臺灣博碩士論文加值系統

發展遲緩（developmental delay）是指六歲以下的兒童，在認知、語言表達、粗細動作、情緒發展、人際溝通、與日常生活等方面，有一種或多種以上比同齡兒童的發展落後，其成因相當複雜。智能發展障礙（intellectual disability）則常在幼兒期以發展遲緩形式表現。臨床上針對兒童進行早期療育評估時，經初步排除社會心理因素與環境因子後，通常會考量是否因遺傳因素致病。基因拷貝數變異（copy number variations, CNVs）被指出是可能引致發展遲緩的遺傳因素之一。目前應用上仍以微陣列比較基因體雜合法（array comparative genomic hybridization, aCGH）為主要的CNV偵測工具，然而近年來次世代定序技術的興起與成熟，為研究人類疾病的遺傳基礎提供了新的方法，方便研究者針對基因體變異（包含CNVs與單一鹼基變異等）進行更全面的鑑測與高解析度的序列分析。本篇研究旨在探討全外顯子體定序（whole exome sequencing, WES）相較於現行的aCGH作為發展遲緩第一線檢測工具之效率。
本篇研究對象為受診斷為整體發展遲緩或智能障礙的322名兒童。所有受試者皆已完成aCGH檢測，總體的陽性檢出率為17.1%。我們收取34名個案檢體進行WES檢測，其中24名包含該個案的父母樣本。本研究中以Agilent SureSelect target enrichment system進行富集（enrichment）於Illumina HiSeq2000平台完成WES。後續資料分析則是利用Varseq v2.1.0進行。
在aCGH未有陽性檢出的個案中，我們透過trio analysis，除了個案以外亦納入父母的樣本進行分析，期能在其定序資料中找到最可能造成個體發展遲緩的致病變異。在14個目前已完成分析的trios中，我們發現了4個已知的致病基因變異：TUBA1A (p.Arg214His)、TMEM240 (p.Val115Met)、TUBB2B (p.Ala248Val)、及SMARCA2 (p.Pro883Leu)；其中TUBA1A (p.Arg214His) 與SMARCA2 (p.Pro883Leu)則分別與該個體所呈現的平腦症第三型(Lissencephaly 3)與Nicolaides-Baraitser syndrome之疾病表徵吻合。此外，我們也在12個個案中發現可能與發展遲緩或智能障礙有關的CNVs。
我們亦納入了10個先前aCGH已檢出帶有CNVs的個案，希望能夠探討aCGH與WES檢測結果的一致性。在這10個個案中，aCGH共在13個基因體區域中探測到CNVs；藉由WES的CNV偵測技術，亦在其中11個區域發現變異。
在目前已完成WES資料分析的14 trios與10 singletons中，平均每個個案可偵測到115個p<0.01的CNVs。這些CNVs的大小範圍落在119個鹼基對至1500萬個鹼基對；平均而言，每個個案約有91個<100kb的CNVs、23個大小介於100kb至1Mb的CNVs、與1個超過1Mb的CNV。在這些CNVs中，基因重複（duplications）佔約65%。
我們透過定量聚合酶連鎖反應，評估WES所偵測到的CNVs之精準性與正確性。我們將CNV calls依照其類別與大小分為六個項次，並取出各項次中1%的CNV calls進行檢測；換言之，我們從14 trios與10 singletons的WES資料中所偵測到的2764個CNVs中，取出30個CNVs進行驗證，其中有2個CNVs為先前研究指出可能與發展遲緩或智能障礙相關，另有3個CNVs落在先前aCGH所偵測到的區域之中。在所有以qPCR進行驗證的CNVs中，12個（40%）的DNA相對量值（relative quantity）與其CNV類別吻合。
在此我們希望呈示WES偵測CNVs與SNVs的能力。以WES的多功能性、相對低廉的價格、與加快診斷之潛力，可望作為發展遲緩新的第一線檢測技術。

Developmental delay (DD) describes the condition when a child reaches developmental milestones in cognitive, speech/language, fine/gross motor, emotional, social/personal skills and activities of living later than the expected time during infancy and early childhood. Multiple factors may contribute to such delay. Intellectual disability (ID) may also be reflected as DD in early childhood. Clinically, when evaluating a child during early intervention, the pediatrician may consider the probability of genomic aberrations after ruling out socio-psychological or environmental factors. Copy number variations (CNVs) have been regarded as one of the major causes of DD. While array comparative genomic hybridization (aCGH) has been the current golden standard of CNV detection, next generation sequencing (NGS) techniques have evolved into a novel strategy for studying the genetic basis of human diseases, facilitating comprehensive characterization of genomic aberrations, inclusive of both CNVs and single nucleotide variants (SNVs), and analysis of high-resolution sequence data. The aim of this study is to determine the efficiency of whole exome sequencing (WES) as a first-tier diagnostic test in comparison with aCGH for DD.
We have enrolled 322 subjects diagnosed with global developmental delay or intellectual disability of unknown cause. All individuals have completed aCGH tests (Positive rate: 17.1%). WES was performed on 34 cases, 24 of whom include both parents, with Agilent SureSelect target enrichment system using Illumina HiSeq2000. Analysis of WES data was conducted using Varseq v2.1.0.
In cases whose aCGH tests revealed no positive findings, trio analyses were conducted in hopes of identifying causal variants most closely related to the conditions in the afflicted individuals. We have discovered 4 known rare pathogenic variants that may contribute to GDD/ID out of the 14 trios analyzed so far; they are TUBA1A (p.Arg214His), TMEM240 (p.Val115Met), TUBB2B (p.Ala248Val), and SMARCA2 (p.Pro883Leu). Moreover, 2 of these variants, TUBA1A (p.Arg214His) and SMARCA2 (p.Pro883Leu), correspond with the clinical phenotypes of the affected children, lissencephaly 3 and Nicolaides-Baraitser syndrome, respectively. Furthermore, CNVs in regions that are previously reported to be linked with DD/ID were also discovered in 12 of the cases.
We have also included 10 singletons with positive findings in aCGH tests in order to determine the consistency in CNV detection between aCGH and WES tests. Out of the 13 CNVs called using aCGH, we detected CNVs in 11 regions by analyzing WES data. It is also noticed that CNV calling in WES data is more powerful in calling smaller CNV events.
Among the 14 trios and 10 probands that have been analyzed so far, 115 CNVs with p-values<0.01 were called per case on average. Spans of these CNVs ranged from 119bp to 15Mbp, with approximately 91 CNVs <100kb, 23 CNVs 100kb-1Mb, and 1 CNVs >1Mb in each case. Duplications account for 65.0% confident CNV calls.
Further validation by real-time quantitative PCR (qPCR) was conducted to confirm the precision and accuracy of CNV detection results by WES. CNV calls were divided into 6 strata according to their types and spans. In the 14 trios and 10 singletons, 1% of CNV calls have been drawn from each stratum (30 out of the total 2764 CNVs) for validation, 2 of which were detected in aCGH-negative cases and were previously reported to be associated with DD/ID, and 3 of which lay in the genomic regions that were previously called using aCGH. A total of 12 CNVs (40%) out of the 30 tested CNVs have at least one region that have RQ values that are suggestive or indicative of their CNV types (losses or gains).
Here we shall demonstrate the capacity of WES for detecting CNVs and SNVs. WES may be considered a promising first-tier diagnostic tool for its versatility, moderate cost, and the potential to reduce diagnostic odyssey. 

Acknowledgements......i
摘要......iii
Abstract......v
Table of Contents......vii
Introduction......1
Specific Aims......9
Materials and Methods......10
Results......16
Discussion......30
References......34
Figures......47
Tables......92
Appendices......108

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