Project I - Human genetics of meningomyelocele and risk mitigation by folic acid

项目 I - 脑膜脊髓膨出的人类遗传学和叶酸降低风险

• 批准号: 10300070
• 负责人: JOSEPH G GLEESON
• 金额: $ 40.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10300070
• 关键词: Algorithms; Alleles; American; Animal Model; Bioinformatics; Birth; Brain Stem; Candidate Disease Gene; Childhood; Clinical; Conceptions; Congenital Abnormality; Consultations; Copy Number Polymorphism; Coupled; Creation of ventriculo-peritoneal shunt; DNA; Data; Defect; Development; Disease; Drops; Enrollment; Ensure; Epigenetic Process; Exclusion Criteria; Family; Folic Acid; Future; Gene Mutation; Genes; Genetic; Genetic Transcription; Genotype; Health Care Costs; Heritability; Human; Human Genetics; Incidence; Individual; Inherited; International; Learning Disabilities; Life; Link; Meningomyelocele; Methylation; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Mutate; Mutation; Mutation Analysis; National Institute of Child Health and Human Development; Neural Tube Defects; Neural tube; Odds Ratio; Outcome; Patients; Phenotype; Proteins; Protocols documentation; Rana; Recurrence; Repeat Surgery; Risk; Risk Factors; Sampling; Seizures; Shunt Device; Spinal Dysraphism; Structural Congenital Anomalies; System; Testing; Time; Variant; Work; autism spectrum disorder; base; cohort; data harmonization; data integrity; de novo mutation; dietary; disability; exome sequencing; folic acid supplementation; fortification; gene environment interaction; gene function; gene network; genetic architecture; genetic variant; genome sequencing; genomic variation; human disease; human model; inclusion criteria; mortality; prenatal; programs; recruit; risk mitigation; social media; tool; whole genome

Abstract – Project I: Human genetics of meningomyelocele and risk mitigation by folic acid This project focuses on the characterization of genomic variation in human patients with Meningomyelocele (MM), the most common CNS birth defect, with heritability estimated at 70-75% 1,2, and a cumulative incidence of 3.72/10,000 live US births. MM is a debilitating structural birth defect, the most common form of NTD compatible with life, and with substantial associated morbidity and mortality. National folic acid (FA) supplementation has reduced incidence >3-fold, but there is little understanding of the mechanism of this Gene-Environment interaction (GXE). Here we propose to study the molecular basis of human MM through a world-wide recruitment of trios with narrowly defined inclusion/exclusion criteria, stratified by prenatal FA exposure. We hypothesize that de novo mutations (DNMs) make a critical contribution to the risk of MM, and that FA increases the mutational burden required for phenotypic expressivity. MM shares features with other severe childhood diseases that show strong DNM contributions such as congenital structural disorders and autism. Our preliminary data point to a strong DNM contribution to MM, but like autism, these DNM increase risk but likely act with other factors to determine risk. We propose to ascertain a total of 2000 carefully phenotyped MM trios, recruited worldwide, stratified based upon national dietary FA supplementation status at the time of conception (+FA:fortified vs -FA:nonfortified). Trios will undergo whole genome sequencing (WGS), then analyzed for de novo and inherited mutations as risk factors, compared with control trios. Results from Project I will be incorporated into workflow of Project II and III to model mutations, and results from Project II and III will be used to refine WGS analysis in Project I. Project I will rely on Core B to identify candidate FA-responsive genes from changes in epigenetic signatures, and on Core C for bioinformatic analysis. Project I has already: 1] Founded the Spina Bifida Sequencing Consortium and enrolled a cohort of >1500 MM trios using social media, and historic cohorts, stratified as +FA or -FA. 2] Extracted and QC’d DNA from >700 of these trios. 3] Competed successfully for NICHDs Gabriella Miller-Kids First program access for 1000 WGS samples. 4] Performed sequencing on 600 trios, as well as optimized algorithms to achieve uniform mutation calling. 5] Identified 12 MM candidate genes, including 3 recurrently mutated genes, and one recurrent copy number variant (CNV). 6] Found that +FA trios but not -FA trios demonstrate a striking accumulation of damaging DNMs compared with controls. We will test the model that de novo and inherited mutations interact with FA to determine risk. The application proposes to complete recruitment, identify de novo and inherited gene mutations in MM, correlate with maternal FA exposure, and uncover mechanisms of disease within a clinical context.

摘要 - 项目I：脑膜纤维膨出和叶酸降低风险的人类遗传学 该项目的重点是脑膜瘤患者的基因组变异的表征 （MM），最常见的CNS先天缺陷，遗传力估计为70-75％1,2，累积事件 3.72/10,000 Live US出生。 MM是一种令人衰弱的结构性先天缺陷，是NTD的最常见形式 与生活兼容，并与实质性的发病率和死亡率相吻合。国家叶酸（FA） 补充减少了事件> 3倍，但对此机制几乎没有理解 基因环境相互作用（GXE）。在这里，我们建议通过A研究人MM的分子基础 通过狭义定义的包含/排除标准，全球范围招募三重奏，由产前FA分层 接触。我们假设从头突变（DNM）对MM的风险做出了关键的贡献，并且 FA增加了表型表达性所需的突变伯嫩。 MM与其他分享功能 严重的儿童疾病，表现出强大的DNM贡献，例如先天性结构性疾病和 自闭症。我们的初步数据表明，DNM对MM有很强的贡献，但与自闭症一样，这些DNM增加 风险，但可能与其他因素一起起作用以确定风险。我们建议仔细确定总计2000 表型MM三重奏，全球招募，根据国家饮食FA状态进行分层 在概念时（+FA：强化与FA：不舒服）。三重奏将进行整个基因组测序 （WG），然后分析了从头开始，并将其作为危险因素与对照组相比。结果 从项目中，我将被纳入项目II和III的工作流程中，以建模突变，并从 项目II和III将用于完善项目I中的WGS分析。项目我将依靠核心B来识别 候选FA响应基因来自表观遗传学特征的变化以及生物信息的核心C 分析。我已经有：1]建立了脊柱裂，并招募了一群 使用社交媒体和历史悠久的队列，分为 +FA或-FA，> 1500 mm三重奏。 2]提取和QC DNA 从这些三重奏中的700个开始。 3]成功竞争Nichds Gabriella Miller-Kids首次访问 1000 WGS样品。 4]对600个三重奏进行测序以及优化的算法以达到均匀 突变呼唤。 5]鉴定出12 mm候选基因，包括3个经常突变的基因，一个 经过复制号变体（CNV）。 6]发现 +fa trios，但没有-fa三重奏表现出罢工 与对照组相比，损害DNM的积累。我们将测试从头开始并继承的模型 突变与FA相互作用以确定风险。申请提案完成招聘，确定DE MM中的Novo和遗传基因突变，与母体FA暴露相关，并发现了机制 在临床背景下疾病。