Pediatric Mendelian Genomics Research Center

儿科孟德尔基因组学研究中心

• 批准号: 10215895
• 负责人: Eric J. Vilain
• 金额: $ 256.47万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10215895
• 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; Databases; Diagnosis; Diagnostic; 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; disease phenotype; exome sequencing; gene discovery; genetic testing; genetic variant; genome-wide; genomic data; improved; industry partner; innovation; mRNA Expression; novel; patient registry; recruit; repository; symposium; transcriptome; transcriptome sequencing; variant of unknown significance; whole genome

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 给医疗保健系统带来痛苦和负担。包括外显子组测序在内的临床方法已导致 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 变异以及结构和拷贝数变异。由于数量庞大，这对解释提出了挑战 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 提供全面且负担得起的基因检测的专业知识。我们的中心将联合世界级 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，分为致病性与良性分类，并共享 通过与 MGRC 社区合作获取信息。为了应对这些挑战，本提案 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 分析通过长读长测序、光学图谱和 RNA 测序增强的全基因组。 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 数据通过数据协调中心与整个 MGRC 社区共享。通过我们的行业 通过合作，临床有效的产品线将迅速扩大规模，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。