Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

Abstract

We report the updated classification of inborn errors of immunity, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 55 novel monogenic gene defects, and 1 phenocopy due to autoantibodies, that have either been discovered since the previous update (published January 2020) or were characterized earlier but have since been confirmed or expanded in subsequent studies. While variants in additional genes associated with immune diseases have been reported in the literature, this update includes only those that the committee assessed that reached the necessary threshold to represent novel inborn errors of immunity. There are now a total of 485 inborn errors of immunity. These advances in discovering the genetic causes of human immune diseases continue to significantly further our understanding of molecular, cellular, and immunological mechanisms of disease pathogenesis, thereby simultaneously enhancing immunological knowledge and improving patient diagnosis and management. This report is designed to serve as a resource for immunologists and geneticists pursuing the molecular diagnosis of individuals with heritable immunological disorders and for the scientific dissection of cellular and molecular mechanisms underlying monogenic and related human immune diseases.

Keywords: IUIS Committee update; Inborn errors of immunity; autoinflammatory disorders; immune dysregulation; primary immunodeficiencies.

Fig. 1

Accumulative discovery of novel inborn errors of immunity: 1980–2022. (A) The number of genetic defects underlying monogenic immune disorders as reported in the indicated year. (B) The number of pathogenic variants listed in each Table of the IUIS IEI committee 2022 report. The numbers in each column correspond to the number of genes reported in the 2019 IUIS update (blue bars) [4, 5], the number of new genes for each Table contained in this report (red bars), and the total number of genes for each Table (black number). Note: The 14 conditions listed for Table 10 are either phenocopies of germline IEI due to somatic variants or neutralizing autoAbs. Somatic variants in UBA1 are also listed in Table 10, although there is currently no IEI resulting from germline UBA1 variants [97]