Project Description Narrative:
Genetic information has become integral to the health and well-being of patients suffering from various diseases. DNA codes for proteins. When DNA mutations (genomic variants) alter the code, the gene produces proteins with different shapes and abnormal functions. DNA sequencing allows physicians access to a patient’s genome (all genes). Certain DNA mutations are linked to specific diseases. However, most mutations have uncertain effects on the encoded protein (VUS). Therefore, how the altered proteins from mutated genes cause disease remains largely unknown. As such, more advanced methods are necessary to understand how genomic variants alter protein structure and dynamics, to aid diagnosis. Because the DNA mutations associated with undiagnosed diseases are rare, often unique to a few patients, understanding them has been slower than common mutations.
Standard interpretation currently leaves ~70% of rare disease cases undiagnosed. Genomic Medicine seeks to advance the interpretation of disease-causing mutations through improved technologies for analyzing genetic data. However, current genomic approaches examine data projected on linear sequences. The most advanced approach to interpreting genomics is deep computational structural genomics, or 3D-genomics –a translational team science approach integrating biology, chemistry, bioinformatics, computer science, and cutting-edge analyses of 3D protein models, to significantly enhance variant interpretation.
This project’s research team aims to use 3D-gemomics to improve the diagnostic rate in its rare disease clinics (yielding positive personal, medical, and financial impacts); discover new diseases; reveal new disease subtypes; and unraveling new mechanisms of diseases. They will focus on pediatric populations because diseases caused by single gene alterations (monogenic diseases) are typically diagnosed early in life. However, many rare diseases have late-onset or can be managed into adulthood, making their focus beneficial for individuals of all ages.