D3.399 - An SYK Variant with Variable Spectrum of Immunodeficiency and Immune Dysregulation: Case Series

Spleen tyrosine kinase (SYK) is a pivotal molecule expressed in various immune cells and non-immune cells, including T and B lymphocytes, NK cells, macrophages, and intestinal epithelial cells. It is involved in signal transduction pathways that mediate immune and inflammatory activation. Mutations in SYK have been reported to be associated with primary immunodeficiency and autoinflammatory syndromes.

Following identification of the index case harboring the SYK variant, we retrospectively searched the previously sequenced genomic data within our institutional database for cases with the same SYK variant. Nine additional cases were gathered. Where necessary, patients were contacted to provide supplemental clinical and laboratory evaluation for further phenotypic characterization.

We describe a cohort of 10 patients carrying the same SYK variant, which has never been reported, with heterogeneous spectrum of manifestations ranging from asymptomatic to a significant immune dysfunction. Ages ranged from 10–77 years with variable onset of disease but the majority were adults. Around 60% had recurrent infections, 40% had autoimmunity and autoinflammatory syndromes (periodic fever, rash, arthritis, vitiligo, enteropathy, cytopenias, lymphadenopathy, organomegaly, recurrent first-trimester abortions, amyotrophic lateral sclerosis). Laboratory evaluation revealed immune abnormalities in 40% of the cases including hypogammaglobulinemia, combined T, B, or NK cell abnormalities, and elevated inflammatory markers.

The phenotypic variability observed in this small cohort is consistent with previous broad spectrum SYK-associated disorders, suggesting the potential pathogenicity of the identified variant. Further functional studies are underway to elucidate the biological impact of this variant.