Genetic risk factors for severe scoliosis

严重脊柱侧凸的遗传危险因素

• 批准号: 10219960
• 负责人: Matthew Barrett Dobbs
• 金额: $ 67.26万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-20 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10219960
• 关键词: 16p11.2; Address; Adolescent; Affect; African; African American; Age; Aortic Aneurysm; Award; Benign; Biological Assay; Cardiac; Child; Chromosomes; Classification; Clinical; Code; Collagen; Collagen Gene; Data; Data Set; Disease; Distal; Early Diagnosis; Electronic Health Record; Ethnic Origin; European; FBN1; FURIN gene; Frequencies; Funding; Genes; Genetic; Genetic study; Goals; Human Genetics; Idiopathic scoliosis; Individual; Knowledge; Laboratories; Legal patent; Life; Link; Longevity; MADH3 gene; Methodology; Methods; Modeling; Multicenter Studies; Musculoskeletal; Neurologic; Older Population; Operative Surgical Procedures; Pain; Paper; Parents; Participant; Pathogenesis; Pathogenicity; Pathway interactions; Patient Recruitments; Patients; Persons; Phenotype; Population; Population Heterogeneity; Prevention strategy; Progress Reports; Publishing; Reporting; Research; Risk; Risk Factors; Speed; Spinal Fusion; Surgical complication; Testing; Time; Transforming Growth Factor beta; Underrepresented Minority; Underserved Population; Variant; Work; Zebrafish; base; clinical application; clinical practice; cohort; comorbidity; cost; exome; functional genomics; gene discovery; genetic disorder diagnosis; genetic risk factor; genetic testing; genetic variant; genome-wide; health care disparity; high throughput screening; improved; mutation screening; novel; patient population; personalized diagnostics; personalized medicine; precision medicine; prevent; protein function; public health relevance; rare variant; recruit; risk variant; scoliosis; tertiary care; treatment strategy; variant of unknown significance; whole genome

PROJECT SUMMARY/ABSTRACT Adolescent idiopathic scoliosis affects up to 3% of children from all ethnicities. African Americans present with larger curves, report greater pain, and have more surgical complications. Healthcare disparities also increase the risk for curve progression and serious, life-threatening neurologic and cardiac complications, many of which can be prevented with early diagnosis. In the initial funding period, we identified several important risk factors for severe scoliosis, including rare variants in fibrillin-1 (FBN1), musculoskeletal collagen genes, and distal chromosome 16p11.2 duplications that confer >10-fold increased risk. However, it is not yet known whether risk factors are generalizable to diverse patient populations. Even when genes are known, precisely determining the pathogenicity of individual human genetic variants remains a bottleneck because of the high frequency of variants of uncertain significance, meaning that there is insufficient clinical or functional data to assign them as either pathogenic or benign. In an era of Precision Medicine, there is an unmet need to change the clinical practice paradigm for scoliosis, however, our ability to interpret genetic data in underserved populations remains limited. Our central hypothesis is that genetic data, when combined with functional analysis, improves the diagnostic precision of variant interpretation for scoliosis and related conditions. To accomplish these goals, we will study a cohort of 1000 African American scoliosis patients recruited during the initial funding period in order to determine whether known risk factors are generalizable to African Americans, and to identify risk variants that can only be identified by studying individuals of African ancestry. Second, we will identify phenotypes associated with scoliosis risk variants in an older population using a gene-first approach that leverages the Geisinger DiscovEHR dataset consisting of >175,000 participants with linked electronic health record and exome sequence data. Finally, to test the hypothesis that knowledge of functional effects improves genetic variant classification, we will utilize high-throughput assays developed in our laboratory for deep mutational scanning. The effects of every possible coding variants in three genes associated with scoliosis and life-threatening aortic aneurysm (COL3A1, SMAD3, and FBN1) will be quantified. Computational classifiers to predict pathogenicity of variant alleles will be built based on our functional data. Variants will be validated in zebrafish models of scoliosis. Renewal of this multicenter study of scoliosis will speed up the pace of gene discovery and its clinical application for patients of all ages and ethnicities. By comprehensively and quantitatively determining the effects of genetic variants on protein function, as well as their impact on diverse individuals across the lifespan, we move closer to the goal of precision medicine for scoliosis.

项目总结/摘要 青少年特发性脊柱侧凸影响了所有种族中高达3%的儿童。非裔美国人目前与 更大的曲线，报告更大的疼痛，并有更多的手术并发症。医疗保健差距也在扩大 弯曲进展和严重的、危及生命的神经系统和心脏并发症的风险，其中许多 可以通过早期诊断来预防。在最初的融资期间，我们确定了几个重要的风险因素， 严重脊柱侧凸，包括骨胶原蛋白-1（FBN 1）、肌肉骨骼胶原基因和远端 染色体16p11.2重复，使风险增加>10倍。然而，目前尚不清楚风险是否 这些因素可推广到不同的患者群体。即使基因是已知的， 个体人类遗传变异的致病性仍然是一个瓶颈，因为高频率的 意义不确定的变异，这意味着没有足够的临床或功能数据将其分配为 致病的或良性的。在精准医学时代，有一个未满足的需求，改变临床 然而，脊柱侧凸的实践范例，我们在服务不足的人群中解释遗传数据的能力仍然存在， 有限公司我们的中心假设是，遗传数据，当与功能分析相结合时， 脊柱侧凸和相关疾病的不同解释的诊断精度。为了实现这些目标，我们 将研究在最初资助期间招募的1000名非洲裔美国脊柱侧凸患者， 以确定已知的风险因素是否可推广到非洲裔美国人，并确定风险变异， 只能通过研究非洲血统的个体来识别。第二，我们将确定相关的表型 使用基因优先的方法，利用Geisinger DiscovEHR数据集由> 175，000名参与者组成，具有相关的电子健康记录和外显子组序列 数据最后，为了检验功能效应的知识改善遗传变异分类的假设， 我们将利用我们实验室开发的高通量分析进行深度突变扫描。的影响 与脊柱侧凸和危及生命的主动脉瘤相关的三个基因中的每一个可能的编码变体 （COL 3A 1、SMAD 3和FBN 1）将被定量。预测变异致病性的计算分类器 将根据我们的功能数据构建等位基因。变体将在脊椎侧凸的斑马鱼模型中进行验证。 更新这项多中心脊柱侧凸研究将加快基因发现及其临床应用的步伐 所有年龄和种族的患者。通过全面、定量地确定遗传因素对 蛋白质功能的变异，以及它们对整个生命周期中不同个体的影响，我们更接近于 脊柱侧凸精准医疗的目标。