本文選題：遺傳性痙攣性截癱 + 基因診斷��； 參考：《貴陽醫(yī)學(xué)院》2015年碩士論文

【摘要】：目的:通過對兩個擬診遺傳性痙攣性截癱(HSP)家系的臨床觀察,先證者進(jìn)行全外顯子組測序,家系成員內(nèi)基因驗證,以建立HSP診斷流程,提高兒科醫(yī)生對HSP認(rèn)識,填充HSP基因庫,為貴州省開展神經(jīng)系統(tǒng)遺傳性疾病的基因診斷奠定基礎(chǔ)。方法:①收集兩個擬診HSP家系先證者的臨床資料,包括癥狀、體征、影像學(xué)及神經(jīng)電生理結(jié)果,收集血樣,繪制家系遺傳圖,分析兩個家系遺傳方式及可能基因分型。②前往家系居住地,采集兩家系各成員共17人的臨床資料及血液樣本,提取DNA并保存。③先證者DNA進(jìn)行全外顯子組測序。④應(yīng)用Sanger測序檢測家系其他成員及對照組,進(jìn)行變異解釋及對候選變異基因驗證。結(jié)果:①兩個家系先證者均以緩慢進(jìn)展的錐體束損傷為主要臨床特點(diǎn),結(jié)合神經(jīng)電生理、脊髓、頭顱MRI結(jié)果,及患者家族史,排除其他疾病后臨床擬診為HSP。②家系一有3名患者,兩代發(fā)病,其余兩名患者臨床表現(xiàn)與先證者相似,但有不同,其中一名患者伴有耳聾,另一患者出現(xiàn)發(fā)育異常、智能低下;家系二有6名患者,連續(xù)四代發(fā)病,臨床表現(xiàn)與先證者相同,僅嚴(yán)重程度不一,有早現(xiàn)現(xiàn)象;③基因分析:家系一先證者全外顯子組測序結(jié)果提示致病基因為SPG3A、SPG11、SPG12、SPG48,驗證家系其他成員上述基因均正常;家系二先證者全外顯子組測序結(jié)果及Sanger測序驗證發(fā)現(xiàn)BICD2為致病基因(c.1203GT,p.Gln401His,錯義突變)。結(jié)論:兩個擬診HSP家系中家系一臨床表現(xiàn)較復(fù)雜,基因診斷提示該家系為多基因遺傳病可能性大,排除HSP。家系二明確致病基因為BICD2,查閱基因庫及文獻(xiàn)提示該基因突變與HSP發(fā)病相關(guān),結(jié)合臨床及輔助檢查結(jié)果,診斷為HSP。本研究提高了臨床醫(yī)生對HSP的認(rèn)識,提醒我們基因病的診斷需重視家系遺傳方式,臨床分析與基因診斷的結(jié)合提高了HSP確診率,為我院基因診斷、產(chǎn)前基因篩查技術(shù)的開展奠定基礎(chǔ)。
[Abstract]:Objective: through the clinical observation of two families with hereditary spastic paraplegia, the proband was sequenced in the whole exon group, and the gene was verified in the family members to establish the diagnostic procedure of HSP, to improve the knowledge of HSP among pediatricians, and to fill the HSP gene bank. To lay a foundation for genetic diagnosis of genetic diseases of nervous system in Guizhou province. Methods the clinical data of two prospective HSP probands were collected, including symptoms, signs, imaging and neuroelectrophysiological results. Blood samples were collected and family genetic maps were drawn. The genetic patterns and possible genotyping of two families were analyzed. The clinical data and blood samples of 17 members of the two families were collected. Extraction of DNA and preservation of probands DNA sequencing of total exon group. Other members of family and control group were detected by Sanger sequencing for mutation interpretation and validation of candidate mutation genes. Results the proband of two families had the main clinical features of slow progressive pyramidal tract injury, combined with neurophysiology, spinal cord, cranial MRI results, and family history of the patients. After the exclusion of other diseases, the clinical diagnosis was that there were 3 patients in the HSP.2 pedigree with two generations of disease. The other two patients had similar clinical manifestations to the proband, but there were differences. One patient was accompanied with deafness, the other patient had abnormal development and low intelligence. There were 6 patients in the second family. The clinical manifestation was the same as that of the proband, but the severity was different. 3 Gene analysis: the total exon sequence of the proband showed that the pathogenic gene was SPG3A1SPG11, SPG12 and SPG48, which confirmed that the above genes were normal in other members of the pedigree. The results of total exon sequencing and Sanger sequencing in the second probands showed that BICD2 was a pathogenic gene, c. 1203GTP. Gln401. Hisand missense mutation. Conclusion: the clinical manifestations of one pedigree in two prospective HSP families are more complicated. Gene diagnosis indicates that this family is more likely to have polygenic genetic disease and is excluded from this family. The second family identified the pathogenicity gene as BICD2. It was suggested that the mutation of BICD2 gene was associated with the pathogenesis of HSP, and was diagnosed as HSP2 in combination with clinical and auxiliary examination results. This study has improved the clinicians' understanding of HSP, reminded us that the diagnosis of gene diseases should pay attention to the genetic mode of families, and the combination of clinical analysis and gene diagnosis has improved the rate of diagnosis of HSP, which is helpful for gene diagnosis in our hospital. The development of prenatal gene screening technology lay the foundation.
【學(xué)位授予單位】：貴陽醫(yī)學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號】：R682.22

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