article · Journal of Human Immunity
An updated classification of inborn errors of immunity catalogues 508 genes and 17 phenocopies, incorporating 67 novel single-gene defects and two phenocopies confirmed or discovered since mid-2022. The additions reflect a rigorous assessment by an international expert committee using standardised criteria. Entries account for phenotypic variations, classifying pathogenic variants by their most consistent clinical outcomes while separating gain-of-function and loss-of-function variations within the same gene. The resource supports geneticists, immunologists, and varied medical specialists who encounter patients with diverse presentations, including dermatological, neurological, and respiratory symptoms. Beyond clarifying diagnostic boundaries, detailing these underlying genetic alterations illuminates basic cellular mechanisms and immunological pathways. This foundation aids clinical diagnosis and patient care while supporting future efforts to create interventions that address the fundamental biological causes of these disorders rather than managing only their symptoms.
Genetic immune disorders present with diverse symptoms that often obscure their underlying cause. By mapping hundreds of validated genetic defects and their clinical manifestations, this classification equips doctors across multiple specialisms to identify rare inherited conditions accurately. Earlier and more precise diagnosis helps healthcare teams choose appropriate management plans and guides research towards therapies that correct root biological defects instead of merely treating symptoms.
This reference framework directly enables the development and updating of clinical molecular diagnostic panels and genetic testing services. Primary users include diagnostic laboratories, clinical geneticists, and healthcare providers across various medical disciplines. The information is directly applicable for diagnostic standardisation, whilst the fundamental mechanistic insights provide an early-stage starting point for pharmaceutical and biotechnology developers seeking specific molecular targets for disease-modifying therapies.
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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.
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DOI: 10.70962/jhi.20250003
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