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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊偉勛,陳沛隆 | |
| dc.contributor.author | Yu-Lin Fan Chiang | en |
| dc.contributor.author | 范姜郁琳 | zh_TW |
| dc.date.accessioned | 2021-06-17T02:01:41Z | - |
| dc.date.available | 2019-08-28 | |
| dc.date.copyright | 2017-08-28 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-07-19 | |
| dc.identifier.citation | 1. Goldfinger, J.Z., et al., Thoracic aortic aneurysm and dissection. Journal of the American College of Cardiology, 2014. 64(16): p. 1725-1739.
2. Milewicz, D.M. and E. Regalado, Thoracic aortic aneurysms and aortic dissections. 2012. 3. Bradley, T.J., et al., The Expanding Clinical Spectrum of Extracardiovascular and Cardiovascular Manifestations of Heritable Thoracic Aortic Aneurysm and Dissection. Can J Cardiol, 2016. 32(1): p. 86-99. 4. Cury, M., F. Zeidan, and A.C. Lobato, Aortic disease in the young: genetic aneurysm syndromes, connective tissue disorders, and familial aortic aneurysms and dissections. International journal of vascular medicine, 2013. 2013. 5. Ziganshin, B.A., et al., Routine genetic testing for thoracic aortic aneurysm and dissection in a clinical setting. The Annals of thoracic surgery, 2015. 100(5): p. 1604-1611. 6. De Paepe, A., et al., Revised diagnostic criteria for the Marfan syndrome. American journal of medical genetics, 1996. 62(4): p. 417-426. 7. De Backer, J., L. Campens, and A. De Paepe, Genes in thoracic aortic aneurysms/dissections - do they matter? Ann Cardiothorac Surg, 2013. 2(1): p. 73-82. 8. Bowdin, S.C., et al., Genetic Testing in Thoracic Aortic Disease--When, Why, and How? Can J Cardiol, 2016. 32(1): p. 131-4. 9. Matkar, P.N., et al., Overview of Marfan Syndrome: knowns and unknowns. Journal of Controversies in Biomedical Research, 2015. 1(1): p. 51. 10. Ágg, B., et al., Possible extracardiac predictors of aortic dissection in Marfan syndrome. BMC cardiovascular disorders, 2014. 14(1): p. 1. 11. Pagon, R., et al., Marfan Syndrome--GeneReviews (®). 12. Byers, P.H., Determination of the molecular basis of Marfan syndrome: a growth industry. J Clin Invest, 2004. 114(2): p. 161-3. 13. De Backer, J., Marfan and Sartans: time to wake up! Eur Heart J, 2015. 36(32): p. 2131-3. 14. MacCarrick, G., et al., Loeys-Dietz syndrome: a primer for diagnosis and management. Genetics in Medicine, 2014. 16(8): p. 576-587. 15. Pannu, H., et al., Mutations in transforming growth factor-β receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation, 2005. 112(4): p. 513-520. 16. Coucke, P.J., et al., Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nature genetics, 2006. 38(4): p. 452-457. 17. Van Der Linde, D., et al., Aneurysm-osteoarthritis syndrome with visceral and iliac artery aneurysms. Journal of vascular surgery, 2013. 57(1): p. 96-102. 18. Tassabehji, M., et al., An elastin gene mutation producing abnormal tropoelastin and abnormal elastic fibres in a patient with autosomal dominant cutis laxa. Human molecular genetics, 1998. 7(6): p. 1021-1028. 19. Sermon, K., A. Van Steirteghem, and I. Liebaers, Preimplantation genetic diagnosis. The Lancet, 2004. 363(9421): p. 1633-1641. 20. Milewicz, D.M., et al., Fibrillin-1 (FBN1) mutations in patients with thoracic aortic aneurysms. Circulation, 1996. 94(11): p. 2708-2711. 21. Loeys, B.L., et al., A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nature genetics, 2005. 37(3): p. 275-281. 22. Singh, K.K., et al., TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys‐Dietz syndrome. Human mutation, 2006. 27(8): p. 770-777. 23. Nakao, A., et al., TGF‐β receptor‐mediated signalling through Smad2, Smad3 and Smad4. The EMBO journal, 1997. 16(17): p. 5353-5362. 24. Renard, M., et al., Novel MYH11 and ACTA2 mutations reveal a role for enhanced TGFβ signaling in FTAAD. International journal of cardiology, 2013. 165(2): p. 314-321. 25. Guo, D.-C., et al., Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nature genetics, 2007. 39(12): p. 1488-1493. 26. Luyckx, I., et al., Two novel MYLK nonsense mutations causing thoracic aortic aneurysms/dissections in patients without apparent family history. Clinical Genetics, 2017. 27. Lindsay, M.E., et al., Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm. Nature genetics, 2012. 44(8): p. 922-927. 28. Bertoli-Avella, A.M., et al., Mutations in a TGF-β ligand, TGFB3, cause syndromic aortic aneurysms and dissections. Journal of the American College of Cardiology, 2015. 65(13): p. 1324-1336. 29. Kontusaari, S., et al., A mutation in the gene for type III procollagen (COL3A1) in a family with aortic aneurysms. Journal of Clinical Investigation, 1990. 86(5): p. 1465. 30. Guo, D.-c., et al., Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. The American Journal of Human Genetics, 2013. 93(2): p. 398-404. 31. Barbier, M., et al., MFAP5 loss-of-function mutations underscore the involvement of matrix alteration in the pathogenesis of familial thoracic aortic aneurysms and dissections. The American Journal of Human Genetics, 2014. 95(6): p. 736-743. 32. Guo, D.-c., et al., MAT2A mutations predispose individuals to thoracic aortic aneurysms. The American Journal of Human Genetics, 2015. 96(1): p. 170-177. 33. Garg, V., et al., Mutations in NOTCH1 cause aortic valve disease. Nature, 2005. 437(7056): p. 270-274. 34. Zenker, M., et al., A dual phenotype of periventricular nodular heterotopia and frontometaphyseal dysplasia in one patient caused by a single FLNA mutation leading to two functionally different aberrant transcripts. The American Journal of Human Genetics, 2004. 74(4): p. 731-737. 35. Al-Hassnan, Z.N., et al., Recessively inherited severe aortic aneurysm caused by mutated EFEMP2. The American journal of cardiology, 2012. 109(11): p. 1677-1680. 36. Putnam, E.A., et al., Fibrillin–2 (FBN2) mutations result in the Marfan–like disorder, congenital contractural arachnodactyly. Nature genetics, 1995. 11(4): p. 456-458. 37. Drera, B., et al., Two novel SLC2A10/GLUT10 mutations in a patient with arterial tortuosity syndrome. American journal of medical genetics. Part A, 2007. 143(2): p. 216. 38. Hannuksela, M., et al., Screening for familial thoracic aortic aneurysms with aortic imaging does not detect all potential carriers of the disease. Aorta, 2015. 3(1): p. 1. 39. Giunta, C., A. Randolph, and B. Steinmann, Mutation analysis of the PLOD1 gene: an efficient multistep approach to the molecular diagnosis of the kyphoscoliotic type of Ehlers-Danlos syndrome (EDS VIA). Molecular genetics and metabolism, 2005. 86(1): p. 269-276. 40. Knebelmann, B., et al., Spectrum of mutations in the COL4A5 collagen gene in X-linked Alport syndrome. American journal of human genetics, 1996. 59(6): p. 1221. 41. Wang, F., et al., Detection of mutations in the COL4A5 gene by analyzing cDNA of skin fibroblasts. Kidney international, 2005. 67(4): p. 1268-1274. 42. Loeys, B.L., et al., The revised Ghent nosology for the Marfan syndrome. Journal of medical genetics, 2010. 47(7): p. 476-485. 43. Sanger, F., S. Nicklen, and A.R. Coulson, DNA sequencing with chain-terminating inhibitors. Proceedings of the national academy of sciences, 1977. 74(12): p. 5463-5467. 44. Metzker, M.L., Sequencing technologies—the next generation. Nature reviews genetics, 2010. 11(1): p. 31-46. 45. Mardis, E.R., Next-generation DNA sequencing methods. Annu. Rev. Genomics Hum. Genet., 2008. 9: p. 387-402. 46. Li, H. and R. Durbin, Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics, 2009. 25(14): p. 1754-1760. 47. McKenna, A., et al., The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome research, 2010. 20(9): p. 1297-1303. 48. Wang, K., M. Li, and H. Hakonarson, ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic acids research, 2010. 38(16): p. e164-e164. 49. Kumar, P., S. Henikoff, and P.C. Ng, Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nature protocols, 2009. 4(7): p. 1073-1081. 50. Adzhubei, I.A., et al., A method and server for predicting damaging missense mutations. Nature methods, 2010. 7(4): p. 248-249. 51. Sherry, S.T., et al., dbSNP: the NCBI database of genetic variation. Nucleic acids research, 2001. 29(1): p. 308-311. 52. Consortium, G.P., An integrated map of genetic variation from 1,092 human genomes. Nature, 2012. 491(7422): p. 56-65. 53. Tabor, H.K., et al., Pathogenic variants for Mendelian and complex traits in exomes of 6,517 European and African Americans: implications for the return of incidental results. The American Journal of Human Genetics, 2014. 95(2): p. 183-193. 54. Lek, M., et al., Analysis of protein-coding genetic variation in 60,706 humans. Nature, 2016. 536(7616): p. 285-291. 55. Landrum, M.J., et al., ClinVar: public archive of interpretations of clinically relevant variants. Nucleic acids research, 2016. 44(D1): p. D862-D868. 56. Robinson, J.T., et al., Integrative genomics viewer. Nature biotechnology, 2011. 29(1): p. 24-26. 57. Béroud, C., et al., UMD (Universal mutation database): a generic software to build and analyze locus-specific databases. Human mutation, 2000. 15(1): p. 86. 58. Collod‐Béroud, G., et al., Update of the UMD‐FBN1 mutation database and creation of an FBN1 polymorphism database. Human mutation, 2003. 22(3): p. 199-208. 59. Frédéric, M.Y., et al., The FBN2 gene: new mutations, locus‐specific database (Universal Mutation Database FBN2), and genotype‐phenotype correlations. Human mutation, 2009. 30(2): p. 181-190. 60. Richards, S., et al., Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in medicine: official journal of the American College of Medical Genetics, 2015. 17(5): p. 405-424. 61. Faivre, L., et al., Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. The American Journal of Human Genetics, 2007. 81(3): p. 454-466. 62. de Bustamante, A.D., et al., Phenotypic variability in Marfan syndrome in a family with a novel nonsense FBN1 gene mutation. Revista Española de Cardiología, 2012. 65(04): p. 380-381. 63. Villamizar, C., et al., Paucity of skeletal manifestations in Hispanic families with FBN1 mutations. European journal of medical genetics, 2010. 53(2): p. 80-84. 64. Yang, H., et al., Genetic testing of the FBN1 gene in Chinese patients with Marfan/Marfan-like syndrome. Clinica Chimica Acta, 2016. 459: p. 30-35. 65. Stheneur, C., et al., Identification of the minimal combination of clinical features in probands for efficient mutation detection in the FBN1 gene. European Journal of Human Genetics, 2009. 17(9): p. 1121-1128. 66. Den Dunnen, J.T. and S.E. Antonarakis, Mutation nomenclature extensions and suggestions to describe complex mutations: a discussion. Human mutation, 2000. 15(1): p. 7. 67. Faivre, L., et al., Pathogenic FBN1 mutations in 146 adults not meeting clinical diagnostic criteria for Marfan syndrome: further delineation of type 1 fibrillinopathies and focus on patients with an isolated major criterion. American Journal of Medical Genetics Part A, 2009. 149(5): p. 854-860. 68. Frederic, M.Y., et al., A new locus‐specific database (LSDB) for mutations in the TGFBR2 gene: UMD‐TGFBR2. Human mutation, 2008. 29(1): p. 33-38. 69. Lennon, R., et al., Coinheritance of COL4A5 and MYO1E mutations accentuate the severity of kidney disease. Pediatric nephrology, 2015. 30(9): p. 1459-1465. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/67976 | - |
| dc.description.abstract | 胸腔主動脈瘤剝離症候群（Thoracic Aortic Aneurysm and Dissection syndrome，TAAD）根據臨床表徵可以細分兩個主要的類別：（1）綜合症型（Syndromic），常伴隨有多組器官受損，主要包括Marfan syndrome（MFS）、Loeys-Dietz syndrome（LDS）、Ehlers-Danlos syndrome（EDS）、Aneurysms-Osteoarthritis syndrome（AOS），以及transforming growth factor-β(TGF-β) signaling pathway相關疾病；（2）非綜合症型（Non-syndromic），只在主動脈發生病症，一般分為家族性TAAD及偶發性TAAD。然而多樣化的臨床表徵或症狀不明確，常使醫師診斷上造成困難，也帶給患者及其家庭成員莫大的痛苦。
本研究利用臺大醫院「心臟內科門診」、「小兒心臟科門診」及「基因醫學部門診」臨床確診為TAAD- Aneurysm/Dissection的30位病患及19位TAAD-non Aneurysm/Dissection但臨床表徵疑似馬凡氏症候群(MFS )的病患所提供的血液，以次世代定序技術針對Syndromic TAAD與Non-syndromic TAAD相關的27個基因進行基因檢測，其檢出率為49.0%(24/49)，其中30位確診為TAAD- Aneurysm/Dissection個案的檢出率為63.3%(19/30)，19位TAAD-non Aneurysm/Dissection個案的檢出率為26.3%(5/19)，以Sanger sequencing驗證結果，正確率為100%(20/20)。依據ACMG（American College of Medical Genetics and Genomics）準則的判斷，在Pathogenic/Likely pathogenic的基因變異中有8個FBN1及1個FBN2是目前尚未被報告過的基因變異點位。 NGS與傳統基因定序方法相較之下，NGS主要是結合微製程技術以達成高通量定序，能夠同時讀取上百萬條DNA的序列，所以可以大量降低成本，且速度更快，幫助病人確立基因診斷，找出造成胸腔主動脈擴大剝離症的原因，了解本土病患的基因變異分布情形，並將進一步尋找新的致病基因，擴展我們對此疾病的理解。 | zh_TW |
| dc.description.abstract | Thoracic Aortic Aneurysm and Dissection syndrome (TAAD) can be divided into two main categories according to clinical features: (1) Syndromic, often accompanied by multiple groups of organ damage, including Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), Ehlers-Danlos syndrome (EDS), Aneurysms-Osteoarthritis syndrome (AOS), and transforming growth factor-β signaling related diseases; (2) Non-syndromic, only in the aortic disease, generally divided into familial TAAD and sporadic TAAD. However, the diversity of clinical features or symptoms are not clear, and it not only resulting in the difficulties of clinical diagnosis, but also suffering greater pain to patients and their families.
In this study, we enrolled patients from National Taiwan University Hospital 'Cardiology Outpatient', 'Pediatric Cardiology Outpatient' and 'Department of Medical Genetics';30 patients with clinically diagnosed TAAD- Aneurysm/Dissection, and 19 patients with TAAD-non Aneurysm/Dissection but the clinical manifestations of suspected Marian syndrome (MFS) were included. We extracted gDNA from peripheral blood of these 49 patients, and detected 27 genes related to Syndromic TAAD and Non-syndromic TAAD by next-generation sequencing (NGS). Total detection rate was 49.0% (24/49), with 63.3% (19/30) for 30 TAAD- Aneurysm/Dissection diagnosed patients, and 26.3% (5/19) for 19 TAAD-non Aneurysm/Dissection cases. The accuracy rate was 100% (20/20) for the doubling check with Sanger sequencing. According to the ACMG (American College of Medical Genetics and Genomics) guidelines, we found 8 variants on FBN1 and 1 variant on FBN2 to be pathogenic or likely pathogenic, and they were genetic variants which not yet been reported so far. Comparing with traditional sequencing methods, NGS is a combination of micro-technologies to do millions of DNA sequencing simultaneously; it generates high throughputs with high resolution within several days, which help us to save time and money. With this method, we can help patients to find out their causes of thoracic aorta. Furthermore, the understanding of genetic composition of Taiwan patients expands our understanding of this disease. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-17T02:01:41Z (GMT). No. of bitstreams: 1 ntu-106-P04448006-1.pdf: 4670229 bytes, checksum: 1ce95216656b3c8eb1940d645a006792 (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | 口試委員會審定書…………………………………………………………………….I
誌謝……………………………………………………………………………………..II 中文摘要……………………………………………………………………………….III Abstract………………………………………………………………………………….V 第一章、 研究背景與動機………………………………………………………...1 1.1. Thoracic Aortic Aneurysm and Dissection疾病介紹……………………...1 1.2. Thoracic Aortic Aneurysm and Dissection的臨床特徵…………………...3 1.2.1 Marfan syndrome 3 1.2.2 Loeys-Dietz syndrome 4 1.2.3 Ehlers-Danlos syndrome 4 1.2.4 TAAD Syndrome與其相關的基因 5 1.3. Thoracic Aortic Aneurysm and Dissection的診斷及檢查………………...5 1.4. 研究目的…………………………………………………………………...5 第二章、 研究方法………………………………………………………………...8 2.1. 研究對象來源及條件……………………………………………………...8 2.1.1受試者來源…………………………………………………………………………………………8 2.1.2 受試者納入排除條件…………………………………………………………………..8 2.1.3 檢體來源與取得………………………………………………………………………………9 2.2 次世代定序檢測……………………………………………………………..9 2.2.1 DNA的萃取 9 2.2.2 DNA濃度測量 10 2.2.3 TAAD syndrome基因檢測平台 11 2.2.4 次世代定序（Illumina，MiSeq）原理 11 2.2.5 定序結果判讀 13 2.3 PCR驗證(Sanger定序分析)……………………………………………..14 2.3.1 DNA 引子(Primer)之製備 14 2.3.2 聚合酶連鎖反應 15 2.4 實驗器材與材料………………………………………………………….20 第三章、 結果…………………………………………………………………….22 3.1. 次世代定序分析(Illumina system)定序結果…………………………….22 3.2. Sanger sequencing定序結果……………………………………………..30 3.3. TAAD基因檢測結果判定 ……………………………………………….33 3.4 Family testing for segregation…………………………………………….35 第四章、 討論…………………………………………………………………….43 第五章、 結論…………………………………………………………………….47 參考文獻……………………………………………………………………………….49 附錄 54 | |
| dc.language.iso | zh-TW | |
| dc.subject | 次世代定序 | zh_TW |
| dc.subject | ACMG | zh_TW |
| dc.subject | 胸腔主動脈瘤剝離症候群 | zh_TW |
| dc.subject | Thoracic Aortic Aneurysm and Dissection syndrome(TAAD) | en |
| dc.subject | next-generation sequencing(NGS) | en |
| dc.subject | American College of Medical Genetics and Genomics(ACMG) | en |
| dc.title | 應用次世代定序技術建立胸腔主動脈瘤剝離症候群基因檢測平台 | zh_TW |
| dc.title | Application of Next Generation Sequencing to Establish the Genetic Testing Platform for Thoracic Aortic Aneurysm and Dissection Syndrome | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 邱馨慧,游治節 | |
| dc.subject.keyword | 胸腔主動脈瘤剝離症候群,次世代定序,ACMG, | zh_TW |
| dc.subject.keyword | Thoracic Aortic Aneurysm and Dissection syndrome(TAAD),next-generation sequencing(NGS),American College of Medical Genetics and Genomics(ACMG), | en |
| dc.relation.page | 63 | |
| dc.identifier.doi | 10.6342/NTU201701713 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2017-07-19 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| 顯示於系所單位： | 分子醫學研究所 | |
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