Elucidating the Genetic Etiology of Intellectual Disability in African, Asian, and European Families

阐明非洲、亚洲和欧洲家庭智力障碍的遗传病因

• 批准号: 10660541
• 负责人: SUZANNE M LEAL
• 金额: $ 58.47万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-14 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660541
• 关键词: 3-Dimensional; Adult; Affect; Africa; African; African American population; African ancestry; American; Americas; Animal Model; Asia; Asian; Asian population; Brain; Candidate Disease Gene; Cells; Clinical; Collection; Color; Coniferophyta; Consanguinity; Copy Number Polymorphism; DNA; Data; Data Analyses; Data Set; Databases; Developed Countries; Developing Countries; Development; Diagnosis; Diagnostic; Dideoxy Chain Termination DNA Sequencing; Dimensions; Disease; Environmental Exposure; Etiology; Europe; European; Evaluation; Exclusion; Expression Profiling; Extended Family; FMR1 repeat expansion; Family; Family Study; Family member; Female; Finland; Founder Generation; Fragile X Syndrome; Frequencies; Future; Gene Expression; Gene Frequency; Genes; Genetic; Genetic Predisposition to Disease; Genetic Screening; Genomics; Human; Hungary; Impaired cognition; Infection; Intellectual functioning disability; Knowledge; Mali; Minority Groups; Modality; Modeling; Molecular; Mus; Nervous System; Neurodevelopmental Disorder; Nuclear; Nuclear Family; Pakistan; Parents; Pathogenicity; Phenotype; Play; Population; Proteins; Public Health; Resources; Role; Sampling; Sequence Analysis; Severities; Single Nucleotide Polymorphism; Slave; Structure; Techniques; Testing; Therapeutic Intervention; Time; Trauma; Untranslated RNA; Validation; Variant; Visualization; X Inactivation; X-linked intellectual disability; causal variant; cell type; digital; early screening; exome; exome sequencing; gene function; genetic pedigree; genome sequencing; improved; insertion/deletion mutation; insight; member; minority health; next generation sequencing; novel; proband; protein function; segregation; sequencing platform; single-cell RNA sequencing; spatiotemporal; therapeutic development; therapy development; tool; trait; whole genome

PROJECT SUMMARY/ABSTRACT Intellectual disability (ID) affects 1-3% of the world population. Six and a half million Americans have been diagnosed with ID. Identification of genes and variants that cause ID in a variety of populations. i.e., African, Asian, and European is highly beneficial for understanding brain mechanism and function, development of treatment modalities, and diagnosis through genetic screening. Although >1000 genes have been identified for ID, most genes remain to be uncovered. For this study we will ascertain 500 ID families from Finland, Hungary (Romani and Magyar), Mali, and Pakistan. Families with ID due to a FMR1 repeat expansion (Fragile X syndrome) or environmental exposures (trauma or infection) will be excluded. The studied will consist of trios (affected proband and parents), nuclear and extended families including those with consanguinity. Next-generation sequencing will be performed on DNA samples obtained from the proband and his/her parents for the trios and on average three affected members for the nuclear/extended families. Analysis of the sequence data will be performed by implementing tools developed in house that are incorporated in Jupyter Notebooks using information on variant frequency, deleterious status, and conservation as well as database annotations on clinical etiology, animal models, and brain expression. Candidate variants will be validated and for nuclear/extended families tested for segregation with ID using DNA samples obtained from all available family members. Three-dimensional protein modeling will be performed to investigate how identified variants affect protein function. Once a putatively causal ID variant is identified, we will screen our collection of ID pedigrees and use GeneMatcher to find additional ID families that segregate potentially pathogenic variants within the same gene. For newly identified ID genes, spatiotemporal expression profiling will be performed in the developing and adult brain and nervous system to provide additional evidence of the gene’s involvement in ID etiology and to better understand how disruption of the gene can impact brain function. ID has been understudied in African populations. The study of West Africans (Mali) should bring about new knowledge which can directly impact African Americans since their ancestors were brought to the Americas from West Africa through the trans-Atlantic slave trade. Pakistani families due to their size and structure are highly beneficial in identify ID genes. The Hungarian Romani and the Finnish both belong to founder populations which can aid in variant identification. This unique resource of families from Africa, Asia, and Europe will aid in better understanding of the genetic etiology of ID and the role genetic plays in brain function. The new knowledge obtained from this study should be beneficial to the health of minority and non-minority American populations.

项目总结/摘要 智力残疾（ID）影响世界人口的1-3%。六百五十万美国人 诊断出患有ID。识别导致各种人群ID的基因和变体。也就是说，非洲人， 亚洲人和欧洲人对了解大脑的机制和功能， 治疗方式和通过基因筛查进行诊断。虽然已经发现了超过1000个基因， 对于ID，大多数基因仍有待发现。 在这项研究中，我们将确定来自芬兰、匈牙利（罗姆人和马扎尔人）、马里和 巴基斯坦由于FMR 1重复扩增（脆性X综合征）或环境暴露导致ID的家族 （创伤或感染）将被排除。研究将包括三人（受影响的先证者和父母），核 以及包括有血缘关系的大家庭。下一代测序将在 从先证者和他/她的父母那里获得的DNA样本为三人组，平均三人受影响 核心/大家庭的成员。序列数据的分析将通过实施 内部开发的工具，这些工具使用有关可变频率的信息， 有害状态和保存以及临床病因学、动物模型和 大脑表达将验证候选变体，并对核心/大家族进行分离检测 从所有可用的家庭成员那里获取DNA样本进行身份验证。三维蛋白质建模 将进行研究如何识别的变体影响蛋白质功能。一旦一个脓毒症的病因ID 一旦确定了变异，我们将筛选我们收集的ID谱系，并使用GeneMatcher查找其他ID 在同一基因内分离潜在致病性变异的家族。对于新鉴定的ID基因， 时空表达谱将在发育和成人大脑和神经系统中进行 为该基因参与ID病因学提供额外的证据，并更好地了解如何破坏 会影响大脑功能 ID在非洲人群中研究不足。对西非人（马里）的研究应该带来新的 这些知识可以直接影响非洲裔美国人，因为他们的祖先被带到美洲。 从西非通过跨大西洋奴隶贸易。巴基斯坦家庭由于其规模和结构， 对鉴定ID基因非常有益。匈牙利罗姆人和芬兰人都属于创始人 可以帮助变异识别的群体。这种独特的资源，来自非洲，亚洲， 欧洲将有助于更好地了解ID的遗传病因学和遗传在脑功能中的作用。 本研究所获得的新知识应有益于少数民族和非少数民族的健康 美国人口。