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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊偉勛 | |
| dc.contributor.author | Shin-Yi Wei | en |
| dc.contributor.author | 魏欣怡 | zh_TW |
| dc.date.accessioned | 2021-06-16T23:39:34Z | - |
| dc.date.available | 2015-09-18 | |
| dc.date.copyright | 2012-09-18 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-07-25 | |
| dc.identifier.citation | 1. Oppelt, P., et al., Clinical aspects of Mayer-Rokitansky-Kuester-Hauser syndrome: recommendations for clinical diagnosis and staging. Hum Reprod, 2006. 21(3): p. 792-7.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/65378 | - |
| dc.description.abstract | 臨床上造成女性原發型無月經(Primary amenorrhea)的第二常見原因：MRKH 症候群(Mayer-Rokitansky-Kuester-Hauser syndrome)，此病主要影響女性生殖系統，造成陰道及子宮的發育不全，有時也會伴隨其他病徵，發生率約為1/4000~5000，患者染色體通常為正常核型46, XX，至今尚未發現致病基因。目前有部分文獻顯示此症有家族性關聯，支持此病屬於多基因遺傳模式，但其遺傳外顯率的不完全性(incomplete degree of penetrance)及遺傳表現度的變異性(variable expressivity)，導致此病成為一個不典型的體染色體顯性遺傳模式。
關於此症的突變位點跟致病基因，一直以來有很多臆測，有些想法已被證實沒有臨床意義或無直接相關性，有些變異則尚待確認，某些片段的變異更是屢被提出，2011年時，有研究表示此症患者身上及家族中有一些重複性的拷貝數變異(Copy number variants,簡稱CNVs)發生率偏高(14%)。 肇因於人類基因解碼完成，基因研究有了強大的資料庫做為後盾，再加上基因檢測技術及相關電腦統計軟體的快速進展，次世代基因定序(Next Generation sequencing,簡稱NGS)系統跟基因晶片技術也愈趨成熟，許多以往不容易發現的基因缺損現在都能被偵測到。 本研究主要期望能夠從CNVs的部份尋找MRKH 症候群的基因決定因子。 藉由臨床門診收集MRKH 症候群的個案，利用人類全外顯子定序(Whole Exome Sequencing,簡稱WES)以及晶片偵測CNVs，兩者交叉比對，尋找與此症可能有所關聯的變異點，最後找出兩個loss-of-function的CNVs和四個基因可能和MRKH syndrome有關，HNRNPCL1、LOC649330 和 OR4M2同時有兩位以上的個案發生缺失變異點，OR2T2則是有超過兩個以上的變異點存在。希冀此研究結果能解決MRKH 症候群的某些疑問，未來能應用於臨床諮詢，甚至更進一步將基因醫學代入實際醫療，改善現今MRKH syndrome的醫療模式及生育計畫。 | zh_TW |
| dc.description.abstract | Mayer-Rokitansky-Kuester-Hauser syndrome (MRKH Syndrome) is the second most common cause of primary amenorrhea. The incidence of MRKH syndrome has been estimated as 1 in 4000-5000 female births. It is characterized by congenital aplasia of the uterus and the vagina in women showing normal development of secondary sexual characteristics and a normal 46, XX karyotype. The majority of cases appears to be sporadic, however, family cases have also been described. The mode of inheritance seems to be autosomal dominant with an incomplete degree of penetrance and variable expressivity. The etiology has remained quite unclear until now.
There are lots of hypothesis of the mutation site and associated gene about MRKH syndrome. Some variants that often investigated still need to be confirmed. In 2011, reports show there is high incidence (14%) of recurrent copy number variants (CNVs) in patients with MRKH syndrome. Recent advances in Next Generation Sequencing (NGS) and array technologies have brought a paradigm shift in how medical researchers investigate both rare and common human disorders. The genetic association of MRKH syndrome was analyzed over few years. However, their role in MRKH syndrome has not been subsequently demonstrated. This is also the first report of NGS application in recent MRKH syndrome study. In this study, 5 patients with MRKH syndrome were included, and were selected by uterine and vaginal agenesis. To explore the genetic determinants of MRKH syndrome, we performed Whole Exome Sequencing (WES) and SNP Array 6.0 in 5 cases. We could delineate two relevant chromosomal regions (1p36.21: chr1:12883040-12925851 and 15q11.2: chr15:22357379-22384101) and suggest that HNRNPCL1、LOC649330、OR4M2 and OR2T2 are candidate genes for MRKH syndrome. Each of HNRNPCL1、LOC649330 and OR4M2 has been found mutation within more than 2 cases. There were over 2 loss-of-function deletion site in OR2T2. These findings would help improve genetic testing, treatment and counseling of MRKH syndrome. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T23:39:34Z (GMT). No. of bitstreams: 1 ntu-101-P99448008-1.pdf: 3081638 bytes, checksum: f0f0257ff5cac67394c1edf5a13fffee (MD5) Previous issue date: 2012 | en |
| dc.description.tableofcontents | 口試委員會審定書 #
中文摘要 i ABSTRACT ii 目錄 iv 圖片目錄 vii 表格目錄 ix 附錄目錄 xi Chapter 1 前言 1 1.1 MRKH症候群(MRKH syndrome) 1 1.1.1 介紹 1 1.1.2 治療 3 1.1.3 探討疾病與基因的相關性 4 1.1.4 過去關於MRKH症候群之遺傳學研究 9 1.2 基因變異性(Genetic Variation) 14 1.2.1 拷貝數變異(Copy number variants) 14 1.2.2 拷貝數變異的分析(Analysis of copy number variants) 16 1.3 次世代基因定序(Next Generation Sequence) 16 1.3.1 全外顯子定序(Whole Exome Sequencing) 19 Chapter 2 研究動機 21 Chapter 3 材料與方法 23 3.1 個案收集 25 3.2 萃取Genomic DNA 25 3.3 Affymetrix Genotyping Array 26 3.3.1 SNP Array 6.0分析 26 3.4 人類全外顯子定序(Whole Human Exome Sequencing) 27 3.4.1 WES 分析 27 3.5 統計 28 3.6 DNA引子序列設計 28 3.7 聚合脢連鎖反應 29 3.8 即時定量聚合脢連鎖反應 30 3.8.1 qPCR結果分析 31 3.9 洋菜膠體電泳 32 3.10 PCR產物定序 32 3.11 定序比對 33 Chapter 4 結果 34 4.1 SNP Array 6.0及WES的統計結果 34 4.1.1 SNP Array 6.0與過去文獻報告的點位比對 34 4.1.2 SNP Array 6.0至少有兩位個案發生變異的區間與WES的點位做交集 36 4.1.3 WES結果中顯示同一個基因有發生兩個以上變異的位點與SNP Array 6.0的變異區間做交集 40 4.1.4 包含20個變異點位的CNVs 42 4.2 qPCR確認deletion site 45 4.3 定序確認突變點位 51 4.4 結論 62 Chapter 5 討論 64 5.1 CNVs的檢測與實驗技術(包含SNP Array 6.0 及WES)的討論 64 5.2 龐大數據資料的分析與確認 65 5.3 基因檢測與遺傳諮詢 67 5.4 實驗未來展望 70 Chapter 6 參考文獻 72 Chapter 7 附錄 80 | |
| dc.language.iso | zh-TW | |
| dc.subject | MRKH症候群 | zh_TW |
| dc.subject | 原發型無月經 | zh_TW |
| dc.subject | 基因晶片 | zh_TW |
| dc.subject | 次世代基因定序 | zh_TW |
| dc.subject | 拷貝數變異 | zh_TW |
| dc.subject | 全外顯子基因定序 | zh_TW |
| dc.subject | MRKH Syndrome | en |
| dc.subject | primary amenorrhea | en |
| dc.subject | Copy number variants | en |
| dc.subject | Next Generation sequencing | en |
| dc.subject | Whole Exome Sequencing | en |
| dc.title | 尋找MRKH症候群可能之基因決定因子 | zh_TW |
| dc.title | Searching for the genetic determinants of Mayer-Rokitansky-Kuester-Hauser (MRKH) syndrome | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 陳沛隆,陳美州 | |
| dc.subject.keyword | MRKH症候群,原發型無月經,拷貝數變異,次世代基因定序,基因晶片,全外顯子基因定序, | zh_TW |
| dc.subject.keyword | MRKH Syndrome,primary amenorrhea,Copy number variants,Next Generation sequencing,Whole Exome Sequencing, | en |
| dc.relation.page | 87 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2012-07-25 | |
| 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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