Complete gene knockouts in autism: identification and functional characterization

自闭症的完整基因敲除：鉴定和功能表征

• 批准号: 10170434
• 负责人: Timothy Wei-Wen Yu
• 金额: $ 44.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-21 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170434
• 关键词: Affect; Attention; Behavior; Biological; Biological Process; Biology; Brain; Candidate Disease Gene; Case-Control Studies; Catalogs; Categories; Cell Line; Clustered Regularly Interspaced Short Palindromic Repeats; Collection; Complex; Data; Data Set; Defect; Development; Disease; Functional disorder; Future; Gender; Gene Frequency; General Population; Generations; Genes; Genetic Screening; Genetic study; Genome; Goals; Individual; Investigation; Knock-out; Language Delays; Large-Scale Sequencing; Lead; Link; Modeling; Molecular; Mutation; National Institute of Mental Health; Neurobiology; Neurons; Nuclear Hormone Receptors; Pathogenesis; Pathway interactions; Pattern; Phase; Phenotype; Population; Publishing; Research; Risk; Sample Size; Sampling; Social Behavior; Social Interaction; Stereotyping; Steroids; Structure; Synapses; Testing; Transcription Coactivator; Validation; Variant; Work; autism spectrum disorder; biobank; chromatin remodeling; cohort; de novo mutation; disorder risk; exome; experimental study; genetic architecture; human population genetics; human tissue; improved; individuals with autism spectrum disorder; insight; interest; knockout gene; male; novel; rare variant; risk variant; transcription factor; whole genome

PROJECT SUMMARY The overarching goal of the proposed research is to improve our understanding of the neurobiological basis of autism spectrum disorders (ASDs). In this project we will analyze sequencing data collected from tens of thousands of individuals with and without ASD, and examine the rate at which gene knockouts (mutations that disrupt both functional copies of a gene) occur. Gene knockouts, while rare, can reveal critical biological pathways that teach us about the basis of disease. We will compare and contrast rates and patterns of these knockouts between cases and controls, study the effect of gender, and relate these patterns to the known preponderance of males with ASD. We will also use this data to generate a catalog of specific genes that are knocked out more frequently in individuals with ASD than in the general population. Finally, from this catalog, the strongest gene candidates will be chosen for neurobiological functional studies, to provide insight into how dysfunction may alter brain development and plasticity in autistic individuals.

项目摘要 这项研究的总体目标是提高我们对神经生物学的理解。 自闭症谱系障碍（ASD）的基础。在这个项目中，我们将分析从数十个国家收集的测序数据， 成千上万的患有和不患有ASD的个体，并检查基因敲除（突变） 破坏基因的两个功能拷贝）发生。基因敲除虽然罕见，但可以揭示关键的生物学特性。 告诉我们疾病的基础。 我们将比较和对比病例和对照组之间这些基因敲除的比率和模式， 性别的影响，并将这些模式与ASD男性的已知优势联系起来。我们还将 使用这些数据来生成一个特定基因的目录，这些基因在患有 ASD比一般人群。最后，从这个目录中，最强的候选基因将被选择用于 神经生物学功能研究，以深入了解功能障碍如何改变大脑发育， 自闭症个体的可塑性。

项目成果

Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior.

• DOI: 10.1038/s41436-021-01114-z
• 发表时间: 2021-06
• 期刊: GENETICS IN MEDICINE
• 影响因子: 8.8
• 作者: Harris, Holly K.;Nakayama, Tojo;Lai, Jenny;Zhao, Boxun;Argyrou, Nikoleta;Gubbels, Cynthia S.;Soucy, Aubrie;Genetti, Casie A.;Suslovitch, Victoria;Rodan, Lance H.;Tiller, George E.;Lesca, Gaetan;Gripp, Karen W.;Asadollahi, Reza;Hamosh, Ada;Applegate, Carolyn D.;Turnpenny, Peter D.;Simon, Marleen E. H.;Volker-Touw, Catharina M. L.;van Gassen, Koen L. I.;van Binsbergen, Ellen;Pfundt, Rolph;Gardeitchik, Thatjana;de Vries, Bert B. A.;Immken, LaDonna L.;Buchanan, Catherine;Willing, Marcia;Toler, Tomi L.;Fassi, Emily;Baker, Laura;Vansenne, Fleur;Wang, Xiadong;Ambrus, Julian L., Jr.;Fannemel, Madeleine;Posey, Jennifer E.;Agolini, Emanuele;Novelli, Antonio;Rauch, Anita;Boonsawat, Paranchai;Fagerberg, Christina R.;Larsen, Martin J.;Kibaek, Maria;Labalme, Audrey;Poisson, Alice;Payne, Katelyn K.;Walsh, Laurence E.;Aldinger, Kimberly A.;Balciuniene, Jorune;Skraban, Cara;Gray, Christopher;Murrell, Jill;Bupp, Caleb P.;Pascolini, Giulia;Grammatico, Paola;Broly, Martin;Kury, Sebastien;Nizon, Mathilde;Rasool, Iqra Ghulam;Zahoor, Muhammad Yasir;Kraus, Cornelia;Reis, Andre;Iqbal, Muhammad;Uguen, Kevin;Audebert-Bellanger, Severine;Ferec, Claude;Redon, Sylvia;Baker, Janice;Wu, Yunhong;Zampino, Guiseppe;Syrbe, Steffan;Brosse, Ines;Jamra, Rami Abou;Dobyns, William B.;Cohen, Lilian L.;Blomhoff, Anne;Mignot, Cyril;Keren, Boris;Courtin, Thomas;Agrawal, Pankaj B.;Beggs, Alan H.;Yu, Timothy W.
• 通讯作者: Yu, Timothy W.