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Genetically transitional disease: conceptual understanding and applicability to rheumatic disease

Nature Reviews Rheumatology volume 20, pages 301–310 (2024)Cite this article

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Abstract

In genomic medicine, the concept of genetically transitional disease (GTD) refers to cases in which gene mutation is necessary but not sufficient to cause disease. In this Perspective, we apply this novel concept to rheumatic diseases, which have been linked to hundreds of genetic variants via association studies. These variants are in the ‘grey zone’ between monogenic variants with large effect sizes and common susceptibility alleles with small effect sizes. Among genes associated with rare autoinflammatory diseases, many low-frequency and/or low-penetrance variants are known to increase susceptibility to systemic inflammation. In autoimmune diseases, hundreds of HLA and non-HLA genetic variants have been revealed to be modest- to moderate-risk alleles. These diseases can be reclassified as GTDs. The same concept could apply to many other human diseases. GTD could improve the reporting of genetic testing results, diagnostic yields, genetic counselling and selection of therapy, as well as facilitating research using a novel approach to human genetic diseases.

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Fig. 1: GTD-related working nosology for genetic disease and examples.
Fig. 2: Germline and somatic mutations associated with diseases.

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Acknowledgements

The authors are grateful to L. Hastings for assistance with the figures.

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Authors and Affiliations

  1. Department of Rheumatology, Hospital for Special Surgery, New York, NY, USA

    Timothy B. Niewold

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

    Ivona Aksentijevich

  3. Division of Rheumatology, Allergy and Immunology, Stony Brook University Renaissance School of Medicine, Stony Brook, NY, USA

    Peter D. Gorevic & Qingping Yao

  4. Center for Integrative Genomics, School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA

    Greg Gibson

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  1. Timothy B. Niewold
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  2. Ivona Aksentijevich
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  4. Greg Gibson
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  5. Qingping Yao
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All authors researched data for the article and substantially contributed to discussion of content, writing and reviewing/editing of the manuscript.

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Correspondence to Qingping Yao.

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ClinVar: https://www.ncbi.nlm.nih.gov/clinvar/intro/

Infevers: https://infevers.umai-montpellier.fr/web/index.php

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Niewold, T.B., Aksentijevich, I., Gorevic, P.D. et al. Genetically transitional disease: conceptual understanding and applicability to rheumatic disease. Nat Rev Rheumatol 20, 301–310 (2024). https://doi.org/10.1038/s41584-024-01086-9

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