Tuesday, April 1, 2025
4/1/2025
Genome-first approach to treatable genetic conditions in adults - PROJECT SUMMARY/ABSTRACT: This proposal details a five-year research career development program focused on the identification of individuals in a hospital-based biobank with genomic variants associated with undiagnosed treatable genetic disorders. The proposed research, which builds upon my prior research and clinical experience, requires mastery of new skills related to the identification of individuals at risk for monogenic disorders in unselected populations. I have assembled an internationally-renowned team of mentors, whose areas of expertise span several domains of genomics research and medicine. My mentors include Dr. Robert Green, an expert in the medical, behavioral, and economic outcomes associated with the implementation of genomic medicine; Dr. Heidi Rehm, an expert in variant curation and gene-disease relationships; and Dr. Pradeep Natarajan, an expert in computational and integrative genomics. Through the proposed research and training, I will develop interdisciplinary skills that will enable me to transition to independence as a physician-scientist. Although monogenic genetic disorders are individually rare, they are estimated to collectively affect 1.5–6.2% of the global population. Most individuals with genetic conditions present to medical care after the development of symptoms and receive diagnoses following lengthy and expensive diagnostic odysseys. As the number of treatable genetic conditions grows, the need to identify at-risk individuals early has become more urgent. Population-based genomic sequencing, also known as a “genome-first approach,” provides an opportunity to improve public health outcomes by screening individuals for genetic disorders prior to the onset of symptoms. At this time, however, little is known about the penetrance and health outcomes of individuals with genetic risk variants from unselected populations. In this project, I propose to: 1) identify the prevalence of individuals with risk variants for a range of treatable monogenic conditions in both the hospital-based Mass General Brigham Biobank (MGBB) and U.K. Biobank (UKB), 2) recontact individuals in the MGBB who have genotypes associated with treatable inherited metabolic disorders (IMDs) to identify variables associated with disease expression, and 3) determine if metabolic profiling in the UKB can be used to predict outcomes in individuals with risk variants for a subset of IMDs. This work represents a step toward determining the best uses of genome-first medicine, eventually accelerating access to genomic risk-stratification, appropriate follow-up, orthogonal testing, and care for people with rare genetic disorders.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).