The process begins with 164 adult patients who had a history of consultation at the Department of Rheumatology, Institute of Science Tokyo between March 2018 and September 2024. These patients exhibited clinical features such as recurrent infections, autoimmune manifestations, chronic inflammations, and family history. 72 patients were excluded due to the absence of genetic testing (33 patients) or incomplete clinical information (43 patients), leaving 88 patients for genetic testing. Genetic testing was performed in two main locations: at the Department of Rheumatology, Institute of Science Tokyo (59 patients) and at other departments or institutions (29 patients). The testing involved targeted gene panels at Kazusa DNA Research Institute, an extended 400-gene panel under the PIDJ framework, the Initiative on Rare and Undiagnosed Disease (IRUD) framework, in-house testing, and unknown methods. Following genetic testing, 7 patients were excluded because the testing was performed before they were 18 years old. Further refinement based on ACMG/AMP criteria led to the exclusion of 17 patients with suspected familial Mediterranean fever (FMF) lacking molecular support and 14 patients whose identified variants did not fulfill the ACMG/AMP criteria for pathogenic or likely pathogenic classification. The final analytic cohort consisted of 50 adult patients, who were classified into three groups: immunodeficiency (ID) with 17 patients, autoinflammatory disorders (AID) with 24 patients, and non-ID/AID with 9 patients.
Study design and clinical classification framework. Flowchart illustrating the inclusion criteria, classification process, and genetic testing pathways for adult patients with clinical suspicion of IEI. Between March 2018 and September 2024, 164 adult patients presenting with recurrent infections, autoimmune manifestations, chronic inflammation, or suggestive family history were evaluated. After excluding patients without genetic testing (n = 33) or with incomplete clinical information (n = 43), 88 patients underwent genetic testing. Prior to downstream analyses, 17 patients with clinical familial Mediterranean fever (FMF) lacking molecular support, 14 patients whose identified variants did not fulfill ACMG/AMP criteria for pathogenic or likely pathogenic classification, and 7 patients tested before 18 years of age were excluded. Following result review, the final cohort consisted of 50 adult patients. Patients were classified into three groups—ID (n = 17), AID (n = 24), and non-ID/AID (n = 9)—based on clinical features. Genetic testing was performed using four platforms depending on clinical judgment: (1) targeted panels at KDRI, (2) the expanded 400-gene panel under the PIDJ initiative, (3) the IRUD, and (4) in-house sequencing. A detailed genetic testing workflow and platform-specific information are provided in Fig. S5.