贵州省两个拟诊遗传性痉挛性截瘫家系收集及基因分析

发布时间：2018-04-26 03:34

本文选题：遗传性痉挛性截瘫 + 基因诊断　；参考：《贵阳医学院》2015年硕士论文

【摘要】：目的:通过对两个拟诊遗传性痉挛性截瘫(HSP)家系的临床观察,先证者进行全外显子组测序,家系成员内基因验证,以建立HSP诊断流程,提高儿科医生对HSP认识,填充HSP基因库,为贵州省开展神经系统遗传性疾病的基因诊断奠定基础。方法:①收集两个拟诊HSP家系先证者的临床资料,包括症状、体征、影像学及神经电生理结果,收集血样,绘制家系遗传图,分析两个家系遗传方式及可能基因分型。②前往家系居住地,采集两家系各成员共17人的临床资料及血液样本,提取DNA并保存。③先证者DNA进行全外显子组测序。④应用Sanger测序检测家系其他成员及对照组,进行变异解释及对候选变异基因验证。结果:①两个家系先证者均以缓慢进展的锥体束损伤为主要临床特点,结合神经电生理、脊髓、头颅MRI结果,及患者家族史,排除其他疾病后临床拟诊为HSP。②家系一有3名患者,两代发病,其余两名患者临床表现与先证者相似,但有不同,其中一名患者伴有耳聋,另一患者出现发育异常、智能低下;家系二有6名患者,连续四代发病,临床表现与先证者相同,仅严重程度不一,有早现现象;③基因分析:家系一先证者全外显子组测序结果提示致病基因为SPG3A、SPG11、SPG12、SPG48,验证家系其他成员上述基因均正常;家系二先证者全外显子组测序结果及Sanger测序验证发现BICD2为致病基因(c.1203GT,p.Gln401His,错义突变)。结论:两个拟诊HSP家系中家系一临床表现较复杂,基因诊断提示该家系为多基因遗传病可能性大,排除HSP。家系二明确致病基因为BICD2,查阅基因库及文献提示该基因突变与HSP发病相关,结合临床及辅助检查结果,诊断为HSP。本研究提高了临床医生对HSP的认识,提醒我们基因病的诊断需重视家系遗传方式,临床分析与基因诊断的结合提高了HSP确诊率,为我院基因诊断、产前基因筛查技术的开展奠定基础。
[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.
【学位授予单位】：贵阳医学院
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R682.22

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