Inborn errors of immunity (IEI) are monogenic disorders characterized by considerable phenotypic variability and genetic heterogeneity, for which genetic confirmation is essential to establish an accurate diagnosis and guide appropriate treatment. In Japan, genetic testing for IEI is covered by the national health insurance system. As of October 2025, clinicians select the most appropriate panel from among 32 available gene panels (comprising a total of 312 genes) based on the clinical diagnosis. However, owing to the broad phenotypic spectrum of IEI—wherein identical gene variants can manifest as distinct clinical presentations, and conversely, similar clinical features may result from mutations in different genes—selecting the optimal panel is inherently challenging, and the current insurance-covered testing system has recognized limitations. Against this background, a pilot study on the secondary use of unanalyzed next-generation sequencing (NGS) data generated as a by-product of insurance-covered testing was launched in 2023 at nine principal institutions across Japan, including the Department of Pediatrics at Hiroshima University. This initiative enabled a comprehensive evaluation of more than 242 IEI-associated genes. In the pilot study, 160 patients with undiagnosed IEI were analyzed, and a definitive genetic diagnosis was established in 15 cases (9.4%). Building on these results, the program was expanded in February 2025 under the auspices of the Japanese Society for Immunodeficiencies and Autoinflammatory Diseases (JSIAD), with 91 institutions across Japan enrolled as collaborative sites.
In this presentation, we report the current progress of the JSIAD-led secondary analysis program for unanalyzed NGS data. For cases in which a definitive genetic diagnosis was established, we cross-reference the findings with the originally selected insurance-covered gene panel and correlate discrepancies with the clinical phenotype, thereby identifying limitations of the current testing framework. Furthermore, drawing on the cumulative findings of this research, we discuss future directions for genetic testing strategies in IEI.
