Next-generation sequencing is a valuable tool to help diagnose inborn errors of immunity (IEIs) because it can interrogate many genes concurrently and has enabled a quick expansion of IEI-related genes. While exome sequencing (ES) can analyze novel and established IEI genes, fixed multigene panel tests (MGPTs) are still broadly used. The aim of this study was to examine the molecular diagnosis (MolDx) rate from both MGPT and ES and the phenotypic pattern of patients referred for ES.
Patients were referred for MGPT and/or ES between March 2017 and May 2024 at a diagnostic laboratory. MGPT contained up to 574 genes and were curated based on the International Union of Immunological Societies phenotypic classification list of IEI-related genes and expert opinion. Patients in the ES cohort were selected based on clinician-provided ICD-10 and Human Phenotype Ontology (HPO) terms. We required patients in the ES cohort to have at least one HPO term under “abnormality of the immune system.” Odds ratios (OR) and p-values were calculated using G-tests; p-values < 0.05 were considered statistically significant.
The overall MolDx was higher in the ES cohort (378/2,167; 17.4%) versus MGPT (3,754/40,994; 9.2%) (OR 2.1, p < 2.2 × 10-16). Of the 121 patients in the cohort tested by both ES and MGPT, 11 had discordant results due to a non-IEI–related finding on ES (n = 8) or MGPT (n = 1), technical differences (n = 1), and novel gene not available on MGPT (n = 1). There were 42 unique genes that were reported from ES; 16 (38.1%) were also available on MGPT at the time of testing. Out of the 26 (61.9%) genes that were not available on MGPT, 2 were related to IEI conditions, while the remainders were not primary IEI conditions (e.g., neurological conditions causing epilepsy and/or neurodevelopmental disorders or skeletal/dermatological/dental conditions).
Despite the growing number of genes associated with IEIs, the increase in MolDx rate from ES cannot be exclusively attributed to novel IEI-related genes. This difference may be explained by the indication for testing, which suggests patients who present with an IEI phenotype and involvement with another organ system may benefit from ES. Granular characterization of the phenotypic spectrum of patients who receive a MolDx from ES is warranted.
