UM1HG011989

Molecular Phenotyping of ~100,000 Coding Variants across Mendelian Disease Genes - Abstract

The last four decades have produced an enormous catalog of human genomic variants which has the potential to revolutionize human genetics. Among the variants identified in the human "variome" so far, some appear benign, i.e. they don't seem to confer any particular phenotype. However, a significant proportion are associated or potentially associated with one or more genetically inherited disorders. Unfortunately, an even greater percentage of observed human variants, specifically 99% of missense variants, remain uninterpreted or annotated as variants of unknown significance (VUSS).

To translate this huge amount of genetic information into general principles underlying genotype-phenotype relationships, as well as molecular mechanisms responsible for the development of inherited disease, there is an urgent need for large-scale, systematic, high throughput "functional characterization" projects. These projects are envisioned within the new "Impact of Genomic Variation on Function" (IGVF) consortium proposed by NHGRI.

Although most monogenic Mendelian disorders are individually rare, when combined, these diseases affect 20 million Americans. The ClinVar database describes within 3,671 Mendelian disease genes over 260,000 missense variants classified as pathogenic, benign, or VUSS. However, we currently lack strong and comprehensive evidence to systematically analyze coding variants across the spectrum of human Mendelian diseases.

We propose to functionally characterize ~100,000 variants across most of the known Mendelian disease-associated genes. This will be done by comparing wild-type, or "reference", gene products and their corresponding variants for a rich array of fundamental protein properties and phenotypic impacts. These include protein stability (expression), subcellular localization, cell viability, cell morphology, and the ability to mediate macromolecular interactions with protein partners.

Our Variant Characterization across the Mendelian Proteome (VarChamp) center will generate a searchable and widely available catalog of these variant effects via the IGVF data and administrative coordinating centers (DACCS). This catalog will assist in the "predictive modeling projects" to carry out variant effect predictive modeling using this data.

In addition to providing a rich source of functional information on tens of thousands of genomic variants in the next five years, all of our concepts, technologies, and resources generated during this project are exportable and will be shared to enable others, both inside and outside the IGVF consortium, to leverage our approach in their own studies and expand the catalog.

Dana-Farber Cancer Institute

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]

Boston, Massachusetts 022155418 United States

Single Zip Code

Systematic Characterization of Genomic Variation on Genomic Function and Phenotype (UM1 Clinical Trial Not Allowed) (RFA-HG-20-043)

Amendment Since initial award the total obligations have increased 752% from $973,088 to $8,292,746.