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.