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| ???org.dspace.app.webui.jsptag.ItemTag.dcfield??? | Value | Language |
|---|---|---|
| dc.contributor.advisor | 陳沛隆(Pei-Lung Chen) | |
| dc.contributor.author | Ming-Yu Lo | en |
| dc.contributor.author | 駱明瑜 | zh_TW |
| dc.date.accessioned | 2022-11-25T05:33:51Z | - |
| dc.date.available | 2023-08-31 | |
| dc.date.copyright | 2021-08-31 | |
| dc.date.issued | 2021 | |
| dc.date.submitted | 2021-08-19 | |
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Carss, K.J., et al., Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease. Am J Hum Genet, 2017. 100(1): p. 75-90. 86. Hilgert, N., et al., Phenotypic variability of patients homozygous for the GJB2 mutation 35delG cannot be explained by the influence of one major modifier gene. Eur J Hum Genet, 2009. 17(4): p. 517-24. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/82000 | - |
| dc.description.abstract | "結節硬化症是一種罕見的體染色體顯性遺傳疾病，因TSC1或TSC2基因的致病變異導致全身多處器官和組織產生錯構瘤。目前臨床上確診為結節硬化症的病人，以傳統的血液檢體與常規的基因檢測流程約有88%可發現致病變異，但仍有10~20%無法發現致病變異位點，懷疑可能是低比例鑲嵌型、致病位點位於深部內含子內，以及存在其他變異形式導致無法被檢測出。 本研究中將收集臨床診斷為結節硬化症，在常規的次世代定序基因檢測未發現致病位點共15個病人，經由SpliceAI、Mutect2等生資工具、皮膚檢體來進行更深入分析。在SpliceAI工具中有2個病人發現有內含子的位點造成剪接變異，也有文獻證實該變異位點的致病性。1位病人經由皮膚組織發現為21 %鑲嵌型致病位點，血液檢體為4 %鑲嵌比例。因此選用可檢測10 %以下鑲嵌型變異位點的Mutect2工具，進一步發現5位病人帶有<10 %低比例鑲嵌型致病位點。另外其他致病變異形式的研究，包含microRNA 結合位置序列的分析、大片段缺失、FLCN致病位點的分析等，目前沒有發現可能的致病位點。經由本研究，共有8位病人發現造成結節硬化症的致病位點，檢測率額外增加5 %，提升為93%。 本研究中有一結節硬化症合併多重原發性癌症家族，經由周邊血液的全基因體定序，分析癌症相關基因，發現MSH2的致病位點，符合病人免疫組織化學染色發現無MSH2及MSH6蛋白表現的結果，結合MSH2致病變異以及病人皮脂腺瘤與臟器的惡性腫瘤，推測病人應為Muir-Torre syndrome (MTS)患者。 聽力損失是最常見的先天性感覺障礙之一，約有50%的感音型聽損可歸因於遺傳因素，其中以GJB2基因變異佔大多數，GJB2合成的間隙連接蛋白connexin26 (Cx26)本身或與其他的間隙連接蛋白會聚合成同構或是異構六聚體的通道作運輸。在台灣聽損病患GJB2, c.109G>A (p.V37I)致病位點佔極大比例。而GJB2基因型與聽損嚴重程度有關，臨床經驗上基因型為p.V37I同型合子或複合異合子時，表現型通常為輕中度聽損，然而有少數病人p.V37I同型合子或是複合異型合子卻是重度以上聽損表現。推測原因可能為GJB2其他的變異位點或是調控區域的影響，因此將p.V37I同型合子患者分為重度及輕度聽損兩組，結果兩組GJB2的變異位點發生頻率沒有明顯的差異，此外檢視重度聽損病患GJB2內含子的調控區域，亦沒有發現缺失；另外去進行上述兩組的其他間隙蛋白變異位點比較，結果仍沒有明顯差異。最後推測是否是其他基因變異造成聽損的差異性表現，結果發現在45位病人中有6位(13%)帶有第2個聽損基因且符合症狀的致病變異位點，因此，p.V37I基因型的重度聽損表現，並非來自於GJB2其他變異位點或是調控區域的缺失，其他間隙蛋白的影響可能不明顯，部分患者的聽損表現與其第2個聽損基因影響有關聯。 " | zh_TW |
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| dc.description.tableofcontents | "誌謝 i 中文摘要 ii ABSTRACT iv 目 錄 vii 圖目錄 xiii 表目錄 xv 第 一 節 結節硬化症 1 第 1 章 研究背景與動機 1 1.1 結節硬化症的疾病介紹 1 1.2 結節硬化症的致病機轉 1 1.3 結節硬化症的臨床表徵 2 1.4 結節硬化症之診斷標準 2 1.4.1 臨床診斷標準 2 1.4.2 基因診斷標準 3 1.5 結節硬化症資料庫 4 1.5.1 結節硬化症LOVD資料庫 4 1.5.2 CinVar資料庫 4 1.5.3 臺灣本土結節硬化症整合型資料庫 4 1.6 結節硬化症在基因檢測判讀上的難題 5 1.6.1 未找到致病變異點 5 1.6.2 找到無法判讀其致病性的變異點(VUS) 5 1.6.3 臨床症狀相似的其他疾病 6 1.7 遺傳諮詢 (genetic counseling) 6 1.8 生物資訊分析工具 6 1.8.1 SpliceAI 工具 6 1.8.2 Mutect2工具 7 1.9 研究目標 7 第 2 章 研究方法 9 2.1 研究對象 9 2.1.1 受試者來源與收案標準: 9 2.1.2 檢體 9 2.2 研究方法 9 2.2.1 DNA萃取 9 2.2.2偵測DNA品質 10 2.2.3 TSC panel 10 2.2.4次世代定序 (Next-generation sequencing, NGS) 11 2.2.5全基因定序分析(Whole Genome Sequencing, WGS) 13 2.2.5.1 定序分析 13 2.2.5.2 癌症基因分析 13 2.2.6 變異位點致病性的判讀 14 2.2.6.1 結節硬化症資料庫 (LOVD) 14 2.2.6.2 ClinVar資料庫 15 2.2.6.3 變異點致病性的綜合判讀準則 15 2.2.6.4 聚合酶連鎖反應(PCR)及傳統定序(Sanger) 15 2.3 REDCap (Research Electronic Data Capture)資料庫 15 第 3 章 研究結果 16 3.1 剪接變異分析與SpliceAI工具使用 16 3.2 鑲嵌位點分析 19 3.2.1皮膚檢體的鑲嵌變異位點分析 19 3.2.2 Mutect2生物資訊工具使用 19 3.3 MicroRNA 序列與結合位置之研究 29 3.3.1 MicroRNA序列之變異位點分析 29 3.3.2 MicroRNA結合位置(binding site)上之變異位點分析 29 3.4 FLCN基因檢視 29 3.5 拷貝數變異(Copy number variation, CNV)之研究 29 3.6 次世代定序結果統計與分析 29 3.7 結節硬化症患者合併多重原發性癌症之研究 32 3.7.1案例報告 32 3.7.2 全基因體定序結果與分析 33 3.8 遺傳諮詢 36 3.8.1案例一(TTSC00559) 36 3.8.2 案例二(TTSC00546, TSC429) 37 3.8.3 案例三(TTSC00572) 38 第 4 章 討論 39 4.1 臺灣的結節硬化症流行病學資料 39 4.2 基因檢測檢出率 39 4.3 結節硬化症患者合併多重原發性癌症之研究 40 4.4 未來展望 41 第 二 節 聽損基因GJB2, p.V37I之研究 42 第 1 章 研究背景與動機 42 1.1 感音型聽損 42 1.2 聽損的遺傳基因研究 42 1.3 GJB2基因與Connexin26的蛋白分子結構及功能 43 1.4 GJB2 基因與表型的相關性 44 1.5 GJB2 基因p.V37I變異致病機制推測與研究進展 45 1.6 聽損基因位點資料庫 46 1.6.1 Deafness Variation Database (DVD) 46 1.6.2 CinVar資料庫 46 1.7 研究目標 47 第 2 章 研究方法 48 2.1 研究對象 48 2.1.1 受試者來源與收案標準: 48 2.1.2 檢體 48 2.2 研究方法 48 2.2.1 周邊血液白血球DNA萃取 48 2.2.2 偵測DNA品質 48 2.2.3 Deafness 220 gene panel 49 2.2.4 次世代定序 (Next-generation sequencing, NGS) 51 2.2.5 統計方法 53 2.2.6 變異位點致病性的判讀 53 2.2.6.1 Deafness Variation Database (DVD) 53 2.2.6.2 ClinVar資料庫 53 2.2.6.3 變異點致病性的綜合判讀準則 53 2.2.6.4 聚合酶連鎖反應(PCR)及傳統定序(sanger sequencing) 53 第 3 章 研究結果 54 3.1 GJB2基因全長及調控區域分析 54 3.1.1 GJB2的變異位點分析 54 3.1.2 GJB2大片段缺失分析 54 3.2 其他間隙連接蛋白基因變異位點比較分析 57 3.3 其他聽損基因的致病變異位點之分析 60 第 4 章 討論 66 4.1 GJB2基因全長與調控區域之討論 66 4.2 其他間隙連接蛋白之分析討論 66 4.3 其他聽損基因之分析討論 67 4.4 未來展望 68 參考文獻 69 附錄 74 附錄一、15名臨床確診基因未確診之TSC病人資料 74 附錄二、TSC變異列表 75 附錄三、PCR primer 85 " | |
| dc.language.iso | zh-TW | |
| dc.subject | 剪接位變異 | zh_TW |
| dc.subject | 結節硬化症 | zh_TW |
| dc.subject | 全基因體定序 | zh_TW |
| dc.subject | Muir-Torre syndrome | zh_TW |
| dc.subject | 感音型聽損 | zh_TW |
| dc.subject | GJB2 | zh_TW |
| dc.subject | p.V37I位點 | zh_TW |
| dc.subject | 間隙連接蛋白 | zh_TW |
| dc.subject | Mutect2工具 | zh_TW |
| dc.subject | 基因的調控區域 | zh_TW |
| dc.subject | SpliceAI工具 | zh_TW |
| dc.subject | 次世代定序 | zh_TW |
| dc.subject | 低比例鑲嵌型 | zh_TW |
| dc.subject | next-generation sequencing | en |
| dc.subject | Tuberous Sclerosis Complex | en |
| dc.subject | splicing mutation | en |
| dc.subject | low percentage mosaicism | en |
| dc.subject | SpliceAI tool | en |
| dc.subject | Mutect2 tool | en |
| dc.subject | whole genome sequencing | en |
| dc.subject | Muir-Torre syndrome | en |
| dc.subject | sensorineural hearing impairment | en |
| dc.subject | GJB2 | en |
| dc.subject | p.V37I variant | en |
| dc.subject | gap proteins | en |
| dc.subject | GJB2 regulatory regions | en |
| dc.title | 基因未診斷病人之基因研究: 將次世代定序用於結節硬化症及聽損 | zh_TW |
| dc.title | Genetic Study in Previously Genetically Undiagnosed Patients: Next-generation Sequencing for TSC and Deafness | en |
| dc.date.schoolyear | 109-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 吳振吉(Hsin-Tsai Liu),楊偉勛(Chih-Yang Tseng) | |
| dc.subject.keyword | 結節硬化症,剪接位變異,低比例鑲嵌型,次世代定序,SpliceAI工具,Mutect2工具,全基因體定序,Muir-Torre syndrome,感音型聽損,GJB2, p.V37I位點,間隙連接蛋白,基因的調控區域, | zh_TW |
| dc.subject.keyword | Tuberous Sclerosis Complex,splicing mutation,low percentage mosaicism,next-generation sequencing,SpliceAI tool,Mutect2 tool,whole genome sequencing,Muir-Torre syndrome,sensorineural hearing impairment,GJB2, p.V37I variant,gap proteins,GJB2 regulatory regions, | en |
| dc.relation.page | 85 | |
| dc.identifier.doi | 10.6342/NTU202102458 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2021-08-20 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| dc.date.embargo-lift | 2023-08-31 | - |
| Appears in Collections: | 分子醫學研究所 | |
Files in This Item:
| File | Size | Format | |
|---|---|---|---|
| U0001-1808202110442400.pdf Access limited in NTU ip range | 3.9 MB | Adobe PDF |
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