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

Abstract

SummaryThe gene PIK3CD codes for the catalytic subunit of phosphoinositide 3-kinase d (PI3Kd), 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 PI3Kd 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.

PI3Kδ and primary immunodeficiencies

“…The US cohort were identified on the basis of persistent viremia with herpes-family viruses, which are commonly associated with altered T cell or natural killer (NK) cell function, in addition to frequent airway infections2. Because both B cells and T cells are affected in these patients, APDS should be characterised as a combined immunodeficiency1–5.…”

“…Many patients develop benign lymphadenopathy, often associated with hepatosplenomegaly, and there is a substantially increased risk of B cell lymphoma associated with APDS (Box 1). Increased susceptibility to viral infection and poor recall responses of memory T cells differentiate APDS from isolated hypogammaglobulinemia 1–4, hence APDS should be considered a combined immunodeficiency5. More than 100 patients have been reported to date with APDS, but the precise incidence is not yet known6, 7.…”

Old and new faces of neutropenia in children

“…37 Of note, patients formerly diagnosed with one of the above diseases were recently found to have an abnormal T-cell hyperproliferation due to pathogenic mutations upregulating mTor (mammalian target of rapamycin), 39 as in the case of the defective function of phosphoinositide 3-kinase δ (PI3Kδ). 40 Other mutations may either generate deficiency of the suppressing T-cell molecule CTLA-4, 41 or impair its exposure on the cell membrane because of the deficiency of another anchor protein named LRBA (LPSResponsive beige-like anchor protein deficiency). 42 These immune dysregulation diseases have a heterogeneous clinical phenotype which may include neutropenia.…”

Activated PI3-kinase δ Syndrome: Long-term Follow-up after Cord Blood Transplantation

“…To the Editor It has recently been reported that mutations in the PI3Kδ gene can lead to a hyperactive enzyme and induce a primary immune deficiency called activated PI3Kδ syndrome (APDS) or p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI) disease [1][2][3][4][5][6]. Mutations in either the catalytic subunit gene PIK3CD [1,4] or regulatory subunit gene PIK3R1 [2,5,6] can cause a similar disease.…”

“…Hyper activated PI3Kδ disorders remain a rare cause of immune deficiency, presenting as CID or hyper-IgM syndromes. We therefore suggest that these patients without a molecular diagnosis should be assessed for mutations in PIK3CD and PIK3R1 [3]. The oncogenic risk in APDS also needs to be monitored carefully over time, especially since some patients with APDS developed B cell lymphoma [4], but no cases of leukemia or solid tumor have been reported to date.…”