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.

项目摘要 罕见的遗传疾病（RGD）为认知遗传结构提供了一个重要的窗口 和行为变化。他们还提出了有关特发性与 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，大多数遗传研究都集中在欧洲血统的人群上，这意味着很少 有关其他人群中RGD表达和可变性的已知。为了解决这些差距，我们将利用 正在进行的Neurodev南非收集到遗传和表型中的1,000名儿童 2-17，确定自闭症谱系障碍，智力残疾/全球发育迟缓，以及 开普敦的注意力缺陷多动障碍。该系列还包括1,000个案例父母， 1,000个无关的，祖先匹配的控件。我们将在基因上表征所有3,000名NeuroDev参与者 为了在NeuroDev样本中识别和研究估计的300例RGD病例。我们建议使用 医疗记录数据以进一步表征所有神经电磁病例，并结合详细信息 作为核心收集活动的一部分收集的表型数据将为 基于RGD和特发神经精神疾病的表型比较 和行为数据，大脑成像，听力学数据）。通过汇总数据，我们将比较表型 基于RGD和特发性神经精神疾病的特征，并突出显示差异的要点 对于解决未来研究的异质性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涉及的RGD的可变表达性中的作用，在 全基因组遗传疾病的遗传风险和祖先变异的术语。这些分析将 解决了有关RGD的生物学和呈现的几个关键问题，及其与之的关系 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调查 - 宽水。