AbstractSH2B3is a negative regulator of multiple cytokine receptor signalling pathways in haematopoietic tissue. To date, a single kindred has been described with germline biallelic loss‐of‐functionSH2B3variants characterized by early onset developmental delay, hepatosplenomegaly and autoimmune thyroiditis/hepatitis. Herein, we described two further unrelated kindreds with germline biallelic loss‐of‐functionSH2B3variants that show striking phenotypic similarity to each other as well as to the previous kindred of myeloproliferation and multi‐organ autoimmunity. One proband also suffered severe thrombotic complications. CRISPR‐Cas9 gene editing of zebrafishsh2b3created assorted deleterious variants in F0 crispants, which manifest significantly increased number of macrophages and thrombocytes, partially replicating the human phenotype. Treatment of thesh2b3crispant fish with ruxolitinib intercepted this myeloproliferative phenotype. Skin‐derived fibroblasts from one patient demonstrated increased phosphorylation of JAK2 and STAT5 after stimulation with IL‐3, GH, GM‐CSF and EPO compared to healthy controls. In conclusion, these additional probands and functional data in combination with the previous kindred provide sufficient evidence for biallelic homozygous deleterious variants inSH2B3to be considered a valid gene‐disease association for a clinical syndrome of bone marrow myeloproliferation and multi‐organ autoimmune manifestations.