Molecular Diagnosis of Inherited Immune Disorders

Primary immunodeficiency diseases are a heterogeneous group of rare inherited disorders of innate or adaptive immune system function. Patients with primary immunodeficiencies typically present with recurrent and severe infections in infancy or young adulthood. More recently, the co-occurrence of autoimmune, benign lymphoproliferative, atopic, and malignant complications has been described. The diagnosis of a primary immunodeficiency disorder requires a thorough assessment of a patient's underlying immune system function. Historically, this has been accomplished at the time of symptomatic presentation by measuring immunoglobulins, complement components, protective antibody titers, or immune cell counts in the peripheral blood. Although these data can be used to critically assess the degree of immune dysregulation in the patient, this approach fall short in at least 2 regards. First, this assessment often occurs after the patient has suffered life-threatening infectious or autoinflammatory complications. Second, these data fail to uncover an underlying molecular cause of the patient's primary immune dysfunction, prohibiting the use of molecularly targeted therapeutic interventions. Within the last decade, the field of primary immunodeficiency diagnostics has been revolutionized by 2 major molecular advancements: (1) the onset of newborn screening in 2008, and (2) the onset of next-generation sequencing in 2010. In this article, the techniques of newborn screening and next-generation sequencing are reviewed and their respective impacts on the field of primary immunodeficiency disorders are discussed with a specific emphasis on severe combined immune deficiency and common variable immune deficiency.