The Research Of Whole-exome Sequencing On Juvenile Myoclonic Epilepsy Patients And Its Clinical Significance

ObjectiveTo explore the genetic diagnosis of juvenile myoclonic epilepsy (JME) patients by whole-exome sequencing (WES) in order to provide evidence for the pathogenesis and treatment of patients with JME.MethodsFrom June 2015 to December 2016, we selected 29 outpatients with JME at the Department of Neurology, Xijing Hospital. All 29 patients underwent WES and the sequencing results were compared with the NCBI database to find the mutation sites of pathogenic or possible pathogenic gene. The genetic diagnoses were made after Sanger sequencing and their related relatives’ verification of the correlated mutation sites.ResultsIn all the 29 patents with JME, the mutations were found in 23 patients, with 21 mutation sites (three patients with the same mutation site), including 20 missense mutations and one frame shift mutation. Six of the 20 missense mutations were CLCN2 gene mutations (c.1834G>A p.R612C,c.1991A>T p.E664V,c.1141C>G p.P381A,c.2006G>A p.A669V, c.1141G>C p.P381A, c.1705G>A p.G569S), three were CACNA1H(c.1735G>A p.D579N, c.5468G>A p.R1823H, c.3646G>A p.D1216N), two were CHD2(c.927C>G p.I309M, c.2291A>C p.H764P) and the remaining mutations were as follows:SCN2A c.1571G>A p.R524Q, LAMC3 c.1675A>G p.I559V, GRIN2A c.2636A>G p.K879R, EFHC1 c.268A>G p.M90V, CHRNA2 c.1073G>T p.S358I, GABRA1 c.116C>T p.T39I, CACNB4 c.1550C>T p.R517Q, KCNT1 c.3317G>A p.R1106Q, CACNA1D c.2206A>G p.M736V. One frame shift mutation was DEPDC5 c.3225_c.3226insGр.V1076Gfs*85. Six of the 23 patients were novel mutation sites and has not yet been reported, including 5 missense mutations (CLCN2 c.1834G>A p.R612C, EFHC1с.268A>G p.M90V, GABRA1 c.116C>T p.T39I, CACNB4 c.1550C>T p.R517Q, CHD2 c.2291A>C p.H764P) and one frame shift mutation (DEPDC5 c.3225_c.3226insG p.V1076Gfs*85). All these changes of protein translation caused by above mutations were harmful to protein function. The gene mutations of eight patients were associated with other types of epilepsy except JME. In the six patients with CLCN2 mutations, three of them showed myoclonic seizures (MS) with generalized tonic—clonic seizures (GTCS),two showed MS with GTCS and absence seizures (AS) and one showed only MS. Four of the six patients accepted valproate therapy with three patients’s seizure reducing 100%, one patient total seizure reducing 75%-99%. Two of the six patients underwent levetiracetam therapy and the total seizure reductions of them were both 50%-74%. CACNA1H mutations were found in five patients with the same seizure type of MS with GTCS. Two of the five patients were in valproate monotherapy and others accepted two antiepileptic drugs. Their GTCS reductions were all 100%, while MS reductions were all 75%-99%.Two of the five patients attempted to reduce antiepileptic drug(s) before MS not controlling and the GTCS relapsed in the course of anti epileptic drug(s) reduction.ConclusionsTwenty-three pathogenic or potentially pathogenic mutations were found in the 29 JME patients underwent WES. Six novel mutations were found. The gene mutations associated with other types of epilepsy except JME were found in eight of the 23 patients.It was suggested that the same gene background might be found between JME and other types of epilepsy. JME patients with CACNA1H mutations were likely manifested MS with GTCS. In these patients, GTCS may be easily controlled after accepted antiepileptic drug(s) and the drug withdrawal of these patients would be careful consideration. In a word, WES provides clues for genetic diagnosis of JME patients, and provides a certain evidence for the pathogenesis, the diagnosis and the treatment of JME patients.