Genetic risk factors for severe scoliosis

严重脊柱侧弯的遗传危险因素

• 批准号: 10674014
• 负责人: Matthew Barrett Dobbs
• 金额: $ 61.59万
• 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/10674014
• 关键词: 16p11.2; Adolescent; Affect; African American; African American population; African ancestry; 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 ancestry; 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 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; clinical application; clinical practice; cohort; comorbidity; cost; diverse data; 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.

项目摘要/摘要 青少年特发性脊柱侧弯影响所有种族高达3%的儿童。非洲裔美国人与 曲线越大，报告的疼痛越大，手术并发症也越多。医疗保健差距也在扩大 曲线型进展和严重的危及生命的神经和心脏并发症的风险，其中许多 早期诊断是可以预防的。在最初的融资阶段，我们确定了以下几个重要的风险因素 严重的脊柱侧弯，包括纤维蛋白-1(FBN1)、肌肉骨骼胶原基因和远端的罕见变异 染色体16p11.2的重复使患病风险增加10倍。然而，目前尚不清楚风险是否 这些因素适用于不同的患者群体。即使在基因已知的情况下，准确地确定 个体人类基因变异的致病性仍然是一个瓶颈，因为 不确定意义的变体，这意味着没有足够的临床或功能数据来指定它们为 致病的或良性的。在精准医学的时代，有一种尚未得到满足的需求，即改变临床 然而，脊柱侧弯的实践范例，我们在服务不足的人群中解释基因数据的能力仍然存在 有限的。我们的中心假设是，当基因数据与功能分析相结合时，可以改善 脊柱侧弯及相关疾病变异解释的诊断准确性。为了实现这些目标，我们 将研究在最初的资助期招募的1000名非裔美国人脊柱侧弯患者的队列 确定已知的风险因素是否适用于非裔美国人，并确定 只有通过研究非洲血统的人才能确定。第二，我们将确定相关的表型 使用利用盖辛格的基因优先方法在老年人群中发现脊柱侧弯风险变异 DiscovEHR数据集由175,000名参与者组成，带有链接的电子健康记录和外显子序列 数据。最后，为了检验功能效应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 与脊柱侧弯和危及生命的主动脉瘤相关的三个基因中所有可能的编码变异 (COL3A1、SMAD3和FBN1)将被量化。用于预测变异体致病性的计算分类器 等位基因将基于我们的功能数据来构建。变种将在斑马鱼脊柱侧弯模型中得到验证。 这项多中心脊柱侧弯研究的更新将加快基因发现和临床应用的步伐 适用于所有年龄和种族的患者。通过全面和定量地确定基因的影响 蛋白质功能的变异，以及它们在一生中对不同个体的影响，我们更接近于 脊柱侧弯精准医学的目标。

项目成果

Quantitative determination of SLC2A1 variant functional effects in GLUT1 deficiency syndrome.

• DOI: 10.1002/acn3.51767
• 发表时间: 2023-05
• 期刊: Annals of clinical and translational neurology
• 影响因子: 5.3
• 作者: Tayebi N;Leon-Ricardo B;McCall K;Mehinovic E;Engelstad K;Huynh V;Turner TN;Weisenberg J;Thio LL;Hruz P;Williams RSB;De Vivo DC;Petit V;Haller G;Gurnett CA
• 通讯作者: Gurnett CA

MYH3-associated distal arthrogryposis zebrafish model is normalized with para-aminoblebbistatin.

• DOI: 10.15252/emmm.202012356
• 发表时间: 2020-11-06
• 期刊: EMBO molecular medicine
• 影响因子: 11.1
• 作者: Whittle J;Antunes L;Harris M;Upshaw Z;Sepich DS;Johnson AN;Mokalled M;Solnica-Krezel L;Dobbs MB;Gurnett CA
• 通讯作者: Gurnett CA

Models of Distal Arthrogryposis and Lethal Congenital Contracture Syndrome.

• DOI: 10.3390/genes12060943
• 发表时间: 2021-06-20
• 期刊: Genes
• 影响因子: 3.5
• 作者: Whittle J;Johnson A;Dobbs MB;Gurnett CA
• 通讯作者: Gurnett CA

Mutations in Kinesin family member 6 reveal specific role in ependymal cell ciliogenesis and human neurological development.

驱动蛋白家族成员 6 的突变揭示了室管膜细胞纤毛发生和人类神经发育中的特定作用。

• DOI: 10.1371/journal.pgen.1007817
• 发表时间: 2018-11
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Konjikusic MJ;Yeetong P;Boswell CW;Lee C;Roberson EC;Ittiwut R;Suphapeetiporn K;Ciruna B;Gurnett CA;Wallingford JB;Shotelersuk V;Gray RS
• 通讯作者: Gray RS

Genetic Risk for Aortic Aneurysm in Adolescent Idiopathic Scoliosis.

• DOI: 10.2106/jbjs.o.00290
• 发表时间: 2015-09
• 期刊: The Journal of bone and joint surgery. American volume
• 作者: Gabe Haller;David M. Alvarado;M. Willing;A. Braverman;K. Bridwell;Michael Kelly;L. Lenke;S. Luhmann;C. Gurnett;M. Dobbs