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To date, a single kindred has been described with germline biallelic loss\u2010of\u2010function <jats:italic>SH2B3<\/jats:italic> variants characterized by early onset developmental delay, hepatosplenomegaly and autoimmune thyroiditis\/hepatitis. Herein, we described two further unrelated kindreds with germline biallelic loss\u2010of\u2010function <jats:italic>SH2B3<\/jats:italic> variants that show striking phenotypic similarity to each other as well as to the previous kindred of myeloproliferation and multi\u2010organ autoimmunity. One proband also suffered severe thrombotic complications. CRISPR\u2010Cas9 gene editing of zebrafish <jats:italic>sh2b3<\/jats:italic> created assorted deleterious variants in F0 crispants, which manifest significantly increased number of macrophages and thrombocytes, partially replicating the human phenotype. Treatment of the <jats:italic>sh2b3<\/jats:italic> crispant fish with ruxolitinib intercepted this myeloproliferative phenotype. Skin\u2010derived fibroblasts from one patient demonstrated increased phosphorylation of JAK2 and STAT5 after stimulation with IL\u20103, GH, GM\u2010CSF 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 in <jats:italic>SH2B3<\/jats:italic> to be considered a valid gene\u2010disease association for a clinical syndrome of bone marrow myeloproliferation and multi\u2010organ autoimmune manifestations.<\/jats:p>","DOI":"10.1002\/jha2.698","type":"journal-article","created":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T01:29:46Z","timestamp":1682904586000},"page":"463-469","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Biallelic deleterious germline <i>SH2B3<\/i> variants cause a novel syndrome of myeloproliferation and multi\u2010organ autoimmunity"],"prefix":"10.1002","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9902-0022","authenticated-orcid":false,"given":"Piers","family":"Blombery","sequence":"first","affiliation":[{"name":"Clinical Haematology Peter MacCallum Cancer Centre\/Royal Melbourne Hospital  Melbourne Victoria Australia"},{"name":"University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5337-778X","authenticated-orcid":false,"given":"Vahid","family":"Pazhakh","sequence":"additional","affiliation":[{"name":"Clinical Haematology Peter MacCallum Cancer Centre\/Royal Melbourne Hospital  Melbourne Victoria Australia"},{"name":"Australian Regenerative Medicine Institute Monash University  Clayton Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana S.","family":"Albuquerque","sequence":"additional","affiliation":[{"name":"Institute of Immunity and 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