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.

项目摘要/摘要 智力残疾（ID）影响着世界人口的1-3％。六百万美国人 诊断为ID。识别引起各种人群中ID的基因和变体。即非洲， 亚洲和欧洲对理解大脑机制和功能非常有益 通过基因筛查的治疗方式和诊断。虽然已经鉴定出> 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（Romani和Magyar），Mali和Mali和 巴基斯坦。由于FMR1重复扩张（脆弱的X综合征）或环境暴露，具有ID的家庭 （创伤或感染）将被排除。该工作室将包括三重奏（受影响的证据和父母），核 以及包括血缘关系的大家庭。下一代测序将在 从问题和他/她的父母获得三重奏，平均三个受影响的DNA样本 核/大家庭的成员。序列数据的分析将通过实施执行 使用有关变异频率的信息，在jupyter笔记本中开发的工具， 有害状态，保护以及有关临床病因，动物模型和的数据库注释 大脑表达。候选变体将得到验证，并为经过隔离测试的核/扩展家庭 使用来自所有可用家庭成员的DNA样品的ID。三维蛋白质建模 将进行研究以研究已鉴定的变体如何影响蛋白质功能。曾经是一个推测的因果ID 标识了变体，我们将筛选我们的ID谱系集合，并使用GeneMatcher查找其他ID 在同一基因内隔离潜在的致病变异的家族。对于新确定的ID基因， 时空表达分析将在发展中心和成人大脑和神经系统中进行 提供该基因参与ID病因的其他证据，并更好地了解如何破坏 该基因可以影响大脑功能。 ID已在非洲人口中被理解。西非人（马里）的研究应带来新的 自从他们的祖先被带到美洲以来可能会直接影响非洲裔美国人的知识 从西非到跨大西洋奴隶贸易。巴基斯坦家庭的大小和结构是 在识别ID基因方面非常有益。匈牙利罗马尼和芬兰人都属于创始人 可以帮助变异识别的人群。非洲，亚洲和 欧洲将有助于更好地理解ID的遗传病因和遗传作用在大脑功能中的作用。 从这项研究中获得的新知识应有益于少数族裔和非终点的健康 美国人口。