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ORIGINAL ARTICLE

Whole exome sequencing identifies a novel SCN1A mutation in genetic (idiopathic) generalized epilepsy and juvenile myoclonic epilepsy subtypes Chung-Kin Chan 1,2 & Joyce Siew-Yong Low 1,2 & Kheng-Seang Lim 1 & Siew-Kee Low 3 & Chong-Tin Tan 1 & Ching-Ching Ng 2 Received: 20 June 2019 / Accepted: 22 October 2019 # Fondazione Società Italiana di Neurologia 2019

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

Introduction

Chung-Kin Chan and Joyce Siew-Yong Low contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10072-019-04122-9) contains supplementary material, which is available to authorized users. * Kheng-Seang Lim [email protected] * Ching-Ching Ng [email protected] 1

Division of Neurology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

2

Genetics and Molecular Biology, Institute of Biological Sciences, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia

3

Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan

Genetic (idiopathic) generalized epilepsy (GGE) is a group of age-related epilepsies characterized by generalized seizures with EEG showing generalized spikes, polyspikes, or spike/ polyspike-and-wave complexes. GGE is a common form of epilepsy, affecting about 0.3% of the general population and account for 30% of all epilepsies [1]. Previous familial aggregation [2] and twin studies [3] have indicated the presence of a genetic component in GGE predisposition. Previous studies revealed that several genes in the ion channel and transporter synthesis are causing susceptibility to GGE. SCN1A, which is responsible in encoding the poreforming unit of sodium ion channel [4], has been shown to be as

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