Joint Center for Mendelian Genomics

摘要 尽管基因组技术最近取得了进展，但超过一半的基因导致了严重的孟德尔病毒 疾病仍未被发现。识别导致罕见疾病的基因可以产生关键的新见解 人类生物学，使这些疾病以及更常见的疾病的治疗方法得以发展 条件。然而，目前的方法不足以检测或正确解释许多变体 很可能导致罕见的疾病。组装一个罕见疾病背后的完整基因目录将 需要全新的基因发现和变异解释方法。联合研究中心 由博德研究所、波士顿儿童医院和洛克菲勒大学领导的孟德尔基因组公司已经 组建了一个大型的国际合作者网络，拥有世界一流的基因组记录 方法发展和孟德尔基因的发现。我们中心的全球临床研究团队已经 拥有强大的领域专业知识和更广泛的协作网络，提供超过35,000个现有的 来自16,000多个孟德尔家庭的表型样本用于基因组分析以及强大的来源 持续和多样化的招聘。我们将应用深度、高质量的外显子组测序，分析超过10,000个 外显子组，系统地发现蛋白质编码区或其附近的因果变异。其次，我们将使用 7000例无聚合酶链式反应全基因组测序和新变种调用综合发现方法 来自外显子组的样本--未解决的家庭。最后，我们将应用与疾病相关的转录组测序 孟德尔患者的组织和细胞系专注于寻找改变基因表达或 文字记录拼接。我们将实施一个强大的变异评估和疾病基因分析框架 发现，利用我们的研究人员在统计遗传学方面的世界领先地位，功能性 注释和临床变异解释，以及访问超过250,000个外显子组和基因组数据 参考样本，为孟德尔基因发现建立一个系统的管道，应用于所有患者 由该中心进行测序，并向外部调查人员免费提供。对于许多罕见的疾病， 要有信心地发现致病基因，将需要在世界各地的各个中心汇总病例。至 实现这一点，我们将为临床基因组学数据共享设立一个新的标准，通过快速释放基因和 将表型数据转移到国际数据库网络，加快协作并促进强大 疾病基因发现。

Abstract Despite recent advances in genomic technology, more than half of the genes underlying severe Mendelian disease remain undiscovered. Identifying the genes responsible for rare diseases can yield critical new insights into human biology, empowering the development of therapies for these diseases as well as more common conditions. However, current approaches are inadequate to detect or correctly interpret many of the variants likely to cause rare diseases. Assembling a complete catalogue of genes that underlie rare diseases will require fundamentally new approaches to gene discovery and variant interpretation. The Joint Center for Mendelian Genomics, led by the Broad Institute, Boston Children's Hospital, and Rockefeller University, has assembled a large, international network of collaborators with a world-class track record of both genomic methods development and Mendelian gene discovery. Our Center's global team of clinical investigators has both strong domain expertise and access to wider collaborative networks, providing over 35,000 existing well- phenotyped samples from over 16,000 Mendelian families for genomic analysis as well as strong sources of ongoing and diverse recruitment. We will apply deep, high-quality exome sequencing, analyzing over 10,000 exomes, to systematically discover causal variants in or near protein-coding regions. Secondly, we will use PCR-free whole-genome sequencing and novel variant- calling methods for comprehensive discovery in 7,000 samples from exome-unsolved families. Finally, we will apply transcriptome sequencing of disease-relevant tissues and cell lines from Mendelian patients to focus the search for variants altering gene expression or transcript splicing. We will implement a robust analytical framework for variant assessment and disease gene discovery, taking advantage of our investigators' world-leading roles in statistical genetics, functional annotation, and clinical variant interpretation, as well as access to exome and genome data from over 250,000 reference samples, to build a systematic pipeline for Mendelian gene discovery applied across all patients sequenced by the Center, and also made freely available to external investigators. For many rare diseases, confident discovery of causal genes will require aggregation of cases across centers around the world. To enable this, we will set a new standard for data sharing in clinical genomics by rapidly releasing genetic and phenotype data to an international network of databases, accelerating collaboration and facilitating robust disease gene discovery.