本文選題：馬凡綜合征 + Ion��； 參考：《北京協(xié)和醫(yī)學院》2017年博士論文

【摘要】：研究內(nèi)容一 125例中國馬凡綜合征患者致病基因突變篩查馬凡綜合征(Marfan syndrome,MFS)是一種常染色體顯性遺傳的結(jié)締組織病,在人群中發(fā)病頻率為1/3000-1/5000。通過高通量測序?qū)FS相關(guān)基因FBN1、TGFBR1、TGFBR2進行檢測,是對患者進行明確診斷,指導手術(shù)及藥物治療的有效手段。研究目的:繪制中國MFS人群突變譜;進行中國MFS基因型表型關(guān)聯(lián)分析;為中國MFS患者提供明確診斷、指導治療、預(yù)后評估及遺傳咨詢;對未篩查到致病變異的家系進行全外顯子組測序(WES)以期發(fā)現(xiàn)新的可能致病基因。研究對象和方法:1.研究對象:125例中國MFS患者及家系成員;2.研究方法:(1)高通量二代測序:通過Ion torrent測序平臺對125例患者進行靶基因測序,測序Panel(靶基因引物庫)中包含3個明確的MFS致病基因;對二代測序結(jié)果進行篩選;并對所篩選到的結(jié)果進行Sanger測序驗證;(2)家系分析:對通過Ion torrent PGM測序未發(fā)現(xiàn)疑似致病變異的有家族史的患者進行了 STR marker家系連鎖分析,確定連鎖區(qū)域。對致病基因連鎖在FBN1基因的家系,進行FBN1基因重測序或整個FBN1基因測序;對于FBN1基因不連鎖的家系,進行全外顯子組測序分析,以期發(fā)現(xiàn)新的致病基因。對一個類馬凡的雙胞胎家系進行全外顯子組測序分析。(3)MLPA檢測大片段插入/缺失突變:對未發(fā)現(xiàn)致病變異患者進行多重連接依賴式探針擴增技術(shù)(MLPA)檢測患者是否攜帶FBN1基因DNA大片段的插入/缺失突變;通過定量PCR的方法對MLPA結(jié)果進行驗證,并且通過步移法來縮短斷裂點上下游的序列;Long Range PCR(長片段PCR)進行擴增和測序,確定具體斷裂點;提取FBN1基因48-53號外顯子缺失的患者血管組織RNA,進行轉(zhuǎn)錄水平分析;(4)對高通量測序篩選和MLPA檢測到的變異進行基因型表型關(guān)聯(lián)性分析。實驗結(jié)果:1.高通量測序結(jié)果:在125例患者中,96例患者發(fā)現(xiàn)100個疑似的致病變異,其中55個為新突變(55.0%);97個(97.0%)疑似的致病變異位于FBN1基因,2個(2.0%)位于TGFBR1基因,1個(1.0%)位于TGFBR2基因;所有變異中包含有34個(34.0%)半胱氨酸的錯義突變;21個(21.0%)非半胱氨酸錯義突變;11個(11.0%)剪接位點突變;11個(11.0%)移碼突變和15個(15.0%)無義突變;攜帶兩個疑似致病變異的患者:發(fā)現(xiàn)3例患者攜帶兩個疑似的致病變異;對家系成員測序分析,發(fā)現(xiàn)其中1例患者為復(fù)合雜合,而另2例為的兩個致病變異發(fā)生在同一等位基因;2.家系研究:在一個家系中發(fā)現(xiàn)FBN1基因附近marker與疾病表型連鎖,通過對FBN1基因重測序發(fā)現(xiàn)41號外顯子發(fā)生移碼插入突變;與FBN1不連鎖家系,經(jīng)過醫(yī)學外顯子組基因高通量測序,發(fā)現(xiàn)位于SMAD3基因突變;發(fā)現(xiàn)CKB基因為雙胞胎家系候選致病基因。3.基因組重排檢測結(jié)果:通過MLPA檢測,共發(fā)現(xiàn)有4例患者分別攜帶有FBN1基因的6號,48-53號,49-50號和1-36號外顯子的大片段缺失,通過長片段PCR(Long Range PCR)進行長片段擴增和測序,確定該4例患者分別缺失了16,551bp,10,346bp,4,563 bp和 187,067bp;通過分析患者血管組織mRNA水平發(fā)現(xiàn)缺失的48-53號為非移碼缺失缺失,其后的mRNA在體內(nèi)保持穩(wěn)定不被降解,由此推測6號和49-50號外顯子缺失可能也為非移碼缺失。而1-36號外顯子缺失突變范圍包含F(xiàn)BN1基因上游11.5kb,使缺失的等位基因不能正常轉(zhuǎn)錄翻譯。4.基因型表型相關(guān)性分析:發(fā)現(xiàn)攜帶半胱氨酸錯義突變的患者和攜帶剪接位點突變的患者與攜帶截短突變的患者相比,更容易患晶狀體脫位,兩例色氨酸突變?yōu)榫彼岬幕颊呤�。心血管方�?攜帶截短(PTC)突變的患者相較于剪接位點突變的患者更容易患主動脈夾層。攜帶FBN1基因p.C123G變異患者表現(xiàn)為罕見的頸總動脈夾層。5.結(jié)合以往研究報道對大片段缺失的患者進行基因型—表型分析發(fā)現(xiàn),大片段非移碼缺失突變患者表型取決于缺失位置及片段大小,但傾向于嚴重新生兒型MFS。大片段缺失(FBN1)引起單倍劑量不足導致的MFS,癥狀多表現(xiàn)為經(jīng)典的MFS癥狀。結(jié)論:1.本研究通過PGM測序技術(shù),檢測到中國MFS人群中103個疑似的致病突變,其中有55個為新突變,豐富了 MFS的基因突變譜;2.攜帶FBN1基因剪接位點突變和半胱氨酸錯義突變的患者相對于攜帶PTC的患者更傾向于患晶狀體脫位;而PTC變異導致的患者,更傾向于患主動脈夾層;攜帶FBN1基因PTC突變的患者與攜帶TGFBR1/2基因突變的患者表型類似,均表現(xiàn)為不易患晶狀體異位,易患主動脈夾層。提示MFS患者眼部異常與原纖維蛋白-1結(jié)構(gòu)變化相關(guān),主動脈夾層與TGFp信號通路改變相關(guān)。3.MLPA是檢測MFS大片段缺失/重復(fù)的有效手段,攜帶非移碼缺失突變的患者傾向于表現(xiàn)為新生兒MFS,單倍劑量不足引起的MFS多表現(xiàn)為經(jīng)典型;4.復(fù)合雜合變異也能夠?qū)е翸FS,對馬凡綜合征的產(chǎn)前篩查具有重要提示作用。研究內(nèi)容二 成人支氣管擴張致病基因篩查及病因?qū)W研究支氣管擴張(Bronchiectasis,簡稱支擴)是一種常見的氣道炎癥疾病,因反復(fù)氣道感染和炎癥造成支氣管和細支氣管管腔異常擴張,關(guān)于該病尤其是非囊性纖維化支氣管擴張(non-CF bronchiectasis,NCFB)的病因、發(fā)病機制及疾病進展過程等的相關(guān)研究國內(nèi)仍較匱乏。支氣管擴張是一種異質(zhì)性很強的疾病,目前對該病的治療手段有限,嚴重影響著患者的生活質(zhì)量。目前對支氣管擴張的病因?qū)W評估分類研究僅能解釋約50%的患者�；颊叩牟∫�?qū)W明確有助于患者的管理,改善患者治療方法以及鞏固長期療效。研究目的:研究中國成人支氣管擴張患者病因組成。從遺傳學角度揭示支氣管擴張患者的遺傳易感性,為支氣管擴張患者病因?qū)W分類提供新的標準。研究對象和方法:1.研究對象:知情同意基礎(chǔ)上收集192例中國成人支氣管擴張患者以及100例確診無肺部疾病的正常對照個體外周血;2.研究方法:(1)192例支氣管擴張患者的病因?qū)W分類;(2)高通量測序:通過Ion torrent PGM測序平臺對192例支擴患者以及100例正常個體進行靶基因Panel測序;測序完成后數(shù)據(jù)通過wANNOVAR網(wǎng)站注釋VCF格式的原始文件;對二代測序結(jié)果進行常規(guī)篩選,保留可能致病的變異位點;通過致病性軟件對變異位點進行致病性判斷;對所篩選到的結(jié)果進行Sanger測序驗證,根據(jù)變異類型進行分類統(tǒng)計;(3)對192例患者及100例正常對照進行CFTR基因8號內(nèi)含子區(qū)域(TG)m Tn重復(fù)序列的PCR擴增,使用ABI3730型號的DNA測序分析儀器測序后分析(TG)m Tn重復(fù)次數(shù);(4)分析CFTR基因雙等位基因突變和CFTR/ENaC基因雙重雜合變異,以及分析CFTR基因V470M多態(tài);篩選囊性纖維化(PCD)相關(guān)致病基因的純合變異,復(fù)合雜合突變;比較192例患者與100例正常個體的PCD相關(guān)致病基因的突變頻率。(4)基因型—表型分析,統(tǒng)計攜帶DNAH5,DNAH11雙等位基因突變和CFTR/ENaC雙重雜合變異的患者的表型,比較各個基因突變導致的患者的支氣管擴張嚴重程度綜合評分(BSI值)。(5)對發(fā)現(xiàn)致病變異的患者進行病因?qū)W統(tǒng)計,并統(tǒng)計遺傳因素在支氣管擴張發(fā)病中所占的比例。實驗結(jié)果:(1)本研究對中國成人支氣管擴張患者人群進行了病因?qū)W分類,發(fā)現(xiàn)31.8%患者為特發(fā)性,27.6%的患者為感染后發(fā)病,13.0%的患者為免疫缺陷,4.2%的患者為哮喘,3.1%的患者為胃食管反流,其他類型為8.3%。(2)通過CFTR基因和上皮鈉離子轉(zhuǎn)運蛋白基因(ENaC)的基因篩查,共發(fā)現(xiàn)3例患者攜帶位于CFTR基因的復(fù)合雜合突變,其中1例患者為IVS8 5T(TGmT5)純合變異攜帶者;另外發(fā)現(xiàn)2例患者攜帶CFTR/ENaC基因雙重雜合突變;CFTR基因V470M多態(tài),在純合M470/M470背景下,發(fā)現(xiàn)12例患者攜帶CFTR基因致病變異,正常對照組為1例,支擴組顯著多于正常對照組(6.3%vs.1.0%,P=0.039);(3)PCD相關(guān)基因突變篩查:發(fā)現(xiàn)20例患者攜帶PCD相關(guān)基因雙等位基因突變(10.4%,20/192),其中14例攜帶DNAH11基因雙等位基因突變,4例攜帶DNAH5基因復(fù)合雜合突變,1例攜帶CCDC40基因復(fù)合雜合突變,1例攜帶HEATR2純合突變。并且發(fā)現(xiàn)1例攜帶位于X染色體的RPGR基因突變;在100例正常個體中發(fā)現(xiàn)有3例攜帶位于DNAH11基因的雙突變。(4)基因型—表型關(guān)聯(lián)性分析:發(fā)現(xiàn)攜帶有DNAH5基因突變的患者相比攜帶DNAH11基因突變患者,其表型要嚴重(BSI平均值:8.8 vs.4.2);攜帶CFTR/ENaC基因雙重雜合子的患者癥狀表型要比攜帶CFTR基因復(fù)合雜合的患者癥狀嚴重(CFTR/ENaCBSI=10 Vs CFTR/CFTR BSI=5.2)。(5)共有 26 例患者發(fā)現(xiàn)攜帶可能致病的致病變異,占到患者總?cè)藬?shù)的13.54%。這些患者中16例病因?qū)W為特發(fā)性,5例為結(jié)核感染后發(fā)病,2例為反流,1例為1gG1免疫缺陷,1例為哮喘和1例麻疹感染后發(fā)病。結(jié)論:本研究對中國成人支氣管擴張患者人群進行了病因?qū)W分析,發(fā)現(xiàn)31.8%患者病因?qū)W為特發(fā)性,27.6%的患者為感染后發(fā)病。通過PGM測序分析支氣管擴張患者,發(fā)現(xiàn)在CFTR基因純合M470背景下,發(fā)生一個CFTR基因的致病變異,極可能導致支氣管擴張;DNAH5基因突變導致的支擴要比DNAH11和CFTR基因突變導致的支擴癥狀嚴重;共有13.54%的患者發(fā)病可能是由遺傳因素導致,本研究為支氣管擴張病因?qū)W分類提供了新的標準,對支擴的預(yù)防及臨床預(yù)后有著重要的意義。
[Abstract]:A 125 case of Marfan syndrome (MFS) is an autosomal dominant connective tissue disease in Chinese Marfan syndrome. The frequency of the disease is 1/3000-1/5000. through high throughput sequencing of the MFS related gene FBN1, TGFBR1, and TGFBR2, which is a definite diagnosis for the patients. Effective means of operation and drug therapy. Objective: to draw a mutation spectrum of Chinese MFS population; to conduct a Chinese MFS genotype phenotype correlation analysis; provide a clear diagnosis, guide treatment, prognostic evaluation and genetic counseling for Chinese MFS patients; a new exon sequence (WES) for a family that has not been screened for pathogenic variation (WES) is to be found in order to discover new Possible pathogenic genes. Research objects and methods: 1. subjects: 125 Chinese MFS patients and family members; 2. research methods: (1) high throughput two generation sequencing: the target gene was sequenced by the Ion torrent sequencing platform, and the sequencing of Panel (target gene primer Library) contained 3 clear MFS pathogenic genes; the two generation sequencing results were screened. The selected results were verified by Sanger sequencing; (2) family analysis: a STR marker family linkage analysis was carried out for patients with family history of a family history that did not find suspected pathogenic variation through the Ion torrent PGM sequencing. The linkage region was determined by the linkage of the pathogenic gene to the FBN1 based family, and the FBN1 gene resequencing or the whole FBN1 gene was carried out. Sequencing analysis, sequencing analysis of exon group for FBN1 gene unlinked families, in order to find new pathogenic genes. Sequence analysis of a total exon group for a twin family of Marfan. (3) MLPA detection of large fragment insertion / deletion mutation: multiple connection dependent probe amplification (MLPA) for patients with no pathogenic mutation (MLPA ) whether the patients carry the insertion / deletion mutation of the FBN1 gene DNA fragment, verify the MLPA results by quantitative PCR, and shorten the upstream and downstream sequences of the breakpoint by step method; Long Range PCR (long fragment PCR) amplifes and sequenced the specific breakpoints, and extracts the patients with the deletion of the exon 48-53 of the FBN1 gene. Vascular tissue RNA, transcriptional analysis; (4) genotype phenotype correlation analysis of high throughput sequencing screening and MLPA detected mutations. Results: 1. high throughput sequencing results: among 125 patients, 96 patients found 100 suspected mutations, 55 of which were new mutations (55%); 97 (97%) suspected ectopia. In the FBN1 gene, 2 (2%) are located in the TGFBR1 gene and 1 (1%) are in the TGFBR2 gene; all the variations contain 34 (34%) cysteine missense mutations; 21 (21%) non cysteine missense mutations; 11 (11%) splice site mutations; 11 (11%) code mutation and 15 (15%) nonsense mutations; carry a patient with suspected pathogenic variation: 3 patients were found to carry two suspected mutations; 1 of them were complex heterozygous and two of the other 2 were in the same allele in the other 2 cases. 2. families found that the FBN1 gene was linked to the marker disease phenotype in a family and found 41 by resequencing the FBN1 gene. The exons of the exons were inserted into the mutation, and the gene mutation was found in the SMAD3 gene by high throughput sequencing of the exon gene of the FBN1, and the CKB gene was the result of the.3. genome rearrangement of the candidate gene for the twin family of the twins: the total of 4 patients with the FBN1 gene, 48-53, respectively, were detected by MLPA. The large fragment deletion of 49-50 and 1-36 exons was amplified and sequenced by long fragment PCR (Long Range PCR). The 4 patients were determined to be missing 16551bp, 10346bp, 4563 BP, and 187067bp, and the deletion of the missing 48-53 was found to be a non graft deletion by analyzing the mRNA level of the patient's vascular tissue, and the subsequent mRNA was preserved in the body. The deletion of the 6 and 49-50 exons may also be a non transcoding deletion, and the deletion mutation range of the exon 1-36 of the exon 1-36 contains the upstream 11.5kb of the FBN1 gene, making the deletion of the allele non normal transcriptional translation.4. genotype phenotype correlation analysis: the patients carrying the cysteine missense mutation and the carrying scissors are found. Patients with truncated mutations are more likely to suffer from lens dislocation than those with truncated mutations, two patients with tryptophan mutation to arginine blindness. Cardiovascular, patients carrying truncated (PTC) mutations are more likely to suffer from aortic dissection than patients with mutations in the splice site. Patients with the FBN1 gene p.C123G variation are rare. The genotypic phenotypic analysis of the common carotid artery dissection.5. combined with previous reports on patients with large segment deletion found that the phenotype of the large segment of the non shift code deletion mutation depends on the missing location and size of the fragment, but tends to be the MFS with multiple symptoms of the severe neonatal type MFS. deletion (FBN1). The classic MFS symptoms. Conclusion: 1. this study detected 103 suspected mutations in the Chinese MFS population by PGM sequencing technology, of which 55 were new mutations and enriched the gene mutation spectrum of MFS; 2. patients with FBN1 gene splicing and cysteine missense mutations were more prone to crystalline than those with PTC. The patients with PTC mutation tend to suffer from aortic dissection, and the patients carrying the FBN1 gene PTC mutation are similar to those with the TGFBR1/2 gene mutation, all of which are not susceptible to ectopic lens ectopic and dissection of the aorta, suggesting that the abnormalities of the eyes in MFS patients are associated with the changes in the structure of the fibrin -1, and the aortic dissection and TG Fp signaling pathway change related.3.MLPA is an effective means to detect the deletion / repetition of the large MFS fragments. The patients with non graft deletion mutations tend to show MFS in the newborn, and the MFS of a single dose of low dose of MFS is a classic type; 4. complex heterozygous variation can also lead to MFS, which has an important hint for the prenatal screening of Marfan syndrome. Study two adult bronchiectasis gene screening and etiology study of bronchiectasis (Bronchiectasis, abbreviated bronchiectasis) is a common airway inflammation disease, resulting in abnormal bronchiolotracheal dilatation due to repeated airway infection and inflammation, and the disease, especially the non cystic fibrosis bronchiectasis (non-CF bron) The etiology, pathogenesis, and progression of chiectasis, NCFB, are still scarce in China. Bronchiectasis is a very heterogeneous disease, and the treatment of this disease is limited, which seriously affects the quality of life of the patients. At present, the classification of the etiology assessment of bronchiectasis can only explain about 50% of the patients. The etiology of the patients is clearly helpful to the management of the patients, to improve the patient's treatment and to consolidate the long-term effect. Research objectives: To study the etiology of bronchiectasis in Chinese adults. The genetic susceptibility of bronchiectasis patients is revealed from the genetic perspective. Image and method: 1. subjects: on the basis of informed consent, 192 cases of Chinese adult bronchiectasis and 100 cases of normal controlled peripheral blood without lung disease were collected; 2. study methods: (1) the etiological classification of 192 cases of bronchiectasis; (2) high throughput test: 192 patients with bronchiectasis through Ion PGM sequencing platform The target gene Panel sequencing was carried out in 100 normal individuals; the original data were annotated by the wANNOVAR website by the sequencing of the target gene, and the two generation sequencing results were routinely screened to preserve the potentially pathogenic mutation sites; the pathogenic software was used to determine the pathogenicity of the ectopic sites, and the selected results were sequenced by Sanger sequencing. (3) PCR amplification of the CFTR gene 8 intron (TG) m Tn repeat sequence was carried out in 192 patients and 100 normal controls, and DNA sequencing analysis instrument of ABI3730 model was used for sequencing analysis (TG) m Tn repetition, and (4) analysis of the double allele mutation of CFTR gene and dual heterozygosity of CFTR/ENaC genes. Mutation, and analysis of the CFTR gene V470M polymorphism; screening the homozygous variation and complex heterozygous mutation of the cystic fibrosis (PCD) related pathogenic genes; comparing the mutation frequency of the PCD related pathogenic genes in 192 patients and 100 normal individuals. (4) genotype phenotype analysis, statistics carrying DNAH5, DNAH11 double allele mutation and CFTR/ENaC double heterozygosity. The phenotypes of different patients were compared with the overall score of bronchiectasis severity (BSI) in patients with various gene mutations. (5) the etiological statistics of patients who were found to be found and the proportion of genetic factors in bronchiectasis were statistically analyzed. (1) this study was used in Chinese adults with bronchiectasis. The etiological classification was carried out in 31.8% patients, 27.6% of the patients were infected after infection, 13% of the patients were immune deficiency, 4.2% of the patients were asthma, 3.1% of the patients were gastroesophageal reflux, and the other types were 8.3%. (2) gene screening by CFTR gene and epithelial sodium ion transfer egg Bai Jiyin (ENaC) gene screening, and 3 patients were found to carry the position. In the compound heterozygous mutation of the CFTR gene, 1 patients were IVS8 5T (TGmT5) homozygous carriers. In addition, 2 patients carried the CFTR/ENaC gene double heterozygous mutation, and the CFTR gene V470M polymorphism. In the homozygous M470/M470 background, 12 patients were found to carry the CFTR gene mutation, the normal control group was 1 cases, and the bronchiectasis group was significantly more than the normal group. The control group (6.3%vs.1.0%, P=0.039); (3) PCD related gene mutation screening: 20 cases were found to carry the PCD related gene mutation (10.4%, 20/192), of which 14 cases carried the DNAH11 gene double allele mutation, 4 cases carried the DNAH5 gene compound heterozygous mutation, 1 cases carried the CCDC40 gene complex heterozygous mutation, 1 cases carried the HEATR2 homozygous mutation. And 1 cases of RPGR gene mutations were found on the X chromosome; 3 cases were found to carry double mutations in the DNAH11 gene in 100 normal individuals. (4) genotype phenotype correlation analysis: it was found that patients carrying DNAH5 mutations were more serious than those with DNAH11 gene mutations (BSI mean: 8.8 vs.4.2), and CF with CF. The symptomatic phenotype of the TR/ENaC gene double heterozygote was more severe than the patient carrying the complex CFTR gene (CFTR/ENaCBSI=10 Vs CFTR/CFTR BSI=5.2). (5) a total of 26 patients were found to carry the possible pathogenetic variation, and 16 of the patients with the total number of patients were idiopathic and 5 were tuberculosis. 2 cases were reflux, 1 cases were 1gG1 immune deficiency, 1 cases were asthma and 1 cases of measles infection. Conclusion: This study analyzed the etiological analysis of Chinese adults with bronchiectasis, and found that 31.8% patients were idiopathic and 27.6% of the patients were infected with post infection. PGM sequencing was used to analyze bronchiectasis patients and found in CF In the context of TR gene homozygous M470, a pathogenetic variation of the CFTR gene may lead to bronchiectasis, and the extension of the DNAH5 gene mutation is more severe than that caused by the mutation of the DNAH11 and CFTR genes; a total of 13.54% of the patients may be caused by genetic factors, and this study provides the classification of the etiology of bronchiectasis. The new standard is of great importance to the prevention and prognosis of bronchiectasis.

【學位授予單位】：北京協(xié)和醫(yī)學院
【學位級別】：博士
【學位授予年份】：2017
【分類號】：R562.22;R596

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