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| Primary immunodeficiency or monogenic inflammatory bowel disease v4.190 | LCP2 | Achchuthan Shanmugasundram Phenotypes for gene: LCP2 were changed from SCID; combined T and B cell immunodeficiency; severe neutrophil defects; impaired platelet aggregation to ?Immunodeficiency 81, OMIM:619374 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v4.182 | SCGN |
Achchuthan Shanmugasundram changed review comment from: As reviewed by Hannah Knight, PMID:31663849 reported three siblings with homozygous missense SCGN variant and with early-onset ulcerative colitis. Functional studies demonstrated that SCGN variant identified impacted the localisation of the SNARE complex partner, SNAP25, leading to impaired hormone release. In addition, SCGN knockout mouse model recapitulated impaired hormone release and susceptibility to DSS-induced colitis. This gene has not been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: As reviewed by Hannah Knight, PMID:31663849 reported three siblings with homozygous missense SCGN variant and with early-onset ulcerative colitis. Functional studies demonstrated that SCGN variant identified impacted the localisation of the SNARE complex partner, SNAP25, leading to impaired hormone release. In addition, SCGN knockout mouse model recapitulated impaired hormone release and susceptibility to DSS-induced colitis. This gene has not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v4.167 | STAT4 | Achchuthan Shanmugasundram Phenotypes for gene: STAT4 were changed from Paracoccidioidomycosis; Impaired IFN-γ Immunity; {Systemic lupus erythematosus, susceptibility to, 11}, 612253 to Disabling pansclerotic morphea of childhood, OMIM:620443; {Systemic lupus erythematosus, susceptibility to, 11}, OMIM:612253 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v4.80 | TFRC |
Achchuthan Shanmugasundram changed review comment from: PMID:26642240 - c.58T>C (p.Tyr20His) variant was present in homozygous state in patients A1 and A2 from the family from Kuwait and unaffected father had the same variant in heterozygous state. This variant segregated perfectly with the combined immunodeficiency phenotype in 34 available family members and was absent from multiple variant databases and 731 genotyped controls. The same homozygous variant was found in patient B1 from Western Saudi Arabian family, while this variant was present in heterozygous state in his parents and his sister. Although the families were from different geographic regions and not known to be related, Patient B1 shares a homozygous haplotype with the five genotyped patients from Family A across a 3.3 Mb interval at chromosome 3q29-ter that includes TFRC, suggesting identical by descent inheritance of the mutation from an unknown common ancestor. Functional evidence shows that this substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts. In addition, transgenic mice homozygous for the human TFRC mutation Y20H were viable and recapitulated the human phenotype. PMID:32851577 - Eight patients from six different tribes of Arab descent were identified with the same previously reported homozygous variant (p.Tyr20His) and they all presented with recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive in early life. This gene has been associated with relevant phenotypes in both OMIM (MIM #616740) and Gene2Phenotype (with 'limited' rating in the DD panel).; to: PMID:26642240 - c.58T>C (p.Tyr20His) variant was present in homozygous state in patients A1 and A2 from the family from Kuwait and unaffected father had the same variant in heterozygous state. This variant segregated perfectly with the immunodeficiency phenotype in 34 available family members and was absent from multiple variant databases and 731 genotyped controls. The same homozygous variant was found in patient B1 from Western Saudi Arabian family, while this variant was present in heterozygous state in his parents and his sister. Although the families were from different geographic regions and not known to be related, Patient B1 shares a homozygous haplotype with the five genotyped patients from Family A across a 3.3 Mb interval at chromosome 3q29-ter that includes TFRC, suggesting identical by descent inheritance of the mutation from an unknown common ancestor. Functional evidence shows that this substitution disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 expression on the cell surface. Iron citrate rescued the lymphocyte defects, and expression of wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts. In addition, transgenic mice homozygous for the human TFRC mutation Y20H were viable and recapitulated the human phenotype. PMID:32851577 - Eight patients from six different tribes of Arab descent were identified with the same previously reported homozygous variant (p.Tyr20His) and they all presented with recurrent sinopulmonary infections, chronic diarrhea, and failure to thrive in early life. This gene has been associated with relevant phenotypes in both OMIM (MIM #616740) and Gene2Phenotype (with 'limited' rating in the DD panel). |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v4.52 | RELA | Achchuthan Shanmugasundram Phenotypes for gene: RELA were changed from Mucocutaneous ulceration, chronic, 618287; RelA haplosufficiency; Mucosal ulceration, impaired NFkB activation; Immunodeficiencies affecting cellular and humoral immunity to Autoinflammatory disease, familial, Behcet-like-3, OMIM:618287 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v4.25 | ARPC5 | Achchuthan Shanmugasundram Phenotypes for gene: ARPC5 were changed from immunodeficiency; autoimmunity; inflammation; dysmorphisms; impaired wound healing; scoliosis; pneumatoceles; anemia to combined immunodeficiency, MONDO:0015131 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v4.22 | ARPC5 |
Boaz Palterer gene: ARPC5 was added gene: ARPC5 was added to Primary immunodeficiency or monogenic inflammatory bowel disease. Sources: Literature Mode of inheritance for gene: ARPC5 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ARPC5 were set to immunodeficiency; autoimmunity; inflammation; dysmorphisms; impaired wound healing; scoliosis; pneumatoceles; anemia Penetrance for gene: ARPC5 were set to unknown Review for gene: ARPC5 was set to GREEN Added comment: Nunes-Santos et al. described 2 unrelated patients from 2 kindreds woith germline biallelic null mutations in ARPC5 presenting with a complex actinopathy phenotype of increased susceptibility to infections, autoimmunity, inflammation, and dysmorphisms. There is strong biological rationale: ARPC5 is part of the Arp2/3 complex, related to WAS in Wiskott-Aldrich syndrome and ARPC1B deficiency. Strong functional ex vivo and in vitro data is presented. ( https://doi.org/10.1038/s41467-023-39272-0 ) Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.526 | TLR8 |
Zornitza Stark changed review comment from: PMID 34981838: Monozygotic male twins, hemizygous for the G572V (maternally inherited), who had severe autoimmune haemolytic anaemia (AIHA) worsening with infections, and autoinflammation presenting as fevers, enteritis, arthritis and CNS vasculitis. Functional showed variant causes impaired stability of the TLR8 protein, cross-reactivity to TLR7 ligands and reduced ability of TLR8 to attenuate TLR7 signaling.; to: PMID 34981838: Monozygotic male twins, hemizygous for the G572V (maternally inherited), who had severe autoimmune haemolytic anaemia (AIHA) worsening with infections, and autoinflammation presenting as fevers, enteritis, arthritis and CNS vasculitis. Functional showed variant causes impaired stability of the TLR8 protein, cross-reactivity to TLR7 ligands and reduced ability of TLR8 to attenuate TLR7 signaling. Further evidence for germline variants causing disease. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.526 | CRACR2A |
Zornitza Stark gene: CRACR2A was added gene: CRACR2A was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: CRACR2A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CRACR2A were set to PMID:34908525 Phenotypes for gene: CRACR2A were set to late onset combined immunodeficiency Review for gene: CRACR2A was set to RED Added comment: PMID:34908525 - one patient compound het (missense and PTC) with late onset combined immunodeficiency (current chest infections, panhypogammaglobulinemia and CD4+T cell lymphopenia). Functional studies showed defective JNK phosphorylation, defective SOCE and impaired cytokine production. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.524 | PSMB9 | Arina Puzriakova edited their review of gene: PSMB9: Added comment: Kanazawa et al., 2021 (PMID: 34819510) identified a further two unrelated Japanese patients with the same de novo PSMB9 heterozygous missense variant as that identified in the previous study (c.467G>A/p.G156D). Both individuals displayed severe autoinflammatory phenotypes and pulmonary hypertension and later also manifested combined immunodeficiency with periodic inflammatory exacerbation. The variant lead to impaired immunoproteasome maturation and activity, and the proteasome defect and immunodeficient phenotypes were recapitulated in Psmb9(G156D/+) mice.; Changed publications to: 33727065, 34819510; Changed phenotypes to: Proteasome-associated autoinflammatory syndrome 3, digenic, OMIM:617591 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v2.413 | MPEG1 |
Zornitza Stark gene: MPEG1 was added gene: MPEG1 was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: MPEG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: MPEG1 were set to 33224153; 33692780; 28422754 Phenotypes for gene: MPEG1 were set to Immunodeficiency 77, MIM# 619223 Review for gene: MPEG1 was set to GREEN gene: MPEG1 was marked as current diagnostic Added comment: Immunodeficiency-77 (IMD77) is an immunologic disorder characterized by recurrent and persistent polymicrobial infections with multiple unusual organisms. Skin and pulmonary infections are the most common, consistent with increased susceptibility to epithelial cell infections. The age at onset is highly variable: some patients have recurrent infections from childhood, whereas others present in late adulthood. The limited number of reported patients are all female, suggesting incomplete penetrance or a possible sex-influenced trait. Patient cells, mainly macrophages, show impaired killing of intracellular bacteria and organisms, including nontubercular mycobacteria, although there is also impaired killing of other organisms, such as Pseudomonas, Candida, and Aspergillus. Four individuals reported, functional data, including animal model. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.401 | MAP1LC3B2 |
Boaz Palterer gene: MAP1LC3B2 was added gene: MAP1LC3B2 was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: MAP1LC3B2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: MAP1LC3B2 were set to 33310865 Phenotypes for gene: MAP1LC3B2 were set to Mollaret’s meningitis; recurrent HSV2 meningitis Penetrance for gene: MAP1LC3B2 were set to unknown Review for gene: MAP1LC3B2 was set to RED Added comment: Hait et al. described a single patient with a rare heterozygous variant in MAP1LC3B2 presenting with recurrent HSV2 meningitis (Mollaret's meningitis). They showed that the mutations caused impaired HSV2-induced autophagy leading to increased viral replication and apoptosis of patient fibroblasts. The defect was rescued by the introduction of WT MAP1LC3B2 into patient fibroblasts. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.401 | ATG4A |
Boaz Palterer gene: ATG4A was added gene: ATG4A was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: ATG4A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ATG4A were set to 33310865 Phenotypes for gene: ATG4A were set to Mollaret’s meningitis; recurrent HSV2 meningitis Penetrance for gene: ATG4A were set to unknown Review for gene: ATG4A was set to RED Added comment: Hait et al. described a single patient with a rare heterozygous variant in ATG4 presenting with recurrent HSV2 meningitis (Mollaret's meningitis). They showed that the mutations caused impaired HSV2-induced autophagy leading to increased viral replication and apoptosis of patient fibroblasts. The defect was rescued by the introduction of WT ATG4 into patient fibroblasts. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.401 | POU2AF1 |
Boaz Palterer gene: POU2AF1 was added gene: POU2AF1 was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: POU2AF1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POU2AF1 were set to 33571536 Phenotypes for gene: POU2AF1 were set to Agammaglobulinemia; Immunodeficiency; Bob1 deficiency Penetrance for gene: POU2AF1 were set to unknown Review for gene: POU2AF1 was set to RED Added comment: Kury et al. described a single patient from consanguineous parents carrying a homozygous frameshift mutation in POU2AF1, encoding for Bob1, presenting with agammaglobulinemia with normal B cells. Functional data showed that Bob1 deficiency ex vivo and in a mouse KO model reduced B-cell responsiveness, impaired plasmablast formation and immunoglobulin secretion. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.392 | RHOG |
Boaz Palterer gene: RHOG was added gene: RHOG was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: RHOG was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RHOG were set to 33513601 Phenotypes for gene: RHOG were set to HLH; hemophagocytic lymphohistiocytosis Penetrance for gene: RHOG were set to unknown Review for gene: RHOG was set to RED Added comment: One patient with HLH and impaired cytotoxic T lymphocyte and natural killer (NK) cell exocytosis functions, bearing biallelic deleterious mutations in the RhoG gene. Experimental ablation of RHOG in a model cell line and primary CTLs confirmed that RhoG engages in a protein-protein interaction with Munc13-4, an exocytosis protein essential for cytotoxic granules fusion with the plasma membrane. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.392 | STXBP3 |
Kelsey Jones gene: STXBP3 was added gene: STXBP3 was added to Primary immunodeficiency. Sources: Expert Review Mode of inheritance for gene: STXBP3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: STXBP3 were set to PMID: 33346580 Phenotypes for gene: STXBP3 were set to Very Early Onset Inflammatory Bowel Disease; Sensorineural hearing loss Penetrance for gene: STXBP3 were set to unknown Review for gene: STXBP3 was set to AMBER Added comment: Described as a monogenic cause of VEOIBD (recognised criteria for the R15 panel) in a report published in abstract form (DOI: https://doi.org/10.1053/j.gastro.2017.11.120). 8 patients from 4 unrelated families with defects in STXBP3 reportedly associated with VEO-IBD, bilateral sensorineural hearing loss, and impaired cytotoxic T-lymphocyte function (granule release, stimulated CD107a upregulation). Included on a monogenic IBD gene panel proposed by The Paediatric IBD Porto Group of ESPGHAN (PMID: 33346580). Sources: Expert Review |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.379 | LCP2 |
Boaz Palterer gene: LCP2 was added gene: LCP2 was added to Primary immunodeficiency. Sources: Literature Mode of inheritance for gene: LCP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LCP2 were set to 33231617 Phenotypes for gene: LCP2 were set to SCID; combined T and B cell immunodeficiency; severe neutrophil defects; impaired platelet aggregation Penetrance for gene: LCP2 were set to unknown Review for gene: LCP2 was set to AMBER Added comment: One patient with severe combined immunodeficiency was found to have biallelic mutations in SLP76. Sources: Literature |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.368 | AP3D1 |
Eleanor Williams edited their review of gene: AP3D1: Added comment: Provisionally associated with Hermansky-Pudlak syndrome 10 #617050 (AR) in OMIM. PMID: 30472485 - Mohammad et al 2019 - 1 family with parents who were first cousins with three affected children who presented similarly with severe seizures, developmental delay, albinism, and immunodeficiency. Whole exome sequencing identified homozygosity for AP3D1 deleterious sequence variant (NM_001261826.3:c.1978delG: p.Ala660Argfs*54) which co-segregated with the phenotype. The variant is not found in the gnomAD database or in an in-house database of 284 exome or Middle Eastern population specific database. PMID: 26744459 - Ammann et al 2016 - report a patient with consanguineous Turkish parents presenting with albinism, neutropenia, immunodeficiency, neurodevelopmental delay, generalized seizures, and impaired hearing. Whole exome sequencing identified a homozygous mutation in AP3D1 (c.3565_3566delGT) that leads to destabilization of the adaptor protein 3 (AP3) complex.; Changed rating: AMBER; Changed phenotypes: Hermansky-Pudlak syndrome 10, 617050; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.220 | AIRE | Eleanor Williams Classified gene: AIRE as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v2.220 | AIRE | 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 v2.220 | AIRE | Eleanor Williams Gene: aire has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v2.209 | AIRE |
Eleanor Williams Source Other was added to AIRE. Publications for gene AIRE were updated from 28911151; 29437776; 29108822; 9398839; 9837820; 9888391; 10677297; 11836330; 19758376; 11600535; 19807739 to 19758376; 29949487; 29108822; 28257655; 19807739; 10677297; 9398839; 11600535; 29483906; 9888391; 28911151; 9735375; 11836330; 29437776; 9837820; 30565240 Rating Changed from Green List (high evidence) to Red List (low evidence) |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.208 | AIRE | Eleanor Williams reviewed gene: AIRE: Rating: ; Mode of pathogenicity: ; Publications: 29483906, 9735375, 28257655, 30565240, 29949487; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v2.203 | STAT4 | Arina Puzriakova Phenotypes for gene: STAT4 were changed from {Systemic lupus erythematosus, susceptibility to, 11}, 612253 to Paracoccidioidomycosis; Impaired IFN-γ Immunity; {Systemic lupus erythematosus, susceptibility to, 11}, 612253 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v2.199 | STAT4 | Boaz Palterer reviewed gene: STAT4: Rating: RED; Mode of pathogenicity: None; Publications: 29029192; Phenotypes: Paracoccidioidomycosis, Impaired IFN-γ Immunity; Mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v2.195 | MAGT1 | Eleanor Williams Phenotypes for gene: MAGT1 were changed from Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia; Chronic active EBV, lymphoproliferation, combined immunodeficiency, impaired t cell function; XMEN syndrome; Immunodeficiency, X-linked, with magnesium defect; Epstein-Barr virus infection and neoplasia (XMEN); Combined immunodeficiency; EBV infection, lymphoma, viral infections, respiratory and GI infections; Diseases of Immune Dysregulation; Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia, 300853 to Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia 300853; Chronic active EBV, lymphoproliferation, combined immunodeficiency, impaired t cell function; XMEN syndrome; Immunodeficiency, X-linked, with magnesium defect; Epstein-Barr virus infection and neoplasia (XMEN); Combined immunodeficiency; EBV infection, lymphoma, viral infections, respiratory and GI infections; Diseases of Immune Dysregulation | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v2.194 | MAGT1 | Eleanor Williams Phenotypes for gene: MAGT1 were changed from Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia; Chronic active EBV, lymphoproliferation, combined immunodeficiency, impaired t cell function; XMEN syndrome; Immunodeficiency, X-linked, with magnesium defect; Epstein-Barr virus infection and neoplasia (XMEN); Combined immunodeficiency; EBV infection, lymphoma, viral infections, respiratory and GI infections; Diseases of Immune Dysregulation to Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia; Chronic active EBV, lymphoproliferation, combined immunodeficiency, impaired t cell function; XMEN syndrome; Immunodeficiency, X-linked, with magnesium defect; Epstein-Barr virus infection and neoplasia (XMEN); Combined immunodeficiency; EBV infection, lymphoma, viral infections, respiratory and GI infections; Diseases of Immune Dysregulation; Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia, 300853 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v2.124 | BCL11B |
Eleanor Williams changed review comment from: Associated with Immunodeficiency 49 #617237 (AD) in OMIM. PMID: 29985992 - Lessel et al 2018 - identified de novo heterozygous germline mutations in BCL11B in nine unrelated patients, namely six frameshift, two nonsense and one missense mutation. A further patient inherited a heterozygous frameshift mutation, p.(Asp534Thrfs*29), transmitted from an affected mother with. All analysed individuals exhibited developmental delay and intellectual disability and a severe reduction of peripheral ILC2s and impaired T cell development, but no overt immune deficiency. Patient E:II-1 was the only patient with suspected immunodeficiency diagnosed upon newborn screening. Other de-novo variants were also detected in some patients. PMID: 27959755 - Punwani et al 2016 - an infant with "leaky" SCID as well as craniofacial and dermal abnormalities and the absence of a corpus callosum. Exome sequencing revealed a heterozygous de novo missense mutation, p.N441K, in BCL11B. The mutant protein had dominant negative activity, which prevented the wild-type BCL11B to bind DNA, thereby arresting development of the T-cell lineage and disrupting hematopoietic stem-cell migration. bcl11ba-deficient zebrafish recapitulated the phenotype.; to: Associated with Immunodeficiency 49 #617237 (AD) in OMIM. PMID: 29985992 - Lessel et al 2018 - identified de novo heterozygous germline mutations in BCL11B in nine unrelated patients, namely six frameshift, two nonsense and one missense mutation. A further patient inherited a heterozygous frameshift mutation, p.(Asp534Thrfs*29), transmitted from an affected mother with. All analysed individuals exhibited developmental delay and intellectual disability and a severe reduction of peripheral ILC2s and impaired T cell development, but no overt immune deficiency. Patient E:II-1, with a missense variant, was the only patient with suspected immunodeficiency diagnosed upon newborn screening. Other de-novo variants were also detected in some patients. PMID: 27959755 - Punwani et al 2016 - an infant with "leaky" SCID as well as craniofacial and dermal abnormalities and the absence of a corpus callosum. Exome sequencing revealed a heterozygous de novo missense mutation, p.N441K, in BCL11B. The mutant protein had dominant negative activity, which prevented the wild-type BCL11B to bind DNA, thereby arresting development of the T-cell lineage and disrupting hematopoietic stem-cell migration. bcl11ba-deficient zebrafish recapitulated the phenotype. |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.53 | NFKBID | Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. The only variants are structural rearrangements that include NFKBID amongst other genes. PMID 26973645 reports "heterozygous mutation in the nfkbid gene encoding the atypical IκB protein IκBNS led to reduced steady state IgM and IgG3 antibody levels and impaired response to vaccination with TI-2 antigens in mice". Thus, variants in human NFKBID may also result in reduced levels of IgM and IgG3 and compromized vaccination responses. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 | REL | Zornitza Stark reviewed gene: REL: Rating: RED; Mode of pathogenicity: None; Publications: 31103457; Phenotypes: Combined immunodeficiency, T cells: normal, decreased memory CD4, poor proliferation, B cells: low, mostly naive, few switched memory B cells, impaired proliferation, Recurrent infections with bacteria, mycobacteria, salmonella and opportunistic organisms, Defective innate immunity; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v2.51 | RELA | Zornitza Stark reviewed gene: RELA: Rating: AMBER; Mode of pathogenicity: None; Publications: 28600438, 29305315; Phenotypes: Mucocutaneous ulceration, chronic, MIM# 618287, Impaired NFkB activation, reduced production of inflammatory cytokines, autoimmune cytopaenias; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v2.34 | TNFRSF4 |
Louise Daugherty Source IUIS Classification December 2019 was added to TNFRSF4. Added phenotypes Impaired immunity to HHV8, Kaposis sarcoma; Immunodeficiencies affecting cellular and humoral immunity for gene: TNFRSF4 Publications for gene TNFRSF4 were updated from to 32048120; 32086639 |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v2.13 | RELA |
Louise Daugherty gene: RELA was added gene: RELA was added to Primary immunodeficiency. Sources: IUIS Classification December 2019 Mode of inheritance for gene: RELA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RELA were set to 32048120; 32086639 Phenotypes for gene: RELA were set to Mucocutaneous ulceration, chronic, 618287; RelA haplosufficiency; Mucosal ulceration, impaired NFkB activation; Immunodeficiencies affecting cellular and humoral immunity |
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| Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 | AIRE | Louise Daugherty commented on gene: AIRE: 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 | AIRE | Louise Daugherty commented on gene: AIRE: 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 | AIRE | Kimberly Gilmour reviewed gene: AIRE: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v1.94 | AIRE | Tracy Briggs reviewed gene: AIRE: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v1.60 | AIRE | Louise Daugherty Source NHS GMS was added to AIRE. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v1.59 | AIRE | Louise Daugherty Source North West GLH was added to AIRE. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v1.58 | AIRE | Louise Daugherty Source London North GLH was added to AIRE. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease v1.16 | RIPK1 | Louise Daugherty edited their review of gene: RIPK1: Added comment: From OMIM : Lourenco et al. (2018) PMID: 30026316 reports 4 patients from 3 unrelated consanguineous families with immunodeficiency-57 identifying homozygous loss-of-function mutations in the RIPK1 gene. The variants segregated with the disorder in the families and were not found in the gnomAD database. Functional studies of patient cells showed impaired mitogen-activated protein kinase activation, impaired phosphorylation of downstream signaling molecules, impaired proinflammatory signaling downstream of TNFR1 and TLR3 and defective secretion of certain cytokines. Similar results were observed in vitro in a monocyte-like cell line with CRISPR/Cas9-mediated knockdown of RAPK1. The findings indicated that RIPK1 plays a critical role in the human immune system.; Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | AIRE | Louise Daugherty commented on gene: AIRE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | AIRE | Louise Daugherty marked gene: AIRE as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | AIRE | Sophie Hambleton reviewed gene: AIRE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | AIRE | Louise Daugherty classified AIRE as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | AIRE | Louise Daugherty commented on AIRE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | AIRE | Louise Daugherty edited their review of AIRE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | AIRE | Louise Daugherty commented on AIRE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | AIRE | Louise Daugherty commented on AIRE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | AIRE | Louise Daugherty commented on AIRE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | AIRE | Louise Daugherty reviewed AIRE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Primary immunodeficiency or monogenic inflammatory bowel disease | AIRE | Louise Daugherty Added gene to panel | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||