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Spleen Tyrosine Kinase (SYK) is a critical immune signaling molecule and therapeutic target. We identified damaging monoallelic SYK variants in six patients with immune deficiency, systemic disease such as colitis, arthritis and skin inflammation, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling indicating gain-of-function. A knock-in (SYK S544Y ) mouse model of a patient variant (p.S550Y) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wildtype mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease.

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