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A large genome-first study found that pathogenic variants linked to systemic autoinflammatory diseases are present in about 0.02% of the population — and more than half of those carriers show real inflammatory symptoms. Despite this, these conditions remain widely underdiagnosed. Researchers say clinicians should lower the threshold for genetic testing and stay alert to the diverse ways these diseases can present.
A new study published in The Lancet Rheumatology used a genome-first approach to uncover just how underdiagnosed systemic autoinflammatory diseases (SAIDs) really are. Analyzing whole exome sequencing data from over 640,000 participants across two major biobanks — Geisinger MyCode (US) and the UK Biobank — researchers identified pathogenic or likely pathogenic variants in 28 SAID-related genes. About 0.02% of participants carried these variants, and 51% of them showed clinically relevant inflammatory features, suggesting many cases are going undetected.
The study found that carriers were significantly more likely to have diagnoses of rheumatic autoimmune disorders, fever, and arthritis, and were more likely to be on immunosuppressive medications. Yet no single clinical phenotype consistently distinguished disease-causing gene carriers across both cohorts, highlighting just how heterogeneous these conditions can be.
By the Numbers:
Why it matters: SAIDs are treatable — but only if they're caught. This study makes a compelling case for broader genetic testing in patients with unexplained inflammatory symptoms, which could lead to earlier, more targeted therapies and better outcomes.
