussion of the c.3628G-T transversion in the SCN4A gene, resulting in a cys1209-to-phe (C1209F) substitution, that was found in compound heterozygous state in a patient with classic congenital myopathy-22A (CMYO22A; 620351), by Zaharieva et al. (2016), see 603967.0034.
In 3 affected sibs from a consanguineous Sudanese family (family 5) with severe fetal congenital myopathy-22B (CMYO22B; 620369), Zaharieva et al. (2016) identified a homozygous c.1144C-A transversion in the SCN4A gene, resulting in a pro382-to-thr (P382T) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in the ExAC database. Electrophysiologic studies in HEK293 cells transfected with the mutation showed that it resulted in a complete loss of channel function. All 3 patients died prior to delivery or shortly after birth. They had contractures, muscle hypoplasia, and hydrops with pulmonary hypoplasia. The carrier parents were clinically unaffected.
In 3 sibs, born of unrelated Australian parents (family 6), with severe fetal congenital myopathy-22B (CMYO22B; 620369), Zaharieva et al. (2016) identified compound heterozygous mutations in the SCN4A gene: a c.608T-A transversion, resulting in a met203-to-lys (M203K) substitution, and a c.4779C-A transversion, resulting in a tyr1593-to-ter (Y1593X; 603967.0038) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Neither mutation was present in the ExAC database. Electrophysiologic studies in HEK293 cells transfected with the M203K mutation showed that it was a hypomorphic allele causing reduced current amplitude; the voltage dependence of activation and fast inactivation was shifted in the depolarizing direction. The Y1593X nonsense mutation was predicted to cause nonsense-mediated mRNA decay and a complete loss of channel function. All patients died in utero or shortly after birth. They had muscle hypoplasia, contractures, and hydrops with pulmonary hypoplasia. The carrier parents were clinically unaffected.
For discussion of the c.4779C-A transversion in the SCN4A gene, resulting in a tyr1593-to-ter (Y1593X) substitution, that was found in compound heterozygous state in 3 sibs with severe fetal congenital myopathy-22B (CMYO22B; 620369) by Zaharieva et al. (2016), see 603967.0037.
In 2 brothers, born of unrelated parents of East Indian descent, with classic congenital myopathy-22A (CMYO22A; 620351), Gonorazky et al. (2017) identified compound heterozygous missense mutations in the SCN4A gene: a c.1123T-C transition (c.1123T-C, NM_000334.4), resulting in a cys375-to-arg (C375R) substitution, and a c.3425G-A transition, resulting in an arg1142-to-gln (R1142Q; 603967.0040) substitution. The mutations, which were found by exome sequencing, segregated with the disorder in the family. In vitro electrophysiologic studies in HEK293 cells showed that the C375R mutation abolished sodium activity and caused a complete loss of SCN4A function, whereas the R1142Q mutation was hypomorphic with reduced peak current densities due to a 4-mV depolarizing shift of activation. Fast inactivation properties of the R1142Q mutant channel were also mildly affected. The patients, who were 21 and 18 years of age, showed hypotonia at birth, proximal muscle weakness of the upper and lower limbs, difficulty walking, and facial muscle weakness. Both also had scaphocephaly due to synostosis of the sagittal and metopic sutures.
For discussion of the c.3425G-A transition (c.3425G-A, NM_000334.4) in the SCN4A gene, resulting in an arg1142-to-gln (R1142Q) substitution, that was found in compound heterozygous state in 2 sibs with classic congenital myopathy-22A (CMYO22A; 620351) by Gonorazky et al. (2017), see 603967.0039.
Congenital Myasthenic Syndrome 16
In a 26-year-old Lebanese woman, born of consanguineous parents, with congenital myasthenic syndrome-16 (CMS16; 614198), Habbout et al. (2016) identified a homozygous c.4360C-T transition (c.4360C-T, NM_000334.4) in exon 24 of the SCN4A gene, resulting in an arg1454-to-trp (R1454W) substitution in the DIVS4 domain. Each unaffected parent was heterozygous for the mutation. In vitro functional expression studies showed that the mutation resulted in a loss-of-function effect, with slowed current decay, slowed fast inactivation, and increased activation time compared to wildtype. Slowed inactivation was also disturbed. Current density was not affected, but there was a decrease in current amplitude in response to repetitive stimulation above 10 Hz. The findings thus showed a combination of gating behaviors that favor the inactivation state; defective inactivation may induce fatigable weakness during muscle firing. The phenotype in this patient comprised both CMS and normokalemic periodic paralysis.
Classic Congenital Myopathy 22A
For discussion of the c.4360C-T transition in the SCN4A gene, resulting in an R1454W mutation, that was found in compound heterozygous state in a patient with classic congenital myopathy-22A (CMYO22A; 620351) by Berghold et al. (2022), see 603967.0042. Berghold et al. (2022) noted that the R1454W variant was present at a low frequency (1.6 x 10(-5)) in heterozygous state in the gnomAD database.
In an 18-year-old girl, born of unrelated parents, with classic congenital myopathy-22A (CMYO22A; 620351), Berghold et al. (2022) identified compound heterozygous missense mutations in the SCN4A gene: a c.3615C-G transversion (c.3615C-G, NM_000334.4), resulting in an asn1205-to-lys (N1205K) substitution at a conserved region in domain III, and R1454W (603967.0041). The mutations, which were found by whole-exome sequencing, were inherited from the unaffected parents. R1454W, located in the voltage sensor of domain IV, had been demonstrated to be a loss-of-function variant by Habbout et al. (2016). N1205K, located in a region forming the channel pore, was a novel variant. It was not present in the gnomAD database. Functional studies of N1205K were not performed, but it was predicted to cause a loss of function based on studies of paralogous variants in other SCNA genes.
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