Background: Activated phosphoinositide3-kinase (PI3K) _ syndrome 1 (APDS1) is a novel inborn errors of immunity (IEIs) caused by heterozygous gain of function mutations in PI3K_ catalytic p110_ (PIK3CD). APDS1 has a spectrum of clinical manifestations. Recurrent respiratory infections, lymphoproliferation, hepatosplenomegaly , hyper-IgM syndrome and autoimmunity are the common symptoms of this disease. Case presentation: Patient 1 presented with recurrent respiratory infections, hepatosplenomegaly and hyperIgM syndrome. Patient 2 developed early onset systemic lupus erythematosus (SLE)-like disease with resistant thrombocytopenia. c.3061 G>A and c.2314G>A variants in the PIK3CD gene were detected by whole exome sequencing in two patients respectively . c.2314G>A variant in PIK3CD gene of patient 2 is a newly report. After genetic diagnosis, two patients received sirolimus treatment and sirolimus alleviated clinical manifestations, including hepatosplenomegaly in patient 1 and thrombocytopenia in patient 2. Conclusion: Genetics diagnosis should be considered in patients with complicated clinical manifestations with no or insufficient response to the conventional therapies. If whole exome sequencing suggests a variant in PIK3CD gene, sirolimus may relieve hepatosplenomegaly and resistant thrombocytopenia. This is the first report of c.2314G>A variant in PIK3CD gene. 387