Whole Exome Sequencing in Inborn Errors of Immunity

Conclusion and Future Directions

NGS has revolutionized the diagnostic and research approach to monogenic diseases, inborn errors of immunity in particular. For this reason, physicians treating the patients affected by these disorders wish to be familiar with these techniques, and know their strengths and weaknesses.

We have, here, reviewed the process of WGS and targeted panel sequencing, including WES; the steps required to find the disease-causing variant, starting from the genetic hypothesis steps and then proceeding with a gene-level and a variant-level approach; and finally some common pitfalls of these methods. Based on the growing expertise and growing technical opportunities now available in this field, both the exome kits as well as the annotations tools are becoming more and more precise in identifying inborn errors of immunity causative mutations, but we should be ready to revisit all assumptions in the screening pipeline when they fail to detect a pathogenic variant.

Thanks to continuous technologic advancements, the cost of WGS is rapidly decreasing and it will soon become as cheap as WES, with the advantage of being more accurate in detecting mutations. As a diagnostic approach, we therefore propose to first sequence a targeted panel of genes or the exome, then extending the investigation to the entire genome if no adequate candidate gene or variant is found. The biggest challenge will remain the validation of new candidate mutations, which is absolutely required to prove the disease-causing nature of a genetic variant.^[4]

Our ever-expanding molecular understanding of inborn errors of immunity is paving the way for targeted therapy, such as the use of Janus Kinase 1/2 inhibitors in signal transducer and activator of transcription 1 (STAT1) GOF mutations or inhibitors of the PI3K catalytic subunit p110δ in PIK3CD GOF mutations,^[66] gene therapy, and soon gene-editing technology. In this way, WES will not only have revolutionized genetic diagnosis, but also medicine as a whole.

Curr Opin Allergy Clin Immunol. 2017;17(6):421-430. © 2017 Lippincott Williams & Wilkins