Joint Center for Mendelian Genomics

 描述（由申请人提供）：尽管基因组技术最近取得了进展，但严重孟德尔疾病的潜在基因中仍有一半以上未被发现。确定罕见疾病的基因可以对人类生物学产生重要的新见解，从而为这些疾病以及更常见疾病的治疗方法的开发提供支持。然而，目前的方法不足以检测或正确解释许多可能导致罕见疾病的变异。组装一个完整的罕见疾病基因目录将需要从根本上新的方法来发现基因和变异解释。 由布罗德研究所、波士顿儿童医院和洛克菲勒大学领导的孟德尔基因组学联合中心已经组建了一个庞大的国际合作者网络，在基因组方法开发和孟德尔基因发现方面都有世界一流的记录。我们中心的全球临床研究团队拥有强大的领域专业知识和更广泛的合作网络，提供来自16，000多个孟德尔家族的35，000多个现有的良好表型样本进行基因组分析，以及持续和多样化的招募的强大来源。 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，以系统地发现蛋白质编码区或附近的因果变异。其次，我们将使用无PCR的全基因组测序和新的变异识别方法，在来自外显子组未解决的家族的7,000个样本中进行全面发现。最后，我们将应用转录组测序的疾病相关的组织和细胞系从孟德尔患者集中寻找改变基因表达或转录剪接的变体。 我们将实施一个强大的变异评估和疾病基因发现的分析框架，利用我们的研究人员在统计遗传学，功能注释和临床变异解释方面的世界领先地位，以及从超过250，000个参考样本中获得外显子组和基因组数据，为孟德尔基因发现建立一个系统的管道，适用于中心测序的所有患者，并免费提供给外部调查人员。 对于许多罕见疾病来说，要有信心地发现致病基因，就需要在世界各地的中心聚集病例。为了实现这一目标，我们将通过快速向国际数据库网络发布遗传和表型数据，加速合作并促进强大的疾病基因发现，为临床基因组学的数据共享设定新标准。

 DESCRIPTION (provided by applicant): 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 accessto 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.