本文選題：兒童失神癲癇 + SCN1A�。� 參考：《山西醫(yī)科大學(xué)》2017年碩士論文

【摘要】：目的:兒童失神癲癇(Childhood Absence Epilepsy,CAE)是一種常見的遺傳性全面性癲癇,研究表明半數(shù)以上兒童癲癇與遺傳因素相關(guān),目前,雖報(bào)道了一系列與兒童失神癲癇相關(guān)的基因,但其發(fā)病原因和致病機(jī)制尚不明確。本研究通過(guò)靶向捕獲二代測(cè)序技術(shù)對(duì)100例兒童失神癲癇患兒進(jìn)行測(cè)序,以期發(fā)現(xiàn)新的易感基因及致病性突變,為探討兒童失神癲癇的致病機(jī)制提供依據(jù),并有利于了解其他類型遺傳性全面性癲癇綜合征可能的發(fā)病機(jī)制。此外,對(duì)遺傳性癲癇的臨床診治、遺傳咨詢及基礎(chǔ)研究也具有積極意義。方法:選取從北京大學(xué)第一醫(yī)院神經(jīng)科門診收集的100例不明原因CAE患兒臨床資料和外周血標(biāo)本,應(yīng)用靶向捕獲二代測(cè)序?qū)ζ溥M(jìn)行511個(gè)癲癇相關(guān)基因的突變篩查,篩選出可能的致病突變。然后,應(yīng)用一代測(cè)序(Sanger測(cè)序法)驗(yàn)證突變的父母來(lái)源,結(jié)合生物學(xué)、基因?qū)W及臨床表現(xiàn)明確其致病性,對(duì)氨基酸序列進(jìn)行保守性分析,得出致病性突變。結(jié)果:本研究在100例兒童失神癲癇患兒中共發(fā)現(xiàn)1131個(gè)基因變異,最終從3例CAE患兒中發(fā)現(xiàn)3個(gè)變異為致病性突變,分別為SCN1A(c.5,399TA)、SCN8A(c.2,371GT)和CLCN2(c.481GA),均為新生突變(de novo),Polyphen2軟件對(duì)3個(gè)突變蛋白的功能預(yù)測(cè)為很可能致病(probably damaged);從1例CAE患兒中發(fā)現(xiàn)2個(gè)變異GPR98(c.5815GA和c.16252GT),基因變異分別來(lái)自母親和父親,Polyphen2軟件對(duì)前者變異蛋白的功能預(yù)測(cè)為很可能致病(probably damaged),對(duì)后者的功能預(yù)測(cè)為良性(benign)。根據(jù)人類基因突變數(shù)據(jù)庫(kù)(Human Gene Mutation Database,HGMD),這5個(gè)突變均位于高度保守區(qū)域,均為未報(bào)道的突變(novel mutation)。結(jié)論:SCN1A、SCN8A、CLCN2和GPR98可能是兒童失神癲癇的易感基因。我們的發(fā)現(xiàn)不僅擴(kuò)展了SCN1A、SCN8A、CLCN2以及GPR98的疾病譜,而且發(fā)現(xiàn)了可能致病的兒童失神癲癇易感基因。
[Abstract]:Objective: childhood Absence EpilepsyCae) is a common type of hereditary comprehensive epilepsy. Studies have shown that more than half of children with epilepsy are related to genetic factors. At present, a series of genes related to childhood aphasia epilepsy have been reported. However, the causes and pathogenesis of the disease are still unclear. In this study, 100 children with aphasia were sequenced by targeting capture second-generation sequencing technique, in order to find new susceptible genes and pathogenicity mutations, and to provide evidence for exploring the pathogenic mechanism of childhood aphasia. It is helpful to understand the possible pathogenesis of other types of hereditary comprehensive epilepsy syndrome. In addition, the clinical diagnosis and treatment of hereditary epilepsy, genetic counseling and basic research are also of positive significance. Methods: the clinical data and peripheral blood samples of 100 children with CAE of unknown origin were collected from the Department of Neurology, first Hospital of Peking University, and 511 epileptic-related gene mutations were screened by target capture second generation sequencing. A possible pathogenic mutation was screened out. Then, the parental origin of the mutation was verified by Sanger sequencing method. The pathogenicity of the mutation was confirmed by biological, genetic and clinical manifestations. The amino acid sequence was conservatively analyzed and the pathogenicity mutation was obtained. Results: in this study, 1131 gene mutations were found in 100 children with aphasic epilepsy, and 3 mutations were found as pathogenicity mutations in 3 children. SCN1AU c. 5399TAA (SCN8An c. 2371GTT) and CLCN2C. 481GAA, respectively. The function of the new mutation de novophin Polyphen2 software predicted that the three mutant proteins were likely to be possibly damaged.Two mutations of GPR98 c. 5815GA and c. 16252 GTN were found in a case of CAE, and the genetic variation was derived from mother and father Polyphen2 software respectively. The function of mutant protein was predicted to be probably probable and the function of the latter to be benign. According to the human gene mutation database, Human Gene mutation Database (HGMDA), the five mutations are all located in highly conserved regions, all of which are novel mutation. Conclusion the two genes, CLCN2 and GPR98, may be susceptible to aphasia in children. Our findings not only extend the disease spectrum of SCN1A, SCN8, CLCN2 and GPR98, but also reveal the susceptibility gene to epilepsy in children with possible pathogenicity.
【學(xué)位授予單位】：山西醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R742.1

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本文編號(hào)：2037249