Abstract
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.
| Original language | English |
|---|---|
| Pages (from-to) | 1970-1980 |
| Number of pages | 11 |
| Journal | Epilepsia |
| Volume | 63 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2022 |
| Externally published | Yes |
Bibliographical note
Funding Information:Research reported in this publication was supported by a Dravet Syndrome Foundation grant to MFH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Dravet Syndrome Foundation. TRC and YP were partially supported by the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH) award U54NS108874. I.H. was supported by The Hartwell Foundation through an Individual Biomedical Research Award. This work was also supported by the NINDS (K02 NS112600), the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the Intellectual and Developmental Disabilities Research Center (IDDRC) at Children's Hospital of Philadelphia and the University of Pennsylvania (U54 HD086984), and by intramural funds of the Children's Hospital of Philadelphia through the Epilepsy NeuroGenetics Initiative (ENGIN). Research reported in this publication was also supported by the National Center for Advancing Translational Sciences of the NIH under Award Number UL1TR001878. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This project was also supported in part by the Institute for Translational Medicine and Therapeutics' (ITMAT) Transdisciplinary Program in Translational Medicine and Therapeutics at the Perelman School of Medicine of the University of Pennsylvania. The study also received support through the EuroEPINOMICS-Rare Epilepsy Syndrome (RES) Consortium, and by the German Research Foundation (DFG; HE5415/3-1, HE5415/5-1, HE5415/6-1 to I.H.), including the DFG/FNR INTER Research Unit FOR2715 (He5415/7-1 to I.H.)
Funding Information:
Research reported in this publication was supported by a Dravet Syndrome Foundation grant to MFH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Dravet Syndrome Foundation. TRC and YP were partially supported by the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH) award U54NS108874. I.H. was supported by The Hartwell Foundation through an Individual Biomedical Research Award. This work was also supported by the NINDS (K02 NS112600), the Eunice Kennedy Shriver National Institute of Child Health and Human Development through the Intellectual and Developmental Disabilities Research Center (IDDRC) at Children's Hospital of Philadelphia and the University of Pennsylvania (U54 HD086984), and by intramural funds of the Children's Hospital of Philadelphia through the Epilepsy NeuroGenetics Initiative (ENGIN). Research reported in this publication was also supported by the National Center for Advancing Translational Sciences of the NIH under Award Number UL1TR001878. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This project was also supported in part by the Institute for Translational Medicine and Therapeutics' (ITMAT) Transdisciplinary Program in Translational Medicine and Therapeutics at the Perelman School of Medicine of the University of Pennsylvania. The study also received support through the EuroEPINOMICS‐Rare Epilepsy Syndrome (RES) Consortium, and by the German Research Foundation (DFG; HE5415/3‐1, HE5415/5‐1, HE5415/6‐1 to I.H.), including the DFG/FNR INTER Research Unit FOR2715 (He5415/7‐1 to I.H.)
Publisher Copyright:
© 2022 International League Against Epilepsy.
Keywords
- SCN1A-related epilepsy
- biophysical properties
- co-expressed variants
- modifier gene
- whole exome sequencing