Diagnostic Yield and Advantages of Exome/Genome Sequencing in Inborn Errors of Immunity

The rapid annual increase in conditions classified as inborn errors of immunity (IEI), along with associated genetic variants, creates diagnostic challenges. The comprehensive nature of exome sequencing (ES) and genome sequencing (GS) makes these technologies suitable for diagnosing IEIs. We examined the diagnostic rate (Dx) of ES/GS in a cohort of individuals with suspected IEI. Individuals were tested by ES/GS at a single clinical laboratory between 2013 and 2025 and were eligible for inclusion if testing was ordered by 1) an allergist/immunologist, or 2) any provider and containing at least one clinician-provided immune ICD-10 code (as defined by American Academy of Allergy, Asthma & Immunology [AAAAI]). Principal component analysis determined genetic ancestry. A total of 2,044 individuals with suspected IEI received ES/GS, 38.3% of whom had known targeted gene panel testing prior to ES/GS. At least one molecular diagnosis (positive or possible finding) was identified in 33.7% of the cohort (689/2,044). Diagnostic findings were consistent with the individual’s immune phenotype (immune-Dx) for 40.9% (282/689) of positive cases, including 47 individuals who had both immune and nonimmune diagnostic findings. The rate of immune-Dx findings was higher among individuals who were <18 at the time of testing (15.8%) compared to those who were ≥18 (10.7%; odds ratio [OR] 1.56; P = 0.001). There were no significant differences in the rate of immune-Dx findings among individuals of European (13.1%) and non-European (14.4%) ancestry (OR 1.11; P = 0.47). Diagnostic results in 275 cases were on the International Union of Immunological Societies (IUIS) 2024 classification list; the most prevalent categories were antibody deficiencies (26.6%) and CIDs with associated features (21.1%). The percentage of the cohort with candidate gene findings (6.0%) was larger than that found for all indications (4.4%) across ES/GS tested cases (OR 1.38; P = 0.001). The use of ES/GS in individuals with suspected IEI at a single large laboratory demonstrates equity in immune-Dx across populations. ES/GS can provide additional information, such as nonimmune diagnoses that are relevant for the individual, dual diagnoses, and candidate gene findings that may be upgraded in the future. ES/GS is an equitable diagnostic approach, important in the context of the rapidly growing list of IEI-associated genes.