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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
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dc.contributor.advisor | 簡穎秀(Yin-Hsiu Chien 簡穎秀) | |
dc.contributor.author | Ming-Cheng Kuo | en |
dc.contributor.author | 郭明正 | zh_TW |
dc.date.accessioned | 2021-05-19T17:40:16Z | - |
dc.date.available | 2022-08-28 | |
dc.date.available | 2021-05-19T17:40:16Z | - |
dc.date.copyright | 2019-08-28 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-08-12 | |
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Current Opinion in Pediatrics. 2000;12(6):603-9. 8. Jobling R, D’Souza R, Baker N, Lara-Corrales I, Mendoza-Londono R, Dupuis L, et al. The collagenopathies: review of clinical phenotypes and molecular correlations. Current rheumatology reports. 2014;16(1):394. 9. Faivre L, Merrer ML, Douvier S, Laurent N, Thauvin‐Robinet C, Rousseau T, et al. Recurrence of achondrogenesis type II within the same family: evidence for germline mosaicism. American Journal of Medical Genetics Part A. 2004;126(3):308-12. 10. Kannu P, Bateman J, Savarirayan R. Clinical phenotypes associated with type II collagen mutations. Journal of paediatrics and child health. 2012;48(2):E38-E43. 11. Gilbert‐Barnes E, Langer Jr LO, Opitz JM, Laxova R, Sotelo‐Arila C. Kniest dysplasia: radiologic, histopathological, and scanning electronmicroscopic findings. American journal of medical genetics. 1996;63(1):34-45. 12. Wilkin DJ, Artz AS, South S, Lachman RS, Rimoin DL, Wilcox WR, et al. Small deletions in the type II collagen triple helix produce Kniest dysplasia. American journal of medical genetics. 1999;85(2):105-12. 13. Miyamoto Y, Matsuda T, Kitoh H, Haga N, Ohashi H, Nishimura G, et al. A recurrent mutation in type II collagen gene causes Legg-Calve-Perthes disease in a Japanese family. Human genetics. 2007;121(5):625-9. 14. Beighton P, Paepe AD, Steinmann B, Tsipouras P, Wenstrup RJ. Ehlers‐Danlos syndromes: revised nosology, Villefranche, 1997. American journal of medical genetics. 1998;77(1):31-7. 15. Schwarze U, Hata R-I, McKusick VA, Shinkai H, Hoyme HE, Pyeritz RE, et al. Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway. The American Journal of Human Genetics. 2004;74(5):917-30. 16. Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers–Danlos syndrome type IV, the vascular type. New England Journal of Medicine. 2000;342(10):673-80. 17. De Paepe A, Malfait F. The Ehlers–Danlos syndrome, a disorder with many faces. Clinical genetics. 2012;82(1):1-11. 18. Cortini F, Marinelli B, Pesatori AC, Seia M, Seresini A, Giannone V, et al. Clinical Application of NGS Tools in the Diagnosis of Collagenopathies. Exploratory Research and Hypothesis in Medicine. 2017;2(3):57-62. 19. Sule G, Campeau P, Zhang V, Nagamani S, Dawson B, Grover M, et al. Next-generation sequencing for disorders of low and high bone mineral density. Osteoporosis International. 2013;24(8):2253. 20. Polla DL, Cardoso MT, Silva MC, Cardoso IC, Medina CT, Araujo R, et al. Use of targeted exome sequencing for molecular diagnosis of skeletal disorders. PloS one. 2015;10(9):e0138314. 21. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, 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. 2015;17(5):405. 22. Symoens S, Syx D, Malfait F, Callewaert B, De Backer J, Vanakker O, et al. Comprehensive molecular analysis demonstrates type V collagen mutations in over 90% of patients with classic EDS and allows to refine diagnostic criteria. Human mutation. 2012;33(10):1485-93. 23. Heinrich T, Nanda I, Rehn M, Zollner U, Ernestus K, Wirth C, et al. Co-Occurence of Reciprocal Translocation and COL2A1 Mutation in a Fetus with Severe Skeletal Dysplasia: Implications for Genetic Counseling. Cytogenetic and genome research. 2015;145(1):25-8. 24. Al Kaissi A, Laccone F, Karner C, Ganger R, Klaushofer K, Grill F. Hüftdysplasie und Morbus Scheuermann bei einem Mädchen mit Typ-II-Kollagenopathie. Der Orthopäde. 2013;42(11):963-8. 25. Cho SY, Ki C-S, Sohn YB, Kim SJ, Maeng SH, Jin D-K. Osteogenesis imperfecta Type VI with severe bony deformities caused by novel compound heterozygous mutations in SERPINF1. Journal of Korean medical science. 2013;28(7):1107-10. 26. Dai J, Kim O, Cho T-J, Schmidt-Rimpler M, Tonoki H, Takikawa K, et al. Novel and recurrent TRPV4 mutations and their association with distinct phenotypes within the TRPV4 dysplasia family. Journal of medical genetics. 2010;47(10):704-9. 27. Vorster A, Beighton P, Ramesar R. Spondyloepimetaphyseal dysplasia with joint laxity (Beighton type); mutation analysis in eight affected South African families. Clinical genetics. 2015;87(5):492-5. 28. Forlino A, Marini JC. Osteogenesis imperfecta. The Lancet. 2016;387(10028):1657-71. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/7214 | - |
dc.description.abstract | 背景
膠原蛋白是人體結締組織中含量最豐富的蛋白質,由於膠原蛋白病變是異質性遺傳疾病(heterogeneous genetic disorder),許多不同基因變異可能造成相同類似的症狀。因此,在診斷這類疾病往往需要檢測不同基因,才能找到致病原因。傳統桑格定序(Sanger sequencing)對於處理多個基因或外顯子顯得耗費時間和成本,因此,次世代定序(Next Generation Sequencing;NGS)則能同時提供多個基因進行平行定序,具有縮短時間和降低成本的優勢。 目的 我們希望藉由次世代定序目標區間定序套組(NGS-based targeted gene panel),對於疑似膠原蛋白病變的患者,提供精確快速有效率的臨床分子診斷,並進一步去了解膠原蛋白病變的基因型和表現型相關性。 方法 本次研究收錄從2016年1月到2018年12月這段期間,疑似膠原蛋白病變的30位患者,其中有26位患者使用次世代定序目標區間定序套組,4位進行外顯子定序套組(Exome panel)檢測。8例臨床診斷為Elhers-Dalnos syndrome (EDS),22例臨床診斷為骨骼發育不良Skeletal dysplasia。 結果 19位患者有確定的分子診斷,診斷率為63% (n=19/30)。8位在臨床診斷為EDS患者,有4位找到致病基因,分別是1位PRDM5(Brittle cornea syndrome 2),2 位COL5A1(Classical EDS,cEDS)和1位COL3A1(Vascular EDS,vEDS)變異,診斷率為50%(n= 4/8)。22位骨骼發育不良患者,有4位是COL1A1和1位是COL1A2(Osteogenesis imperfect,OI)變異,4位是COL2A1 (COL2A1-related collagenopathy),其他基因型包括SERPINF1(OI type VI,n = 2),WNT1(OI type XV,n = 1),ITIM5(OI type V,n = 1),TRPV4(Spondylometaphyseal dysplasia,Kozlowski型,n = 1)和B3GALT6(Spondyloepimetaphyseal dysplasia with joint laxity,n = 1),診斷率為68%(n=15/22)。 結論 本次研究使用次世代定序骨骼關節疾病套組(OI、EDS、Osteopetrosis、Marfanoid、others)相關基因共56個,相較其他相關基因研究套組有較佳的分子診斷率。因此,可以做為臨床有效的診斷工具和成為診斷膠原蛋白病變的標準方法。 | zh_TW |
dc.description.abstract | Background
Collagen is the most abundant protein found in the connective tissue of the human body. Collagenopathy is a heterogeneous genetic disease, and many different genetic variations may cause similar symptoms. Sanger sequencing is too time-consuming and costly for processing multiple genes or exons. Next-generation sequencing (NGS) enables massive parallel sequencing of multiple genes at the same time, and it also has the advantage of reducing time and cost. Aim We try to apply the NGS-based targeted gene panel and offer accurate, fast and effective clinical molecular diagnosis for patients who were suspected with collagenopathies, and to further understand the correlation between genotypes and phenotypes. Methods The study was included thirty patients suspected of having collagenopathies from January 2016 to December 2018, and twenty-six of them used the NGS-based targeted gene panel. Four cases were tested by Exome panel. Eight of them were diagnosed as Elhers-Dalnos syndrome (EDS), and the other were distinguished as skeletal dysplasia. Results There were nineteen patients with molecular diagnosis, and the diagnostic rate was 63% (n=19/30). There were four patients with genetic variations in the clinical diagnosis of EDS, including PRDM5 (Brittle cornea syndrome 2, n=1), COL5A1 (Classical EDS,cEDS, n=2) and COL3A1 (Vascular EDS,vEDS, n=1) with the diagnostic yield of 50% (n=4/8). Twenty-two patients were diagnosed with skeletal dysplasia, four cases were COL1A1 and one case was COL1A2 (Osteogenesis imperfect, OI) variation, four cases were COL2A1(COL2A1-related collagenopathy), and other genotypes were included SERPINF1 (OI type VI, n = 2), WNT1 (OI type XV, n = 1), ITIM5 (OI type V, n = 1), TRPV4 (Spondylometaphyseal dysplasia, Kozlowski type, n = 1) and B3GALT6 (Spondyloepimetaphyseal dysplasia with joint laxity, n = 1). The diagnosis rate was 68% (n=15/22). Conclusions This study was utilized to fifty-six genes related to skeletal joint disease (OI、EDS、Osteopetrosis、Marfanoid、others) in the NGS-based targeted gene panel, which has a better molecular diagnostic rate than other related studies so that it can be used as a clinically effective diagnostic tool and standards for diagnosis of collagenopathies. | en |
dc.description.provenance | Made available in DSpace on 2021-05-19T17:40:16Z (GMT). No. of bitstreams: 1 ntu-108-P06448012-1.pdf: 1149857 bytes, checksum: 20ecff7a874d0f62fc91c44e4c5a0b57 (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | 中文摘要 5
Abstract 7 第一章、研究背景與動機 9 1.1 膠原蛋白 9 1.2 膠原蛋白病變和臨床表現型 10 1.3 次世代定序在膠原蛋白病變的研究 11 1.4 研究動機 13 第二章、研究方法 14 第三章、 結果 17 第四章、 討論 26 第五章、參考文獻 29 | |
dc.language.iso | zh-TW | |
dc.title | 次世代定序在膠原蛋白病變的臨床應用 | zh_TW |
dc.title | Clinical Application of Next Generation Sequencing in the Diagnosis of Collagenopathies | en |
dc.type | Thesis | |
dc.date.schoolyear | 107-2 | |
dc.description.degree | 碩士 | |
dc.contributor.coadvisor | 李妮鍾(Ni-Chung Lee 李妮鍾) | |
dc.contributor.oralexamcommittee | 胡務亮(Wuh-Liang Hwu 胡務亮) | |
dc.subject.keyword | 膠原蛋白,膠原蛋白病變,異質性遺傳疾病,次世代定序,目標區間定序套組,外顯子定序套組, | zh_TW |
dc.subject.keyword | collagen,collagenopathy,heterogeneous genetic disorder,next generation sequencing,NGS-based targeted gene panel,Exome panel, | en |
dc.relation.page | 58 | |
dc.identifier.doi | 10.6342/NTU201902431 | |
dc.rights.note | 同意授權(全球公開) | |
dc.date.accepted | 2019-08-13 | |
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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