Whole exome sequencing identifies a novel SCN1A mutation in genetic (idiopathic) generalized epilepsy and juvenile myoclonic epilepsy subtypes

Abstract

Introduction

Genetic (idiopathic) generalized epilepsy (GGE) is a common form of epilepsy characterized by unknown aetiology and a presence of genetic component in its predisposition.

Methods

To understand the genetic factor in a family with GGE, we performed whole exome sequencing (WES) on a trio of a juvenile myoclonic epilepsy/febrile seizure (JME/FS) proband with JME/FS mother and healthy father. Sanger sequencing was carried out for validation of WES results and variant detection in other family members.

Results

Predictably damaging variant found in affected proband and mother but absent in healthy father in SCN1A gene was found to be associated with generalized epilepsy and febrile seizure. The novel non-synonymous substitution (c.5753C>T, p.S1918F) in SCN1A was found in all family members with GGE, of which 4/8 were JME subtypes, and/or febrile seizure, while 3 healthy family member controls did not have the mutation. This mutation was also absent in 41 GGE patients and 414 healthy Malaysian Chinese controls.

Conclusion

The mutation is likely to affect interaction between the sodium channel and calmodulin and subsequently interrupt calmodulin-dependent modulation of the channel.

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Acknowledgments

We are grateful to the affected family and all individuals participating in this study.

Funding

This research is supported by High Impact Research MOHE Grant (UM.C/625/1/HIR/MOHE/MED/45) from the Ministry of Higher Education Malaysia.

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Correspondence to Kheng-Seang Lim or Ching-Ching Ng.

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This study was approved by the Medical Ethics Committee of University Malaya Medical Centre (MEC reference number: 944.3). Written consent was obtained from all subjects.

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ESM 1

Summary of whole exome sequencing quality control (PDF 108 kb)

ESM 2

Protein alignments of Nav 1.1 demonstrate high homology of amino acid residue p.Ser1918 (shown in red box) across a set of divergent species (PDF 140 kb)

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Chan, CK., Low, J.SY., Lim, KS. et al. Whole exome sequencing identifies a novel SCN1A mutation in genetic (idiopathic) generalized epilepsy and juvenile myoclonic epilepsy subtypes. Neurol Sci 41, 591–598 (2020). https://doi.org/10.1007/s10072-019-04122-9

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Keywords

  • SCN1A
  • Juvenile myoclonic epilepsy (JME)
  • Genetic generalized epilepsy (GGE)
  • Febrile seizure (FS)