U01HG011762

Stanford Mendelian Genomics Research Center - Rapid advances in genomics have ushered in new opportunities for Mendelian disease discovery and diagnosis. In the last decade, exome and genome sequencing have moved from the research domain to clinical practice. These approaches have identified new disease genes and causative variants for approximately 30% of individuals suffering from a rare genetic disease.

We believe that the systematic application of promising new genomics assays coupled with innovative computational approaches will foster discovery, benefiting the 70% of symptomatic individuals without a genetic diagnosis. To this end, we will apply long-read whole genome sequencing, RNA-sequencing, epigenomics assays, metabolomics, and targeted in vitro and in vivo assays to evaluate a cohort of undiagnosed individuals suspected to have a Mendelian disorder.

Our approach will be augmented through the development and application of computational strategies enabling improved gene and phenotype matching, integrative multi-omics analysis, and variant interpretation. This work is expected to establish a new frontier in Mendelian disease discovery.

Our Mendelian Genomics Research Center (MRGC) team has developed key prior expertise and leadership in the use of diverse state-of-the-art experimental and computational methods for the diagnosis and discovery of Mendelian disorders. We hypothesize that the next phase of Mendelian genomics research will be defined by assessing and deploying the most effective 'omics' strategies. We propose that ongoing and iterative integration of functional genomics data into the translational genomics toolkit will significantly increase discovery of new gene and variant disease associations beyond the capabilities of DNA-sequencing assays alone.

To facilitate this, we will comprehensively study 400 individuals and their immediate family members (N= 900 total) with Mendelian disease where exome sequencing has not yielded a genetic diagnosis. These represent a select cohort of hard-to-solve cases intractable to DNA sequencing to date.

In Aim 1, individuals recruited into the study will undergo short-read and long-read whole genome sequencing, RNA-seq, ATAC-seq, and methylC-seq across multiple commonly used cell/tissue types, as well as metabolomics and lipidomics assays. This dataset will define a holistic view of emerging genomics approaches for Mendelian disease diagnosis and facilitate evaluation of the relative merits of each approach.

In Aim 2, we focus on computational innovations that will improve integration of these multi-omics data in gene and variant interpretation by integrating functional genomics outliers and advanced statistical learning approaches. These methods will be applicable broadly across the MGRC and the world.

In Aim 3, we apply state-of-the-art targeted approaches, including massively-parallel reporter assays, induced pluripotent stem cell functional genomics, CRISPR screens for modifier genes, and engineered mouse models to detect and validate novel causal variants and genes. Work at our site will potentiate the broad impact of the MGRC by providing a platform for functional genomics research, validation, and diagnosis in Mendelian disease.

The Leland Stanford Junior University

NHGRI SUPPORTS THE DEVELOPMENT OF RESOURCES AND TECHNOLOGIES THAT WILL ACCELERATE GENOME RESEARCH AND ITS APPLICATION TO HUMAN HEALTH AND GENOMIC MEDICINE. A CRITICAL PART OF THE NHGRI MISSION CONTINUES TO BE THE STUDY OF THE ETHICAL, LEGAL AND SOCIAL IMPLICATIONS (ELSI) OF GENOME RESEARCH. NHGRI ALSO SUPPORTS THE TRAINING AND CAREER DEVELOPMENT OF INVESTIGATORS AND THE DISSEMINATION OF GENOME INFORMATION TO THE PUBLIC AND TO HEALTH PROFESSIONALS. THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM IS USED TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM IS USED TO FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.172 - Human Genome Research

National Human Genome Research Institute (NHGRI) [HHS - NIH]

Stanford, California 94305 United States

Single Zip Code

Mendelian Genomics Research Centers (U01 Clinical Trial Optional) (RFA-HG-20-007)

Amendment Since initial award the total obligations have increased 402% from $2,836,860 to $14,229,424.