Journal
EPILEPSIA
Volume 63, Issue 8, Pages 1970-1980Publisher
WILEY
DOI: 10.1111/epi.17296
Keywords
biophysical properties; co-expressed variants; modifier gene; SCN1A-related epilepsy; whole exome sequencing
Categories
Funding
- Institute for Translational Medicine and Therapeutics
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [U54 HD086984]
- DFG/ FNR INTER Research Unit FOR2715 [He5415/7-1]
- National Center for Advancing Translational Sciences [UL1TR001878]
- National Institute of Neurological Disorders and Stroke [K02 NS112600, U54NS108874]
- Hartwell Foundation
- Deutsche Forschungsgemeinschaft [HE5415/3-1, HE5415/5-1, HE5415/6-1]
- EuroEPINOMICS-Rare Epilepsy Syndrome (RES) Consortium
- Children's Hospital of Philadelphia
- Dravet Syndrome Foundation
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The study found that the second variant in the SCN1A gene, L375S, may counteract the loss-of-function effect of K1372E, preventing individuals carrying both alleles from exhibiting epilepsy-related symptoms.
Objective Family members carrying the same SCN1A variant often exhibit differences in the clinical severity of epilepsy. This variable expressivity suggests that other factors aside from the primary sodium channel variant influence the clinical manifestation. However, identifying such factors has proven challenging in humans. Methods We perform whole exome sequencing (WES) in a large family in which an SCN1A variant (p.K1372E) is segregating that is associated with a broad spectrum of phenotypes ranging from lack of epilepsy, to febrile seizures and absence seizures, to Dravet syndrome. We assessed the hypothesis that the severity of the SCN1A-related phenotype was affected by alternate alleles at a modifier locus (or loci). Results One of our top candidates identified by WES was a second variant in the SCN1A gene (p.L375S) that was shared exclusively by unaffected carriers of the K1372E allele. To test the hypothesized that L375S variant nullifies the loss-of-function effect of K1372E, we transiently expressed Nav1.1 carrying the two variants in HEK293T cells and compared their biophysical properties with the wild-type (WT) variant, and then co-expressed WT with K1372E or L375S with K1372E in equal quantity and tested the functional consequence. The data demonstrated that co-expression of the L375S and K1372E alleles reversed the loss-of-function property brought by the K1372E variant, whereas WT-K1372E co-expression remained partial loss-of-function. Significance These results support the hypothesis that L375S counteracts the loss-of-function effect of K1372E such that individuals carrying both alleles in trans do not present epilepsy-related symptoms. We demonstrate that monogenic epilepsies with wide expressivity can be modified by additional variants in the disease gene, providing a novel framework for the gene-phenotype relationship in genetic epilepsies.
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