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

项目总结/摘要 脑性瘫痪（CP）是一种主要的神经发育障碍，影响估计1：323个人。 CP会影响运动流的发展，CP患者可能会有行走，说话，进食， 用他们的手。一些人可能有不自主的肌肉激活和/或运动，这可能是痛苦的和/或痛苦的。 破坏性，影响生活质量和包容性。虽然环境介导的CP原因，如 已知围产期中风、早产、产前感染或缺氧会导致某些人患CP。 与此同时，我们小组和其他人最近的研究结果表明，对于多达三分之一的CP患者， 基因突变可能是他们CP症状的原因。确定CP的遗传基础是重要的 因为我们的数据表明，确定患者CP的遗传原因可以导致 管理> 20%的时间，这一数字预计将稳步增长。 CP的遗传形式可能在大约一半的病例中零星发生。然而，1/3的 据估计，CP的遗传病例表现出常染色体隐性遗传，其中父母双方都是 不受影响的携带者。目前对合作伙伴关系的研究主要集中在亲子三人组的研究。 我们提出了一种不同的方法，而不是集中在多个受影响的儿童与CP间的家庭， 有血缘关系我们已经招募了数百个这样的家庭与医生同事合作， 中东、非洲和东南亚。研究像这样高度遗传信息的家庭， 有望成为脑性麻痹相关基因发现的有力途径。 我们在研究中登记的家庭的体征和症状一直在努力 编目，包括多个专家的评估，以及面部照片和患者的收集 突出他们运动障碍的视频。这些资源，以及详细的实验室和 放射性评估将使我们能够全面地对我们所拥有的个人的症状进行分类， 合作进行这些研究。然后，我们将进行全外显子组测序，以确定基因组中的变化。 基因组发现在受影响的家庭成员，但不是在健康的个人。一旦一个候选基因 一旦确定，我们将与世界各地的同事联系，寻找具有类似症状的患者， 在同一个基因中的变异。然后，我们将进行一系列的实验室分析，以证实或反驳 CP候选基因的作用。这将包括经典的和大规模平行的无偏研究， RNA、蛋白质和/或代谢物，以及在互补研究、基于细胞的测定、果蝇模型中的评估 和人诱导多能干细胞-神经元/星形胶质细胞。影响：我们预计， 这种方法将使我们能够识别几十个新的CP相关基因，这反过来将有助于临床 随着基于机制的疗法的不断发展，诊断和管理方面的进展也在不断发展。

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.