Primary Immunodeficiencies (PI) include more than 550 monogenic disorders presenting with recurrent infections, autoimmunity, and significant morbidity. Early molecular diagnosis is essential for guiding targeted treatment, improving outcomes, and reducing the prolonged and costly diagnostic odyssey that many patients experience. To address global barriers to genetic testing, the Jeffrey Modell Foundation (JMF) established Jeffrey’s Insights, a no-cost next-generation sequencing (NGS) program delivered through the global Jeffrey Modell Centers Network (JMCN). The program leverages expert immunologist selection to identify patients with a high pretest probability of PI and facilitate access to high-quality molecular diagnostics.
From January 2019 to June 2025, 5,991 individuals across 60 countries underwent targeted NGS through partnering clinical laboratories (Invitae, now a part of Labcorp, and Veritas Intercontinental). Across five progressively expanded PI gene panels (207–576 genes), the overall molecular diagnostic yield was 22.7%, with 1,357 patients receiving a confirmed or likely molecular diagnosis. Diagnostic yield remained statistically consistent across panel iterations, underscoring the value of expert clinician-guided patient selection. Regional diagnostic rates varied, with the highest yields observed in Australia/New Zealand (40.9%), Asia (31.6%), and the Middle East/Africa (31.3%). Among diagnosed individuals, 76.5% were children, and diagnostic yield was highest in patients younger than five years (26%), highlighting the importance of early testing. A subset of patients had dual or triple molecular diagnoses, emphasizing the complexity of blended phenotypes.
A total of 1,482 patients had clinician-reported follow-up. NGS altered clinical diagnosis in 38%, disease management in 37%, treatment in 33%, and genetic counseling in 51%. Relevant therapies were identified for 47% of patients, and 31% experienced improved clinical outcomes directly attributable to sequencing results. Questionnaire responses revealed substantial pretesting healthcare utilization, including frequent emergency department visits, hospitalizations, and intensive care unit (ICU) admissions, as well as significant global barriers to accessing NGS, with cost and lack of insurance coverage identified as major limitations.
This global evaluation demonstrates that early, immunologist-guided NGS provides substantial diagnostic and clinical benefit for suspected PI. These findings strongly support the use of NGS as a first-tier diagnostic test for PI and emphasize the urgent need to expand access to genomic testing worldwide.
