基于全外显子组分析的孤独症易感基因筛查
文献类型：学位论文
| 作者 | 毕澄
|
| 学位类别 | 博士 |
| 答辩日期 | 2014 |
| 授予单位 | 中国科学院心理研究所 |
| 授予地点 | 北京 |
| 导师 | 孙中生 |
| 关键词 | 孤独症谱系障碍 新生突变 ANK3 全外显子测序 |
| 其他题名 | Identification of mutations associated with autism susceptibility by exome sequencing |
| 学位专业 | 理学博士 |
| 中文摘要 | 摘要：孤独症谱系障碍（Autistic Spectrum Disorders，ASD ）是一组严重影响儿童健康、高度遗传性的神经发育障碍性疾病。由于ASD 具有高度遗传异质性，传统的研究方法面临诸多挑战。新一代测序技术的应用已成为加速鉴定ASD 遗传病因的 有力工具。在本研究中，我们对20 个ASD 患者进行了全外显子组分析，共发现10,007个错义突变，93 个无义突变，503 个可变剪切，19 个通读突变和 315 个移码突变，经过公共数据库和华大基因2000 外显子数据库过滤以及突变功能预测后，共找到68 个新的潜在有害突变。经IPA 分析发现其中7 个突变基因参与突触功能和神经发育（ABCA1, ANK3, CLCN6, HTR3A, RIPK2, SLIT3 和 UNC13B），随后经父母基因型检测发现ANK3 突变是新生突变，考虑到其在神经系统的重要功能和新生突变的潜在作用，我们对其它47 个ASD 样品进行了ANK3 基因测序验证，最终在4 个样品中发现了3 个不同的错义突变，其中c.4705T>G (p.S1569A)是两患者共同拥有的新生突变。由于ANK3 与精神分裂症和双相情感障碍的显著相关性，我们的发现支持ANK3 是ASD 易感性相关基因，并暗示ASDs 和其他神经精神疾病可能具有共同的致病机制。此外，其它 6 个孤独症候选基因都与UBC（ubiquitin C ）相联系，提示这一通路可能与孤独症易感性相关，为研究这些基因的相互作用和孤独症致病原理提供了先期基础。 |
| 英文摘要 | ABSTRACT: Autism spectrum disorders (ASDs) are common neurodevelopmental disorders with a strong genetic etiology. However, due to the extreme genetic heterogeneity of ASDs, traditional approaches for gene discovery are challenging. Next-generation sequencing technologies offer an opportunity to accelerate the identification of the genetic causes of ASDs. Here, we report the results of whole-exome sequence in a cohort of 20 ASD patients. We identified a total of 10,007 missense variants, 93 nonsense variants, 503 splice site variants, 19 readthrough stop codons, and 315 frameshift indel mutations. After filtration against the public SNPs database, the 2000 Caucasian exomes database at BGI-Shenzhen and SIFT prediction; the total number of potentially damaged novel SNVs possibly associated with ASDs was reduced to 68. IPA result indicates that seven genes with novel mutations (ABCA1, ANK3, CLCN6, HTR3A, RIPK2, SLIT3 and UNC13B) are implicated in synaptic function and neurodevelopment. Genotyping data of parents show that the novel mutation in ANK3 is de novo. Considering the function of ANK3 in neural system and possible importance of de novo mutations in ASD, we sequenced ANK3 in additional 47 ASD samples. Totally, we identified three different missense mutations in ANK3 in four unrelated ASD patients, one of which, c.4705T>G (p.S1569A), is a recurrent de novo mutation. Given the fact that ANK3 has been shown to strongly associate with schizophrenia and bipolar disorder, our findings support an association between ANK3 mutations and ASD susceptibility and imply a shared molecular pathophysiology between ASDs and other neuropsychiatric disorders. Moreover, the protein network analysis identified a network that is centered at ubiquitin C (UBC) with connections across six genes. Our findings inplcate their contribution to the genetic susceptibility of ASD and warrant further studies of the role of these genes and associated networks in ASDs mechanism. |
| 学科主题 | 心理学 |
| 语种 | 中文 |
| 源URL | [http://ir.psych.ac.cn/handle/311026/19485]  |
| 专题 | 心理研究所_健康与遗传心理学研究室 |
| 作者单位 | 中国科学院心理研究所 |
| 推荐引用方式 GB/T 7714 | 毕澄. 基于全外显子组分析的孤独症易感基因筛查[D]. 北京. 中国科学院心理研究所. 2014. |
入库方式： OAI收割
来源：心理研究所
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