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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
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
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
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
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.
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
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
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/
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
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
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