Alternative titles; symbols
HGNC Approved Gene Symbol: SCN2A
Cytogenetic location: 2q24.3 Genomic coordinates (GRCh38): 2:165,239,414-165,392,304 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q24.3 | Developmental and epileptic encephalopathy 11 | 613721 | Autosomal dominant | 3 |
| Episodic ataxia, type 9 | 618924 | Autosomal dominant | 3 | |
| Seizures, benign familial infantile, 3 | 607745 | Autosomal dominant | 3 |
The SCN2A gene encodes the voltage-gated sodium channel Na(v)1.2, which plays an important role in the initiation and conduction of action potentials. SCN2A is expressed in axon initiation segments and at nodes of Ranvier in myelinated nerve fibers during early development, and is later expressed in unmyelinated axons (summary by Wolff et al., 2017).
In many cell types the sodium channel is responsible for generation and propagation of action potentials, chiefly in nerve and muscle. Voltage-sensitive sodium channels are heteromeric complexes consisting of a large glycosylated alpha subunit (approximately 260 kD) and 2 smaller beta subunits (33-39 kD). See SCN1A (182389).
Noda et al. (1986) isolated cDNAs derived from 2 distinct rat brain mRNAs encoding large polypeptides of the brain sodium channels (designated I and II). They noted that sodium channels purified from rat brain and skeletal muscle contain a single large polypeptide subunit and 2 or 3 smaller polypeptide subunits.
From a rat hypothalamic cDNA library, Cooperman et al. (1987) cloned and sequenced a 1,134-bp fragment corresponding to part of the brain type II sodium channel; the fragment spanned the fourth repeated homology unit within the alpha subunit between amino acids 1577 and 1960.
Using a probe derived from a human spinal cord sodium channel cDNA to screen a human cerebral frontal cortex cDNA library, Ahmed et al. (1992) constructed a full-length cDNA from 3 overlapping clones corresponding to the sodium channel II alpha subunit. The predicted 2,005-amino acid protein shows 97% sequence identity to the rat brain sodium channel II. The SCN2A protein contains 4 internal homology repeats, each of which contains 8 potential transmembrane segments, and multiple glycosylation and phosphorylation sites. Transient expression of the SCN2A gene in CHO cells displayed voltage-dependent, sodium-selective, and tetrodotoxin-sensitive currents, biophysical and pharmacologic properties characteristic of sodium channels.
By PCR, EST database analysis, and 5-prime and 3-prime RACE of human fetal brain and cochlea cDNA libraries, Kasai et al. (2001) cloned a splice variant of SCN2A that included a 5-prime noncoding exon. They also identified SCN2A transcripts that differed in inclusion of exon 6A or 6N. PCR amplification detected SCN2A transcripts with exon 6A in adult human brain, exon 6N in fetal human brain and lymphocytes, and neither exon 6 in lymphocytes.
The SCN2A gene contains 26 coding exons (Ahmed et al., 1992).
Kasai et al. (2001) determined that the SCN2A gene spans approximately 120 kb and has 29 exons, including a noncoding alternative first exon and alternative exon 6.
By fluorescence in situ hybridization, Ahmed et al. (1992) mapped the SCN2A1 gene to 2q23-q24.3.
Using a panel of rodent-human somatic cell hybrids and in situ hybridization, Litt et al. (1988, 1989) mapped the human SCN2A1 gene to human 2q21-q33.
Han et al. (1991) devised a general strategy for gene mapping, which they termed CM-PCR (chromosome microdissection-PCR), based upon PCR amplification of a target sequence within a single microdissected Giemsa-banded chromosomal segment. Using this method, they mapped the SCN2A1 gene to 2q22-q23.
By physical mapping by pulsed field gel electrophoresis, Malo et al. (1991) established that the murine Scn2a and Scn3a genes are physically linked and are separated by a maximum distance of 600 kb. The Scn1a gene and Scn2a are also tightly linked, separated by a distance of 0.7 cM. The authors concluded that the 3 isoforms of the brain sodium channel alpha subunit are encoded by 3 distinct genes that share a common ancestral origin as revealed both by conservation of amino acid sequence similarities and by chromosomal location.
Kasai et al. (2001) determined that the human SCN2A and SCN3A genes are oriented head-to-head, separated by 40 kb.
Lu et al. (1992) assessed the relative distribution between SCN1A and SCN2A based on a ligase detection strategy. Relative to SCN1A, SCN2A was found to be predominant in the more caudal regions of the central nervous system.
Some nonexcitable cells, such as Schwann cells and astrocytes, also express voltage sensitive sodium channels. Black et al. (1995) demonstrated expression of type 2 brain sodium channels in embryonic rat osteoblasts, using both in situ hybridization and staining with specific antibodies. Expression of sodium channel 1 or the fetal sodium channel 3 was not detected.
Garrido et al. (2003) showed that the cytoplasmic loop connecting domains II and III of the NaV1 (SCN2A) subunit contains a determinant conferring compartmentalization in the axonal initial segment of rat hippocampal neurons. Expression of a soluble NaV1.2 II-III linker protein led to the disorganization of endogenous sodium channels. The motif was sufficient to redirect a somatodendritic potassium channel to the axonal initial segment, a process involving association with ankyrin G (600465). Garrido et al. (2003) concluded that this motif may play a fundamental role in controlling electrical excitability during development and plasticity.
Bosmans et al. (2008) used 4-fold symmetric voltage-activated potassium channels as reporters to examine the contributions of individual S3b-S4 paddle motifs within the voltage-activated sodium channel voltage sensors to the kinetics of voltage sensor activation and to forming toxin receptors. Their results uncovered binding sites for toxins from tarantula and scorpion venom on each of the 4 paddle motifs in the voltage-activated sodium channels and revealed how paddle-specific interactions can be used to reshape this channel activity. One paddle motif is unique in that it slows voltage sensor activation, and toxins selectively targeting this motif impeded voltage-activated sodium channel inactivation.
In HEK293T cells transfected with SCN2A, Thomas et al. (2009) found that an increase in temperature from 37 to 41 degrees C hyperpolarized the voltage dependence of activation and speeded the rate of inactivation. Computer modeling predicted that increasing gating rates increased the firing of action potentials but did not alter firing threshold. However, when the voltage dependence of activation was shifted to that at 41 degrees C, the firing rate increased, consistent with increased excitability. Immunohistochemical studies showed expression of SCN2A in the axon initial segment of mouse cortical and hippocampal neurons. Overall, the findings suggested that the SCN2A channel is sensitive to temperature changes, which likely contributes to the genesis of febrile seizures.
Liao et al. (2010) observed differential expression of the NaV1.2 channel during mouse development. Using immunohistochemistry and RT-PCR in mouse brain slices, Liao et al. (2010) found that NaV1.2 channels were expressed early in development at axon initial segments of principal neurons in the hippocampus and cortex, but their expression was later diminished and gradually replaced by NaV1.6 (SCN8A; 600702) during maturation. This finding provides a plausible explanation for the transient expression of seizures that occur due to a gain-of-function of mutant NaV1.2 channels. In addition, there was an increase in NaV1.2 staining of unmyelinated parallel fibers of granule cells in the molecular layer of the mouse cerebellum during postnatal development.
Benign Familial Infantile Seizures
In affected members of 6 families with benign familial neonatal-infantile seizures (BFIS3; 607745), Berkovic et al. (2004) identified heterozygous mutations in the SCN2A gene (182390.0004-182390.0007). Three families had the same mutation (182390.0006) which arose independently according to haplotype analysis.
Developmental and Epileptic Encephalopathy 11
Ogiwara et al. (2009) reported 2 unrelated patients with developmental and epileptic encephalopathy-11 (DEE11; 613721) resulting from different de novo heterozygous missense mutations in the SCN2A gene (E1211K, 182390.0009 and I1473M, 182390.0010, respectively). The reports of these patients significantly expanded the phenotype resulting from SCN2A mutations and indicated that SCN2A is a candidate gene underlying intractable childhood epilepsies. In vitro functional expression studies showed that both E1211K and I1473M altered the channel properties of SCN2A to a greater extent than the BFIS3 mutations, suggesting a mechanism for more severe epileptic phenotypes.
Trump et al. (2016) identified de novo heterozygous mutations in 11 (3%) of 400 patients with early-onset seizures. All except 1 were missense variants; the 1 patient with a frameshift was diagnosed with autism with seizures. Functional studies of the variants were not performed.
In a large cohort of over 50 newly identified patients and previously reported patients with DEE11, Wolff et al. (2017) identified and reviewed previously reported heterozygous mutations in the SCN2A gene (see, e.g., 182390.0006; 182390.0011; 182390.0017-182390.0018). The majority of the mutations were missense variants affecting conserved residues, and there was no obvious correlation between location of the mutation and phenotype. A few patients with later onset and a relatively milder phenotype had nonsense, frameshift, or splice site mutations that were predicted to result in a loss of function. In vitro functional expression studies were performed for 4 missense mutations. Two mutations (V423L and F1597L), observed in patients with severe early-onset epilepsy, resulted in a gain-of-function effect with changes in the activation and inactivation curves and increased current. Two other missense mutations (G899S and P1622S), identified in children with slightly later onset of seizures, were loss-of-function mutations, resulting in decreased channel availability and membrane excitability. Ten patients had mutations at amino acid position 1882. R1882G resulted in benign infantile seizures, sometimes with late-onset episodic ataxia. In contrast, R1882Q (182390.0020), R1882L, and R1882P resulted in severe phenotypes with intellectual disability. Other recurrent mutations associated with DEE11 included L1342P and R853Q (182390.0019). Functional studies of these latter mutations were not performed.
In patients with DEE11, Berecki et al. (2018) identified de novo heterozygous missense mutations in the SCN2A gene. The R1182Q mutation (182390.0020), which resulted in a gain-of-function effect, was associated with onset of seizures in the first days of life and was not clearly associated with severe abnormal movements. In contrast, the R853Q mutation (182390.0019), which was demonstrated to result in a loss-of-function effect with decreased neuronal excitability, was associated with later onset of seizures between 6 and 8 months and high occurrence of involuntary movements, including choreoathetosis, dystonia, and pyramidal signs.
Episodic Ataxia Type 9
In an 11-year-old boy with episodic ataxia type 9 (EA9; 618924), Liao et al. (2010) identified a de novo heterozygous missense mutation in the SCN2A gene (A263V; 182390.0011). Electrophysiologic studies showed that the A263V mutation resulted in a 3-fold increase in persistent sodium current, indicating a profound gain of function. Other changes including slowed fast inactivation and accelerated recovery of slow inactivation. These findings were consistent with a gain-of-function effect and neuronal hyperexcitability.
In 2 unrelated patients with EA9, Johannesen et al. (2016) and Gorman and King (2017) independently identified a de novo A263V mutation in the SCN2A gene. Functional studies of the variant were not performed.
In 3 unrelated patients with EA9, Schwarz et al. (2016) identified heterozygous mutations in the SCN2A gene (182390.0011; 182390.0013-182390.0014). In vitro functional electrophysiologic studies in transfected cells showed that the newly reported mutations resulted in a gain-of-function effect with increased cell membrane excitability, although the studies suggested that there were different molecular mechanisms.
In a 5-year-old boy with EA9, Leach et al. (2016) identified a de novo heterozygous missense mutation in the SCN2A gene (G1634D; 182390.0015). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies of the variant were not performed.
In a woman and her 2 sons with EA9, Fazeli et al. (2018) identified a heterozygous missense mutation in the SCN2A gene (L1650P; 182390.0016). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases. Functional studies of the variant were not performed.
Associations Pending Confirmation
Sanders et al. (2012) used whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sib pairs, to demonstrate that highly disruptive nonsense and splice site de novo mutations in brain-expressed genes are associated with autism spectrum disorders (209850) and carry large effects. Among a total of 279 identified de novo coding mutations, there was a single instance in probands, and none in sibs, in which 2 independent nonsense variants disrupted the same gene, SCN2A.
In a 7-year-old boy with autism spectrum disorder, Tavassoli et al. (2014) identified a de novo heterozygous splice site mutation (c.476+1G-A) in the SCN2A gene. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP or other genomic databases. Studies of patient cells showed that the mutation resulted in a truncated protein and/or caused nonsense-mediated mRNA decay. The patient had social and communicative impairment, repetitive behaviors, sensory reactivity issues, and poor adaptive and cognitive skills. He did not have a history of seizures. Three other de novo mutations were also found in the patient, but the SCN2A variant was considered most likely to contribute to the phenotype.
By gene targeting, Planells-Cases et al. (2000) generated mice deficient in Scn2a. Heterozygous mutant mice developed normally and displayed no gross morphologic anomalies. Scn2a-null mice were initially indistinguishable from heterozygous littermates, but they died within 1 to 2 days of birth with severe hypoxia. Scn2a-null mice were pallid, dyspneic or gasping, and cyanotic. They showed no seizure activity. Analysis of Scn2a mRNA and protein indicated that knockout was incomplete, but residual Scn2a levels were insufficient to allow survival. Examination of Scn2a-null brains revealed no neuroanatomic abnormalities; however, these mice had increased neuronal apoptosis, particularly in the brainstem. Sodium channel currents recorded from cultured hippocampal neurons of Scn2a-null mice were attenuated. Planells-Cases et al. (2000) concluded that Scn2a expression is redundant for mouse embryonic development, but Scn2a is required postnatally, particularly in brainstem areas involved in respiratory regulation.
Li et al. (2021) developed a mouse model (Q/+) with a heterozygous R1882Q (182390.0020) gain-of-function mutation in the Scn2a gene. The mice had higher action potential frequency in pyramidal neurons from brain slices compared to wildtype mice, had frequent seizures, and died before day P30. The Q/+ mice were treated with intracerebroventricular administration of an antisense oligonucleotide (ASO) targeting Scn2a on day 1 of life, which resulted in 73.9% reduction in Scn2a protein levels compared to untreated mice. Treated mice had improved survival, and survival was further extended with a second intracerebroventricular administration of the Scn2a-targeted ASO. The treated Q/+ mice had an improved behavioral phenotype and decreased seizure frequency on days P40 through P45, although seizure frequency increased in the treated mice by days P56 through P78. Treatment with a higher dose of Scn2a-targeted ASO improved survival in the Q/+ mice compared to a lower dose of ASO but the mice had more pathologic behaviors. Goldberg (2021) commented that the widespread distribution of Scn2a-targeted ASO achieved in the mouse brain by Li et al. (2021) is not likely to be achievable in humans, and that information about the extent of ASO distribution in mouse brain required to attain a treatment effect is needed.
Sugawara et al. (2001) reported a C-to-T transition in the SCN2A gene, resulting in an arg188-to-trp (R188W) substitution, in a 6-year-old Japanese boy with childhood seizures (BFIS3; 607745) and normal development. He had onset of febrile seizures at age 8 months, and later had 5 episodes of brief afebrile atonic seizures lasting less than 10 seconds since age 4 years. EEG showed single spikes over the right frontal region. Both parents, who were not related, had a history of febrile seizures in childhood. Genetic analysis identified a heterozygous R188W mutation in the boy and the father, but not the mother. In vitro functional expression studies showed that the mutant channel inactivated more slowly than wildtype, whereas channel conductance was not affected. Although Sugawara et al. (2001) suggested a link to GEFS+ (604233), they noted that assignment of the phenotype in this patient was difficult because both parents had febrile seizures, which have a high frequency in the general population. Berkovic et al. (2004) concluded that there is little support for an association between SCN2A and GEFS+, despite the report of Sugawara et al. (2001). Berkovic et al. (2004) also stated that seizures with fever occasionally do occur in BFNIS.
In a family with benign familial neonatal-infantile seizures (BFIS3; 607745), Heron et al. (2002) identified a 3988C-T transition in the SCN2A gene, resulting in a leu1330-to-phe (L1330F) substitution. The family was Australian of Irish origin with 7 affected individuals over 4 generations.
In an Ashkenazi Jewish family from Canada with benign familial neonatal-infantile seizures (BFIS3; 607745), originally described by Shevell et al. (1986), Heron et al. (2002) identified a 4687C-G transversion in exon 25 of the SCN2A gene, resulting in a leu1563-to-val (L1563V) substitution.
In affected members of a family with benign familial neonatal-infantile seizures (BFIS3; 607745) originally reported by Kaplan and Lacey (1983), Berkovic et al. (2004) identified a val892-to-ile (V892I) change in the SCN2A gene.
In affected members of a family with benign familial neonatal-infantile seizures (BFIS3; 607745) originally reported by Malacarne et al. (2001), Berkovic et al. (2004) identified an arg223-to-gln (R223Q) change in the SCN2A gene.
Seizures, Benign Familial Infantile, 3
In affected members of 3 families (E, F, and H) with benign familial neonatal-infantile seizures (BFIS3; 607745), Berkovic et al. (2004) identified a 3956G-A transition in the SCN2A gene, resulting in an arg1319-to-gln (R1319Q) substitution.
Developmental and Epileptic Encephalopathy 11
In 2 unrelated patients (patient 31 and 36) with developmental and epileptic encephalopathy-11 (DEE11; 613721), Wolff et al. (2017) identified a heterozygous R1319Q mutation in the SCN2A gene that was shown to have occurred de novo in one. Functional studies of the variant were not performed. The patients presented at 5 days and 2 months of age, respectively, with myoclonic or generalized tonic-clonic and focal seizures. Both became seizure-free between 8 and 13 months. One patients was only 14 months of age, but showed severe cognitive impairment, hypotonia, and limb hypertonia. The other patient, who was 4 years old, had moderately impaired intellectual development and autism spectrum disorder. The authors emphasized the early seizure remission in both patients.
In affected members of a family with benign familial neonatal-infantile seizures (BFIS3; 607745), Berkovic et al. (2004) identified a leu1003-to-ile (L1003I) change in the SCN2A gene.
In a 29-year-old Japanese woman with delayed onset of developmental and epileptic encephalopathy-11 (DEE11; 613721), Kamiya et al. (2004) identified a de novo heterozygous c.304C-T transition in the SCN2A gene, resulting in an arg102-to-ter (R102X) substitution, causing truncation of the protein before the first transmembrane segment. The patient had onset of seizures at age 1 year, 7 months, and thereafter became hyperkinetic and autistic. The EEG was reported to show only slow waves initially, but after 3 years, spike activity appeared and increased. Convulsive and atonic seizures continued throughout childhood and were difficult to treat. She had severe intellectual and psychomotor retardation but no paralysis. Brain MRI showed moderate diffuse brain atrophy. Electrophysiologic studies in HEK293 cells showed that the R102X mutant protein was nonfunctional when expressed in isolation, and shifted the voltage dependence of inactivation of wildtype channels in the hyperpolarizing direction, consistent with a dominant-negative effect.
In a 22-year-old man with developmental and epileptic encephalopathy-11 (DEE11; 613721), Ogiwara et al. (2009) identified a de novo heterozygous c.3631G-A transition in the SCN2A gene, resulting in a glu1211-to-lys (E1211K) substitution. The patient had onset of infantile spasms at age 11 months, which evolved to frequent occurrence of refractory tonic-clonic seizures at age 2 to 3 years. He also showed marked developmental delay and severe intellectual disability in infancy and childhood. Febrile seizures occurred after age 10 years. After an episode of status epilepticus at age 17 years, he became quadriplegic and speechless. In vitro electrophysiologic studies indicated that the E1211K mutant channel had properties compatible with both augmented and reduced channel activities. There was an 18-mV hyperpolarizing shift in the voltage dependence of activation, as well as a 22-mV hyperpolarizing shift in the voltage dependence of steady-state inactivation and slowed recovery from inactivation.
In a girl with developmental and epileptic encephalopathy-11 (DEE11; 613721), Ogiwara et al. (2009) identified a de novo heterozygous 4419A-G transition in the SCN2A gene, resulting in an ile1473-to-met (I1473M) substitution. She developed tonic or tonic-clonic seizures from age 1 month, and also had early infantile status epilepticus with a highly suppressed EEG with ictal burst activities, hyponatremia, and megalencephaly. The seizures responded to treatment with lidocaine. She died at age 7 years and 8 months from unknown causes. In vitro electrophysiologic studies indicated that the I1473M mutant channel caused a 14-mV hyperpolarizing shift in the voltage dependence of activation, resulting in hyperexcitability.
Episodic Ataxia Type 9
In an 11-year-old boy with episodic ataxia type 9 (EA9; 618924), Liao et al. (2010) identified a de novo heterozygous c.788C-T transition in the SCN2A gene, resulting in an ala263-to-val (A263V) substitution in a highly conserved residue in the S5 segment of transdomain I. The mutation was not found in 93 controls. Electrophysiologic studies showed that the A263V mutation resulted in a 3-fold increase in persistent sodium current, indicating a profound gain of function. Other changes including slowed fast inactivation and accelerated recovery of slow inactivation. These findings were consistent with a gain-of-function effect and neuronal hyperexcitability.
Schwarz et al. (2016) reported a boy (patient 3) with EA9 who carried a de novo A263V mutation in the SCN2A gene. In 2 unrelated patients with EA9, Johannesen et al. (2016) and Gorman and King (2017) independently identified a de novo A263V mutation in the SCN2A gene. Functional studies of the variant were not performed.
Developmental and Epileptic Encephalopathy 11
Wolff et al. (2017) identified a de novo A263V mutation in a 13-year-old patient (patient 34) with developmental and epileptic encephalopathy-11 (DEE11; 613721). He presented at 3 weeks of age with intractable seizures. He had severely impaired intellectual development and microcephaly. Brain imaging showed atrophy and hypomyelination. He died at 13 years of age. The report expanded the phenotype associated with this mutation.
Phenotypic Overlap
Touma et al. (2013) reported a pair of monozygotic twin boys who carried the same de novo heterozygous A263V mutation identified in the patient reported by Liao et al. (2010). On the first day of life, both boys developed refractory seizures (up to 60 per day) associated with a burst-suppression pattern on EEG. One twin died on day 19 from iatrogenic cardiopulmonary arrest. The other twin became seizure-free on medication at age 8 months, and seizure-free without medication at age 2 years; this corresponded to improvement of the EEG abnormalities. The surviving twin showed global developmental delay; he could say short sentences but had head lag, axial hypotonia, and inability to crawl. Brain imaging of the surviving twin showed diffuse signal abnormalities in the basal ganglia and brainstem suggestive of cytotoxic edema; these abnormalities improved with age. The phenotype was reminiscent of developmental and epileptic encephalopathy-11 (613721). However, the seizure remission was also consistent with EA9, even though episodic ataxia was not reported. The surviving patient was only 2.5 years of age at the time of the report.
In affected members of a Bulgarian family with autosomal dominant benign familial infantile seizures-3 (BFIS3; 607745), Liao et al. (2010) identified a heterozygous 754A-G transition in the SCN2A gene, resulting in a met252-to-val (M252V) substitution in a highly conserved residue in segment S5 of domain 1. The mutation was present in 2 affected sibs, their affected maternal grandfather, and in their asymptomatic mother. The phenotype was characterized by onset of seizures before age 4 months, response to pharmacotherapy, and complete resolution of the seizures by age 2 years with no neurologic sequelae. Expression of the mutation in the neonatal SCN2A splice variant resulted in increased persistent and noninactivating current, whereas expression of the mutation in the adult SCN2A splice variant resulted in only a slightly and not significantly increased current. Thus, the increased neuronal firing would disappear as soon as the neonatal variant is no longer expressed. These findings corresponded to the observed phenotype.
In a boy (patient 1) with episodic ataxia type 9 (EA9; 618924), Schwarz et al. (2016) identified a de novo heterozygous c.5644C-G transversion (c.5644C-G, NM_021007.2) in the SCN2A gene, resulting in an arg1882-to-gly (R1882G) substitution at a highly conserved residue. In vitro functional electrophysiologic studies in cells transfected with the mutation showed that it caused a hyperpolarizing effect on the activation curve, consistent with a gain-of-function effect and increased cell membrane excitability. Current density was normal.
In a girl (patient 2) with episodic ataxia type 9 (EA9; 618924), Schwarz et al. (2016) identified heterozygosity for 2 missense mutations in cis in the SCN2A gene: a c.5644C-G transversion, resulting in an R1882G (182390.0013) substitution, and a c.4565G-C transversion (c.4565G-C, NM_021007.2), resulting in a a gly1522-to-ala (G1522A) substitution. The latter was a polymorphism (allele frequency of 7.3 x 10(-4) in the ExAC database), inherited from the unaffected father, whereas R1882G occurred de novo in the patient. In vitro functional electrophysiologic studies in transfected cells showed that the double mutation resulted in an increase in current density and a significant shift of the steady-state fast inactivation curve towards more depolarized potentials. The total SCN2A protein levels were also increased compared to controls or to each individual mutation. The findings were consistent with a gain-of-function effect and increased cell membrane excitability, but a different molecular mechanism than that of R1882G alone.
In a 5-year-old boy with episodic ataxia type 9 (EA9; 618924), Leach et al. (2016) identified a de novo heterozygous transition (chr2.166,245,217G-A, GRCh37) in the SCN2A gene, resulting in a gly1634-to-asp (G1634D) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC database. Functional studies of the variant were not performed.
In a woman and her 2 sons with episodic ataxia type 9 (EA9; 618924), Fazeli et al. (2018) identified a heterozygous c.4949T-C transition (c.4949T-C, NM_021007) in the SCN2A gene, resulting in a leu1650-to-pro (L1650P) substitution at a highly conserved residue in a cytoplasmic loop within domain IV. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases. Functional studies of the variant were not performed. None of the 3 patients had seizures. However, Fazeli et al. (2018) noted that a de novo heterozygous L1650P mutation had previously been reported in a patient with developmental and epileptic encephalopathy-11 (DEE11; 613721) by Trump et al. (2016). These findings indicated phenotypic variability associated with this mutation, and suggested that genotype/phenotype correlations are challenging with SCN2A.
Passi and Mohammad (2021) identified a heterozygous L1650P mutation in a 15-month-old boy with EA9. The mutation, which was found by clinical exome panel sequencing, was inherited from his father, who had a history of episodic hemiplegia in childhood that resolved without neurologic sequelae. Functional studies of the variant were not performed. The findings expanded the phenotypic spectrum associated with this mutation.
In 2 unrelated patients (patients 10 and 33) with developmental and epileptic encephalopathy-11 (DEE11; 613721), Wolff et al. (2017) identified a de novo heterozygous val423-to-leu (V423L) substitution in the SCN2A gene. In vitro functional expression studies showed that the mutation resulted in a gain-of-function effect, with a change in the slope of activation and an increased and persistent sodium current compared to wildtype. Both patients developed intractable seizures in the first days of life, resulting in death in 1 patient at age 34 months. The other patient had severe intellectual disability and spasticity. Even though the V423L mutation resulted in a gain-of-function effect, the patients did not respond to sodium channel blockers.
In a 3-year-old child (patient 52) with developmental and epileptic encephalopathy-11 (DEE11; 613721), Wolff et al. (2017) identified a de novo heterozygous pro1622-to-ser (P1622S) substitution in the SCN2A gene. In vitro functional expression studies showed that the mutation resulted in a loss-of-function effect. The most prominent change of the mutant channel was a significant hyperpolarizing shift of the fast inactivation curve, predicting a decrease of channel availability and decreased membrane excitability in neurons compared to wildtype. The patient had onset of intractable myoclonic seizures at 2 years of age. He had moderately impaired development, autism spectrum disorder, ataxia, and microcephaly. Seizure reduction was achieved with topiramate.
In 3 unrelated patients (46, 50, and 56) with developmental and epileptic encephalopathy-11 (DEE11; 613721), Wolff et al. (2017) identified a heterozygous arg853-to-gln (R853Q) substitution at a conserved residue in the SCN2A gene. The mutation was shown to have occurred de novo in 2 of the patients. The patients had slightly later onset of intractable seizures between 8 months and 3 years of age. Other features included abnormal movements, such as dystonia, choreoathetosis, and pyramidal signs. Functional studies of the variant were not performed.
In 3 unrelated patients with DEE11, Berecki et al. (2018) identified a heterozygous R853Q mutation in the SCN2A gene that was shown to have occurred de novo in 2 of them. In vitro functional expression studies showed that the R853Q mutation resulted in a loss-of-function effect with decreased neuronal excitability. The patients had onset of seizures between 6 and 8 months and also showed involuntary movements.
In 2 unrelated patients (patients 3 and 10) with developmental and epileptic encephalopathy-11 (DEE11; 613721), Howell et al. (2015) identified a de novo heterozygous c.5645G-A transition in the SCN2A gene, resulting in an arg1882-to-gln (R1882Q) substitution at a highly conserved residue. The mutations were found by whole-exome or targeted sequencing; functional studies were not performed. Both patients had onset of seizures on the first day of life and responded to phenytoin.
A de novo heterozygous R1882Q mutation was found in 2 additional unrelated DEE11 patients (patients 52 and 53) by Trump et al. (2016) and in a patient (patient 19) by Wolff et al. (2017). The patient reported by Wolff et al. (2017) responded to carbamazepine.
In 4 unrelated patients with DEE11, Berecki et al. (2018) identified a de novo heterozygous R1882Q mutation in the SCN2A gene. In vitro functional expression studies showed that the R1882Q mutation resulted in a gain-of-function effect with increased neuronal excitability. Two patients had opisthotonus, 1 had oculogyric crises, and another had dystonia. Two of the 4 patients responded to phenytoin treatment.
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