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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 簡穎秀 | zh_TW |
| dc.contributor.advisor | Yin-Hsiu Chien | en |
| dc.contributor.author | 許晉婕 | zh_TW |
| dc.contributor.author | Chin-Chieh Hsu | en |
| dc.date.accessioned | 2023-09-24T16:10:02Z | - |
| dc.date.available | 2023-11-09 | - |
| dc.date.copyright | 2023-09-23 | - |
| dc.date.issued | 2023 | - |
| dc.date.submitted | 2023-08-02 | - |
| dc.identifier.citation | 1.Hambuch, T.M., et al., Chapter 2 - Clinical Genome Sequencing, in Clinical Genomics, S. Kulkarni and J. Pfeifer, Editors. 2015, Academic Press: Boston. p. 21-35.
2.McCarthy, M.I., et al., Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat Rev Genet, 2008. 9(5): p. 356-69. 3.Deans, C. and K.A. Maggert, What do you mean, "epigenetic"? Genetics, 2015. 199(4): p. 887-96. 4.Jung, H.U., et al., Gene-environment interaction explains a part of missing heritability in human body mass index. Commun Biol, 2023. 6(1): p. 324. 5.Yunis, J.J. and M.E. Chandler, High-resolution chromosome analysis in clinical medicine. Prog Clin Pathol, 1978. 7: p. 267-88. 6.Trask, B.J., Fluorescence in situ hybridization: applications in cytogenetics and gene mapping. Trends Genet, 1991. 7(5): p. 149-54. 7.Craddock, K.J., W.L. Lam, and M.S. Tsao, Applications of array-CGH for lung cancer. Methods Mol Biol, 2013. 973: p. 297-324. 8.Kang, J.U. and S.H. Koo, Evolving applications of microarray technology in postnatal diagnosis (review). Int J Mol Med, 2012. 30(2): p. 223-8. 9.Yoon, S., et al., Sensitive and accurate detection of copy number variants using read depth of coverage. Genome Res, 2009. 19(9): p. 1586-92. 10.Kallioniemi, A., et al., Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science, 1992. 258(5083): p. 818-21. 11.Chou, L.S., E. Lyon, and R. Mao, Molecular diagnosis utility of multiplex ligation-dependent probe amplification. Expert Opin Med Diagn, 2008. 2(4): p. 373-85. 12.Xie, C. and M.T. Tammi, CNV-seq, a new method to detect copy number variation using high-throughput sequencing. BMC Bioinformatics, 2009. 10: p. 80. 13.Gordeeva, V., et al., Benchmarking germline CNV calling tools from exome sequencing data. Sci Rep, 2021. 11(1): p. 14416. 14.Babadi, M., et al., Abstract 2287: Precise common and rare germline CNV calling with GATK. Cancer Research, 2018. 78(13_Supplement): p. 2287-2287. 15.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. Genet Med, 2015. 17(5): p. 405-24. 16.Lin, S.Y., et al., Rapid Trio Exome Sequencing for Autosomal Recessive Renal Tubular Dysgenesis in Recurrent Oligohydramnios. Front Genet, 2021. 12: p. 606970. 17.Team, G. GermlineCNVCaller. August 03, 2020 11:01; Available from: https://gatk.broadinstitute.org/hc/en-us/articles/360047217671-GermlineCNVCaller. 18.OMIM Data Downloads. 19.Lek, M., et al., Analysis of protein-coding genetic variation in 60,706 humans. Nature, 2016. 536(7616): p. 285-91. 20.Samocha, K.E., et al., A framework for the interpretation of de novo mutation in human disease. Nat Genet, 2014. 46(9): p. 944-50. 21.Collins, R.L., et al., A cross-disorder dosage sensitivity map of the human genome. Cell, 2022. 185(16): p. 3041-3055.e25. 22.Karczewski, K.J., et al., The mutational constraint spectrum quantified from variation in 141,456 humans. Nature, 2020. 581(7809): p. 434-443. 23.# 619033 VISSERS-BODMER SYNDROME; VIBOS. 24.# 619314 BURATTI-HAREL SYNDROME; BURHAS. Available from: https://www.omim.org/entry/619314. 25.GeneReviews 1q21.1 Recurrent Microdeletion. 26.Nord, A., S.J. Salipante, and C. Pritchard, Chapter 11 - Copy Number Variant Detection Using Next-Generation Sequencing, in Clinical Genomics, S. Kulkarni and J. Pfeifer, Editors. 2015, Academic Press: Boston. p. 165-187. 27.Hastings, P.J., et al., Mechanisms of change in gene copy number. Nat Rev Genet, 2009. 10(8): p. 551-64. 28.Kim, P.M., et al., Analysis of copy number variants and segmental duplications in the human genome: Evidence for a change in the process of formation in recent evolutionary history. Genome Res, 2008. 18(12): p. 1865-74. 29.Høyer, H., et al., Copy number variations in a population-based study of Charcot-Marie-Tooth disease. Biomed Res Int, 2015. 2015: p. 960404. 30.Riggs, E.R., et al., Copy number variant discrepancy resolution using the ClinGen dosage sensitivity map results in updated clinical interpretations in ClinVar. Hum Mutat, 2018. 39(11): p. 1650-1659. 31.Bragin, E., et al., DECIPHER: database for the interpretation of phenotype-linked plausibly pathogenic sequence and copy-number variation. Nucleic Acids Research, 2014. 42(D1): p. D993-D1000. 32.Royer-Bertrand, B., et al., CNV Detection from Exome Sequencing Data in Routine Diagnostics of Rare Genetic Disorders: Opportunities and Limitations. Genes (Basel), 2021. 12(9). 33.Strom, S.P., et al., A Streamlined Approach to Prader-Willi and Angelman Syndrome Molecular Diagnostics. Front Genet, 2021. 12: p. 608889. 34.Dong, X., et al., Clinical exome sequencing as the first-tier test for diagnosing developmental disorders covering both CNV and SNV: a Chinese cohort. J Med Genet, 2020. 57(8): p. 558-566. 35.Sawyer, S.L., et al., Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care. Clin Genet, 2016. 89(3): p. 275-84. 36.Mergnac, J.P., et al., Diagnostic yield of clinical exome sequencing as a first-tier genetic test for the diagnosis of genetic disorders in pediatric patients: results from a referral center study. Hum Genet, 2022. 141(7): p. 1269-1278. 37.Arteche-López, A., et al., Towards a Change in the Diagnostic Algorithm of Autism Spectrum Disorders: Evidence Supporting Whole Exome Sequencing as a First-Tier Test. Genes (Basel), 2021. 12(4). 38.Stark, Z., et al., A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders. Genet Med, 2016. 18(11): p. 1090-1096. 39.Srivastava, S., et al., Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genet Med, 2019. 21(11): p. 2413-2421. 40.Lee, H., et al., Clinical exome sequencing for genetic identification of rare Mendelian disorders. Jama, 2014. 312(18): p. 1880-7. 41.Yang, Y., et al., Molecular findings among patients referred for clinical whole-exome sequencing. Jama, 2014. 312(18): p. 1870-9. 42.Nowakowska, B., Clinical interpretation of copy number variants in the human genome. J Appl Genet, 2017. 58(4): p. 449-457. 43.Allison, S.J., J. Stafford, and D.O. Anumba, The effect of stress and anxiety associated with maternal prenatal diagnosis on feto-maternal attachment. BMC Womens Health, 2011. 11: p. 33. 44.Grossman, T.B. and S.T. Chasen, Abortion for Fetal Genetic Abnormalities: Type of Abnormality and Gestational Age at Diagnosis. AJP Rep, 2020. 10(1): p. e87-e92. 45.Haghparast, E., M. Faramarzi, and R. Hassanzadeh, Psychiatric symptoms and pregnancy distress in subsequent pregnancy after spontaneous abortion history. Pak J Med Sci, 2016. 32(5): p. 1097-1101. 46.Biggs, M.A., et al., Does abortion increase women's risk for post-traumatic stress? Findings from a prospective longitudinal cohort study. BMJ Open, 2016. 6(2): p. e009698. 47.Mehrtash, B., et al., GATK-gCNV: A Rare Copy Number Variant Discovery Algorithm and Its Application to Exome Sequencing in the UK Biobank. bioRxiv, 2022: p. 2022.08.25.504851. 48.「生資無價系列專題」- Variant Calling 的戰況分析. Available from: https://chungtsai.medium.com/%E7%B2%BE%E6%BA%96%E9%86%AB%E7%99%82-variant-calling-%E7%9A%84%E6%88%B0%E6%B3%81%E5%88%86%E6%9E%90-97e77d0730c8. | - |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/90241 | - |
| dc.description.abstract | 背景
基因變異常造成許多臨床疾病，小自單一或數個核苷酸變異、大至數千或數萬個鹼基對的拷貝數異常、甚至是染色體數目異常，在臨床基因診斷時均須納入鑑別。全外顯子定序(WES)可精準地分析單一核苷酸異常(SNV)或小範圍的核苷酸插入或缺失(small indel)，亦可利用讀深法(read of coverage)產生gCNV檔，分析較大範圍的拷貝數異常(exome CNV)。 目的 本研究旨於利用exome CNV再次分析WES的個案資料，搭配Decipher線上資料庫，探討是否可以偵測SNV及small indel之外的拷貝數異常(CNV)，並提升基因診斷率。 方法 將WES原始資料以GATK gCNV caller工具產出gCNV檔，利用MViewer篩選>5 Kb並包含Mendeliome基因或OMIM基因的CNV片段，查詢Decipher是否有已知的CNV syndrome與該片段重疊，並篩選每段CNV是否帶有高pLI/pHaplo/pTriplo值的Mendeliome或OMIM基因。最後比對高pLI/pHaplo/pTriplo值的Mendeliome或OMIM基因之表現型，嘗試找出與個案表現型符合的致病CNV片段，並計算診斷率。 結果 在130位再次分析的個案中，共有5位利用Exome CNV找到CNV syndrome或致病CNV(包含Klinefelter syndrome、Vissers-Bodmer syndrome、1q21.1 recurrent microdeletion、17p11.2 duplication syndrome)，針對拷貝數異常的診斷率為3.85%。利用exome CNV，可將WES的診斷率自44.62提升至47.69，共3.07%。 結論 Exome CNV可以成功利用WES原始資料偵測拷貝數異常，搭配Decipher資料庫參考pLI/pHaplo/pTriplo值及Mendeliome基因、OMIM基因之表現型，可以提高WES的基因診斷率。然而，本研究流程仍需要更多個案數及驗證。 | zh_TW |
| dc.description.abstract | Background
Genetic variations bring many clinical diseases, ranging from single nucleotide variation (SNV), small indel to copy number variation or chromosomal diseases. Genetic testing should assess all levels of variations to make precise genetic diagnosis. WES brings much information about SNV and small indel, which is also able to evaluate copy number variation by analyzing reads of coverage (exome CNV). Aim Using exome CNV to re-analyze possible pathogenic CNV from the WES cohort, and calculate the genetic yields of WES and exome CNV. Methods Total 130 cases were enrolled in the study. We reviewed all the CNVs from the 130 cases that are larger than 5 Kb and containing Mendeliome genes or OMIM genes. The pathogenic CNV was filtered out if compatible with CNV syndrome reported on Decipher, or had genes with high pLI/pHaplo/pTriplo values and similar phenotypes. The diagnostic rate of exome CNV was presented. Results 6 of 130 cases were found having pathogenic CNV from exome CNV, including Klinefelter syndrome, Vissers-Bodmer syndrome, 1q21.1 recurrent microdeletion and 17p11.2 duplication syndrome. The diagnostic rate of exome CNV was 3.85%. By adding exome CNV, the diagnostic yield of WES improved to 47.69% from 44.62%. Conclusions Exome CNV can detect pathogenic CNV and improve diagnostic rate of WES by 3.06%. However, further study that enrolls more cases is needed to complete validation. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2023-09-24T16:10:02Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2023-09-24T16:10:02Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 目錄
誌謝 3 中文摘要 4 Abstract 5 第一章、 研究介紹 (Introduction) 11 一、基因體的組成 11 二、遺傳疾病的成因 11 三、遺傳疾病的分子診斷 12 四、遺傳疾病分子診斷在臨床未解的問題 13 五、用NGS診斷拷貝數變異的新進展 14 六、研究目的 16 第二章、 研究方法及材料 (Material and Method) 17 一、資料來源 17 二、WES使用的平台及WES SNV/indel致病性判斷 17 三、Exome CNV的產生方式及致病性判斷 17 四、個案紀錄表內容及分類方式 18 五、Exome CNV的初步驗證(validation) 18 第三章、 研究結果 (Result) 19 一、基本資料分析(demographic data)及研究流程圖(flowchart) 19 二、CNV盛行率及種類分布 19 三、研究流程圖(flowchart)及Exome CNV的陽性診斷率 19 四、Exome CNV陽性個案列表 20 五、Exome CNV VUS個案列表 21 六、WES SNV及exome CNV的診斷率比較 21 七、嘗試以array CGH驗證Exome CNV (validation) 21 第四章、 討論 (Discussion) 23 一、CNV的形成機轉 23 二、Deletion v.s. duplication，哪個比較容易致病？ 23 三、現行策略的限制 24 四、Exome CNV的優勢與劣勢 25 五、什麼時候該做WES？ 26 六、產前與產後的遺傳診斷：倫理議題 27 七、未來展望 28 第五章、 研究結論 (Conclusion) 29 第六章、 參考資料 (Reference) 29 | - |
| dc.language.iso | zh_TW | - |
| dc.title | 以Exome CNV再分析全外顯子定序個案之致病性拷貝數變異 | zh_TW |
| dc.title | Reanalyze Pathogenic Copy Number Variations Using Exome CNV in WES Cohort | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 111-2 | - |
| dc.description.degree | 碩士 | - |
| dc.contributor.oralexamcommittee | 李妮鍾;胡務亮;詹耀龍 | zh_TW |
| dc.contributor.oralexamcommittee | Ni-Chung Lee;Wuh-Liang Hwu;Yao-Lung Chang | en |
| dc.subject.keyword | 全外顯子定序,次世代定序,拷貝數異常,基因診斷, | zh_TW |
| dc.subject.keyword | Whole exome sequencing,next generation sequencing,copy number variation, | en |
| dc.relation.page | 55 | - |
| dc.identifier.doi | 10.6342/NTU202302212 | - |
| dc.rights.note | 同意授權(全球公開) | - |
| dc.date.accepted | 2023-08-04 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 分子醫學研究所 | - |
| 顯示於系所單位： | 分子醫學研究所 | |
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