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Primary immunodeficiency or monogenic inflammatory bowel disease v9.81 SH2B3 Achchuthan Shanmugasundram Classified gene: SH2B3 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v9.81 SH2B3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are over 10 unrelated patients with biallelic SH2B3 germline variants and with myeloproliferation and autoimmunity. Hence, this gene can be promoted to green rating in the next GMS update.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.81 SH2B3 Achchuthan Shanmugasundram Gene: sh2b3 has been classified as Amber List (Moderate Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.80 SH2B3 Achchuthan Shanmugasundram Tag Q3_26_promote_green tag was added to gene: SH2B3.
Primary immunodeficiency or monogenic inflammatory bowel disease v9.80 SH2B3 Achchuthan Shanmugasundram changed review comment from: PMID:23908464 (2013) reported two siblings from a consanguineous family of Eastern European Ashkenazi Jewish descent presenting with growth retardation, mild developmental delay, chronic hepatitis, and Hashimoto autoimmune thyroiditis. One of them (sister) developed B-precursor acute lymphoblastic leukemia (ALL). They were identified with germline homozygous frameshift variant in SH2B3 gene (c.671insGGCCCCG/ p. Asp231Gly fs*38).

PMID:37206266 (2023) reported two further unrelated families with biallelic loss-of-function variants in SH2B3 gene (c.441_468del/ p.Arg148Profs*40 in patient 1 and c.1204G>A/ p.Val402Met in patient 2). These patients showed striking phenotypic similarity to each other as well as to the previous family from PMID:23908464 (2013) - presenting with myeloproliferation and multi-organ autoimmunity. One of these probands also suffered severe thrombotic complications. CRISPR-Cas9 gene editing of zebrafish sh2b3 created assorted deleterious variants in F0 crispants, which manifested significantly increased number of macrophages and thrombocytes, partially replicating the human phenotype.

PMID:40481232 (2025) reported ten patients with Germline SH2B3 variants, which included biallelic variants in eight patients (homozygous in seven and compound heterozygous in one) and monoallelic variants in two. However, both patients with germline heterozygous variants had homozygous variants in hematopoietic cells. Of the ten patients, eight (six with biallelic and two with monoallelic germline variants) presented with a myeloproliferative disease characterized by leukocytosis with a leukoerythoblastic picture, low blast percentage in BM and splenomegaly, at birth or in the first months of life.

Biallelic variants in this gene has not yet been associated with any relevant phenotypes in OMIM (last accessed 07 August 2026). This gene has been associated with Semidominant inheritance for SH2B3-related immune system disorder (MONDO:1060195) by Childhood, Adolescent and Young Adult Cancer Predisposition GCEP on ClinGen with 'Definitive' rating (https://search.clinicalgenome.org/CCID:009335).; to: PMID:23908464 (2013) reported two siblings from a consanguineous family of Eastern European Ashkenazi Jewish descent presenting with growth retardation, mild developmental delay, chronic hepatitis, and Hashimoto autoimmune thyroiditis. One of them (sister) developed B-precursor acute lymphoblastic leukemia (ALL). They were identified with germline homozygous frameshift variant in SH2B3 gene (c.671insGGCCCCG/ p. Asp231Gly fs*38).

PMID:37206266 (2023) reported two further unrelated families with biallelic loss-of-function variants in SH2B3 gene (c.441_468del/ p.Arg148Profs*40 in patient 1 and c.1204G>A/ p.Val402Met in patient 2). These patients showed striking phenotypic similarity to each other as well as to the previous family from PMID:23908464 (2013) - presenting with myeloproliferation and multi-organ autoimmunity. One of these probands also suffered severe thrombotic complications. CRISPR-Cas9 gene editing of zebrafish sh2b3 created assorted deleterious variants in F0 crispants, which manifested significantly increased number of macrophages and thrombocytes, partially replicating the human phenotype.

PMID:40481232 (2025) reported ten patients with germline SH2B3 variants, which included biallelic variants in eight patients (homozygous in seven and compound heterozygous in one) and monoallelic variants in two. However, both patients with germline heterozygous variants had homozygous variants in hematopoietic cells. Of the ten patients, eight (six with biallelic and two with monoallelic germline variants) presented with a myeloproliferative disease characterized by leukocytosis with a leukoerythoblastic picture, low blast percentage in BM and splenomegaly, at birth or in the first months of life.

Biallelic variants in this gene has not yet been associated with any relevant phenotypes in OMIM (last accessed 07 August 2026). This gene has been associated with Semidominant inheritance for SH2B3-related immune system disorder (MONDO:1060195) by Childhood, Adolescent and Young Adult Cancer Predisposition GCEP on ClinGen with 'Definitive' rating (https://search.clinicalgenome.org/CCID:009335).
Primary immunodeficiency or monogenic inflammatory bowel disease v9.80 SH2B3 Achchuthan Shanmugasundram Publications for gene: SH2B3 were set to 37206266
Primary immunodeficiency or monogenic inflammatory bowel disease v9.79 SH2B3 Achchuthan Shanmugasundram Phenotypes for gene: SH2B3 were changed from Myeloproliferative disorder; Autoimmunity; Hepatosplenomegaly; Thrombosis; Autoimmune thyroiditis; Autoimmune hepatitis; Global developmental delay to SH2B3-related immune system disorder, MONDO:1060195
Primary immunodeficiency or monogenic inflammatory bowel disease v9.78 SH2B3 Achchuthan Shanmugasundram reviewed gene: SH2B3: Rating: GREEN; Mode of pathogenicity: None; Publications: 23908464, 37206266, 40481232; Phenotypes: SH2B3-related immune system disorder, MONDO:1060195; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 SH2B3 Boaz Palterer gene: SH2B3 was added
gene: SH2B3 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature,Expert list
Mode of inheritance for gene: SH2B3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SH2B3 were set to 37206266
Phenotypes for gene: SH2B3 were set to Myeloproliferative disorder; Autoimmunity; Hepatosplenomegaly; Thrombosis; Autoimmune thyroiditis; Autoimmune hepatitis; Global developmental delay
Penetrance for gene: SH2B3 were set to unknown
Review for gene: SH2B3 was set to RED
Added comment: Blombery et al. described 2 patients from 2 kindreds, harboring biallelic loss-of-function mutations in the SH2B3 gene. They presented with early-onset developmental delay, hepatosplenomegaly, multi-organ autoimmunity (including autoimmune thyroiditis and hepatitis), bone marrow myeloproliferation, and severe thrombotic complications. The underlying mechanism was validated ex vivo using patient-derived fibroblasts, demonstrating that upon stimulation with various cytokines (including IL-3, GH, GM-CSF, and EPO), the mutant cells exhibited significantly increased phosphorylation and hyperactivation of JAK2 and STAT5 signaling. The phenotype and mechanism were further validated in vivo using CRISPR-Cas9 engineered zebrafish animal models (sh2b3 F0 crispants). These models successfully recreated the myeloproliferative phenotype, presenting with a significantly increased number of macrophages and thrombocytes. Furthermore, rescue and treatment experiments demonstrated that administering the JAK1/2 inhibitor ruxolitinib to the mutant fish successfully intercepted and resolved the myeloproliferative defect.
Sources: Literature, Expert list