全外显子测序技术在主动脉夹层及腹主动脉瘤致病基因的鉴定研究

发布时间：2018-03-25 21:36

  本文选题：主动脉夹层　切入点：腹主动脉瘤　出处：《南京大学》2017年硕士论文

【摘要】：研究背景:主动脉夹层(thoracic aorta dissection,TAD)和腹主动脉瘤(abdominal aorta aneurysm,AAA)都是严重威胁人类健康的疾病。这两种疾病一般起病隐匿,一旦发生主动脉破裂,预后极其不良。TAD是一种单基因遗传病。目前研究已证实可导致TAD疾病有数十种基因。多种综合征疾病可表现为TAD,比如马凡综合征(Marfan syndrome)、Loeys-Dietz syndrome(LDS)、Ehlers-Danlos syndrome(血管型)、Turner syndrome等。这些疾病常常在患者成年前发病,致死率非常高。但由于临床表型在不同疾病或同一种疾病中不尽相同,也有少部分综合征患者临床症状轻微,在成年甚至中年才有TAD表现,这些因素都增加了临床医生诊断TAD病因的难度。AAA一般发病年龄超过60岁,是一种多基因共同致病、受环境等外界因素影响的疾病。高龄的AAA患者的病因主要为高血压、吸烟和动脉粥样硬化形成。但年轻的AAA患者,尤其是有家族史的患者,临床医生往往无法提供病因诊断、生活指导、生育及遗传咨询。在过去的30多年中,学者一直在研究AAA的致病基因,但成果不尽人意。有些成果甚至互相矛盾。像TAD一样,AAA也可以由多种综合征疾病导致,病因诊断困难。全外显子组测序(Whole Exome Sequencing,WES)能够对基因组全部外显子进行测序分析,可以高效地发现已知致病基因的突变甚至可以发现新的致病基因。目的:鉴定主动脉夹层和腹主动脉瘤的致病基因。方法:运用WES技术对3例Stanford B型主动脉夹层患者、1例腹主动脉瘤患者进行测序分析。结果:我们发现2例Stanford B型主动脉夹层存在FBN1基因突变分别为c.G6953A(p.C2318Y)和 c.4786T(p.RJ596X);发现 1 例 Stanford B 型主动脉夹层存在PKD2基因突变c.C1774T(p.R592X);首次鉴定了 TGFBR1(rs113605875,exon9,c.G1460A,p.R487Q)基因为 AAA 的致病基因;首次报道了由TGFBR1基因突变导致的AAA家系。结论:与高龄散发的主动脉夹层和腹主动脉瘤不同,我们建议对早发的患者进行病因研究,必要时可运用WES技术以明确病因。致病基因的鉴定不仅有助于临床诊断,而且有助于临床决策、生活方式指导、药物治疗、定期筛查、生育及遗传咨询。
[Abstract]:Background: thoracic aorta dissectiontad (TAD) and abdominal aortic aneurysm (ACA) are serious diseases that threaten human health. The prognosis is extremely poor. Tad is a single gene hereditary disease. Dozens of genes have been found to cause TAD disease. Many syndromes can be manifested as tat, such as Marfan's syndrome, Loeys-Dietz syndromes, DDS, Ehlers-Danlos syndrome.These diseases are vascular type Turner syndrome, et al. The disease often begins before the patient reaches adulthood. The mortality rate is very high. However, because the clinical phenotype is different in different diseases or the same disease, there are a few patients with mild clinical symptoms, and only in adulthood and even in middle age have TAD manifestations. These factors make it more difficult for clinicians to diagnose the etiology of TAD. The general age of onset of TAD is over 60 years old. It is a disease caused by many genes and other external factors. The main cause of elderly patients with AAA is hypertension. Smoking and atherosclerosis. But in young AAA patients, especially those with a family history, clinicians are often unable to provide etiological diagnosis, life guidance, fertility and genetic counseling. Researchers have been studying the genes that cause AAA, but the results have not been satisfactory. Some of the results are even contradictory. Like TAD, triple-A can be caused by multiple syndromes. It is difficult to diagnose the etiology. Whole Exome sequencingus can be sequenced to analyze all exons of the genome. The mutation of known pathogenic genes and even new ones can be found efficiently. Objective: to identify the pathogenic genes of aortic dissection and abdominal aortic aneurysm. Methods: three cases of Stanford B type aortic dissection were studied by WES technique. One patient with abdominal aortic aneurysm was sequenced. Results: two patients with Stanford B aortic dissection had FBN1 gene mutation of c. G 6953 A p. C2318Y and c. 4786 TMP. RJ596XG, and 1 case of Stanford B aortic dissection had PKD2 gene mutation. The TGFBR1 rs113605875 exon9cG1460A p. R487Q) gene was identified as the pathogenicity gene of AAA for the first time. The AAA pedigree caused by TGFBR1 gene mutation was reported for the first time. Conclusion: unlike the elderly patients with sporadic aortic dissection and abdominal aortic aneurysm, we suggest that the etiology of early onset patients should be studied. The identification of pathogenic genes is useful not only for clinical diagnosis, but also for clinical decision making, lifestyle guidance, drug therapy, regular screening, fertility and genetic counseling.
【学位授予单位】：南京大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R543.1
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本文编号：1664976