Resolving the polygenic aetiology of a late onset combined immune deficiency caused by NFKB1 haploinsufficiency and modified by PIK3R1 and TNFRSF13B variants.

Hargreaves CE., Dhalla F., Patel AM., de Oteyza ACG., Bateman E., Miller J., Anzilotti C., Ayers L., Grimbacher B., Patel SY.

Genetic variants in PIK3CD, PIK3R1 and NFKB1 cause the primary immune deficiencies, activated PI3Kδ syndrome (APDS) 1, APDS2 and NFκB1 haploinsufficiency, respectively. We have identified a family with known or potentially pathogenic variants NFKB1, TNFRSF13B and PIK3R1. The study's aim was to describe their associated immune and cellular phenotypes and compare with individuals with monogenic disease. NFκB1 pathway function was measured by immunoblotting and PI3Kδ pathway activity by phospho-flow cytometry. p105/p50 expression was absent in two individuals but elevated pS6 only in the index case. Transfection of primary T cells demonstrated increased basal pS6 signalling due to mutant PIK3R1, but not mutant NFKB1 or their wildtype forms. We report on the presence of pathogenic variant NFKB1, with likely modifying variants in TNFRSF13B and PIK3R1 in a family. We describe immune features of both NFκB1 haploinsufficiency and APDS2, and the inhibition of excessive PI3K signalling by rapamycin in vitro.

DOI

10.1016/j.clim.2021.108910

Type

Journal article

Publication Date

2022-01-01T00:00:00+00:00

Volume

234

Keywords

Activated phosphoinositol 3-kinase delta syndrome, Combined immune deficiency, NF-kappaB1 haploinsufficiency, NFKB1, PIK3CD, PIK3R1, Adolescent, Adult, Class Ia Phosphatidylinositol 3-Kinase, Female, Haploinsufficiency, Humans, Immunologic Deficiency Syndromes, Male, Mutation, NF-kappa B p50 Subunit, Transmembrane Activator and CAML Interactor Protein, Young Adult

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