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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
Primary immunodeficiency or monogenic inflammatory bowel disease v4.57 MCTS1 Boaz Palterer gene: MCTS1 was added
gene: MCTS1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: MCTS1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Phenotypes for gene: MCTS1 were set to MSMD; non tubercular mycobacteria infection; BCGtis; BCG infection
Penetrance for gene: MCTS1 were set to Complete
Review for gene: MCTS1 was set to GREEN
Added comment: Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria
https://doi.org/10.1016/j.cell.2023.09.024

Bohlen et al. identified 6 male subjects from 5 kindreds with LOF MCTS-1 variants with MSMD.
Extensive ex-vivo functional validation and mouse model.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.221 AK2 Eleanor Williams Classified gene: AK2 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.221 AK2 Eleanor Williams Added comment: Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.
Primary immunodeficiency or monogenic inflammatory bowel disease v2.221 AK2 Eleanor Williams Gene: ak2 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 AK2 Eleanor Williams Source Other was added to AK2.
Publications for gene AK2 were updated from 19043416; 19043417 to 19043416; 19043417
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 AK2 Eleanor Williams reviewed gene: AK2: Rating: ; Mode of pathogenicity: ; Publications: 19043417; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 AK2 Louise Daugherty commented on gene: AK2: Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is enough evidence to rate this gene Green.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 AK2 Louise Daugherty commented on gene: AK2: Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is enough evidence to rate this gene Green.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 AK2 Kimberly Gilmour commented on gene: AK2: agree with green gene
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 AK2 Tracy Briggs reviewed gene: AK2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v1.60 AK2 Louise Daugherty Source NHS GMS was added to AK2.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.59 AK2 Louise Daugherty Source North West GLH was added to AK2.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.58 AK2 Louise Daugherty Source London North GLH was added to AK2.
Primary immunodeficiency or monogenic inflammatory bowel disease AK2 Louise Daugherty commented on gene: AK2
Primary immunodeficiency or monogenic inflammatory bowel disease AK2 Louise Daugherty marked gene: AK2 as ready
Primary immunodeficiency or monogenic inflammatory bowel disease AK2 Louise Daugherty commented on AK2
Primary immunodeficiency or monogenic inflammatory bowel disease AK2 Louise Daugherty commented on AK2
Primary immunodeficiency or monogenic inflammatory bowel disease AK2 Louise Daugherty reviewed AK2
Primary immunodeficiency or monogenic inflammatory bowel disease AK2 Louise Daugherty Added gene to panel