# Novel SYK Variant Causes Enhanced SYK Autophosphorylation and PI3K Activation in an Antibody-Deficient Patient

## TL;DR

A new SYK gene variant causes abnormal immune signaling and low antibody levels in a patient with a rare immune disorder.

## Contribution

A novel SYK variant is identified that causes gain-of-function effects in B-cell receptor signaling.

## Key findings

- The SYK R590Q variant leads to enhanced autophosphorylation and PI3K/MAPK signaling in B cells.
- Flow cytometry of phospho-S6 can help diagnose B-cell signaling defects in immune disorders.
- The patient had reduced memory B cells and atypical autoinflammatory disease features.

## Abstract

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.

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.

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.

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.

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.

The online version contains supplementary material available at 10.1007/s10875-025-01950-7.

A novel monoallelic missense variant in SYK is identified in a patient with hypogammaglobulinemia and atypical autoinflammatory disease.Increased SYK autophosphorylation and enhanced tonic PI3K and MAPK signaling are indicative of a gain-of-function effect.Flowcytometric detection of phosphorylated S6 can provide a rapid functional evaluation of genetic variants affecting B-cell receptor signaling.

A novel monoallelic missense variant in SYK is identified in a patient with hypogammaglobulinemia and atypical autoinflammatory disease.

Increased SYK autophosphorylation and enhanced tonic PI3K and MAPK signaling are indicative of a gain-of-function effect.

Flowcytometric detection of phosphorylated S6 can provide a rapid functional evaluation of genetic variants affecting B-cell receptor signaling.

The online version contains supplementary material available at 10.1007/s10875-025-01950-7.