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: 10380765
• 负责人: Kirsty Donald
• 金额: $ 110.94万
• 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/10380765
• 关键词: 16p11.2; Address; African; African ancestry; 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; Syndrome; Variant; War; aged; analysis pipeline; autism spectrum disorder; base; behavioral impairment; behavioral phenotyping; 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.

项目概要 罕见遗传性疾病（RGD）为了解认知遗传结构提供了重要窗口 和行为变化。他们还对特发性和特发性之间的关系提出了疑问。 认知和行为障碍的综合征形式，以及遗传背景在 RGD 表达中的作用。 此外，迄今为止，大多数遗传学研究都集中在欧洲血统的人群上，这意味着很少有研究 了解其他群体中的 RGD 表达和变异性。为了弥补这些差距，我们将利用 NeuroDev 南非正在进行的收集工作，旨在对 1,000 名 1,000 岁儿童进行遗传和表型特征分析 2-17，确定自闭症谱系障碍、智力障碍/全面发育迟缓，以及 开普敦的注意力缺陷多动症。该收藏还包括 1,000 名案例家长和 1,000 个不相关、血统匹配的对照。我们将对所有 3,000 名 NeuroDev 参与者进行基因表征 为了识别和调查 NeuroDev 样本中估计的 300 个 RGD 病例。我们建议使用 医疗记录数据可进一步描述所有 NeuroDev 病例的特征，并结合详细的 作为核心收集活动一部分收集的表型数据将为 基于 RGD 的和特发性神经精神疾病（例如维度认知障碍）的表型比较 以及行为数据、脑成像、听力学数据）。通过汇总数据，我们将比较表型 基于 RGD 的特发性神经精神疾病的特征并突出分歧点，这将 对于解决未来研究以及最终治疗试验中的异质性很有用。最后，我们 考虑遗传背景在神经精神相关 RGD 的可变表达性中的作用， 行为障碍和祖先变异的全基因组遗传风险。这些分析将 解决了有关 RGD 的生物学和呈现及其与 认知和行为障碍。这些数据的广泛共享将允许在现场进行进一步的调查 宽层次。