Clinical and genetic findings of individuals tested using the navigateAPDS genetic testing program

Inborn errors of immunity (IEIs), including activated phosphoinositide-3-kinase delta 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.

To investigate the clinical utility of the navigateAPDS sponsored program established to increase MolDx of APDS through broad genetic testing.

The eligibility criteria to receive sponsored testing included APDS clinical features.

Between March 2021 and September 2024, a total of 7811 patients across the United States and Canada underwent genetic testing. The median age at time of testing was 33 (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 Food and Drug Administration-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 131 received a variant of uncertain significance (VUS). Patients with APDS had a median age at time of symptom onset of 3 (range, 0-44) years and a median diagnostic delay of 13 (range, 0-50) years. Of the 13 APDS-causing variants identified, 5 were novel for APDS.

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 are crucial in elucidating the genetic contribution to the clinical spectrum of IEIs and APDS.