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

Abstract

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.

Figure 1

Spectrum of bronchial disease in family A siblings. Chest computed tomography (CT) scans of siblings 1, 2 and 3 (a,b,c) showing minimal bronchiectasis in sibling 1 (a), moderate bronchiectasis in sibling 2 (b) and unaffected lung tissue in sibling 3 (c).

Figure 2

Lung disease in sporadic patient 1 (SP1). Axial chest computed tomography (CT) scans of SP1 demonstrating pronounced bronchiectasis, mediastinal lymphadenopathy, peribronchial inflammation but no interstitial disease.

Figure 3

Massive splenomegaly in sporadic patient 1 (SP1). Ventral (a) and lateral (b) images of abdomen in SP1 showing massive splenomegaly.

Figure 4

Lung disease in sporadic patient 2 (SP2). Axial chest computed tomography (CT) scans of SP2 demonstrating mucus impaction of the left middle lobe, moderate bronchiectasis, interstitial disease and enlargement of mediastinal lymph nodes.