Scalable generation and functional classification of genetic variants in inborn errors of immunity to accelerate clinical diagnosis and treatment.

ABSTRACT: Next-generation sequencing is pivotal for diagnosing inborn errors of immunity (IEI) but predominantly yields variants of uncertain significance (VUS), creating clinical ambiguity. Activated PI3Kδ syndrome (APDS) is caused by gain-of-function (GOF) variants in PIK3CD or PIK3R1, which encode the PI3Kδ heterodimer. We performed massively parallel base editing of PIK3CD/PIK3R1 in human T cells and mapped thousands of variants to a clinically important readout (phospho-AKT/S6), nominating >100 VUS and unannotated variants for functional classification and validating 27 hits. Leniolisib, an FDA-approved PI3Kδ inhibitor, rescued aberrant signaling and dysfunction in GOF-harboring T cells and revealed partially drug-resistant PIK3R1 hotspots that responded to novel combination therapies of leniol

SUBMITTER: Walsh ZH 

PROVIDER: S-EPMC12514753 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature