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

基本信息

批准号：
10533744
负责人：
JOSEPH G GLEESON
金额：
$ 34.28万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
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/10533744
关键词：
Algorithms Alleles American Animal Model Bioinformatics Birth Brain Stem Candidate Disease Gene Child 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 candidate identification 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

项目摘要

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：人类脑膜瘤和叶酸降低风险的人类遗传学该项目的重点是脑膜销售患者的基因组变异的表征（MM），最常见的CNS出生缺陷，遗传力估计为70-75％1,2，累积发生率 3.72/10,000 Live US出生。与生命兼容，并与死亡和死亡率相关。补充的发病率降低了3倍，但对Tris机制的了解很少基因 - 环境相互作用（GXE）。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分层我们假设从头突变（DNM）对MM的风险做出了关键的贡献 FA增加了表型表达性所需的突变负担。严重的儿童疾病，表现出强大的DNM贡献，例如先天性结构障碍和自闭症。风险，但可能与其他因素一起行动以确定风险。表型MM三重奏，全球招募，根据国家饮食FA状态进行分层在受孕时（WG）随后分析了从头开始，并将其遗传的突变与对照三人相比。从项目中，我将纳入项目II和III的工作流程中，以建模突变，并从项目II和III将用于完善项目中的WGS分析，我将依靠核心B来识别来自表观遗传学特征变化的候选FA响应基因，以及生物信息的核心C 分析。 > 1500毫米三重奏，使用社交媒体和历史悠久的人群，分为 +fa或-fa。从这些三重奏中的700个。 1000 wgs样本。突变呼叫5]鉴定出12 mm候选基因，包括3个复发基因经过的副本编号变体（CNV）。与对照相比，损坏的DNM的积累。突变与FA相互作用以确定申请的风险。 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。