Multidisciplinary genomic evaluation reveals adult inborn errors of immunity with rheumatic features

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Abstract
Multidisciplinary genomic evaluation is increasingly recognized for its diagnostic and therapeutic implications in adults with suspected inborn errors of immunity (IEI) presenting with rheumatic and musculoskeletal disease (RMD) phenotypes. We retrospectively analyzed 50 adults with suspected IEI who underwent genetic testing and were pre-classified into immunodeficiency (ID), autoinflammatory disorders (AID), and non-ID/AID groups. Genetic findings, clinical classification, treatment modifications, and exploratory machine learning analyses were evaluated. A final genetic diagnosis consistent with IEI was identified in 15 patients (30.0%), with the highest yield in the non-ID/AID group (44.4%). Variants were most frequently associated with autoinflammatory diseases (40.0%). Four patients, all initially classified as non-ID/AID, were reclassified based on genetic findings and IUIS classification. Treatment was modified in 12 patients, including eight genetically diagnosed patients and three genotype-driven interventions. Two patients died from disease-related complications. Machine learning analyses provided heterogeneous feature contributions across groups. These findings highlight the utility of multidisciplinary genomic evaluation for refining diagnoses in challenging adult patients.

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