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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.102 | PSMB8 |
Achchuthan Shanmugasundram changed review comment from: There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with 'definitive' rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026). PMID:41253591 (2026) reported the identification of a novel de novo heterozygous PSMB8 variant, p.G209R (c.625G>A/C), identified in 8 unrelated patients (6/8 de novo, 2/8 assumed de novo) presenting with a chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/ proteasome-associated autoinflammatory syndrome (CANDLE/ PRAAS) phenotype featuring neonatal-onset systemic inflammation, panniculitis, lipodystrophy, cytopenias (anaemia 8/8, lymphopenia and hypogammaglobulinemia 7/8), recurrent viral/bacterial/fungal infections, and porto-sinusoidal vascular liver disease with nodular regenerative hyperplasia—phenotypically broader and more severe than biallelic PSMB8-CANDLE. Structural modelling, transfection, and knockout cell studies showed that the PSMB8 p.G209R variant sterically disrupts the β5i–β4 (PSMB2) interface, arresting propeptide processing and 20S maturation in ~75% of assembling immunoproteasomes—directly demonstrating a dominant-negative mechanism rather than simple haploinsufficiency. PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease. Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID. Monoallelic variants are not yet associated with any phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 13 August 2026).; to: There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with 'definitive' rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026). PMID:41253591 (2026) reported the identification of a novel de novo heterozygous PSMB8 variant, p.G209R (c.625G>A/C), identified in 8 unrelated patients (6/8 de novo, 2/8 assumed de novo) presenting with a chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/ proteasome-associated autoinflammatory syndrome (CANDLE/ PRAAS) phenotype featuring neonatal-onset systemic inflammation, panniculitis, lipodystrophy, cytopenias (anaemia 8/8, lymphopenia and hypogammaglobulinemia 7/8), recurrent viral/bacterial/fungal infections, and porto-sinusoidal vascular liver disease with nodular regenerative hyperplasia—phenotypically broader and more severe than biallelic PSMB8-CANDLE. Structural modelling, transfection, and knockout cell studies showed that the PSMB8 p.G209R variant sterically disrupts the β5i–β4 (PSMB2) interface, arresting propeptide processing and 20S maturation in ~75% of assembling immunoproteasomes, directly demonstrating a dominant-negative mechanism rather than simple haploinsufficiency. PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease. Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID. Monoallelic variants are not yet associated with any phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 13 August 2026). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.101 | PSMB8 |
Achchuthan Shanmugasundram changed review comment from: There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with 'definitive' rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026). PMID:41253591 (2026) reported the identification of a novel de novo heterozygous PSMB8 variant, p.G209R (c.625G>A/C), identified in 8 unrelated patients (6/8 de novo, 2/8 assumed de novo) presenting with a chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/ proteasome-associated autoinflammatory syndrome (CANDLE/ PRAAS) phenotype featuring neonatal-onset systemic inflammation, panniculitis, lipodystrophy, cytopenias (anaemia 8/8, lymphopenia and hypogammaglobulinemia 7/8), recurrent viral/bacterial/fungal infections, and porto-sinusoidal vascular liver disease with nodular regenerative hyperplasia—phenotypically broader and more severe than biallelic PSMB8-CANDLE. Structural modelling, transfection, and knockout cell studies showed that the PSMB8 p.G209R variant sterically disrupts the β5i–β4 (PSMB2) interface, arresting propeptide processing and 20S maturation in ~75% of assembling immunoproteasomes—directly demonstrating a dominant-negative mechanism rather than simple haploinsufficiency. PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease. Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID. Monoallelic variants are not yet associated with any phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 13 August 2026).; to: There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with 'definitive' rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026). PMID:41253591 (2026) reported the identification of a novel de novo heterozygous PSMB8 variant, p.G209R (c.625G>A/C), identified in 8 unrelated patients (6/8 de novo, 2/8 assumed de novo) presenting with a chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/ proteasome-associated autoinflammatory syndrome (CANDLE/ PRAAS) phenotype featuring neonatal-onset systemic inflammation, panniculitis, lipodystrophy, cytopenias (anaemia 8/8, lymphopenia and hypogammaglobulinemia 7/8), recurrent viral/bacterial/fungal infections, and porto-sinusoidal vascular liver disease with nodular regenerative hyperplasia—phenotypically broader and more severe than biallelic PSMB8-CANDLE. Structural modelling, transfection, and knockout cell studies showed that the PSMB8 p.G209R variant sterically disrupts the β5i–β4 (PSMB2) interface, arresting propeptide processing and 20S maturation in ~75% of assembling immunoproteasomes—directly demonstrating a dominant-negative mechanism rather than simple haploinsufficiency. PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease. Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID. Monoallelic variants are not yet associated with any phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 13 August 2026). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.101 | PSMB8 |
Achchuthan Shanmugasundram changed review comment from: PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease. Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID. There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with definitive rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026).; to: There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with 'definitive' rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026). PMID:41253591 (2026) reported the identification of a novel de novo heterozygous PSMB8 variant, p.G209R (c.625G>A/C), identified in 8 unrelated patients (6/8 de novo, 2/8 assumed de novo) presenting with a chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/ proteasome-associated autoinflammatory syndrome (CANDLE/ PRAAS) phenotype featuring neonatal-onset systemic inflammation, panniculitis, lipodystrophy, cytopenias (anaemia 8/8, lymphopenia and hypogammaglobulinemia 7/8), recurrent viral/bacterial/fungal infections, and porto-sinusoidal vascular liver disease with nodular regenerative hyperplasia—phenotypically broader and more severe than biallelic PSMB8-CANDLE. Structural modelling, transfection, and knockout cell studies showed that the PSMB8 p.G209R variant sterically disrupts the β5i–β4 (PSMB2) interface, arresting propeptide processing and 20S maturation in ~75% of assembling immunoproteasomes—directly demonstrating a dominant-negative mechanism rather than simple haploinsufficiency. PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease. Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID. Monoallelic variants are not yet associated with any phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 13 August 2026). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.99 | PSMB8 |
Achchuthan Shanmugasundram changed review comment from: PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease. There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with definitive rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026).; to: PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease. Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID. There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with definitive rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.93 | NFATC2 | Achchuthan Shanmugasundram Phenotypes for gene: NFATC2 were changed from progressive joint contractures; osteochondromas; B cell malignancy; diarrhea; chronic lung disease; hypogammaglobulinemia to ?Joint contracture, osteochondromas, and B-cell lymphoma, OMIM:620232; joint contractures, osteochondromas, and B-cell lymphoma, MONDO:0859369; lymphoproliferative syndrome, MONDO:0016537 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.87 | ZBTB7B | Achchuthan Shanmugasundram Phenotypes for gene: ZBTB7B were changed from inborn error of immunity, MONDO:0003778 to inborn error of immunity, MONDO:0003778; interstitial lung disease, MONDO:0015925; Global developmental delay, HP:0001263 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.86 | ZBTB7B | Achchuthan Shanmugasundram edited their review of gene: ZBTB7B: Changed phenotypes to: inborn error of immunity, MONDO:0003778, interstitial lung disease, MONDO:0015925, Global developmental delay, HP:0001263 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.85 | ZBTB7B | Achchuthan Shanmugasundram Phenotypes for gene: ZBTB7B were changed from CD4+ T-cell deficiency; Allergic disease; Interstitial lung disease; Corneal neovascularization; Corneal scarring; Global developmental delay; Growth failure to inborn error of immunity, MONDO:0003778 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.49 | FGR | Achchuthan Shanmugasundram Phenotypes for gene: FGR were changed from Autoinflammatory disease; Cutaneous vasculitis; Lung inflammation; Lung fibrosis; Interstitial lung disease to chronic recurrent multifocal osteomyelitis, MONDO:0009813; vasculitis, MONDO:0018882 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.27 | SEPT6 |
Ida Ertmanska edited their review of gene: SEPT6: Added comment: PMID: 42088107 Gunderman et al., 2026 2 male sibs with severe nonsyndromic congenital neutropenia, absent circulating B cells, marrow mature myeloid, and rare plasma cell accumulation, as well as tetraploidy, with disease reversal following myeloablative HSCT. Older sibling had T-cell receptor excision circles (TRECs) of 9 copies (normal >20), while younger brother had 0 copies. No infectious symptoms were present. WGS detected a hemizygous SEPTIN6 (NM_145799.4) c.1282T>A; p.*428Kext*9 variant in both brothers (het in the unaffected mother) - diagnosed with X-linked SEPTIN6-related immunodeficiency. PMID: 34677878 Renella et al., 2023 Report of a Caucasian male proband, presented with severe neutropenia associated with dysmyelopoiesis and tetraploidy as a newborn. The absolute neutrophil count (ANC) was 0.5 G/L at birth, subsequently 0-0.2 G/L. At age 1 year he underwent an allogeneic HLA-DQ-mismatched unrelated HSCT. WGS detected a hemizygous c.1282T>C, p.*428Glnext*9 variant in SEPT6. Second somatic SEPT6 variant was detected in cis: c.43C>T, p.Arg15* (14% of reads). This gene is not yet associated with a disease entity in OMIM, ClinGen, or G2P (accessed 29th July 2026).; Changed rating: AMBER; Changed publications to: 42088107, 34677878; Changed phenotypes to: severe congenital neutropenia, MONDO:0018542, Immunodeficiency, HP:0002721; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.27 | HCK | Ida Ertmanska Phenotypes for gene: HCK were changed from Autoinflammatory disease; Cutaneous vasculitis; Lung inflammation; Lung fibrosis; Interstitial lung disease to Autoinflammation with pulmonary and cutaneous vasculitis, OMIM:620296 autoinflammation with pulmonary and cutaneous vasculitis, MONDO:0957204 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v9.18 | ZBTB7B |
Boaz Palterer gene: ZBTB7B was added gene: ZBTB7B was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: ZBTB7B was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ZBTB7B were set to 40392549 Phenotypes for gene: ZBTB7B were set to CD4+ T-cell deficiency; Allergic disease; Interstitial lung disease; Corneal neovascularization; Corneal scarring; Global developmental delay; Growth failure Penetrance for gene: ZBTB7B were set to unknown Review for gene: ZBTB7B was set to RED Added comment: Vaseghi-Shanjani et al. described 1 patient from 1 kindred, harboring a de novo heterozygous mutation in the ZBTB7B gene encoding ThPOK. They presented with persistent CD4+ T cell deficiency, allergy, interstitial lung disease, corneal vascularization and scarring, developmental delay, and growth failure. The underlying mechanism and phenotype were validated in vitro using lentivirally transduced healthy control T cells and fibroblasts, demonstrating impaired T cell receptor activation and increased profibrotic gene expression. The study did not specify whether the phenotype was successfully recreated with complete knockout (KO) models or if the defect was corrected via rescue experiments. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.9 | NFATC2 |
Boaz Palterer gene: NFATC2 was added gene: NFATC2 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: NFATC2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NFATC2 were set to 35789258 Phenotypes for gene: NFATC2 were set to progressive joint contractures; osteochondromas; B cell malignancy; diarrhea; chronic lung disease; hypogammaglobulinemia Penetrance for gene: NFATC2 were set to unknown Review for gene: NFATC2 was set to RED Added comment: NFATC2 (also known as NFAT1) encodes the nuclear factor of activated T cells 2, a critical calcium/calcineurin-dependent transcription factor essential for T cell activation, immune homeostasis, and cell fate regulation. Sharma et al. identified 1 patient from 1 family carrying a homozygous pathogenic NFATC2 frameshift variant (p.Tyr675Thrfs*18) presenting with progressive joint contractures, osteochondromas, and B cell malignancy. Bustamante-Ogando et al. identified 1 patient from 1 family carrying compound heterozygous NFATC2 missense variants (p.Gly408Arg/p.Arg646Gln) presenting with severe early-onset immunodeficiency, recurrent sinopulmonary infections, bloody diarrhea, chronic lung disease, and pan-hypogammaglobulinemia. ( https://doi.org/10.70962/LASID2025abstract.69 ) Sources: Literature |
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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 |
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| 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 |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v9.5 | PLCG1 |
Ida Ertmanska gene: PLCG1 was added gene: PLCG1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Q2_26_promote_green tags were added to gene: PLCG1. Mode of inheritance for gene: PLCG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: PLCG1 were set to 37422272; 40862571 Phenotypes for gene: PLCG1 were set to ?Immune dysregulation, autoimmunity, and autoinflammation, OMIM:620514; immune dysregulation, autoimmunity, and autoinflammation, MONDO:0957790 Review for gene: PLCG1 was set to GREEN Added comment: PMID: 40862571 Ma et al., 2025 (based on pre-print mentioned in previous reviews) Report of seven individuals from 4 unrelated families with heterozygous missense variants in PLCG1: 3 individuals with de novo het variants: c.3056A>G, p.(Asp1019Gly)], [c.1139A>G, p.(His380Arg)] and [c.3494A>G, p.(Asp1165Gly)]. Individuals 4–7 are from the same family, and all carry the PLCG1 variant [c.1789C>T p.(Leu597Phe)]. Phenotypic spectrum: hearing loss (5/7, mild to profound), cardiac septal defects (3/6), and other less specific syndromic findings. Abnormal brain MRI findings in 2/3 assessed. Various immunological issues included: P3: T lymphocytopenia, recurrent pulmonary infections; P4: joint inflammation, tarsal synovitis, recurrent respiratory and lung infections, as well as inflammatory lymphadenopathy; P5: immune thrombocytopenic purpura, polyarthritis, autoimmune pulmonary fibrosis, pneumococcal sepsis with chronic thrombocytopenia and IgA and IgG2 deficiency; P6: history of recurrent upper respiratory and lung infections due to a mild IgA and IgG2 deficiency; PMID: 37422272 Tao et al., 2024 7yo female patient with a de novo p.S1021F variant in PLCG1 and early-onset immune dysregulation disease: recurrent skin ecchymosis, epistaxis and gingival bleeding, lymphadenopathy. No mention of hearing loss. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v8.99 | FGR |
Boaz Palterer gene: FGR was added gene: FGR was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: FGR was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: FGR were set to Autoinflammatory disease; Cutaneous vasculitis; Lung inflammation; Lung fibrosis; Interstitial lung disease Penetrance for gene: FGR were set to unknown Mode of pathogenicity for gene: FGR was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: FGR was set to RED Added comment: Price-Kuehne et al. described very large kindred with autosomal dominant Gain of function due to loss of regulatory tyrosine in FGR https://link.springer.com/article/10.1007/s10875-026-01998-z Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v8.73 | AIRE |
Ida Ertmanska changed review comment from: MONOALLELIC REPORTS: PMID: 11600535 Cetani et al., 2001 Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. No immunodeficiency noted. PMID: 29129473 Abbott et al., 2017 17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent. PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance. Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes. Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes. BIALLELIC REPORTS: PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia, Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. No immunodeficiency or inflammatory bowel disease was reported in the cohort (40 patients). AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025).; to: MONOALLELIC REPORTS: PMID: 11600535 Cetani et al., 2001 Italian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. Proband: 38yo female, diagnosed with idiopathic hypoparathyroidism at age 5 yrs; recurrent oral candidiasis since adolescence, enamel dysplasia. Affected individuals (either with hypothyroid autoimmune thyroiditis or APECED phenotype) were heterozygous for c.682G>T, p.(Gly228Trp) - variant not in gnomAD v4, Revel score = 0.74. Variant segregated with disease. Only the coding sequence of AIRE was investigated. PMID: 29129473 Abbott et al., 2017 17yo Caucasian man with type I diabetes (T1DM) onset at age 3; mother had rheumatoid arthritis; no immunodeficiency. Seq method: panel of 345 genes with known immunologic function; 6 candidate variants were identified, but c.739C>T, p.Arg247Cys was reported as diagnostic, also present in the mother. Variant is present in a heterozygous state in 48 individuals in gnomAD v4; Revel score = 0.45 (Uncertain). Anti-cytokine antibodies typically seen in APECED were absent. PMID: 37235056 Oftedal et al., 2023 11 unrelated patients with heterozygous AIRE mutations. Affected individuals presented with: Enteropathy, gastritis, UC (5/11), vitiligo (2/11), immunodeficiency (2/11), pernicious anemia (2/11). Some variants did not segregate with disease in the families - incomplete penetrance. Family VI - I-I - American male - het for c.977C>T, p.P326L - phenotype: Immunodeficiency, recurrent oropharyngeal candidiasis, migraines, and chronic diarrhea; negative for autoantibodies tested. Variant present in gnomAD v4 - 28 heterozygotes. Family XI, I-I - Danish male, het for c.1399G>C, p.G467R; phenotype: immunodeficiency; autoantibodies: Positive IgM RA, 21-OH, SSC, anti-GPIa-IIa, anti-GPIIb-IIIa, anti-GPIb-IX, anti-GPIV, otherwise negative. Variant present in gnomAD v4 - 112 heterozygotes. BIALLELIC REPORTS: PMID 19393987 Pavlic and Waltimo-Sirén, 2009 Patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type I (APS 1). Family 1 - female patient A, 9yo, oldest child of three siblings - compound heterozygote with R257X / 653-7_-5delCTC mutations in AIRE. Presented with hypoplastic enamel, hypoparathyroidism (HPT), hypoadrenocorticism, and chronic mucocutaneous candidiasis (CMC). Siblings asymptomatic, not genotyped. Family 2 - female proband (patient B) with APECED harboured compound het mutations in AIRE: p.Arg257Ter; p.Thr16Met. Unaffected family members were either carriers or WT. Similarly affected brother (patient C), who harboured the same variants in AIRE. Patient B presented with ectodermal dystrophy and HPT at age 5, and CMC at age 11. BIALLELIC: PMID: 25926518 Borgault et al., 2015 Report of 5 molecularly confirmed cases with APS1 (age range: 19 months–44 years). P3: female, c.967_c.979del13/c.967_c.979del13 - systemic findings: Mucocutaneous candidiasis, Hypoparathyoidism, Adrenal insufficiency, Osteopenia, Vitiligo, Sicca syndrome, Multiple bacterial/fungal infections PMID: 27253668 Bruserud et al., 2016 Report of fifty-two patients from 34 Norwegian families with biallelic variants in AIRE (relatedness?). Enamel hypoplasia, hypoparathyroidism, and CMC were the most frequent components. No immunodeficiency noted. PMID: 31905445 Suh et al., 2019 10yo female Korean patient; compound het for c.1513delG (p.Ala505ProfsTer16) and c.1360dupC (p.His454ProfsTer50); presented with Primary adrenal insufficiency, Chronic mucocutaneous candidiasis (since 6 months of age), Dental enamel dysplasia & Hyperpigmentation. PMID: 35521792 Cranston et al., 2022 Patient 15: age 19 at time of report, compound het. variants c.769C>T, p.(Arg257Ter); c.967_979del13, p.(Leu323fs) in AIRE. Presented with hypoparathyroidism, nail dystrophy, enamel hypoplasia, alopecia, tubulointerstitial nephritis. Patient 19: onset at age 6, homozygous for c.967_979del13, p.(Leu323fs) - Mutation associated with uniparental isodisomy. Phenotype: hypoparathyroidism, enamel hypoplasia, and adrenal insufficiency. No immunodeficiency or inflammatory bowel disease was reported in the cohort (40 patients). AIRE is linked to AR & AD Autoimmune polyendocrinopathy syndrome , type I, with or without reversible metaphyseal dysplasia, 240300 (OMIM, accessed 5th Nov 2025). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v8.7 | COPA | Arina Puzriakova Phenotypes for gene: COPA were changed from Autoimmune inflammatoy arthritis and interstial lung disease, 616414; Autoimmune interstitial lung disease-arthritis syndrome; COPA syndrome; Autoimmune inflammatory arthritis and interstitial lung disease with Th17 dysregulation and autoantibody production; Autoinflammatory Disorders to {Autoinflammation and autoimmunity, systemic, with immune dysregulation}, OMIM:616414 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v7.6 | RELB |
Achchuthan Shanmugasundram commented on gene: RELB: PMID:26385063 reported three male patients from a related kindred with primary immunodeficiency and with a homozygous truncating variant in RELB (p.Tyr397Ter). All had recurrent upper and lower respiratory infections, one had ecthyma gangrenosum and developed a polyarticular arthritis with joint swelling, and another had a urinary tract infection. PMID:36402602 reported three siblings presenting with predominately severe autoimmune manifestations involving the liver, gut, lung, and skin, as well as repeated infections. They were identified with homozygous p.Pro364Leu variant. PMID:39231201 reported two unrelated adult patients with either homozygous (p.Q72Tfs*152) or compound heterozygous (p.Glu145Lys & p.Pro364Leu) loss-of-function variants. Both of them presented with combined immunodeficiency with early-onset severe bacterial, viral, and fungal diseases. Functional evidence is also available from all three publications mentioned above. This gene has been associated with immunodeficiency phenotype in OMIM (MIM #617585). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v5.9 | IL6ST | Achchuthan Shanmugasundram Phenotypes for gene: IL6ST were changed from Hyper-IgE recurrent infection syndrome 4, autosomal recessive 618523; Stuve-Wiedemann-like syndrome: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response.; Hyper-IgE syndrome, autosomal dominant to Hyper-IgE syndrome 4A, autosomal dominant, with recurrent infections, OMIM:619752; ?Immunodeficiency 94 with autoinflammation and dysmorphic facies, OMIM:619750; Hyper-IgE syndrome 4B, autosomal recessive, with recurrent infections, OMIM:618523; Stuve-Wiedemann syndrome 2, OMIM:619751 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v4.197 | IKBKG | Arina Puzriakova Phenotypes for gene: IKBKG were changed from Immunodeficiency 33, 300636; Ectodermal dysplasia, hypohidrotic, with immune deficiency 300291; Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency, 300301; Immunodeficiency, isolated, 300584; Invasive pneumococcal disease, recurrent isolated, 2,300640; Defects of TLR/NFkappa-B signalling; Anhidrotic ectodermal dysplasia (in some), various infections (bacteria, mycobacteria, viruses and fungi), colitis, conical teeth, variable defects of skin, hair and teeth, monocyte dysfunction; Combined immunodeficiencies with associated or syndromic features to Ectodermal dysplasia and immunodeficiency 1, OMIM:300291; Immunodeficiency 33, OMIM:300636 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v4.193 | SMARCAL1 | Arina Puzriakova Added comment: Comment on phenotypes: Previous (overwritten) phenotypes: Schimke disease;Short stature, spondiloepiphyseal dysplasia, intrauterine growth retardation, nephropathy, bacterial, viral, fungal infections, may present as SCID, bone marrow failure;Combined immunodeficiencies with associated or syndromic features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v4.193 | SMARCAL1 | Arina Puzriakova Phenotypes for gene: SMARCAL1 were changed from Schimke immunoosseous dysplasia 242900; Schimke disease; Short stature, spondiloepiphyseal dysplasia, intrauterine growth retardation, nephropathy, bacterial, viral, fungal infections, may present as SCID, bone marrow failure; Combined immunodeficiencies with associated or syndromic features to Schimke immunoosseous dysplasia, OMIM:242900 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v4.163 | ANKZF1 |
Hannah Knight gene: ANKZF1 was added gene: ANKZF1 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: ANKZF1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: ANKZF1 were set to PMID: 28302725; PMID: 36857589 Phenotypes for gene: ANKZF1 were set to Inflammatory bowel disease Review for gene: ANKZF1 was set to AMBER Added comment: PMID: 28302725 (2017) identified two infantile-onset IBD patients with biallelic ANKZF1 variants + some functional work: One homozygous for R585Q - although this variant is very common in gnomAD One compound heterozygous for E152K and V32_Q87del Also two patients with one heterozygous variants PMID: 36857589 (2023) also identified a de novo variant (p.Leu415Val) in a young patient with IBD Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.553 | IKBKB | Arina Puzriakova Phenotypes for gene: IKBKB were changed from Immunodeficiency 15, 615592; Combined immunodeficiency; Recurrent bacterial, viral, fungal infections, opportunistic infections; Immunodeficiencies affecting cellular and humoral immunity to Immunodeficiency 15A, OMIM:618204 (AD); Immunodeficiency 15B, OMIM:615592 (AR); Combined immunodeficiency; Recurrent bacterial, viral, fungal infections, opportunistic infections; Immunodeficiencies affecting cellular and humoral immunity | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v2.550 | HCK |
Boaz Palterer gene: HCK was added gene: HCK was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: HCK was set to Unknown Publications for gene: HCK were set to 34536415 Phenotypes for gene: HCK were set to Autoinflammatory disease; Cutaneous vasculitis; Lung inflammation; Lung fibrosis; Interstitial lung disease Penetrance for gene: HCK were set to unknown Mode of pathogenicity for gene: HCK was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: HCK was set to RED Added comment: Kanderova et al. described a single patient with an autoinflammatory phenotype characterized by early-onset cutaneous vasculitis and lung inflammation leading to fibrosis. A de novo truncating mutation (p.Tyr515*) in the HCK leading to the loss of the C-terminal inhibitory tyrosine Tyr522 was identified. Variant pathogenicity was confirmed ex vivo in primary cells and in vitro in transduced cell lines. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.534 | MASP2 | Arina Puzriakova Phenotypes for gene: MASP2 were changed from Mannan-binding lectin serine protease (MASP) deficiency; Pyogenic infections, inflammatory lung disease, autoimmunity; Complement Deficiencies; MASP2 deficiency 613791 to MASP2 deficiency, OMIM:613791; Mannan-binding lectin serine protease (MASP) deficiency; Pyogenic infections, inflammatory lung disease, autoimmunity | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v2.521 | TMEM173 | Arina Puzriakova Phenotypes for gene: TMEM173 were changed from STING-associated vasculopathy, infantile-onset 615934; Type 1 interferonopathies; Skin vasculopathy, inflammatory lung disease, systemic autoinflammation and ICC, FCL; Autoinflammatory Disorders to STING-associated vasculopathy, infantile-onset, OMIM:615934; Type 1 interferonopathies; Skin vasculopathy, inflammatory lung disease, systemic autoinflammation and ICC; Autoinflammatory Disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v2.498 | RHBDF2 |
Boaz Palterer gene: RHBDF2 was added gene: RHBDF2 was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: RHBDF2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: RHBDF2 were set to Pneumonia; Colitis; Immunodeficiency Penetrance for gene: RHBDF2 were set to unknown Review for gene: RHBDF2 was set to RED Added comment: iRHOM deficiency with Respiratory and Intestinal inflammation and cytokine Secretion defect’ (IRIS): Kubo et al. (https://www.nature.com/articles/s41590-021-01093-y) described a new immunodeficiency disease due to loss-of-function mutations in RHBDF2, the gene encoding iRHOM2, in 4 subjects across two kindreds with recurrent infections in different organs. The disease presentation is pleiotropic, with one patient with recurrent pneumonia but no colon involvement, another had recurrent infectious hemorrhagic colitis but no lung involvement and the other two experienced recurrent respiratory infections. They replicated the phenotype in a KO mouse model and provided functional data. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.452 | ARHGAP42 |
Zornitza Stark gene: ARHGAP42 was added gene: ARHGAP42 was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: ARHGAP42 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARHGAP42 were set to 34232960 Phenotypes for gene: ARHGAP42 were set to Interstitial lung disease; systemic hypertension; immunological abnormalities Review for gene: ARHGAP42 was set to RED Added comment: Single individual reported with homozygous LoF variant, chILD disorder, systemic hypertension, and immunological findings. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.434 | IPO8 |
Ivone Leong Added comment: Comment on publications: PMID: 34010604. 12 individuals from 9 families. 11/12 dilatation of the ascending aorta, 6/12 other abnormalities in great vessels (including ascending aortic aneurysm and carotid artery tortuosity), 6/10 heart malformations, 9/12 dysmorphic features (including proptossi, micrognathia, hypertelorism, frontal bossing and abnormal palate), 12/12 skeletal abnormalities (including hyperlaxity, recurrent joint dislocations, scoliosis, pectus and arachnodactyly), 8/12 skin hyperextensibility, 11/12 umbilical hernia, 7/12 developmental delay or intellectual disability (did not mention severity), 2/12 retinal detachment, 3/12 bilateral cataract (one patient had it at age of 45), 3/3 hyperIgE and IgG, 3/4 hypoIgA, 4/5 hypereosinophilia, 5/12 intestinal inflammation and 6/12 allergic symptoms. Patients were aged between 1 year - 62 years old). PMID: 34010605. 7 individuals from 6 families. 7/7 dysmorphic features (including frontal bossing, hypertelorism, retrognathia and palate abnormalities), 7/7 skeletal findings (including arachnodactyly, joint hypermobility, scoliosis, pectus excavatum and pes planum), 7/7 developmental delay, 2/7 ID (1 mild ID and no severity for the other patient), 5/7 atrial septal defect, 4/7 ventricular septal defect, 6/7 cardiovascular abnormalities with aortic root and/orascending aortic aneurysm, 2/7 marked arterial tortuosity, 5/7 umbilical hernia, 2/7 bruise easily. Authors noted that despite patients having severe aneurysm phenotype none experienced arterial or aortic dissection and concluded that it may be because of the patients' young age (1 year - 19 years old). The study did not look at the immunological profile of the patients. The study also describes a knockout mouse model which recapitulates the human phenotype. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.413 | ZNFX1 |
Boaz Palterer edited their review of gene: ZNFX1: Added comment: Multisystem Inflammation and Susceptibility to Viral infections in Human ZNFX1 Deficiency 15 patients from 8 families with an autosomal recessive immunodeficiency characterized by severe infections by both RNA and DNA viruses and virally triggered inflammatory episodes with hemophagocytic-lymphohistiocytosis-like disease, early-onset seizures, as well as renal and lung disease. https://www.jacionline.org/article/S0091-6749(21)00613-8/fulltext; Changed rating: GREEN; Changed phenotypes: Multisystem inflammatory disoder, viral infections, HLH |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.196 | DOCK8 | Eleanor Williams Phenotypes for gene: DOCK8 were changed from Hyper-IgE recurrent infection syndrome, autosomal recessive; Hyper-IgE recurrent infection syndrome; impaired T cell function, Atopy, cutaneous viral infections; Combined immunodeficiency; Hyper IgE syndrome (HIES); Low NK cells with poor function, eosinophilia, recurrent infections, cutaneous viral, fungal and staphylococcal infections, severe atopy, cancer diathesis; Immunodeficiencies affecting cellular and humoral immunity to Hyper-IgE recurrent infection syndrome, autosomal recessive, 243700; Hyper-IgE recurrent infection syndrome; impaired T cell function, Atopy, cutaneous viral infections; Combined immunodeficiency; Hyper IgE syndrome (HIES); Low NK cells with poor function, eosinophilia, recurrent infections, cutaneous viral, fungal and staphylococcal infections, severe atopy, cancer diathesis; Immunodeficiencies affecting cellular and humoral immunity | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v2.157 | IL6ST | Sarah Leigh Phenotypes for gene: IL6ST were changed from Eosinophilia; Eczema; Bacterial infections, boiles, eczema, pulmonary abscesses, pneumatoceles, bone fractures, scoliosis, retention of primary teeth, craniosynostosis; Abnormal acute-phase responses; Recurrent infections; Elevated IgE; Combined immunodeficiencies with associated or syndromic features to Hyper-IgE recurrent infection syndrome 4, autosomal recessive 618523; Stuve-Wiedemann-like syndrome: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response.; Hyper-IgE syndrome, autosomal dominant | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v2.86 | IRF4 |
Zornitza Stark gene: IRF4 was added gene: IRF4 was added to Primary immunodeficiency. Sources: Expert list Mode of inheritance for gene: IRF4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: IRF4 were set to 29537367 Phenotypes for gene: IRF4 were set to Whipple's disease; [Skin/hair/eye pigmentation, variation in, 8] 611724 Review for gene: IRF4 was set to RED Added comment: Single family reported with Whipple's disease and a rare missense in IRF4. Younger healthy carrier members of the family had the same variant as older affected individuals, leading the authors to speculate about age-dependent penetrance. GWAS indicates separate link with skin/hair/eye pigmentation. Sources: Expert list |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 | ZNF341 | Zornitza Stark reviewed gene: ZNF341: Rating: GREEN; Mode of pathogenicity: None; Publications: 29907691, 29907690; Phenotypes: Hyper-IgE recurrent infection syndrome 3, autosomal recessive, MIM# 618282, Mild facial dysmorphism, Early onset eczema, Recurrent bacterial skin infections, abscesses, Recurrent respiratory infections, lung abscesses and pneumothoraces, Hyperextensible joints, bone fractures, retention of primary teeth; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 | IL6ST | Zornitza Stark reviewed gene: IL6ST: Rating: GREEN; Mode of pathogenicity: None; Publications: 32207811, 28747427, 30309848, 12370259, 16041381, 31914175; Phenotypes: Hyper-IgE recurrent infection syndrome 4, autosomal recessive, MIM# 618523, Stuve-Wiedemann-like syndrome: skeletal dysplasia, neonatal lung dysfunction, thrombocytopenia, dermatitis, defective acute-phase response., Hyper-IgE syndrome, autosomal dominant; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 | FCHO1 | Zornitza Stark reviewed gene: FCHO1: Rating: GREEN; Mode of pathogenicity: None; Publications: 32098969, 30822429; Phenotypes: Combined immunodeficiency, T cells: low, poor proliferation, B cells: normal number, Recurrent infections (viral, mycobacteria, bacterial, fungal), lymphoproliferation, Failure to thrive, Increased activation-induced T-cell death, Defective clathrin-mediated endocytosis; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v2.37 | TMEM173 |
Ellen McDonagh Added comment: Comment on publications: Additional evidence added to the publication list, provided by Abdelazeem Elhabyan. Comments from Abdelazeem Elhabyan: GenBank - https://www.ncbi.nlm.nih.gov/gene?term=(human%5BOrganism%5D)%20AND%20TMEM173%5BGene%20Name%5D) This gene encodes a five transmembrane protein that functions as a major regulator of the innate immune response to viral and bacterial infections. The encoded protein is a pattern recognition receptor that detects cytosolic nucleic acids and transmits signals that activate type I interferon responses. Hypothesis: This gene is involved in interferon 1 pathway which is directly related to viral innate immune response. Upregulation may be associated with a protective effect or autoinflammatory response with aggravating effect. This is to be determined by clinical trials. Highest organ of expression is the lung in genbank (Pneumonia caused by corona) RPKM ,\mean is 37 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069765/ Extracellular vesicles released by virally infected cells(HSV) that carry STING can induce protective effect against viral replication in neighbouring non infected cells https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146713/ Virulent Poxviruses Inhibit DNA Sensing by Preventing STING Activation https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5923072/ The gene is involved in acute pancreatitis in mice https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112120/ |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.34 | RHOH |
Louise Daugherty Source IUIS Classification December 2019 was added to RHOH. Added phenotypes HPV infection, lung granulomas, molluscum contagiosum, lymphoma; Immunodeficiencies affecting cellular and humoral immunity for gene: RHOH Publications for gene RHOH were updated from 22850876; 24189071 to 32048120; 22850876; 24189071; 32086639 |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.34 | MASP2 |
Louise Daugherty Source IUIS Classification December 2019 was added to MASP2. Added phenotypes Pyogenic infections, inflammatory lung disease, autoimmunity; Complement Deficiencies for gene: MASP2 Publications for gene MASP2 were updated from 24658431 to 32048120; 24658431; 32086639 |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v1.130 | RET | Louise Daugherty commented on gene: RET: MEN2 / MTC - ?relevant phenotype / Hirschsprung in LOF | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 | UNG | Louise Daugherty commented on gene: UNG: 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 | UNG | Louise Daugherty commented on gene: UNG: 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 | UNG | Kimberly Gilmour reviewed gene: UNG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 | UNG | Tracy Briggs reviewed gene: UNG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v1.79 | MASP2 | Louise Daugherty Phenotypes for gene: MASP2 were changed from to MASP2 deficiency 613791; Mannan-binding lectin serine protease (MASP) deficiency; Pyogenic infections, inflammatory lung disease, autoimmunity; Complement Deficiencies | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v1.77 | ERCC3 | Louise Daugherty Phenotypes for gene: ERCC3 were changed from MASP2 deficiency 613791; Mannan-binding lectin serine protease (MASP) deficiency; Pyogenic infections, inflammatory lung disease, autoimmunity; Complement Deficiencies to none | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v1.74 | ERCC3 | Louise Daugherty Phenotypes for gene: ERCC3 were changed from to MASP2 deficiency 613791; Mannan-binding lectin serine protease (MASP) deficiency; Pyogenic infections, inflammatory lung disease, autoimmunity; Complement Deficiencies | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v1.60 | UNG | Louise Daugherty Source NHS GMS was added to UNG. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v1.59 | UNG | Louise Daugherty Source North West GLH was added to UNG. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v1.58 | UNG | Louise Daugherty Source London North GLH was added to UNG. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | UNG | Louise Daugherty commented on gene: UNG | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | UNG | Louise Daugherty marked gene: UNG as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | UNG | Louise Daugherty classified UNG as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | UNG | Louise Daugherty edited their review of gene: UNG | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | UNG | Louise Daugherty commented on UNG | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | UNG | Louise Daugherty commented on UNG | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | UNG | Louise Daugherty commented on UNG | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | UNG | Louise Daugherty reviewed UNG | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | UNG | Louise Daugherty Added gene to panel | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||