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).

项目概要 在跨领域和跨领域的基因研究中，非洲血统的人的代表性严重不足。 学科。总的来说，这一点通过像 gnomAD 这样的大型遗传数据库的构建最为明显。 其中只有 14% 的人有非洲血统。其中绝大多数有非洲血统 个人是非裔美国人，最常见的是西非和欧洲血统的混合体。 这意味着东非人口以及生活在非洲大陆的其他非洲人甚至更进一步 迄今为止，在遗传学研究中代表性不足。如果非洲血统个体在遗传方面的代表性仍然不足 研究中，他们将继续不太可能获得准确的基因诊断，也不太可能从中受益 基因组医学的进展。在这里，我们将使用来自 gnomAD、NeuroDev 和 NeuroGAP-Psychosis 的数据来 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 非洲血统的类型（目标 1）。管道改进将通过 seqr 立即提供， AnVIL 上提供的开放获取分析平台，供医学遗传学界使用。我们将 对 NeuroDev Kenya 项目 (NDK) 的所有参与者进行基因表征，并使用这些数据进行测试和 改进这一渠道并为参与者确定遗传诊断（目标 2）。使用 NDK 3 小时的数据 医学、认知和行为电池，我们将对罕见遗传进行最大的表型表征 迄今为止东非个体的疾病（目标 3）。正如 NHGRI Atlas 倡议所述，综合症 不同种族的神经发育障碍的表型表现通常有所不同。这 相对常见的遗传性疾病（例如 DDX3X 和 22q11.2 缺失综合征）的表现尚未发现 在非欧洲人群中得到了很好的表征。在协作分析中，我们将比较表型 NDK 病例概况和非洲发育障碍研究中的病例概况 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，本工作生成的所有数据（例如遗传数据、HPO 术语）和算法都将被 公开发布，以迅速改善非洲的医学遗传学研究和资源 社区（目标 4）。