| Background:Febrile seizures and epilepsy are inextricably linked.A considerable number of children with febrile seizures may turn into epilepsy.According to statistics,the probability of simple febrile seizures developing into epilepsy is 1.0%-1.5%.The probability of complex febrile seizures developing into epilepsy is 4%-15%.However,the prognosis of epilepsy and febrile seizures is very different,and it also has a great difference and influence on the mental and economic burden of the family.Gene detection is a hot issue in the study of the relationship between febrile seizures and epilepsy in recent years.High-throughput gene sequencing provides a more accurate basis for the study of epilepsy genetics.To provide more powerful diagnosis and treatment ideas for the occurrence,evolution,treatment and prognosis of epilepsy,and to provide more basis for further clarifying the etiology,early diagnosis,individualized treatment and guiding prognosis of epilepsy.Therefore,we conducted in-depth studies on the clinical phenotypes and related pathogenic genes of children with febrile seizures,and explore the important role and mechanism of these genes in children with febrile seizures,so as to guide the treatment and prognosis.Objective:To summarize and analyze the clinical manifestations of epilepsy in children with febrile seizuresthe expression of related genes,and to explore the important role of these genes in children with febrile seizures,and to further explore the pathogenic genes that may cause epilepsy in children with febrile seizures,so as to provide diagnostic basis and guide treatment and prognosis for children with febrile seizures.Methods:The clinical details of 51 children with epilepsy with febrile seizures diagnosed and treated in the outpatient clinic and ward of the Department of Pediatric Neurology of Shandong Provincial Hospital from January 2017 to January 2020 were collected,including sex,age,family history,type and age of first seizures,interval between seizures,number of seizures,history of birth and development,etc.),according to whether there is a family history of febrile convulsion or epilepsy.The patients were divided into positive family history group(n=28)and negative family history group(n=23).After obtaining the consent of the child’s parents and signing the informed consent form,Peripheral blood samples of the children themselves and their parents were collected,with a volume of 2-4 ml,and stored in a refrigerator at 4℃.High-throughput sequencing technology was applied to complete exon gene sequencing screening,and the identified mutation sites were verified by first-generation stable sequencing(Sanger).Results:1.Among 51 children with epilepsy,7 children were found to have positive pathogenic genes,including generalized tonic clonic seizures in 30 cases,complex partial seizures in 10 cases,simple partial seizures in 6 cases,tonic seizures in 5 cases,eyelid myoclonic seizures in 4 cases,myoclonic seizures in 3 cases,absence seizures in 2 cases,myoclonic seizures in 2 cases,behavioral termination seizures in 2 cases,atonic seizures in 1 case and hyperkinesia in 1 case.There were 9 children with more than two kinds of seizures at the same time,and positive pathogenic genes were detected in 6 of them.2.Among 51 children with epilepsy caused by febrile seizures,8 gene variation sites were detected in 7 children,including 6 cases of simple febrile convulsion and 1 case of complex febrile seizures.Among the 8 gene variation sites highly related to clinical phenotype,5 mutations originated from mothers and 3 mutations were spontaneous mutations.One case had two mutations in the same gene,which were CACNA1H(c.2061de1C,p.P689Qfs*4)andCACNA1H(c.5407C>T,p.R1803C),which were frameshift mutation and missense mutation,respectively.One case is SCN1A(c.4252-4A>G),is a splice mutation,which has been reported in HGMD database and is related to Dravet syndrome.ACMG guidelines determine that it is a pathogenic mutation.One case is GABRB3(c.5G>Agrap.W2X),which is a nonsense mutation,which has been reported in HGMD database,and is related to epileptic encephalopathy and early onset,and the ACMG guidelines determine that it is a suspected pathogenic mutation;one case is SCN1B(c.133C>Tdcep.R45C),which is a missense mutation;one case is CHD2(c.4036G>T,p.V1346L),which is a missense mutation;and one case is SPTAN(c.3101 A>G,p.N 1034S),which is a missense mutation.One case was SCN1B(c.491G>C,p.R164T),which was missense mutation.All the ACMG guidelines were judged to be of unknown meaning.3.It was found that there were 26 gene variants in 22 children:ATP 1A2,SCN 9A,CACNA1H,TSC2,BSN,KCNT1,GRIN2A,HDAC4,KCNH5,DEPDC5,TS C2,KCNQ2,ALG13,ZEB2,RYR3,KCNMA1,ARHGEF9,FLNA,NID2,AARS,DEPDC5,TSCN9A,SCN2A,GABRD,HCN1,PRRT2,including 31 suspicious gene variants,17 from fathers and 14 from mothers.Four loci TSC2(p.T1330 M,c.3989C>T),TSCN9A(p.V1034I,c.3100G>A),SCN2A(p.M1128T,c.3383T>C)andPRRT2(p.P216H,c.647C>A)were reported in the literature da tabase,in which TSCN9A(p.V1034I,c.3100G>A)and PRRT2(p.P216H,c.647C>A)were located in the hot spot of mutation,but the amino acid change s caused by mutations at the same position reported in the literature databa se were different.4.Child 1 has a large sample of data supporting the susceptibility site ATP7A,previously reported to be associated with epilepsy.5.88 meaningless mutations were found in this study.6.No gene mutation was found in 6 children.Conclusion:1.Children with epilepsy caused by febrile seizures have various forms of seizures,and generalized tonic clonic seizures are the most common.At the same time,there are a variety of seizure forms,and the positive rate of gene detection is higher.2.SCN1A gene splicing mutation(c.4252-4A>G)and GABRB3 gene nonsense mutation(c.5G>A,p.W2X)were detected,which further supported.the correlation between these two gene loci and febrile seizures onset epilepsy.3.The results showed that SCN1B gene missense mutation(c.1 33C>T,p.R45 C),(c.491 G>C,p.R164T),CACNA1H gene frameshift mutation(c.2061d e1C,p.P689Qfs*4),missense mutation(c.5407C>T,p.R1803 C),CHD 2 gene missense mutation(c.4036G>T,p.V1346L)were detected.These fo ur loci have not been reported before,which have certain significance to expand the gene spectrum of children with febrile convulsion onset epilepsy.4.SPTAN1 and ATP7A genes were detected,which had not been reported in the past.They may be related to the onset of febrile seizures and need more clinical data to prove.5.8 gene variation sites highly related to clinical phenotype were detected in the negative family history group,which may be related to the small sam ple size and need to be further studied in the future. |
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