Identification of a novel de novo gain-of-function mutation of PIK3CD in a patient with activated phosphoinositide 3-kinase δ syndrome.

Activated phosphoinositide 3-kinase δ (PI3Kδ) syndrome is a newly defined and relatively common primary immunodeficiency, which is caused by heterozygous gain-of-function (GOF) mutations in PIK3CD or PIK3R1. Here, we report a novel de novo GOF mutation (c.1570 T > A, p.Y524N) in PIK3CD in a 6-year-old Chinese girl. The patient suffered recurrent sinopulmonary infection, bronchiectasis, lymphoproliferation, herpesvirus infection, and distinctive nodular lymphoid hyperplasia of mucosal surfaces. Immunological analysis revealed increased CD4+ T cell senescence and B cell immaturity. Further analysis revealed an increase in almost all CD4+ T cell subsets to varying degrees, including effector T cells and Treg cells. Increased levels of plasma T cell-related cytokines corroborated these results. Hyperactivation of the PI3Kδ-Akt-mTOR signaling pathway was also confirmed. Treatment with rapamycin ameliorated the lymphoproliferative immunodeficiency caused by hyperactivation of mTOR. These results expand genetic spectrum of APDS and will facilitate further study of the genotype-phenotype correlation in those with PIK3CD mutations.