Genomic analysis of the Multiplex, Autozygous Populations in Cerebral Palsy (MAP CP) cohort: a focused approach to a complex disease

脑瘫 (MAP CP) 群体中多重自合子群体的基因组分析：针对复杂疾病的集中方法

• 批准号: 10586755
• 负责人: Michael C Kruer
• 金额: $ 67.04万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586755
• 关键词: Accounting; Affect; Africa; Biological Assay; Biological Models; Blood; Brain; Brain Hypoxia-Ischemia; Candidate Disease Gene; Caring; Catalogs; Cells; Cerebral Palsy; Child; Childhood; Clinical; Collaborations; Collection; Communities; Complement; Complex; Consanguinity; Consent; Copy Number Polymorphism; DNA Sequence Alteration; Data; Data Set; Development; Diagnosis; Disease; Drosophila genus; Eating; Enrollment; Environment; Etiology; Exhibits; Face; Family; Family member; Far East; Fathers; Genes; Genetic; Genetic Diseases; Genome; Genomics; Hand; Haplotypes; Human; In Vitro; Individual; Induced pluripotent stem cell derived neurons; Infection; Inherited; Knock-out; Laboratories; Maps; Mediating; Middle East; Modeling; Molecular; Morphology; Mothers; Motor; Movement; Movement Disorders; Mutation; Neurobiology; Neurodevelopmental Disorder; Neurologic; Neurons; Nucleotides; Oxygen; Pain; Parents; Pathway interactions; Patients; Persons; Phenotype; Physical Function; Physicians; Play; Population; Proteins; Quality of life; RNA; RNA Splicing; Radiology Specialty; Research; Research Personnel; Resources; Risk Factors; Role; Sampling; Series; Side; Signs and Symptoms; Site; Smooth Muscle; Southeastern Asia; Specialist; Stream; Stroke; Structure-Activity Relationship; Symptoms; System; Time; Validation; Variant; Walking; Yeasts; astrocyte progenitor; autosome; cell type; clinical care; cohort; consanguineous family; disability; exome; exome sequencing; fly; functional genomics; gene discovery; gene environment interaction; hypoxic ischemic injury; identity by descent; implicit bias; improved; in vivo; in vivo Model; insertion/deletion mutation; insight; loss of function; mutant; novel; perinatal stroke; premature; prenatal; pressure; protein function; protein structure; segregation; variant of interest; variant of unknown significance

PROJECT SUMMARY/ABSTRACT Cerebral palsy (CP) is a major neurodevelopmental disorder affecting an estimated 1:323 individuals. CP affects the motor stream of development, and people with CP may have difficulty walking, talking, eating, or using their hands. Some may have involuntary muscle activation and/or movements that may be painful and/or disruptive, affecting quality of life and inclusion. Although environmentally-mediated causes of CP such as perinatal stroke, prematurity, prenatal infection or lack of oxygen have been known to lead to CP for some time, recent findings from our group and others indicates that for as many as one-third of individuals with CP, a genetic mutation may be the cause of their CP symptoms. Identifying the genetic basis of CP is important because our data suggests that the identification of a genetic cause of a patient’s CP can lead to a change in management > 20% of the time and this number is expected to grow steadily. Genetic forms of CP may occur sporadically in approximately one-half of cases. However, ~1/3 of genetic cases of CP are estimated to exhibit autosomal recessive inheritance, wherein both parents are unaffected carriers of the condition. Most current research in CP is focused on parent-child trio-based studies. We propose a different approach, focusing instead on families with multiple affected children with CP inter- related by blood. We have enrolled hundreds of such families in collaborations with physician colleagues in the Middle East, Africa and Southeast Asia. Studying highly genetically-informative families such as these is anticipated to represent a powerful approach for cerebral palsy-associated gene discovery. The signs and symptoms of the families we have enrolled in our studies have been diligently catalogued, including assessments by multiple specialists, and the collection of facial photographs and patient videos that highlight their movement disorders. These resources, as well as detailed laboratory and radiological assessments will allow us to comprehensively catalog the symptoms of the individuals we have partnered with for these studies. We will then perform whole exome sequencing to identify changes in the genome found in affected members of the family but not in healthy individuals. Once a candidate gene is identified, we will connect with colleagues worldwide to find patients with similar symptoms who harbor variant(s) in the same gene. We will then conduct a series of laboratory analyses in order to confirm or refute a role for the candidate gene in CP. This will include both classic and massively parallel unbiased studies of RNA, protein, and/or metabolites, and assessment in complementation studies, cell-based assays, fly models and human induced pluripotent stem cell-neurons/astrocytes from patient samples. Impact: We anticipate that this approach will allow us to identify dozens of novel CP-associated genes, which in turn will facilitate clinical advances in diagnosis and management as mechanism-based therapies continue to be developed.

项目概要/摘要 脑瘫 (CP) 是一种主要的神经发育障碍，影响估计 1:323 人。 脑性瘫痪会影响发育的运动流，患有脑性瘫痪的人可能会出现行走、说话、进食或活动困难。 有些人可能会出现不自主的肌肉激活和/或运动，这些运动可能会导致疼痛和/或 尽管环境介导的脑瘫原因，例如，具有破坏性，影响生活质量和包容性。 已知围产期中风、早产、产前感染或缺氧会导致某些人发生脑瘫 我们小组和其他人的最新研究结果表明，对于多达三分之一的脑瘫患者来说， 基因突变可能是导致 CP 症状的原因，识别 CP 的遗传基础非常重要。 因为我们的数据表明，确定患者 CP 的遗传原因可以导致 CP 的改变 管理> 20％的时间，并且这个数字预计将稳步增长。 遗传性 CP 可能在大约一半的病例中偶发，但也有约 1/3 的病例会出现这种情况。 CP 遗传病例估计表现出常染色体隐性遗传，尽管父母双方都是 目前大多数脑瘫的研究都集中在亲子三人组的研究上。 我们提出了一种不同的方法，重点关注有多名患有脑瘫的儿童的家庭。 我们与该中心的医生同事合作，招募了数百个这样的家庭。 研究中东、非洲和东南亚等具有高度遗传信息的家庭。 预计将代表一种发现脑瘫相关基因的强大方法。 我们已认真研究了参与研究的家庭的体征和症状 编目，包括多位专家的评估，以及面部照片和患者的收集 强调他们的运动障碍的视频，以及详细的实验室和信息。 放射学评估将使我们能够对个人的症状进行全面分类 然后我们将进行全外显子组测序以识别变化。 一旦找到候选基因，就会在受影响的家庭成员中发现基因组，但在健康个体中却找不到。 确定后，我们将与世界各地的同事联系，寻找具有类似症状的患者 然后，我们将进行一系列实验室分析，以确认或反驳某个基因。 候选基因在 CP 中的作用这将包括经典的和大规模平行的无偏见研究。 RNA、蛋白质和/或代谢物，以及互补研究、基于细胞的测定、苍蝇模型中的评估 以及来自患者样本的人类诱导多能干细胞神经元/星形胶质细胞的影响：我们预计这一点。 这种方法将使我们能够识别数十种新的 CP 相关基因，这反过来又将促进临床 随着基于机制的疗法的不断发展，诊断和管理方面取得了进展。