The Mutations Of CACNA1H Gene And Idiopathic Generalized Epilepsy

Objective:Genes of patients with Idiopathic generalized epilepsy were sequenced by the whole exome sequencing to screen the patients with the mutation of CACNA1 H gene,from the gene level to Clinical level,in order to explore the relationship between CACNA1 H variations and IGE subtype and provide the theoretical basis for individual treatment of these patients.Methods:From June 2015 to June 2017,153 patients were selected with IGE at the Department of Neurology,XiJing Hospital,China.The genes of these patients were sequenced by the whole exome sequencing.40 patients with CACNA1 H variations were screened by WES results.The selected variation sites were verified by Sanger sequencing to determine the final entry.Rating all variation sites with reference to the American Society of Medical Genetics and Genome guidelines determine the nature of the variations.Results:153 patients diagnosed with IGE from June 2015 to June 2017 at the Department of Neurology,XiJing Hospital,whose genes were sequenced by the whole exome sequencing.38 patients were screened into the group whose WES results showing CACNA1 H variations,accounting for 24.8%.There were 19 males and 19 females at the age of 4?33 years old,the age of onset of 1?25 years.The WES results showed that 30 variation sites of CACNA1 H in all of the 38 patients,including 25 missense mutations,2 split-site mutations,2 truncated mutations and 1 non-coding region mutation.Some patients also have mutations in other genes.The frequency of the other gene mutation from high to low was SCN9A(n=6),GPR98(n=6),CASR(n=3)and CLCN2(n=3).1.In the 153 patients diagnosed as IGE,whose genes were sequenced by the whole exome sequencing,38 patients had the mutation of CACNA1 H with or without other genes,accounting for 24.8%.In 38 patients with IGE,30 mutation sites of CACNA1 H gene were screened according to the ACMG guidelines,including 2 truncated mutations: p.728,Y>Xfs1,p.171,W>X(2177),three missense mutations: p.E282 KV,p.A748 V,p.G773 D.The rest are variance unknown sites.2.38 patients with the mutations of CACNA1 H gene included several common and rare subtypes of IGE,including 12 cases of epilepsy with generalized tonic-clonic seizures only,12 cases of juvenile myoclonic epilepsy,4 cases of generalized epilepsy with febrile seizures plus or febrile seizures plus,3 cases of childhood absence epilepsy or juvenile absence epilepsy,3 cases of unclassifiable epilepsy,2 cases of benign infantile myoclonic epilepsy,1 case of epilepsy with myoclonic atonic seizures and 1 case of myoclonic absence epilepsy.3.Among 38 patients with IGE,10 patients had the pathogenic or likely pathogenic mutation sites of CACNA1 H gene,including 6 males and 4 females.Among these patients,3 cases belonged to EGTCS,3 cases belonged to JME,2 cases belonged to GEFS+,1 case belonged to JAE and 1 case belonged to BMEI.After medication,5 cases achieved Seizure free,3 cases had seizure reduction more than 50%,and 2 cases had seizure reduction less than 50%.The two patients with seizure reduction less than 50% had a common p.A748 V missense mutation of CACNA1 H gene.4.Among 38 patients with IGE,there were 11 cases only with CACNA1 H gene mutation,21 cases with one other gene mutation,5 cases with 2 other gene mutations,and 1 case with 3 other gene mutations.In these 27 patients with IGE,5 mutation sites of the SCN9 A gene were found,5 mutation sites of the GPR98 gene were found,2 mutation sites of the CLCN2 gene were found,2 mutation sites of the CASR gene were found.None of these mutations are rated as pathogenic or possibly pathogenic,but the frameshift mutation site of CASR,p.F714Sfs27,can be rated as a pathogenic site according to the ACMG guidelines.In this case,the mutation site of the CACNA1 H gene is rated as a variance unknown site.The patient with frameshift mutation of CASR gene had the phenotype of GEFS+,which has reached Seizure free after single drug treatment with LEV.Conclusions:1.The mutation of CACNA1 H gene is more common in IGE patients.2.The mutation of CACNA1 H gene may occur in different subtypes of IGE patients,including EGTCS,CAE,JMES,GEFS,BMEI,MAS and MAE.3.Which gene plays a leading role in the pathogenesis of epilepsy in IGE patients with the mutation of CACNA1 H and others remains to be further studied.