Results And Clinical Significance Of Total Exon Sequencing Of Autosomal Dominant Nocturnal Frontal Epilepsy Patients In Northeast China.

Objectives:By collecting and analyzing the clinical data of patients with autosomal dominant nocturnal frontal lobe epilepsy(ADNFLE)and sequencing the whole exome,the clinical characteristics and gene diagnosis of ADNFLE patients were made clear,so as to provide basis for the pathogenesis and diagnosis and treatment of ADNFLE.Methods:From June 2014 to December 2019,8 families with ADNFLE diagnosed in the epilepsy clinic of Neurology Department of the first hospital of Jilin University were enrolled in Wes.By comparing with the database and bioinformatics analysis,the gene mutation site was preliminarily screened,and the site was verified in the first generation and related relatives.According to the ACM in 2015 G)Combined with the "standards and guidelines for interpretation of sequence variation" issued by the society of molecular pathology,we screened out pathogenic or possibly pathogenic mutations,made clear the gene diagnosis of these ADNFLE patients,and analyzed the therapeutic effect of different variants combined with the clinical medication effect.Results:(1)There were 147 members in 14 families,including 49 patients,23 males and 26 females.All of them showed autosomal dominant inheritance.Nine families had patients in each generation.The age of onset ranged from 4 to 25 years,and the average age of onset was 14.6 years.Attack types: deflection ankylosis 19 cases(38.78%),postural ankylosis 16 cases(32.65%),focal autonomic nerve 7 cases(14.29%),hyper motor 4 cases(8.16%),unilateral clonic movement 8 cases(16.33%),general absence 7 cases(14.29%),vocal seizure 15 cases(30.61%),panic attack 3 cases(6.12%),focal to bilateral tonic-clonic seizures(FBTCS)22 cases(44.90%).Among them,27 patients(55.10%)had aura symptoms,22 patients(44.90%)had awareness impairment during seizures,and some patients had cluster seizures,which occurred at least once a day and more than 10 times at most.Only one patient had seizures during the day,while the rest had seizures during nighttime sleep.Twelve probands underwent 24-hour long-range EEG monitoring.Among them,11 cases had abnormal interval,1 case had bilateral discharge and 10 cases had unilateral discharge.Among them,6 cases had frontal discharge,4 cases had temporal discharge,10 cases had epileptic discharge and 3 cases had slow wave.One proband was monitored at the onset stage.EEG showed sharp and slow waves in frontal region with prominent background.All the imaging examinations were normal.Follow-up of the patients(0.1 to 5 years)showed that most of the patients took carbamazepine and oxcarbazepine to obtain good therapeutic effect.Only one patient adjusted to use a variety of antiepileptic drugs had poor therapeutic effect.(2)Gene test results of 8 probands:A total of 22 suspicious sites were found after Wes in 8 probands,all of which were measure mutations(two of them detected the same mutation site).Among them,there are three newly found mutations in ADNFLE related genes,namely,(1)CHRNA4 gene c.384-133 c > T,(2)DEPDC5 gene c.624 + 167 a > C,and(3)KCNT1 gene(lack),which have not been reported before.There are four newly discovered and possibly pathogenic mutation sites,which are respectively(1)SLC2A1 gene c.649 a > C,(2)LGI1 gene c.817 c > t,(3)CACNA1H gene c.4045 g > A,(4)SCN9A gene c.2225 g > T.there is no previous literature report on the above sites,but provean predicted harmful.There are 12 other newly discovered gene mutations,which are respectively(1)LGI1 gene c.817C>T,(2)ADRA2B gene c.561C>G,(3)COL4A2 gene c.3169C>A,(4)ATP1A2 gene c.2563+4C>T,(5)CHRNA4 gene c.384-133C>T,(6)KMT2C gene c.12557G>A,(7)RELN gene c.6430A>G,(8)SATB2 gene c.881G>A,(9)MAF gene c.1055T>C,(10)FLNA gene c.6023-10C>G,(11)ABCD1 gene c.901-10C>T,(12)KCNT2 gene c.1185+8T.There is no previous literature report on the above-mentioned loci,and provean prediction may be harmful,benign or without prediction results,so the pathogenicity cannot be ruled out.Further clinical and basic research is needed.There are 4 other pathogenic or possible pathogenic mutations,respectively,NPRL3 gene c.1270 c > t,PROKR2 gene c.533 g > C,SCN9 A gene c.2359 a > G,NOTCH3 genec.709G>Aheterozygous mutations.The above loci have been reported in the literature,and provean predicted that they are harmful.Conclusion:(1)Summary of data from 14 families: The average age of onset of ADNFLE was 14.6 years old.The characteristics of ADNFLE are characterized by a series of regular and shortterm motor seizures at night.The physical examination and imaging of the nervous system are normal.The EEG during sleep sometimes shows epileptic discharge in the frontal area.Carbamazepine is more effective in treatment and has a good prognosis.The clinical data of 14 families provide a basis for the diagnosis and treatment of clinicians.(2)In this study,we detected 22 pathogenic or possibly pathogenic genes and 18 new suspicious mutation sites in 8 probands,including 3 reported ADNFLE related gene mutations,7 reported harmful ones by provean,and 4 reported mutations.Wes provides the clue of gene diagnosis for ADNFLE patients,and also provides a certain basis for the pathogenesis and precise treatment of ADNFLE.