家族性皮质肌阵挛性震颤癫痫—家系的致病基因定位研究

发布时间：2018-01-09 14:29

本文关键词：家族性皮质肌阵挛性震颤癫痫—家系的致病基因定位研究　出处：《浙江大学》2017年硕士论文　论文类型：学位论文

【摘要】：研究背景:家族性皮质肌阵挛性震颤癫痫(Familial cortical myoclonic tremor with epilepsy,FCMTE)是一组遗传模式为常染色体显性遗传的疾病,主要临床表现为成年起病、上肢为主的皮质肌阵挛性震颤、伴或不伴癫痫发作,无小脑性共济失调或痴呆的良性病程。自1990年FCMTE被首次报道以来,已经有超过80个家系被报道,4个致病基因区间被定位:FCMTE1(8q22.3-q24.13),FCMTE2(2p11.2-q12.2),FCMTE3(5p15.31-p15.1)和FCMTE4(3q26.32-3q28)。除位于2p11.2-q12.2的ADRA2B基因突变在两个FCMTE2家系被报道,定位于其它致病基因区间的家系均尚未报道相关致病基因突变。研究目的:对一中国FCMTE家系进行致病基因定位研究。研究方法:采集一中国的FCMTE家系,对家系内成员进行详细的病史采集、完整的神经系统专科查体以及相关的电生理检查明确其临床表型。利用IlluminaHuman Omini ZhongHua-8 BeadChip基因芯片对所选定的20位家庭成员进行全基因组扫描,通过连锁分析及单体型分析,以确定该家系的致病基因区间。研究结果:该家系内有现存患者10例,其中8例患者有震颤与癫痫,2例患者目前仅有震颤。震颤平均起病年龄28岁(9-45岁),癫痫平均起病年龄36岁(31-42岁)。在该家系部分患者中行电生理检查发现存在典型的巨大体感诱发电位和长潜伏期皮质反射。根据遗传模式、临床症状及电生理检查结果,该家系可确定为FCMTE家系。利用全基因组扫描的数据,通过连锁分析发现仅在8号染色体上约17.4Mb的区间内12个单核苷酸多态上得到大于3的LOD值,最高LOD值为3.185。单体型分析将该家系的致病基因区间定位于8q22.3-q24.13上rs506389至rs12544067之间约20.25Mb区间内。研究结论:我们采集一中国的FCMTE家系,其遗传模式、临床表现及电生理检查结果均符合FCMTE的诊断标准。进一步遗传学研究将其致病基因定位于8q22.3-q24.13,与日本团队及本团队所报道过的FCMTE1家系定位结果相符,为鉴定FCMTE1的致病基因打下基础。
[Abstract]:Background: familial cortical myoclonic tremor with epilepsy. FCMTEA is a group of autosomal dominant diseases with major clinical manifestations of adult onset, upper limb myoclonic tremor, with or without epileptic seizures. No benign course of cerebellar ataxia or dementia. Since FCMTE was first reported in 1990, more than 80 families have been reported. The four pathogenetic gene regions were mapped to 8q22.3-q24.13FCMTE2FCMTE2 (2p11.2-q12.2). FCMTE3 (5p15.31-p15.1) and FCMTE4 (3q26.32-3q28). Except for 2p11.2-q12.2 ADRA2B gene mutations were reported in two FCMTE2 families. No related mutations have been reported in families located in other pathogenetic gene regions. Objective: to study the pathogenicity gene mapping of a Chinese FCMTE family. A Chinese FCMTE pedigree was collected. The family members were collected in detail. Complete physical examination of the nervous system and related electrophysiological examination to determine its clinical phenotype. Using IlluminaHuman Omini ZhongHua-8. The genomes of 20 selected family members were scanned by BeadChip gene chip. Linkage analysis and haplotype analysis were used to determine the gene interval of the family. Results: there were 10 patients in this family, 8 of them had tremor and epilepsy. Only tremor is present in 2 patients. The average onset age of tremor is 28 years old to 9-45 years old. The mean onset age of epilepsy was 36 years old and 31-42 years old. Electrophysiological examination showed that there were typical giant somatosensory evoked potentials and long latency cortical reflexes in some of the patients. Clinical symptoms and electrophysiological examination results, the family can be identified as FCMTE pedigree, using the whole genome scanning data. Linkage analysis showed that only 12 single nucleotide polymorphisms on chromosome 8, about 17.4 Mb, were found to have a LOD value greater than 3. The maximum LOD value was 3.185.Haplotype analysis mapped the range of pathogenic genes between rs506389 and rs12544067 on 8q22.3-q24.13. Within the range of 25 Mb. Conclusions of the study:. We collected a Chinese FCMTE family. The genetic pattern, clinical manifestation and electrophysiological examination results were in accordance with the diagnostic criteria of FCMTE. Further genetic studies located the pathogenicity gene at 8q22.3-q24.13. The results were consistent with the FCMTE1 pedigree loci reported by the Japanese team and our team, which laid the foundation for the identification of the pathogenic gene of FCMTE1.
【学位授予单位】：浙江大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R742.1

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