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Somatic mutations in autoinflammatory and autoimmune disease

Nature Reviews Rheumatology volume 20, pages 683–698 (2024)Cite this article

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Abstract

Somatic mutations (also known as acquired mutations) are emerging as common, age-related processes that occur in all cells throughout the body. Somatic mutations are canonically linked to malignant processes but over the past decade have been increasingly causally connected to benign diseases including rheumatic conditions. Here we outline the contribution of somatic mutations to complex and monogenic immunological diseases with a detailed review of unique aspects associated with such causes. Somatic mutations can cause early- or late-onset rheumatic monogenic diseases but also contribute to the pathogenesis of complex inflammatory and immune-mediated diseases, affect disease progression and define new clinical subtypes. Although even variants with a low variant allele fraction can be pathogenic, clonal dynamics could lead to changes over time in the proportion of mutant cells, with possible phenotypic consequences for the individual. Thus, somatic mutagenesis and clonal expansion have relevant implications in genetic testing and counselling. On the basis of both increased recognition of somatic diseases in clinical practice and improved technical and bioinformatic processes, we hypothesize that there will be an ever-expanding list of somatic mutations in various genes leading to inflammatory conditions, particularly in late-onset disease.

Key points

  • Somatic mutations, even at low allele fractions, can have a role in the pathogenesis of monogenic and complex rheumatological diseases, in both early-onset and late-onset conditions.

  • Somatic mutagenesis and clonal expansions are dynamic processes and a change in clinical phenotype might warrant repeated genetic testing.

  • Identification of somatic mutations has major implications for genetic counselling.

  • The identification of pathogenic somatic mutations in patients with immune-mediated disease can inform treatment decisions.

  • As new methodologies and resources for somatic variant detection and interpretation are emerging, they will be instrumental for reshaping disease taxonomy in rheumatology.

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Fig. 1: Overview of possible origins, distributions and transmission of variants.
Fig. 2: Evolution and outcomes of clonal expansions due to somatic mutagenesis.
Fig. 3: Methodologies for the detection of somatic mutations.

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Change history

  • 25 October 2024

    In the version of the article initially published, the surname of co-reviewer Mikko Myllymäki was misspelt as Myllmyaki and has now been corrected in the HTML and PDF versions of the article.

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Acknowledgements

The authors of this Review were in part supported by the Intramural Research Program of the National Institutes of Health (NIH), National Human Genome Research Institute. D.B.B is supported by the NIH (R00AR078205) and the Arthritis National Research Foundation.

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Authors and Affiliations

  1. Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    Sofia Torreggiani & Ivona Aksentijevich

  2. Epidemiology and Human Genetics, Graduate Program in Life Sciences, University of Maryland School of Medicine, Baltimore, MD, USA

    Sofia Torreggiani

  3. Center for Human Genetics and Genomics, New York University Grossman School of Medicine, New York, NY, USA

    Flore S. Castellan & David B. Beck

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All authors researched data for the article, contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission. S.T., F.C. and D.B.B. wrote the article.

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Glossary

Allele bias

The preferential amplification or detection of one allele over another.

Gonadal mosaicism

A condition in which post-zygotic variants occur exclusively in germinal cells, typically without any phenotype in the carrier, but with the potential to lead to disease owing to apparent de novo germline mutations in the offspring.

Gonosomal mosaicism

A condition in which post-zygotic variants occur in a combination of somatic and germinal cells; carriers of gonosomal mosaicism could have a phenotype or not depending on the variant, and the fraction and type of mutant cells, and can transmit their variant to their offspring as a germline variant.

Mutation burden

The number of mutations present in the investigated genome, often expressed as the number of mutations per megabase.

Revertant mosaicism

A condition in which the effect of a germline disease-causing variant is corrected by a second spontaneous mutation event in a somatic cell, conferring a selective advantage to the revertant clone and leading to its expansion.

Somatic mosaicism

A condition in which post-zygotic mutations occur exclusively in somatic cells with possible phenotypic consequences in the carrier, but no potential to be transmitted to the offspring.

Variant allele fraction

The proportion of reads supporting the variant allele relative to the total number of reads at that genomic location.

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Torreggiani, S., Castellan, F.S., Aksentijevich, I. et al. Somatic mutations in autoinflammatory and autoimmune disease. Nat Rev Rheumatol 20, 683–698 (2024). https://doi.org/10.1038/s41584-024-01168-8

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