Investigating the Genetic Landscape of Cerebral Palsy

研究脑瘫的遗传景观

基本信息

批准号：
10408839
负责人：
Siddharth Srivastava
金额：
$ 19.6万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10408839
关键词：
Address Affect Ataxia Attention Biological Boston Cerebral Palsy Characteristics Child Child Development Childhood Chorea Classification Scheme Clinical Communication Data Development Diagnostic Disease Dystonia Enrollment Etiology Face Functional disorder Future Genes Genetic Genetic Diseases Genomics Goals Healthcare Hospitals Image Inborn Errors of Metabolism Individual Institutionalized Child Knowledge Lead Magnetic Resonance Imaging Measures Medical Medical Care Costs Mendelian disorder Molecular Diagnosis Motor Neurodevelopmental Disability Neurodevelopmental Disorder Neurodevelopmental Impairment Neurologic Participant Pathogenicity Patients Pattern Perinatal Persons Phenotype Pilot Projects Play Population Precision therapeutics Predictive Factor Prevalence Prospective cohort Rare Diseases Reproducibility Research Risk Factors Role Scientist Severities Statistical Models Subgroup Symptoms Therapeutic Training United States Variant Work career development clinical practice cohort comorbidity disability economic impact exome exome sequencing genetic analysis genetic disorder diagnosis genetic testing health care economics instrument intrauterine infection neonatal hypoxic-ischemic brain injury neuroimaging patient population premature prospective spasticity

项目摘要

PROJECT SUMMARY/ABSTRACT Cerebral palsy (CP) is the most common childhood-onset motor disability, affecting 764,000 individuals in the United States alone. The lifetime medical costs for a single individual with CP are estimated at $1.4M, which represents a substantial healthcare and economic impact. A diverse set of risk factors contributes to CP, including prematurity, intrauterine infection, and hypoxic ischemic encephalopathy. In approximately 20% of cases, there are no clear perinatal risk factors (“cryptogenic CP”). There is accumulating evidence from rare familial cases and a growing number of isolated cases suggesting that cryptogenic CP may result in part from single gene disorders, including over 50 treatable inborn errors of metabolism. However, these studies have involved small numbers of participants, with patient populations characterized using administrative data with limited attention to precise clinical characterization. The full breadth of the genetic landscape of CP is unknown. We hypothesize that a substantial portion of individuals with cryptogenic CP will have a pathogenic or likely pathogenic variant in a single gene providing an explanation for their symptoms. We propose rigorously phenotyping a large prospective cohort of individuals with both cryptogenic and non-cryptogenic CP who have undergone exome sequencing through an institutional genomics pilot study, and then analyzing exome sequencing data to determine the presence of single gene disorders in each subgroup. To accomplish these goals, we will classify patients as cryptogenic CP or non-cryptogenic CP. We will systematically, rigorously, and longitudinally characterize neurological, motor, communication, and neuroimaging phenotypes using research measures validated for CP. Next, we will analyze exome data using an institutional pipeline for variant interpretation. Finally, we will build a statistical model that correlates the presence of a genetic disorder with phenotypic measures in order to help predict which individuals with CP are most likely to have a single gene disorder. If applied to the population at large, the proposed work could lead to identification of single gene disorders in thousands of individuals with CP, including treatable conditions where a molecular diagnosis may positively alter a child's developmental trajectory. Determining etiology represents a first step in understanding the biological substrates of CP needed for developing rational therapeutics for this highly prevalent condition.

项目概要/摘要脑瘫 (CP) 是最常见的儿童期发病的运动障碍，影响 764,000 人仅在美国，单个 CP 患者的终生医疗费用估计为 140 万美元，这对医疗保健和经济产生了巨大的影响，多种风险因素都会导致 CP，包括早产、宫内感染和缺氧缺血性脑病，约占 20%。病例中，没有明确的围产期危险因素（“隐源性 CP”），但有来自罕见病例的越来越多的证据。隐源性 CP 的部分原因可能是家族性病例和越来越多的孤立病例单基因疾病，包括 50 多种可治疗的先天性代谢缺陷。涉及少量人群，使用管理数据对患者人群进行特征描述对精确临床特征的关注有限。未知。我们发现，很大一部分患有隐源性 CP 的个体都会患有致病性或我们提出了单个基因中可能的致病变异，为其症状提供了严格的解释。对一大批具有隐源性和非隐源性 CP 的个体进行表型分析，这些人患有通过机构基因组学试点研究进行转基因外显子组测序，然后分析外显子组测序数据以确定每个亚组中是否存在单基因疾病。为了实现这些目标，我们将患者分为隐源性 CP 或非隐源性 CP。系统地、严格地、纵向地描述神经、运动、沟通和使用针对 CP 验证的研究措施来分析神经影像表型接下来，我们将使用分析外显子组数据。最后，我们将建立一个关联变量的统计模型。通过表型测量来帮助预测哪些患有 CP 的个体存在遗传性疾病最有可能患有单基因疾病。如果应用于广大人群，拟议的工作可能会导致单基因的鉴定数以千计的脑瘫患者患有多种疾病，包括分子诊断可治疗的疾病积极改变孩子的发育轨迹是理解的第一步。为这种高度流行的疾病开发合理的治疗方法所需的 CP 生物底物。