Improving Genetic Diagnosis for African Ancestry Populations

改善非洲血统人群的基因诊断

• 批准号: 10736833
• 负责人: Anne O'Donnell-Luria
• 金额: $ 61.63万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736833
• 关键词: 22q11; 22q11.2; Address; Affect; Africa; African; African American population; African ancestry; Age; Algorithms; Alleles; American; Atlases; Behavioral; Blood; Candidate Disease Gene; Child; Classification; ClinVar; Cognitive; Communities; Constitution; Constitutional; Copy Number Polymorphism; Country; County; DNA; Data; Development; Diagnosis; Diagnostic; Discipline; Disease; Environmental Exposure; Ethnic Population; European ancestry; Family; Frequencies; Funding; Gene Frequency; Genetic; Genetic Databases; Genetic Diseases; Genetic Research; Genetic Variation; Genetic study; Genome; Genomic medicine; Genomics; Hour; Human; Human Genetics; Human Genome; Income; Individual; Kenya; Medical; Medical Genetics; Mendelian disorder; National Human Genome Research Institute; National Institute of Child Health and Human Development; Neurodevelopmental Disorder; Parents; Participant; Persons; Phenotype; Population; Population Heterogeneity; Probability; Psychoses; Rare Diseases; Resources; Sampling; Syndrome; Testing; Variant; Work; aggregation database; clinical diagnostics; cohort; developmental disease; disorder risk; exome; expectation; genetic analysis; genetic disorder diagnosis; genetic resource; genome annotation; genome sequencing; genome-wide; improved; in utero; malformation; phenotypic data; postnatal; rare genetic disorder

Project Summary People of African ancestry have been grossly underrepresented in genetic studies, across domains and disciplines. In aggregate, this is most visible through the constitution of large genetic databases like gnomAD, in which only 14% of individuals have some African ancestry. The great majority of those African-ancestry individuals are African American, and most commonly have a mixture of West African and European ancestry. This means that East African populations, and other Africans living on the African continent, are even further underrepresented in genetic studies to date. If African ancestry individuals remain underrepresented in genetic research, they will continue to be less likely to receive accurate genetic diagnoses and less likely to benefit from advances in genomic medicine. Here, we will use data from gnomAD, NeuroDev and NeuroGAP-Psychosis to address this representation gap and to improve medical genetic and diagnostic pipelines for individuals of all types of African ancestry (Aim 1). The pipeline improvements will be made immediately available through seqr, an open access analysis platform that is available on AnVIL for use by the medical genetics community. We will genetically characterize all participants from the NeuroDev Kenya project (NDK) and use this data to test and improve this pipeline and identify genetic diagnoses for participants (Aim 2). Using data from NDK’s 3 hour medical, cognitive and behavioral battery, we will conduct the largest phenotypic characterization of rare genetic disorders in East African individuals to date (Aim 3). As described by the NHGRI Atlas initiative, syndromic neurodevelopmental disorders often vary in their phenotypic presentation between ethnic groups. The presentations of relatively common genetic disorders (e.g. DDX3X and 22q11.2 deletion syndromes) have not been well characterized in non-European populations. In a collaborative analysis, we will compare the phenotypic profiles of NDK cases and cases from the Deciphering Developmental Disorders Africa study with common genetic disorders against those observed in European ancestry cases, as described in GeneReviews and the G2MH network. Lastly, all data (e.g. genetic data, HPO terms) and algorithms generated by this work will be made publicly available in order to rapidly improve medical genetics research and resources for African communities (Aim 4).

项目摘要 非洲血统的人在基因研究中的代表性严重不足， 学科总的来说，这一点在gnomAD等大型基因数据库的构建中最为明显， 只有14%的个体有非洲血统。绝大多数的非洲血统 个体是非洲裔美国人，并且最常见的是具有西非和欧洲血统的混合物。 这意味着东非人口和生活在非洲大陆的其他非洲人， 在基因研究中的代表性不足。如果非洲血统的个体在遗传学上仍然代表不足， 研究，他们将继续不太可能获得准确的基因诊断，也不太可能受益于 基因组医学的进展在这里，我们将使用来自gnomAD，NeuroDev和NeuroGAP精神病的数据， 解决这一代表性差距，并改善所有人的医学遗传和诊断渠道 非洲血统类型（目标1）。管道改进将立即通过seqr提供， AnVIL是一个开放获取的分析平台，可供医学遗传学界使用。我们将 从基因上描述所有参与者从NeuroDev肯尼亚项目（NDK），并使用这些数据来测试和 改善这一渠道，并为参与者确定遗传诊断（目标2）。使用NDK的3小时数据 医学，认知和行为电池，我们将进行最大的罕见遗传的表型表征 迄今为止东非个体的疾病（目标3）。正如NHGRI Atlas倡议所述，综合征 神经发育障碍在不同种族群体之间的表型表现常常不同。的 相对常见的遗传性疾病（如DDX3X和22q11.2缺失综合征）的表现没有 在非欧洲人群中得到了很好的表征。在合作分析中，我们将比较 NDK病例和来自非洲解密发育障碍研究的病例的概况， 与欧洲血统病例中观察到的遗传性疾病相比，如GeneReviews和 G2MH网络。最后，这项工作产生的所有数据（例如基因数据、HPO术语）和算法将被 公开提供，以迅速改善非洲人的医学遗传学研究和资源， 社区（目标4）。