Genetic Testing in Clinical Immunology: What to Know and How to Do It

Genetically driven immune diseases are immune-mediated disorders involving germline and/or somatic host genetic changes that make a major contribution to disease pathogenesis. These conditions, which include the inborn errors of immunity, may predispose patients to the development of immunodeficiency, immune dysregulation, atopy, autoinflammation or hyperinflammation, and malignancy. Since the development of massively parallel sequencing, also known as next-generation sequencing, and its introduction into clinical use, clinical genetic testing has expanded exponentially across medical specialties, including clinical immunology, with approximately 28% of patients with suspected genetically driven immune diseases undergoing genetic testing in the United States. Despite rapid uptake, knowledge gaps persist regarding when to order genetic testing, how to choose the appropriate assay, and how to interpret the results in clinical context. In this review, we provide a practical framework for genetic testing strategy and interpretation and discuss current limitations, as well as emerging advances that may help further enhance diagnostic yield and clinical impact.