Next-generation sequencing for inborn errors of immunity

Inborn errors of immunity (IEIs) include several hundred gene defects affecting various components of the immune system. As with other constitutional disorders, next-generation sequencing (NGS) is a powerful tool for the diagnosis of these diseases. While NGS can provide molecular confirmation of disease in a patient with a suspected or classic phenotype, it can also identify new molecular defects of the immune system, expand gene-disease phenotypes, clarify mechanism of disease, pattern of inheritance or identify new gene-disease associations. Multiple clinical specialties are involved in the diagnosis and management of patients with IEI, and most have no formal genetic training or expertise. To effectively utilize NGS tools and data in clinical practice, it is relevant and pragmatic to obtain a modicum of knowledge about genetic terminology, the variety of platforms and tools available for high-throughput genomic analysis, the interpretation and implementation of such data in clinical practice. There is considerable variability not only in the technologies and analytical tools used for NGS but in the bioinformatics approach to variant identification and interpretation. The ability to provide a molecular basis for disease has the potential to alter therapeutic management and longer-term treatment of the disease, including developing personalized approaches with molecularly targeted therapies. This review is intended for the clinical specialist or diagnostic immunologist who works in the area of inborn errors of immunity, and provides an overview of the need for genetic testing in these patients (the “why” aspect), the various technologies and analytical approaches, bioinformatics tools, resources, and challenges (the “how” aspect), and the clinical evidence for identifying which patients might be best served by such testing (the “when” aspect).