The finding of a new heterozygous mutation site of the SCN2A gene in a monozygotic twin family carrying and exhibiting genetic epilepsy with febrile seizures plus (GEFS plus ) using targeted next-generation sequencing

Objectives: Generalized epilepsy with febrile seizures plus (GEFS+) is a new epilepsy syndrome named by the International League Against Epilepsy (IIAE) in 2001. The SCN2A gene encoding alpha 2 subunit of the neuronal sodium channel has been reported to be associated with BFNIS, GFES +, Dravet syndrome and some intractable childhood epilepsies. This study aimed to develop an approach based on next-generation sequencing to determine the genetic defects in a monozygotic twin family with GEFS+. Patients and methods: We collected a twin family with GEFS+. The DNA of the twin patients was extracted from their peripheral venous whole blood. A total of 308 known genes related to epilepsies were selected for deep exon resequencing. The patients family's DNA was sequenced through Sanger's sequencing for expanded validation. Through systematic data analysis using established bioinformatics pipeline and segregation analysis techniques, a number of genetic variants were released. Results: Through detailed data analysis, we found a new heterozygous mutation c.1399G > A on exon11 of SCN2A (Nav1.2) which has not been reported in the HGMD (Human Gene Mutation Database), in the twin patients. Then we tested and verified the presence of the same mutation site in all individuals of the family. Asymptomatic individuals of this family didn't show this mutation. Conclusion: The methodology provides a reliable strategy for routine gene diagnosis of GEFS+. This observation of a potentially pathogenic mutation of SCN2A (Nav1.2) indicates that this gene should be further evaluated in order to determine possible routes of causation of GEFS+.