Genetic testing advances have uncovered numerous variants of uncertain significance (VUS) in autoinflammatory diseases, complicating diagnoses and treatment decisions. As VUS quantity rises, the… PMID:42191839, Nat Rev Rheumatol 2026, @NatRevRheumatol https://doi.org/10.1038/s41584-026-01380-8
Decoding variants of uncertain significance in systemic autoinflammatory diseases | Nature Reviews Rheumatology
The development and implementation of genetic testing has revolutionized the diagnostic landscape of autoinflammatory diseases, leading to an exponential increase in the identification of disease-associated genetic variants. Yet a substantial proportion of these are considered variants of uncertain significance (VUS), complicating both diagnosis and therapeutic decision-making. This challenge is relevant not only for monogenic systemic autoinflammatory diseases, but also in the context of genetically complex disorders that can involve multiple low-penetrance variants. Advances in protein structure prediction tools, machine learning and artificial intelligence provide powerful computational frameworks for the classification of variants; however, their predictive accuracy must be benchmarked against functional assays, particularly with respect to gain-of-function variants. Functional screening approaches benefit from both technological progress and expanding knowledge of the innate immun
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