Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee

TLDR

Inborn errors of immunity arise from pathogenic variants that, despite similar mutation classes, can produce a spectrum of phenotypes; these are classified by consistently reported phenotype and by gain‑ or loss‑of‑function effects, providing a framework that informs diagnosis and therapy development. This report updates the classification of IEIs to include 508 genes and 17 phenocopies, serving as a resource for clinicians, geneticists, and other medical specialists, and highlighting the need to dissect underlying mechanisms to expand monogenic disease knowledge. The update was produced by the IUIS Expert Committee through rigorous review of new genetic descriptions using established IEI criteria. The update identifies 67 novel monogenic defects and 2 phenocopies caused by neutralizing anti‑cytokine autoantibodies or somatic mutations, confirmed or expanded since the 2022 update.

Abstract

This report provides an updated classification of inborn errors of immunity (IEIs) involving 508 different genes and 17 phenocopies. Of these, we report 67 novel monogenic defects and 2 phenocopies due to neutralizing anti-cytokine autoantibodies or somatic mutations, which either have been discovered since the previous update (published June 2022) or were reported earlier but have been recently confirmed and/or expanded. The new additions were made after rigorous review of new genetic descriptions of IEIs by the International Union of Immunological Societies (IUIS) Expert Committee using criteria established to define IEI. Although similar pathogenic variants in one gene, in terms of both classes of mutation (missense, nonsense, etc.) and impact on protein function, can result in a spectrum of phenotypic manifestations, they are herein classified according to the most consistently reported phenotype. In addition, because different variants in a single gene can result in recognizable diseases due to gain or loss of function, such cases are classified according to their clinical manifestations as a distinct entry in the same or a different table depending on the associated phenotype. This report will serve as a valuable resource for clinical immunologists and geneticists involved in the molecular diagnosis of individuals with heritable and acquired immunological disorders. Moreover, we expect this report to also serve as a valuable resource for all disciplines of medicine, since patients with IEIs may be first seen by rheumatologists, hematologists, allergists, dermatologists, neurologists, gastroenterologists, and pulmonologists, depending upon their spectrum of presenting clinical features. Finally, expanding the known monogenic and related causes of human immune diseases requires dissection of underlying cellular and molecular mechanisms, which reveals fundamental requirements for specific genes, pathways, processes, and even cell types. Such knowledge may not only contribute to improved patient diagnosis and management but also pave the way to the development and implementation of therapies that target the cause—rather than the symptoms—of these conditions.