Background/Purpose: Inborn errors of immunity (IEI), including autoinflammatory diseases and primary immune regulation disease (PIRD), are unfamiliar to many adult rheumatologists, leading to potential ascertainment bias and health disparities for adults with suspected IEI. While genetic testing is a cornerstone for diagnostic testing in pediatric autoinflammatory clinics, data from adult rheumatology clinics are limited. This study evaluates genetic diagnostic rates in an adult cohort with suspected IEI, including autoinflammatory diseases, at a single tertiary care center, comparing outcomes to pediatric benchmarks.

Methods: We retrospectively analyzed a cohort of 155 adult patients referred to our rheumatology immunogenetics clinic between 2022-2025 for suspected IEI, including autoinflammatory syndromes and PIRD. Patients underwent targeted array-based genetic testing (n = 68, 574 genes); somatic variant testing for UBA1 and other genes associated with myelodysplastic syndrome (MDS) (n = 6, 302 genes); or whole exome sequencing (n = 2) to identify potential disease-causal or disease-contributory variants. Clinical phenotypes, inflammatory markers (CRP, ESR, SAA, ferritin, 28-gene interferon score, S100A8/9, S100A12), family pedigrees, and demographic data were correlated with genetic findings. Variants were classified per American College of Medical Genetics and Genomics guidelines.

Results: Variants of interest (pathogenic, likely pathogenic, variant of uncertain significance/VUS) were identified in 30% (24/80) of the tested patients. Of these, 24 were ACMG P/LP and 70 were VUS. Functional testing revealed a potential causal role for 24 genes and contributory for 45 genes. IEI diagnoses included familial Mediterranean fever, HA20, NAIAD, DiGeorge syndrome, Trisomy 8, and others. An additional 45 patients were found to have variants that were not disease-causal but affected management (i.e. enhanced cancer screening) due to risk for other conditions. Of the six patients tested for VEXAS, four had pathogenic UBA1 variants, and one had clinically significant MDS-associated variants in other genes. The genetic diagnostic rate was comparable to pediatric IEI cohorts (15–35%). Approximately 60% of patients did not obtain a genetic diagnosis; this could be to variants in novel IEI-causal genes or to non-genetic etiologies.

Conclusion: This single-center study demonstrates that rheumatology immunogenetics clinics achieve similar genetic diagnostic rates (33%) in adult and pediatric cohorts, underscoring the prevalence and significance of IEI in adults. The identification of VEXAS and MDS-causal variants further highlights the clinical relevance of targeted testing in this population. These findings advocate for increased availability of adult immunogenetics clinics to enable personalized management and genetic counseling. Multicenter studies are needed to validate novel variants and address undiagnosed cases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/high-diagnostic-rate-of-genetic-testing-in-adult-patients-with-autoinflammation-a-single-center-experience/