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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99956完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 許書睿 | zh_TW |
| dc.contributor.advisor | Shu-Jui Hsu | en |
| dc.contributor.author | 江鈺婷 | zh_TW |
| dc.contributor.author | Yu-Ting Chiang | en |
| dc.date.accessioned | 2025-09-22T16:08:06Z | - |
| dc.date.available | 2025-09-23 | - |
| dc.date.copyright | 2025-09-22 | - |
| dc.date.issued | 2025 | - |
| dc.date.submitted | 2025-07-31 | - |
| dc.identifier.citation | Morton, C.C. and W.E. Nance, Newborn hearing screening--a silent revolution. N Engl J Med, 2006. 354(20): p. 2151-64.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/99956 | - |
| dc.description.abstract | 遺傳性聽力損傷（hereditary hearing impairment, HHI）是一種常見的遺傳疾病，具有高度的基因異質性與表現型變異性，因而診斷上充滿挑戰。雖然短片段的次世代定序（short-read next-generation sequencing, srNGS）已廣泛應用於臨床診斷，但針對遺傳性聽力損傷的診斷率僅約40%，顯示尚有改進診斷分析策略的需求。
本研究透過分析短片段與長片段定序資料，針對遺傳性聽力損傷未解的遺傳成因進行探討，與發展相關臨床檢測應用，主要包括三個方向： 1.GJB2相關的表現型變異性：重新分析短片段定序基因套組（short-read panel, srPanel）資料，發現除GJB2以外的聽力損傷相關基因致病變異，另有一可能影響表現型的修飾基因變異CRYL1 rs14236，可能與帶有GJB2 p.V37I同型合子的聽力損傷病人所觀察到的較嚴重聽損有關。 2.結構變異（structural variant, SV）的發現：建立一套整合長片段全基因體定序（long-read whole-genome sequencing, lrWGS）與短片段全基因體定序(short-read whole-genome sequencing, srWGS)資料的分析流程，成功從過去無法診斷家庭中找出新的可能致病非編碼區域缺失變異。 3.具成本效益的長片段定序套組 (long-read panel, lrPanel) 開發與應用：設計並驗證一個客製化長片段定序套組，針對短片段定序難以準確分析的STRC基因及其他容易出現結構變異的聽力相關基因進行分析，達成將長片段定序應用於臨床聽力損傷分子診斷的可能。 本研究利用短片段及長片段定序技術與發展分析策略，釐清未解的遺傳性聽力損傷遺傳病因，提供臨床參考依據，進而提升診斷率。 | zh_TW |
| dc.description.abstract | Hereditary hearing impairment (HHI) is a common genetic disorder characterized by high genetic heterogeneity and phenotypic variability, making diagnosis challenging. Although short-read next-generation sequencing (srNGS) is widely used in clinical diagnostics, the diagnostic yield for HHI remains around 40%, highlighting the need for improved strategies.
This study investigates unresolved genetic causes of HHI and develops clinical testing approaches using both short- and long-read sequencing through three strategies: 1. GJB2-related phenotypic variability: Reanalysis of short-read panel (srPanel) data revealed additional pathogenic variants in other deafness genes and a potential modifier variant, CRYL1 rs14236, which may contribute to the more severe hearing loss observed in GJB2 p.V37I homozygotes. 2. Discovery of structural variants (SVs): A comprehensive analysis pipeline combining long-read whole-genome sequencing (lrWGS) with short-read WGS was developed, enabling the identification of novel non-coding deletions in previously undiagnosed families. 3. Cost-effective clinical application: A custom long-read panel targeting the STRC gene—difficult to analyze with srNGS—and other SV-prone deafness genes was developed and validated for clinical use. Overall, this study demonstrates how integrating multiple sequencing technologies and tailored analysis strategies can resolve complex genetic cases and improve the diagnostic outcomes of HHI. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2025-09-22T16:08:06Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2025-09-22T16:08:06Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員審定書 I
致謝 II 中文摘要 III Abstract IV 目錄 V 圖目錄 IX 表目錄 XI Chapter 1. Introduction 1 1.1. Hereditary hearing impairment (HHI) 1 1.2. Gap junction beta-2 protein (GJB2) gene 2 1.3. Stereocilin (STRC) gene 3 1.4. High-throughput sequencing 5 1.5. Structural variant (SV) 7 1.6. Standards of variant annotation and interpretation 9 1.7. Research framework and objective 15 Chapter 2. Exploring Genetic Factors of Phenotypic Variability in GJB2-Related Hearing Loss 16 2.1. Overview 16 2.2. Materials and Methods 16 2.2.1. GJB2 p.V37I homozygote recruitment and hearing loss level classification 16 2.2.2. Short-read next-generation sequencing (srNGS) panel 17 2.2.3. SNV/INDEL calling from short-read panel and pathogenicity interpretation 18 2.2.4. Case–control association analyses 19 2.3. Results 20 2.3.1. Study workflow and study subject selection 20 2.3.2. Pathogenic variants identified by individual short-read panel re-analyses 22 2.3.3. Phenotypic modifier variant CRYL1 rs14236 identified by case-control association 24 2.3.4. Evidence supporting CRYL1 rs14236 as a genetic modifier 25 2.4. Discussion 30 Chapter 3. Using Long-Read WGS to Detect Structural Variants in Hearing-Impaired Patients Negative by Short-Read WGS 34 3.1. Overview 34 3.2. Materials and Methods 37 3.2.1. Collection of study cases and whole-genome sequencing (WGS) data 37 3.2.1.1. Recruitment of study cases and deafness multiplex families for WGS 37 3.2.1.2. Short-read and long-read WGS 38 3.2.2. SV calling and performance evaluation 38 3.2.2.1. Variant calling from WGS data 38 3.2.2.2. HG002 SV benchmarking 39 3.2.3. SV annotation and prioritization 39 3.2.3.1. SV annotation and prioritization by AnnotSV and SvAnna 39 3.2.3.2. Establishment of deafness gene virtual panels 40 3.2.3.3. Datasets and databases for in-house SV annotation pipeline 41 3.2.3.4. In-house SV ranking pipeline 42 3.2.3.5. HPRC samples as SV ranking false positives 49 3.2.4. HG002 deletion set with deletion spike-in for SV prioritization comparison 50 3.3. Results 51 3.3.1. SV calling and performance evaluation 51 3.3.1.1. lrWGS outperforms srWGS in SV detection 51 3.3.1.2. Detection of STRC CNVs in HHI patients via lrWGS and Paraphase 57 3.3.2. SV annotation and prioritization 58 3.3.2.1. AnnotSV-based annotation and classification of CNVs in HHI patients 58 I. Family-based analysis of joint CNVs from srWGS using AnnotSV 58 II. Analysis of CNVs in individual HHI patients using lrWGS and AnnotSV 59 III. Limitations of AnnotSV 61 3.3.2.2. Screening for translocations and inversions in 754 deafness genes from lrWGS data 62 3.3.2.3. SvAnna-based prioritization of SVs from lrWGS in HHI patients 64 3.3.2.4. Optimizing SV matching parameters for enhanced in-house SV annotation and ranking pipeline 66 3.3.3. SV prioritization comparison: AnnotSV, SvAnna, and In-house pipeline 71 3.3.3.1. Comparison of SV scoring criteria and enhancements by the In-house pipeline 71 I. ACMG/ClinGen CNV scoring system and AnnotSV 71 II. SvAnna 72 III. Enhancements by the In-house pipeline 73 3.3.3.2. Comparison of SV prioritization performance using HG002 lrWGS deletions with spike-in deletions 74 3.3.4. Multiplex family reports 80 3.3.4.1. Families with suspect findings 80 I. MDD0046 Family 80 II. MDD0065 Family 88 III.MDD0117 Family 97 3.3.4.2. Families without suspect findings 103 I. DE7604 Family 103 II. MDD0026 Family 107 III.MDD0050 Family 109 IV.MDD0057 Family 115 V. MDD00140 Family 120 3.4. Discussion 126 Chapter 4. Developing a Long-Read Diagnostic Panel for Hereditary Hearing Impairment 131 4.1. Overview 131 4.2. Materials and Methods 131 4.2.1. Validation sample selection for long-read panel SV calling 131 4.2.2. DNA library preparation and sequencing of long-read panel 132 4.2.3. Long-read panel SV calling workflow 132 4.2.4. HG002 SV benchmarking in long-read panel targeted regions 133 4.3. Results 133 4.3.1. Long-read panel design and targeted gene selection 133 4.3.2. Coverage analysis of long-read panel target regions 134 4.3.3. SV calling performance evaluation in long-read panel targeted regions with HG002 benchmarking 139 4.3.4. SV detection comparison between long-read panel and lrWGS of deafness patients 142 4.3.5. STRC CNV analysis of the long-read panel 145 4.3.6. SV discovery of the long-read panel 148 4.4. Discussion 151 Conclusions 155 Acknowledgements 155 References 156 Appendix 166 個人著作列表 170 | - |
| dc.language.iso | en | - |
| dc.subject | 遺傳性聽力損傷 | zh_TW |
| dc.subject | 結構變異 | zh_TW |
| dc.subject | 長片段定序 | zh_TW |
| dc.subject | 短片段定序 | zh_TW |
| dc.subject | 全基因組定序 | zh_TW |
| dc.subject | 定序套組 | zh_TW |
| dc.subject | Structural variant | en |
| dc.subject | Hereditary hearing impairment | en |
| dc.subject | Target panel sequencing | en |
| dc.subject | Whole-genome sequencing | en |
| dc.subject | Short-read sequencing | en |
| dc.subject | Long-read sequencing | en |
| dc.title | 應用長片段與短片段DNA序列分析以解決遺傳性聽損之診斷挑戰 | zh_TW |
| dc.title | Applying Long-Read and Short-Read DNA Sequencing to Address Diagnostic Challenges in Hereditary Hearing Impairment | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 113-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.oralexamcommittee | 吳振吉;陳沛隆;馮嬿臻;陳弘昕 | zh_TW |
| dc.contributor.oralexamcommittee | Chen-Chi Wu;Pei-Lung Chen;Yen-Chen Feng;Hung-Hsin Chen | en |
| dc.subject.keyword | 遺傳性聽力損傷,結構變異,長片段定序,短片段定序,全基因組定序,定序套組, | zh_TW |
| dc.subject.keyword | Hereditary hearing impairment,Structural variant,Long-read sequencing,Short-read sequencing,Whole-genome sequencing,Target panel sequencing, | en |
| dc.relation.page | 170 | - |
| dc.identifier.doi | 10.6342/NTU202502984 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2025-07-31 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 基因體暨蛋白體醫學研究所 | - |
| dc.date.embargo-lift | 2030-07-30 | - |
| 顯示於系所單位： | 基因體暨蛋白體醫學研究所 | |
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