Rare genetic disorders in NeuroDev: Insight into the genetic and phenotypic heterogeneity of ID, ASD and ADHD in South African Populations

NeuroDev 中的罕见遗传性疾病：深入了解南非人群中 ID、ASD 和 ADHD 的遗传和表型异质性

• 批准号: 9761029
• 负责人: Kirsty Donald
• 金额: $ 115.27万
• 依托单位: BROAD INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761029
• 关键词: 16p11.2; Address; African; Attention deficit hyperactivity disorder; Audiology; Behavior; Behavior Disorders; Behavioral; Biological; Biology; Blood Tests; Brain imaging; Caring; Cell Line; Child; Cognition; Cognition Disorders; Cognitive; Collection; Consent; Copy Number Polymorphism; Data; Data Aggregation; Development; Developmental Delay Disorders; Dimensions; Endocrine; European; Funding; Genetic; Genetic Risk; Genetic Variation; Genetic study; Genomics; Genotype; Heterogeneity; Hospital Records; Hospitals; Image; Impaired cognition; Individual; Institutes; Intellectual functioning disability; Investigation; Link; Medical; Medical Records; Mendelian disorder; Metabolic; National Institute of Mental Health; Nature; Outcome; Paper; Parents; Participant; Pediatric Hospitals; Penetrance; Phenotype; Population; Positioning Attribute; Red Cross; Research; Resources; Risk; Role; Sampling; South Africa; South African; Structure; Syndrome; Variant; War; aged; analysis pipeline; autism spectrum disorder; base; behavioral impairment; clinical Diagnosis; cohort; data sharing; database of Genotypes and Phenotypes; exome sequencing; genetic architecture; genetic disorder diagnosis; genome sequencing; genome-wide; genomic data; heart imaging; improved; insight; loss of function mutation; neurophysiology; neuropsychiatric disorder; neuropsychiatry; phenotypic data; pleiotropism; rare genetic disorder; repository; transcriptome sequencing; treatment trial; whole genome

Project Summary Rare genetic disorders (RGDs) have provided a significant window into the genetic architecture of cognitive and behavioral variation. They have also posed questions about the relationship between idiopathic and syndromic forms of cognitive and behavioral disorders, and the role of genetic background in RGD expression. Further, most genetic studies to date have focused on populations of European ancestry, meaning little is known about RGD expression and variability in other populations. To address these gaps, we will leverage the ongoing NeuroDev South Africa collection to genetically and phenotypically characterize 1,000 children aged 2-17, ascertained for Autism Spectrum Disorders, Intellectual Disability/Global Developmental Delay, and Attention Deficit Hyperactive Disorder in Cape Town. The collection also includes 1,000 case parents and 1,000 unrelated, ancestry-matched controls. We will genetically characterize all 3,000 NeuroDev participants in order to identify and investigate an estimated 300 RGD cases in the NeuroDev sample. We propose to use medical record data to further characterize all NeuroDev cases which, in conjunction with the detailed phenotype data collected as part of the core collection activity, will create uncommon opportunities for the phenotypic comparison of RGD-based and idiopathic neuropsychiatric disorders (e.g. dimensional cognitive and behavioral data, brain imaging, audiology data). With the aggregated data, we will compare the phenotypic features of RGD-based and idiopathic neuropsychiatric disorders and highlight points of divergence, which will be useful for addressing heterogeneity in future research, as well as in eventual treatment trials. Lastly, we consider the role of genetic background in the variable expressivity of neuropsychiatrically-involved RGDs, in terms of both genome-wide genetic risk for behavioral disorders and ancestral variation. These analyses will address several critical questions about the biology and presentation of RGDs, as well as their relationship to cognitive and behavioral disorders. The wide sharing of these data will permit further investigation at the field- wide level.

项目总结