Phenotype Analysis And Screening For SCN1A Gene Mutation In Families With Generalized Epilepsy With Febrile Seizures Plus

Background:Generalized epilepsy with febrile seizures plus (GEFS+) is a common epileptic syndrome which is described by families. Since reported by Scheffer and Berkovic in1997, more and more attention was paid on GEFS+,and which joined on epileptic syndrome classification as a kind of new syndrome in2001by International League Against Epilepsy. most research show an autosomal dominant inheritance pattern with incomplete penetrance in GEFS+.It has genetic and phenotypic heterogeneity.there are several clinical phenotype in a family and that the genetic mechanism is complex.The common phenotypes are FS and FS+,the unfrequent pheretypes include FS+with absence seizures;FS+with myoclonic seizures;FS+with atonic seizures;and even severer syndromes such as MAE and Dravet.GEFS+is a kind of channelopathy,the abnormality of channel function and regulation is always resulted from the abnormal expression of these genes,which causes abnormal excitation of the nneurons and the occurrence of seizures. It reported increased gradually at home and abroad in recent years. The recent research abroad mainly concentrated in the family of pathogenic genes and genetic mechanism which identified5kinds of ion channel protein subunit gene related to GEFS+are SCN1A、SCN2A、SCN1B. GABRG2、GABRD respectively encoding voltage-gated sodiumal、α2、β1and chlorine ion channel coding ligand gating GABAA receptory2、δ.A lot of researchs have been made on SCNIA Of foreign families of GEFS+in recent years and that many mutation loci have been found, but the detection rate is only10%that chromosomes genetic mechanism is not fully clear at present.The molecular biology research is rare in our country that lacking of large sample and complete information,and only reported few SCNIA mutation families which can not react of SCNIA gene mutations and clinical phenotype of GEFS+families in China.In this experiment we made careful clinical analysis for the10GEFS+families and summarized its phenotypes and genetic patterns.The mutation screening of SCN1A was made to the members of families in order to find the new mutations and characteristics of molecular biology.Objective:To summarize the phenotypes and identify SCNIA mutation in families with generalized epilepsy with febrile seizures plus (GEFS+). Methods:Genomic DNA was extracted from peripheral blood lymphocytes of the proband and vailable members in the GEFS+families. The phenotypes of the affected members were analyzed. The coding regions and flanking intronic regions of the SCNIA gene were screened for mutations using PCR and direct DNA sequencing.Results:In10GEFS+families,there were33affected members, ranging from2to7affected members in each familv. Their phenotypes included febrile seizures(FS)in11(33.3%), febrile seizures plus(Fs+)in11(33.3%), FS with partial seizures in1(3.0%), afebrile generalized tonic-clonic seizures (AGTCS) in3(9.1%), Dravet syndrome in1(3.0%).childhood absence epilepsy in1(3.0%). unclassified seizures in5(15.2%). Three families were found with SCN1A mutations, including one families with missense mutation (glul444-lys)and two family with silent mutation:One has exon15synonymous mutations (c.2592G>A),another exists both exon9(c.1212G> A) and26exons (c.5385G> A) mutations.Conclusion:1、GEFS+is a common epileptic syndrome in the childhood,with phenotypic heterogeneity.The common phenotypes are FS and FS+.The unfrequent phenotypes include FS+with absence seizure,FS+with myoclonic seizure.2、A new missense mutation and three synonymous mutation was found in our study. One of the families has synonymous mutation in two exon. Genetic mechanism is complex in GEFS+families that needs further research3、The10GEFS+families we collected havecomplete clinical data which can establish the foundation for the research of molecular biology.