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Inborn errors of immunity: an expanding universe of disease and genetic architecture

Nature Reviews Genetics volume 25, pages 184–195 (2024)Cite this article

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Abstract

Inborn errors of immunity (IEIs) are generally considered to be rare monogenic disorders of the immune system that cause immunodeficiency, autoinflammation, autoimmunity, allergy and/or cancer. Here, we discuss evidence that IEIs need not be rare disorders or exclusively affect the immune system. Namely, an increasing number of patients with IEIs present with severe dysregulations of the central nervous, digestive, renal or pulmonary systems. Current challenges in the diagnosis of IEIs that result from the segregated practice of specialized medicine could thus be mitigated, in part, by immunogenetic approaches. Starting with a brief historical overview of IEIs, we then discuss the technological advances that are facilitating the immunogenetic study of IEIs, progress in understanding disease penetrance in IEIs, the expanding universe of IEIs affecting distal organ systems and the future of genetic, biochemical and medical discoveries in this field.

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Fig. 1: Ten key historical events that advanced the study of inborn errors of immunity.
Fig. 2: The relationship between allele frequency and disease severity for causal genetic lesions of inborn errors of immunity.
Fig. 3: A hierarchy of genetic alterations influences the penetrance and expressivity of inborn errors of immunity.
Fig. 4: Epigenetic and genetic modifiers determine the penetrance and expressivity of inborn errors of immunity.
Fig. 5: Effects of mosaicism on the penetrance and expressivity of inborn errors of immunity.
Fig. 6: The promise of reverse genetics approaches for the identification of undiagnosed inborn errors of immunity.

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Acknowledgements

This work was supported by National Institute of Allergy and Infectious Disease grants R01 AI148963, R01 AI127372, R01 AI150300, R01 HD108467 and R01 AI151029 awarded to D.B. Y.T.A. was supported by T32 training grant T32 AI078892. The authors apologize to colleagues whose work they could not cite or could only superficially discuss owing to space limitations.

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  1. Center for Inborn Errors of Immunity, Precision Immunology Institute, Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Yemsratch T. Akalu & Dusan Bogunovic

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  1. Yemsratch T. Akalu
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  2. Dusan Bogunovic
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Both authors contributed equally to all aspects of the article.

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Correspondence to Dusan Bogunovic.

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D.B. is a founder and part owner of Lab11 Therapeutics. Y.T.A. declares no competing interests.

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Related links

African Genome Variation Project: https://www.sanger.ac.uk/collaboration/african-genome-variation-project

All of Us Research Program: https://allofus.nih.gov

International Union of Immunological Societies (IUIS) Inborn Errors of Immunity Committee: https://iuis.org/committees/iei

Mount Sinai Million Health Discoveries Program: https://icahn.mssm.edu/research/ipm/programs/mount-sinai-million

UK Biobank: https://www.ukbiobank.ac.uk

Glossary

Agammaglobulinemia

A rare disorder characterized by complete or near-complete lack of serum antibodies and circulating B cells owing to early termination of B cell development.

Aicardi–Goutières syndrome

(AGS). A rare type I interferonopathy that affects the brain, immune system and skin.

Common variable immunodeficiency

(CVID). The most common form of primary immunodeficiency characterized by antibody deficiency, increased susceptibility to infection, autoimmune manifestations and impaired vaccine responses.

Chronic granulomatous disease

A rare condition, mainly affecting phagocytic cells of the immune system, that is characterized by an increased susceptibility to bacterial and fungal infections, as well as the development of granulomas.

Di George syndrome

A primary immune deficiency associated with susceptibility to infections, owing to an absent or poorly developed thymus.

Genetic theory of infectious disease

A theory proposing that the genetic background of the host is a determinant of resistance or susceptibility to a given microorganism.

Incomplete penetrance

The occurrence of individuals having a disease-causing mutation who develop partial or no disease.

Monoallelic expression

The maintenance of expression of an autosomal gene from a single allele in a somatic cell over time.

Nonsense-mediated decay

A mechanism to reduce errors in gene expression by eliminating mRNA transcripts that contain premature stop codons.

Primary immune deficiencies

A varied group of disorders that result from genetic defects that impair the development and/or function of the immune system, mostly presenting as severe recurrent infections and occasionally with an increased incidence of autoimmunity and malignancies.

Type I interferonopathy

An inherited disorder involving a central role for dysregulation of the type I interferon pathway in disease pathogenesis.

Severe combined immunodeficiency

(SCID). A very rare life-threatening genetic disorder in which there is combined absence of T cell and B cell function.

Wiskott–Aldrich syndrome

A rare X-linked recessive immunodeficiency that is characterized by abnormal bleeding resulting from a reduced number of platelets in the blood.

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Akalu, Y.T., Bogunovic, D. Inborn errors of immunity: an expanding universe of disease and genetic architecture. Nat Rev Genet 25, 184–195 (2024). https://doi.org/10.1038/s41576-023-00656-z

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