Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency

Clin Exp Immunol. 2016 Feb;183(2):221-9. doi: 10.1111/cei.12706. Epub 2015 Nov 9.


The gene PIK3CD codes for the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), and is expressed solely in leucocytes. Activating mutations of PIK3CD have been described to cause an autosomal dominant immunodeficiency that shares clinical features with common variable immunodeficiency (CVID). We screened a cohort of 669 molecularly undefined primary immunodeficiency patients for five reported mutations (four gain-of-function mutations in PIK3CD and a loss of function mutation in PIK3R1) using pyrosequencing. PIK3CD mutations were identified in three siblings diagnosed with CVID and two sporadic cases with a combined immunodeficiency (CID). The PIK3R1 mutation was not identified in the cohort. Our patients with activated PI3Kδ syndrome (APDS) showed a range of clinical and immunological findings, even within a single family, but shared a reduction in naive T cells. PIK3CD gain of function mutations are more likely to occur in patients with defective B and T cell responses and should be screened for in CVID and CID, but are less likely in patients with a pure B cell/hypogammaglobulinaemia phenotype.

Keywords: B cells; PI3Kδ; common variable immunodeficiency; hypogammaglobulinaemia; primary immunodeficiency.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Agammaglobulinemia / diagnosis
  • Agammaglobulinemia / genetics
  • Agammaglobulinemia / immunology
  • B-Lymphocytes / immunology
  • Child
  • Class I Phosphatidylinositol 3-Kinases / genetics*
  • Class I Phosphatidylinositol 3-Kinases / metabolism*
  • Common Variable Immunodeficiency / genetics*
  • Common Variable Immunodeficiency / immunology
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunologic Deficiency Syndromes / genetics*
  • Immunologic Deficiency Syndromes / immunology
  • Immunophenotyping
  • Male
  • Middle Aged
  • Mutation*
  • Siblings
  • T-Lymphocytes / immunology
  • Young Adult


  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CD protein, human