Clinical and Genetic Findings of Individuals Tested via the navigateAPDS Genetic Testing Program.
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BACKGROUND: Inborn errors of immunity (IEI), including activated PI3Kδ syndrome (APDS), are underdiagnosed due to factors including heterogenous clinical manifestations, lack of awareness, and limited genetic testing access. Genetic testing may establish the molecular diagnosis (MolDx) of numerous IEIs, which may result in management changes. OBJECTIVE: The navigateAPDS sponsored program was established to increase MolDx of APDS through broad genetic testing; here we investigated its clinical utility. METHODS: The eligibility criteria to receive sponsored testing included APDS clinical features. RESULTS: Between March 2021 and September 2024, 7,811 patients across the US and Canada underwent genetic testing. The median age at time of testing was 33 years (range, 0-89 years) and the most selected eligibility criterion was severe, recurrent sinopulmonary infections. Of the 630 patients who received a positive MolDx, 377 (60%) had disorder-associated clinical actionability; 73 (12%) had FDA-approved treatments available. The most identified IEIs included genetically defined common variable immune deficiency and APDS. Of the patients with variants in PIK3CD or PIK3R1, 35 received an APDS MolDx and 129 received a variant of uncertain significance (VUS). Patients with APDS had a median age at time of symptom onset of 3 years (range, 0-44 years), and a median diagnostic delay of 13 years (range, 0-50 years). Of the 13 APDS-causing variants identified, 5 were novel for APDS. CONCLUSION: These findings demonstrate that broad genetic testing for IEIs is useful and may contribute to disease management changes and improved health outcomes. Variant identification and VUS resolution is crucial in elucidating the genetic contribution to the clinical spectrum of IEIs and APDS.
