2016-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/672966摘要：自閉症類群為一種在溝通能力缺損、社會互動障礙並帶有重複性行為及興趣的疾病。近因其發生率與盛行率在過去被低估，且自閉症類群是兒童期開始的神經發育異常並具有高遺傳性(遺傳率 90%)，為嚴重的慢性化障礙疾病，十年來自閉症研究已然成為國際上最熱門的研究課題。截至目前為止仍缺乏實驗室的診斷方法，也無有效的預防及治療方法；因此分子基因學研究被認為是迫切需要的，以了解其病因與病理機制和臨床症狀之相關性。由於基因體微晶片的發展，帶動發現自閉症患者的基因體異常；當前的研究顯示 10-25% 的自閉症患者與基因套數變異有關。過去我們的研究團隊在國科會國家型基因體研究補分析的 339位患者當中，有約 5%的人帶有大於 900 kb的基因套數變異，約 120人帶有大於 500 kb；然而，基因套數變異是 de novo或是來自父母的，是否為致病性的仍是未明的。 研究目的: 1. 比對中研院基因體中心之對照組，找出重要致病基因套數變異; 2. 評估帶有大於 500 kb基因套數變異病患的家族之臨床、精神病理、以及社會功能，並分析其基因套數變異以釐清病患基因套數變異來源; 3. 評估有基因套數變異病患之臨床、精神病理、以及社會功能，並追蹤其與時變化; 4. 比較病患的臨床表徵在新發生(de novo)與經遺傳而來的基因套數變異之間的不同; 5. 以途徑分析的方法分析基因套數變異所含括的基因，以找出可能的致病基因，並以基因表現實驗驗證之; 6. 比較(1)有 CNV病患/無 CNV病患/對照組、(2)病患/未患病手足/對照組之臨床表徵是否不同。 方法: 我們將重新評估帶有大於 500 kb基因套數變異的病患；並募集他們的父母(約 200人)及手足(約 40人)，評估其臨床、精神病理、以及社會功能，並分析父母基因套數變異以釐清變異的來源。家族分析將有助於發現致病性的基因套數變異，並藉由路徑分析找出自閉症可能的致病機轉，最後將以基因表現實驗驗證之。我們也將分析基因與臨床表徵之間的關係以期將來提供更完整的臨床服務之參考。 預期結果: 本研究將提供華人及亞洲自閉症患者在臨床特徵、基因變異套數之來源及致病機轉的第一手資料，本研究的結果將對自閉症的基礎及臨床研究有貢獻，並為發展有效的自閉症診斷工具與治療方式鋪路。<br> Abstract: Autism spectrum disorder (ASD) is a childhood-onset neurodevelopmental disorder, characterized by impaired communication and social reciprocity, and repetitive behaviors and interests. ASD is a clinically and genetically heterogeneous complex disease with a high genetic basis in its pathogenesis. Due to its high heritability (90%), severe long-term impairment, lacking available laboratory diagnosis, effective prevention or biological treatment, ASD has been prioritized for molecular genetic studies. Recently, the advancement of molecular cytogenetics, array-based comparative genomic hybridization technology (Array CGH), facilitates the detection of copy number variations (CNVs) of genomic DNA in 10-25% of patients with ASD. With the support from National Science Council of Taiwan (96HD008), we conducted CNV analysis in 339 ASD patients previously, and found that approximately 5% of these patients carried large segments (> 900 kb) of CNVs. We further identified approximately 120 probands with CNVs larger than 500 kb. However, whether these CNVs are de novo or from parents, are pathogenic or not needs to be validated. Specific Aims: 1. To identify important and pathogenic CNVs by comparing with the controls provided by NCGM, Academia Sinica; 2. To assess parents and siblings of ASD patients who were found to have ~500 kb CNVs in our previous study [96HD008] using clinical, psychopathological, and social measures for family study and also to conduct CNV analysis in the families to determine the origin of the CNVs; 3. To conduct a follow-up assessments of clinical features, and social and neuropsychological functions of ASD probands with CNV to examine the phenotype changes over time; 4. To study the clinical phenotypes between de novo and inherited groups to reveal the pathogenic CNVs; 5. To conduct pathway analysis of genes involved in the CNVs, and to confirm the pathogenic genes by conducting gene expression analysis; 6. To investigate the associations of clinical phenotypes such as autistic tendency, and social impairments between (1) probands with/without CNVs/controls, and (2) probands/unaffected siblings/controls. Methods: We will reassess around 120 ASD probands who had CNV (> 500 kb). Their parents (n~200) and siblings (n~40) will be recruited for the assessements of possibility of ASD using clinical, psychopathological, and social measures. The parents and siblings of ASD probands with CNV (> 500 kb) findings will also receive CNV analysis using Affymetrix-6.0 to confirm the origin of CNV. This family analysis will help to conclude pathogenic CNVs, and pathway analysis will then be used to reveal the pathogenesis of ASD. Gene expression will be analyzed to confirm the expression level. Genotype-phenotype correlation will be analyzed to translate the findings into clinical service for patients with ASD. Anticipated results: This study will provide the first data about the clinical characteristics of individuals with ASD and the origin and pathogenesis of CNVs in ethnic Chinese population and in Asian. The findings from this work are expected to contribute to the basic and clinical research on ASD and pave the way to the development of efficient diagnosis tool and treatment in ASD in the future.自閉症類群病因基因基因套數變異家族研究Autism spectrum disorders (ASD)etiologygenecopy number variations (CNV)family study