Joint Center for Mendelian Genomics

尽管基因组技术最近取得了进展，但超过一半的严重孟德尔遗传病的基因 疾病仍未被发现。确定罕见疾病的基因可以产生重要的新见解 进入人类生物学，使这些疾病的治疗方法的发展，以及更常见的 条件然而，目前的方法不足以检测或正确解释许多变体 可能导致罕见疾病。收集一个完整的罕见疾病基因目录， 需要从根本上新的方法来发现基因和解释变异。联合中心 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， 组建了一个大型的国际合作者网络，在基因组和生物技术领域都有世界级的记录。 方法开发和孟德尔基因发现。我们中心的全球临床研究团队 强大的领域专业知识和更广泛的合作网络，提供超过35，000个现有的良好， 来自16，000多个孟德尔家族的表型样本用于基因组分析，以及来自 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，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全基因组测序和新的变异识别方法，用于在7000个 exome-unsolved未解决的家庭。最后，我们将应用转录组测序的疾病相关的 来自孟德尔患者的组织和细胞系，重点寻找改变基因表达或 转录剪接。我们将实施一个强大的分析框架，用于变异评估和疾病基因分析。 发现，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，以及访问超过250，000个外显子组和基因组数据， 参考样本，以建立适用于所有患者的孟德尔基因发现的系统管道 由该中心测序，并免费提供给外部调查人员。对于许多罕见疾病， 要有信心地发现致病基因，就需要将世界各地的病例集中起来。到 为此，我们将通过快速发布基因和 表型数据到国际数据库网络，加速合作，促进强大的 疾病基因发现

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.