De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis

Abstract

Objectives To determine the incidence of pathogenic SCN8A variants in a cohort of epilepsy patients referred for clinical genetic testing. We also investigated the contribution of SCN8A to autism spectrum disorder, intellectual disability, and neuromuscular disorders in individuals referred for clinical genetic testing at the same testing laboratory. Methods Sequence data from 275 epilepsy panels screened by Emory Genetics Laboratory were reviewed for variants in SCN8A. Additional cases with variants in SCN8A were ascertained from other testing laboratories. Parental samples were tested for variant segregation and clinical histories were examined. SCN8A variants detected from gene panel analyses for autism spectrum disorder, intellectual disability, and neuromuscular disorders were also examined. Results Five variants in SCN8A were identified in five individuals with epilepsy. Three variants were de novo, one was inherited from an affected parent, and one was inherited from an unaffected parent. Four of the individuals have epilepsy and developmental delay/intellectual disability. The remaining individual has a milder epilepsy presentation without cognitive impairment. We also identified an amino acid substitution at an evolutionarily conserved SCN8A residue in a patient who was screened on the autism spectrum disorder panel. Additionally, we examined the distribution of pathogenic SCN8A variants across the Nav1.6 channel and identified four distinct clusters of variants. These clusters are primarily located in regions of the channel that are important for the kinetics of channel inactivation. Conclusions Variants in SCN8A may be responsible for a spectrum of epilepsies as well as other neurodevelopmental disorders without seizures. The predominant pathogenic mechanism appears to involve disruption of channel inactivation, leading to gain-of-function effects.

The spectrum of intermediate SCN8A‐related epilepsy

“…Ile763Val, Gly1475Arg, Arg1617Gln, Ala1650Val, and Arg1872Gln were all seen in this study, as well as in patients with DEE. Ile763Val has previously been described in a patient with intractable epilepsy and moderate ID, 30 whereas we found it in two patients with focal epilepsy and mild ID (#5 and #6).…”

“…All variants were located at highly conserved residues and were predicted to be possibly damaging according to computational prediction software (see Materials and Methods and Web Resources). Mining the available literature and databases, nine variants were found to be recurrent either within this study or overall; Ile763Val, 30 Val891Met, 31 Gly1475Arg, 10,32 Gly1483Lys, 17 Phe1588Leu, Arg1617Gln, 5,7,8,33,34 Ala1650Val 5,7,35 (different amino acid substitution, see Discussion section), Arg1872Gln 7,12,36 and Asn1877Ser, 30,35,37 with five of them (amino acid positions 763, 1475, 1617,1650, and 1872) seen in severe DEE phenotypes as well.…”

Biallelic inherited SCN8A variants, a rare cause of SCN8A‐related developmental and epileptic encephalopathy

“…10,[13][14][15] The less severe familial SCN8A-related disorders show an autosomal dominant pattern of inheritance, whereas the large majority of EIEE13 cases occur de novo. [1][2][3][4][5][7][8][9][13][14][15] A similar pattern has been reported for SCN2A, in which GOF variants cause early onset seizures, and LOF variants tend to be associated with later onset seizures or with ID or ASD without epilepsy. 16 In the mouse, homozygosity for partial LOF alleles of Scn8a results in movement disorders including ataxia, tremor, and dystonia, whereas complete LOF results in juvenile lethality with loss of ambulation.…”

“…1 The phenotypic spectrum observed in several hundred individuals now includes a range of epilepsies including benign familial infantile seizures with or without paroxysmal dyskinesia, 2 less severe epilepsies with or without comorbid intellectual disability (ID), [3][4][5][6] and severe early onset DEEs. 1 The phenotypic spectrum observed in several hundred individuals now includes a range of epilepsies including benign familial infantile seizures with or without paroxysmal dyskinesia, 2 less severe epilepsies with or without comorbid intellectual disability (ID), [3][4][5][6] and severe early onset DEEs.…”

“…SCN8A, encoding the voltage-gated sodium channel Na v 1.6, was first implicated in developmental and epileptic encephalopathy (DEE) in 2012 in a heterozygous individual with a de novo variant. 1 The phenotypic spectrum observed in several hundred individuals now includes a range of epilepsies including benign familial infantile seizures with or without paroxysmal dyskinesia, 2 less severe epilepsies with or without comorbid intellectual disability (ID), [3][4][5][6] and severe early onset DEEs. 1,7,8 Severe SCN8A DEE (Mendelian Inheritance in Man EIEE13) is characterized by intractable seizures with an average age at seizure onset of 4 months, cognitive deterioration, pyramidal/extrapyramidal signs, progressive cerebral atrophy, and visual impairment leading to cortical blindness.…”