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. Two 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 Na_v1.6 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.

Keywords: Epilepsy; Gene panel analysis; SCN8A; Sodium channels.

Figure 1. Location within the Na_v1.6 channel (A) and evolutionary conservation (B) of the SCN8A variants examined in this study

(A) Location of the variants reported in this study in the Na_v1.6 channel. Roman numerals correspond to the four repeat domains of the channel (DI–DIV). Cylinders represent the six transmembrane segments of each domain. Filled circles denote de novo epilepsy variants. Open circles indicate inherited epilepsy variants. The grey triangle indicates a variant detected from an autism panel. (B) Protein alignment of the human, mouse, rat, zebrafish, and fruit fly VGSC α-subunits. hNa_v1.6: human, mNa_v1.6: mouse, rNa_v1.6: rat, zNa_v1.6: zebrafish, Dm para: Drosophila melanogaster.

Figure 2. Pedigree of Patient 4 showing the inheritance pattern of the SCN8A and GRIN2A variants

Filled symbols indicate affected individuals. The arrow denotes Patient 4.

Figure 3. Distribution of pathogenic epilepsy variants across the Na_v1.6 α-subunit

The filled circles denote the location of pathogenic epilepsy variants reported to be de novo. The open circles denote inherited variants. The four clusters are indicated by lettered circles with arrows.