Expanding Variant-Aware Strategies for Rare Disease Diagnosis

Abstract

Rare diseases are collectively far more common than their designation might imply, and they represent a significant source of global disease burden, infant mortality, and healthcare costs. Expansive sequencing technologies such as genome sequencing represent some of the most efficient ways to diagnose patients with suspected genetic disease, and the clinical use of sequencing has expanded greatly in recent years. Genome sequencing, one of the most comprehensive sequencing technologies, is estimated to deliver a diagnosis to an impressive 34-48% of sequenced patients. The remaining patients have little recourse for receiving a molecular diagnosis and the subsequent treatment, prognosis, or genetic counseling that diagnosis allows. Limited knowledge of genome function, and limited ability to interpret the effects of genetic changes, represent crucial translational hurdles that prevent clinicians from fully leveraging the power of sequencing technology to diagnose patients. Increasingly, the challenges of rare disease diagnosis are becoming not how to sequence patients and collect genetic information, but how to interpret the wealth of genetic information obtained by sequencing. This thesis document will introduce new methods which span clinical and research approaches to interpret the significance of genetic variants and deliver precise diagnoses to rare disease patients.