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Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 PTPN6 Boaz Palterer changed review comment from: Conference presentation CIS 2026 (https://clinimmsoc.org/BaseV69/CIS2026abstracts-FINAL.pdf)
Farsh Moussavi-Harami described in six children from four unrelated kindreds presenting with severe infant-onset hemolytic anemia, life-threatening inflammatory, lung disease, and severe pulmonary infections. Exome sequencing revealed biallelic coding variants in PTPN6. All SHP1 variants areabsent from gnomAD and are predicted to be damaging by multiple prediction algorithms. The variants are all clustered within the SHP1 phosphatase domain, which mediates the removal of phosphate groups from signaling proteins. Functional studies demonstrate that these variants destabilize SHP1 protein levels and markedly reduce or abolish the SHP1 phosphatase activity. These mutant SHP1 proteins also fail to appropriately downregulate ERK signaling following cell stimulation. Bulk RNA sequencing (RNA-seq) from one affected patient showedprofoundly heightened inflammatory gene signatures, placing this individual as an outlier relative to a pediatric septic shock cohort,particularly within IL-6/STAT3, TNFα/NFkB, and general inflammatory pathways. These findings parallel phenotypes observed in SHP1-deficient mouse models, which also develop hyperinflammatory disease and anemia due to loss of SHP1-mediated negative regulation.Collectively, these clinical and experimental data establish PTPN6 loss-of-function as the cause of a severe, newly recognized PIRD characterized by infant-onset severe anemia and life-threatening inflammatory pulmonary disease.
Sources: Other; to: Conference presentation CIS 2026 (https://doi.org/10.70962/cis2026abstract.18)
Farsh Moussavi-Harami described in six children from four unrelated kindreds presenting with severe infant-onset hemolytic anemia, life-threatening inflammatory, lung disease, and severe pulmonary infections. Exome sequencing revealed biallelic coding variants in PTPN6. All SHP1 variants areabsent from gnomAD and are predicted to be damaging by multiple prediction algorithms. The variants are all clustered within the SHP1 phosphatase domain, which mediates the removal of phosphate groups from signaling proteins. Functional studies demonstrate that these variants destabilize SHP1 protein levels and markedly reduce or abolish the SHP1 phosphatase activity. These mutant SHP1 proteins also fail to appropriately downregulate ERK signaling following cell stimulation. Bulk RNA sequencing (RNA-seq) from one affected patient showedprofoundly heightened inflammatory gene signatures, placing this individual as an outlier relative to a pediatric septic shock cohort,particularly within IL-6/STAT3, TNFα/NFkB, and general inflammatory pathways. These findings parallel phenotypes observed in SHP1-deficient mouse models, which also develop hyperinflammatory disease and anemia due to loss of SHP1-mediated negative regulation.Collectively, these clinical and experimental data establish PTPN6 loss-of-function as the cause of a severe, newly recognized PIRD characterized by infant-onset severe anemia and life-threatening inflammatory pulmonary disease.
Sources: Other
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 PTPN6 Boaz Palterer gene: PTPN6 was added
gene: PTPN6 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Other
Mode of inheritance for gene: PTPN6 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: PTPN6 were set to Autoimmune cytopenias; hemolytic anemia; interstitial lung disease
Penetrance for gene: PTPN6 were set to unknown
Review for gene: PTPN6 was set to GREEN
Added comment: Conference presentation CIS 2026 (https://clinimmsoc.org/BaseV69/CIS2026abstracts-FINAL.pdf)
Farsh Moussavi-Harami described in six children from four unrelated kindreds presenting with severe infant-onset hemolytic anemia, life-threatening inflammatory, lung disease, and severe pulmonary infections. Exome sequencing revealed biallelic coding variants in PTPN6. All SHP1 variants areabsent from gnomAD and are predicted to be damaging by multiple prediction algorithms. The variants are all clustered within the SHP1 phosphatase domain, which mediates the removal of phosphate groups from signaling proteins. Functional studies demonstrate that these variants destabilize SHP1 protein levels and markedly reduce or abolish the SHP1 phosphatase activity. These mutant SHP1 proteins also fail to appropriately downregulate ERK signaling following cell stimulation. Bulk RNA sequencing (RNA-seq) from one affected patient showedprofoundly heightened inflammatory gene signatures, placing this individual as an outlier relative to a pediatric septic shock cohort,particularly within IL-6/STAT3, TNFα/NFkB, and general inflammatory pathways. These findings parallel phenotypes observed in SHP1-deficient mouse models, which also develop hyperinflammatory disease and anemia due to loss of SHP1-mediated negative regulation.Collectively, these clinical and experimental data establish PTPN6 loss-of-function as the cause of a severe, newly recognized PIRD characterized by infant-onset severe anemia and life-threatening inflammatory pulmonary disease.
Sources: Other
Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 OSMR Boaz Palterer gene: OSMR was added
gene: OSMR was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature
Mode of inheritance for gene: OSMR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OSMR were set to 42221229
Phenotypes for gene: OSMR were set to Atopic dermatitis; eosinophilia; elevated IgE
Penetrance for gene: OSMR were set to unknown
Review for gene: OSMR was set to GREEN
Added comment: Samra et al. identified 10 affected individuals from seven unrelated families with germline biallelic loss-of-function variants in OSMR who shared a phenotype of early-onset, severe, widespread atopic dermatitis with peripheral eosinophilia and markedly elevated serum IgE. All patient-derived OSMRβ variants failed to localize to the cell surface, resulting in selective loss of OSM-dependent signaling. Patient cells showed markedly reduced OSM-induced phosphorylation of STAT1, STAT3, and STAT5, while signaling through other IL-6 family receptor complexes remained intact. Transcriptomic profiling of patient primary dermal fibroblasts revealed consistent downstream effects, including loss of interferon-responsive and inflammatory gene programs. Re-expression of wild-type OSMR restored receptor surface expression, STAT activation, and transcriptional responses, confirming a causal loss-of-function mechanism. Together, these findings establish biallelic OSMR deficiency as a novel primary atopic disorder.
Sources: Literature
Primary immunodeficiency or monogenic inflammatory bowel disease v2.314 STAT3 Eleanor Williams Classified gene: STAT3 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.314 STAT3 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 v2.314 STAT3 Eleanor Williams Gene: stat3 has been classified as Green List (High Evidence).
Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 STAT3 Eleanor Williams Source Other was added to STAT3.
Publications for gene STAT3 were updated from 17676033; 17881745; 25038750; 25359994 to 28402852; 25349174; 17881745; 17676033; 25359994; 25038750
Rating Changed from Green List (high evidence) to Red List (low evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 STAT3 Eleanor Williams edited their review of gene: STAT3: Added comment: The following PubMed IDs were added to entity STAT3: 25349174;28402852;25359994;25038750. These publications have been associated with OMIM phenotype MIM#615952, which is listed for this entity, by the immunedysregulation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.; Changed publications: 25349174, 28402852, 25359994, 25038750
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 STAT3 Louise Daugherty commented on gene: STAT3: 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 STAT3 Louise Daugherty edited their review of gene: STAT3: Added comment: 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.; Changed rating: GREEN
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 STAT3 Kimberly Gilmour reviewed gene: STAT3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 STAT3 Tracy Briggs reviewed gene: STAT3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Primary immunodeficiency or monogenic inflammatory bowel disease v1.60 STAT3 Louise Daugherty Source NHS GMS was added to STAT3.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.59 STAT3 Louise Daugherty Source North West GLH was added to STAT3.
Primary immunodeficiency or monogenic inflammatory bowel disease v1.58 STAT3 Louise Daugherty Source London North GLH was added to STAT3.
Primary immunodeficiency or monogenic inflammatory bowel disease STAT3 Louise Daugherty commented on gene: STAT3
Primary immunodeficiency or monogenic inflammatory bowel disease STAT3 Louise Daugherty marked gene: STAT3 as ready
Primary immunodeficiency or monogenic inflammatory bowel disease STAT3 Sophie Hambleton reviewed gene: STAT3
Primary immunodeficiency or monogenic inflammatory bowel disease STAT3 Eleanor Williams edited their review of STAT3
Primary immunodeficiency or monogenic inflammatory bowel disease STAT3 Eleanor Williams edited their review of STAT3
Primary immunodeficiency or monogenic inflammatory bowel disease STAT3 Eleanor Williams edited their review of STAT3
Primary immunodeficiency or monogenic inflammatory bowel disease STAT3 Eleanor Williams classified STAT3 as Green List (high evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease STAT3 Louise Daugherty classified STAT3 as Amber List (moderate evidence)
Primary immunodeficiency or monogenic inflammatory bowel disease STAT3 Louise Daugherty commented on STAT3
Primary immunodeficiency or monogenic inflammatory bowel disease STAT3 Louise Daugherty commented on STAT3
Primary immunodeficiency or monogenic inflammatory bowel disease STAT3 Louise Daugherty commented on STAT3
Primary immunodeficiency or monogenic inflammatory bowel disease STAT3 Louise Daugherty reviewed STAT3
Primary immunodeficiency or monogenic inflammatory bowel disease STAT3 Louise Daugherty Added gene to panel