A Focused Approach to the Diagnosis of Primary Immunodeficiencies

Abstract

Primary immunodeficiencies (PIDs) are genetic disorders impairing host immunity, leading to life-threatening infections, autoimmunity, and/or malignancies. Early diagnosis is the mainstay of treatment for PIDs. Delays in diagnosis can result in increased morbidity and mortality. Genomic technologies have been critical for expediting the discovery of novel genetic defects underlying PIDs, expanding our knowledge of the complex clinical phenotypes associated with PIDs, and in shifting paradigms of PID pathogenesis. Once considered Mendelian, monogenic, and completely penetrant disorders, genomic studies have redefined PIDs as a heterogeneous group of diseases found in the global population that may arise through multigenic defects, non-germline transmission, and with variable penetrance. The hierarchal approach, starting with PID targeted next-generation sequencing, is the most efficient approach for finding the causative mutation/s. This thesis seeks to focus on how genomic technologies, specifically next generation sequencing, are being applied to the diagnosis of PIDs, with a focus on the advantages and challenges of applying these approaches on a clinical scale.