Broad Institute Mendelian Genomic Research Center

Broad Institute, Inc., Cambridge MA

Investigators

Linked publications & trials

Abstract

Despite recent advances in genomic technologies and methods, more than half of the genes underlying severe Mendelian disease remain undiscovered. Deciphering these gene-disease associations has already yielded critical new insights into human biology and novel therapeutic development for rare diseases, as well as more common conditions. To date, the vast majority of discoveries have derived from coding variation across families. Exome sequencing in large cohorts that utilizes increasingly sophisticated analytic methods thus remains an efficient strategy for Mendelian gene discovery, and its relative value is amplified with open data sharing through platforms like Matchmaker Exchange, ClinVar, and AnVIL. There are also complementary approaches for the discovery and annotation of variants cryptic to exome sequencing, including alternative sequencing technologies, improved variant calling and genome assembly, novel analytic methods, and high-throughput genome engineering to inform recognition of functional variants that cause rare phenotypes.  The Broad Institute Center for Mendelian Genomics (Broad CMG) has a network of collaborators with an exemplary track record in developing new technologies and analytic methods to discover genes associated with Mendelian disorders and distribute these data to the broader biomedical community. We are leaders in data sharing, and have dedicated considerable effort toward the development of widely adopted platforms and resources to facilitate open sharing of variants, data, and interpretation tools. Our program has sequenced over 15,000 samples that have consent for sharing in controlled-access data repositories. We share all metadata and phenotype data in AnVIL and have developed software solutions to empower analysis and data sharing including seqr for genomic analysis and Matchmaker Exchange submissions, and the Genome Aggregation Database (gnomAD) for reference population short and structural variant allele frequencies.  Our Broad Institute Mendelian Genomics Research Center (Broad MGRC) brings together complementary approaches and extraordinary expertise to solve the underpinnings of Mendelian disease. Building on the foundation of our Broad CMG program, we will perform exome and genome sequencing in thousands of deeply phenotyped families, identify all classes of variation with advanced methods, and apply our robust analytical framework for gene discovery. We will further leverage emerging technologies, methods, analytic frameworks, and functional modeling to discover novel genes and variants missed by standard exome analysis, and gain insights into their functional mechanisms. We will build on our strong track record of data sharing, with rapid sharing of candidate genes, phenotype, metadata and genomic sequence files through many platforms including Matchmaker Exchange, AnVIL, and ClinVar, as well as continuing to release all of our methods as open source software. Finally, we will rapidly return results to patients to enable their direct use in diagnosis and treatment.