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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳沛隆(Pei Lung Chen) | |
| dc.contributor.author | Ping-Chun Wu | en |
| dc.contributor.author | 吳秉純 | zh_TW |
| dc.date.accessioned | 2021-06-15T12:50:04Z | - |
| dc.date.available | 2018-08-26 | |
| dc.date.copyright | 2016-08-26 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-07-20 | |
| dc.identifier.citation | 1 Iglesias, C. G. et al. Epidemiology of adult polycystic kidney disease, Olmsted County, Minnesota: 1935-1980. American journal of kidney diseases : the official journal of the National Kidney Foundation 2, 630-639 (1983).
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Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene. American journal of human genetics 61, 843-851, doi:10.1086/514888 (1997). 26 Chang, M. Y. & Ong, A. C. New treatments for autosomal dominant polycystic kidney disease. British journal of clinical pharmacology 76, 524-535, doi:10.1111/bcp.12136 (2013). 27 Loftus, B. J. et al. Genome duplications and other features in 12 Mb of DNA sequence from human chromosome 16p and 16q. Genomics 60, 295-308, doi:10.1006/geno.1999.5927 (1999). 28 Symmons, O., Varadi, A. & Aranyi, T. How segmental duplications shape our genome: recent evolution of ABCC6 and PKD1 Mendelian disease genes. Molecular biology and evolution 25, 2601-2613, doi:10.1093/molbev/msn202 (2008). 29 Bogdanova, N. et al. Homologues to the first gene for autosomal dominant polycystic kidney disease are pseudogenes. Genomics 74, 333-341, doi:10.1006/geno.2001.6568 (2001). 30 Garcia-Gonzalez, M. A. et al. 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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 17, 405-424, doi:10.1038/gim.2015.30 (2015). 40 Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754-1760, doi:10.1093/bioinformatics/btp324 (2009). 41 Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078-2079, doi:10.1093/bioinformatics/btp352 (2009). 42 McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome research 20, 1297-1303, doi:10.1101/gr.107524.110 (2010). 43 DePristo, M. A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nature genetics 43, 491-498, doi:10.1038/ng.806 (2011). 44 Wang, K., Li, M. & Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic acids research 38, e164, doi:10.1093/nar/gkq603 (2010). 45 Robinson, J. T. et al. Integrative genomics viewer. Nature biotechnology 29, 24-26, doi:10.1038/nbt.1754 (2011). 46 Kumar, P., Henikoff, S. & Ng, P. C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nature protocols 4, 1073-1081, doi:10.1038/nprot.2009.86 (2009). 47 Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. Nature methods 7, 248-249, doi:10.1038/nmeth0410-248 (2010). 48 Rozen, S. & Skaletsky, H. Primer3 on the WWW for general users and for biologist programmers. Methods in molecular biology 132, 365-386 (2000). 49 Qi, X. P. et al. Genetic diagnosis of autosomal dominant polycystic kidney disease by targeted capture and next-generation sequencing: utility and limitations. Gene 516, 93-100, doi:10.1016/j.gene.2012.12.060 (2013). 50 Rossetti, S. et al. Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease. Kidney international 75, 848-855, doi:10.1038/ki.2008.686 (2009). 51 Pei, Y. et al. A missense mutation in PKD1 attenuates the severity of renal disease. Kidney international 81, 412-417, doi:10.1038/ki.2011.370 (2012). 52 Rossetti, S. et al. Association of mutation position in polycystic kidney disease 1 (PKD1) gene and development of a vascular phenotype. Lancet 361, 2196-2201, doi:10.1016/S0140-6736(03)13773-7 (2003). 53 Porath, B. et al. Mutations in GANAB, Encoding the Glucosidase IIalpha Subunit, Cause Autosomal-Dominant Polycystic Kidney and Liver Disease. 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Whole-genome sequencing overcomes pseudogene homology to diagnose autosomal dominant polycystic kidney disease. European journal of human genetics : EJHG, doi:10.1038/ejhg.2016.48 (2016). 60 Tan, A. Y. et al. Autosomal dominant polycystic kidney disease caused by somatic and germline mosaicism. Clinical genetics 87, 373-377, doi:10.1111/cge.12383 (2015). 61 O'Brien, K. et al. Congenital hepatic fibrosis and portal hypertension in autosomal dominant polycystic kidney disease. Journal of pediatric gastroenterology and nutrition 54, 83-89, doi:10.1097/MPG.0b013e318228330c (2012). 62 Rossetti, S. et al. Mutation analysis of the entire PKD1 gene: genetic and diagnostic implications. American journal of human genetics 68, 46-63, doi:10.1086/316939 (2001). 63 Vouk, K. et al. PKD1 and PKD2 mutations in Slovenian families with autosomal dominant polycystic kidney disease. BMC medical genetics 7, 6, doi:10.1186/1471-2350-7-6 (2006). 64 Harris, P. C. & Torres, V. E. in GeneReviews(R) (eds R. A. 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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/50638 | - |
| dc.description.abstract | 自體顯性多囊性腎臟病為最常見之遺傳性腎臟病，全球發生率約為四百分之一至千分之一。此屬晚發性腎臟疾病，患者通常於三、四十歲後出現雙側腎臟水泡等病徵，疾病惡化至末期腎衰竭時則需依靠腹膜透析或腎移植治療。已知兩個致病基因PKD1及PKD2，但由於兩基因所含外顯子的數目龐大且有六個與PKD1高度相似的同源偽基因，故為此病做基因檢測有相當的難度與挑戰。在這個研究裡我們使用目前的標準檢測方式-長片段聚合酶連鎖反應，並且利用訂製探針來捕捉基因所在區域，包含對於GC比例高的區域做兩次的基因捕捉，接著使用次世代定序來做基因檢測。基因檢測結果經由生物資訊分析及資料過濾流程後，所有疑似致病變異點都依照疾病資料庫PKDB及ACMG的準則判定，並用Sanger定序法做驗證。同時也利用生物資訊分析偽基因對於基因檢測的影響。
在61個病患家族裡，我們對於自體顯性多囊性腎臟病的診斷率為70% (41/59)，對於自體隱性多囊性腎臟病的檢出率為50% (1/2)。其中自體顯性多囊性腎臟病的家族中有16個皆帶有相同的變異點(PKD2 c.2407C>T, p.R803X)，我們發展出利用限制酶處理的快速篩檢方式，能在2.5小時內完成此變異點的篩檢。在生物資訊分析偽基因的干擾部分，利用現行次世代定序讀取的配對型，300bp片段長度，我們能將干擾降至4%以下。 本研究結果顯示，我們能利用次世代定序為自體顯性多囊性腎臟病提供一個可信靠的基因檢測平台，並有高達70%的檢出率。利用探針捕捉方式更大量的節省手工操作的人力及時間。我們並發展適合所有分生實驗室的快速篩檢，能在短時間內針對族群內常見變異點做出正確的診斷。合併快速篩檢並次世代定序，我們能為病患提供可信的基因檢測結果，更提供他們判斷家屬成員或者未發病之年輕成員帶有疾病的依據，以利他們及早確認診斷，也許之後更能依照基因的變異給予更合適的治療方式。 | zh_TW |
| dc.description.abstract | ADPKD stands for autosomal dominant polycystic kidney disease, it affects 1/400~1/1000 individuals worldwide. It is a late on-set disease and patients often require dialysis or renal transplant when progressed into ESRD (end-stage renal disease). PKD1 and PKD2 are the causative genes for ADPKD. The large number of exons and homologous pseudogenes of PKD1 makes genetic testing challenging. In this study we perform both LRPCR (long-range polymerase chain reaction), the gold standard testing for PKD1, and probe capture as target enrichment methods, combined with region enhancement to improve coverage on high GC-content exons for NGS (next-generation sequencing) testing. All possible pathogenic variants were classified according to PKDB (PKD database) or ACMG guideline followed by Sanger sequencing for validation. We also perform bioinformatics analysis to estimate the interference of the pseudogenes.
In the 61-family cohorts, we gave 70% diagnostic rate (41/59) for ADPKD patients and 50% (1/2) for ARPKD patients. With 27% (16/59) of the ADPKD patients in our study carried the same variant, we also developed a screening method of RFLP for ADPKD hotspot (PKD2 c.2407C>T, p.R803X), that allowed us to perform fast diagnostic in less than 2.5 hours. The bioinformatics analysis also showed that with longer read length with paired-end reads, we can minimize the interference of pseudogenes to as low as 4% of total reads. In conclusion, we are able to provide confident genetic testing result utilizing NGS with diagnostic rate of 70% that requires no intensive labor work prior or additional sequencing after NGS, great coverage for high GC-content with double capture for region enhancement. Finally, we develop a speedy screening test that can be performed within 2.5 hours targeting PKD2 hotspot in our population that greatly reduces costs and may be carried in most testing laboratories. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T12:50:04Z (GMT). No. of bitstreams: 1 ntu-105-P03448006-1.pdf: 3415295 bytes, checksum: 9c5f8ce3da5e8d7a5e94d2f5e1843048 (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | Verification letter from the Oral Examination Committee…………………………….... i
Acknowledgements…………………………………………………………………….. ii English Abstract……………………………………………………………………….. iii Chinese Abstract……………………………………………………………………….. iv Table of Content……………………………………………………………………….. vi List of Figures………………………………………………………………………….. ix List of Tables…………………………………………………………………………... xi Section A: Genetic Testing of ADPKD 1. Background…………………………………………………………………………. 1 1.1 Introduction to ADPKD………………………………………………………… 1 1.2 Clinical Symptoms of ADPKD………………………………………………… 1 1.3 Diagnosis and Treatment of ADPKD…………………………………………... 3 1.4 Genetics and Genetic Testing of ADPKD……………………………………… 5 1.5 NGS as genetic testing for ADPKD……………………………………………. 6 2. Aim of this study…………………………………………………………………… 7 3. Materials and methods……………………………………………………………… 8 3.1 Subjects…………………………………………………………………………. 8 3.2 Sample preparation……………………………………………………………... 8 3.3 Target enrichment method…………………………………………………….. 10 3.4 Next-generation sequencing…………………………………………………... 13 3.5 Data analysis and bioinformatics……………………………………………… 13 3.6 Variant filtration, classification and confirmation…………………………….. 14 3.7 Endonuclease Digestion of PKD2 hotspot……………………………………. 14 3.8 Paternity Testing………………………………………………………………. 16 4. Results…………………………………………………………………………….. 16 4.1 LRPCR vs. Nimblegen Capture………………………………………………. 16 4.2 Region Enhancement………………………………………………………….. 18 4.3 Pooling of LRPCR…………………………………………………………….. 21 4.4 Genetic Testing Findings……………………………………………………… 21 4.5 Endonuclease Digestion of PKD2 hotspot……………………………………. 24 5. Discussion…………………………………………………………………………. 29 5.1 LRPCR as target enrichment method…………………………………………. 29 5.2 Probe capture as target enrichment method…………………………………… 30 5.3 Genetic findings and variant classification………….………………………… 31 5.4 RFLP as cost-effective screening for ADPKD hotspot……………………….. 33 Section B: Distinguishing PKD1 from psuedogenes 1. Background……………………………………………………………………….. 35 1.1 PKD1 and pseudogenes……………………………………………………….. 35 1.2 How they distinguished using LRPCR………………………………………... 35 2. Material and methods……………………………………………………………... 35 2.1 MQ=0 at PKD1 pseudogenes and non pseudogenes region ………………….. 35 2.2 Simulating different read length setting………………………………………. 36 2.3 Simulating pair end and single end reads……………………………………... 36 2.4 Comparison of sequence alignment of PKD1 and pseudogenes……………… 37 3. Results…………………………………………………………………………….. 37 3.1 Pseudogenes vs. non pseudogenes part of PKD1……………………………... 37 3.2 Different read lengths, single, paired end……………………………………... 39 3.3 Alignment analysis of PKD1 and pseudogenes……………………………….. 39 4. Discussion…………………………………………………………………………. 42 Section C: Genetic counseling 1. PKD047………...…………………………………………………………………. 49 2. PKD019………...…………………………………………………………………. 53 3. PKD074………...…………………………………………………………………. 55 Conclusion………...…………………………………………………………………... 58 References………...…………………………………………………………………... 60 | |
| dc.language.iso | en | |
| dc.subject | 偽基因 | zh_TW |
| dc.subject | 偽基因 | zh_TW |
| dc.subject | 次世代定序 | zh_TW |
| dc.subject | 多囊腎 | zh_TW |
| dc.subject | 基因檢測 | zh_TW |
| dc.subject | 多囊腎 | zh_TW |
| dc.subject | 基因檢測 | zh_TW |
| dc.subject | 次世代定序 | zh_TW |
| dc.subject | pseudogenes | en |
| dc.subject | Next-generation sequencing | en |
| dc.subject | PKD | en |
| dc.subject | pseudogenes | en |
| dc.subject | PKD | en |
| dc.subject | Next-generation sequencing | en |
| dc.subject | genetic testing | en |
| dc.subject | genetic testing | en |
| dc.title | 以次世代定序為自體顯性多囊性腎臟病之基因檢測 | zh_TW |
| dc.title | Next-generation sequencing-based genetic testing of autosomal dominant polycystic kidney disease | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 謝豐舟,楊偉勛,高芷華 | |
| dc.subject.keyword | 多囊腎,基因檢測,次世代定序,偽基因, | zh_TW |
| dc.subject.keyword | PKD,Next-generation sequencing,genetic testing,pseudogenes, | en |
| dc.relation.page | 70 | |
| dc.identifier.doi | 10.6342/NTU201601124 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2016-07-21 | |
| 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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