Pediatric Mendelian Genomics Research Center

摘要 孟德尔疾病，特别是那些在儿童时期出现的疾病，是一种主要的疾病负担， 使医疗系统遭受痛苦和负担。包括外显子组测序在内的临床方法已经导致了 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选择也在增加。 疾病，但仅限于寻找小的编码和剪接变异，错过了大多数非编码 变体以及结构和拷贝数变体。这对解释提出了挑战，因为 必须分析可能导致疾病的变异。 为了加快孟德尔病基因发现和临床应用的步伐，我们提出了一个 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， 提供全面和负担得起的基因检测的专业知识。我们的中心将联合世界一流的 将基础和转化研究与创新方法相结合的专家， 编码和非编码序列变化的鉴定和功能研究， 发现新的孟德尔基因变异，并鉴定当前测序中未检测到的变异 管道，将不确定的变异区分为致病和良性分类，并分享 通过与MGRC社区合作提供信息。为了应对这些挑战，本提案 将实现以下具体目标： 目标1：确定孟德尔疾病的新原因-发现：我们的中心将招募可能患有 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 通过长读测序、光学图谱和RNA-seq分析全基因组。 目的2：重新分类不确定的变体并研究未诊断的孟德尔遗传病的机制 条件-消除歧义：不确定的变异和候选基因将进一步研究使用整体 转录组分析、RNA-seq、CRE-seq和功能建模。 目标3：交流研究成果，以促进对新的和罕见的孟德尔遗传的转化研究 条件-传播：我们的中心致力于数据共享和传播，并将确保 通过数据协调中心与整个MGRC社区共享数据。通过我们的行业 合作伙伴关系，临床有效的管道将迅速扩大到全球临床实施。 我们的整体方法为未确诊的患者提供了一个有效和直接的诊断途径。 孟德尔条件，促进基因发现和不确定意义的变异体的重新分类 通过创新方法的组合，并将允许个人，家庭和医疗保健提供者， 改善疾病管理。

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.