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

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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Publication Details

Journal
Journal of Human Immunity
Published
2025-04-15
DOI
https://doi.org/10.70962/jhi.20250003
Citations
183
Primary Topic
Immunodeficiency and Autoimmune Disorders
Type
article
Field-Weighted Citation Impact
145.14

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article

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

Kathleen E. Sullivan, Helen C. Su, Charlotte Cunningham‐Rundles, Ivona Aksentijevich et al.
183 citations
Journal of Human Immunity
Immunodeficiency and Autoimmune Disorders
145.14
article

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

Kathleen E. Sullivan, Helen C. Su, Charlotte Cunningham‐Rundles, Ivona Aksentijevich, Nima Rezaei, M. Cecilia Poli, Sophie Hambleton, Isabelle Meyts, Tomohiro Morio, Raz Somech, Ahmed Aziz Bousfiha, Anne Puel, Capucine Pïcard, Troy R. Torgerson, Stuart G. Tangye, Mikko Seppänen, Christoph A. Klein
article en
183 citations

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.

Journal of Human ImmunityVol. 1(1)
Tokyo Medical and Dental University (JP), National Institutes of Health (US), Children's Hospital of Philadelphia (US), Universidad del Desarrollo (CL), University of Helsinki (FI), Garvan Institute of Medical Research (AU), Inserm (FR), Université Paris Cité (FR), Sheba Medical Center (IL), Helsinki University Hospital (FI), Hospital for Sick Children (CA), Clínica Alemana (CL), UNSW Sydney (AU), Université Paris Nanterre (FR), Clinical Research Institute (US), National Human Genome Research Institute (US), Hospital Roberto del Rio (CL), Allen Institute for Immunology (US), National Institute of Allergy and Infectious Diseases (US), Institut des Maladies Génétiques Imagine (FR), Tehran University of Medical Sciences (IR), University of Newcastle Australia (AU), University of Pennsylvania (US), Ludwig-Maximilians-Universität München (DE), Rockefeller University (US), Newcastle University (GB), Philadelphia University (US), Icahn School of Medicine at Mount Sinai (US), University of Hassan II Casablanca (MA), KU Leuven (BE)
Jeffrey Modell Foundation, Fonds Wetenschappelijk Onderzoek, National Institutes of Health, National Health and Medical Research Council, Fondo Nacional de Desarrollo Científico, Tecnológico y de Innovación Tecnológica, National Institute of Allergy and Infectious Diseases
Partnerships for the goals
Openalex Percentile: Top 0%
Immunodeficiency and Autoimmune Disorders
145.14
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