Pediatric Mendelian Genomics Research Center

儿科孟德尔基因组学研究中心

基本信息

批准号：
10415121
负责人：
Eric J. Vilain
金额：
$ 255.9万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2022-10-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10415121
关键词：
Address Affect Alleles Basic Science Benign Candidate Disease Gene Child Childhood Classification ClinVar Clinical Clinical Research Code Collaborations Consanguinity Copy Number Polymorphism Data Data Coordinating Center Diagnosis Disease Disease Management Enrollment Ensure Evaluation Family Family member Genes Genetic Genetic Counseling Genomics Goals Health Personnel Healthcare Systems Hospitals Individual Investigation Mendelian disorder Methods Modeling Molecular Optics Pathogenicity Patients Phenotype Population Population Heterogeneity Process Proxy Public Health Publications Publishing RNA Splicing Rare Diseases Reproducibility Research Research Institute Sampling Source Standardization Structure Syndrome System Taxes Technology Testing Tissues Translating Translational Research Untranslated RNA Variant burden of illness clinical implementation clinical practice cohort community center data dissemination data sharing diagnostic strategy disease phenotype exome sequencing gene discovery genetic testing genetic variant genome-wide genomic data improved industry partner innovation mRNA Expression novel patient registry public database recruit repository symposium transcriptome transcriptome sequencing variant of unknown significance whole genome

项目摘要

ABSTRACT Mendelian conditions, particularly those presenting during childhood, are a major disease burden causing suffering and taxing the healthcare system. Clinical approaches including exome sequencing have led to a rapid increase in the number of conditions with known genetic causes and new treatment options for many rare diseases, but are restricted to finding small coding and splice junction variants, missing most non-coding variants as well as structural and copy number variants. This challenges interpretation due to the vast number of variants that must be analyzed for possibly causing a disease. To accelerate the pace of Mendelian disease gene discovery and clinical implementation, we propose a Pediatric Mendelian Genomics Research Center (MGRC), leveraging the broad pediatric clinical and research expertise of Children’s National Hospital and Research Institute in a partnership with Invitae’s expertise in providing comprehensive and affordable genetic testing. Our Center will unite world class experts combining basic and translational research with innovative approaches to phenotyping, variant identification and functional investigation of both coding and non-coding sequence changes with the goals of discovering novel Mendelian gene variations and identifying variants not detected on current sequencing pipelines, disambiguating uncertain variants into disease-causing versus benign categorizations, and sharing information by working collaboratively with the MGRC community. To answer these challenges, this proposal will address the following Specific Aims: Aim 1: Identify novel causes of Mendelian conditions - Discover: Our center will enroll patients with likely Mendelian diseases and previously non-diagnostic tests (2,600 samples per year) then systematically re- analyze whole genomes augmented with long read sequencing, optical mapping, and RNA-seq. Aim 2: Reclassify uncertain variants and investigate the mechanisms of undiagnosed Mendelian conditions - Disambiguate: Uncertain variants and candidate genes will be further investigated using whole transcriptome analysis, RNA-seq, CRE-seq, and functional modeling. Aim 3: Communicate research results to enable translational research on new and rare Mendelian conditions - Disseminate: Our center is committed to data sharing and dissemination and will ensure that data is shared with the entire MGRC community through the data coordinating center. Through our industry partnership, clinically valid pipelines will be rapidly scaled for clinical implementation globally. Our overall approach provides an efficient and direct path to diagnosis for patients affected with undiagnosed Mendelian conditions, promotes gene discovery and reclassification of Variants of Uncertain Significance through a combination of innovative approaches, and will allow individuals, families and healthcare providers to improve the management of disease.

抽象的孟德尔病症，特别是在儿童时期出现的病症，是导致疾病的主要负担包括外显子组测序在内的临床方法给医疗保健系统带来了痛苦和负担。已知遗传原因的疾病数量迅速增加，许多罕见疾病的新治疗方案也随之增加疾病，但仅限于寻找小的编码和剪接连接变异，缺少大多数非编码由于数量巨大，这给解释带来了挑战。必须分析可能导致疾病的变异体。为了加快孟德尔疾病基因发现和临床实施的步伐，我们提出了儿科孟德尔基因组学研究中心 (MGRC)，利用广泛的儿科临床和国家儿童医院和研究所与 Invitae 合作的研究专业知识我们的中心将汇集世界一流的专业知识，提供全面且负担得起的基因检测。专家将基础研究和转化研究与表型、变异的创新方法相结合编码和非编码序列变化的鉴定和功能研究，目的是发现新的孟德尔基因变异并识别当前测序未检测到的变异管道，将不确定的变异消除歧义，分为致病与良性分类，并共享为了应对这些挑战，本提案通过与 MGRC 社区合作来获取信息。将解决以下具体目标：目标 1：确定孟德尔病症的新病因 - 发现：我们中心将招募可能患有以下疾病的患者孟德尔疾病和以前的非诊断测试（每年 2,600 个样本）然后系统地重新进行分析通过长读长测序、光学图谱和 RNA 测序增强的整个基因组。目标 2：对不确定变异进行重新分类并研究未确诊孟德尔变异的机制条件 - 消除歧义：将使用整体进一步研究不确定的变异和候选基因转录组分析、RNA-seq、CRE-seq 和功能建模。目标 3：交流研究成果，以实现新的和稀有孟德尔的转化研究条件 - 传播：我们中心致力于数据共享和传播，并将确保数据通过我们的行业数据协调中心与整个 MGRC 社区共享。通过合作，临床有效的管道将迅速扩大规模，以便在全球范围内进行临床实施。我们的整体方法为未确诊的患者提供了一条有效且直接的诊断途径孟德尔条件，促进基因发现和不确定意义变异的重新分类通过创新方法的结合，将使个人、家庭和医疗保健提供者能够改善疾病管理。