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

Abstract

Objective: Monoallelic de novo gain-of-function variants in the voltage-gated sodium channel SCN8A are one of the recurrent causes of severe developmental and epileptic encephalopathy (DEE). In addition, a small number of de novo or inherited monoallelic loss-of-function variants have been found in patients with intellectual disability, autism spectrum disorder, or movement disorders. Inherited monoallelic variants causing either gain or loss-of-function are also associated with less severe conditions such as benign familial infantile seizures and isolated movement disorders. In all three categories, the affected individuals are heterozygous for a SCN8A variant in combination with a wild-type allele. In the present study, we describe two unusual families with severely affected individuals who inherited biallelic variants of SCN8A. Methods: We identified two families with biallelic SCN8A variants by diagnostic gene panel sequencing. Functional analysis of the variants was performed using voltage clamp recordings from transfected ND7/23 cells. Results: We identified three probands from two unrelated families with DEE due to biallelic SCN8A variants. Each parent of an affected individual carried a single heterozygous SCN8A variant and exhibited mild cognitive impairment without seizures. In both families, functional analysis demonstrated segregation of one allele with complete loss-of-function, and one allele with altered biophysical properties consistent with partial loss-of-function. Significance: These studies demonstrate that SCN8A DEE may, in rare cases, result from inheritance of two variants, both of which exhibit reduced channel activity. In these families, heterozygosity for the dominant variants results in less severe disease than biallelic inheritance of two variant alleles. The clinical consequences of variants 2278 | WENGERT ET al.

Utility of genetic testing for therapeutic decision‐making in adults with epilepsy

“…18 In the pediatric cohort, PPRT2 and KCNQ2 are among the most common genetic findings, whereas we did not see these genes at all in our cohort. Additionally, we found just a single patient with a variant in SCN8A, 19 and none with variants in SCN2A, even though these genes are some of the most common genetic causes of epilepsy 7 (Johannesen et al, manuscript in preparation). The same characteristics are found in a recent study by Borlot et al, where they found one patient with an SCN2A variant, one patient with a pathogenic variant in KCNQ2 (who had been seizure-free for several years, illustrating a stable epilepsy), and none with SCN8A.…”

“…However, reports on adults harboring these variants are extremely limited. 19 The genes causing self-limiting epilepsy, such as PPRT2, will not be seen at our center at all. Furthermore, the TSC1 and TSC2 genes are not seen in our cohort, primarily because these patients have been diagnosed in childhood (as tuberous sclerosis is a relatively recognizable diagnosis) and are not referred for genetic testing as adults.…”

Genotype-phenotype correlations in SCN8A-related disorders reveal prognostic and therapeutic implications

“…Twenty-one variants were deleterious, either frameshift, stop or splice-site variants. Three patients had biallelic missense variants 34 . Sixty-one recurring missense variants were found in 244 affected individuals.…”

Epilepsy-Related Voltage-Gated Sodium Channelopathies: A Review

“…Consequently, electrophysiological changes such as increased current density, shifting steady-state activation, and inactivation to negative and positive values, respectively, enhanced persistent current, accelerated recovery from inactivation, and delayed fast inactivation can cause gain-of-function (GoF) in the channel. Also, decreased current density, positive shift in steady-state activation, negative shift in steady-state inactivation, and slower recovery from inactivation can cause loss-of-function (LoF) ( Mantegazza et al., 2005 ; Liao et al., 2010 ; Lossin et al., 2012 ; Catterall, 2014b ; Vanoye et al., 2014 ; Wagnon et al., 2017 ; Yang et al., 2018 ; Zaman et al., 2018 ; Wengert et al., 2019 ; Zhang S. et al., 2020 ).…”