Alternative titles; symbols
HGNC Approved Gene Symbol: SCN8A
SNOMEDCT: 765170001;
Cytogenetic location: 12q13.13 Genomic coordinates (GRCh38) : 12:51,591,233-51,812,864 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.13 | ?Myoclonus, familial, 2 | 618364 | Autosomal dominant | 3 |
| Cognitive impairment with or without cerebellar ataxia | 614306 | Autosomal dominant | 3 | |
| Developmental and epileptic encephalopathy 13 | 614558 | Autosomal dominant | 3 | |
| Seizures, benign familial infantile, 5 | 617080 | Autosomal dominant | 3 |
Voltage-dependent sodium channels, such as SCN8A, are responsible for the initial membrane depolarization that occurs during generation of action potentials in most electrically excitable cells (Plummer et al., 1998).
Plummer et al. (1998) isolated and sequenced genomic fragments containing the exons of a novel human voltage-gated sodium channel designated SCN8A. SCN8A encodes a 1,980-amino acid protein that shares close to 99% sequence identity with the mouse protein. It contains several consensus sites for phosphorylation of serine and threonine residues that are also conserved in other sodium channel family members.
Plummer et al. (1997) identified 2 alternatively spliced exons of SCN8A, 18N and 18A, that encode transmembrane segments S3 and S4 in domain III. Exon 18N is expressed in fetal brain and nonneuronal tissues. Transcripts with exon 18N have a conserved in-frame stop codon that predicts the synthesis of a truncated, 2-domain protein. The proportion of transcripts containing exon 18N is highest in mouse fetal brain between embryonic day (E) 12.5 and E14.5; at E18.5 and later, the 18A transcript predominates.
Plummer et al. (1998) determined that the SCN8A gene contains 28 exons and identified an additional pair of alternatively spliced exons, 5N and 5A, that encode transmembrane segments of domain I. Exons 5N and 5A differ by a single amino acid difference at position 7. Plummer et al. (1998) also found that major and minor protein transcripts are generated by 2 alternative splice donor sites for exon 10B; the minor transcript contains 11 extra amino acids.
Drews et al. (2007) identified 4 untranslated 5-prime exons, which they designated 1a through 1d, in the mouse and human SCN8A genes. These exons are mutually exclusive, and each is alternatively spliced to the first coding exon. Exon 1a overlaps with an inserted LINE element, and the 70-kb interval between the 5-prime noncoding exons and the first coding exon contains 58% repetitive elements and simple repeats. The Scn8a genes of lower vertebrates contain only a single 5-prime untranslated exon that corresponds to mouse and human exon 1c. Exon 1c contains conserved functional YY1 (600013) and REST (600571) sites.
Active invasion of the dendritic tree by action potentials generated in the axon is essential for associative synaptic plasticity and neuronal ensemble formation. In cortical pyramidal cells, this action potential back-propagation is supported by dendritic voltage-gated sodium channels. Using a highly sensitive electron microscopic immunogold technique, Lorincz and Nusser (2010) revealed the presence of the Nav1.6 subunit in hippocampal CA1 pyramidal cell proximal and distal dendrites. Here, the subunit density is lower by a factor of 35 to 80 than that found in axon initial segments. A gradual decrease in Nav1.6 density along the proximodistal axis of the dendritic tree was also detected without any labeling in dendritic spines. Lorincz and Nusser (2010) concluded that their results revealed the characteristic subcellular distribution of the Nav1.6 subunit, identifying this molecule as a key substrate enabling dendritic excitability.
Kohrman et al. (1995) assigned the mouse Scn8a gene to chromosome 15 by interspecific backcross analysis and the human SCN8A gene to chromosome 12 by hybridization to a somatic cell hybrid mapping panel. Burgess et al. (1995) mapped the human homolog to 12q13 by fluorescence in situ hybridization. By physical mapping on a YAC contig, Plummer et al. (1998) localized the SCN8A gene to 12q13.1.
Cognitive Impairment with or without Cerebellar Ataxia
Because SCN8A is widely expressed in neurons of the central and peripheral nervous systems, and because mutations in the mouse ortholog result in ataxia and other movement disorders, Trudeau et al. (2006) screened the 26 coding exons of SCN8A in 151 patients with inherited or sporadic ataxia. They found a 2-bp deletion in exon 24 (600702.0001) in a 9-year-old boy with mental retardation, pancerebellar atrophy, and ataxia (CIAT; 614306). Three additional family members who were heterozygous for this mutation exhibited milder cognitive behavioral deficits including attention deficit-hyperactivity disorder (ADHD; 143465). No additional occurrence of this mutation was observed in 625 unrelated DNA samples (1,250 chromosomes).
In 2 unrelated children with CIAT, Wagnon et al. (2017) identified de novo heterozygous missense mutations in the SCN8A gene (G964R, 600702.0013 and E1218K, 600702.0014). The mutations, which were found by exome sequencing, occurred at highly conserved residues in transmembrane domains. In vitro functional expression studies in transfected cells showed that both mutations caused a complete loss of channel activity. Wagnon et al. (2017) suggested that loss of neuronal activity due to the mutation may alter the dynamics of synaptic plasticity during maturation and lead to aberrant cerebral circuitry and intellectual disability.
Developmental and Epileptic Encephalopathy 13
In a girl with developmental and epileptic encephalopathy-13 (DEE13; 614558), Veeramah et al. (2012) identified a de novo heterozygous mutation in the SCN8A gene (N1768D; 600702.0002). In vitro functional expression studies showed that the mutation caused a dominant gain-of-function effect, with neuronal hyperexcitability, persistent sodium currents, incomplete channel inactivation, increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency.
Carvill et al. (2013) identified a heterozygous mutation in the SCN8A gene (L1290V; 600702.0003) in a boy with DEE13. The mutation was inherited from his father, who was found to be somatic mosaic for the mutation. No further clinical information was provided. The patient was part of a cohort of 500 cases of epileptic encephalopathy who underwent sequencing of candidate genes; he was the only patient found to carry an SCN8A mutation.
In 7 unrelated patients with DEE13, Ohba et al. (2014) identified 7 different de novo heterozygous missense mutations in the SCN8A gene (see, e.g., 600702.0004-600702.0006). Whole-exome or targeted capture sequencing detected mutations in 6 (10%) of 60 patients with early-onset epileptic encephalopathy and in 1 (16.7%) of 6 patients diagnosed clinically with malignant migrating partial seizures in infancy (MMPSI). Functional studies of the variants were not performed, but all occurred at highly conserved residues scattered throughout the gene with variable predicted effects. There were no apparent genotype-phenotype correlations.
Benign Familial Infantile Seizures 5
In 16 patients from 3 unrelated families with benign familial infantile seizures-5 (BFIS5; 617080), Gardella et al. (2016) identified a heterozygous missense mutation in the SCN8A gene (E1483K; 600702.0010). The variant, which was found by exome sequencing in 2 of the families and confirmed by Sanger sequencing, segregated with the disorder in all 3 families, with evidence of incomplete penetrance. Linkage analysis excluded a founder effect. Although functional studies of the mutation were not performed, Gardella et al. (2016) postulated that it caused a small gain-of-function effect resulting from impaired channel inactivation.
In a father and son with BFIS5, Anand et al. (2016) identified a heterozygous missense mutation in the SCN8A gene (N1877S; 600702.0011). Functional studies of the variant were not performed, but Anand et al. (2016) noted that the same variant has been identified in patients with a more severe disorder, including developmental delay, epileptic encephalopathy, and intellectual disability (DEE13). The benign phenotype in the father and son suggested that they may carry additional variants in other genes that offer a protective effect. Sanger sequencing excluded somatic mosaicism for the SCN8A mutation in the father.
Familial Myoclonic Epilepsy 2
In 3 affected members of a family with myoclonic epilepsy-2 (MYOCL2; 618364), Wagnon et al. (2018) identified a heterozygous missense mutation in the SCN8A gene (P1719R; 600702.0012). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family in those who agreed to testing. In vitro functional expression studies in transfected neuron-derived cells showed that the mutation caused a partial loss of function, manifest as decreased inward sodium current compared to controls.
In 2 unrelated patients with developmental delay, impaired intellectual development, and early-onset seizures, Blanchard et al. (2015) identified 2 different de novo heterozygous missense mutations in the SCN8A gene (N984K, 600702.0008 and G1451S, 600702.0009). The patients were ascertained from a cohort of 500 patients with intellectual disability and 100 patients with a movement disorder who underwent exome sequencing. In vitro functional expression studies showed that the N984K mutation resulted in increased channel opening and increased neuronal excitability, consistent with a gain of function, whereas the G1451S mutation resulted in decreased current density, consistent with a loss of function. The patient with the N984K mutation had onset of intractable seizures at age 6 weeks and severe developmental delay with no speech and inability to sit independently at age 7 years; the patient with the G1451S mutation had a slightly less severe phenotype, with onset of seizures at age 18 months, moderate to severe developmental delay, spastic tetraplegia, ataxia, and nystagmus with cerebellar atrophy at age 33 years. Blanchard et al. (2015) concluded that SCN8A mutations resulting in a gain of function may result in a more severe phenotype, but noted that the G1451S mutation may also have some gain-of-function effects that were not detected in the cellular assay. A third unrelated patient with severe developmental delay (IQ of 55), dysmorphic features, and no seizures had a heterozygous D58N variant in the SCN8A gene, but functional studies showed normal SCN8A channel activity, suggesting that the variant may not be pathogenic. This patient also carried a heterozygous R95Q variant in the RING1 gene (602045), but functional studies of the variant were not performed.
The mouse neurologic mutant 'motor endplate disease' (med) is characterized by early-onset progressive paralysis of the hindlimbs, severe muscle atrophy, degeneration of Purkinje cells, and juvenile lethality. Burgess et al. (1995) isolated a voltage-gated sodium channel gene, Scn8a, from the flanking region of a transgene-induced allele of med. Scn8a is expressed in brain and spinal cord but not in skeletal muscle or heart, and encodes a predicted protein of 1,732 amino acids. An intragenic deletion at the site of transgene insertion resulted in loss of expression. The gene is closely related to other sodium channel alpha subunits: SCN1A (182389), SCN2A (182390), SCN3A (182391), SCN4A (603967), SCN5A (600163), and SCN6A (182392). Kohrman et al. (1996) identified a missense mutation in Scn8a that is associated with cerebellar ataxia in the 'jolting' mutant, a mild allele of the med locus. Kohrman et al. (1996) described the molecular changes in Scn8a underlying 2 other spontaneous mutants, med and med(J). The med mutation was caused by insertion of a truncated LINE element into exon 2 of Scn8a. The med transcript was spliced from exon 1 to a cryptic acceptor site in intron 2. In the med(J) allele, a 4-bp deletion within 5-prime donor site of exon 3 resulted in splicing from exon 1 to exon 4. Both mutant transcripts altered the reading frame with premature stop codons close to the N terminus of the protein. Loss of Scn8a expression resulted in progressive paralysis and early death. Intron 2 of Scn8a is flanked by minor class AT-AC splice sites. The observed splicing patterns of the med and med(J) mutant transcripts provided evidence for preferential in vivo splicing between donor and acceptor sites of the same class. The apparent functional incompatibility may be a consequence of the different composition of spliceosomes bound to major and minor splice sites. The unusual pattern of exon skipping in these mutant identified Scn8a as a member of a small group of genes containing introns with nonstandard AT-AC splice sites. AT-AC introns are processed by alternative splicing machinery that includes U11 and U12 (RNU12; 620204) snRNPs. Meisler et al. (1997) reviewed how the analysis of molecular defects in mouse mutants can identify candidate genes for human neurologic disorders, as illustrated by Scn8a among other genes.
Sprunger et al. (1999) studied the mouse mutant med(J), which contains a splice site mutation in the neuronal sodium channel Scn8a that results in a very low level of expression. On the C57BL/6J genetic background, med(J) homozygotes exhibited progressive paralysis and juvenile lethality. The C3H genetic background had an ameliorating effect, producing viable adults with a novel dystonic phenotype. The dystonic mice exhibited movement-induced, sustained abnormal postures of the trunk and limbs. Sprunger et al. (1999) mapped a dominant modifier locus responsible for the difference between strains to a 4.5 +/- 1.3-cM interval on mouse chromosome 3. These findings established a role for ion channels in dystonia and demonstrated the impact of genetic background on its severity and progression. This new model suggested to Sprunger et al. (1999) that SCN8A on 12q13 and SCNM1 (which by comparative mapping is presumably located on 1p21-q21) may contribute to human inherited dystonia.
The dystonia demonstrated by Sprunger et al. (1999) in association with the Scn8a mutation was the first to be related to mutation in an ion channel. Furthermore, the med(J) mouse differed from other animal models with dystonia in that the condition persisted to adulthood and was not associated with neurodegeneration. Sprunger et al. (1999) suggested that the med(J) mutation should be classified as a hypomorphic allele because a low level of full-length Scn8a transcripts was demonstrated in homozygotes, indicating normal splicing at low efficiency. Homozygotes for null alleles of Scn8a could not survive even in the presence of 2 copies of the Scnm1(H) modifier allele. Thus, prevention of paralysis and survival to adulthood required both a low level of wildtype transcript and at least 1 copy of the dominant allele of Scnm1. C57BL/6J carries a recessive allele of Scmn1 that, in combination with a hypomorphic level of Scn8a, resulted in paralysis and lethality.
De Repentigny et al. (2001) described a spontaneous autosomal recessive mutation in the mouse, which they termed 'degenerating muscle' (dmu), that is characterized by skeletal and cardiac muscle degeneration. Dmu mice are weak and have great difficulty in moving due to muscle atrophy and wasting in the hindquarters. Histopathologic observations and ultrastructural analysis revealed muscle degeneration in both skeletal and cardiac muscle, but no abnormalities in sciatic nerves. Using linkage analysis, the authors mapped the dmu locus to the distal portion of mouse chromosome 15 in a region syntenic to human chromosome 12q13. Intact transcripts for Scn8a were present in dmu mice, but their levels were dramatically reduced. Furthermore, genetic complementation crosses between dmu and med mice revealed that they are allelic. The authors concluded that at least a portion of the dmu phenotype may be caused by a downregulation of Scn8a.
Kearney et al. (2002) described a sensitive allele of the unlinked modifier locus, Scnm1, which results in juvenile lethality in C57BL/6J mice carrying the med(J) mutation. The modifier acts on the splicing efficiency of the mutant splice donor site in Scn8a, and mutant mice display either 90% or 95% reduction in the proportion of correctly spliced mRNA, depending on modifier genotype. The abundance of the channel protein, NaV1.6, is also reduced by an order of magnitude in med(J) mice, resulting in delayed maturation of nodes of Ranvier, slowed nerve conduction velocity, reduced muscle mass, and reduction of brain metabolic activity.
Martin et al. (2007) showed that Scn8a(med) and Scn8a(med-jo) mice, which carry the heterozygous 'jolting' point mutation, were more resistant to pharmacologically induced seizures than wildtype littermates, suggesting that altered Scn8a function reduces neuronal excitability. They also showed that the seizure severity of heterozygous Scn1a +/- mice (see Yu et al., 2006), which is a mouse model for severe myoclonic epilepsy of infancy (SMEI; 607208), was ameliorated by the Scn8a(med-jo) allele. Double-heterozygous Scn1a +/- and Scn8a +/(med-jo) mice had seizure thresholds that were comparable to wildtype littermates, and the Scn8a(med-jo) allele was also able to rescue the premature lethality of Scn1a +/- mice and extended the life span of Scn1a -/- mice. The authors hypothesized that the opposing effects of Scn1a and Scn8a dysfunction on seizure thresholds result from differences in the cell types that are influenced by the respective sodium channel subtypes. Scn1a mutants result in reduced sodium currents in inhibitory GABAergic interneurons of the hippocampus and cortex, whereas Scn8a mutants affect excitatory pyramidal cells of the hippocampus and cortex, suggesting that reduced excitability of these cells may underlie the elevated seizure resistance of Scn8a-mutant mice. Martin et al. (2007) suggested that their results demonstrated that genetic interactions can alter seizure severity, and supported the hypothesis that genetic modifiers, including the SCN8A gene, contribute to the clinical variability observed in SMEI and GEFS+.
By ENU-induced mutagenesis screen in mice, Papale et al. (2009) generated a val929-to-phe (V929F) mutation in the Scn8a gene. This residue in the pore loop of domain 2 is evolutionarily conserved. Electroencephalography (EEG) revealed well-defined spike-wave discharges (SWD), the hallmark of absence epilepsy (see 600131), in V929F-heterozygous mice and in mice heterozygous for either the Scn8a(med) or Scn8a(med-jo) mutations. Genetic background had a significant effect on SWD, with mutants on the C3HeB/FeJ strain showing a higher incidence than on C57BL/6J. Papale et al. (2009) suggested that the SCN8A gene may be a candidate gene for absence epilepsy in humans.
Letko et al. (2019) identified a homozygous missense variant (gly1633 to val, G1633V) in the SCN8A gene in 4 Alpine Dachsbracke dogs affected with spinocerebellar ataxia characterized by ataxia, tremor, loss of balance and axonal degeneration. Pathogenicity of the mutation was supported by genotyping studies in over 200 dogs of this breed.
In a 9-year-old boy with mental retardation, pancerebellar atrophy, and ataxia (CIAT; 614306), Trudeau et al. (2006) identified heterozygosity for a 2-bp deletion in exon 24 of the SCN8A gene, which introduced a translation termination codon into the pore loop of domain 4, resulting in removal of the C-terminal cytoplasmic domain and predicting loss of channel function (Pro1719ArgfsTer6). The authors stated in the text that the deletion removed nucleotides 5156 and 5157, and in Figure 1 that it removed nucleotides 5157 and 5158. Three additional heterozygous family members exhibited milder cognitive and behavioral deficits including attention deficit-hyperactivity disorder (ADHD; 143465). Trudeau et al. (2006) noted that it was unclear whether the relatives of the proband had a milder version of the neurologic abnormalities seen in the proband due to haploinsufficiency for SCN8A, or if the proband's symptoms were caused by an unrelated developmental disorder.
In a girl with developmental and epileptic encephalopathy-13 (DEE13; 614558), Veeramah et al. (2012) identified a de novo heterozygous c.5302A-G transition (c.5302A-G, NM_014191.2) in the SCN8A gene, resulting in an asn1768-to-asp (N1768D) substitution in a highly conserved residue in the final transmembrane segment adjacent to the C-terminal cytoplasmic domain. The mutation was identified by whole-genome sequencing. Expression of the mutant protein in a neuronal cell line showed that it caused persistent sodium currents, incomplete channel inactivation, and a depolarizing shift in the voltage dependence of steady-state fast inactivation. Current-clamp analysis in rat hippocampal neurons transfected with the mutant protein showed increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency, consistent with a dominant gain-of-function phenotype. All of these studies were consistent with neuronal hyperexcitability. Whole-genome sequencing also identified putative recessive variants in the NRP2 (602070) and UNC13C (614568) genes in the proband, which may have contributed to the phenotype. The patient developed refractory generalized seizures at age 6 months. At age 4 years, the seizure phenotype changed to epileptic spasms, followed by regression of speech and language skills. She also had developmental delay, intellectual disability, autism, hypotonia, and difficulties with coordination and balance. Initial electroencephalogram (EEG) showed bifrontal spikes and brief bursts of generalized spike-wave activity. Later EEG showed diffuse slowing, multifocal spikes, and frontally predominant generalized spikes. Brain MRI was normal. The patient died suddenly at age 15 years. There was no family history of a similar disorder.
In a boy (patient T2939) with developmental and epileptic encephalopathy-13 (DEE13; 614558), Carvill et al. (2013) identified a heterozygous c.3868C-G transversion (c.3868C-G, NM_001177984.2) in the SCN8A gene, resulting in a leu1290-to-val (L1290V) substitution. The patient had onset of seizures at age 18 months. The mutation was inherited from the father, who was found to be somatic mosaic for the mutation.
In a 2-year-old Japanese girl (patient 4) with developmental and epileptic encephalopathy-13 (DEE13; 614558), Ohba et al. (2014) identified a de novo heterozygous c.4850G-A transition (c.4850G-A, NM_014191.3) in the SCN8A gene, resulting in an arg1617-to-gln (R1617Q) substitution at a highly conserved residue in the S4 transmembrane segment that plays a role in voltage sensing. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the Exome Sequencing Project database or in 408 in-house control exomes. Functional studies of the variant were not performed. The patient had onset of seizures at 3 months of age.
In a 6-year-old Japanese boy (patient 1) with developmental and epileptic encephalopathy-13 (DEE13; 614558), Ohba et al. (2014) identified a de novo heterozygous c.4398C-A transversion (c.4398C-A, NM_014191.3) in the SCN8A gene, resulting in an asn1466-to-lys (N1466K) substitution at a highly conserved residue in the linker region between domains III and IV that forms an inactivation gate. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the Exome Sequencing Project database or in 408 in-house control exomes. Functional studies of the variant were not performed. The patient had onset of intractable seizures on day 3 of life.
In a 6-year-old Israeli boy (patient 5) with developmental and epileptic encephalopathy-13 (DEE13; 614558), Ohba et al. (2014) identified a de novo heterozygous c.4397A-C transversion (c.4397A-C, NM_014191.3) in the SCN8A gene, resulting in an asn1466-to-thr (N1466T) substitution at a highly conserved residue in the linker region between domains III and IV that forms an inactivation gate. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the Exome Sequencing Project database or in 408 in-house control exomes. Functional studies of the variant were not performed. The patient had onset of seizures at 4 months of age.
In a 3-year-old girl with developmental and epileptic encephalopathy-13 (DEE13; 614558), de Kovel et al. (2014) identified a de novo heterozygous c.667A-G transition in the SCN8A gene, resulting in an arg223-to-gly (R223G) substitution at a highly conserved residue in the voltage-sensing transmembrane segment 4 of domain 1 (D1S4). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. In vitro cellular functional expression studies showed that the mutant protein had significantly reduced stability (about 20% of wildtype) and that the mutant channel had reduced peak current amplitude (20% of wildtype) at 37 degrees C. There was a 3-fold increase in the ramp current at 30 degrees C, but this was still a significant reduction in terms of absolute current levels. The findings were consistent with a loss-of-function effect. De Kovel et al. (2014) noted that SCN8A is expressed in inhibitory neurons, where a loss of function may yield an epileptic phenotype. The patient had onset of seizures at 6 months of age.
In a 7-year-old girl with developmental and epileptic encephalopathy-13 (DEE13; 614558), Blanchard et al. (2015) identified a de novo heterozygous c.2952C-G transversion (c.2952C-G, NM_014191.2) in the SCN8A gene, resulting in an asn984-to-lys (N984K) substitution at a highly conserved residue adjacent to the transmembrane segment of the channel. The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells showed that the mutation caused a 10-mV hyperpolarization shift, predicting premature channel opening and neuronal hyperactivity. The findings were consistent with a gain of function. The patient had onset of intractable seizures at 6 weeks of age.
In a 33-year-old man with developmental and epileptic encephalopathy-13 (DEE13; 614558), Blanchard et al. (2015) identified a de novo heterozygous c.4351G-A transition (c.4351G-A, NM_014191.2) in the SCN8A gene, resulting in a gly1451-to-ser (G1451S) substitution at a conserved residue in transmembrane segment D3S6. The mutation was found by exome sequencing and confirmed by Sanger sequencing. In vitro functional expression studies in HEK293 cells showed that the mutation caused a 10-fold decrease in current density compared to wildtype, consistent with a loss of function. However, Blanchard et al. (2015) postulated that the mutant protein may also have a dominant effect. The patient had onset of seizures at 18 months of age.
In 16 patients from 3 unrelated families with benign familial infantile seizures-5 (BFIS5; 617080), Gardella et al. (2016) identified a heterozygous c.4447G-A transition in the SCN8A gene, resulting in a glu1483-to-lys (E1483K) substitution at a highly conserved residue in the intracellular loop between domains III and IV. The variant, which was found by exome sequencing in 2 of the families and confirmed by Sanger sequencing, segregated with the disorder in all 3 families, with evidence of incomplete penetrance. The mutation was not found in the dbSNP (build 138), 1000 Genomes Project, Exome Variant Server, or ExAC databases. Linkage analysis excluded a founder effect. Although functional studies of the mutation were not performed, Gardella et al. (2016) postulated that it caused a small gain-of-function effect resulting from impaired channel inactivation.
In a father and son with benign familial infantile seizures-5 (BFIS5; 617080), Anand et al. (2016) identified a heterozygous c.5630A-G transition (c.5630A-G, NM_014191.3) in the SCN8A gene, resulting in an asn1877-to-ser (N1877S) substitution in a conserved region that contains binding sites for interacting proteins. The mutation, which was found by next generation sequence analysis, was not present in the dbSNP, 1000 Genomes Project, or the Exome Variant Server databases. The authors stated that the same variant had been described by several laboratories, including ClinVar (SCV000152660.1) and GeneDx (SCV000242923.2), in patients with epilepsy, developmental delay, and intellectual disability, consistent with developmental and epileptic encephalopathy-13 (DEE13; 614558). Functional studies of the variant were not performed by Anand et al. (2016). The benign phenotype in the father and son suggested that they may carry additional variants in other genes that offer a protective effect. Sanger sequencing of the father did not show somatic mosaicism for the SCN8A mutation.
In 3 affected members of a family with myoclonic epilepsy-2 (MYOCL2; 618364), Wagnon et al. (2018) identified a heterozygous c.5156C-G transversion (c.5156C-G, NM_014191.3) in the SCN8A gene, resulting in a pro1719-to-arg (P1719R) substitution in the conserved pore loop of domain IV that confers sodium selectivity to the channel. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family in those who agreed to testing. The variant was not found in the gnomAD database. In vitro functional expression studies in transfected neuron-derived cells showed that the mutation caused a partial loss of function, manifest as decreased inward sodium current, compared to controls.
In a 7-year-old girl (patient 1) with cognitive impairment without cerebellar ataxia (CIAT; 614306), Wagnon et al. (2017) identified a de novo heterozygous c.2890G-C transversion in the SCN8A gene, resulting in a gly964-to-arg (G964R) substitution at a highly conserved residue in transmembrane segment 6 of domain II. The mutation, which was found by exome sequencing, was not found in the ExAC database. The patient also carried a heterozygous frameshift variant (c.167delT) in the GJB2 gene (121011) that was inherited from an unaffected parent. In vitro functional expression studies in transfected cells showed that the G964R mutation caused a complete loss of channel activity.
In a 10-year-old boy (patient 2) with cognitive impairment and a history of ataxia (CIAT; 614306), Wagnon et al. (2017) identified a de novo heterozygous c.3652G-A transition in the SCN8A gene, resulting in a glu1218-to-lys (E1218K) substitution at a highly conserved residue in transmembrane segment 1 of domain III. The mutation, which was found by exome sequencing, was not found in the ExAC database. The variant was not found in the unaffected mother; the father was not available for testing. The patient also carried a heterozygous missense variant (A174T) in the PDHA1 gene (300502) that was inherited from an unaffected grandparent. In vitro functional expression studies in transfected cells showed that the E1218K mutation caused a complete loss of channel activity. There was also a decreased amount of mutant protein, suggesting reduced stability.
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