From Genes to Care: Real-World Insights into PIK3CD and PIK3R1 Variant Resolution and Targeted Therapy

When treating patients with suspected Activated PI3Kδ Syndrome (APDS), the diagnostic journey often hinges on one essential step - resolving variants of uncertain significance (VUS). A new multi-institutional study by Suhet et al. (University of South Florida, UCLA, Emory, and collaborators) highlights how bridging genetic uncertainty leads to real therapeutic impact.

APDS arises from activating variants in PIK3CD or PIK3R1, which dysregulate the PI3K–mTOR signaling pathway. Yet, in the real world, many patients present with ambiguous molecular findings, delaying precision treatment. The study followed 23 patients across 15 families with suspected or confirmed APDS. Genetic variants were classified using ACMG criteria, and functional assays were performed to probe mTOR pathway activation - critical in determining if a VUS truly drives disease.

Key Findings:

Three pathogenic PIK3CD variants were confirmed across seven patients (five carried the common p.Glu1021Lys hotspot); one VUS was successfully reclassified as pathogenic.

Two variants were deemed benign, avoiding unnecessary intervention, while others remain unresolved.

Similarly, three pathogenic PIK3R1 variants were validated, with additional missense VUS under study.

Of the confirmed APDS cases, five patients initiated or qualified for targeted therapy with leniolisib, the PI3Kδ inhibitor, though real-world access was hindered by age, weight, insurance, and communication barriers.

The takeaway: Functional testing - especially of the mTOR pathway - is crucial to distinguish pathogenic from benign variants, enabling rational use of targeted therapies. As this study shows, variant interpretation is not just an academic exercise; it directly determines who gains access to transformative precision treatments.

References:

https://www.sciencedirect.com/science/article/pii/S0091674925019815