Abstract
BACKGROUND: Inborn errors of immunity (IEI) affecting B-cell receptor signaling cause predominantly antibody deficiency (PAD) with varying degrees of severity. Recently, four heterozygous variants in SYK were reported to cause hypogammaglobulinemia, multiorgan inflammatory disease and diffuse large B-cell lymphoma. OBJECTIVE: We aimed to unravel the genetic and functional cause of PAD in a 43-year-old female presenting with hypogammaglobulinemia, congenital heart disease and pulmonary hypertension requiring lung transplantation. METHODS: Patient gDNA was subjected to whole-exome and Sanger sequencing. Blood B- and T-cell subsets, as well as tonic and antigen-receptor induced expression levels of phosphorylated-SYK, phosphorylated-ribosomal S6 and phosphorylated p38 were evaluated by flow cytometry. RESULTS: A novel heterozygous missense SYK variant was identified, mutating a residue in the protein kinase domain (c.1769G > A; p.R590Q), which is highly conserved across vertebrates. While total B- and T-cell numbers were within the normal range, the patient had reduced unswitched and class-switched memory B-cell numbers. Resting B cells from the patient demonstrated enhanced autophosphorylation of SYK, and tonic and ligand-induced phospho-S6 levels. Spontaneous SYK autophosphorylation, S6 and p38 phosphorylation were recapitulated in a pre-clinical cell model, i.e. expression of the SYK R590Q variant in HEK293T cells. CONCLUSIONS: We identified a novel gain-of-function variant in SYK to underlie hypogammaglobulinemia and atypical autoinflammatory disease. Flowcytometric screening for phospho-S6 in lymphocytes of IEI patients can guide genetic diagnosis of B-cell signaling abnormalities.