Jeffrey's Insights: Next-generation sequencing for primary immunodeficiency diagnosis, 2019-2025

Primary immunodeficiencies (PI), or inborn errors of immunity (IEI), are a clinically heterogeneous group of more than 550 monogenic disorders for which early molecular diagnosis is essential to guide management and improve outcomes. To address global barriers to genetic testing, the Jeffrey Modell Foundation implemented Jeffrey's Insights, a no-cost next-generation sequencing (NGS) program delivered through the global Jeffrey Modell Centers Network. From 2019 to 2025, 5,991 patients across 59 countries underwent NGS testing, resulting in a molecular diagnostic yield of 22.7%. Molecular diagnostic yields were highest in Australia and New Zealand (40.9%), Asia (31.6%), and the Middle East and Africa (31.3%). Among 1,482 patients with clinician-reported follow-up, NGS altered diagnosis (38.1%), management (37.0%), treatment (32.8%), and genetic counseling (50.6%), and improved clinical outcomes (31.3%). Physicians reported on healthcare utilization and barriers to care prior to testing. These findings underscore the value of NGS as an available first-tier test for suspected PI and highlight the need for broader global access to genomic diagnostics.