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| COVID-19 research v1.138 | IL21R | Arina Puzriakova Phenotypes for gene: IL21R were changed from Combined immunodeficiency; Atypical Severe Combined Immunodeficiency (Atypical SCID); Immunodeficiency 56, 615207; Immunodeficiencies affecting cellular and humoral immunity; Omenn syndrome; Immunodeficiency, primary, autosomal recessive, IL21R-related; IL-21R deficiency; Severe combined immunodeficiency (SCID); Recurrent infections, Pneumocystis jiroveci, Cryptosporidium infections and liver disease to Immunodeficiency 56, OMIM:615207; Atypical Severe Combined Immunodeficiency (Atypical SCID); Combined immunodeficiency; Omenn syndrome; Recurrent infections, Pneumocystis jiroveci, Cryptosporidium infections and liver disease; Immunodeficiencies affecting cellular and humoral immunity | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v1.135 | STAT5B | Arina Puzriakova Phenotypes for gene: STAT5B were changed from Combined immunodeficiency; T-B+ SCID; Growth-hormone insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstitial pneumonitis, autoimmunity; Growth hormone insensitivity with immunodeficiency 245590; Combined immunodeficiencies with associated or syndromic features to Growth hormone insensitivity with immune dysregulation 1, autosomal recessive, OMIM:245590; Growth hormone insensitivity with immune dysregulation 2, autosomal dominant, OMIM:618985; T-B+ SCID; Combined immunodeficiency; Growth-hormone insensitive dwarfism, dysmorphic features, eczema, lymphocytic interstitial pneumonitis, autoimmunity; Combined immunodeficiencies with associated or syndromic features | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v1.134 | TERT | Arina Puzriakova Phenotypes for gene: TERT were changed from Bone marrow failure; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay to Dyskeratosis congenita, autosomal dominant 2, OMIM:613989; Dyskeratosis congenita, autosomal recessive 4, OMIM:613989 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v1.133 | ADAR | Arina Puzriakova Phenotypes for gene: ADAR were changed from Fever Syndromes and Related Diseases, Aicardi-Goutieres syndrome 6, 615010; Type 1 interferonopathies; Autoinflammatory Disorders; AGS6; Classical AGS, BSN, SP to Aicardi-Goutieres syndrome 6, OMIM:615010; Fever Syndromes and Related Diseases; Type 1 interferonopathies; Autoinflammatory Disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v1.131 | TGFB1 | Arina Puzriakova Phenotypes for gene: TGFB1 were changed from Inflammatory bowel disease, immunodeficiency, and encephalopathy, 618213; IBD, immunodeficiency, recurrent viral infections, microcephaly, and encephalopathy; TGFB1 deficiency; Diseases of Immune Dysregulation to Inflammatory bowel disease, immunodeficiency, and encephalopathy, OMIM:618213 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v1.111 | CARD14 | Arina Puzriakova Phenotypes for gene: CARD14 were changed from Other autoinflammatory diseases with known genetic defect; Psoriasis 2, 602723; Autoinflammatory Disorders; Pityriasis rubra pilaris,173200; immune dysregulation; CARD14 mediated psoriasis; Psoriasis to Pityriasis rubra pilaris, OMIM:173200; Psoriasis 2, OMIM:602723; Autoinflammatory Disorders | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v1.102 | PLCG2 | Arina Puzriakova Phenotypes for gene: PLCG2 were changed from Other autoinflammatory diseases with known genetic defect; Cold urticaria hypogammaglobulinemia, autoinflammation; Familial cold autoinflammatory syndrome 3 614468; Familial cold autoinflammatory syndrome 3; Autoinflammatory Disorders; Hypogammaglobulinaemia, cold induced urticaria, autoinflammatory; Autoinflammation, antibody deficiency, and immune dysregulation syndrome 614878 to Autoinflammation, antibody deficiency, and immune dysregulation syndrome, OMIM:614878; Familial cold autoinflammatory syndrome 3, OMIM:614468; Hypogammaglobulinaemia, cold induced urticaria, autoinflammatory | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v1.90 | FLNA |
Sarah Leigh gene: FLNA was added gene: FLNA was added to COVID-19 research. Sources: Literature Mode of inheritance for gene: FLNA was set to Unknown Publications for gene: FLNA were set to DOI:10.3390/genes12111842 Review for gene: FLNA was set to AMBER Added comment: DOI: 10.3390/genes12111842 reports: Results based on DSC and SSC metrics demonstrated a different selective pressure on three genes (MUC5AC, ABCA7, FLNA) between Qatari and Italian populations. This study highlighted the genetic differences between Qatari and Italian populations and identified a subset of genes involved in innate immunity and host-pathogen interaction. Sources: Literature |
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| COVID-19 research v1.88 | ABCA7 |
Sarah Leigh gene: ABCA7 was added gene: ABCA7 was added to COVID-19 research. Sources: Literature Mode of inheritance for gene: ABCA7 was set to Unknown Publications for gene: ABCA7 were set to DOI:10.3390/genes12111842 Review for gene: ABCA7 was set to AMBER Added comment: DOI: 10.3390/genes12111842 reports: Results based on DSC and SSC metrics demonstrated a different selective pressure on three genes (MUC5AC, ABCA7, FLNA) between Qatari and Italian populations. This study highlighted the genetic differences between Qatari and Italian populations and identified a subset of genes involved in innate immunity and host-pathogen interaction. Sources: Literature |
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| COVID-19 research v1.87 | MUC5AC |
Sarah Leigh gene: MUC5AC was added gene: MUC5AC was added to COVID-19 research. Sources: Literature Mode of inheritance for gene: MUC5AC was set to Unknown Publications for gene: MUC5AC were set to 10.3390/genes12111842 Review for gene: MUC5AC was set to AMBER Added comment: DOI: 10.3390/genes12111842 reports: Results based on DSC and SSC metrics demonstrated a different selective pressure on three genes (MUC5AC, ABCA7, FLNA) between Qatari and Italian populations. This study highlighted the genetic differences between Qatari and Italian populations and identified a subset of genes involved in innate immunity and host-pathogen interaction. Sources: Literature |
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| COVID-19 research v1.77 | ARPC1B | Arina Puzriakova Phenotypes for gene: ARPC1B were changed from inflammatory predisposition; Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease, 617718; Mild thrombocytopenia with normal sized platelets, recurrent invasive infections, colitis, vasculitis, autoantibodies (ANA, ANCA), eosinophilia, defective Arp2/3, filament branching; Immunodeficiency with thrombocytopenia; Combined immunodeficiencies with associated or syndromic features; Thrombocytopenia & Immune Deficiency to Immunodeficiency 71 with inflammatory disease and congenital thrombocytopenia, OMIM:617718; Combined immune deficiency with or without thrombocytopenia; Inflammatory predisposition | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v1.71 | MPI | Arina Puzriakova Phenotypes for gene: MPI were changed from to Congenital disorder of glycosylation, type Ib, OMIM:602579; MPI-CDG, MONDO:0011257 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v1.65 | ALOXE3 |
Arina Puzriakova gene: ALOXE3 was added gene: ALOXE3 was added to COVID-19 research. Sources: Literature Mode of inheritance for gene: ALOXE3 was set to Unknown Added comment: Preprint: https://doi.org/10.1101/2020.07.01.20144592 Using UK Biobank data of 5,871 participants tested for COVID-19, including 193 deaths from 1,412 confirmed infections, authors identified 5 novel risk variants in 4 genes (ERAP2, BRF2, TMEM181, ALOXE3) associated with death from SARS-CoV-2 infection. Two ALOXE3 SNP (rs147149459, rs151256885) identified. Furthermore, it has been shown that ALOXE3 is upregulated by SARS-CoV in human airway epithelial cultures. However, whether genetic variants have any physiological role on SARS-CoV-2 infection is yet to be determined. Sources: Literature |
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| COVID-19 research v1.64 | BRF2 |
Arina Puzriakova gene: BRF2 was added gene: BRF2 was added to COVID-19 research. Sources: Literature Mode of inheritance for gene: BRF2 was set to Unknown Added comment: Preprint: https://doi.org/10.1101/2020.07.01.20144592 Using UK Biobank data of 5,871 participants tested for COVID-19, including 193 deaths from 1,412 confirmed infections, authors identified 5 novel risk variants in 4 genes (ERAP2, BRF2, TMEM181, ALOXE3) associated with death from SARS-CoV-2 infection. Structural analysis showed the BRF2 SNP (rs138763430, D9N) at the Zn Ribbon domain alters the electrostatic potential surface, which in turn impacts the fundamental property of the domain to recognise nucleotide binding partners. Thus authors speculate that this variant most likely negatively alters the selectivity of the protein. However, whether this genetic variant has any physiological role on SARS-CoV-2 infection is yet to be determined. Sources: Literature |
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| COVID-19 research v1.52 | IFNG |
Sarah Leigh changed review comment from: IFNG was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). "Illumina review: From OMIM: Interferon-gamma (IFNG), or type II interferon, is a cytokine critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control. The importance of IFNG in the immune system stems in part from its ability to inhibit viral replication directly, but most importantly derives from its immunostimulatory and immunomodulatory effects. IFNG is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 (186940) and CD8 (see 186910) cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops (PMID: 178981204; Schoenborn and Wilson, 2007). From OMIM: PMID: 17215375: Huang et al. (2007) The IFNG gene SNP, -764 C>G (rs2069707) in the proximal promoter region next to the binding motif for HSF1 , was significantly associated with sustained virologic response to IFNA therapy in a cohort of hepatitis C virus-positive patients compared to a cohorts who had spontaneously cleared HCV infection or who had chronic HCV infection. Luciferase reporter and EMSA analyses showed that the -764G allele had 2- to 3-fold higher promoter activity and stronger binding affinity for HSF1 than the -764C allele. Huang et al. (2007) concluded that the -764C-G SNP is functionally important in determining viral clearance and treatment response in HCV-infected patients. From OMIM PMID: 12854077: An et al. (2003) reported an association between a SNP in the IFNG promoter region, -173 G>T, and progression to AIDS. In individuals with the rare -179T allele, but not in those with the -179G allele, IFNG is inducible by TNF. An et al. (2003) studied 298 African American HIV-1 seroconverters and found that the -179T allele was associated with accelerated progression to a CD4 cell count below 200 and to AIDS. They noted that the SNP is present in 4% of African Americans and in only 0.02% of European Americans. PMID: 26458193 Wei et al. (2017) Eleven independent case-control studies were selected for the meta-analysis, comprising a total of 1527 HBV cases and 1467 healthy subjects. carriers of the IFN-γ A allele were more likely to develop HBV infection than those without in all five genetic models (all p < 0.05). According to the ethnicity-based sub-group analysis, a significant difference of the IFN-γ rs2430561 T > A (IFN-γ +874T/A) polymorphism was detected associated with the increased risk of HBV infection in Asians and European-derived populations in the majority of the groups. ; to: IFNG was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: From OMIM: Interferon-gamma (IFNG), or type II interferon, is a cytokine critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control. The importance of IFNG in the immune system stems in part from its ability to inhibit viral replication directly, but most importantly derives from its immunostimulatory and immunomodulatory effects. IFNG is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 (186940) and CD8 (see 186910) cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops (PMID: 17981204; Schoenborn and Wilson, 2007). From OMIM: PMID: 17215375: Huang et al. (2007) The IFNG gene SNP, -764 C>G (rs2069707) in the proximal promoter region next to the binding motif for HSF1 , was significantly associated with sustained virologic response to IFNA therapy in a cohort of hepatitis C virus-positive patients compared to a cohorts who had spontaneously cleared HCV infection or who had chronic HCV infection. Luciferase reporter and EMSA analyses showed that the -764G allele had 2- to 3-fold higher promoter activity and stronger binding affinity for HSF1 than the -764C allele. Huang et al. (2007) concluded that the -764C-G SNP is functionally important in determining viral clearance and treatment response in HCV-infected patients. From OMIM PMID: 12854077: An et al. (2003) reported an association between a SNP in the IFNG promoter region, -173 G>T, and progression to AIDS. In individuals with the rare -179T allele, but not in those with the -179G allele, IFNG is inducible by TNF. An et al. (2003) studied 298 African American HIV-1 seroconverters and found that the -179T allele was associated with accelerated progression to a CD4 cell count below 200 and to AIDS. They noted that the SNP is present in 4% of African Americans and in only 0.02% of European Americans. PMID: 26458193 Wei et al. (2017) Eleven independent case-control studies were selected for the meta-analysis, comprising a total of 1527 HBV cases and 1467 healthy subjects. carriers of the IFN-γ A allele were more likely to develop HBV infection than those without in all five genetic models (all p < 0.05). According to the ethnicity-based sub-group analysis, a significant difference of the IFN-γ rs2430561 T > A (IFN-γ +874T/A) polymorphism was detected associated with the increased risk of HBV infection in Asians and European-derived populations in the majority of the groups. |
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| COVID-19 research v1.50 | FUT2 | Sarah Leigh Added comment: Comment on list classification: Variants in FUT2 are responsible for resistance to Norovirus infection in certain populations (PMID 30845670). This gene is Green on the Viral Resistance panel (https://panelapp.genomicsengland.co.uk/panels/928/gene/FUT2/#!review) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v1.38 | TNF |
Sarah Leigh changed review comment from: TNF was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: TNF was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: PMID: 10719836: Herbein et al. (Review) TNF is a proinflammatory cytokine plays a key role in the host response to viral infection. TNF enhances or inhibits viral replication depending on the virus involved and the cell type infected. The binding of TNF to the TNF receptors can activate, differentiate, or kill target cells thereby interfering with the viral life cycle. In contrast, viruses have evolved to appropriate the TNF/TNFR pathway to evade immune responses and favor viral dissemination. From OMIM: PMID: 12915457;Kim et al. (2003) To investigate whether TNF-alpha promoter polymorphisms are associated with clearance of hepatitis B virus (HBV) infection, Kim et al. (2003) genotyped 1,400 Korean subjects, 1,109 of whom were chronic HBV carriers and 291 who spontaneously recovered. The TNF promoter alleles that were previously reported to be associated with higher plasma levels (presence of -308A or the absence of -863A alleles), were strongly associated with the resolution of HBV infection. Haplotype analysis revealed that TNF-alpha haplotype 1 (-1031T; -863C; -857C; -308G; -238G; -163G) and haplotype 2 (-1031C; -863A; -857C; -308G; -238G; -163G) were significantly associated with HBV clearance, showing protective antibody production and persistent HBV infection, respectively (P = 0.003-0.02). From OMIM: PMID: 11506397 Quasney et al. The presence of the A allele at the TNF-alpha-308 site was overrepresented among adults with HIV dementia compared to those without dementia (0.28 vs 0.07; OR 5.5; 95% CI 1.8-17.0) and a healthy control population (0.28 vs 0.11). The increased frequency of the A allele in HlV-infected adults with dementia suggests that this locus may play a role in the pathophysiology of dementia and suggests a genetic predisposition for the development of HIV dementia. PMID: 26657940 García-Ramírez et al. (2015) - 145 patients with influenza A (H1N1) (pA/H1N1), 133 patients with influenza-like illness (ILI), and 360 asymptomatic healthy contacts (AHCs) were included from a Mexican population were studied. The TNF-238 GA genotype was associated with an increased risk of disease severity (OR =16.06, p = 0.007). PMID: 31986264: Huang et al. (2020) Study of 41 patients admitted to hospital with laboratory-confirmed 2019-nCoV. Compared with non-ICU patients, ICU patients had higher plasma levels of proinflammatory cytokines and chemokines including IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. |
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| COVID-19 research v1.37 | NUP214 |
Sarah Leigh changed review comment from: NUP214 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility); to: NUP214 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility). Illumina review: PMID 31178128: Fichtman et al. (2019) reported four patients from two unrelated families with fever-induced, partially reversible acute encephalopathy and regression, progressive microcephaly, and brain atrophy. Febrile episodes were associated with viral infections. Exome sequencing identified that both affected individuals from family A were homozygous for the NUP214 NM_005085.3; c.112C>T (p.Arg38Cys) missense variant. A frameshift variant, c.1574delC (p.Pro525LeufsTer6) and a missense variant c.1159C>T (p.Pro387Ser), found in a compound heterozygous state were identified in the NUP214 gene in the two affected individuals from family B. The missense variants affected highly conserved residues and were present at a low frequency in gnomAD. Functional studies on primary skin fibroblasts derived from one case (family A1) supported pathogenicity of the p.Arg38Cys variant; NUP214 and NUP88 protein levels were reduced in while the total number and density of nuclear pore complexes remained normal. Nuclear transport assays revealed defects in the classical protein import and mRNA export pathways in affected cells. |
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| COVID-19 research v1.35 | IL7 |
Sarah Leigh changed review comment from: IL7 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility); to: IL7 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility). Illumina review: PMID 25981006 – Horev et al. (2015) reported three cases from one consanguineous Arab family characterized by severe CD41T-cell lymphopenia, generalized verrucosis due to HPV infections, predisposition to opportunistic C. neoformans meningitis, and recurrent squamous cell carcinomas of the skin in sun-exposed areas. Whole exome sequencing analysis of one case (patient 3) identified a homozygous variant in the IL 7 gene, c.205A>T ( p.Arg69Ter). PMID: 31900472 Kosumi et al. (2020) reported two generalized verrucosis (GV) patients homozygous for a novel mutation in the start codon of IL7. IL-7 deficiency was not accompanied CD4 T lymphocytopenia, circulating CD4 T-cells were not depleted in one of the patients, suggesting a GV pathogenesis other than poor T-cell development. |
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| COVID-19 research v1.34 | IL4R |
Sarah Leigh changed review comment from: IL4R was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: IL4R was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). "Illumina review: IL4R (interleukin 4 receptor), encodes the alpha chain of the interleukin-4 receptor [29], is a type I transmembrane protein that can bind both IL-4 (interleukin 4) and IL-13 (interleukin13) to regulate IgE production. From OMIM: PMID: 16189667 Soriano et al. (2005) By analysis of IL4R allele and genotype frequencies in individuals with different risk factors for human immunodeficiency virus (HIV) acquisition and different rates of progression to acquired immunodeficiency syndrome (AIDS), Soriano et al. (2005) determined that the V50 allele predominated in HIV-positive long-term nonprogressors (LTNPs), whereas the I50 allele predominated in healthy controls, typical progressors, and those at risk for infection due to sexual exposure or treatment of hemophilia. Homozygosity for V50 was increased in LTNPs compared with other groups. Soriano et al. (2005) concluded that V50 homozygosity appears to be associated with slow progression to AIDS after HIV infection. PMID: 30228077: Useche et al.(2019) A case-control study to evaluate possible associations between SNPs in IL4R and IL6R genes and clinical dengue in children from two Colombian populations, Huila and Antioquia. The study included 298 symptomatic children and 648 asymptomatic controls. The IL4R-rs1805016 GG genotype associated with clinical dengue in the pooled and Huila samples. No association of these polymorphisms in the sample of Antioquia. PMID: 29287219: Yu et al. (2018) Fifty-five chronic hepatitis B (CHB) patients, fifty-three self-healing HBV (SH) patients and 53 healthy controls (HC) were recruited, 404 cytokine and cytokine receptor related genes sequenced using NGS. The authors suggest that the IL4R SNPs; rs1805012 (p.Cys431Arg) and rs1805011 (p.Glu400Ala) are associated with chronic hepatitis B, there was no significant difference between the frequency of these variants between the CHB patients and the SH patients. PMID: 31141539 Naget et al. EBV infection represses IL4R expression. Isolated EBV-positive and EBV-negative subclones from the DLBCL derived cell line DOHH-2 showed that EBV-encoded factors LMP1 and LMP2A activated the expression of HLX via STAT3. HLX in turn repressed NKX6-3, SPIB and IL4R which normally mediate plasma cell differentiation. |
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| COVID-19 research v1.32 | IL18BP |
Sarah Leigh changed review comment from: IL18BP was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility); to: IL18BP was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility). Illumina review: The IL18BP gene is located on chromosome 11 at 11q13.4 and encodes the interleukin 18 binding protein , a soluble inhibitor which mediates of the proinflammatory cytokine interleukin 18, an amplifier of natural killer (NK) cells, through a negative feedback loop (Harms et al. 2017). The IL18BP gene has been recently identified as candidate gene associated with a susceptibility to fulminant viral hepatitis (FVH), a form of acute liver failure that occurs in up to 0.5% of individuals following infection with liver-tropic viruses, most commonly hepatitis A or B. The proposed inheritance pattern is autosomal recessive with loss of function as a mechanism of disease. In 2019, Belkaya et al. describe an 11 year-old female child of Algerian ancestry who died of FVH following an acute hepatitis A infection. Through whole exome sequencing, she was found to be homozygous for an IL18BP deletion, c.508-19_528del. Her parents and one of her brothers were found to be heterozygous for the variant and a second brother did not carry the variant. Experiments using Epstein Barr virus-transformed B cells transfected with the c.508-19_528del variant and an in vitro bioassay suggest that the variant results in 3 abnormal novel transcripts which produce non-functional proteins with reduced expression. Additional experimental evidence described in the same publication include evaluation of liver tissue from the proband and a second individual with FVH, which showed elevated IL-18 staining compared to controls, functional experiments in a selection of human cell types which showed the upregulation of IL -18BP expression is in response to several inflammatory cytokines, and a cell culture model in which hepatitis A positive and negative hepatocytes were cultured with NK where stimulation with IL-18 resulted in hepatocyte death and treatment with IL-18BP resulted in a rescue. In summary, Belkaya et al. presents plausible clinical and experimental evidence suggesting that a susceptibility to FVH may be caused by a congenital absence or reduction of IL18BP. The gene disease association is currently limited as this is the first and only publication describing an association between IL18BP and FVH. |
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| COVID-19 research v1.32 | IL18BP | Sarah Leigh Phenotypes for gene: IL18BP were changed from Defects in intrinsic and innate immunity; IL-18BP deficiency; inborn errors of immunity related to leukocytes to {?Hepatitis, fulminant viral, susceptibility to} 618549; Defects in intrinsic and innate immunity; IL-18BP deficiency; inborn errors of immunity related to leukocytes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v1.30 | IFNG |
Sarah Leigh changed review comment from: IFNG was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: IFNG was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). "Illumina review: From OMIM: Interferon-gamma (IFNG), or type II interferon, is a cytokine critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control. The importance of IFNG in the immune system stems in part from its ability to inhibit viral replication directly, but most importantly derives from its immunostimulatory and immunomodulatory effects. IFNG is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 (186940) and CD8 (see 186910) cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops (PMID: 178981204; Schoenborn and Wilson, 2007). From OMIM: PMID: 17215375: Huang et al. (2007) The IFNG gene SNP, -764 C>G (rs2069707) in the proximal promoter region next to the binding motif for HSF1 , was significantly associated with sustained virologic response to IFNA therapy in a cohort of hepatitis C virus-positive patients compared to a cohorts who had spontaneously cleared HCV infection or who had chronic HCV infection. Luciferase reporter and EMSA analyses showed that the -764G allele had 2- to 3-fold higher promoter activity and stronger binding affinity for HSF1 than the -764C allele. Huang et al. (2007) concluded that the -764C-G SNP is functionally important in determining viral clearance and treatment response in HCV-infected patients. From OMIM PMID: 12854077: An et al. (2003) reported an association between a SNP in the IFNG promoter region, -173 G>T, and progression to AIDS. In individuals with the rare -179T allele, but not in those with the -179G allele, IFNG is inducible by TNF. An et al. (2003) studied 298 African American HIV-1 seroconverters and found that the -179T allele was associated with accelerated progression to a CD4 cell count below 200 and to AIDS. They noted that the SNP is present in 4% of African Americans and in only 0.02% of European Americans. PMID: 26458193 Wei et al. (2017) Eleven independent case-control studies were selected for the meta-analysis, comprising a total of 1527 HBV cases and 1467 healthy subjects. carriers of the IFN-γ A allele were more likely to develop HBV infection than those without in all five genetic models (all p < 0.05). According to the ethnicity-based sub-group analysis, a significant difference of the IFN-γ rs2430561 T > A (IFN-γ +874T/A) polymorphism was detected associated with the increased risk of HBV infection in Asians and European-derived populations in the majority of the groups. |
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| COVID-19 research v1.29 | IFITM3 |
Sarah Leigh changed review comment from: IFITM3 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: IFITM3 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: PMID: 20064371 Brass et al. (2009) used a functional genomic screen to identify IFITM3 as an antiviral restriction factor in influenza A H1N1 viral infection. Further characterization showed IFITM3 inhibits the early replication of flaviviruses, including dengue virus and West Nile virus. PMID: 27384652 Gorman et al. (2016) Ifitm3(-/-) mice are more vulnerable to lethal WNV infection than their wildtype littermates, this was associated with greater virus accumulation in peripheral organs and central nervous system tissues. PMID: 22446628 Everitt et al. (2012). Ifitm3(-/-) mice display fulminant viral pneumonia when challenged with a normally low-pathogenicity influenza virus, a phenotype which may be rescued by the re-introduction of Ifitm3. PMID: 22446628 Everitt et al. (2012). A statistically significant number of hospitalized with seasonal or pandemic influenza H1N1/09 viruses subjects show enrichment for a minor IFITM3 allele (SNP rs12252-C). This SNP alters a splice acceptor site, and functional assays show the minor CC genotype IFITM3 has reduced influenza virus restriction in vitro. PMID: 23361009 Zhang et al. (2013) In a Han Chinese patient population, the rs12252-C, CC genotype was found in 69% of Chinese patients with severe pandemic influenza A H1N1/09 virus infection compared with 25% in those with mild infection. The CC genotype was estimated to confer a sixfold greater risk for severe infection than the CT and TT genotypes. PMID: 25942469 Yang et al. (2015) performed meta-analysis of four studies consisting of 445 cases and 4180 controls. A significant association between a minor IFITM3 allele (SNP rs12252-C) with severe influenza susceptibility, but not in mild influenza subjects, in both UK Caucasians and Han Chinese population was confirmed. The rs12252-C allele causes a 23.7% higher chance of infection and also constitutes a risk factor for more severe influenza. |
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| COVID-19 research v1.27 | HLA-DQB1 |
Sarah Leigh changed review comment from: HLA-DQB1 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: HLA-DQB1 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: HLA-DQB1 alleles may have a role in influencing viral infection and pathogenesis: PMID:10609818: Thirsz et al. (1999) - The distribution of MHC class II alleles was compared between patients with self-limiting infection (n=85) and matched patients with persistent infection (n=170); between patients with mild (n=321) and severe (n=321) histological injury; and between patients who responded to interferon (n=96) and those who did not (n=192). The results of these comparisons were confirmed with a second-stage study of self-limiting infection (n=52) versus persistent infection (n=152). Self-limiting HCV infection was associated with HLA-DRB1*1101 (odds ratio 2.14 [95% CI 1.11-4.12]; p=0.013) and HLA-DQB1*0301 (2.22 [1.24-3.96], p=0.004). Persistent HCV infection was associated with HLA-DRB1*0701 (2.04 [1.03-4.17], p=0.027), and HLA-DRB4*0101 (2.38 [1.29-4.35], p=0.002). These results were confirmed in the second-stage study. No significant associations were found between MHC class II alleles and severe histological injury or response to interferon therapy. PMID:30563535 - Ou et al. (2019) - found that HLA-DQB1*06:03 protected against HBV infection. Levels of IFN-γ and IL-4 were significantly elevated in HBV cases with HLA-DQB1*06:05 (vs. HLA-DQB1*05:03), and the HBV group had higher DQB1 mRNA expression than the healthy control group with HLA-DQB1*05:03 and HLA-DQB1*06:02. The meta-analysis revealed that HLA-DQB1*04:01, HLA-DQB1*05:02, HLA-DQB1*05:03, and HLA-DQB1*06:01 were risk factors for HBV infection susceptibility, while HLA-DQB1*05:01, HLA-DQB1*06:03, and HLA-DQB1*06:04 protected against HBV infection. Spontaneous HBV clearance was associated withHLA-DQB1*06:04, while chronic HBV infection was associated with HLA-DQB1*02:01 and HLA-DQB105:02. DBQ1 typing can be used to identify patients who have elevated risks of HBV infection. PMID 31254396: Huang et al. (2019) - Recently reported a high prevalence and spontaneous clearance rate of HCV in a cohort of Chinese Li ethnicity who were infected with new variants of HCV genotype 6. In this study found that the distribution of HLA class I and class II alleles in HCV infected individuals of Chinese Li ethnicity (n = 143) was distinct from that of Chinese Han ethnicity. HLA-DRB1*11:01 and DQB1*03:01 were more prevalent in Chinese Li subjects who cleared HCV spontaneously than those who were chronically infected (P = .036 and P = .024, respectively), which were consistent with the previous report regarding the Chinese Han population. Multivariate logistic regression analysis showed that DQB1*03:01 (odds ratio = 3.899, P = .017), but not DRB1*11:01, associated with HCV spontaneous clearance, independent of age, sex, and IFNL3 genotype. Because DQB1*03:01 and DRB1*11:01 were tightly linked because of linkage disequilibrium, results clearly supported the associations of these two alleles with HCV spontaneous clearance in Chinese Li as well as Han ethnicity. PMID:23710940 - Chaaithanya et al. (2013) - study investigated the association of polymorphisms in the human leucocyte antigen class II genes with susceptibility or protection against CHIKV. Lower frequency of HLA-DQB1*03:03 was observed in CHIKV patients compared with the control population. Significantly lower frequency of glutamic acid at position 86 of peptide-binding pocket 1 coding HLA-DQB1 genotypes was observed in CHIKV patients compared with healthy controls. HLA-DQB1 alleles and critical amino acid differences in the peptide-binding pockets of HLA-DQB1 alleles might have role in influencing infection and pathogenesis of CHIKV. |
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| COVID-19 research v1.24 | FUT2 |
Sarah Leigh changed review comment from: FUT2 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: FUT2 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: PMID: 30845670: Nordgren et al. (2019) (Review) The FUT2 gene encodes FUT2 enzyme, which catalyzes the transfer of fucose to the terminal galactose on glycan chains of cell surface glycoproteins and glycolipids, allowing the synthesis of histo-blood group antigens (HBGAs). The FUT2 gene is expressed predominately in epithelial (mucosal) tissues. Individuals with inactivated FUT2 enzyme, known as “non secretors” do not express blood group antigens in these tissues and are resistant to several norovirus genotypes. FUT2 polymorphisms with known effect on secretor status are present in different populations and are reviewed by Nordgren et al. (2019). |
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| COVID-19 research v1.23 | DPP4 |
Sarah Leigh changed review comment from: DPP4 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 2 grouping (experimental and/or genetic evidence, suggesting a biological role linking to corona viruses, may not be a GDA); to: DPP4 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 2 grouping (experimental and/or genetic evidence, suggesting a biological role linking to corona viruses, may not be a GDA). "Illumina review: Cell surface glycoprotein receptor involved in the costimulatory signal essential for T-cell receptor (TCR)-mediated T-cell activation. DPP4 acts as a receptor for MERS-CoV - PMID: 24554656 - Barlan et al. (2014). MERS virus cell entry begins with the receptor-binding domains (RBDs) of the MERS-CoV protein virus spike (S) protein binding to blades 4 and 5 of the 8-blade propeller domain of DPP4. PMID:23486063 - Raj et al. (2013) - identified DPP4 as a functional receptor for hCoV-EMS (MERS CoV). Evidence from mouse models of involvment in susceptibility to MERS-CoV infection. PMID:24599590 - Zhao et al. (2014) - noted that rodents are not susceptible to MERS-CoV. They used an adenovirus vector expressing human DPP4 to generate mice sensitized to infection with MERS-CoV. These mice developed pneumonia characterized by extensive inflammatory cell infiltration with virus clearance after 6 to 8 days in a type I IFN- and T cell-dependent manner. Treatment with poly(I:C) was also efficacious in this model. PMID: 25589660 - Agrawal et al. (2015) developed a transgenic mouse model expressing human DPP4 that was susceptible to MERS-CoV infection, with high titers of virus detectable in brain and lung and later in other organs. PMID: 26124093 - Pascal et al. (2015) - obtained a mouse model susceptible to intranasal infection with MERS-CoV. Human monoclonal antibodies binding to the MERS-CoV S protein neutralized all variants of the virus and prevented entry into target cells. The antibodies could both prevent and treat mice humanized for DPP4. Pascal et al. (2015) concluded that the model will be valuable for assessing treatments for MERS-CoV infection and disease. PMID:31883094 - Leist et al. (2020) - generated a mouse model susceptible to MERS-CoV infection - used C57BL/6J mice and CRISPR/Cas9 to substitute human residues at positions 288 and 330 (A288L and T330R). Strollo et al. (2020) and Bassedine et al. (2020) suggested that DPP4 could affect severity of infection and also be a therapeutic target: PMID:32336077 - Strollo et al. (2020) - propose a role for DDP4 as a functional receptor for SARS-CoV-2 and ask the question if DPP4 is directly involved in SARS-CoV-2 cell adhesion/virulence, and whether DPP4 inhibition might be a therapeutic strategy for preventing infection. PMID:32394639 - Bassedine et al. (2020) - modeling of the structure of SARS-CoV-2 spike glycoprotein predicts that it can interact with human DPP4 in addition to ACE2. Notes that increased DPP4 expression and activity are associated with diabetes, obesity, and metabolic syndrome, all of which have been reported to influence COVID‐19 severity. DPP4 inhibitors (gliptins), which vary in their interactions with the active site of the enzyme, may have immunomodulatory and cardioprotective effects that could be beneficial in COVID‐19 cases. PMID:31964246 - Keline-Weber at al. (2020) - Identified 14 polymorphisms in DPP4 from public databases that alter amino acid residus required for MERS-CoV S binding. Introduction of the respective variants into DPP4 revealed that all except one (Δ346-348) were compatible with robust DPP4 expression. Four polymorphisms (K267E, K267N, A291P and Δ346-348) strongly reduced binding of MERS-CoV S to DPP4 and S protein-driven host cell entry, as determined using soluble S protein and S protein bearing rhabdoviral vectors, respectively. Two polymorphisms (K267E and A291P) were analyzed in the context of authentic MERS-CoV and were found to attenuate viral replication. Collectively, we identified naturally-occurring polymorphisms in DPP4 that negatively impact cellular entry of MERS-CoV and might thus modulate MERS development in infected patients. |
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| COVID-19 research v1.21 | CX3CR1 |
Sarah Leigh changed review comment from: CX3CR1 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: CX3CR1 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: Receptor for the CX3C chemokine fractalkine (CX3CL1); binds to CX3CL1 and mediates both its adhesive and migratory functions. Acts as coreceptor with CD4 for HIV-1 virus envelope protein (in vitro) (PMID:9726990). Associated with rapid progression to AIDS from HIV1 infection. PMID:14607932: Garin et al. (2003) - identified two novel isoforms of the human chemokine receptor CX3CR1, produced by alternative splicing that appear to be more potent HIV coreceptors. PMID:10731151: Faure et al. (2000) - CX3CR1 is an HIV coreceptor as well as a leukocyte chemotactic/adhesion receptor for fractalkine. Faure et al. (2000) identified 2 single nucleotide polymorphisms in the CX3CR1 gene in Caucasians and demonstrated that HIV-infected patients homozygous for I249/M280 progressed to AIDS more rapidly than those with other haplotypes (relative risk = 2.13, P = 0.039). Functional CX3CR1 analysis showed that fractalkine binding is reduced among patients homozygous for this particular haplotype. Concluded that CX3CR1-I249/M280 is a recessive genetic risk factor for HIV/AIDS. PMID 28228284: Zhivaki et al. (2017) - Upregulated in RSV infection affecting severity of infection. Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in infants and is characterized by pulmonary infiltration of B cells in fatal cases. Identified a population of neonatal regulatory B lymphocytes (nBreg cells) that produced interleukin 10 (IL-10) in response to RSV infection. The polyreactive B cell receptor of nBreg cells interacted with RSV protein F and induced upregulation of chemokine receptor CX3CR1. CX3CR1 interacted with RSV glycoprotein G, leading to nBreg cell infection and IL-10 production that dampened T helper 1 (Th1) cytokine production. In the respiratory tract of neonates with severe RSV-induced acute bronchiolitis, RSV-infected nBreg cell frequencies correlated with increased viral load and decreased blood memory Th1 cell frequencies. Thus, the frequency of nBreg cells is predictive of the severity of acute bronchiolitis disease and nBreg cell activity may constitute an early-life host response that favors microbial pathogenesis. PMID unavailable: Strickland et al. (2020) - Pulmonary infection with C. neoformans (opportunistic fungal pathogen and leading cause of death in HIV-affected inividuals) enhanced CX3CR1 expression in the lung. Following infection, mice lacking CX3CR1 had significantly higher pulmonary fungal burdens, as well as decreased survival times compared to wild type mice. These infected CX3CR1 knockout mice also displayed higher expression of pro-inflammatory cytokines including MIP-2, MCP-1 and CCL7, but lower expression of anti-inflammatory cytokines such as IL-10. CX3CR1 deficiency resulted in mice having dramatically enhanced neutrophil accumulation in the lungs following infection.Depletion of neutrophils drastically improved lung CFU in infected knockout mice, indicating that excessive inflammation drove fungal growth. These data indicate that CX3CR1 expression is essential for host resistance to pulmonary cryptococcal infection by inhibiting excessive lung inflammation. |
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| COVID-19 research v1.19 | CPT2 |
Sarah Leigh changed review comment from: CPT2 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility); to: CPT2 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility). "Illumina review: Evidence suggests that susceptibility to infection-induced acute encephalopathy-4 (IIAE4) is conferred by heterozygous or homozygous variation in the CPT2 gene on chromosome 1p32. PMID:20934285: Shinohara et al. (2011) - found 352C variant at a significantly higher frequency in 29 Japanese patients with IIAE compared to controls. Pathogens included influenza, adenovirus, HHV6. mycoplasma and rotovirus. No correlation between good and poor prognosis. PMID: 21697855: Mak et al. (2011) - Showed heterozygosity for the CPT2 F352C variant and homozygosity for the CPT2 V368I variant in two unrelated Chinese individuals with fatal virally-induced acute encephalopathy. PMID: 15811315: Chen et al. (2005) - thermolabile phenotype of compound heterozygotes for F352C and V368I which showed a higher frequency in Japanese influenza-associated encephalopathy patients than healthy volunteers. PMID 18306170: Yao et al. (2008) - large proportion of patients suffering from disabling or fatal IAE, with transiently elevated serum acylcarnitine during high fever, exhibit a thermolabile phenotype of compound homozygous/heterozygous variants in CPT2. Among the variants, three compound variations found in patients with severe encephalopathy; [c.1055T>G (p.Phe352Cys); c.1102G>A (p.Val368Ile)], [c.1511C>T (p.Pro504Leu); c.1813G>C (p.Val605Leu)], and [c.1055T>G (p.Phe352Cys); c.1102G>A (p.Val368Ile); c.1813G>C (p.Val605Leu)], showed reduced activities, thermal instability, and short half-lives compared with the wild type. |
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| COVID-19 research v1.17 | CLEC4M |
Sarah Leigh changed review comment from: CLEC4M was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 2 grouping (experimental and/or genetic evidence, suggesting a biological role linking to corona viruses, may not be a GDA); to: CLEC4M was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 2 grouping (experimental and/or genetic evidence, suggesting a biological role linking to corona viruses, may not be a GDA). Illumina review: CLEC4M is a C-type lectin gene serving as cell adhesion receptor and pathogen recognition receptor. It functions as a cellular receptor for variety of viruses, including HIV-1, hepatitis C, Ebola, and SARS-coronavirus. A highly polymorphic variable number tandem repeat (VNTR) at the neck-region of CLEC4M had been associated with genetic predisposition to some infectious diseases, however, genetic association studies have shown conflicting results about these associations (PMID:16991095;16369534;12738250;16364081;17321900;18697825;17534354;17534355). From OMIM: Associated with protection against SARs infection. PMID: 15496474: Jeffers et al. (2004) identified the cellular gylcoprotein CD209L (CLEC4M) as as an alternative receptor for SARS-CoV. CD209L is expressed in human lung in type II alveolar cells and endothelial cells, both potential targets for SARS-CoV. Several other enveloped viruses, including Ebola and Sindbis, also use CD209L as a portal of entry, and HIV and hepatitis C virus can bind to CD209L on cell membranes but do not use it to mediate virus entry. Jeffers et al. (2004) suggested that the large S glycoprotein of SARS-CoV may use both ACE2 and CD209L in virus infection and pathogenesis. PMID 16369534: Chan et al. (2006) - demonstrated that individuals homozygous for CLEC4M tandem repeats are less susceptible to SARS infection. CLEC4M was expressed in both non-SARS and SARS-CoV-infected lung. Compared with cells heterozygous for CLEC4M, cells homozygous for CLEC4M showed higher binding capacity for SARS-CoV, higher proteasome-dependent viral degradation, and a lower capacity for trans infection. Thus, homozygosity for CLEC4M plays a protective role during SARS infection. PMID: 17534354: Tang et al. (2007) - performed genotyping studies in SARS patients and controls and found no support for an association between homozygosity for CLEC4M and protection against SARS. PMID:17534355: Zhi et al. (2007) also failed to replicate the study by Chan et al. (2006). Chan et al. (2007) disputed the validity of both studies. PMID 18697825:Li et al. (2008) - genotyped SNPs in CLEC4M and other genes in the C-type lectin cluster in 181 Chinese SARS patients and 172 controls from an ethnically matched population and found no significant association with disease predisposition or prognosis. However, they detected a population stratification of the CLEC4M variable number tandem repeat (VNTR) alleles in a sample of 1,145 Han Chinese from different parts of China (northeast, south, and southwest). Analysis extended to 742 individuals from 7 ethnic minorities showed that those located along the Silk Road in northwestern China, where there is significant admixture with the European gene pool, had a low level of homozygosity, similar to European populations. Li et al. (2008) concluded that there is no SARS predisposition allele in the lectin gene cluster at chromosome 19p13.3, and that the previously reported association with polymorphisms in the CLEC4M neck region may be due to population stratification. |
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| COVID-19 research v1.16 | CIB1 |
Sarah Leigh changed review comment from: CIB1 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility); to: CIB1 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility). "Illumina review: From OMIM: Susceptibility to epidermodysplasia verruciformis-3 is conferred by homozygous variation in the CIB1 gene. Epidermodysplasia verruciformis-3 is characterized by onset in childhood or early adulthood of persistent disseminated flat warts and pityriasis versicolor-like lesions of the skin that are induced by cutaneous human papillomaviruses (HPVs) of the beta genus. Some patients develop nonmelanoma skin cancer, particularly on areas of the body exposed to the sun. Patients are otherwise healthy and normally resistant to other microorganisms, including other viruses and skintropic pathogens, and even all other cutaneous and mucosal HPVs. Gene:disease relationship with autosomal recessive epidermodysplasia verruciformis curated using the ClinGen framework for gene curation. The CIB1 gene is located on chromosome 15 at 15q26.1 and encodes calcium and integrin binding 1. This protein forms a complex with the products of the TMC6 (EVER1) and TMC8 (EVER2) genes. The CIB1/EVER1/EVER2 complex acts to restrict transcription of human papillomaviruses. The CIB1 gene was first reported in relation to autosomal recessive epidermodysplasia verruciformis in 2018 (PMID: 300068544). Five unique homozygous variants in this gene were reported in at least five probands including two frameshift, one stop-gained, one stop-lost, and one canonical splice variant. The evidence supporting the GDR includes segregation data - linkage analysis across three unrelated families of differing geographic origin resulted in a LOD score of 16.7. This gene-disease relationship is also supported by expression data and a shared biochemical function with additional genes that are also associated with the disease (PMID: 300068544). In summary, the GDR between CIB1 and autosomal recessive epidermodysplasia verruciformis is classified as strong using the ClinGen framework. |
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| COVID-19 research v1.15 | CD209 |
Sarah Leigh changed review comment from: CD209 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: CD209 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: One SNP associated with susceptibility to HIV infection, severity of dengue disease, increased risk of TB and severity of SARS infection. Pathogen-recognition receptor expressed on the surface of immature dendritic cells (DCs) and involved in initiation of primary immune response. Thought to mediate the endocytosis of pathogens which are subsequently degraded in lysosomal compartments. The receptor returns to the cell membrane surface and the pathogen-derived antigens are presented to resting T-cells via MHC class II proteins to initiate the adaptive immune response. From OMIM:The C-type lectin receptors are involved in the primary interface between host and pathogens. PMID:15564514: Martin et al. (2004) - European Americans at risk for parenteral HIV infection were more likely to carry the -336C SNP in the promoter of DCSIGN. This association was not observed in those at risk for mucosally acquired infection. Although the -336C SNP was common in African Americans, no significant association with risk of infection was observed in this group. PMID:15838506: Sakuntabhai et al. (2005) found that the same CD209 promoter polymorphism reported by Martin et al. (2004) (-336A>G in this study), was associated with severity of dengue disease. Specifically, the G allele of the variant was associated with strong protection against dengue fever as opposed to dengue hemorrhagic fever. PMID:16379498:Barreiro et al. (2006) looked at CD209 polymorphisms in 351 TB patients and 360 healthy controls from a South African Coloured population living in communities with some of the highest reported incidence rates of TB in the world. Identified two variants in the CD209 promoter, -871A and -336G, that were associated with increased risk of TB. PMID:20864747: Chan et al. (2010) - A single nucleotide polymorphism in the promoter region of the DC-SIGN gene is associated with disease severity in SARS. In the DC_SIGN promoter region, a single SNP, -336A>G has been found to affect transcription of DC-SIGN in vitro and is associated with susceptibility for HIV-1 and M. tuberculosis infectsions and with the severity of dengue (PMID:15838506;15838506;16379498). Large case-control study - genotyped the SNP in 824 SARS patients and 471 controls. Showed no association with susceptibility to infection but SARS patients carrying the DC-SIGN promoter -336G variant had lower risk of having higher lactate dehydrogenase levels on admission, an independent prognostic indicator for severity of SARS-CoV infection. In vitro functional studies demonstrated that the DC-SIGN -336G promoter provided a less effective binding site and lower promoter activity, which may lead to reduced DC-SIGN protein expression and hence may contribute to a reduced immune-response with reduced lung injury during the progression of SARS infection. |
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| COVID-19 research v1.14 | CCR5 |
Sarah Leigh changed review comment from: CCR5 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: CCR5 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: Cytokine receptor. From OMIM: Variation in the CCR5 gene is associated with susceptibility to West Nile Virus (PMID 16230476;21935451;19247438). Numerous studies additionally demonstrate variation in CCR5 is associated with resistance / susceptibility to HIV and HBV infection. PMID 24098976: Zapata et al. (2013) - main genetic factor related to HIV-1 resistance is the CCR5-Δ32 variant. The CCR5-Δ32 variant along with SNPs in the CCR5 promoter and the CCR2-V64I variant have been included in seven human haplogroups (HH) previously associated with resistance/susceptibility to HIV-1 infection and different rates of AIDS progression. This study determined the association of the CCR5 promoter SNPs, the CCR5-Δ32 mutation, CCR2-V64I SNP, and HH frequencies with resistance/susceptibility to HIV-1 infection in a cohort of HIV-1-serodiscordant couples from Colombia. The CCR5-Δ32 allele is not responsible for HIV-1 resistance in this HESN group; however, the CCR2-I allele could be protective, while the 29G allele might increase the likelihood of acquiring HIV-1 infection. HHG1 and the AGACCAC-CCR2-I-CCR5 wild-type haplotype might promote HIV-1 infection while HHF2 might be related to resistance. PMID 31686727: Moudi et al. (2019) - study evaluated the association between the CCR5-Δ32, CCR5-2459A/G, MCP-1-2518A/G, VDR-APa1A/C, VDR-Taq1T/C SNPs and HBV susceptibility, in samples of Iranian populations. Significant associations with susceptibility to chronic HBV infection was observed with CCR5-2459A/G, MCP1-2518A/G, VDR-APa1A/C, VDR-Taq1T/C polymorphisms. In addition, no association of the CCR5D32 SNP with the disease was found. PMID:31100442 - Koor et al. (2019) - 9 CCR5 haplotypes are defined by seven 5'UTR SNPs in HIV-1 disease. Study identified key SNPs in HIV-1 control in both controllers and progressors. |
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| COVID-19 research v1.1 | DAG1 |
Rebecca Foulger changed review comment from: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): The DAG1 gene encodes 2 dystroglycan proteins, both of which are dystrophin-associated glycoproteins (DAGs) (OMIM:128239). Alpha-Dystroglycan (a-DG) is a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus (Imperiali et al. 2005; Kunz et al. 2009; Rojek et al. 2007). PubMed 16254364: Imperiali et al. (2005) - alpha-Dystroglycan (a-DG) was identified as a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus. Arenaviruses are enveloped, single-stranded RNA viruses with a bisegmented ambisense genome. Susceptibility toward LCMV infection differed in various cell lines despite them expressing comparable levels of DG, suggesting that posttranslational modifications of a-DG would be involved in viral receptor function. Demonstrated that glycosylation of a-DG, and in particular, O mannosylation, which is a rare type of O-linked glycosylation in mammals, is essential for LCMV receptor function. Cells that are defective in components of the O-mannosylation pathway showed strikingly reduced LCMV infectibility. As defective O mannosylation is associated with severe clinical symptoms in mammals such as congenital muscular dystrophies, it is likely that LCMV and potentially other arenaviruses may have selected this conserved and crucial posttranslational modification as the primary target structure for cell entry and infection. PMID 19324387: Kunz et al. (2009) - Old World arenaviruses LCMV (lymphocytic choriomeningitis virus) and LASV (Lassa virus) enter the host cell predominantly via a novel and unusual endocytotic pathway independent of clathrin, caveolin, dynamin, and actin. Infection of cells with LCMV and LASV depends on DG, this unusual endocytotic pathway could be related to normal cellular trafficking of the DG complex. Arenavirus particles may target DG for an endocytotic pathway not normally used in uninfected cells thereby inducing an entry route specifically tailored to the pathogen's needs. PMID 17360738: Rojek et al. (2007) - Found that protein O mannosylation of α-DG is crucial for the binding of arenaviruses of distinct phylogenetic origins, including LFV, Mobala virus, and clade C New World arenaviruses. Observed that overexpression of LARGE in cells deficient in O mannosylation resulted in highly glycosylated α-DG that was functional as a receptor for arenaviruses. Demonstrate that arenaviruses recognize the same highly conserved O-glycan structures on α-DG involved in ECM protein binding, indicating a strikingly similar mechanism of receptor recognition by pathogen- and host-derived ligands. PMID 21185048: Oldstone et al. (2011) - Dendritic cells (DC)s express the highest levels of α-DG and are the sentinel cells that LCMV, and presumably also LFV, infect. The resultant infection of DCs compromises DC function. Determinant of injury is the displacement of laminin or other ECM molecules that bind to the same site on α-DG that LCMV and LFV seek. When ECM molecules are pushed aside, the virus destabilizes membranes and causes interference with ECM signals that are required to maintain homeostasis. PMID 15857984: Kunz et al. (2005) Show that LFV (Lassa fever virus) binds to α-DG with high affinity in the low-nanomolar range. Recombinant vesicular stomatitis virus pseudotyped with LFV glycoprotein (GP) adopted the receptor binding characteristics of LFV and depended on α-DG for infection of cells. LFV was found to efficiently compete with laminin α1 and α2 chains for α-DG binding. LCMV uses the same domains of α-DG for binding that are used in LFV binding. Findings indicate a high degree of conservation in the receptor binding characteristics between the highly human-pathogenic LFV and murine-immunosuppressive LCMV isolates.; to: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): The DAG1 gene encodes 2 dystroglycan proteins, both of which are dystrophin-associated glycoproteins (DAGs) (OMIM:128239). Alpha-Dystroglycan (a-DG) is a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus (Imperiali et al. 2005; Kunz et al. 2009; Rojek et al. 2007). PubMed 16254364: Imperiali et al. (2005) - alpha-Dystroglycan (a-DG) was identified as a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus. Arenaviruses are enveloped, single-stranded RNA viruses with a bisegmented ambisense genome. Susceptibility toward LCMV infection differed in various cell lines despite them expressing comparable levels of DG, suggesting that posttranslational modifications of a-DG would be involved in viral receptor function. Demonstrated that glycosylation of a-DG, and in particular, O mannosylation, which is a rare type of O-linked glycosylation in mammals, is essential for LCMV receptor function. Cells that are defective in components of the O-mannosylation pathway showed strikingly reduced LCMV infectibility. As defective O mannosylation is associated with severe clinical symptoms in mammals such as congenital muscular dystrophies, it is likely that LCMV and potentially other arenaviruses may have selected this conserved and crucial posttranslational modification as the primary target structure for cell entry and infection. PMID 19324387: Kunz et al. (2009) - Old World arenaviruses LCMV (lymphocytic choriomeningitis virus) and LASV (Lassa virus) enter the host cell predominantly via a novel and unusual endocytotic pathway independent of clathrin, caveolin, dynamin, and actin. Infection of cells with LCMV and LASV depends on DG, this unusual endocytotic pathway could be related to normal cellular trafficking of the DG complex. Arenavirus particles may target DG for an endocytotic pathway not normally used in uninfected cells thereby inducing an entry route specifically tailored to the pathogen's needs. PMID 17360738: Rojek et al. (2007) - Found that protein O mannosylation of α-DG is crucial for the binding of arenaviruses of distinct phylogenetic origins, including LFV, Mobala virus, and clade C New World arenaviruses. Observed that overexpression of LARGE in cells deficient in O mannosylation resulted in highly glycosylated α-DG that was functional as a receptor for arenaviruses. Demonstrate that arenaviruses recognize the same highly conserved O-glycan structures on α-DG involved in ECM protein binding, indicating a strikingly similar mechanism of receptor recognition by pathogen- and host-derived ligands. PMID 21185048: Oldstone et al. (2011) - Dendritic cells (DC)s express the highest levels of α-DG and are the sentinel cells that LCMV, and presumably also LFV, infect. The resultant infection of DCs compromises DC function. Determinant of injury is the displacement of laminin or other ECM molecules that bind to the same site on α-DG that LCMV and LFV seek. When ECM molecules are pushed aside, the virus destabilizes membranes and causes interference with ECM signals that are required to maintain homeostasis. PMID 15857984: Kunz et al. (2005) show that LFV (Lassa fever virus) binds to α-DG with high affinity in the low-nanomolar range. Recombinant vesicular stomatitis virus pseudotyped with LFV glycoprotein (GP) adopted the receptor binding characteristics of LFV and depended on α-DG for infection of cells. LFV was found to efficiently compete with laminin α1 and α2 chains for α-DG binding. LCMV uses the same domains of α-DG for binding that are used in LFV binding. Findings indicate a high degree of conservation in the receptor binding characteristics between the highly human-pathogenic LFV and murine-immunosuppressive LCMV isolates. |
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| COVID-19 research v0.373 | IRF5 |
Rebecca Foulger commented on gene: IRF5: PMID:30457675. Chow et al., 2019 examined IRF5-dependent gene expression and found that loss of IRF5 in mice resulted in modest and subtle changes in the expression of West Nile Virus (WNV)-regulated genes. 15320958 |
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| COVID-19 research v0.373 | IRF5 | Rebecca Foulger commented on gene: IRF5: PMID:21240265. Krausgruber et al., 2011 state that polymorphisms in IRF5 that lead to higher mRNA expression are associated with many autoimmune diseases. Global gene expression analysis demonstrated that exogenous IRF5 upregulated or downregulated expression of established phenotypic markers of M1 or M2 macrophages, respectively, defining a role for IRF5 as a transcriptional repressor. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.371 | TNFSF10 | Rebecca Foulger Added comment: Comment on list classification: Kept the Amber rating initially suggested by Illumina curation team: plays a role in viral surveillance, and virus can modulate TNFSF10 (TRAIL) signaling. Many studies look at expression levels following infection. No direct susceptibility studies, so Amber appropriate. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.369 | TNFSF10 | Rebecca Foulger changed review comment from: Summary of literature: TNFSF10/TRAIL is a death ligand that contributes to immune surveillance against virus-infected cells via the death receptor TNFRSF10B/DR5. TNFSF10 binding induces the caspase cascade to kill the virus-infected cell. Many viruses evade antiviral immunity by modulating TNFSF10 receptor signaling.; to: Summary of literature: TNFSF10/TRAIL is a death ligand that contributes to immune surveillance against virus-infected cells via the death receptor DR5. TNFSF10 binding induces the caspase cascade to kill the virus-infected cell. Many viruses evade antiviral immunity by modulating TNFSF10 receptor signaling. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.369 | TNFSF10 | Rebecca Foulger commented on gene: TNFSF10: Summary of literature: TNFSF10/TRAIL is a death ligand that contributes to immune surveillance against virus-infected cells via the death receptor TNFRSF10B/DR5. TNFSF10 binding induces the caspase cascade to kill the virus-infected cell. Many viruses evade antiviral immunity by modulating TNFSF10 receptor signaling. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.366 | TPH1 |
Sarah Leigh changed review comment from: TPH1 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping). Using lymphocytic choriomeningitis virus in a Cd8-positive T cell-dependent mouse model of immunopathologic hepatitis, PMID 18516052 showed that Tph1-deficient mice, but not wildtype mice, normalized hepatic microcirculatory dysfunction, accelerated clearance of virus from liver, and reduced Cd8-positive T cell-dependent liver cell damage (reviewed by Alison Coffey and team, Illumina).; to: TPH1 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping). TPH1 is part of the pathway for the synthesis of the neurotrasmitter serotonin. Using lymphocytic choriomeningitis virus in a Cd8-positive T cell-dependent mouse model of immunopathologic hepatitis, PMID 18516052 showed that Tph1-deficient mice, but not wildtype mice, normalized hepatic microcirculatory dysfunction, accelerated clearance of virus from liver, and reduced Cd8-positive T cell-dependent liver cell damage, therefore it has been concluded that vasoactive serotonin supports virus persistence in liver and aggravates virus-induced immunopathology. (reviewed by Alison Coffey and team, Illumina). |
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| COVID-19 research v0.365 | TNFSF4 |
Sarah Leigh changed review comment from: TNFSF4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping). Tumor necrosis factor (TNF) family cytokines function as prominent mediators of immune regulation and the inflammatory response. Most TNF family cytokines are expressed as type II transmembrane proteins, with homology confined to approximately 150 C-terminal residues. The TNF ligands interact with a parallel family of receptors (reviewed by Alison Coffey and team, Illumina). TNFSF4 is a cell surface glycoprotein antigen that is expressed in T-cell leukemia virus type 1 (HTLV-1) infected human cells (PMID 7913952;8076595). Functional analysis showed that anti-TNFSF4 monoclonal antibody inhibited T-cell proliferation (PMID 11359859).; to: TNFSF4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping). Tumor necrosis factor (TNF) family cytokines function as prominent mediators of immune regulation and the inflammatory response. Most TNF family cytokines are expressed as type II transmembrane proteins, with homology confined to approximately 150 C-terminal residues. The TNF ligands interact with a parallel family of receptors (reviewed by Alison Coffey and team, Illumina). TNFSF4 is a cell surface glycoprotein antigen that is expressed in T-cell leukemia virus type 1 (HTLV-1) infected human cells (PMID 7913952;8076595). Functional analysis showed that anti-TNFSF4 monoclonal antibody inhibited T-cell proliferation (PMID 11359859). PMID 31725732: suggests that TNFSF4, one of the major causative cytokine factors in African swine fever virus pathogenesis, via inducing apoptosis. |
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| COVID-19 research v0.364 | TLR4 | Sarah Leigh changed review comment from: Comment on list classification: Although this gene has not been associated with a phenotype in OMIM nor Gen2Phen, an animal model and two population studies indicate that deletion or the minor alleles of rs4986790 or rs4986791 are all associated with susceptibility to respiratory syncytial virus (RSV). The recently published article speculates that TLR4 could be involved in recognizing SARS‐CoV‐2 and proposes the selective targeting of TLR4‐spike protein interaction to treat COVID‐19 (PMID 32383269).; to: Comment on list classification: Although this gene has not been associated with a phenotype in OMIM nor Gen2Phen, an animal model and two population studies indicate that deletion or the minor alleles of rs4986790 or rs4986791 are all associated with susceptibility to respiratory syncytial virus (RSV). The recently published article speculates that TLR4 could be involved in recognizing SARS‐CoV‐2 and proposes the selective targeting of TLR4‐spike protein interaction to treat COVID‐19 (PMID 32383269). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.364 | TLR4 |
Sarah Leigh changed review comment from: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping). PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina). PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T399I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection. PMID 17709532 also found that the same minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for p.D299G and p.T399I compared with control frequencies of 10.5% and 6.5%, respectively. PMID 32383269 reports that: cell surface TLR4 is most likely to be involved in recognizing molecular patterns from SARS‐CoV‐2 and speculates that selective targeting of TLR4‐spike protein interaction by designing competitive TLR4‐antagonists could pave a new way to treat COVID‐19.; to: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping). PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina). PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T399I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection. PMID 17709532 also found that the same minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for p.D299G and p.T399I compared with control frequencies of 10.5% and 6.5%, respectively. PMID 32391647 reports: Hyperactivated B cell and TLR4 signalling pathway were observed in WT HBV-carrier mice, while TLR4 ablation failed to induce B cell hyperactivation, and downstream MyD88 and NF-κB were also not altered. Taken together, TLR4 pathway plays a pivotal role in B cell hyperactivation during CHB, which might serve as a promising target for B cell function restoration. PMID 32383269 reports that: cell surface TLR4 is most likely to be involved in recognizing molecular patterns from SARS‐CoV‐2 and speculates that selective targeting of TLR4‐spike protein interaction by designing competitive TLR4‐antagonists could pave a new way to treat COVID‐19. |
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| COVID-19 research v0.362 | TLR4 | Sarah Leigh changed review comment from: Comment on list classification: Although this gene has not been associated with a phenotype in OMIM nor Gen2Phen, an animal model and two population studies indicate that deletion or the minor alleles of rs4986790 or rs4986791 are all associated with susceptibility to respiratory syncytial virus (RSV).; to: Comment on list classification: Although this gene has not been associated with a phenotype in OMIM nor Gen2Phen, an animal model and two population studies indicate that deletion or the minor alleles of rs4986790 or rs4986791 are all associated with susceptibility to respiratory syncytial virus (RSV). The recently published article speculates that TLR4 could be involved in recognizing SARS‐CoV‐2 and proposes the selective targeting of TLR4‐spike protein interaction to treat COVID‐19 (PMID 32383269). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.362 | TLR4 |
Sarah Leigh changed review comment from: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping). PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina). PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T399I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection. PMID 17709532 also found that the same minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for p.D299G and p.T399I compared with control frequencies of 10.5% and 6.5%, respectively.; to: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping). PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina). PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T399I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection. PMID 17709532 also found that the same minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for p.D299G and p.T399I compared with control frequencies of 10.5% and 6.5%, respectively. PMID 32383269 reports that: cell surface TLR4 is most likely to be involved in recognizing molecular patterns from SARS‐CoV‐2 and speculates that selective targeting of TLR4‐spike protein interaction by designing competitive TLR4‐antagonists could pave a new way to treat COVID‐19. |
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| COVID-19 research v0.351 | TLR4 |
Sarah Leigh changed review comment from: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping). PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina). PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T359I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection. PMID 17709532 also found that the same minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for D299G and T399I compared with control frequencies of 10.5% and 6.5%, respectively.; to: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping). PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina). PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T399I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection. PMID 17709532 also found that the same minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for p.D299G and p.T399I compared with control frequencies of 10.5% and 6.5%, respectively. |
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| COVID-19 research v0.351 | TLR4 |
Sarah Leigh changed review comment from: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping). PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina). PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T359I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection. PMID 17709532 also found that the minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for D299G and T399I compared with control frequencies of 10.5% and 6.5%, respectively.; to: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping). PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina). PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T359I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection. PMID 17709532 also found that the same minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for D299G and T399I compared with control frequencies of 10.5% and 6.5%, respectively. |
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| COVID-19 research v0.350 | TLR4 |
Sarah Leigh changed review comment from: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping). PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses. PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T359I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection. PMID 17709532 also found that the minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for D299G and T399I compared with control frequencies of 10.5% and 6.5%, respectively.; to: TLR4 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping). PMID 1106249 found that proinflammatory cytokine responses to respiratory syncytial virus (RSV) F protein were reduced in mice with deletions of Tlr4. The lungs of Tlr4 -/- mice had high levels of infectious virus and were either unable to clear the virus or took longer to clear it, in comparison with wt mice. Suggesting that TLR4 is involved in innate immune responses to viruses (reviewed by Alison Coffey and team, Illumina). PMID 17579031 showed that: production of IL8, IL6, and other cytokines in response to RSV was reduced in bronchial epithelial cells transfected with TLR4 constructs containing rs4986790 p.D299G or rs4986791 p.T359I, compared with cells expressing TLR4 with major alleles. The authors suggest that these variants compromise the first-line defense against RSV and confer increased susceptibility to severe bronchiolitis after RSV infection. PMID 17709532 also found that the minor alleles were assosiated with symptomatic RSV disease in a mostly premature population, with 89.5% and 87.6% of patients being heterozygous for D299G and T399I compared with control frequencies of 10.5% and 6.5%, respectively. |
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| COVID-19 research v0.350 | TLR4 | Sarah Leigh Added comment: Comment on list classification: Although this gene has not been associated with a phenotype in OMIM nor Gen2Phen, an animal model and two population studies indicate that deletion or the minor alleles of rs4986790 or rs4986791 are all associated with susceptibility to respiratory syncytial virus (RSV). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.349 | HDAC6 |
Rebecca Foulger commented on gene: HDAC6: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): Histone deacetylase 6 (HDAC6) is a unique cytoplasmic deacetylase that regulates various important biological processes by preventing protein aggregation and deacetylating different non-histone substrates. Growing evidence has indicated a dual role for HDAC6 in viral infection and pathogenesis: HDAC6 may represent a host defence mechanism against viral infection by modulating microtubule acetylation, triggering antiviral immune response and stimulating protective autophagy, or it may be hijacked by the virus to enhance proinflammatory response (Zheng et al, 2017). HDAC6 promotes the aggresome/autophagic degradation of the viral polyprotein Pr55Gag to inhibit HIV-1 production and infection (Hernández et al, 2019). Depletion of HDAC6 expression (in vitro) led to impaired antiviral responses against RNA viruses, but not against DNA viruses. HDAC6 knockout mice were highly susceptible to RNA virus infections compared to wildtype mice (Choi et al, 2016). Overexpression of Hdac6 enhances resistance to virus infection in embryonic stem cells and in mice (Wang et al, 2015). Literature: PMID: 27959772 - Zheng et al. (2017) (Review) This review highlights current data illustrating the complexity and importance of HDAC6 in viral pathogenesis. HDAC6 has both proviral and antiviral effects. HDAC6 can inhibit infection of both RNA and DNA virus by modulating microtubule (MT) cytoskeleton and stimulating selective autophagy and restrict viral diffusion by triggering antiviral immune response. However, RNA viruses can also utilize HDAC6-mediated aggresome pathway or proinflammatory response to facilitate viral pathogenesis (Fig 1 and Table 1) • HDAC6 triggers antiviral gene expression upon RNA virus infection (Fig 3a) • HDAC6 interacts with Vif or A3G and competes for Vif–A3G interaction through its BUZ domain, impairs the incorporation of Vif into nascent virions and finally controls HIV-1 infectiveness (Fig 4) • HDAC6 facilitates viral uncoating and pathogenesis (Fig 5) Findings support exploration of a potential therapeutic role for restricting viral pathogenesis by targeting HDAC6. PMID: 31736889: Hernández et al. (2019) - HIV Nef is a central auxiliary protein in HIV infection and pathogenesis. Results from the study indicate that HDAC6 promotes the aggresome/autophagic degradation of the viral polyprotein Pr55Gag to inhibit HIV-1 production • HIV-1 Nef viral protein induces HDAC6 Degradation (Enzyme degradation by recombinant HIV-1 Nef in HEK-293T cells in both endogenous and over expressed HDAC6 is shown in Fig 1) • Mutated Nef protein Nef-PPAA did not promote HDAC6 degradation (Figure 3A, quantified in Figure 3B). This fact may indicate that this motif is involved in Nef-mediated HDAC6 interaction and/or processing, or that a conformational change in the mutated viral protein abrogates the degradative activity observed with the wt-Nef (Figures 1–3) • Nef assures viral production and infection by targeting HDAC6, stabilizing Pr55Gag and Vif, thereby facilitating Pr55Gag location and aggregation at plasma membrane, and subsequent virus production and infection capacity (events summarized by schematic illustrations in Figure 10) PMID: 26746851: Choi et al. (2016) - HDAC6 plays an important role in the antiviral immune response by producing IFNs and proinflammatory cytokines in responses to foreign RNA viruses. HDAC6+/+ and HDAC6-/- mice were intravenously infected with vesicular stomatitis virus (VSV, Indiana strain). Results show that • HDAC6-/- mice are more susceptible to VSV-Indiana infection than HDAC6+/+ mice and showed significantly decreased survival rate (Fig 1A) • Virus titers were significantly higher and IFN-b and IL-6 production was markedly lower in HDAC6-/- mice than in HDAC6+/+ mice (Fig 1D and E) • Role of HDAC6 in cytokine induction by poly(I:C), which is a synthetic double-stranded RNA (dsRNA): Intravenous injection of poly(I:C) caused the rapid and robust induction of IFN-b and IL-6 in HDAC6+/+ mice; however, induction of these cytokines was significantly reduced in HDAC6-/-mice (Fig 1F). In vitro • HDAC6 deficiency reduces the innate immune response on mouse macrophage and mouse embryonic fibroblast (Fig 3) • HDAC6 and RIG-I transiently interact in response to RNA viral infection (Fig 5A and B) and HDAC6 regulates the binding of RIG-I to 50 pppdsRNA by deacetylating RIG-I (Fig 5G) PMID: 25482409 Wang et al. (2015) - This is another study that provides a proof of principle of antivirus function by Hdac6 in vivo. HDAC6 overexpression significantly enhances resistance to avian H5N1 virus infection and extends the survival rate in Hdac6tg mice (transgenic) (Fig 2). Also, ES cells overexpressing Hdac6 displayed resistance to infection by adenovirus at high titers (Fig 1). |
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| COVID-19 research v0.349 | DAG1 |
Rebecca Foulger commented on gene: DAG1: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): The DAG1 gene encodes 2 dystroglycan proteins, both of which are dystrophin-associated glycoproteins (DAGs) (OMIM:128239). Alpha-Dystroglycan (a-DG) is a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus (Imperiali et al. 2005; Kunz et al. 2009; Rojek et al. 2007). PubMed 16254364: Imperiali et al. (2005) - alpha-Dystroglycan (a-DG) was identified as a common receptor for lymphocytic choriomeningitis virus (LCMV) and several other arenaviruses including the human pathogenic Lassa fever virus. Arenaviruses are enveloped, single-stranded RNA viruses with a bisegmented ambisense genome. Susceptibility toward LCMV infection differed in various cell lines despite them expressing comparable levels of DG, suggesting that posttranslational modifications of a-DG would be involved in viral receptor function. Demonstrated that glycosylation of a-DG, and in particular, O mannosylation, which is a rare type of O-linked glycosylation in mammals, is essential for LCMV receptor function. Cells that are defective in components of the O-mannosylation pathway showed strikingly reduced LCMV infectibility. As defective O mannosylation is associated with severe clinical symptoms in mammals such as congenital muscular dystrophies, it is likely that LCMV and potentially other arenaviruses may have selected this conserved and crucial posttranslational modification as the primary target structure for cell entry and infection. PMID 19324387: Kunz et al. (2009) - Old World arenaviruses LCMV (lymphocytic choriomeningitis virus) and LASV (Lassa virus) enter the host cell predominantly via a novel and unusual endocytotic pathway independent of clathrin, caveolin, dynamin, and actin. Infection of cells with LCMV and LASV depends on DG, this unusual endocytotic pathway could be related to normal cellular trafficking of the DG complex. Arenavirus particles may target DG for an endocytotic pathway not normally used in uninfected cells thereby inducing an entry route specifically tailored to the pathogen's needs. PMID 17360738: Rojek et al. (2007) - Found that protein O mannosylation of α-DG is crucial for the binding of arenaviruses of distinct phylogenetic origins, including LFV, Mobala virus, and clade C New World arenaviruses. Observed that overexpression of LARGE in cells deficient in O mannosylation resulted in highly glycosylated α-DG that was functional as a receptor for arenaviruses. Demonstrate that arenaviruses recognize the same highly conserved O-glycan structures on α-DG involved in ECM protein binding, indicating a strikingly similar mechanism of receptor recognition by pathogen- and host-derived ligands. PMID 21185048: Oldstone et al. (2011) - Dendritic cells (DC)s express the highest levels of α-DG and are the sentinel cells that LCMV, and presumably also LFV, infect. The resultant infection of DCs compromises DC function. Determinant of injury is the displacement of laminin or other ECM molecules that bind to the same site on α-DG that LCMV and LFV seek. When ECM molecules are pushed aside, the virus destabilizes membranes and causes interference with ECM signals that are required to maintain homeostasis. PMID 15857984: Kunz et al. (2005) Show that LFV (Lassa fever virus) binds to α-DG with high affinity in the low-nanomolar range. Recombinant vesicular stomatitis virus pseudotyped with LFV glycoprotein (GP) adopted the receptor binding characteristics of LFV and depended on α-DG for infection of cells. LFV was found to efficiently compete with laminin α1 and α2 chains for α-DG binding. LCMV uses the same domains of α-DG for binding that are used in LFV binding. Findings indicate a high degree of conservation in the receptor binding characteristics between the highly human-pathogenic LFV and murine-immunosuppressive LCMV isolates. |
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| COVID-19 research v0.349 | BECN1 |
Rebecca Foulger commented on gene: BECN1: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): BECN1 encodes the beclin1 protein which is an established regulator of the autophagic pathway. Autophagy is a key mechanism against invading bacteria, parasites, and viruses in innate immune cells including monocytes/macrophages, dendritic cells and neutrophils (reviewed in Tao et al. 2020). Viral proteins such as HIV-1 Nef, ICP34.5 of HSV-1 and M11 of MHV-68 have been shown to interact with Beclin-1 and block the late stage of autophagy, thereby protecting viral particles from degradation (Kyei et al 2009; Orvedahl et al. (2007); Ku et al. (2008) PMID:32265919 Tao et al. 2020 (review) - Autophagy is a key mechanism against invading bacteria, parasites, and viruses in innate immune cells including monocytes/macrophages, dendritic cells (conventional dendritic cells-cDCs and plasmacytoid dendritic cells-pDCs) and neutrophils. BECN1 encodes beclin1 protein which is an established regulator of the autophagic pathway. Viral proteins may target BECN1 to inhibit autophagy. PMID: 19635843 Kyei et al. (2009) - A series of experiments showed that the Nef protein of HIV inhibits the autophagic maturation pathway (fig 5). Macrophages transfected with Nef-GFP showed colocalization of Nef with Beclin-1 and the two proteins were shown to physically interact in immunoprecipitation experiments (Fig6). PMID: 18248095 Ku et al. (2008) - In NIH3T3 cell culture studies, the M11, a viral BCL-2 of murine gamma herpesvirus 68 was shown to bind Beclin-1 and to inhibit to inhibit Beclin-1 mediated autophagy (Fig 4). PMID: 18005679 Orvedahl et al. (2007) - The authors used coimmunoprecipitation experiments in both HEK293 cells and embryonic stem cells to show that the neurovirulence protein of Herpes simplex virus (HSV)-1, ICP34.5, binds to the C terminus of BECN1 (Fig 2). In MCF7 stably expressing BECN1cells, transfection of the ICP34.5 inhibited autophagy (Fig 2). Mutant HSV-1 lacking the ICP34.5 BECN1-binding domain failed to inhibit autophagy in primary sympathetic neurons (Fig 5A) and had impaired ability to cause lethal encephalitis in mice (Fig 6) . |
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| COVID-19 research v0.349 | CXCL8 |
Rebecca Foulger commented on gene: CXCL8: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): • CXCL8 is a proinflammatory chemokine that plays a role in inflammatory response and immune cell trafficking • Multiple studies show IL-8 levels were shown to be elevated in plasma of patients with COVID-19, SARS-CoV, or MERS-CoV compared to controls. These include a number of recent COVID-19 studies (Coperchini et al. 2020). • Higher levels were detected in more severe cases (Gong et al. 2020; Qin et al. 2020; Yan et al. 2020), although one study shows the levels are within the normal range (Qin et al. 2020) • Gong et al. (2020) suggest that IL-8 might be a therapeutic target COVID-19 Literature: PMID 32446778; Coperchini et al. (2020) • Review article describing the involvement of chemokine/chemokine-receptor system in COVID-19 • Discusses the concept of cytokine storm where the immune system is ‘attacking’ the body resulting in acute respiratory distress syndrome. • Multiple studies are mentioned that show high levels of CXCL8 in the plasma and broncho-alveolar fluid in patients with acute respiratory distress syndrome. Reference a paper that notes that pre-treatment with an anti-CXCL8 antibody prevented acute lung injury that generally develops. • In vivo studies showed elevated CXCL8 in patients with SARS-CoV. • In vitro studies where peripheral blood mononuclear cells from healthy donor inoculated with SARS-CoV showed enhancement in the expression of CXCL8 • Similarly, CXCL8 was upregulated in cells lysates when with MERS-CoV infection of polarized airway epithelial cells (higher expression than SARS-CoV). • Higher plasma levels of CXCL8 in patients with COVID-19 compared to healthy controls; however, transcription of CSCL8 was not upregulated MedRxiv; Gong et al. (2020) • Evaluated disease severity in a total of 100 patients with COVID-19 pneumonia • CXCL8 (IL-8 in this paper) was detected in these patients and IL-8 levels were shown to be associated with disease severity (P<0.001); significant differences were noted between critical and severe patients or critical and mild groups (Tables 2 and 3) • Suggest that IL-8 might be a therapeutic target COVID-19 PMID 32161940; Qin et al. (2020) • Retrospective study of 452 patients with COVID-19; severity of COVID-19 defined according to the Fifth Revised Trial Version of the Novel Coronavirus Pneumonia Diagnosis and Treatment Guidance • Clinical and laboratory data were collected • A majority of the severe cases (n=286) had elevated levels of IL-8 (18.4 pg/mL vs 13.7 pg/mL, respectively; p<0.001) compared to the nonsevere cases (n=166), although they were all in the normal (0-62.0 pg/mL) (Table 2) MedRxiv; Yan et al. (2020) • Identified 25 genes that showed highly conserved kinetics in COVID-19 patients • Figure 3F shows expression of CXCL8 and plasma levels of IL-8 from four individuals with COVID-19 compared to four healthy controls was higher in patients especially in the severe stage (p<0.001) PMID 15585888; Chang et al. (2004) • Introduction has a summary of previously published papers and notes that high serum levels of IL-8 were detected during acute phase and associated with lung lesions in patients with SARS in one study. Another study suggests use of corticosteroids in reducing pulmonary inflammation due to IL-8. • Chang et al. (2004) used transient transfection of the SARS-CoV S protein-encoding plasmid on the IL-8 promoter. Measure of IL-8 release in lung cells showed an upregulation of IL-8 release. In addition, a specific region of the S protein was identified as a potentially important region for inducing IL-8 release. There are additional case-control studies suggesting possible association of polymorphisms in CXCL8 and acute bronchiolitis susceptibility (Pinto et al. 2017; PMID 27890033), asthma (Charrad et al. 2017; PMID 28993876), or human papillomavirus infection (weaker evidence; Junior et al. 2016; PMID 27783717). |
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| COVID-19 research v0.349 | VPS11 |
Rebecca Foulger commented on gene: VPS11: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): The VPS11 gene encodes a protein which is part of the homotypic fusion and vacuole protein-sorting (HOPS) complex that mediates fusion of endosome and lysosomes; VPS11 is involved in late-stage endosome to lysosome maturation. In HAP1 cells mutagenized with a retroviral gene-trap vector, mutations in VSP11 were enriched in Ebola virus-resistant cells. In addition, VPS11-deficient cells showed resistance to Ebola and Marburg virus compared to controls. Escape of the Ebola virus to the cytoplasm was blocked in VPS11-deficient cells (Carette et al. 2011). In HeLa cells RNAi downregulation of VPS11 showed decreased relative percentage infection with mouse hepatitis coronavirus (MHV) and feline infectious peritonitis virus, with a larger effect for MHV (Burkard et al. 2014). Similarly, in HEK293 cells, luciferase activity of Ebola virus and SARS-CoV-S were reduced in siRNA downregulated VPS11 cells (Zhou et al. 2016). PMID 21866103; Carette et al. (2011) - Used retroviral gene-trap vector to mutagenize HAP1 cells. Identified genes enriched for mutations in vesicular stomatitis virus bearing the EboV glycoprotein (rVSV-GP-EboV)-resistant cells. Enriched for mutations in VPS11 as well as other subunits of the HOPS complex (six subunits including VPS11), which mediates fusion of endosome and lysosomes; VPS11 is involved in late-stage endosome to lysosome maturation. In addition, VPS11-deficient cells (using gene-trap insertions) showed resistance to infection with Marburg virus or Ebola virus (Figures 1C and Figure S4C) compared to controls. Ebola virus escape to the cytoplasm is blocked in VPS11-deficient cells compared to WT (Figure 3D) PMID 25375324; Burkard et al. (2014) - Evaluated entry of mouse hepatitis coronavirus (MHV) in HeLa cells with GFP-expressing MHV RNAi mediated downregulation of VPS11 (using three different siRNAs) showed the percentage of relative infection was reduced compared to negative siRNA controls (Figure 1C). Luciferase expressing feline infectious peritonitis virus (FIPV) was also evaluated in HeLa cells and RNAi mediated downregulation of VPS11 showed reduced relative infection for two of three siRNAs compared to negative siRNA controls (Figure 10) PMID 26953343; Zhou et al. (2016) - Study to evaluate effects of antibiotics on proteins involved in virus entry. SiRNA-mediated knockdown of VSP11 expression showed decreased relative luciferase activity in HEK293 cells infected with Ebola virus or SARS-CoV-S, but not with vesicular stomatitis virus. In addition, treatment with the glycopeptide antibiotic teicoplanin did not show an effect on the HOPS complex |
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| COVID-19 research v0.349 | RNASEL |
Rebecca Foulger commented on gene: RNASEL: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): RNASEL, also known as 2-5A-dependent RNase is a component of the interferon-regulated 2-5A system that functions in the antiviral interferon pathway. Treatment of cells with interferon results in enhanced levels of both 2-5A-dependent RNase and a group of synthetases that produce 5-prime-triphosphorylated, 2-prime,5-prime-oligoadenylates (2-5A) from ATP. The role of the 2-5A system in the control of viral and cellular growth suggests that defects in the 2-5A-dependent RNase gene could result in reduced immunity to virus infections and cancer (Hassel et al., 1993). Several studies aiming to identify a genetic association between RNASEL and viral susceptibility have failed to identified statistically significant SNPs (Yakub et al. 2005; Arredondo et al. 2012). However, there is sufficient experimental evidence, including a mouse model and in-vitro studies that RNASEL is an important contributor in host defence against several viruses (Gusho et al. 2016 (review); Zhou et al. 1997; Panda et al. 2019). PMID 27595182: Gusho et al. 2016 (review) - RNase L is a unique IFN-regulated endoribonuclease that serves as an important mediator of antiviral innate immunity with possible roles in antibacterial defense and prostate cancer. It is controlled by IFN-inducible oligo-adenylate synthetases (OASs) and double-stranded RNAs (dsRNAs). OAS-RNase L (Fig. 1) pathway, discovered in the mid-1970s, was one of the first IFN-dependent antiviral pathways to be characterized. OASs are IFN-I/-III-inducible genes that are expressed at very low basal levels in many cell types. OASs1-3 act as pathogen recognition receptors that sense dsRNAs and activate the synthesis of 5’-phosphorylated 2’-5’ linked oligoadenylates from ATP (2-5A). 2-5A acts as a second messenger and binds monomeric RNase L, and activates its dimer formation. Active RNase L cleaves cellular and viral RNAs within single-stranded regions. RNA degradation directly and indirectly activates subsequent events, including the elimination of viral genomes, inhibition of cellular and viral protein synthesis; and activation of several cellular signaling pathways, including those involved in autophagy, apoptosis, senescence, IFN-b production, and NLRP3-inflammasome activation as part of its antiviral mechanism (references provided). Authors state that many viruses have evolved or acquired strategies that antagonize the OAS-RNase L pathway to evade antiviral innate immunity. Some, such as Influenza A (IAV), HSV and Vaccinia virus act through an RNA-binding domain which binds to and sequesters dsRNA, the activator of OAS. Others bind directly to monomeric RNase L preventing it from activation by dimerization. Some coronaviruses (MERS-CoV and MHV) are described to act through their ns-domains with 2’-5’ PDE activity that degrades 2-5A and thus prevent activation of RNase L. Some additional evidence of interest: -OAS3 was shown to exert antiviral activity against Dengue virus in an RNase L-dependent manner, indicating that OAS3 synthesizes active 2-5A in sufficient amounts for RNase L activation -RNase L activation by dsRNA signaling or viral infection contributes to IFN-b production, indicating its important role in innate immunity. The ribonuclease function of RNase L is essential for its effect on IFN-b production -Moreover, mice deficient in RNase L had several-fold reduced levels of IFN-b induction after infection with RNA viruses (EMCV and Sendai virus) -Stable expression of wild-type human full-length RNase L, but not ribonuclease dead mutant (R667A), activates IL-1b and caspase 1 secretion in RNase L-deficient THP1 cells after virus infection or 2-5A transfection PMID 9351818: Zhou et al. (1997) RNASEL Mouse model To determine the physiological roles of the 2-5A system, mice were generated with a targeted disruption of the RNase L gene. The antiviral effect of interferon was impaired in RNaseL–/– mice providing the first evidence that the 2-5A system functions as an antiviral pathway in animals. Authors showed that EMCV replicates more efficiently in cells lacking RNase L than in wild type cells, even after interferon treatment, although the effect is relatively small. Next, authors determined that survival of RNaseL-/- mice after EMCV infection was significantly reduced both in presence and absence of IF (Fig 3). Enlarged thymus and reduced level of apoptosis in thymus and spleen were also found (Fig 4-5). PMID 31156620 Panda et al (2019) Interferon regulatory factor-1 (IRF1) regulates expression of RNaseL and knockdown of RNaseL in BEAS-2B cells resulted in significantly increased VSV infection rates. (Fig.6) PMID 22356654 Arredondo et al. 2012 Authors studied allelic variants in RNASEL gene at codon 462 (R462Q, rs486907) for susceptibility to viral infection, prostate cancer and chronic fatigue syndrome. The allelic distribution at codon 462 was 139 (33.9%), 204 (49.8%), and 67 (16.3%) for RR, RQ, and QQ, respectively, in 410 individuals in Spain. There were no significant differences comparing 105 blood donors and 71 patients with HIV-1 infection, 27 with chronic hepatitis C, 67 with prostate cancer, and 107 with chronic fatigue syndrome. In contrast, two-thirds of 18 patients with HTLV-1 infection and 15 with chronic hepatitis B harbored RR (Table 1). Thus, polymorphisms at the RNASEL gene do not seem to influence the susceptibility to common viral infections or conditions potentially of viral etiology. They conclude that the role in influencing the susceptibility to HTLV-1 or HBV chronic infection warrants further examination in larger patient populations. |
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| COVID-19 research v0.349 | PVR |
Rebecca Foulger commented on gene: PVR: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): PVR, or CD155, belongs to a large family of immunoglobulin (Ig)-like molecules called nectins and nectin-like proteins, which mediate cell-cell adhesion, cell migration, and cell polarization through interaction with other nectins. It is both a viral receptor and immunomodulatory protein and is involved in many biological processes. PVR serves as the entry receptor for poliovirus and thereby is responsible for human susceptibility to poliovirus infection. Susceptibility to poliovirus is a function of the presence or absence of the cellular receptor to which the virus binds as the first step in poliovirus replication. Mendelsohn et al. (1986) succeeded in transforming a human poliovirus receptor gene into mouse L cells, which are ordinarily resistant to poliovirus infection because they do not bear a poliovirus receptor. Monoclonal antibody directed against the HeLa cell poliovirus receptor site was used in rosette assays to identify poliovirus-sensitive transformants. Evidence for PVR as a Viral Receptor, regulator of immune function and its role in cancer is described in Bowers et al (2017). CD155-deficient mice develop normally without displaying an overt phenotype. However, the animals are distinguished by distinct deficits in the development of a regular humoral immune response (Maier et al, 2007) Literature: PMID: 28870470 - Bowers et al, 2017 (Review) - PVR is an important cell adhesion protein and is involved in the transendothelial migration of leukocytes. PVR undergoes alternative splicing, generating 4 unique splice forms. Protein isoforms and interactions with Poliovirus are summarized in Table 1. In addition to its role as a receptor for the human poliovirus, several native biological functions have also been uncovered. PVR is an important cell adhesion protein and is involved in the transendothelial migration of leukocytes. Through its interactions with CD226 and TIGIT, transmembrane proteins found on leukocytes, PVR is a key regulator of the cell-mediated immune response. In this review more evidence is available for PVR as a Viral Receptor and PVR as a regulator of immune function PMID: 25113908 - Bolduan et al, 2014 - NL4-3 Vpu protein from HIV downregulates the activating NK cell receptor CD155 from the cell surface by the conserved alanine residues Ala-10, Ala-14 and Ala-18 of its TM domain to evade NK cell mediated immune response against HIV-1 infected cells (Hela cells) PMID: 19815499 - Stanietsky et al, 2009 - TIGIT (a protein expressed by all human NK cells) binds PVR and PVRL2 but not PVRL3 and inhibits NK cytotoxicity directly through its ITIM. PMID: 12943679 - Baury et al, 2003 -As the extracellular domains of the sPVR (soluble PVR) isoforms are identical to the extracellular domain of transmembrane PVR, they can compete with transmembrane PVR for the canyon-like receptor binding site of poliovirus. When sPVR is overexpressed in poliovirus susceptible HeLa cells, it significantly reduces viral entry and viral infectivity PMID: 17621371 - Maier et al, 2007 - In this study, Maier et al explore the expression profile of CD155 on murine hematopoietic cells utilizing newly generated mAb. They report on the establishment and immunological analysis of mice deficient in CD155. CD155-deficient mice (knock out) develop normally without displaying an overt phenotype. However, the animals are distinguished by distinct deficits in the development of a regular humoral immune response. Whereas systemic challenges revealed no differences, orally administered antigen evoked less efficient IgG and IgA antibody responses (Figure 7) despite of normal IgM titers when compared to wild-type mice. Therefore, CD155 may assist in an efficient humoral immune response generated within the intestinal immune system. PMID: 28800489 - Lin et al, 2017 - Amino acid changes in the C’C”D region in poliovirus receptor domain 1 disrupt poliovirus binding. We substituted this region of Pvr into the corresponding region of a murine homolog, nectin-2. The chimeric receptor, nectin-2Pvr(c'c"d), rendered transformed L cells susceptible to infection with poliovirus P1/Mahoney, but not with polioviruses P2/ Lansing and P3/Leon, due to lack of binding. PMID: 2597248 - Kanemaru et al, 2015 - Mice genetically deficient in CD155 or treated with anti-CD155 Ab exhibited attenuated Th1-type contact hypersensitivity. Thus, CD155 plays an important regulatory role in helper T cell differentiation and allergic diseases. |
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| COVID-19 research v0.348 | PTX3 |
Rebecca Foulger commented on gene: PTX3: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): Pentraxins are a superfamily of conserved humoral mediators of innate immunity. PTX3, the prototypic long pentraxin, is a soluble pattern recognition molecule produced by several cell types in response to primary pro-inflammatory signals and microbial recognition. It is involved in the initiation of protective responses against select pathogens, acting as an important mediator of innate immunity against pathogens of fungal, bacterial and viral origin, and as a regulator of inflammation, by modulating complement activation and cell extravasation, and facilitating pathogen recognition by myeloid cells. It is an established biomarker in sepsis, with PTX3 plasma levels associated with severity of the condition, patient survival, and response to therapy. PTX3 has been characterized as a biomarker of severity and outcomes in different infections caused by bacteria, fungi or viruses. Patients with pulmonary aspergillosis, tuberculosis, dengue virus infection, meningococcal disease leptospirosis and shigellosis have increased PTX3 plasma levels that correlate with disease severity and could act as predictor of unfavourable outcomes (PMID 31031772: Porte et al. 2019). Several studies using Ptx3-deficient mice showed an increased susceptibility to fungal, bacterial and viral pathogens (Porte et al. 2019). In contrast, a study in PTX3-deficient (PTX3(-/-)) mice acutely infected with RRV exhibited delayed disease progression and rapid recovery through diminished inflammatory responses and viral replication (Foo et al. 2015). PTX3 administration has shown to be protective also against infections with Influenza virus, murine cytomegalovirus, Neisseria meningitidis, and P. aeruginosa in neonates and during chronic infections by reducing viral load and inflammatory pathology. (PMID 31031772: Porte et al. 2019, PMD 18292565: Reading et al. 2008). PMID: 25695775: Foo et al. (2015) - Found that pentraxin 3 (PTX3) was highly expressed in chikungunya virus (CHIKV) and Ross River virus (RRV) patients during acute disease. Overt expression of PTX3 in CHIKV patients was associated with increased viral load and disease severity. PTX3-deficient (PTX3(-/-)) mice acutely infected with RRV exhibited delayed disease progression and rapid recovery through diminished inflammatory responses and viral replication. Furthermore, binding of the N-terminal domain of PTX3 to RRV facilitated viral entry and replication. PMID: 18292565 - Reading et al. (2008) - Identified the long pentraxin PTX3 as a potent innate inhibitor of influenza viruses both in vitro and in vivo. Human and murine PTX3 bound to influenza virus and mediated a range of antiviral activities, including inhibition of hemagglutination, neutralization of virus infectivity and inhibition of viral neuraminidase. Antiviral activity was associated with binding of the viral hemagglutinin glycoprotein to sialylated ligands present on PTX3. Using a mouse model found PTX3 to be rapidly induced following influenza infection and that PTX3-/- mice were more susceptible than wild-type mice to infection by PTX3-sensitive virus strains. Therapeutic treatment of mice with human PTX3 promoted survival and reduced viral load in the lungs following infection with PTX3-sensitive, but not PTX3-resistant, influenza viruses. PMID 19968561: Bottazzi et al. (2010) (Review) - PTX3 binds to human and murine cytomegalovirus and influenza virus type A (IVA). The interaction between PTX3 and IVA occurs through binding of sialylated ligands on PTX3 to the viral hemagglutinin and results in neutralization of virus infectivity in vitro. Consistently, desialylated PTX3 does not bind IVA and does not neutralize virus infectivity. |
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| COVID-19 research v0.348 | NPC1 |
Rebecca Foulger commented on gene: NPC1: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): NPC1 encodes a polytopic protein that resides in the limiting membrane of late endosomes and lysosomes (LE/LY) and mediates distribution of lipoprotein-derived cholesterol in cells (Cote et al. (2011). NPC1 expression is critical for filovirus infection (EboV and MarV) and the mechanism of infection is not dependent on NPC1 cholesterol transport activity (Carette et al. 2011). Structural studies demonstrate that the C-domain of NPC1 binds to the primed EBOV glycoprotein (Wang et al. 2016; Gong et al. 2016). PMID 21866103: Carette et al. (2011) Genome-wide haploid genetic screen was performed in primary fibroblasts derived from human Niemann-Pick type C1 disease patients to identify host factors required for Filovirus infection. These cells are resistant to infection by EboV and MarV but remain fully susceptible to other unrelated viruses (Figure 2A, B). Resistance of NPC1-deficient cells was not caused by cholesterol transport defects (Fig S8). Infection in these cells was restored by expression of wild type NPC1 (Figure 2C). Similar results were observed in NPC1-null Chinese hamster ovary (CHO) cells, with loss of NPC1 conferring complete resistance to viral infection (Figure S6D) that was reversed by expression of human NPC1 (Figure S6E). Electron micrographs of NPC1 mutant cells infected with rVSV-GP-EboV indicate that NPC1 is required in downstream process in filovirus entry leading to viral membrane fusion and escape from the lysosomal compartment. Knockdown of NPC1 in HUVEC diminished infection by filoviruses (Figure 4D and S18) suggesting that NPC1 is critical for authentic filovirus infection. Furthermore, NPC1+/+ mice rapidly succumb to infection with either filovirus while NPC1−/+ mice were largely protected (Figure 4E). PMID 2186610: Cote et al. (2011) HeLa cells treated with benzylpiperazine adamantane diamide-derived compounds (3.0 and 3.47) developed cytoplasmic vacuoles indicating that that they target one or more proteins involved in regulation of cholesterol uptake in cells. CHO cells lacking NPC1 were completely resistant to infection by this virus and infection of these cells was fully restored when NPC1 was expressed. NPC1 expression but not NPC1-dependent cholesterol transport activity is essential for EboV infection (Fig 2c). 3.0-derived compounds inhibit EboV infection by interfering with binding of cleaved glycoprotein to NPC1 (Fig 4). PMID 26771495: Wang et al. (2016) The crystal structure of the primed glycoprotein (GPcl) of Ebola virus and domain C of NPC1 (NPC1-C) demonstrates that the NPC1-C binds to the primed EBOV GP (Fig 1, 3). Further, it suggests that a membrane-fusion-priming conformational change occurs in GPcl or the binding of GPcl, and this is a unique feature for all the filoviruses. NPC1-interacting compound 3.47 competitively blocks the primed GP binding to the membrane probably binds to the two protruding loops of NPC1-C. Compound U18666A binds to a different site on NPC1 causing endosomal calcium depletion. Furthermore, peptide inhibitors or small molecules, which can easily penetrate the cell membrane and reach the primed GP in the late endosomes could also act as potential therapeutic agents. PMID 27238017: Gong et al. (2016) Full-length human NPC1 and a low-resolution reconstruction of NPC1 in complex with the cleaved glycoprotein (GPcl) of EBOV was determined by single-particle electron cryomicroscopy. NPC1 contains 13 transmembrane segments (TMs) and three lumenal domains, A (NTD), C, and I. TMs 2–13 exhibit a typical resistance-nodulation-cell division fold, among which TMs 3–7 constitute the sterol-sensing domain conserved in several proteins involved in cholesterol metabolism and signaling. EBOV-GPcl binds to NPC1 through the domain C. |
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| COVID-19 research v0.348 | NECTIN1 |
Rebecca Foulger commented on gene: NECTIN1: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): Amino acid substitutions in nectin-1 showed impaired entry of Herpes simplex virus (HSV) into CHO-K1 cells (PMID:1175687;12072525). Nectin-1 knockout mice inoculated with HSV in the hippocampus demonstrated that nectin-1 is necessary for neurologic disease caused by HSV (PMID:19805039). PMID 11756979 - Struyf et al. (2002) - Searched for polymorphisms in HVEM, nectin-1, and nectin-2 via sequencing in individuals shown to immune seronegative for herpes simplex virus (HSV). These individuals showed T cell responses to HSV antigens and did not have anti-HSV antibodies detected in their serum. There were three individuals that were immune seronegative, three with no signs of cellular or humoral immunity, and three with frequent reactivations of HSV who had antibody and T cell responses to HSV. One individual in the study (true seronegative as demonstrated by negative testing for HSV-1 and HSV-2 and no HSV-specific T cell immunity) was identified to have a variant in nectin-1 (c.752G>A, p.Arg199Gln) in addition to one missense variant in HVEM (table 2). This variant was screened for 644 healthy White individuals and 17 were shown to be heterozygous for the p.Arg199Gln variant and one individual had a different missense variant at the same residue. The p.Arg199Gln variant occurs in the first constant-like domain for the protein. A different domain, the N-terminal variable-like domain, has previously been shown as important for virus entry into the cell. PMID 12072525 - Martinez and Spear (2002) - Investigated whether residues 75-77 and 85 of nectin-1 (homologous to regions A and B of nectin-2) are necessary for HSV-1 entry into CHO-K1 cells (which are resistant to the entry of alphaherpesviruses unless they are created to express a gD receptor). When there were mutants involving both residues 77 and 85, there was severely diminished ability of HSV-1 or HSV-2 to enter the cell and was unable to find to soluble forms of HSV-1 and HSV-2 (table 1; fig. 3). Note that these mutants allowed entry of PRV and BHV-1. PMID 19805039 - Kopp et al. (2009) - Nectin-1 knockout (KO) mice were inoculated intracranially and into the hippocampus with herpes simplex virus (HSV) and infection of neurons compared to HVEM KO mice, HVEM/nectin-1 KO mice, and controls. Nectin-1 KO mice were resistant to disease, as were the double KO mice at doses of the virus up to 100x needed to cause disease as compared to the wildtype and HVEM KO mice (Fig. 1). Nectin-1 is necessary for neurologic disease caused by HSV. Viral antigen was not detected in brain sections from double KO mice, but could be detected for nectin-1 KO mice (limited regions), HVEM-KO mice and wildtype (more widespread) (Fig. 2A). HSV was shown to be located to the ventricular surfaces in nectin-1 KO mice and confirmed as non-parenchymal cells (Fig. 2B). |
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| COVID-19 research v0.348 | MIR155 |
Rebecca Foulger commented on gene: MIR155: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): MIR155 (also referred to as BIC) is an endogenous noncoding RNA involved in regulation of the immune response, in particular T-cell differentiation, and in regulation of innate immunity (PMID: 32233818; 217121651;1746328969;20852130). This miRNA has been associated with various virus infections (PMID: 32233818;28139244;23686237;26072128). miR-155-5p expression has been shown to be induced in mice infected with influenza A virus (PMID: 32308197 - in this study, lung injury by ARDS was attenuated by deletion of miR-155, making this miRNA a potential therapeutic target in the context of COVID-19). Through single cell and bulk RNA profiling of SARS-CoV-2 and SARS-CoV infections in three human cell lines (H1299, Caco-2 and Calu-3 cells), Emanuel et al. (2020) (bioRxiv preprint doi: https://doi.org/10.1101/2020.05.05.079194) demonstrated strong expression of the immunity and inflammation-associated microRNA miRNA-155 upon viral infection with both viruses. Both viruses triggered a 16-fold upregulation of one form of miR-155 and a 3-fold upregulation of another. A role for MIR155 in viral susceptibility for a range of viruses and the immune response has also been demonstrated in a series of mouse models: PMID 23601686: In Mir155 -/- mice, Dudda et al. (2013) observed severely reduced accumulation of Cd8-positive T cells during acute and chronic viral infections with impaired control of viral replication. Lack of Mir155 led to an accumulation of Socs1 resulting in defective cytokine signaling through Stat5. Dudda et al. also concluded that MIR155 and its target, SOCS1, are key regulators of CD8-positive T cells. PMID 23275599: Lind et al. (2013) found that mice lacking Mir155 had impaired Cd8 positive T-cell responses to infections with lymphocytic choriomeningitis virus and the intracellular bacteria Listeria monocytogenes and concluded that MIR155 is required for acute CD8-positive T-cell responses and proposed that targeting MIR155 may be useful in modulating immune responses. PMID 24516198: Bhela et al. (2014) – 75 to 80% of MIR155 null mice infected ocularly with herpes simplex virus (HSV)-1 developed herpes simplex encephalitis with elevated viral titers in brain, but not in cornea. Immunohistochemical and flow cytometric analyses in Mir155-null mice showed diminished Cd8-positive T-cell numbers, functionality, and homing capacity. Adoptive transfer of HSV-1-immune Cd8-positive T cells to Mir155-null mice 24 hours after infection provided protection from HSE. The authors concluded that MIR155 deficiency results in enhanced susceptibility of the nervous system to HSV-1 infection. |
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| COVID-19 research v0.348 | KLF2 |
Rebecca Foulger commented on gene: KLF2: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): KLF2 is a member of the Kruppel-like factor (KLF) family of zinc finger transcription factors that function in cell differentiation, quiescence, and homeostasis. It also plays a regulatory role in inflammation-related pathways (Jha and Das 2017). Richardson et al. (2012) showed that KLF2 acts as a host factor that modulates CCR5 expression in CD4 T cells and influences susceptibility to infection with CCR5-dependent HIV-1 strains. Huang et al. (2017) showed through both network analyses and experimental results that KLF2 plays a central role in regulating many genes associated with acute respiratory distress syndrome (ARDS) identified by GWAS and that overexpression of KLF2 in vivo in mice could mitigate lung injury and expression of inflammatory genes, including that induced by influenza A virus. PMID 17141159: Lee et al. (2006) - KLF2 deficient mice die in prenatal stage due to vascular defects, highlighting its crucial role in embryonic development. Lethal high-output heart failure, as found in the KO mice, was also observed in zebrafish embryos after morpholino inhibition of the Klf2 ortholog klf2a. CD4+ T cells from KLF2-deficient mice expressed multiple inflammatory chemokine receptors, suggesting that loss of KLF2 leads to redirection of naïve T cells to nonlymphoid sites (Sebzda et al., 2008). PMID 19592277: Weinreich et al. (2009) - Demonstrated upregulation of the chemokine receptor CXCR3 on KLF2-deficient T cells (Fig. 1). KLF2-deficient T cells also overproduced IL-4 (Fig. 5). PMID 22988032: Richardson et al. (2012) - Tested whether the abundance of KLF2 after T cell activation regulates CCR5 expression and, thus, susceptibility of a T cell to CCR5-dependent HIV-1 strains (R5). Introduced small interfering RNA targeting KLF2 expression and demonstrated that reduced KLF2 expression also resulted in less CCR5 (Fig. 3). Introduction of KLF2 under control of a heterologous promoter could restore CCR5 expression and R5 susceptibility to CD3/28 costimulated T cells and some transformed cell lines (Fig. 5, 6). KLF2 is a host factor that modulates CCR5 expression in CD4 T cells and influences susceptibility to R5 infection. PMID 29125549: (review) Jha and Das (2017) - KLF2 also plays a critical regulatory role in various inflammatory diseases and their pathogenesis. PMID 27855271: Huang et al. (2017) - Animal and in vitro models of acute lung injury were used to characterize KLF2 expression and its downstream effects responding to influenza A virus (A/WSN/33 [H1N1]), tumor necrosis factor-α, LPS, mechanical stretch/ventilation, or microvascular flow to examine the role of the gene in endothelial barrier disruption and cytokine storm in experimental lung injury. Pulmonary Klf2 was down-regulated by inflammation induced by influenza A/WSN/H1N1 virus (H1N1) infection, LPS administration, or LPS administration followed by high tidal volume ventilation in vivo (Fig. 1). It was also down-regulated by pathologic stretch and inflammatory stimuli (Fig. 2). Knockdown of endogenous KLF2 reduces Rac1 activation in human pulmonary microvascular cells, whereas adenovirus-mediated transduction with KLF2 promoted Rac1 activation (Fig. 3). Computational predictive pathway analysis suggested that KLF2 acts to regulate ARDS-associated GWAS genes, including ACE, NAD(P)H, NQO1, SERPINE1/PAI-1, TNF, and NF-kappaB. Expression studies in mice confirmed this regulatory role (Fig. 8). Overexpression of KLF2 in vivo in mice could also mitigate lung injury and expression of inflammatory genes (Fig. 7). |
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| COVID-19 research v0.348 | IRF2 |
Rebecca Foulger commented on gene: IRF2: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): IRF2 encodes interferon regulatory factor 2, a member of the family of transcription factors that play a role in regulating both the innate and adaptive immune response. IRF2 is an antiviral IFN-stimulated gene (ISG) which negatively regulates IFN signalling. (Lukele et al. 2019 -review). In both cell culture and the knock out Irf2-/- mouse model, Irf2 deficiency leads to an increase in susceptibility to viral infection (Schoggins et al. 2011; Karki et al. 2012; Matsuyama et al. 1993; Grieder et al. 1999). Irf2-/- mice also show increased susceptibility to neurotrophic viruses, including SINV and VSV, when compared to wild type mice. The compromised development and maturation of multiple immune cell types in the Irf2−/− mice which lead to reduced B cells and virus specific IgG levels in the brains of infected mice was linked to the pathogenic phenotype (Melody et al. 2016). These data suggest IRF2 may also play an important role in the development of the immune system. PMID: 21478870 Schoggins et al. (2011) - The authors over expressed over 380 ISGs to test their ability to inhibit the replication of viruses including hepatitis C virus (HCV), yellow fever virus (YFV), West Nile virus (WNV), chikungunya virus (CHIKV), Venezuelan equine encephalitis virus (VEEV), and human immunodeficiency virus (HIV-1). Each gene was expressed in a lentiviral construct transfected into various cell lines. Cells were challenged with GFP expressing virus and replication was quantified by flow cytometry. IRF2 was shown to be a anti-HCV ISGs. PMID: 22615998 Karki et al. (2012) - Karki et al. used a library of lentiviruses individually expressing more than 350 ISGs, transduced in HuH-7 cells in the presence of absence of ZAP and identified IRF2 as an enhancer of viral inhibition upon infection with SINV. In confirmatory experiments, when both ZAP and IRF2 were knocked down, viral replication was significantly increased compared to ZAP or IRF2 silencing alone, which supports the results obtained in the ISG overexpression screen and suggests that endogenous ZAP and IRF2 might interact in a synergistic manner (Fig. 5). PMID: 10208925 Grieder et al. (1999) - Irf2−/− mice show increased susceptibility to virulent Venezuelan equine encephalitis (VEE) virus infection even after vaccination with attenuated VEE, suggesting IRF2 is required to mount a protective immune response (Grieder and Vogel, 1999) PMID: 22113474 Gao et al. (2012) - The authors found IRF2 variants to be risk alleles for atopic dermatitis and eczema herpeticum. Eight SNPs were found to be significantly associated with reduced IFN-γ production after stimulation with herpes simplex virus. In the cohort, none of the SNPs showed association with HSV positivity. PMID: 27899441 Melody et al. (2016) - Fig 1. Lrf2 mice show lethality upon peritoneal infection with either SINV or VSV virus (Fig 1) Irf2−/− and WT mice were challenged i.p. with SVN, a neurovirulent but noninvasive strain, which normally replicates only in the periphery without lethality in mice. Approximately 70% of the Irf2−/− mice succumbed to infection with SVN, whereas all of the WT littermate control mice survived (Fig. 1 A), indicating that IRF2 deficiency confers lethal neuroinvasive properties on the normally noninvasive SVN strain. Infection with VSV led to survival of all the WT mice, whereas ∼60% of the Irf2−/− mice suffered from paralysis and succumbed to infection. Staining using Evans blue showed that the integrity of the blood brain barrier is maintained during the infection(fig 2). The survival of lrf-/- mice treated with IFNAR-1 blocking antibody at 2dpi was similar to treatment with a control antibody, suggesting that peripheral elevation of type I IFN signalling is not responsible for the susceptibility (fig 3). Development and maturation of multiple immune cell subsets are compromised in Irf2−/− mice at baseline and upon SVN infection. B cells and virus-specific IgG level are significantly reduced in Irf2 -/- mouse brains, periorbital injection of naïve Bcells from WT mice 1day before infection did not affect lethality in the lrf2-/1 mice. |
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| COVID-19 research v0.348 | IFNE |
Rebecca Foulger commented on gene: IFNE: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): IFNE encodes IFNε, a type I interferon which is constitutively expressed within the epithelial cells of the female reproductive tract (FRT) and plays a role in protection against viral and bacterial infections of the FRT (Marks et al. 2019 review). Ifnε-deficient mice have increased susceptibility to infection of the FRT by Herpes Simplex Virus (HSV)-2 as well as bacterial Chlamydia muridarum(Fung et al. 2013). Ifnε activity has also been shown to reduce the infectivity of HIV through the induction of HIV restriction factors which act to inhibit different stages of the virus replication cycle (Garcia-Minambres et al. 2017; Stifter et al. 2018). PMID: 31734130: Marks et al (2019) Review - IFNE encodes IFNε, a type I interferon which is constitutively expressed within the epithelial cells of the female reproductive tract. Ifnε expression fluctuates during pregnancy and across stages of the reproductive cycle in humans and mice. Unlike other type I interferons IFNε is not regulated by PRR pathways. PMID: 23449591; Fung et al. 2013 - Ifnε-deficient mice had increased susceptibility to infection of the FRT by common sexually transmitted infections (STIs) Herpes Simplex Virus (HSV)-2 (fig 3) as measured by clinical scores of disease day 6 post infection. The Ifnε-deficient mice also showed high viral titres in the spinal cord and brain stem 7 days post infection, consistent with increase replication of the virus and/or retrograde transport of the virus. A similar susceptibility to infection by the bacterial Chlamydia muridarum was also observed (Fig 4). PMID: 28045025 Garcia-Minambres et al. (2017) - Ifnε activity was shown to impair HIV infection through induction of HIV restriction factors which act to inhibit different stages of the viral replication cycle. PMID: 29187603 Stifter et al. (2018) - Using different cell lines and reporter assays to measure interferon type I stimulation, the authors showed that recombinant murine Ifnε inhibited HIV infection in the sup-T1 cell line and in primary peripheral blood lymphocytes and furthermore induced a number of HIV restriction factors. |
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| COVID-19 research v0.348 | FOLR1 |
Rebecca Foulger commented on gene: FOLR1: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): The FOLR1 gene encodes the folate receptor alpha (FR alpha), a glycosyl-phosphatidylinositol-linked (GPI-linked) protein that binds folic acid for transport into the cytoplasm. Chan et al. (2001) used genetic complementation to identify FR-alpha as a cofactor for cellular entry of pseudo Marburg (MBG) virus and EBO-Z pseudotype into otherwise non permissive cells. Further experiments showed FR alpha specifically binds glycoproteins of these viruses to mediate syncytia (Chan et al. 2001). PMID 11461707; Chan et al. (2001) - A complementation screen identified FR alpha as a cofactor for cellular entry of pseudo Marburg (MBG) virus into otherwise non permissive Jurkat-EctR cells (fig 1). FACs analysis showed FR alpha was present on the cell surface of other cell lines permissive for MBG infectivity (Hela cells, Vero E6, human and dog osteosarcoma cells (fig 2). FR alpha specific antagonists inhibited MBG entry (Fig 4) phospholipase C (PLC) cleaves the FR alpha receptor, cells pretreated with PLC showed decreased infectivity. When 293T cells overexpressing MBF GP were co-cultured with cells overexpressing FR alpha syncytia formation was observed, indicating that this type of membrane fusion is also mediated by FRalpha (fig 5). A similar set of experiments showed that FR alpha is also a cofactor for cellular entry of EBO-Z pseudo viruses. Yang et al. (2019) preprint: https://doi.org/10.1101/618306 - Poliovirus (PV), a prototype for human pathogenic positive-sense RNA enteroviruses, transport multiple virions en bloc via infectious extracellular vesicles secreted from host cells. Yang et al. show that in these microvesicles less than 10% of proteins are viral. 168 host cell proteins were identified in the MVs including involved in both caveolar-mediated and mediated endocytic virus entry pathways genes (ITGB1, B2M, FYN, CD55 {DAF}, HLA-A, FLNA, ACTB, RAC1, TFRC {CD71}, FOLR1). |
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| COVID-19 research v0.348 | DICER1 |
Rebecca Foulger changed review comment from: Evidence Summary from Illumina curation team: The DICER1 gene, located on chromosome 14, position q32.13, was discovered in 2001 by Bernstein and is a member of the RNase III family, (also known as dicer 1, ribonuclease III; dicer1, Dcr-1 homolog (Drosophila); multinodular goitre 1). DICER1 is involved in the generation of double-stranded microRNAs (miRNAs), short non-coding RNAs, the cleavage of dsRNA into siRNAs, along with the biogenesis of numerous other small RNAs. There is increasing evidence DICER1 is also involved in regulating many other essential cellular processes such as those related to chromatin remodeling, inflammation, apoptosis and cell survival (Kurzynska-Kokorniak et al. 2015; Song and Rossi, 2017). DICER1 encodes a ∼220-KDa protein (RNase III endoribonuclease) which is a crucial component of the RNA Induced Silencing Complex (RISC) loading complex (RLC), comprised of dicer, Argonaute-2 (AGO-2), and trans-activation-responsive RNA binding protein 2 (TARBP2). The encoded protein is required by the RNA interference (RNAi) and small temporal RNA (stRNA) pathways to produce the active small RNA component which has a role in modulating gene expression at the post-transcriptional level. Research has shown that expression levels of cellular transcript and protein dicer are strictly controlled, with aberrant regulation contributing to carcinogenesis, neurodegenerative, rheumatic and immune system disorders. Studies have concluded that the encoded dicer ribonuclease-dependent processing of dsRNA viral replication intermediates into successive siRNAs is a conserved mammalian immune response to infection by positive-strand RNA viruses (Svobodova et al. 2016 summary & fig1; Li et al. 2013; Ding et al. 2018). Moreover, miRNAs play an important role in host-virus interactions in mammals (See Maillard et al. 2019 REVIEW; Foulkes et al. 2014 REVIEW). IMMUNE SYSTEM The cre-lox method for dicer1 gene knockout has been employed for studies into the role of dicer1 in immune cell development and function. Studies of dicer1 fl/fl mice have indicated short survival times along with severely impaired GMP differentiation into monocytes, neutrophils, myeloid DCs & mature macrophages. (Devasthanam et al. 2014). Results conclude that dicer1 is important in immune response and also vital for cell survival and apoptosis pathways. Muljo et al. (2005) investigated a conditional allele of dicer-1 (dcr-1) within a mouse model and showed that specific dcr-1 deletion in the T-cell lineage, resulted in impaired development of T-cells & aberrant cell differentiation of T-helper cells & cytokine production. Dcr-1 deletion in the thymus resulted in severe block in development of CD8+ T cells and resulted in defective microRNA processing in CD4+ T-cells. The results demonstrate Dicer regulates diverse aspects of T-cell biology along with cytokine production during T-cell differentiation where dicer-deficient T-cells preferentially express interferon-ƴ. VIRUSES Research by Galiana-Arnoux et al. (2006), of DICER in drosophila (drosophila have two dicer genes) have identified that DICER genes (Dcr1, miRNA pathway and Dcr2, RNAi pathway) control production of siRNA and a loss-of-function mutation in Dcr2 resulted in increased susceptibility to three different families of RNA viruses. Qi et al. (2012) research into RNAi gene silencing mechanism show that the B2 protein in Wuhan nodavirus (WhNV) suppresses Dcr2 in drosophila by direct interaction with the PAZ and RNAse III domains therefore blocking processing of dsRNA and siRNA. Evidence of a dicer antiviral system was also reported by Machitani et al. (2016) for mammalian human adenoviruses where DICER1 gene knockdown increased the copy number of adenovirus-encoding small RNAs (VA-RNAs) leading to the promotion of adenovirus replication; conversely, dicer overexpression significantly inhibited viral replication. Modai et al. (2019) conclude that HIV-1 infection inhibits DICER1 by altering miRNA expression. They conclude that upon HIV-1 infection, human miR-186, 210 and 222 directly regulate DICER1 gene expression causing down-regulation of the gene contributing to impaired cell-mediated immunity (fig6). Other methods of inhibition are from viral proteins, termed viral suppressors of RNA silencing, which interact and inhibit dicer ribonuclease activity in HIV-1 and hepatitis C infections. These viral proteins may mediate proteasomal degradation of endoribonuclease dicer through CRL4DCAF1 ubiquitin ligase complex (Klockow et al. 2013), interact directly via the core protein (Chen et al. 2008) or HIV-1 transactivation of transcription (Bennasser and Jeang, 2006). Through these methods they can block dicer interactions with TRBP2 or ADAR1, boost macrophage infection, and subsequently reduce the function of short hairpin RNAs (shRNAs) which thus inhibit RNA silencing. Ultimately these viruses, though various methods, supress the ability of dicer to process dsRNAs into siRNAs boosting viral infection and pathogenesis. Downregulation of DICER1 gene expression has additionally been found in cord blood of infants with severe respiratory syncytial virus (RSV), prior to RSV exposure, indicating this reduced expression may predispose newborns to RSV disease. Inchley et al. (2011) theorize that this occurs via disruption of leukocyte gene regulation of miRNA and direct anti-viral RNAi mechanisms. (Inchley et al. 2011 see section on “Dicer Gene Expression”). Otsuka et al. (2007) have shown using gene-trap methods to obtain viable dicer1 fl/fl mice where dicer1 deficiency caused impairment of miR24 and miR93 production resulting in susceptibility to vesticular stomatitis virus (VSV) and herpes simplex-1 virus, but not other viruses tested. SARS CoV & SARS CoV-2 Recently, Pasquier and Robichon, 2020 (preprint) have investigated the Dicer host immunity system regarding SARs-CoV-2 within a computational approach, concluding SARS-CoV2 may manipulate this system of immunity against its host, requiring further research. Mu et al., 2020 suggest SARs-CoV2 suppresses RNAi thus preventing recognition by the encoded ribonuclease dicer protein Viral suppressors of RNA silencing (VSRs) suppress RNAi at pre or post-dicer level to overcome host defense and establish infection. Cui et al. (2015) from Wuhan University laboratory of virology, identified a novel VSR from coronaviruses (CoVs) including Severe acute respiratory syndrome coronavirus (SARS-CoV) and showed that the coronavirus nucelocaspid protein (N-protein), conserved and expressed in all coronaviruses, suppressed RNAi triggered by either short hairpin RNAs or small interfering RNAs in mammalian cells. They went on to show using mouse hepatitis virus A-59 (MHV-A59) which is closely linked to SARS-CoV in the family coronaviridae, that the viral replication was increased when the N proteins (novel VSR) were expressed but that knockdown of DICER1 gene or Ago2 transcripts facilitated the viral replication specifically in mammalian cells. They demonstrate that the N-protein of CoVs could efficiently inhibit dicer-mediated dsRNA cleavage and post-Dicer activities by sequestering dsRNAs and siRNAs. Kannan et al. (2020) performed clustal W analysis of N-Protein for SARS-CoV and COVID-19 demonstrating 90% sequence identity from an NCBI amino acid blast of both nucleocapsid (N) protein sequences (figure2). They suggest that the N-protein of COVID-19 may also function as a VSR for RNAi to overcome host defense. Ding et al. (2017) show that both MHV and SARS-CoV N proteins can also disrupt protein activator of protein kinase R (PACT), a cellular dsRNA-binding protein which binds to RIG-I and MDA5 to activate interferon (IFN) production to prevent antiviral host response. Literature Review PMID: 17181864: Bennasser and Jeang, 2006 • HIV-1 Tat Interaction With Dicer: Requirement for RNA • Tat-Dicer interaction depends on RNA, requires the helicase domain of Dicer, and is independent of Tat's transactivation domain. PMID: 18325616: Chen et al., 2008 • HCV Core Protein Interacts With Dicer to Antagonize RNA Silencing PMID: 26085159: Cui et al., 2015 • The Nucleocapsid Protein of Coronaviruses Acts as a Viral Suppressor of RNA Silencing in Mammalian Cells PMID: 24303839: Devasthanam et al, 2014 • This study investigates the role of the dicer protein in immune cell development and function using dicer1 cre-lox knockout models to conditionally ablate dicer1 in different immune cell subsets. PMID: 28591694: Ding et al., 2017 • The nucleocapsid proteins of mouse hepatitis virus and severe acute respiratory syndrome coronavirus share the same IFN-β antagonizing mechanism: attenuation of PACT-mediated RIG-I/MDA5 activation PMID: 30015086: Ding et al., 2018 • Antiviral RNA Interference in Mammals: Indicates infection of plants and insects with RNA and DNA viruses triggers Dicer-dependent production of virus-derived small interfering RNAs (vsiRNAs), which subsequently guide specific virus clearance by RNA interference (RNAi). PMID: 25176334: Foulkes et al., 2012-REVIEW • Review of DICER1: DICER1 Mutations, microRNAs and Mechanisms PMID: 16554838: Galiana-Arnoux et al., 2006 • Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila. • https://pubmed.ncbi.nlm.nih.gov/16554838/ or https://www.nature.com/articles/ni1335 PMID: 21385408: Inchley et al., 2011 • Investigates ribonuclease Dicer and analyzed the gene expression of Dicer in newborns of which 37 infants had sufficient cord blood RNA with confirmed RSV disease <1yr. Demonstrates significant reduced Dicer expression in cord blood prior to severe disease in infants <1yr later. Conclude downregulation may predispose infants to RSV disease. PMID: 32141569: Kannan et al., 2020 • COVID-19 (Novel Coronavirus 2019) - Recent Trends • Perform W cluster analysis of COVID-19 and SARS-CoV nucleocapsid (N) protein sequences of the viruses showing 90% amino acid sequence similarity. Suggest the N-protein may be a VSR in RNAi by targeting DICER. PMID: 23849790: Klockow et al., 2013 • The HIV-1 Protein Vpr Targets the Endoribonuclease Dicer for Proteasomal Degradation to Boost Macrophage Infection PMID: 25883138: Kurzynska-Kokorniak et al., 2015 • Investigating the complexity of the mechanisms regulating Dicer gene expression and enzyme activities PMID: 24115437: Li et al, 2013 • Investigates RNA interference pathways in antiviral immunity in mammals overviewing dicer processing of dsRNA viral replication intermediates into siRNAs. PMID: 27273616: Machitani et al., 2016 • Dicer functions as an antiviral system against human adenoviruses via cleavage of adenovirus-encoded noncoding RNA PMID: 30872283: Maillard et al., 2019- REVIEW • Reviewing DICER1 within the anti-viral RNAi pathway in mammals PMID: 30682089: Modai et al, 2019 • HIV-1 infection increases miRNAs which inhibit Dicer PMID: 32291557: Mu et al, 2020 • SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells PMID: 16009718: Muljo et al., 2005 • Indicates absence of dicer results in abberant T-cell differentiation. PMID: 17613256: Otsuka, et al 2007 • Hypersusceptibility to Vesicular Stomatitis Virus Infection in Dicer1-Deficient Mice Is Due to Impaired miR24 and miR93 Expression No PMID: Preprint : Pasquier and Rubichon, 2020 • SARS-CoV-2 might manipulate against its host the immunity RNAi/Dicer/Ago system PMID: 22438534: Qi et al., 2012 • Targeting of Dicer-2 and RNA by a Viral RNA Silencing Suppressor in Drosophila Cells PMID: 28473628: Song and Rossi, 2017 • Molecular Mechanisms of Dicer: Endonuclease and Enzymatic Activity; to: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): The DICER1 gene, located on chromosome 14, position q32.13, was discovered in 2001 by Bernstein and is a member of the RNase III family, (also known as dicer 1, ribonuclease III; dicer1, Dcr-1 homolog (Drosophila); multinodular goitre 1). DICER1 is involved in the generation of double-stranded microRNAs (miRNAs), short non-coding RNAs, the cleavage of dsRNA into siRNAs, along with the biogenesis of numerous other small RNAs. There is increasing evidence DICER1 is also involved in regulating many other essential cellular processes such as those related to chromatin remodeling, inflammation, apoptosis and cell survival (Kurzynska-Kokorniak et al. 2015; Song and Rossi, 2017). DICER1 encodes a ∼220-KDa protein (RNase III endoribonuclease) which is a crucial component of the RNA Induced Silencing Complex (RISC) loading complex (RLC), comprised of dicer, Argonaute-2 (AGO-2), and trans-activation-responsive RNA binding protein 2 (TARBP2). The encoded protein is required by the RNA interference (RNAi) and small temporal RNA (stRNA) pathways to produce the active small RNA component which has a role in modulating gene expression at the post-transcriptional level. Research has shown that expression levels of cellular transcript and protein dicer are strictly controlled, with aberrant regulation contributing to carcinogenesis, neurodegenerative, rheumatic and immune system disorders. Studies have concluded that the encoded dicer ribonuclease-dependent processing of dsRNA viral replication intermediates into successive siRNAs is a conserved mammalian immune response to infection by positive-strand RNA viruses (Svobodova et al. 2016 summary & fig1; Li et al. 2013; Ding et al. 2018). Moreover, miRNAs play an important role in host-virus interactions in mammals (See Maillard et al. 2019 REVIEW; Foulkes et al. 2014 REVIEW). IMMUNE SYSTEM The cre-lox method for dicer1 gene knockout has been employed for studies into the role of dicer1 in immune cell development and function. Studies of dicer1 fl/fl mice have indicated short survival times along with severely impaired GMP differentiation into monocytes, neutrophils, myeloid DCs & mature macrophages. (Devasthanam et al. 2014). Results conclude that dicer1 is important in immune response and also vital for cell survival and apoptosis pathways. Muljo et al. (2005) investigated a conditional allele of dicer-1 (dcr-1) within a mouse model and showed that specific dcr-1 deletion in the T-cell lineage, resulted in impaired development of T-cells & aberrant cell differentiation of T-helper cells & cytokine production. Dcr-1 deletion in the thymus resulted in severe block in development of CD8+ T cells and resulted in defective microRNA processing in CD4+ T-cells. The results demonstrate Dicer regulates diverse aspects of T-cell biology along with cytokine production during T-cell differentiation where dicer-deficient T-cells preferentially express interferon-ƴ. VIRUSES Research by Galiana-Arnoux et al. (2006), of DICER in drosophila (drosophila have two dicer genes) have identified that DICER genes (Dcr1, miRNA pathway and Dcr2, RNAi pathway) control production of siRNA and a loss-of-function mutation in Dcr2 resulted in increased susceptibility to three different families of RNA viruses. Qi et al. (2012) research into RNAi gene silencing mechanism show that the B2 protein in Wuhan nodavirus (WhNV) suppresses Dcr2 in drosophila by direct interaction with the PAZ and RNAse III domains therefore blocking processing of dsRNA and siRNA. Evidence of a dicer antiviral system was also reported by Machitani et al. (2016) for mammalian human adenoviruses where DICER1 gene knockdown increased the copy number of adenovirus-encoding small RNAs (VA-RNAs) leading to the promotion of adenovirus replication; conversely, dicer overexpression significantly inhibited viral replication. Modai et al. (2019) conclude that HIV-1 infection inhibits DICER1 by altering miRNA expression. They conclude that upon HIV-1 infection, human miR-186, 210 and 222 directly regulate DICER1 gene expression causing down-regulation of the gene contributing to impaired cell-mediated immunity (fig6). Other methods of inhibition are from viral proteins, termed viral suppressors of RNA silencing, which interact and inhibit dicer ribonuclease activity in HIV-1 and hepatitis C infections. These viral proteins may mediate proteasomal degradation of endoribonuclease dicer through CRL4DCAF1 ubiquitin ligase complex (Klockow et al. 2013), interact directly via the core protein (Chen et al. 2008) or HIV-1 transactivation of transcription (Bennasser and Jeang, 2006). Through these methods they can block dicer interactions with TRBP2 or ADAR1, boost macrophage infection, and subsequently reduce the function of short hairpin RNAs (shRNAs) which thus inhibit RNA silencing. Ultimately these viruses, though various methods, supress the ability of dicer to process dsRNAs into siRNAs boosting viral infection and pathogenesis. Downregulation of DICER1 gene expression has additionally been found in cord blood of infants with severe respiratory syncytial virus (RSV), prior to RSV exposure, indicating this reduced expression may predispose newborns to RSV disease. Inchley et al. (2011) theorize that this occurs via disruption of leukocyte gene regulation of miRNA and direct anti-viral RNAi mechanisms. (Inchley et al. 2011 see section on “Dicer Gene Expression”). Otsuka et al. (2007) have shown using gene-trap methods to obtain viable dicer1 fl/fl mice where dicer1 deficiency caused impairment of miR24 and miR93 production resulting in susceptibility to vesticular stomatitis virus (VSV) and herpes simplex-1 virus, but not other viruses tested. SARS CoV & SARS CoV-2 Recently, Pasquier and Robichon, 2020 (preprint) have investigated the Dicer host immunity system regarding SARs-CoV-2 within a computational approach, concluding SARS-CoV2 may manipulate this system of immunity against its host, requiring further research. Mu et al., 2020 suggest SARs-CoV2 suppresses RNAi thus preventing recognition by the encoded ribonuclease dicer protein Viral suppressors of RNA silencing (VSRs) suppress RNAi at pre or post-dicer level to overcome host defense and establish infection. Cui et al. (2015) from Wuhan University laboratory of virology, identified a novel VSR from coronaviruses (CoVs) including Severe acute respiratory syndrome coronavirus (SARS-CoV) and showed that the coronavirus nucelocaspid protein (N-protein), conserved and expressed in all coronaviruses, suppressed RNAi triggered by either short hairpin RNAs or small interfering RNAs in mammalian cells. They went on to show using mouse hepatitis virus A-59 (MHV-A59) which is closely linked to SARS-CoV in the family coronaviridae, that the viral replication was increased when the N proteins (novel VSR) were expressed but that knockdown of DICER1 gene or Ago2 transcripts facilitated the viral replication specifically in mammalian cells. They demonstrate that the N-protein of CoVs could efficiently inhibit dicer-mediated dsRNA cleavage and post-Dicer activities by sequestering dsRNAs and siRNAs. Kannan et al. (2020) performed clustal W analysis of N-Protein for SARS-CoV and COVID-19 demonstrating 90% sequence identity from an NCBI amino acid blast of both nucleocapsid (N) protein sequences (figure2). They suggest that the N-protein of COVID-19 may also function as a VSR for RNAi to overcome host defense. Ding et al. (2017) show that both MHV and SARS-CoV N proteins can also disrupt protein activator of protein kinase R (PACT), a cellular dsRNA-binding protein which binds to RIG-I and MDA5 to activate interferon (IFN) production to prevent antiviral host response. Literature Review PMID: 17181864: Bennasser and Jeang, 2006 • HIV-1 Tat Interaction With Dicer: Requirement for RNA • Tat-Dicer interaction depends on RNA, requires the helicase domain of Dicer, and is independent of Tat's transactivation domain. PMID: 18325616: Chen et al., 2008 • HCV Core Protein Interacts With Dicer to Antagonize RNA Silencing PMID: 26085159: Cui et al., 2015 • The Nucleocapsid Protein of Coronaviruses Acts as a Viral Suppressor of RNA Silencing in Mammalian Cells PMID: 24303839: Devasthanam et al, 2014 • This study investigates the role of the dicer protein in immune cell development and function using dicer1 cre-lox knockout models to conditionally ablate dicer1 in different immune cell subsets. PMID: 28591694: Ding et al., 2017 • The nucleocapsid proteins of mouse hepatitis virus and severe acute respiratory syndrome coronavirus share the same IFN-β antagonizing mechanism: attenuation of PACT-mediated RIG-I/MDA5 activation PMID: 30015086: Ding et al., 2018 • Antiviral RNA Interference in Mammals: Indicates infection of plants and insects with RNA and DNA viruses triggers Dicer-dependent production of virus-derived small interfering RNAs (vsiRNAs), which subsequently guide specific virus clearance by RNA interference (RNAi). PMID: 25176334: Foulkes et al., 2012-REVIEW • Review of DICER1: DICER1 Mutations, microRNAs and Mechanisms PMID: 16554838: Galiana-Arnoux et al., 2006 • Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila. • https://pubmed.ncbi.nlm.nih.gov/16554838/ or https://www.nature.com/articles/ni1335 PMID: 21385408: Inchley et al., 2011 • Investigates ribonuclease Dicer and analyzed the gene expression of Dicer in newborns of which 37 infants had sufficient cord blood RNA with confirmed RSV disease <1yr. Demonstrates significant reduced Dicer expression in cord blood prior to severe disease in infants <1yr later. Conclude downregulation may predispose infants to RSV disease. PMID: 32141569: Kannan et al., 2020 • COVID-19 (Novel Coronavirus 2019) - Recent Trends • Perform W cluster analysis of COVID-19 and SARS-CoV nucleocapsid (N) protein sequences of the viruses showing 90% amino acid sequence similarity. Suggest the N-protein may be a VSR in RNAi by targeting DICER. PMID: 23849790: Klockow et al., 2013 • The HIV-1 Protein Vpr Targets the Endoribonuclease Dicer for Proteasomal Degradation to Boost Macrophage Infection PMID: 25883138: Kurzynska-Kokorniak et al., 2015 • Investigating the complexity of the mechanisms regulating Dicer gene expression and enzyme activities PMID: 24115437: Li et al, 2013 • Investigates RNA interference pathways in antiviral immunity in mammals overviewing dicer processing of dsRNA viral replication intermediates into siRNAs. PMID: 27273616: Machitani et al., 2016 • Dicer functions as an antiviral system against human adenoviruses via cleavage of adenovirus-encoded noncoding RNA PMID: 30872283: Maillard et al., 2019- REVIEW • Reviewing DICER1 within the anti-viral RNAi pathway in mammals PMID: 30682089: Modai et al, 2019 • HIV-1 infection increases miRNAs which inhibit Dicer PMID: 32291557: Mu et al, 2020 • SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells PMID: 16009718: Muljo et al., 2005 • Indicates absence of dicer results in abberant T-cell differentiation. PMID: 17613256: Otsuka, et al 2007 • Hypersusceptibility to Vesicular Stomatitis Virus Infection in Dicer1-Deficient Mice Is Due to Impaired miR24 and miR93 Expression No PMID: Preprint : Pasquier and Rubichon, 2020 • SARS-CoV-2 might manipulate against its host the immunity RNAi/Dicer/Ago system PMID: 22438534: Qi et al., 2012 • Targeting of Dicer-2 and RNA by a Viral RNA Silencing Suppressor in Drosophila Cells PMID: 28473628: Song and Rossi, 2017 • Molecular Mechanisms of Dicer: Endonuclease and Enzymatic Activity |
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| COVID-19 research v0.348 | DICER1 |
Rebecca Foulger commented on gene: DICER1: Evidence Summary from Illumina curation team: The DICER1 gene, located on chromosome 14, position q32.13, was discovered in 2001 by Bernstein and is a member of the RNase III family, (also known as dicer 1, ribonuclease III; dicer1, Dcr-1 homolog (Drosophila); multinodular goitre 1). DICER1 is involved in the generation of double-stranded microRNAs (miRNAs), short non-coding RNAs, the cleavage of dsRNA into siRNAs, along with the biogenesis of numerous other small RNAs. There is increasing evidence DICER1 is also involved in regulating many other essential cellular processes such as those related to chromatin remodeling, inflammation, apoptosis and cell survival (Kurzynska-Kokorniak et al. 2015; Song and Rossi, 2017). DICER1 encodes a ∼220-KDa protein (RNase III endoribonuclease) which is a crucial component of the RNA Induced Silencing Complex (RISC) loading complex (RLC), comprised of dicer, Argonaute-2 (AGO-2), and trans-activation-responsive RNA binding protein 2 (TARBP2). The encoded protein is required by the RNA interference (RNAi) and small temporal RNA (stRNA) pathways to produce the active small RNA component which has a role in modulating gene expression at the post-transcriptional level. Research has shown that expression levels of cellular transcript and protein dicer are strictly controlled, with aberrant regulation contributing to carcinogenesis, neurodegenerative, rheumatic and immune system disorders. Studies have concluded that the encoded dicer ribonuclease-dependent processing of dsRNA viral replication intermediates into successive siRNAs is a conserved mammalian immune response to infection by positive-strand RNA viruses (Svobodova et al. 2016 summary & fig1; Li et al. 2013; Ding et al. 2018). Moreover, miRNAs play an important role in host-virus interactions in mammals (See Maillard et al. 2019 REVIEW; Foulkes et al. 2014 REVIEW). IMMUNE SYSTEM The cre-lox method for dicer1 gene knockout has been employed for studies into the role of dicer1 in immune cell development and function. Studies of dicer1 fl/fl mice have indicated short survival times along with severely impaired GMP differentiation into monocytes, neutrophils, myeloid DCs & mature macrophages. (Devasthanam et al. 2014). Results conclude that dicer1 is important in immune response and also vital for cell survival and apoptosis pathways. Muljo et al. (2005) investigated a conditional allele of dicer-1 (dcr-1) within a mouse model and showed that specific dcr-1 deletion in the T-cell lineage, resulted in impaired development of T-cells & aberrant cell differentiation of T-helper cells & cytokine production. Dcr-1 deletion in the thymus resulted in severe block in development of CD8+ T cells and resulted in defective microRNA processing in CD4+ T-cells. The results demonstrate Dicer regulates diverse aspects of T-cell biology along with cytokine production during T-cell differentiation where dicer-deficient T-cells preferentially express interferon-ƴ. VIRUSES Research by Galiana-Arnoux et al. (2006), of DICER in drosophila (drosophila have two dicer genes) have identified that DICER genes (Dcr1, miRNA pathway and Dcr2, RNAi pathway) control production of siRNA and a loss-of-function mutation in Dcr2 resulted in increased susceptibility to three different families of RNA viruses. Qi et al. (2012) research into RNAi gene silencing mechanism show that the B2 protein in Wuhan nodavirus (WhNV) suppresses Dcr2 in drosophila by direct interaction with the PAZ and RNAse III domains therefore blocking processing of dsRNA and siRNA. Evidence of a dicer antiviral system was also reported by Machitani et al. (2016) for mammalian human adenoviruses where DICER1 gene knockdown increased the copy number of adenovirus-encoding small RNAs (VA-RNAs) leading to the promotion of adenovirus replication; conversely, dicer overexpression significantly inhibited viral replication. Modai et al. (2019) conclude that HIV-1 infection inhibits DICER1 by altering miRNA expression. They conclude that upon HIV-1 infection, human miR-186, 210 and 222 directly regulate DICER1 gene expression causing down-regulation of the gene contributing to impaired cell-mediated immunity (fig6). Other methods of inhibition are from viral proteins, termed viral suppressors of RNA silencing, which interact and inhibit dicer ribonuclease activity in HIV-1 and hepatitis C infections. These viral proteins may mediate proteasomal degradation of endoribonuclease dicer through CRL4DCAF1 ubiquitin ligase complex (Klockow et al. 2013), interact directly via the core protein (Chen et al. 2008) or HIV-1 transactivation of transcription (Bennasser and Jeang, 2006). Through these methods they can block dicer interactions with TRBP2 or ADAR1, boost macrophage infection, and subsequently reduce the function of short hairpin RNAs (shRNAs) which thus inhibit RNA silencing. Ultimately these viruses, though various methods, supress the ability of dicer to process dsRNAs into siRNAs boosting viral infection and pathogenesis. Downregulation of DICER1 gene expression has additionally been found in cord blood of infants with severe respiratory syncytial virus (RSV), prior to RSV exposure, indicating this reduced expression may predispose newborns to RSV disease. Inchley et al. (2011) theorize that this occurs via disruption of leukocyte gene regulation of miRNA and direct anti-viral RNAi mechanisms. (Inchley et al. 2011 see section on “Dicer Gene Expression”). Otsuka et al. (2007) have shown using gene-trap methods to obtain viable dicer1 fl/fl mice where dicer1 deficiency caused impairment of miR24 and miR93 production resulting in susceptibility to vesticular stomatitis virus (VSV) and herpes simplex-1 virus, but not other viruses tested. SARS CoV & SARS CoV-2 Recently, Pasquier and Robichon, 2020 (preprint) have investigated the Dicer host immunity system regarding SARs-CoV-2 within a computational approach, concluding SARS-CoV2 may manipulate this system of immunity against its host, requiring further research. Mu et al., 2020 suggest SARs-CoV2 suppresses RNAi thus preventing recognition by the encoded ribonuclease dicer protein Viral suppressors of RNA silencing (VSRs) suppress RNAi at pre or post-dicer level to overcome host defense and establish infection. Cui et al. (2015) from Wuhan University laboratory of virology, identified a novel VSR from coronaviruses (CoVs) including Severe acute respiratory syndrome coronavirus (SARS-CoV) and showed that the coronavirus nucelocaspid protein (N-protein), conserved and expressed in all coronaviruses, suppressed RNAi triggered by either short hairpin RNAs or small interfering RNAs in mammalian cells. They went on to show using mouse hepatitis virus A-59 (MHV-A59) which is closely linked to SARS-CoV in the family coronaviridae, that the viral replication was increased when the N proteins (novel VSR) were expressed but that knockdown of DICER1 gene or Ago2 transcripts facilitated the viral replication specifically in mammalian cells. They demonstrate that the N-protein of CoVs could efficiently inhibit dicer-mediated dsRNA cleavage and post-Dicer activities by sequestering dsRNAs and siRNAs. Kannan et al. (2020) performed clustal W analysis of N-Protein for SARS-CoV and COVID-19 demonstrating 90% sequence identity from an NCBI amino acid blast of both nucleocapsid (N) protein sequences (figure2). They suggest that the N-protein of COVID-19 may also function as a VSR for RNAi to overcome host defense. Ding et al. (2017) show that both MHV and SARS-CoV N proteins can also disrupt protein activator of protein kinase R (PACT), a cellular dsRNA-binding protein which binds to RIG-I and MDA5 to activate interferon (IFN) production to prevent antiviral host response. Literature Review PMID: 17181864: Bennasser and Jeang, 2006 • HIV-1 Tat Interaction With Dicer: Requirement for RNA • Tat-Dicer interaction depends on RNA, requires the helicase domain of Dicer, and is independent of Tat's transactivation domain. PMID: 18325616: Chen et al., 2008 • HCV Core Protein Interacts With Dicer to Antagonize RNA Silencing PMID: 26085159: Cui et al., 2015 • The Nucleocapsid Protein of Coronaviruses Acts as a Viral Suppressor of RNA Silencing in Mammalian Cells PMID: 24303839: Devasthanam et al, 2014 • This study investigates the role of the dicer protein in immune cell development and function using dicer1 cre-lox knockout models to conditionally ablate dicer1 in different immune cell subsets. PMID: 28591694: Ding et al., 2017 • The nucleocapsid proteins of mouse hepatitis virus and severe acute respiratory syndrome coronavirus share the same IFN-β antagonizing mechanism: attenuation of PACT-mediated RIG-I/MDA5 activation PMID: 30015086: Ding et al., 2018 • Antiviral RNA Interference in Mammals: Indicates infection of plants and insects with RNA and DNA viruses triggers Dicer-dependent production of virus-derived small interfering RNAs (vsiRNAs), which subsequently guide specific virus clearance by RNA interference (RNAi). PMID: 25176334: Foulkes et al., 2012-REVIEW • Review of DICER1: DICER1 Mutations, microRNAs and Mechanisms PMID: 16554838: Galiana-Arnoux et al., 2006 • Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila. • https://pubmed.ncbi.nlm.nih.gov/16554838/ or https://www.nature.com/articles/ni1335 PMID: 21385408: Inchley et al., 2011 • Investigates ribonuclease Dicer and analyzed the gene expression of Dicer in newborns of which 37 infants had sufficient cord blood RNA with confirmed RSV disease <1yr. Demonstrates significant reduced Dicer expression in cord blood prior to severe disease in infants <1yr later. Conclude downregulation may predispose infants to RSV disease. PMID: 32141569: Kannan et al., 2020 • COVID-19 (Novel Coronavirus 2019) - Recent Trends • Perform W cluster analysis of COVID-19 and SARS-CoV nucleocapsid (N) protein sequences of the viruses showing 90% amino acid sequence similarity. Suggest the N-protein may be a VSR in RNAi by targeting DICER. PMID: 23849790: Klockow et al., 2013 • The HIV-1 Protein Vpr Targets the Endoribonuclease Dicer for Proteasomal Degradation to Boost Macrophage Infection PMID: 25883138: Kurzynska-Kokorniak et al., 2015 • Investigating the complexity of the mechanisms regulating Dicer gene expression and enzyme activities PMID: 24115437: Li et al, 2013 • Investigates RNA interference pathways in antiviral immunity in mammals overviewing dicer processing of dsRNA viral replication intermediates into siRNAs. PMID: 27273616: Machitani et al., 2016 • Dicer functions as an antiviral system against human adenoviruses via cleavage of adenovirus-encoded noncoding RNA PMID: 30872283: Maillard et al., 2019- REVIEW • Reviewing DICER1 within the anti-viral RNAi pathway in mammals PMID: 30682089: Modai et al, 2019 • HIV-1 infection increases miRNAs which inhibit Dicer PMID: 32291557: Mu et al, 2020 • SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells PMID: 16009718: Muljo et al., 2005 • Indicates absence of dicer results in abberant T-cell differentiation. PMID: 17613256: Otsuka, et al 2007 • Hypersusceptibility to Vesicular Stomatitis Virus Infection in Dicer1-Deficient Mice Is Due to Impaired miR24 and miR93 Expression No PMID: Preprint : Pasquier and Rubichon, 2020 • SARS-CoV-2 might manipulate against its host the immunity RNAi/Dicer/Ago system PMID: 22438534: Qi et al., 2012 • Targeting of Dicer-2 and RNA by a Viral RNA Silencing Suppressor in Drosophila Cells PMID: 28473628: Song and Rossi, 2017 • Molecular Mechanisms of Dicer: Endonuclease and Enzymatic Activity |
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| COVID-19 research v0.348 | CD28 |
Rebecca Foulger commented on gene: CD28: Evidence Summary from Illumina curation team: CD28 is a transmembrane receptor expressed on the surface of T cells and is required for the immune cell activation and proliferation of naïve and memory T cells. CD28 knockout mice have an increased susceptibility to ECTV, a host specific virus which causes mousepox. Upon infection, CD28 deficient mice showed a 40% mortality within 14 days while wild-type control mice did not show any symptoms of disease (Fang et al. 2008). In cell culture experiments, CD28 protein surface levels were found to be downregulated by HIV-1 accessory proteins Nef and Vpu (Pawlak et al. 2018). In severe cases of COVID-19 infection, immuno-dysregulation may lead to a decrease of CD28+ cytotoxic suppressor T cells (Tufan et al. 2020, review) PMID: 29329537; Pawlak et al.(2018) - CD28 is a transmembrane receptor expressed on the surface of T cells. It is essential for immune cell activation and proliferation of naïve and memory T cell. Cell culture experiments using CD4+ Sup-T1 cells or primary CD4+ T cells and infected with VSV-G pseudotyped NL4.3 viruses showed that the HIV-1 accessory proteins Nef and Vpu modify the immune response and increase viral persistence by decreasing the cell surface levels of CD28 (fig.1). PMID: 32299202; Tufan et al. (2020) Review. SARS-CoV-2 infection can lead to immune dysregulation through affecting the subset of T cells. In severe cases of COVID-19 infection, it was observed that the percentage of naïve helper T cells amplifies while the percentage of memory helper T cells and CD28+ cytotoxic suppressor T cells decreases. PMID: 17114476; Fang et al. (2008) - CD28 KO mice in a mousepox-resistant B6 background infected with ECTV showed a 40% mortality 7–14 days PI (Fig. 1A) and all remaining CD28KO mice developed mousepox (Fig. 1, B and C). All control wild-type B6 mice survived the infection without any symptoms of disease. CD28 KO mice that survived past 14 days PI gradually recovered from the disease and survived indefinitely. A comparison of CD8+ T cell responses to ECTV and VACV suggests that the main reason for the susceptibility of CD28 KO mice to mousepox is a reduced response at the early stages of infection. |
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| COVID-19 research v0.348 | CCR2 |
Rebecca Foulger changed review comment from: Evidence Summary from Illumina curation team: CCR2 is a chemokine receptor highly expressed on monocytes which is critical for bone marrow egress of classic monocytes and trafficking to sites of inflammation. Ccr2 deficiency in mice markedly increases mortality in West Nile virus encephalitis, with Ccr2-/- mice showing sustained monocytopenia, reduced accumulation of monocytes in the brain and an increase in cerebral viral load (Lim et al, 2011). CCR2 has been reported to mediate increased susceptibility to post-H1N1 bacterial pneumonia by limiting dendritic cell induction of IL-17 (Gurczynski et al, 2019). Nine SNPs in the CCR2 gene have been associated with susceptibility to and severity of several diseases including HIV and hepatitis C virus infection (Stone et al, 2017 Review; Ngoufack et al, 2019). PMID: 21131425; Lim et al, 2011 - Ccr2-deficiency resulted in markedly increased mortality (~20% survival). This was associated with increased viral load in the CNS of Ccr2-deficient mice on day 12 post-infection. This appeared to be specific to the brain and not in the blood. Monocyte accumulation is strongly reduced in Ccr2-/- mice. Brain tissue from infected Ccr2−/− mice showed markedly fewer immunoreactive cells as evaluated by immunohistochemistry analysis (Fig4). PMID: 30498200; Gurczynski et al, 2019 - H1N1 infected CCR2−/− mice had significantly higher survival as compared to H1N1 infected WT mice which is associated with significantly improved bacterial clearance at 24 and 48 hours (10 fold and 14 fold, respectively) post-bacterial challenge (with MRSA). In comparison to WT H1N1 infected mice, CCR2−/− mice recruited ~3-fold more IL-17 producing γδ-T cells and ~2.5-fold more Th17 cells (Figure 4B). Expression of CCL2 (MCP-1) in the lung is increased following H1N1 infection or H1N1 / MRSA dual infection as measured via qRT-PCR (Fig1).; to: Evidence Summary from Illumina curation team: CCR2 is a chemokine receptor highly expressed on monocytes which is critical for bone marrow egress of classic monocytes and trafficking to sites of inflammation. Ccr2 deficiency in mice markedly increases mortality in West Nile virus encephalitis, with Ccr2-/- mice showing sustained monocytopenia, reduced accumulation of monocytes in the brain and an increase in cerebral viral load (Lim et al, 2011). CCR2 has been reported to mediate increased susceptibility to post-H1N1 bacterial pneumonia by limiting dendritic cell induction of IL-17 (Gurczynski et al, 2019). Nine SNPs in the CCR2 gene have been associated with susceptibility to and severity of several diseases including HIV and hepatitis C virus infection (Stone et al, 2017 Review; Ngoufack et al, 2019). PMID: 21131425; Lim et al, 2011 - Ccr2-deficiency resulted in markedly increased mortality (~20% survival). This was associated with increased viral load in the CNS of Ccr2-deficient mice on day 12 post-infection. This appeared to be specific to the brain and not in the blood. Monocyte accumulation is strongly reduced in Ccr2-/- mice. Brain tissue from infected Ccr2−/− mice showed markedly fewer immunoreactive cells as evaluated by immunohistochemistry analysis (Fig4). PMID: 30498200; Gurczynski et al, 2019 - H1N1 infected CCR2−/− mice had significantly higher survival as compared to H1N1 infected WT mice which is associated with significantly improved bacterial clearance at 24 and 48 hours (10 fold and 14 fold, respectively) post-bacterial challenge (with MRSA). In comparison to WT H1N1 infected mice, CCR2−/− mice recruited ~3-fold more IL-17 producing γδ-T cells and ~2.5-fold more Th17 cells (Figure 4B). Expression of CCL2 (MCP-1) in the lung is increased following H1N1 infection or H1N1 / MRSA dual infection as measured via qRT-PCR (Fig1). |
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| COVID-19 research v0.348 | CCR2 |
Rebecca Foulger changed review comment from: Evidence Summary from Illumina curation team: CCR2 is a chemokine receptor highly expressed on monocytes which is critical for bone marrow egress of classic monocytes and trafficking to sites of inflammation. Ccr2 deficiency in mice markedly increases mortality in West Nile virus encephalitis, with Ccr2-/- mice showing sustained monocytopenia, reduced accumulation of monocytes in the brain and an increase in cerebral viral load (Lim et al, 2011). CCR2 has been reported to mediate increased susceptibility to post-H1N1 bacterial pneumonia by limiting dendritic cell induction of IL-17 (Gurczynski et al, 2019). Nine SNPs in the CCR2 gene have been associated with susceptibility to and severity of several diseases including HIV and hepatitis C virus infection (Stone et al, 2017 Review; Ngoufack et al, 2019). PMID: 21131425; Lim et al, 2011 - Ccr2-deficiency resulted in markedly increased mortality (~20% survival). This was associated with increased viral load in the CNS of Ccr2-deficient mice on day 12 post-infection. This appeared to be specific to the brain and not in the blood. Monocyte accumulation is strongly reduced in Ccr2-/- mice. Brain tissue from infected Ccr2−/− mice showed markedly fewer immunoreactive cells as evaluated by immunohistochemistry analysis (Fig4). PMID: 30498200; Gurczynski et al, 2019 - H1N1 infected CCR2−/− mice had significantly higher survival as compared to H1N1 infected WT mice which is associated with significantly improved bacterial clearance at 24 and 48 hours (10 fold and 14 fold, respectively) post-bacterial challenge (with MRSA). In comparison to WT H1N1 infected mice, CCR2−/− mice recruited ~3-fold more IL-17 producing γδ-T cells and ~2.5-fold more Th17 cells (Figure 4B). Expression of CCL2 (MCP-1) in the lung is increased following H1N1 infection or H1N1 / MRSA dual infection as measured via qRT-PCR (Fig1).; to: Evidence Summary from Illumina curation team: CCR2 is a chemokine receptor highly expressed on monocytes which is critical for bone marrow egress of classic monocytes and trafficking to sites of inflammation. Ccr2 deficiency in mice markedly increases mortality in West Nile virus encephalitis, with Ccr2-/- mice showing sustained monocytopenia, reduced accumulation of monocytes in the brain and an increase in cerebral viral load (Lim et al, 2011). CCR2 has been reported to mediate increased susceptibility to post-H1N1 bacterial pneumonia by limiting dendritic cell induction of IL-17 (Gurczynski et al, 2019). Nine SNPs in the CCR2 gene have been associated with susceptibility to and severity of several diseases including HIV and hepatitis C virus infection (Stone et al, 2017 Review; Ngoufack et al, 2019). PMID: 21131425; Lim et al, 2011 - Ccr2-deficiency resulted in markedly increased mortality (~20% survival). This was associated with increased viral load in the CNS of Ccr2-deficient mice on day 12 post-infection. This appeared to be specific to the brain and not in the blood. Monocyte accumulation is strongly reduced in Ccr2-/- mice. Brain tissue from infected Ccr2−/− mice showed markedly fewer immunoreactive cells as evaluated by immunohistochemistry analysis (Fig4). PMID: 30498200; Gurczynski et al, 2019 - H1N1 infected CCR2−/− mice had significantly higher survival as compared to H1N1 infected WT mice which is associated with significantly improved bacterial clearance at 24 and 48 hours (10 fold and 14 fold, respectively) post-bacterial challenge (with MRSA). In comparison to WT H1N1 infected mice, CCR2−/− mice recruited ~3-fold more IL-17 producing γδ-T cells and ~2.5-fold more Th17 cells (Figure 4B). Expression of CCL2 (MCP-1) in the lung is increased following H1N1 infection or H1N1 / MRSA dual infection as measured via qRT-PCR (Fig1). |
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| COVID-19 research v0.348 | CCR2 |
Rebecca Foulger commented on gene: CCR2: Evidence Summary from Illumina curation team: CCR2 is a chemokine receptor highly expressed on monocytes which is critical for bone marrow egress of classic monocytes and trafficking to sites of inflammation. Ccr2 deficiency in mice markedly increases mortality in West Nile virus encephalitis, with Ccr2-/- mice showing sustained monocytopenia, reduced accumulation of monocytes in the brain and an increase in cerebral viral load (Lim et al, 2011). CCR2 has been reported to mediate increased susceptibility to post-H1N1 bacterial pneumonia by limiting dendritic cell induction of IL-17 (Gurczynski et al, 2019). Nine SNPs in the CCR2 gene have been associated with susceptibility to and severity of several diseases including HIV and hepatitis C virus infection (Stone et al, 2017 Review; Ngoufack et al, 2019). PMID: 21131425; Lim et al, 2011 - Ccr2-deficiency resulted in markedly increased mortality (~20% survival). This was associated with increased viral load in the CNS of Ccr2-deficient mice on day 12 post-infection. This appeared to be specific to the brain and not in the blood. Monocyte accumulation is strongly reduced in Ccr2-/- mice. Brain tissue from infected Ccr2−/− mice showed markedly fewer immunoreactive cells as evaluated by immunohistochemistry analysis (Fig4). PMID: 30498200; Gurczynski et al, 2019 - H1N1 infected CCR2−/− mice had significantly higher survival as compared to H1N1 infected WT mice which is associated with significantly improved bacterial clearance at 24 and 48 hours (10 fold and 14 fold, respectively) post-bacterial challenge (with MRSA). In comparison to WT H1N1 infected mice, CCR2−/− mice recruited ~3-fold more IL-17 producing γδ-T cells and ~2.5-fold more Th17 cells (Figure 4B). Expression of CCL2 (MCP-1) in the lung is increased following H1N1 infection or H1N1 / MRSA dual infection as measured via qRT-PCR (Fig1). |
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| COVID-19 research v0.347 | ATF3 |
Rebecca Foulger changed review comment from: Evidence Summary from Illumina curation team: The Activating Transcription Factor 3 (ATF3) is a member of the ATF/cAMP Responsive Element-Binding (CREB) family of transcription factors which are known to be induced during inflammation and genotoxic stress. The modulation and elevation of ATF3 levels has also been observed in different host cells types upon infection with viruses, including the coronavirus, HCoV-229E and the Japanese encephalitis virus (JEV), a RNA neurotropic flavivirus (Poppe et al. 2016; Sood et al. (2017). In a mouse neuronal cell line infected with JEV, Atf3 was shown to bind to the promoter of viral response genes including Stat1, Irf9, Isg15, and to negatively regulate their expression (Sood et al. (2017). In addition, cellular autophagy was also inhibited by Atf3 negative regulation of the autophagy gene Atg5 in cells infected with the same virus (Sood et al. (2017). Labzin et al. (2015) also showed reduced viral replication in primary bone marrow–derived macrophages derived from Atf3 deficient mice, a phenotype which could be rescued by overexpression of Atf3. PMID: 28355270: Poppe et al. (2016) -The A549 lung epithelial carcinoma cell model was used to assess host cell transcriptional changes upon infection of the corona virus HCoV-229E. At 16 h and 48 h post transfection, cell transcriptomes were analysed by microarray containing 60,000 probes covering annotated genes and non-coding RNAs. Thirty seven genes, including ATF3 were upregulated in response to the HCoV-229E infection when compared to mock transduced cells (Fig 1). Upregulation of ATF3 was confirmed by RT-PCR analysis of laser dissected cells (Fig 1E). PMID 28821775; Sood et al. (2017) - ATF3 is induced following Japanese encephalitis virus (JEV) infection, and regulates cellular antiviral and autophagy pathways in the absence of type I interferons in mouse neuronal cells. ATF3 was induced in mammalian cells following JEV infection, using qRTPCR analysis of transduced cell lines, including mouse Neuro2a, HEK293, HeLa and MEFs ATF3 levels were elevated compared to wildtype (Fig1). Fig2: ATF3 acts as a negative regulator of the antiviral response. Knockdown of ATF3 expression using Atf3 specific siRNA lead to a relative increased expression of viral response genes including Rig1, ifih1, ddx60, Gbp1, compared to controls. Fig4 CHIP analysis showed that ATF3 binds to the promoter of antiviral genes such as Stat1, Irf9, Isg15, Ifit1. Fig5 ATF3 negatively regulates cellular autophagy, in both Neur2a cells and MEFs infected with JEV and treated with Atf3 siRNA showed a relative increase in the expression of cellular autophagy related genes as determined by RTPCR. Fig 6. CHIP analysis showed that ATF3 binds the ATG5 promoter. Taken together this series of experiments demonstrate that, in cells deficient in interferon type I, the increased expression of ATF3 induced by infection of JEV leads to the negative regulation of antiviral genes such as Stat1, Irf9, Isg15 and genes related to cellular autophagy such as ATG5. PMID 26416280; Labzin et al. (2015) - ATF3 limits cellular inflammatory response to microbial infection by regulating the expression of cytokines and chemokines. Primary bone marrow–derived macrophages from ATF3-/- mice infected with LCMV showed reduced viral replication compared to WT (Fig 7). The same cells overexpressing ATF3 constructs showed an increase in viral replication.; to: Evidence Summary from Illumina curation team: The Activating Transcription Factor 3 (ATF3) is a member of the ATF/cAMP Responsive Element-Binding (CREB) family of transcription factors which are known to be induced during inflammation and genotoxic stress. The modulation and elevation of ATF3 levels has also been observed in different host cells types upon infection with viruses, including the coronavirus, HCoV-229E and the Japanese encephalitis virus (JEV), a RNA neurotropic flavivirus (Poppe et al. 2016; Sood et al. (2017). In a mouse neuronal cell line infected with JEV, Atf3 was shown to bind to the promoter of viral response genes including Stat1, Irf9, Isg15, and to negatively regulate their expression (Sood et al. (2017). In addition, cellular autophagy was also inhibited by Atf3 negative regulation of the autophagy gene Atg5 in cells infected with the same virus (Sood et al. (2017). Labzin et al. (2015) also showed reduced viral replication in primary bone marrow–derived macrophages derived from Atf3 deficient mice, a phenotype which could be rescued by overexpression of Atf3. PMID: 28355270: Poppe et al. (2016) -The A549 lung epithelial carcinoma cell model was used to assess host cell transcriptional changes upon infection of the corona virus HCoV-229E. At 16 h and 48 h post transfection, cell transcriptomes were analysed by microarray containing 60,000 probes covering annotated genes and non-coding RNAs. Thirty seven genes, including ATF3 were upregulated in response to the HCoV-229E infection when compared to mock transduced cells (Fig 1). Upregulation of ATF3 was confirmed by RT-PCR analysis of laser dissected cells (Fig 1E). PMID 28821775; Sood et al. (2017) - ATF3 is induced following Japanese encephalitis virus (JEV) infection, and regulates cellular antiviral and autophagy pathways in the absence of type I interferons in mouse neuronal cells. ATF3 was induced in mammalian cells following JEV infection, using qRTPCR analysis of transduced cell lines, including mouse Neuro2a, HEK293, HeLa and MEFs ATF3 levels were elevated compared to wildtype (Fig1). Fig2: ATF3 acts as a negative regulator of the antiviral response. Knockdown of ATF3 expression using Atf3 specific siRNA lead to a relative increased expression of viral response genes including Rig1, ifih1, ddx60, Gbp1, compared to controls. Fig4 CHIP analysis showed that ATF3 binds to the promoter of antiviral genes such as Stat1, Irf9, Isg15, Ifit1. Fig5 ATF3 negatively regulates cellular autophagy, in both Neur2a cells and MEFs infected with JEV and treated with Atf3 siRNA showed a relative increase in the expression of cellular autophagy related genes as determined by RTPCR. Fig 6. CHIP analysis showed that ATF3 binds the ATG5 promoter. Taken together this series of experiments demonstrate that, in cells deficient in interferon type I, the increased expression of ATF3 induced by infection of JEV leads to the negative regulation of antiviral genes such as Stat1, Irf9, Isg15 and genes related to cellular autophagy such as ATG5. PMID 26416280; Labzin et al. (2015) - ATF3 limits cellular inflammatory response to microbial infection by regulating the expression of cytokines and chemokines. Primary bone marrow–derived macrophages from ATF3-/- mice infected with LCMV showed reduced viral replication compared to WT (Fig 7). The same cells overexpressing ATF3 constructs showed an increase in viral replication. |
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| COVID-19 research v0.347 | ATF3 |
Rebecca Foulger commented on gene: ATF3: Evidence Summary from Illumina curation team: The Activating Transcription Factor 3 (ATF3) is a member of the ATF/cAMP Responsive Element-Binding (CREB) family of transcription factors which are known to be induced during inflammation and genotoxic stress. The modulation and elevation of ATF3 levels has also been observed in different host cells types upon infection with viruses, including the coronavirus, HCoV-229E and the Japanese encephalitis virus (JEV), a RNA neurotropic flavivirus (Poppe et al. 2016; Sood et al. (2017). In a mouse neuronal cell line infected with JEV, Atf3 was shown to bind to the promoter of viral response genes including Stat1, Irf9, Isg15, and to negatively regulate their expression (Sood et al. (2017). In addition, cellular autophagy was also inhibited by Atf3 negative regulation of the autophagy gene Atg5 in cells infected with the same virus (Sood et al. (2017). Labzin et al. (2015) also showed reduced viral replication in primary bone marrow–derived macrophages derived from Atf3 deficient mice, a phenotype which could be rescued by overexpression of Atf3. PMID: 28355270: Poppe et al. (2016) -The A549 lung epithelial carcinoma cell model was used to assess host cell transcriptional changes upon infection of the corona virus HCoV-229E. At 16 h and 48 h post transfection, cell transcriptomes were analysed by microarray containing 60,000 probes covering annotated genes and non-coding RNAs. Thirty seven genes, including ATF3 were upregulated in response to the HCoV-229E infection when compared to mock transduced cells (Fig 1). Upregulation of ATF3 was confirmed by RT-PCR analysis of laser dissected cells (Fig 1E). PMID 28821775; Sood et al. (2017) - ATF3 is induced following Japanese encephalitis virus (JEV) infection, and regulates cellular antiviral and autophagy pathways in the absence of type I interferons in mouse neuronal cells. ATF3 was induced in mammalian cells following JEV infection, using qRTPCR analysis of transduced cell lines, including mouse Neuro2a, HEK293, HeLa and MEFs ATF3 levels were elevated compared to wildtype (Fig1). Fig2: ATF3 acts as a negative regulator of the antiviral response. Knockdown of ATF3 expression using Atf3 specific siRNA lead to a relative increased expression of viral response genes including Rig1, ifih1, ddx60, Gbp1, compared to controls. Fig4 CHIP analysis showed that ATF3 binds to the promoter of antiviral genes such as Stat1, Irf9, Isg15, Ifit1. Fig5 ATF3 negatively regulates cellular autophagy, in both Neur2a cells and MEFs infected with JEV and treated with Atf3 siRNA showed a relative increase in the expression of cellular autophagy related genes as determined by RTPCR. Fig 6. CHIP analysis showed that ATF3 binds the ATG5 promoter. Taken together this series of experiments demonstrate that, in cells deficient in interferon type I, the increased expression of ATF3 induced by infection of JEV leads to the negative regulation of antiviral genes such as Stat1, Irf9, Isg15 and genes related to cellular autophagy such as ATG5. PMID 26416280; Labzin et al. (2015) - ATF3 limits cellular inflammatory response to microbial infection by regulating the expression of cytokines and chemokines. Primary bone marrow–derived macrophages from ATF3-/- mice infected with LCMV showed reduced viral replication compared to WT (Fig 7). The same cells overexpressing ATF3 constructs showed an increase in viral replication. |
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| COVID-19 research v0.347 | IRF1 | Julie Taylor commented on gene: IRF1: Evidence Summary from Illumina curation team: IRF1 encodes interferon regulatory factor 1, a member of the family of transcription factors that play a role in regulating both the innate and adaptive immune response. IRF1 is constitutively expressed at a low level but significantly elevated upon IFN-I stimulation, elevated IRF1 further amplifies the IFN response through a positive feedback loop (Lukele et al. 2019, Review). IRF-1 attenuates the replication of several viruses, including hepatitis C virus, West Nile virus (WNV), and EMCV, (Schoggins et al 2011) and IRF1 knock out mice are more susceptible to some viruses, such as EMCV and coxsackievirus B3, than wild type mice (Kimura et al. 1994). Using an IRF1 deficient BEAS2B bronchial epithelial cell line with increased susceptibility to VSV, and multiple strains of influenza viruses, Panda et al. 2019, showed that IRF1 is important for the early expression of types I and III IFNs and ISGs. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | IDE | Alison Coffey commented on gene: IDE: Evidence Summary from Illumina curation team: Insulin-degrading enzyme (IDE), also known as insulysin, is a member of the zinc metalloproteinase family that was initially implicated in insulin degradation. It is highly conserved among different species and has the ability to interact with a variety of functionally unrelated ligands that share little homology in their primary amino acid sequences. Several human viruses use enzymes as receptors. Li et al. (2006) (PMID 17055432) established IDE as a cellular receptor for both cell-free and cell-associated Varicella-zoster virus (VZV), the cause of chickenpox and shingles in humans. VZV is likely spread as cell-free virus to susceptible hosts but transmitted by cell-to-cell spread in the body and in vitro. Li et al. (2006) showed that IDE interacts with the VZV glycoprotein E (gE) (which is essential for virus infection) through its extracellular domain. Downregulation of IDE by siRNA, or blocking of IDE with antibody, with soluble IDE protein extracted from liver, or with bacitracin inhibited VZV infection. Cell-to-cell spread of virus was also impaired by blocking IDE. Transfection of cell lines impaired for VZV infection with a plasmid expressing human IDE resulted in increased entry and enhanced infection with cell-free and cell-associated virus. Li et al. (2010) subsequently reported that a recombinant soluble IDE (rIDE) enhanced VZV infectivity at an early step of infection associated with an increase in virus internalization, and increased cell-to-cell spread. In 2017, Hahn et al. demonstrated that mature HIV-1 p6 protein (stability of which inversely affects the replication capacity of HIV-1) is a substrate for IDE. IDE is both sufficient and required for the degradation of p6, which is approximately 100-fold more efficiently degraded by IDE than its eponymous substrate insulin. An IDE specific inhibitor, 6bK, and exogenous insulin, were both shown to interfere with X4-tropic HIV-1 replication in activated PBMCs, most probably by competing with p6 for degradation by IDE. In addition, an IDE-insensitive p6 mutant of HIV-1 exhibits impaired replication capacity but is insensitive to treatment with insulin or 6bK. Conversely, neither virus release and maturation, nor the amounts of particle associated Vpr and p6 itself were altered in IDE knock out cells. The data support a model in which IDE is responsible for the rapid degradation of p6 entering the cell as part of the incoming virion, a process that appears to be crucial to achieve optimal X4-tropic virus replication. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | DEFA1 | Alison Coffey commented on gene: DEFA1: Evidence Summary from Illumina curation team: DEFA1, or HNP1, is a member of the defensin family of host defense peptides, a group of microbicidal and cytotoxic peptides made by neutrophils. Defensins are known to have a role in innate immunity as a core host-protective component against bacterial, viral and fungal infections (Xu and Wuyaun, 2020). Defensins have direct antiviral activity in cell culture, with varied mechanisms for individual viruses. Defensins also have a potent immunomodulatory activity that can alter innate and adaptive immune responses to viral infection and are able to target multiple steps of host-virus interactions to reduce infectivity of both enveloped and non-enveloped viruses. Targets include viral envelopes, glycoproteins, and capsids or host cells. DEFA1 is well-recognized for its direct anti-HIV activity, it also restrains HIV-1 uptake by inhibiting Env-mediated viral fusion and downregulating host cell surface expression of CD4 and coreceptor CXCR4. Post-entry inhibition of enveloped viruses such as HIV-1 and influenza by DEFA1 is mediated through interfering with cell signaling pathways such as PKC that are required for viral replication (Xu and Wuyaun, 2020). An unpublished study by Kit and Kit (2020), demonstrated in silico that the affinity of human alpha-defensins 1, 2, 3 and 5 to SARS-CoV-2 spike protein is higher than that of the SARS-CoV-2 spike protein towards ACE2. The authors suggest that these alpha-defensins may serve as primary factors in protecting lung tissue from COVID-19 viral infection. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | CXADR | Alison Coffey commented on gene: CXADR: Evidence Summary from Illumina curation team: The coxsackie and adenovirus receptor (CXADR or CAR), also known as CAR-like membrane protein (CLMP), was first identified as a high affinity receptor for adenovirus serotypes 2 and 5 and coxsackie viruses group B. CXADR is developmentally regulated and plays an important role in cardiac development. The protein is a transmembrane receptor and plays a key role in controlling adhesion between adjacent epithelial cells. It is also implicated in controlling both recruitment of immune cells and in tumorigenesis (Zapater et al. 2017). Vehik et al. (2018) concluded that a SNP within the CXADR region is associated with islet autoimmunity. In response to exogenous TNF?, CAR promotes transmigration of leukocytes both in vitro and in vivo. suggesting that CAR may be an important receptor in the control of inflammation. As neutrophils and T cells play a role in host immunity, these data suggest that CAR may be ideally positioned to modulate the immune response from the epithelial or endothelial cell compartments. (Morton et al 2016). CAR expression and infectivity with adenovirus (Ad) are increased in cystic fibrosis airway epithelial cells (Sharma et al. 2017). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | BANF1 | Alison Coffey commented on gene: BANF1: Evidence Summary from Illumina curation team: BANF1 is an abundant, highly conserved DNA binding protein involved in multiple pathways including mitosis, nuclear assembly, viral infection, chromatin and gene regulation and the DNA damage response. It is also essential for early development in metazoans and relevant to human physiology. Variants in the gene are associated with Nestor-Guillermo progeria syndrome (OMIM #614008). Different viral infections can lead to changes in the subcellular distribution of BANF1 infections with a B1 kinase-deficient vaccinia virus cause re-localization at sites of viral DNA accumulation in the cytoplasm, while no change in localization is found during infection with wild-type vaccinia. By contrast, in cells infected with Herpes Simplex Virus Type-1 (HSV-1) BAF localizes to the nucleus, where HSV-1 viral DNA replicates. BANF1 actively protects the genome by intercepting foreign DNA. This protective function is exploited by retroviruses for inhibiting self-destructing autointegration of retroviral DNA, thereby promoting integration of viral DNA into the host chromosome. However, with other viruses, including the poxvirus vaccinia and HSV-1, BANF1 has an antiviral activity by blocking viral DNA replication (PMID 2607214: Jamin et al. 2015). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | VPS33A | Alison Coffey commented on gene: VPS33A: Evidence Summary from Illumina curation team: VPS33A is a member of the Sec1/Munc18-related (SM) protein family and a core component of the class C core vacuole/endosome tethering (CORVET) and the homotypic fusion and protein sorting (HOPS) complexes (Vasilev et al. 2020). Both complexes are heterohexamers and share four subunits. VPS33A, VPS11, VPS16 and VPS18, involved in endolysosomal pathway. Deficiency of VPS33A was shown to affect susceptibility to certain viruses in cell culture, including Ebola and Marburg viruses (Carette et al. 2011), however no human studies confirming this association were identified. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | TLR7 | Alison Coffey commented on gene: TLR7: Evidence Summary from Illumina curation team: The TLR7 gene encodes for toll -like receptor 7 protein, an endosomal receptor that plays a key role in innate and adaptive immunity. Toll-like receptors are pattern recognition receptors, which control host immune response against pathogens through recognition of molecular signatures. TLR7 recognizes uridine-containing single strand RNAs (ssRNAs) of viral origin or guanosine analog (reviewed by Freund et al. 2019). Tlr7 deficient mice show an increased susceptibility to West Nile Virus (Town et al. (2009) and recently, Mukherjee et al. (2019) identified TLR7 polymorphisms associated with susceptibility to viral infections in an East Asian population Mukherjee et al. (2019). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | PDGFRA | Alison Coffey commented on gene: PDGFRA: Evidence Summary from Illumina curation team: The PDGFRA gene encodes the platelet-derived growth factor receptor alpha protein, a tyrosine-protein kinase that acts as a cell-surface receptor for PDGFA, PDGFB and PDGFC, binding of which leads to the activation of several signaling cascades, and plays an essential role in the regulation of embryonic development, cell proliferation, survival and chemotaxis. PDGFRA has been demonstrated to be a critical receptor for human cytomegalovirus infection (PMID 18701889: Soroceanu et al. 2008). Di Pasquale et al. (2003) (PMID 14502277). also confirmed the role of PDGFRA and PDGFRB as receptors for adeno-associated virus type 5 (AAV-5). PMID 18701889: Soroceanu et al. 2008 - PDGFRA is specifically phosphorylated by both laboratory and clinical isolates of human cytomegalovirus (CMV) in various human cell types, resulting in activation of the phosphoinositide-3-kinase signaling pathway. Cells in which PDGFRA was genetically deleted or functionally blocked were nonpermissive to human CMV entry, viral gene expression, or infectious virus production. Reintroducing the human PDGFRA gene into knockout cells restored susceptibility to viral entry and essential viral gene expression. Blockade of receptor function with a humanized PDGFRA blocking antibody (IMC-3G3) or targeted inhibition of its kinase activity with a small molecule (Gleevec) completely inhibited human CMV viral internalization and gene expression in human epithelial, endothelial, and fibroblast cells. Viral entry in cells harboring endogenous PDGFRA was competitively inhibited by pretreatment with PDGF-AA. It was demonstrated that human CMV glycoprotein B directly interacts with PDGFRA, resulting in receptor tyrosine phosphorylation, and that glycoprotein B neutralizing antibodies inhibit human CMV-induced PDGFRA phosphorylation. The authors concluded that PDGFRA is a critical receptor required for human CMV infection, and thus a target for novel antiviral therapies. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | NLRP6 | Alison Coffey commented on gene: NLRP6: Evidence Summary from Illumina curation team: The NLRP6 gene encoding the NOD-like receptor family pyrin domain containing 6 is a member of the NLR family of proteins, that is highly expressed within the intestine and liver. The NLRP6 inflammasome plays an established role in the regulation of inflammation and host defence against microbes. Wang et al. (2015) demonstrated that NLRP6 also regulates intestinal antiviral innate immunity. NLRP6 knockout mice show increased susceptibility to infection from the single stranded RNA viruses; encephalomyocarditis virus and murine norovirus 1(MNV-1). Nlrp6 binds viral RNA via the RNA helicase Dhx15, the complex triggers the induction of type I/III interferons (IFNs) through the mitochondrial antiviral signaling protein (MAVS). Type I/III IFNs stimulate the expression of antiviral IFN-stimulated genes (ISGs), including Nlrp6 itself (Wang et al. 2015). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | MX2 | Alison Coffey commented on gene: MX2: Evidence Summary from Illumina curation team: MX2, also known as MXB is an interferon-induced dynamin like GTPAse with antiviral activity, which has been shown to affect the nuclear uptake and/or stability of the HIV-1 replication complex and the subsequent chromosomal integration of the proviral DNA (Goujon et al. 2013, Liu et al. 2015). However, resistance of several HIV strains to MX2-driven inhibition has been reported (Liu et al. 2015). Inhibition of other viruses, including HCV, Japanese encephalitis virus and Dengue virus of the Flaviviridae family as well as simian immunodeficiency virus and Herpesviruses has been reported (Goujon et al. 2013, Yi et al. 2019). In contrast to MX1, MX2 does not appear to be involved in regulation of several other viral infections, including influenza and Zika virus (Melen et al. 1996; Yi et al. 2019). Additionally, MX2 may be involved in nucleocytoplasmic transport and bears a nuclear localisation signal that appears essential for HCV inhibition (Melen et al. 1996; King et al. 2004, Yi et al. 2019). Of note, MX2 was described as an interferon response marker gene in preprint studies investigating expression profiles and related mechanisms in SARS-CoV-2 infection (Fagone et al. 2020, Li et al. 2020). Overall, inhibition of viral infection by MX2 appears to be virus type- and strain-specific, and some viruses potentially have developed mechanisms to resist MX2 function. No reports of any SNP associations of MX2 with viral susceptibility in humans have been identified. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | KIAA0319L | Alison Coffey commented on gene: KIAA0319L: Evidence Summary from Illumina curation team: KIAA0319L, also known as AAVR or AAVRL, encodes the KIAA0319 like protein, a type-I transmembrane protein which acts as an essential receptor for adeno-associated virus (AAV) and is involved in adeno-associated virus infection through endocytosis system (PMID 26814968: Pillay et al. 2016). Genetic ablation of AAVR renders a wide range of mammalian cell types highly resistant to AAV infection. Adeno-associated virus vectors are widely used in virus-based gene therapy because of their broad tissue tropism, non-pathogenic nature and low immunogenicity. PMID 26814968: Pillay et al. (2016) - used a haploid genetic screen to identify the type I transmembrane protein KIAA0319L as an essential receptor that mediates AAV entry and renamed this protein the AAV receptor (AAVR). The function of AAVR was confirmed by using CRISPRCas9 to knock out the receptor and by using anti-AAVR blocking antibodies; both treatments rendered cells highly resistant to AAV infection with several serotypes, including AAV2, which is the most commonly used serotype for gene therapy in clinical trials. Finally, Aavr knockout mice were more resistant to AAV-mediated gene therapy than mice that expressed AAVR. PMID 28679762: Pillay et al. (2017) - Further defines AAV-AAVR interactions, genetically and biochemically. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | ITGB3 | Alison Coffey commented on gene: ITGB3: Evidence Summary from Illumina curation team: ITGB3 encodes integrin beta-3 (CD61), a member of the integrin family of transmembrane proteins. Integrins are heterodimeric transmembrane proteins involved in cell adhesion and migration, and organization of the cytoskeleton. Integrin b3 has been shown to act as a coreceptor for many viruses including Herpes virus 8/HHV-8, Coxsackievirus A9, Hantaan virus, Cytomegalovirus/HHV-5, and West Nile virus (Gavrilovskaya et al. 2008; Roivainen et al. 1994; Garrigues et al 2008; Schmidt et al. 2013; Wang et al. 2005). Viruses such as the arena virus LASV and Dengue virus may manipulate and increase the expression level of ITGB3 (Zapata et al, 2013; In vitro exposure of human PBMC to a pathogenic arenavirus (LASV) increases the expression of ITGB3 (Zapata et al, 2013; Noisakran et al, 2012). Valdebenito et al. 2019 recently reported a genetic single-nucleotide polymorphism associated with infection susceptibility to Andes virus in a Chilean population. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | ILF3 | Alison Coffey commented on gene: ILF3: Evidence Summary from Illumina curation team: The ILF3 gene encodes two alternatively spliced and ubiquitously expressed RNA binding protein isoforms, NF110 and NF90. NF110 and NF90 have been shown to interact with viral RNAs and proteins to inhibit the replication of a number of viruses, including PV-RIPO, a chimeric poliovirus and human rhinovirus; HIV-1, and vesicular stomatitis virus (VSV) (reviewed Castella et al. 2015). Conversely, NF110 and NF90 have also been associated with the enhancement of viral replication in the case of DNA hepatitis B virus (HBV), ssRNA viruses from the Flaviviridae family, hepatitis C virus and influenza B (FLUBV) (reviewed Castella et al. 2015; Patzina et al, 2017). Recently, Watson et al (2020) demonstrated a role for the ILF3 isoforms in enhancing the translation of IFNB1 and ISGs in response to a viral infection. Depletion of NF90/NF110 from HeLa cells using siRNA resulted in an impaired antiviral activity with a reduction in the expression of ISG proteins and conditioned medium generated in ILF3-depleted cells conferred less resistance to Echovirus 7 infection. The specific depletion of NF110 was shown to cause a decrease in the association of IFNB1 mRNA with the polysomal fractions in poly(I:C) stimulated conditions (Watson et al. 2020). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | IL9 | Alison Coffey commented on gene: IL9: Evidence Summary from Illumina curation team: IL9 encodes interleukin 9, which is a stimulatory cytokine that regulates inflammatory immunity (Goswami and Kaplan 2011). It has been demonstrated that high levels of IL-9 are present in nasopharyngeal aspirate of infants with disease of the respiratory tract caused by the Human respiratory syncytial virus (RSV) (Semple et al. 2007). Studies conducted on mice showed that that the severity of lung pathology correlates with IL-9 cytokine production and that Th9 cells, which produce IL-9, play an important role in the development of airway eosinophilia and bronchial hyperresponsiveness (Dodd et al. 2009; Saeki et al. 2016). IL9 polymorphisms have also been linked to sex-restricted differences in lung function, allergen sensitization, IgE levels, and the severity of respiratory syncytial virus infection (Schuurhof et al. 2010; Aschard et al. 2009). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | IL3 | Alison Coffey commented on gene: IL3: Evidence Summary from Illumina curation team: IL3 encodes a growth-promoting cytokine called interleukin 3, which is a member of the beta common cytokine family. IL-3 (Dougan et al. 2019). IL-3 acts to regulate inflammation induced by pathogens as well as in autoimmune disease and cancer. T cell production of IL-3 during inflammation plays a role in the activation of plasmacytoid dendritic cells during viral infection. IL-3 has also been suggested to play a host-protective role against herpes simplex virus (HSV) infection (Chan et al. 1990). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | IFNA1 | Alison Coffey commented on gene: IFNA1: Evidence Summary from Illumina curation team: IFNA1 encodes IFN alpha, and belongs to the family of type I IFNs which bind to and activate the IFNAR receptor complex. Type I Interferons (IFN-I) mediate numerous immune interactions during viral infections, they establish an antiviral state as well as invoke and regulate innate and adaptive immune cells that eliminate infection (Lukele et al. 2019, review; Wang et al.2019 review). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | GPR183 | Alison Coffey commented on gene: GPR183: Evidence Summary from Illumina curation team: The GPR183 gene has been shown to be upregulated following infection with Epstein-Barr virus and aids in leukocyte migration into airways in response to allergens (Shen et al. 2017). GPR183 knockout mice exhibit enhanced pro-inflammatory cytokine release following an inflammation-inducing stimulus (Ruthiwska et al. 2018). In addition, recent work that has not yet been peer-reviewed found GPR183 expression on macrophages in severe Covid 19 patients (Liao et al.; https://doi.org/10.1101/2020.02.23.20026690). EBV seropositivity was also associated with fever and increased inflammation in Covid 19 patients in non-peer-reviewed work by Chen et al. (10.21203/rs.3.rs-21580/v1). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | GPATCH3 | Alison Coffey commented on gene: GPATCH3: Evidence Summary from Illumina curation team: Nie et al. (2017) showed that GPATCH3 is a negative regulator of the innate immune response to RNA viruses. Reduction of GPATCH3 levels using shRNA resulted in enhanced induction and transcription of SeV (ssRNA virus) downstream antiviral genes such as IFNB1, in multiple cell lines compared to controls. Similar effects were not observed in cells infected with DNA viruses, HCMV or HSV120. Coimmunoprecipitation and colocalisation experiments indicated that GPATCH3 negative regulation is mediated through a direct interaction of mitochondrial localised, MAVS (VISA). MAVS plays an established role in the innate antiviral immune responses against to RNA viruses. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | GNAQ | Alison Coffey commented on gene: GNAQ: Evidence Summary from Illumina curation team: The GNAQ gene encodes the Gq protein alpha subunit and belongs to the Gq/11 subfamily of heterotrimeric G proteins. GNAQ is ubiquitously expressed in mammalian cells and couples a wide variety of receptors to channel proteins, enzymes, and other effector molecules. Wang et al. (2019) found that Gnaq expression was downregulated during viral infection and that Gnaq siRNA transfection of host cells protected against infection from vesicular stomatitis virus (VSV) and HSV type 1 infection. Viral replication was also reduced in Gnaq deficient macrophages in cell culture and Gnaq-deficient mice were more resistant than wildtype mice to VSV infection. Further cell culture experiments showed that Gnaq modulated its antiviral response through the canonical PLC-b/Ca2+ signalling (Wang et al. 2019). PMID: 31324725 Wang et al. (2019) - Wang et al. demonstrated that GNAQ negatively regulates the antiviral innate immune responses in a calcineurin-dependent manner. Viral infection downregulates GNAQ expression in cell culture. mRNA expression levels were measured upon infection with VSV in mouse PEMs, BMMs,the fibroblast line L929 and the macrophage mouse line RAW264.7. Fig1. GNAQ negatively regulates host defence against viruses. Gnaq-specific siRNA knockdown reduced VSV infection in PEMS, overexpression of GNAQ in HEK293 cells increased VSV infection (Fig 2). PEMS and BMMs from myeloid cellspecific Gnaq-deficient mice showed reduced replication of VSV and HSV1 compared to WT. VSV replication and titers in the liver, spleen, and lung of Gnaq-deficient mice were all significantly lower than wt litter mates. Gnaq deficiency increases host resistance to viral infection (Fig 3). IFN-b (both mRNA and protein) was significantly enhanced in Gnaq-knockdown PEMs, Poly I;C (mimicking RNA viral infection), VSV infection and HSV-1 infection enhanced IgnBeta production in Gnaq-knockdown PEMs. In cell lines and in vivo, GNAQ negatively regulates IFN-beta production (Fig 4). GNAQ modulates antiviral innate immune responses through canonical PLC-b/Ca2+ signalling. Chemical inhibitors of the pathway reduced cell resistance to infection (Fig 5). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | CCR7 | Alison Coffey commented on gene: CCR7: Evidence Summary from Illumina curation team: The CCR7 gene encodes the C-C chemokine receptor 7, a chemokine receptor which is a member of the G protein-coupled receptor superfamily. CCR7 plays an important role in the homing of central memory and nave T cells to peripheral lymphoid organs. The binding of CCR7 ligands CCL19 and CCL21 during viral infection promotes activation and differentiation of CCR7 expressing cells, as well as changes in their migration properties to modulate the immune response (reviewed Yan et al. 2019). Some viral proteins target CCR7 and reduce its expression during viral infection (reviewed Yan et al. 2019), for example, the HIV-1 accessory protein, Vpu, interacts directly with CCR7 to cause its retention within the trans Golgi network of primary CD4+ T cells (Ramirez et al. 2014). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | ATG5 | Alison Coffey commented on gene: ATG5: Evidence Summary from Illumina curation team: The ATG5 gene encodes a core autophagy protein which forms a complex with ATG12 and ATG16L that is important for autophagophore elongation. Autophagy plays a key antiviral role in various human infections by modulating different aspects of the immune response (Reviewed Tao et al. 2020; Ahmed et al.2018). ATG5 may play a role in cytokine regulation, in vitro, ATG5 depleted primary human blood macrophages produced lower levels of CXCL10 and IFNa when infected with influenza A virus (Law et al. 2007). ATG5 deficient mice also show reduced Ifn and Il22 secretion when infected with the single stranded RNA vesicular stomatitis virus (VSV) (Lee et al. 2007). Using a mouse model with a conditional depletion of ATG5 within dendritic cells, Lee et al. 2010 showed that ATG5 is required for antigen presentation by dendritic cells, as a result of reduced MHC-II antigen presentation, these mice, when intradermally injected with HSV-1, showed significantly lower IFNgamma production by CD4+ T cells. (Lee et al., 2010). The ATG5 complex is targeted by some viruses to enhance infection, for example, the foot and mouth disease virus (FMDV) targets the ATG5-ATG12 complex for degradation through its viral protein 3Cpro, similarly, depletion of ATG5 and ATG12 in vitro, by siRNA increased susceptibility to FMDV infection by reducing activation of the NF-?B and IRF3 pathways (Fan et al 2017). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | ATG16L1 | Alison Coffey commented on gene: ATG16L1: Evidence Summary from Illumina curation team: The ATG16L gene encodes a core autophagy protein which forms a complex with ATG5 and ATG12 that is important for autophagophore elongation (Lavoie et al. 2019). Autophagy plays a key antiviral role in various human infections by modulating different aspects of the immune response (Reviewed Tao et al. 2020; Ahmed et al. 2018). The ATG16L complex is also targeted by some viruses to enhance infection. The Zika virus protease, targets ATG16L, dramatically depleting its levels during Zika virus infection (Hill et al. 2018). Conversely, Hepatitis B virus (HBV), an enveloped pararetrovirus, stimulates autophagy to favor its production. In vitro, RNA interference-mediated silencing of Atg16L1 interfered with viral core/nucleocapsid (NC) formation and stability, strongly diminishing virus replication (Fletcher et al. 2018). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | AIM2 | Alison Coffey commented on gene: AIM2: Evidence summary from Illumina curation team: AIM2 performs an established role within the innate immune system as a pattern recognition receptor which senses microbial dsDNA. In vitro experiments have shown that AIM2 recognises cytosolic dsDNA from a number of viruses and consequently drives pyroptosis through formation of an inflammasome complex (Sharma et al. 2019). Aim2-deficient mice show an attenuated immune response upon infection with mCNV when compared to wildtype mice (Rathinam et al. 2010). PMID: 31372985 Sharma et al. 2019 (Review) AIM2 encodes a pattern recognition receptor which senses microbial dsDNA. In vitro experiments show AIM2 recognises cytosolic dsDNA from a number of viruses and consequently drives pyroptosis through formation of an inflammasome complex. AIM2 expression is upregulated in response to infection by RNA viruses and contributes to secretion of IL-1beta, the mechanism for the recognition of RNA viruses is unclear. Table 1 summarises the list of in vitro AIM2 virus studies. PMID: 20351692: Rathinam et al. 2010 In vivo, Aim2-deficient mice, Aim2- infected with mCMV have reduced IL-18 concentrations in the serum compared to wildtype mice, and severely attenuated IFN-? production by NK cells, events, which are critical for the early control of viral replication (Figure 7b, d, e) The spleen of infected Aim2-/- mice demonstrated elevated viral titre compared to the wildtype (Fig 7h, i). PMID: 26590313 Schattgen et al. 2018 Aim2 knockout mice, infected with influenza A virus (RNA virus) showed an exaggerated response to immune response. Authors suggest that host DNA released from damaged cells during IAV infection and sensed by AIM2 leads to limitation of immune mediated damage to infected tissues. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.334 | ABCB1 | Ivone Leong edited their review of gene: ABCB1: Added comment: Searching through PubMed, most of the papers related to ABCB1 are to do with drug efficacy and ABCB1's affect on HIV-1 treatments. Therefore, this gene should remain rated Red.; Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.332 | ZFHX3 | Sarah Leigh edited their review of gene: ZFHX3: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.332 | WSCD1 | Sarah Leigh edited their review of gene: WSCD1: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.332 | UNC5CL | Sarah Leigh edited their review of gene: UNC5CL: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.332 | TAPT1 | Sarah Leigh edited their review of gene: TAPT1: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.332 | SPNS3 | Sarah Leigh edited their review of gene: SPNS3: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.332 | RPAIN | Sarah Leigh edited their review of gene: RPAIN: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.332 | PROM1 | Sarah Leigh edited their review of gene: PROM1: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.332 | PKD1L3 | Sarah Leigh edited their review of gene: PKD1L3: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.332 | NUP88 | Sarah Leigh edited their review of gene: NUP88: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.332 | MLKL | Sarah Leigh edited their review of gene: MLKL: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.332 | MIS12 | Sarah Leigh edited their review of gene: MIS12: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.332 | LDB2 | Sarah Leigh edited their review of gene: LDB2: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.332 | KARS | Sarah Leigh edited their review of gene: KARS: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.332 | HYDIN | Sarah Leigh edited their review of gene: HYDIN: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.332 | CC2D2A | Sarah Leigh edited their review of gene: CC2D2A: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.332 | BCAR1 | Sarah Leigh edited their review of gene: BCAR1: Added comment: Using Collaborative Cross mouse genetic reference population, PMID 32348764 studied the genetic regulation of variation in antibody response to influenza A virus (IAV) infection. This enabled the identification of 23 quantitative trait loci (QTL) associated with variation in specific antibody isotypes across time points; this allowed a subset to be found that broadly affect the antibody response to IAV as well as other viruses. This gene is the equivalent human for the mouse gene that was classified as a candidate from one of the QTLs, based on the predicted variant consequences and haplotype-specific expression patterns (PMID 32348764 table 2).; Changed mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.324 | SIGIRR |
Catherine Snow changed review comment from: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus". Currently no gene disease association for SIGIRR. Molgora et al. (2017) reported that IL-1R8 serves as a checkpoint for natural killer (NK) cell maturation and effector function. Its genetic blockade unleashes NK cell-mediated resistance to hepatic carcinogenesis, hematogenous liver and lung metastasis, and cytomegalovirus infection Sources: Expert list; to: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus". Currently no gene disease association for SIGIRR. Molgora et al. (2017) reported that IL-1R8 serves as a checkpoint for natural killer (NK) cell maturation and effector function. Its genetic blockade unleashes NK cell-mediated resistance to hepatic carcinogenesis, hematogenous liver and lung metastasis, and cytomegalovirus infection Li et al. (2019) who worked with mice. Found that stabilization of Sigirr by USP13 describes a novel anti-inflammatory pathway in diseases that could provide a new strategy to modulate immune activation. Sources: Expert list |
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| COVID-19 research v0.320 | SLC2A1 |
Ivone Leong gene: SLC2A1 was added gene: SLC2A1 was added to COVID-19 research. Sources: Expert list Mode of inheritance for gene: SLC2A1 was set to Unknown Publications for gene: SLC2A1 were set to 15767416; 22308487 Review for gene: SLC2A1 was set to AMBER Added comment: GLUT1 is a receptor for HTLV and suggested that perturbations in glucose metabolism resulting from interactions of HTLV envelope glycoproteins with GLUT1 are likely to contribute to HTLV-associated disorders (PMID: 15767416). PMID: 22308487 shows that IL-7 induced upregulation of Glut1 changes glucos uptake and causes T lymphocyptes susceptible to HIV-1 infection. Sources: Expert list |
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| COVID-19 research v0.317 | TBX21 |
Ivone Leong gene: TBX21 was added gene: TBX21 was added to COVID-19 research. Sources: Expert list Mode of inheritance for gene: TBX21 was set to Unknown Publications for gene: TBX21 were set to 15806396; 17378728; 19473434; 29399747 Phenotypes for gene: TBX21 were set to {Asthma, aspirin-induced, susceptibility to}, 208550; susceptibility to chronic HBV and HCV infection Review for gene: TBX21 was set to AMBER Added comment: TBX21 is a Th1-specific T-box transcription factor that controls the expression of the hallmark Th1 cytokine, interferon-gamma (PMID: 15806396). PMID: 17378728 found that variations at allele -1499 and haplotype D (--/AC) in the TBX21 promoter region contribute to susceptibility to HBV infection in the Chinese population. PMID: 19473434 found that T-1993C polymorphism in the TBX21 promoter influences susceptibility to persistent HBV infection. PMID: 29399747 found that rs4794067 (T-1993C) is significantly correlated with increased risk of HCV chronic infection (dominant model: OR = 5.690, 95% CI = 2.024-16.000) and susceptibility (dominant model: OR = 5.658, 95% CI = 2.514-12.735). Sources: Expert list |
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| COVID-19 research v0.311 | SERINC5 |
Catherine Snow changed review comment from: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus". Currently no gene disease association for SERINC5 Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3 inhibited infectivity of human immunodeficiency virus (HIV)-1 and murine leukemia retrovirus (MLV) Sudderuddin et al (2020) found that SERINC5 on the cell surface is down regulated upon HIV infection Sources: Literature; to: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus". Currently no gene disease association for SERINC5. Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3 inhibited infectivity of human immunodeficiency virus (HIV)-1 and murine leukemia retrovirus (MLV) Sudderuddin et al (2020) found that SERINC5 on the cell surface is down regulated upon HIV infection Sources: Literature |
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| COVID-19 research v0.310 | SERINC5 |
Catherine Snow gene: SERINC5 was added gene: SERINC5 was added to COVID-19 research. Sources: Literature Mode of inheritance for gene: SERINC5 was set to Unknown Publications for gene: SERINC5 were set to 26416734; 31918727 Review for gene: SERINC5 was set to AMBER Added comment: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus". Currently no gene disease association for SERINC5 Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3 inhibited infectivity of human immunodeficiency virus (HIV)-1 and murine leukemia retrovirus (MLV) Sudderuddin et al (2020) found that SERINC5 on the cell surface is down regulated upon HIV infection Sources: Literature |
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| COVID-19 research v0.308 | SERINC3 |
Catherine Snow changed review comment from: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus". No current gene disease relationship in OMIM. The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS. Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3 (607165), inhibited infectivity of human immunodeficiency virus (HIV)-1 (see 609423) and murine leukemia retrovirus (MLV) Sources: Literature; to: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus". No current gene disease relationship in OMIM. The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS. Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3, inhibited infectivity of human immunodeficiency virus (HIV)-1 and murine leukemia retrovirus (MLV) Sources: Literature |
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| COVID-19 research v0.307 | SERINC3 |
Catherine Snow changed review comment from: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus". No current gene disease relationship in OMIM. The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS. Sources: Literature; to: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus". No current gene disease relationship in OMIM. The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS. Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3 (607165), inhibited infectivity of human immunodeficiency virus (HIV)-1 (see 609423) and murine leukemia retrovirus (MLV) Sources: Literature |
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| COVID-19 research v0.307 | SERINC3 |
Catherine Snow gene: SERINC3 was added gene: SERINC3 was added to COVID-19 research. Sources: Literature Mode of inheritance for gene: SERINC3 was set to Unknown Review for gene: SERINC3 was set to AMBER Added comment: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus". No current gene disease relationship in OMIM. The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS. Sources: Literature |
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| COVID-19 research v0.306 | SDC1 |
Catherine Snow gene: SDC1 was added gene: SDC1 was added to COVID-19 research. Sources: Literature Mode of inheritance for gene: SDC1 was set to Unknown Publications for gene: SDC1 were set to 12530973 Review for gene: SDC1 was set to RED Added comment: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus". NO gene disease association for SDC1. Bobardt et al. (2003) suggested that SDC-rich endothelial cells lining the vasculature can provide a microenvironment that boosts HIV replication in T cells. Sources: Literature |
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| COVID-19 research v0.305 | SCN4A |
Catherine Snow changed review comment from: No further evidence since. Matthews et al. (2011) reported a family with PMC due to the heterozygous T1313M mutation. Before correct diagnosis, the youngest affected individual presented with neonatal inspiratory stridor and poor feeding. Laryngoscopy showed findings consistent with laryngomalacia. He continued to have stridor for the first 6 months of life, and later motor milestones were mildly delayed. In early childhood, he was noted to have frequent episodic muscle weakness and stiffness associated with cold weather. At age 4 years, he continued to have episodes of inspiratory stridor exacerbated by viral illness, cold weather, and prolonged laughing or crying. His mother, grandfather, and great-uncle reported similar episodes of muscle stiffness and weakness exacerbated by cold and exercise. Sources: Literature; to: No further evidence reported since. Matthews et al. (2011) PMID 21220685 reported a family with PMC due to the heterozygous T1313M mutation. Before correct diagnosis, the youngest affected individual presented with neonatal inspiratory stridor and poor feeding. Laryngoscopy showed findings consistent with laryngomalacia. He continued to have stridor for the first 6 months of life, and later motor milestones were mildly delayed. In early childhood, he was noted to have frequent episodic muscle weakness and stiffness associated with cold weather. At age 4 years, he continued to have episodes of inspiratory stridor exacerbated by viral illness, cold weather, and prolonged laughing or crying. His mother, grandfather, and great-uncle reported similar episodes of muscle stiffness and weakness exacerbated by cold and exercise. Sources: Literature |
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| COVID-19 research v0.305 | SCN4A |
Catherine Snow gene: SCN4A was added gene: SCN4A was added to COVID-19 research. Sources: Literature Mode of inheritance for gene: SCN4A was set to Unknown Publications for gene: SCN4A were set to 21220685 Review for gene: SCN4A was set to RED Added comment: No further evidence since. Matthews et al. (2011) reported a family with PMC due to the heterozygous T1313M mutation. Before correct diagnosis, the youngest affected individual presented with neonatal inspiratory stridor and poor feeding. Laryngoscopy showed findings consistent with laryngomalacia. He continued to have stridor for the first 6 months of life, and later motor milestones were mildly delayed. In early childhood, he was noted to have frequent episodic muscle weakness and stiffness associated with cold weather. At age 4 years, he continued to have episodes of inspiratory stridor exacerbated by viral illness, cold weather, and prolonged laughing or crying. His mother, grandfather, and great-uncle reported similar episodes of muscle stiffness and weakness exacerbated by cold and exercise. Sources: Literature |
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| COVID-19 research v0.304 | SLC6A19 |
Eleanor Williams gene: SLC6A19 was added gene: SLC6A19 was added to COVID-19 research. Sources: Literature Mode of inheritance for gene: SLC6A19 was set to Unknown Added comment: Preprint: Gupta et al https://doi.org/10.1101/2020.05.15.098616 Using the Viral Integrated Structural Evolution Dynamic Database and population genomic databases they identified 47 potential functional missense variants within ACE2/SLC6A19/TMPRSS2, warranting genomic enrichment analyses in SARS-CoV-2 patients. Sources: Literature |
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| COVID-19 research v0.303 | ACE2 |
Eleanor Williams changed review comment from: Preprint: Gupta et al https://doi.org/10.1101/2020.05.15.098616 Using the Viral Integrated Structural Evolution Dynamic Database and population genomic databases they identified 47 potential functional missense variants within ACE2/SLC6A19/TMPRSS2, warranting genomic enrichment analyses in SARS-CoV-2 patients. Two noncoding variants (rs4646118 and rs143185769) found in ~9% of African descent individuals for ACE2 may regulate expression and be related to increased susceptibility of African Americans to SARS-CoV-2.; to: Preprint: Gupta et al https://doi.org/10.1101/2020.05.15.098616 Using the Viral Integrated Structural Evolution Dynamic Database and population genomic databases they identified 47 potential functional missense variants within ACE2/SLC6A19/TMPRSS2, warranting genomic enrichment analyses in SARS-CoV-2 patients. Two noncoding variants (rs4646118 and rs143185769) found in ~9% of African descent individuals for ACE2 may regulate expression and be related to increased susceptibility of African Americans to SARS-CoV-2. |
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| COVID-19 research v0.303 | ACE2 |
Eleanor Williams edited their review of gene: ACE2: Added comment: Preprint: Gupta et al https://doi.org/10.1101/2020.05.15.098616 Using the Viral Integrated Structural Evolution Dynamic Database and population genomic databases they identified 47 potential functional missense variants within ACE2/SLC6A19/TMPRSS2, warranting genomic enrichment analyses in SARS-CoV-2 patients. Two noncoding variants (rs4646118 and rs143185769) found in ~9% of African descent individuals for ACE2 may regulate expression and be related to increased susceptibility of African Americans to SARS-CoV-2.; Changed publications: 32015507, https://doi.org/10.1101/2020.05.15.098616 |
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| COVID-19 research v0.303 | TMPRSS4 |
Eleanor Williams gene: TMPRSS4 was added gene: TMPRSS4 was added to COVID-19 research. Sources: Literature Mode of inheritance for gene: TMPRSS4 was set to Unknown Publications for gene: TMPRSS4 were set to https://doi.org/10.1101/2020.05.12.091314 Added comment: Preprint: Wruck and Adjaye https://doi.org/10.1101/2020.05.12.091314 - describe a meta-analysis focussing on the transcriptome data from human lung epithelial cells including samples infected with SARS-CoV-2 from a study described by Blanco Melo et al.12. The exploration was directed to co-expression with the known CoV-2 receptor ACE2. 72 genes significantly co-expressed with ACE2. Of the transmembrane serine proteases, the most significantly coexpressed with ACE2 was TMPRSS4, suggesting it to be a putative druggable target. Pathway analysis revealed papilloma virus infection amongst the most significantly correlated pathways. Sources: Literature |
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| COVID-19 research v0.302 | TMPRSS11A |
Eleanor Williams gene: TMPRSS11A was added gene: TMPRSS11A was added to COVID-19 research. Sources: Literature Mode of inheritance for gene: TMPRSS11A was set to Unknown Publications for gene: TMPRSS11A were set to https://doi.org/10.1101/2020.05.13.093690 Review for gene: TMPRSS11A was set to RED Added comment: Preprint: Klaassen et al https://doi.org/10.1101/2020.05.13.093690 - performed analysis of variants in FURIN, PLG, PRSS1, TMPRSS11a, MBL2 and OAS1 genes in 143 unrelated individuals from Serbian population and identified 22 variants with potential functional effect. Then used in-silico prediction and comparative population analysis and found 2 rare variants p.Lys48Arg and p.Arg328Gln. For both of these variants, PolyPhen-2, SIFT and MutPred2 algorithms predict benign/tolerated effect but the protein structure of TMPRSS11a is not well known. Sources: Literature |
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| COVID-19 research v0.301 | PRSS1 |
Eleanor Williams gene: PRSS1 was added gene: PRSS1 was added to COVID-19 research. Sources: Literature Mode of inheritance for gene: PRSS1 was set to Unknown Publications for gene: PRSS1 were set to https://doi.org/10.1101/2020.05.13.093690 Added comment: Preprint: Klaassen et al https://doi.org/10.1101/2020.05.13.093690 - performed analysis of variants in FURIN, PLG, PRSS1, TMPRSS11a, MBL2 and OAS1 genes in 143 unrelated individuals from Serbian population and identified 22 variants with potential functional effect. Then used in-silico prediction and comparative population analysis and found two rare variants in the PRSS1 gene, c.592-8C>T and p.Asn54Lys. Variant c.592-8C>T was previously detected in patients with cystic fibrosis presenting with chronic pancreatitis and p.Asn54Lys is predicted to be possibly damaging. Sources: Literature |
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| COVID-19 research v0.300 | PLG |
Eleanor Williams gene: PLG was added gene: PLG was added to COVID-19 research. Sources: Literature Mode of inheritance for gene: PLG was set to Unknown Publications for gene: PLG were set to https://doi.org/10.1101/2020.05.13.093690 Review for gene: PLG was set to RED Added comment: Preprint: Klaassen et al https://doi.org/10.1101/2020.05.13.093690 - performed analysis of variants in FURIN, PLG, PRSS1, TMPRSS11a, MBL2 and OAS1 genes in 143 unrelated individuals from Serbian population and identified 22 variants with potential functional effect. Then used in-silico prediction and comparative population analysis and found 6 rare variants in PLG. p.Arg261His and p.Ala494Val are predicted to be probably damaging/deleterious. Sources: Literature |
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| COVID-19 research v0.299 | FURIN |
Eleanor Williams commented on gene: FURIN: Preprint: Klaassen et al https://doi.org/10.1101/2020.05.13.093690 - performed analysis of variants in FURIN, PLG, PRSS1, TMPRSS11a, MBL2 and OAS1 genes in 143 unrelated individuals from Serbian population and identified 22 variants with potential functional effect. Then used in-silico prediction and comparative population analysis and found two rare variants in FURIN p.Thr33Ala and p.Gly146Ser. p.Gly146Ser. is predicted to be deleterious and may change its ability to cleave furin-like sites in the S protein of the SARS-CoV-2. |
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| COVID-19 research v0.298 | ACE2 | Eleanor Williams commented on gene: ACE2: Preprint: https://doi.org/10.1101/2020.05.12.20098160 - Shovlin and Vizcaychip - variants in 213,158 exomes/genomes were integrated for ACE2 . ACMG/AMP-based pathogenicity criteria were applied. Modelling the ″COVID-resistant ″ state where pathogenic alleles would be beneficial, nine null alleles met PVS1. Thirty-seven variants met PM1 based on critical location +/-PP3 based on computational modelling. Modelling a ″COVID-susceptible ″ state, 31 variants in four upstream open reading frames and 5′ untranslated regions could meet PM1, and may have differential effects if aminoglycoside antibiotics were prescribed for pneumonia and sepsis. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.297 | SCARB1 |
Eleanor Williams gene: SCARB1 was added gene: SCARB1 was added to COVID-19 research. Sources: Literature Mode of inheritance for gene: SCARB1 was set to Unknown Added comment: Not associated with any relevant disease phenotype in OMIM. SCARB1 is also known as SRB1 PMID: 12356718 - Scarselli et al 2002 - Characterization of hepatitis C virus (HCV) envelope glycoprotein E2 binding after chemical or enzymic modification of the cell surface led to the identification of the scavenger receptor type B class I (SR-BI) as the E2 receptor on HepG2 cells. PMID: 28827115 - Sadeghi et al 2017 - SCARB1 rs10846744 (CC) genotype (P=0.001) was strongly associated with sustained virological response PMID: 28363797 - Westhaus et al 2018 - Non-synonymous variants: S112F and T175A have greatly reduced Hepatitus C virus (HCV) receptor function. When present on the cell surface, these variants are impaired in their ability to interact with HCV E2. Non-coding variants: The G allele in rs3782287 is associated with decreased viral load. PMID: 29715527 - Naffari et al 2018 -looked at treatment responses in 395 treatment-naïve patients with chronic Hepatitus C Virus (CHC) genotype 1 treated with pegylated interferon-α and ribavirin. Rapid virologic response (RVR), complete early virologic response (cEVR) , and sustained virologic responseSVR were significantly associated with SCARB1 rs10846744 (CC). Sources: Literature |
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| COVID-19 research v0.289 | MTOR | Rebecca Foulger commented on gene: MTOR: PMID:19543266. Araki et al. (2009) demonstrated that mTOR is a major regulator of memory CD8 T-cell differentiation. Treatment of mice with rapamycin following acute lymphocytic choriomeningitis virus infection enhanced the quantity and quality of virus-specific CD8 T cells. Rapamycin treatment also enhanced memory T-cell responses in nonhuman primates following vaccination with modified vaccinia virus Ankara. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.288 | MTOR |
Rebecca Foulger gene: MTOR was added gene: MTOR was added to COVID-19 research. Sources: Other Mode of inheritance for gene: MTOR was set to Unknown Phenotypes for gene: MTOR were set to 19543266 Added comment: MTOR was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel as Red. Notes from Julie Taylor and Alison Coffey (Illumina): mTOR is a major regulator of memory CD8 T-cell differentiation. Sources: Other |
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| COVID-19 research v0.273 | MICA | Rebecca Foulger Added comment: Comment on list classification: MICA was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, upgraded rating from Red to Amber: A number of publications report association between MICA variants and HBV‐related hepatocellular carcinoma. Additional papers investigate MICA polymorphisms and response to viral infections/recovery (e.g. PMIDs:28925058, 15029237). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.270 | MICA | Rebecca Foulger changed review comment from: Publications on association between MICA variants and hepatitis B virus (HBV) infection and HBV‐related hepatocellular carcinoma (PMIDs:31419949, 29584564).; to: Several publications on association between MICA variants and hepatitis B virus (HBV) infection and HBV‐related hepatocellular carcinoma (PMIDs:31419949, 29584564,25270965). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.270 | MICA | Rebecca Foulger commented on gene: MICA: Publications on association between MICA variants and hepatitis B virus (HBV) infection and HBV‐related hepatocellular carcinoma (PMIDs:31419949, 29584564). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.267 | LILRB1 | Rebecca Foulger commented on gene: LILRB1: PMID:29528338. Davidson et al., 2018 tested whether LILRB1 genotype influences HCMV susceptibility by analysing LILRB1 genotypes (5 SNPs) in a group of 67 Canadian transplant patients. There was no association between LILRB1 SNPs and virus replication within the entire STCS population, but when the analyses were restricted to kidney transplant recipients, a significant association of rs10423364 was found with HCMV infection. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.267 | LILRB1 | Rebecca Foulger commented on gene: LILRB1: PMID:32321755. Yu et al., 2020 studied a polymorphic 3-kb region within LILRB1 intron 1 that binds the transcription factor YY1 to regulate LILRB1 levels. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.267 | LILRB1 | Rebecca Foulger commented on gene: LILRB1: PMID:30461037. Cadena-Mota et al., 2018 show that cytomegalovirus infection has a major effect on LILRB1 expression in NK and other mononuclear cells, and polymorphisms in the LILRB1 regulatory region appear to have a modulatory influence over this effect. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.267 | LILRB1 | Rebecca Foulger Added comment: Comment on list classification: HIVEP1 was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel as Amber. PMID:29528338 study investigates LILRB1 genotype and viral susceptibility and finds an association within transplant patients (but not within the population as a whole). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.265 | KHDRBS1 | Rebecca Foulger Added comment: Comment on list classification: KHDRBS1 (SAM68) was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, added to panel as Amber. Functional evidence to suggest KHDRBS1 (SAM68) may serve as a proviral factor facilitate viral replication through interaction with the viral genome. A number of papers report interaction of KHDRBS1 (SAM68) and viral elements (e.g. PMIDs:26695943, 26202240, 27057671, 15701759) to positive regulate viral infection (although the viral processes affected differ between papers). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.264 | KHDRBS1 |
Rebecca Foulger gene: KHDRBS1 was added gene: KHDRBS1 was added to COVID-19 research. Sources: Other Mode of inheritance for gene: KHDRBS1 was set to Unknown Publications for gene: KHDRBS1 were set to 12529443; 26695943; 26202240; 27057671; 15701759; 31068419 Added comment: PMID:31068419. Qin et al., 2019 report that KHDRBS1 (SAM68) promotes hepatitis C virus (HCV) replication without affecting viral translation. HCV infection triggers the translocation of the SAM68 protein from the nucleus to the cytoplasm, where it interacts with the HCV RNA genome. Sources: Other |
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| COVID-19 research v0.262 | HIVEP1 | Rebecca Foulger Added comment: Comment on publications: Note that PMID:24719322 (Modulation of TLR3, TLR4 and TLR7 Mediated IFN-β, Rantes and TNFα Production by HIVEP1) was withdrawn by the author. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.235 |
Eleanor Williams Panel name changed from Viral susceptibility to COVID-19 research List of related panels changed from to Viral susceptibility |
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| COVID-19 research v0.232 | ACE2 | Eleanor Williams changed review comment from: PMID: 32133153 Cao et al 2020 - Analyzed coding-region variants in ACE2 and the eQTL variants, which may affect the expression of ACE2 using the GTEx database to compare the genomic characteristics of ACE2 among different populations. Their findings indicated that no direct evidence was identified genetically supporting the existence of coronavirus S-protein binding-resistant ACE2 mutants in different populations.; to: PMID: 32133153 Cao et al 2020 - Analyzed coding-region variants in ACE2 and the eQTL variants, which may affect the expression of ACE2 using the GTEx database to compare the genomic characteristics of ACE2 among different populations. Their findings indicated that no direct evidence was identified genetically supporting the existence of coronavirus S-protein binding-resistant ACE2 mutants in different populations. East Asian populations have much higher AFs in the eQTL variants associated with higher ACE2 expression in tissues. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.231 | ACE2 | Eleanor Williams commented on gene: ACE2: PMID: 32133153 Cao et al 2020 - Analyzed coding-region variants in ACE2 and the eQTL variants, which may affect the expression of ACE2 using the GTEx database to compare the genomic characteristics of ACE2 among different populations. Their findings indicated that no direct evidence was identified genetically supporting the existence of coronavirus S-protein binding-resistant ACE2 mutants in different populations. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.226 | SCN5A |
Eleanor Williams changed review comment from: PMID: 32380288 Giudicessi et al 2020 - discuss the potential of p.Ser1103Tyr-SCN5A to exacerbate outcome-related health disparities in the COVID-19 pandemic.; to: PMID: 32380288 Giudicessi et al 2020 - discuss the potential of p.Ser1103Tyr-SCN5A to exacerbate outcome-related health disparities in the COVID-19 pandemic. Keeping red for now, as this paper is speculation - no real data. |
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| COVID-19 research v0.217 | MX1 |
Sarah Leigh gene: MX1 was added gene: MX1 was added to Viral susceptibility. Sources: Literature Mode of inheritance for gene: MX1 was set to Unknown Publications for gene: MX1 were set to 3162334; 14872030; 21935451; https://doi.org/10.1101/2020.05.04.075911 Review for gene: MX1 was set to AMBER Added comment: MX1 is an interferon-induced protein with antiviral activity (PMID 3162334). PMID 14872030 c.-88G>T was more frequent in 40 unrelated Japanese patients with subacute sclerosing panencephalitisis (associated with CNS infection with measles virus), than in 90 controls (0.42 in patients vs 0.29 in controls). Variant c.-88G>T results increased MX1 expression, the authors suggest that MX1 may paradoxically enable persistence of the virus in the CNS by attenuating viral gene expression and preventing complete immunologic clearance. PMID 21935451 concluded that genetic variation in the interferon response pathway is associated with risk for symptomatic West Nile viru infection and disease progression. Preprint https://doi.org/10.1101/2020.05.04.075911 Reports that rs35074065 of TMPRSS2 results in increased expression of the nearby gene MX1. Sources: Literature |
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| COVID-19 research v0.216 | BST2 | Rebecca Foulger Added comment: Comment on list classification: Added to panel as a Red gene: present in latest release of UniProt COVID portal. Plays a role in tethering viruses to the host cell to block viral release. Recent research (PMID:31199522) shows interaction with SARS-CoV spike protein, which inhibits BST2 function and allows viral release. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.215 | BST2 | Rebecca Foulger commented on gene: BST2: PMID:31199522. Wang et al., 2019 show that SARS-CoV spike (S) glycoprotein antagonises the BST2 tethering of SARS-CoV via BST2 downregulation. The authors show colocalization BST2 and SARS-CoV S protein. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.214 | TMPRSS2 | Sarah Leigh changed review comment from: Preprint https://doi.org/10.1101/2020.05.04.075911 reports rs35074065 of TMPRSS2 results in the overexpression of both TMPRSS2 and a nearby gene MX1. rs35074065 overlaps with a transcription factor binding site of an activator (IRF1) and a repressor (IRF2). IRF1 activator can bind to variant delC allele, but IRF2 repressor fails to bind. Thus, in an individual carrying the delC allele, there is only activation, but no repression. On viral entry, IRF1 mediated upregulation of MX1 leads to neutrophil infiltration and processing of 614G mutated Spike protein by neutrophil Elastase. The simultaneous processing of 614G spike protein by TMPRSS2 and Elastase serine proteases facilitates the entry of the 614G subtype into host cells. Thus, SARS-CoV-2, particularly the 614G subtype, has spread more easily and with higher frequency to Europe and North America where the delC allele regulating expression of TMPRSS2 and MX1 host proteins is common, but not to East Asia where this allele is rare.; to: Preprint https://doi.org/10.1101/2020.05.04.075911 reports rs35074065 of TMPRSS2 results in the overexpression of both TMPRSS2 and a nearby gene MX1. rs35074065 overlaps with a transcription factor binding site of an activator (IRF1) and a repressor (IRF2). IRF1 activator can bind to variant delC allele, but IRF2 repressor fails to bind. Thus, in an individual carrying the delC allele of rs35074065, there is only activation, but no repression. On viral entry, IRF1 mediated upregulation of MX1 leads to neutrophil infiltration and processing of 614G variant viral Spike protein by neutrophil Elastase. The simultaneous processing of 614G spike protein by TMPRSS2 and Elastase serine proteases facilitates the entry of the 614G subtype into host cells. Thus, SARS-CoV-2, particularly the 614G subtype, has spread more easily and with higher frequency to Europe and North America where the delC allele regulating expression of TMPRSS2 and MX1 host proteins is common, but not to East Asia where this allele is rare. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.214 | KPNA2 | Rebecca Foulger Added comment: Comment on list classification: Added KPNA2 to the panel as a Red gene. Present in the latest UniProt COVID portal release based on functional data that show an interaction with SARS-COVID viral ORF6 protein. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.206 | ACE2 |
Sarah Leigh changed review comment from: In preprint https://doi.org/10.1101/2020.04.30.20081257 reports increased expression of ACE2 and natriuretic peptides during heart failure, which predisposes to SARS-CoV-2 infection. Modulating the levels of ACE2, NPs therefore may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection. The authors speculated that modulation levels of ACE2 and natriuretic peptides may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection.; to: Preprint: https://doi.org/10.1101/2020.04.30.20081257 reports increased expression of ACE2 and natriuretic peptides during heart failure, which predisposes to SARS-CoV-2 infection. Modulating the levels of ACE2, NPs therefore may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection. The authors speculated that modulation levels of ACE2 and natriuretic peptides may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection. Preprint: https://doi.org/10.1101/2020.05.03.074781 uses mCSM-PPI212 mutation effect predictor for protein-protein complex affinity, primarily validated against published experimental ACE2 variant SARS-CoV S-protein affinities to analysis variants from gnomAD. p.Gly326Glu, predicted to enhances ACE2 binding affinity for SARS-CoV-2 S, therefore a potential risk factor for COVID-19. p.Glu37Lys, p.Gly352Val and p.Asp355Asn predicted to reduce ACE2 affinity for SARS-CoV-2 S, therefore potentially protective against COVID-19. |
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| COVID-19 research v0.205 | ACE2 | Sarah Leigh changed review comment from: In preprint https://doi.org/10.1101/2020.04.30.20081257 reports increased expression of ACE2 and natriuretic peptides during heart failure, which predisposes to SARS-CoV-2 infection. Modulating the levels of ACE2, NPs therefore may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection.; to: In preprint https://doi.org/10.1101/2020.04.30.20081257 reports increased expression of ACE2 and natriuretic peptides during heart failure, which predisposes to SARS-CoV-2 infection. Modulating the levels of ACE2, NPs therefore may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection. The authors speculated that modulation levels of ACE2 and natriuretic peptides may potentially be a novel therapeutic target to prevent the SARS-CoV-2 infection. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.205 | CCR5 | Sarah Leigh edited their review of gene: CCR5: Added comment: Preprint https://doi.org/10.1101/2020.05.02.20084673 reports 10 terminally-ill, critical COVID-19 patients with profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell levels, and SARS-CoV-2 plasma viremia. Treatment with CCR5 blocking antibody leronlimab, results in complete CCR5 receptor occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. From single-cell RNA-sequencing, this effect appears to be a result of reduced transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes.; Changed publications: https://doi.org/10.1101/2020.05.02.20084673 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.204 | IL6 | Sarah Leigh edited their review of gene: IL6: Added comment: Preprint https://doi.org/10.1101/2020.05.02.20084673 reports 10 terminally-ill, critical COVID-19 patients with profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell levels, and SARS-CoV-2 plasma viremia. Treatment with CCR5 blocking antibody leronlimab, results in complete CCR5 receptor occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. From single-cell RNA-sequencing, this effect appears to be a result of reduced transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes.; Changed publications: https://doi.org/10.1101/2020.05.02.20084673 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.203 | IL2RB | Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 5 unrelated families (two families with the same variant had shared ethnic heritage PMID 31040185). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.202 | IL6R | Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 4 variants reported in at least 3 unrelated cases, together with supportive functional studies. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.200 | IFNL3 |
Catherine Snow gene: IFNL3 was added gene: IFNL3 was added to Viral susceptibility. Sources: Literature Mode of inheritance for gene: IFNL3 was set to Unknown Review for gene: IFNL3 was set to AMBER Added comment: IFNL3 was identified in preprint https://doi.org/10.1101/2020.04.26.20080408 "A gene locus that controls expression of ACE2 in virus infection" A GWAS for performed for ACE2 expression in HCV-infected liver tissue from 195 individuals. it was discovered that polymorphisms in the host IFNL region which control expression of IFNL3 and IFNL4 modulate ACE2 expression. Sources: Literature |
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| COVID-19 research v0.199 | IFNL4 |
Catherine Snow changed review comment from: IFNL4 was identified in preprint "A gene locus that controls expression of ACE2 in virus infection" A GWAS for performed for ACE2 expression in HCV-infected liver tissue from 195 individuals. it was discovered that polymorphisms in the host IFNL region which control expression of IFNL3 and IFNL4 modulate ACE2 expression. PMID: 31776283 Investigates the IFNL4 gene - it acts in a counterintuitive manner, as patients with a nonfunctional IFNL4 gene exhibit increased clearance of hepatitis C virus (HCV) but also increased liver inflammation. Sources: Literature; to: IFNL4 was identified in preprint https://doi.org/10.1101/2020.04.26.20080408 "A gene locus that controls expression of ACE2 in virus infection" A GWAS for performed for ACE2 expression in HCV-infected liver tissue from 195 individuals. it was discovered that polymorphisms in the host IFNL region which control expression of IFNL3 and IFNL4 modulate ACE2 expression. PMID: 31776283 Investigates the IFNL4 gene - it acts in a counterintuitive manner, as patients with a nonfunctional IFNL4 gene exhibit increased clearance of hepatitis C virus (HCV) but also increased liver inflammation. Sources: Literature |
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| COVID-19 research v0.199 | IFNL4 |
Catherine Snow gene: IFNL4 was added gene: IFNL4 was added to Viral susceptibility. Sources: Literature Mode of inheritance for gene: IFNL4 was set to Unknown Publications for gene: IFNL4 were set to 31776283 Review for gene: IFNL4 was set to AMBER Added comment: IFNL4 was identified in preprint "A gene locus that controls expression of ACE2 in virus infection" A GWAS for performed for ACE2 expression in HCV-infected liver tissue from 195 individuals. it was discovered that polymorphisms in the host IFNL region which control expression of IFNL3 and IFNL4 modulate ACE2 expression. PMID: 31776283 Investigates the IFNL4 gene - it acts in a counterintuitive manner, as patients with a nonfunctional IFNL4 gene exhibit increased clearance of hepatitis C virus (HCV) but also increased liver inflammation. Sources: Literature |
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| COVID-19 research v0.190 | CDC42 |
Ivone Leong gene: CDC42 was added gene: CDC42 was added to Viral susceptibility. Sources: Expert Review Mode of inheritance for gene: CDC42 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CDC42 were set to 31601675; 32303876; 32231661; 31271789 Phenotypes for gene: CDC42 were set to Neonatal-onset cytopaenia with dyshaematopoiesis; autoinflammation; rash; HLH Review for gene: CDC42 was set to GREEN Added comment: "PMID 31601675: four unrelated individuals with superimposable features, including neonatal-onset cytopenia with dyshematopoiesis, autoinflammation, rash, and HLH. All shared the same de novo CDC42 variant (Chr1:22417990C>T, p.R186C). Another pair of sibs reported in PMID 32303876 with infantile myelofibrosis and myeloproliferation and same variant (parental mosaicism). Yet another individual in PMID 32231661 with different de novo variant, p.Cys81Tyr who in addition developed haematological malignancy and also had syndromic features, including ID. Note other missense variants in this gene cause Takenouchi-Kosaki syndrome, MIM# 616737 Sources: Literature Zornitza Stark (Australian Genomics), 30 Apr 2020" - review copied from Primary immunodeficiency (Version 2.153) "Comment on list classification: Gene added by Zornitza Stark (Australian Genomics) with a suggested Green rating based on evidence she has provided. As well as the listed cases there is another paper (PMID: 31271789) describing 4 unrelated cases with de novo variants in CDC42 (p.C188Y, p.R186C, p.*192C*24). The patients predominantly had systemic autoinflammatory disease and development of HLH. Therefore there is enough evidence to rate this gene as Green. Ivone Leong (Genomics England Curator), 5 May 2020" - review copied from Primary immunodeficiency (Version 2.153) Sources: Expert Review |
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| COVID-19 research v0.185 | PIK3CG |
Ivone Leong gene: PIK3CG was added gene: PIK3CG was added to Viral susceptibility. Sources: Expert list Mode of inheritance for gene: PIK3CG was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PIK3CG were set to 32001535; 31554793 Phenotypes for gene: PIK3CG were set to Immune dysregulation; HLH-like; childhood-onset antibody defects; cytopenias; T lymphocytic pneumonitis and colitis Review for gene: PIK3CG was set to GREEN Added comment: "Two individuals with complex immunological phenotypes reported and a mouse model. Sources: Literature Zornitza Stark (Australian Genomics), 30 Apr 2020" - review copied from Primary immunodeficiency (Version 2.151). "Comment on list classification: Gene added by Zornitza Stark (Australian Genomics) with recommended Green status based on provided evidence. There is enough evidence for this gene to be rated Green. Ivone Leong (Genomics England Curator), 5 May 2020" - review copied from Primary immunodeficiency (Version 2.151). Sources: Expert list |
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| COVID-19 research v0.178 | ABO | Catherine Snow Added comment: Comment on list classification: Identified by expert review. Two preprints and publication relating to ABO and Sars-COV. https://doi.org/10.1101/2020.04.08.20058073 authors found that COVID-19 positive vs negative test results were increased in blood groups A and decreased in blood groups O, consistent with previous results from Wuhan and Shenzhen (https://doi.org/10.1101/2020.03.11.20031096) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.176 | DMD | Sarah Leigh reviewed gene: DMD: Rating: RED; Mode of pathogenicity: ; Publications: 10753926, 12118246; Phenotypes: ; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.173 | IFITM3 |
Ivone Leong Added comment: Comment on list classification: PMID: 32348495 reports that individuals who are homozygous for the C allele of rs12252 SNP in IFITM3 is associated with more severe disease in older patients. This SNP is common in Asian populations (MAF reported on dbSNP for East Asians: 0.57; Europeans: 0.0546). This study was condicted in China with 80 patients who were confirmed to be positive for COVID-19. PMID: 23361009 found that homozygous C allele of rs12252 is in 69% of Chinese patients who were infected with severe pandemic influenza A H1N1/09 virus infection compared with 25% who had mild infection. The homozygous C allele for rs12252 is associated with a 6-fold greater risk for severe infection than CT and TT genotypes. Based on these studies there is enough evidence to promote this gene to Green status. |
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| COVID-19 research v0.171 | POLD1 | Sophie Hambleton changed review comment from: IUIS gene. Biallelic missense variant p.R1060C, that impairs association between POLD1 and POLD2, was associated with combined immunodeficiency in 3 affected members of one kindred. Allelic AD disorders cause alternative phenotypes; to: IUIS gene. Biallelic missense variant p.R1060C, that impairs association between POLD1 and POLD2, was associated with combined immunodeficiency in 3 affected members of one kindred. An unrelated case of combined immunodeficiency reported elsewhere (PMID 31449058) had 3 rare missense variants. Allelic AD disorders cause alternative phenotypes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.171 | IL2RB | Sophie Hambleton reviewed gene: IL2RB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: very early onset inflammatory bowel disease, CMV disease, dermatitis, immune dysregulation; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.165 | TMPRSS2 | Rebecca Foulger commented on gene: TMPRSS2: Preprint http://biorxiv.org/cgi/content/short/2020.04.23.057190 analysed coding region variants in TMPRSS2 and the eQTL variants which may affect gene experssion. They suggest that lung-specific eQTL variants may confer different susceptibility or response to SARS-CoV-2 infection from different populations. In particular, we found that the regulatory region variant rs35074065 is associated with high expression of TMPRSS2 (but lower expression of MX1). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.165 | ACE2 | Rebecca Foulger commented on gene: ACE2: Preprint https://www.biorxiv.org/content/10.1101/2020.04.24.050534v1 conclude that higher expression of ACE2 facilitated by natural variations (with different frequencies in different populations) results in ACE2 homo-dimerization which is disadvantageous for TMPRSS2 mediated cleavage of ACE2. They propose that monomeric ACE2 has higher preferential binding with SARS-CoV-2 S-Protein. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.163 | FANCB | Sophie Hambleton reviewed gene: FANCB: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Fanconi anaemia, bone marrow failure; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.163 | TMPRSS2 | Rebecca Foulger commented on gene: TMPRSS2: Preprint https://www.medrxiv.org/content/10.1101/2020.04.22.20074963v1 Lopera et al shows a LACK of association between genetic variants at ACE2 and TMPRSS2 and human quantitative phenotypes. The authors recognise that the SARS-CoV-2 virus uses ACE2 for cell invasion, and the serine protease TMPRSS2 for S protein priming and therefore they investigated whether genetic variation in these two genes modulates an individual's genetic predisposition to infection and virus clearance. They examined 178 quantitative phenotypes in relation to 1,273 genetic variants located in or near ACE2 and TMPRSS2: none reached the threshold for significance though these variants may play a role in diseases such as hypertension and chronic inflammation that are often observed in the more severe COVID-19 cases. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.163 | ACE2 | Rebecca Foulger commented on gene: ACE2: Preprint https://www.medrxiv.org/content/10.1101/2020.04.22.20074963v1 Lopera et al shows a LACK of association between genetic variants at ACE2 and TMPRSS2 and human quantitative phenotypes. The authors recognise that the SARS-CoV-2 virus uses ACE2 for cell invasion, and the serine protease TMPRSS2 for S protein priming and therefore they investigated whether genetic variation in these two genes modulates an individual's genetic predisposition to infection and virus clearance. They examined 178 quantitative phenotypes in relation to 1,273 genetic variants located in or near ACE2 and TMPRSS2: none reached the threshold for significance though these variants may play a role in diseases such as hypertension and chronic inflammation that are often observed in the more severe COVID-19 cases. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.163 | DEF6 | Sophie Hambleton reviewed gene: DEF6: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Immune dysregulation, combined immunodeficiency, autoimmunity, autoimmune enteropathy, dilated cardiomyopathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.163 | CTSB |
Eleanor Williams changed review comment from: The Covid-19 cell atlas (https://www.covid19cellatlas.org/) lists this gene as a COVID-19/SARS-CoV-2 entry-associated gene. I cannot find reference to the gene in the two publications listed though PMID: 32142651 and 32015507. Sources: Other; to: The Covid-19 cell atlas (https://www.covid19cellatlas.org/) lists this gene as a COVID-19/SARS-CoV-2 entry-associated gene. PMID: 32142651 - Hoffman et al 2020 - Cell journal - CatB/L involved in S protein priming. |
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| COVID-19 research v0.163 | CTSL |
Eleanor Williams changed review comment from: The Covid-19 cell atlas (https://www.covid19cellatlas.org/) lists this gene as a COVID-19/SARS-CoV-2 entry-associated gene. I cannot find reference to the gene in the two publications listed though PMID: 32142651 and 32015507. Sources: Other; to: The Covid-19 cell atlas (https://www.covid19cellatlas.org/) lists this gene as a COVID-19/SARS-CoV-2 entry-associated gene. PMID: 32142651 - Hoffman et al 2020 - Cell journal - CatB/L involved in S protein priming. |
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| COVID-19 research v0.163 | CTSL |
Eleanor Williams gene: CTSL was added gene: CTSL was added to Viral susceptibility. Sources: Other Mode of inheritance for gene: CTSL was set to Unknown Added comment: The Covid-19 cell atlas (https://www.covid19cellatlas.org/) lists this gene as a COVID-19/SARS-CoV-2 entry-associated gene. I cannot find reference to the gene in the two publications listed though PMID: 32142651 and 32015507. Sources: Other |
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| COVID-19 research v0.162 | CTSB |
Eleanor Williams gene: CTSB was added gene: CTSB was added to Viral susceptibility. Sources: Other Mode of inheritance for gene: CTSB was set to Unknown Added comment: The Covid-19 cell atlas (https://www.covid19cellatlas.org/) lists this gene as a COVID-19/SARS-CoV-2 entry-associated gene. I cannot find reference to the gene in the two publications listed though PMID: 32142651 and 32015507. Sources: Other |
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| COVID-19 research v0.160 | TLR3 |
Abdelazeem Elhabyan changed review comment from: These studies demonstrate the deleterious effect of some TLR3 mutations and predisposition to Herpes simplex encephalitis in 4 separate studies on unrelated patients from different countries. TLR3 mutations in 3 children were associated with severe influenza pneumonitis. Finally, 2 other studies evaluate the protective effect of a common polymorphism of TLR3 against HIV infection in repetitively exposed individuals. Accordingly, we might find protective or deleterious effects in COVID19 patients due to different mutations of TLR3. TLR3 is a receptor for dsRNA (intermediate in the replication of many viruses including HSV) which induces IFN response to prevent the cytopathic effects of different viruses. A heterozygous dominant-negative mutation of TLR3 was discovered in 2 unrelated children with HSE. TLR3 mutant fibroblasts from the 2 patients were infected by HSV-1 and vesicular stomatitis virus(VSV).IFNB and IFNL production were impaired in those cells, viral replication was higher and cell survival was lower in the 2 patients' cells when compared with the controls. Blood leukocyte response normally with to poly (I:C) which explains why the disease is not disseminated and also explains the redundant role of TLR3 in blood cells(13). Similar findings were reported in a polish child in 2011, however, the patient here was compound heterozygous for a missense mutation leading to autosomal recessive inheritance of TLR3 deficiency(14). Treatment with IFN alpha and beta canceled the effect of the dominant-negative mutation increasing the causality relationship between TLR3 mutants and viral immune response(13). Relatives of the 2 patients with the same mutation did not show decreased interferon response nor they showed HSE as a complication of HSV which means that this mutation does not have full penetrance(13). In another study, 110 patients with HSE were sequenced (exons of TLR3) to establish a new association of TLR3 mutations and HSE. The study reported 5 novel variants other than those previously described in the literature. 2 of them were not pathogenically demonstrated by in vitro studies while 3 of them were pathogenic with similar findings to those described above. Additionally, they found 3 patients with the same mutations previously described in the literature so the total of patients with deleterious TLR3 mutations would be 6 out of 110. 4 of those 6 patients(66%) with TLR6 mutations had a relapse In contrast to 12 out of 120(total cohort) (10%)(15). In a recent study done on 16 patients with adult-onset HSE using whole-exome sequencing(WES), 1 patient was discovered to have TLR3 deficiency, while 8 other patients had mutations in other genes in the TLR3 pathway(2 patients with a mutation in IRF3, 2 patients with mutations in STAT1, 2 patients with mutations in TRIF, 1 patient with a mutation in TYK2,1 patients with a mutation in MAVS, and finally 1 patient with a mutation in TBK1)(16) A common polymorphism in TLR3(rs3775291) was linked to increased resistance to HIV1 infection by the genotyping study of Spanish and Italian cohorts with a P value of .023 and .029 respectively. The study compared HIV exposed seronegative cohort(IV drug abuse and sexually active ) with controls. Repetitive HIV exposure in the cohort was evidenced by HCV seropositivity. In vitro infection of PBMCs with HIV showed increased resistance in cells carrying the allele and also TLR3 stimulation by TLR3 agonists showed an increased level of expression of CD69, IL-6, and CCL3(17). A similar study was conducted on the Caucasian population showing the protective effect of the allele against HIV infection(18). Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-β and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients’ iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I, and/or III IFN–mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature(PMID: 31217193 ) 13.Zhang SY, Jouanguy E, Ugolini S, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317(5844):1522–1527. doi:10.1126/science.1139522 14.Guo Y, Audry M, Ciancanelli M, et al. Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. J Exp Med. 2011;208(10):2083–2098. doi:10.1084/jem.20101568 15.Lim HK, Seppänen M, Hautala T, et al. TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk. Neurology. 2014;83(21):1888–1897. doi:10.1212/WNL.0000000000000999 16.Mørk N, Kofod-Olsen E, Sørensen KB, et al. Mutations in the TLR3 signaling pathway and beyond in adult patients with herpes simplex encephalitis. Genes Immun. 2015;16(8):552–566. doi:10.1038/gene.2015.46 17.Sironi M, Biasin M, Cagliani R, et al. A common polymorphism in TLR3 confers natural resistance to HIV-1 infection. J Immunol. 2012;188(2):818–823. doi:10.4049/jimmunol.1102179 18.Huik K, Avi R, Pauskar M, et al. Association between TLR3 rs3775291 and resistance to HIV among highly exposed Caucasian intravenous drug users. Infect Genet Evol. 2013;20:78–82. doi:10.1016/j.meegid.2013.08.008 19.Lim HK, Huang SXL, Chen J, et al. Severe influenza pneumonitis in children with inherited TLR3 deficiency. J Exp Med. 2019;216(9):2038–2056. doi:10.1084/jem.20181621; to: These studies demonstrate the deleterious effect of some TLR3 mutations and predisposition to Herpes simplex encephalitis in 4 separate studies on unrelated patients from different countries. TLR3 mutations in 3 children were associated with severe influenza pneumonitis. Finally, 2 other studies evaluate the protective effect of a common polymorphism of TLR3 against HIV infection in repetitively exposed individuals. Accordingly, we might find protective or deleterious effects in COVID19 patients due to different mutations of TLR3. TLR3 is a receptor for dsRNA (intermediate in the replication of many viruses including HSV) which induces IFN response to prevent the cytopathic effects of different viruses. A heterozygous dominant-negative mutation of TLR3 was discovered in 2 unrelated children with HSE. TLR3 mutant fibroblasts from the 2 patients were infected by HSV-1 and vesicular stomatitis virus(VSV).IFNB and IFNL production were impaired in those cells, viral replication was higher and cell survival was lower in the 2 patients' cells when compared with the controls. Blood leukocyte response normally with to poly (I:C) which explains why the disease is not disseminated and also explains the redundant role of TLR3 in blood cells(13). Similar findings were reported in a polish child in 2011, however, the patient here was compound heterozygous for a missense mutation leading to autosomal recessive inheritance of TLR3 deficiency(14). Treatment with IFN alpha and beta canceled the effect of the dominant-negative mutation increasing the causality relationship between TLR3 mutants and viral immune response(13). Relatives of the 2 patients with the same mutation did not show decreased interferon response nor they showed HSE as a complication of HSV which means that this mutation does not have full penetrance(13). In another study, 110 patients with HSE were sequenced (exons of TLR3) to establish a new association of TLR3 mutations and HSE. The study reported 5 novel variants other than those previously described in the literature. 2 of them were not pathogenically demonstrated by in vitro studies while 3 of them were pathogenic with similar findings to those described above. Additionally, they found 3 patients with the same mutations previously described in the literature so the total of patients with deleterious TLR3 mutations would be 6 out of 110. 4 of those 6 patients(66%) with TLR6 mutations had a relapse In contrast to 12 out of 120(total cohort) (10%)(15). In a recent study done on 16 patients with adult-onset HSE using whole-exome sequencing(WES), 1 patient was discovered to have TLR3 deficiency, while 8 other patients had mutations in other genes in the TLR3 pathway(2 patients with a mutation in IRF3, 2 patients with mutations in STAT1, 2 patients with mutations in TRIF, 1 patient with a mutation in TYK2,1 patients with a mutation in MAVS, and finally 1 patient with a mutation in TBK1)(16) A common polymorphism in TLR3(rs3775291) was linked to increased resistance to HIV1 infection by the genotyping study of Spanish and Italian cohorts with a P value of .023 and .029 respectively. The study compared HIV exposed seronegative cohort(IV drug abuse and sexually active ) with controls. Repetitive HIV exposure in the cohort was evidenced by HCV seropositivity. In vitro infection of PBMCs with HIV showed increased resistance in cells carrying the allele and also TLR3 stimulation by TLR3 agonists showed an increased level of expression of CD69, IL-6, and CCL3(17). A similar study was conducted on the Caucasian population showing the protective effect of the allele against HIV infection(18). Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-β and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients’ iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I, and/or III IFN–mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature(PMID: 31217193 ) 13.Zhang SY, Jouanguy E, Ugolini S, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317(5844):1522–1527. doi:10.1126/science.1139522 14.Guo Y, Audry M, Ciancanelli M, et al. Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. J Exp Med. 2011;208(10):2083–2098. doi:10.1084/jem.20101568 15.Lim HK, Seppänen M, Hautala T, et al. TLR3 deficiency in herpes simplex encephalitis: high allelic heterogeneity and recurrence risk. Neurology. 2014;83(21):1888–1897. doi:10.1212/WNL.0000000000000999 16.Mørk N, Kofod-Olsen E, Sørensen KB, et al. Mutations in the TLR3 signaling pathway and beyond in adult patients with herpes simplex encephalitis. Genes Immun. 2015;16(8):552–566. doi:10.1038/gene.2015.46 17.Sironi M, Biasin M, Cagliani R, et al. A common polymorphism in TLR3 confers natural resistance to HIV-1 infection. J Immunol. 2012;188(2):818–823. doi:10.4049/jimmunol.1102179 18.Huik K, Avi R, Pauskar M, et al. Association between TLR3 rs3775291 and resistance to HIV among highly exposed Caucasian intravenous drug users. Infect Genet Evol. 2013;20:78–82. doi:10.1016/j.meegid.2013.08.008 19.Lim HK, Huang SXL, Chen J, et al. Severe influenza pneumonitis in children with inherited TLR3 deficiency. J Exp Med. 2019;216(9):2038–2056. doi:10.1084/jem.20181621 |
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| COVID-19 research v0.152 | SGTA | Rebecca Foulger Added comment: Comment on list classification: Kept rating as Red awaiting expert review. Role for protein in viral infection, but no population studies/SNP analyses yet. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.145 | ACE2 | Rebecca Foulger commented on gene: ACE2: ACE2 gene present in the UniProt COVID portal (https://covid-19.uniprot.org/ 6-April-2020) which provides the latest available pre-release UniProtKB data for the SARS-CoV-2 coronavirus and other entries relating to the COVID-19 outbreak. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.140 | ACE2 |
Eleanor Williams changed review comment from: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.07.024752v1 - Stawiski et al Aassessed ACE2 protein-altering variations from a number of databases including the gnomAD, RotterdamStudy, ALSPAC, GenomeAsia100k, HGDP, TOMMO-3.5kjpnv2, IndiGen, and HGDP. Identified variants that are likely to either increase or decrease the binding affinity of ACE2 to the S-protein and thereby alter the ability of the virus to infect the host cell. Preprint - https://www.biorxiv.org/content/10.1101/2020.03.16.994236v1 Procko Made a library of coding sequence of ACE2 containing all possible single amino acid substitutions at 117 sites spanning the interface with S and lining the substrate cavity. The ACE2 library was transiently expressed in human Expi293F cells and cells were then incubated in medium containing the receptor binding domain of SARS-CoV-2 fused C-terminallyto superfolder GFP. Sorted cells with high and low binding and the transcripts sequenced to identify the variants. Preprint - https://www.medrxiv.org/content/10.1101/2020.04.03.20047977v1 - Renieri et al Using the Network of Italian Genomes (NIG), they mined around 7000 exomes from 5 different Centers looking for ACE2 variants. Identified variants with a potential impact on protein stability. 3 missense changed identified that have never been reported in the Eastern Asia population, were predicted to interfere with protein cleavage and stabilization. Rare truncating variants that are likely to interfere with the internalization process and one missense variant, p.Trp69Cys, predicted to interfere with 2019-nCov spike protein binding were also observed. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.12.037580v1 - Asseleta et al ACE2 SNP rs2285666 (also called G8790A), more common in Italians and Europeans that East Asians. This variant was extensively studied as a potential risk factor for hypertension, type 2 diabetes, and coronary artery disease hence possibly constituting a predisposing factor also for the comorbidities observed in COVID-19 patients. ; to: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.07.024752v1 - Stawiski et al Aassessed ACE2 protein-altering variations from a number of databases including the gnomAD, RotterdamStudy, ALSPAC, GenomeAsia100k, HGDP, TOMMO-3.5kjpnv2, IndiGen, and HGDP. Identified variants that are likely to either increase or decrease the binding affinity of ACE2 to the S-protein and thereby alter the ability of the virus to infect the host cell. Preprint - https://www.biorxiv.org/content/10.1101/2020.03.16.994236v1 Procko Made a library of coding sequence of ACE2 containing all possible single amino acid substitutions at 117 sites spanning the interface with S and lining the substrate cavity. The ACE2 library was transiently expressed in human Expi293F cells and cells were then incubated in medium containing the receptor binding domain of SARS-CoV-2 fused C-terminallyto superfolder GFP. Sorted cells with high and low binding and the transcripts sequenced to identify the variants. Preprint - https://www.medrxiv.org/content/10.1101/2020.04.03.20047977v1 - Renieri et al Using the Network of Italian Genomes (NIG), they mined around 7000 exomes from 5 different Centers looking for ACE2 variants. Identified variants with a potential impact on protein stability. 3 missense changed identified that have never been reported in the Eastern Asia population, were predicted to interfere with protein cleavage and stabilization. Rare truncating variants that are likely to interfere with the internalization process and one missense variant, p.Trp69Cys, predicted to interfere with 2019-nCov spike protein binding were also observed. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.12.037580v1 - Asselta et al ACE2 SNP rs2285666 (also called G8790A), more common in Italians and Europeans that East Asians. This variant was extensively studied as a potential risk factor for hypertension, type 2 diabetes, and coronary artery disease hence possibly constituting a predisposing factor also for the comorbidities observed in COVID-19 patients. |
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| COVID-19 research v0.140 | ACE2 |
Eleanor Williams changed review comment from: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.07.024752v1 - Stawiski et al Aassessed ACE2 protein-altering variations from a number of databases including the gnomAD, RotterdamStudy, ALSPAC, GenomeAsia100k, HGDP, TOMMO-3.5kjpnv2, IndiGen, and HGDP. Identified variants that are likely to either increase or decrease the binding affinity of ACE2 to the S-protein and thereby alter the ability of the virus to infect the host cell. Preprint - https://www.biorxiv.org/content/10.1101/2020.03.16.994236v1 Procko Made a library of coding sequence of ACE2 containing all possible single amino acid substitutions at 117 sites spanning the interface with S and lining the substrate cavity. The ACE2 library was transiently expressed in human Expi293F cells and cells were then incubated in medium containing the receptor binding domain of SARS-CoV-2 fused C-terminallyto superfolder GFP. Sorted cells with high and low binding and the transcripts sequenced to identify the variants. Preprint - https://www.medrxiv.org/content/10.1101/2020.04.03.20047977v1 - Renieri et al Using the Network of Italian Genomes (NIG), they mined around 7000 exomes from 5 different Centers looking for ACE2 variants. Identified variants with a potential impact on protein stability. 3 missense changed identified that have never been reported in the Eastern Asia population, were predicted to interfere with protein cleavage and stabilization. Rare truncating variants that are likely to interfere with the internalization process and one missense variant, p.Trp69Cys, predicted to interfere with 2019-nCov spike protein binding were also observed. ; to: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.07.024752v1 - Stawiski et al Aassessed ACE2 protein-altering variations from a number of databases including the gnomAD, RotterdamStudy, ALSPAC, GenomeAsia100k, HGDP, TOMMO-3.5kjpnv2, IndiGen, and HGDP. Identified variants that are likely to either increase or decrease the binding affinity of ACE2 to the S-protein and thereby alter the ability of the virus to infect the host cell. Preprint - https://www.biorxiv.org/content/10.1101/2020.03.16.994236v1 Procko Made a library of coding sequence of ACE2 containing all possible single amino acid substitutions at 117 sites spanning the interface with S and lining the substrate cavity. The ACE2 library was transiently expressed in human Expi293F cells and cells were then incubated in medium containing the receptor binding domain of SARS-CoV-2 fused C-terminallyto superfolder GFP. Sorted cells with high and low binding and the transcripts sequenced to identify the variants. Preprint - https://www.medrxiv.org/content/10.1101/2020.04.03.20047977v1 - Renieri et al Using the Network of Italian Genomes (NIG), they mined around 7000 exomes from 5 different Centers looking for ACE2 variants. Identified variants with a potential impact on protein stability. 3 missense changed identified that have never been reported in the Eastern Asia population, were predicted to interfere with protein cleavage and stabilization. Rare truncating variants that are likely to interfere with the internalization process and one missense variant, p.Trp69Cys, predicted to interfere with 2019-nCov spike protein binding were also observed. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.12.037580v1 - Asseleta et al ACE2 SNP rs2285666 (also called G8790A), more common in Italians and Europeans that East Asians. This variant was extensively studied as a potential risk factor for hypertension, type 2 diabetes, and coronary artery disease hence possibly constituting a predisposing factor also for the comorbidities observed in COVID-19 patients. |
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| COVID-19 research v0.140 | DMBT1 |
Eleanor Williams gene: DMBT1 was added gene: DMBT1 was added to Viral susceptibility. Sources: Literature Mode of inheritance for gene: DMBT1 was set to Unknown Review for gene: DMBT1 was set to RED Added comment: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.16.045617v1 - Han et al Found using single cell transcriptomics that DMBT1 (a viral binding scavenger) was highly expressed in alveolar type II cells relative to other lung epithelial subsets and its expression positively correlated with ACE2. Sources: Literature |
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| COVID-19 research v0.138 | ACE2 |
Eleanor Williams changed review comment from: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.07.024752v1 - Stawiski et al Aassessed ACE2 protein-altering variations from a number of databases including the gnomAD, RotterdamStudy, ALSPAC, GenomeAsia100k, HGDP, TOMMO-3.5kjpnv2, IndiGen, and HGDP. Identified variants that are likely to either increase or decrease the binding affinity of ACE2 to the S-protein and thereby alter the ability of the virus to infect the host cell. Preprint - https://www.biorxiv.org/content/10.1101/2020.03.16.994236v1 Procko Made a library of coding sequence of ACE2 containing all possible single amino acid substitutions at 117 sites spanning the interface with S and lining the substrate cavity. The ACE2 library was transiently expressed in human Expi293F cells and cells were then incubated in medium containing the receptor binding domain of SARS-CoV-2 fused C-terminallyto superfolder GFP. Sorted cells with high and low binding and the transcripts sequenced to identify the variants.; to: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.07.024752v1 - Stawiski et al Aassessed ACE2 protein-altering variations from a number of databases including the gnomAD, RotterdamStudy, ALSPAC, GenomeAsia100k, HGDP, TOMMO-3.5kjpnv2, IndiGen, and HGDP. Identified variants that are likely to either increase or decrease the binding affinity of ACE2 to the S-protein and thereby alter the ability of the virus to infect the host cell. Preprint - https://www.biorxiv.org/content/10.1101/2020.03.16.994236v1 Procko Made a library of coding sequence of ACE2 containing all possible single amino acid substitutions at 117 sites spanning the interface with S and lining the substrate cavity. The ACE2 library was transiently expressed in human Expi293F cells and cells were then incubated in medium containing the receptor binding domain of SARS-CoV-2 fused C-terminallyto superfolder GFP. Sorted cells with high and low binding and the transcripts sequenced to identify the variants. Preprint - https://www.medrxiv.org/content/10.1101/2020.04.03.20047977v1 - Renieri et al Using the Network of Italian Genomes (NIG), they mined around 7000 exomes from 5 different Centers looking for ACE2 variants. Identified variants with a potential impact on protein stability. 3 missense changed identified that have never been reported in the Eastern Asia population, were predicted to interfere with protein cleavage and stabilization. Rare truncating variants that are likely to interfere with the internalization process and one missense variant, p.Trp69Cys, predicted to interfere with 2019-nCov spike protein binding were also observed. |
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| COVID-19 research v0.137 | ACE2 |
Eleanor Williams changed review comment from: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants.; to: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.07.024752v1 - Stawiski et al Aassessed ACE2 protein-altering variations from a number of databases including the gnomAD, RotterdamStudy, ALSPAC, GenomeAsia100k, HGDP, TOMMO-3.5kjpnv2, IndiGen, and HGDP. Identified variants that are likely to either increase or decrease the binding affinity of ACE2 to the S-protein and thereby alter the ability of the virus to infect the host cell. Preprint - https://www.biorxiv.org/content/10.1101/2020.03.16.994236v1 Procko Made a library of coding sequence of ACE2 containing all possible single amino acid substitutions at 117 sites spanning the interface with S and lining the substrate cavity. The ACE2 library was transiently expressed in human Expi293F cells and cells were then incubated in medium containing the receptor binding domain of SARS-CoV-2 fused C-terminallyto superfolder GFP. Sorted cells with high and low binding and the transcripts sequenced to identify the variants. |
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| COVID-19 research v0.137 | ACE2 |
Eleanor Williams changed review comment from: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations.; to: Preprint - https://www.biorxiv.org/content/10.1101/2020.04.14.041434v1 - Li et al Total death rate is higher in Spain compared to China, so looked differences between the Asian and Caucasian populations for ACE2 polymorphisms using gnomAD v2.1 exomes and compare the variability of hACE2 expression in peripheral blood among eight different populations. Four genetic variants reached statistical significance for differences in MAF between the two populations N720D, K26R, N638S, I468V. Found small differences in expression of hACE2 among various populations. Preprint - https://www.biorxiv.org/content/10.1101/2020.04.05.026633v1 - Gibson et al Analyse ACE2 variants in the gnomAD database and identify 15 missense variants likely to affect the affinity of the human ACE2 protein for the viral spike protein and estimated the change in binding energy of the 15 missense variants. |
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| COVID-19 research v0.137 | ALPI |
Eleanor Williams changed review comment from: Not associated with a phenotype in OMIM or Gene2Phenotype. PMID: 29567797 - Parlato et al 2018- report ALPI mutations in two unrelated patients with severe intestinal inflammation and autoimmunity. WES was used. Patient 1 - non‐consanguineous parents. At 2 years old was diagnosed with coeliac disease from HLA-typing. At age 3 had recurrent abdominal pain, rectal bleeding and severe diarrhoea. Patient 2 - non‐consanguineous parents of Jewish Ashkenazi origin. Age 15 he was diagnosed with ileocolonic Crohn's disease. Compound heterozygous mutations in the ALPI gene were found in both patients. Three variants result in the substitution of residues highly conserved across species (A97T, A350V and A360) and one variant (Q439X) introducing a premature stop codon. Functional studies in HEK293T cells showed that all ALPI mutations were loss of function. ALPI expression was reduced in patients’ biopsies.; to: Not associated with a phenotype in OMIM or Gene2Phenotype. PMID: 29567797 - Parlato et al 2018- report ALPI mutations in two unrelated patients with severe intestinal inflammation and autoimmunity. WES was used. Patient 1 - non‐consanguineous parents. At 2 years old was diagnosed with coeliac disease from HLA-typing. At age 3 had recurrent abdominal pain, rectal bleeding and severe diarrhoea. Patient 2 - non‐consanguineous parents of Jewish Ashkenazi origin. Age 15 he was diagnosed with ileocolonic Crohn's disease. Compound heterozygous mutations in the ALPI gene were found in both patients. Three variants result in the substitution of residues highly conserved across species (A97T, A350V and A360) and one variant (Q439X) introducing a premature stop codon. Functional studies in HEK293T cells showed that all ALPI mutations were loss of function. ALPI expression was reduced in patients’ biopsies. Rated Amber by Zornitza Stark on the PID panel. |
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| COVID-19 research v0.135 | MPO |
Catherine Snow changed review comment from: Comment on list classification: Based on an external review detailing a number of publications where MPO is reviewed because of its association in the regulation of (neutrophil extracellular traps) NET formation upgrading from Amber to Green; to: Comment on list classification: Based on an external review detailing a number of publications where MPO is reviewed because of its association in the regulation of (neutrophil extracellular traps) NET formation upgrading from Amber to Green Should also be noted that elevated levels of inflammatory mediators (including IL-6, IL-8, and MPO) in the airway of chronic/extended or recurrent RSV infection are associated with faster lung function decline in COPD patients. PMID: 32227102 |
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| COVID-19 research v0.134 | MPO | Catherine Snow Added comment: Comment on list classification: Based on an external review detailing a number of publications where MPO is reviewed because of its association in the regulation of (neutrophil extracellular traps) NET formation upgrading from Amber to Green | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.128 | AKT1 |
Sarah Leigh Added comment: Comment on list classification: AKT1 gene product can inhibit apoptosis through phosphorylation, and the inhibition of pro-apoptotic mediators to contribute to the maintenance of the virus latent state and may facilitate transformation of human lymphotropic virus type 1 infected cells (PMID 17931677). |
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| COVID-19 research v0.126 | NOS2 |
Ivone Leong gene: NOS2 was added gene: NOS2 was added to Viral susceptibility. Sources: Expert list Mode of inheritance for gene: NOS2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NOS2 were set to 31995689; 11207313 Review for gene: NOS2 was set to GREEN Added comment: NOS2 is part of the list of genes that confer susceptibility to viral infections on the COVID Human Genetic Effort website (https://www.covidhge.com/). PMID: 31995689 describes a 51 year old man from Iran who had an acute cytomegalovirus (CMV) infection which progressed to CMV disease and later died from it. The researchers found a homozygous variant that causes a frameshift mutation in NOS2 that caused NOS2 deficiency, which might cause the patient to be more susceptible to lethal CMV infection. It is rare for CMV to cause fatality in healthy people; however, Nos2 knockout mice are susceptible to lethal infection with murine CMV (PMID: 11207313). Based on the above evidence NOS2 has been given Green gene status. Sources: Expert list |
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| COVID-19 research v0.119 | HLA-B | Rebecca Foulger commented on gene: HLA-B: PMID:15839463 (Umapathy et al., 2004). Full text is unavailable. Title: Absence of HLA B*46 in Indian population: could it be the cause for protection from SARS epidemic? | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.118 | IL18 | Rebecca Foulger changed review comment from: PMID:25395539 (Zhang et al 2014) report that IL-18 and IL-22 administration to mice offered protection against a broad range of RV inoculation, and may offer broad antibiral therapeutic potential.; to: PMID:25395539 (Zhang et al 2014) report that IL-18 and IL-22 administration to mice offered protection against a broad range of RV inoculation, and may offer broad antiviral therapeutic potential. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.118 | IL22 | Rebecca Foulger changed review comment from: PMID:25395539 (Zhang et al 2014) report that IL-18 and IL-22 administration to mice offered protection against a broad range of RV inoculation, and may offer broad antibiral therapeutic potential.; to: PMID:25395539 (Zhang et al 2014) report that IL-18 and IL-22 administration to mice offered protection against a broad range of RV inoculation, and may offer broad antiviral therapeutic potential. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.113 | IL18 | Rebecca Foulger commented on gene: IL18: PMID:25395539 (Zhang et al 2014) report that IL-18 and IL-22 administration to mice offered protection against a broad range of RV inoculation, and may offer broad antibiral therapeutic potential. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.113 | IL18 | Rebecca Foulger changed review comment from: PMID:15606801 (Van Der Sluijs et al., 2005): IL18 is upregulated in after Influenza infection, and IL18 deficiency is associated with accelerated viral clearance.; to: PMID:15606801 (Van Der Sluijs et al., 2005): IL18 is upregulated in after Influenza infection, and IL18 deficiency is associated with accelerated viral clearance (mouse study). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.108 | RECQL4 | Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 5 variants reported in 3 unrelated cases in which immunodeficiecy was a feature (PMID 16630167; 21143835; 26064716). In addition RECQL4 variants have been implicated in Acrodermatitis Enteropathica caused by SLC39A4 (p.Gly512Trp)(PMID 30174688) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.103 | FANCB | Ivone Leong reviewed gene: FANCB: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Fanconi anemia, complementation group B, 300514; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.103 | IL18BP | Ivone Leong reviewed gene: IL18BP: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Defects in intrinsic and innate immunity, inborn errors of immunity related to leukocytes, IL-18BP deficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.103 | IRF4 | Ivone Leong reviewed gene: IRF4: Rating: GREEN; Mode of pathogenicity: ; Publications: 32086639, 32048120; Phenotypes: Defects in intrinsic and innate immunity, inborn errors of immunity related to leukocytes, IRF4 haploinsufficiency; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.102 | FANCB |
Ivone Leong gene: FANCB was added gene: FANCB was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019 Mode of inheritance for gene: FANCB was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: FANCB were set to 32086639; 32048120 Phenotypes for gene: FANCB were set to Fanconi anemia, complementation group B, 300514 |
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| COVID-19 research v0.102 | IL18BP |
Ivone Leong Source Expert Review Green was added to IL18BP. Source IUIS Classification December 2019 was added to IL18BP. Mode of inheritance for gene IL18BP was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Added phenotypes Defects in intrinsic and innate immunity; IL-18BP deficiency; inborn errors of immunity related to leukocytes for gene: IL18BP Publications for gene IL18BP were updated from PubMed: 31213488 to 32086639; 32048120; PubMed: 31213488 Rating Changed from No List (delete) to Green List (high evidence) |
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| COVID-19 research v0.102 | IRF4 |
Ivone Leong gene: IRF4 was added gene: IRF4 was added to Viral susceptibility. Sources: Expert Review Green,IUIS Classification December 2019 Mode of inheritance for gene: IRF4 was set to Phenotypes for gene: IRF4 were set to Defects in intrinsic and innate immunity; IRF4 haploinsufficiency; inborn errors of immunity related to leukocytes |
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| COVID-19 research v0.93 | RC3H1 |
Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM (lasted edited 01/27/2017) or in Gen2Phen. PMID 31636267 reports a biallelic nonsense variant (p.R688*), in a case with immune dysregulation syndrome characterized by severe hyperinflammation in a consanguineous family. The association of this variant with the phenotype is supported by functional studies and mouse model (PMID 15917799). |
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| COVID-19 research v0.89 | CCL5 | Rebecca Foulger commented on gene: CCL5: PMID:31874580 (Sheng et al. 2019) study suggests that the CCL5 rs2107538 polymorphism was correlated with TB (infectious disease caused by Mycobacterium tuberculosis) susceptibility in Caucasians. The rs2107538 polymorphism is suggested to affect CCL5 expression. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.81 | HLA-DRB1 |
Abdelazeem Elhabyan gene: HLA-DRB1 was added gene: HLA-DRB1 was added to Viral susceptibility. Sources: Literature Mode of inheritance for gene: HLA-DRB1 was set to Unknown Publications for gene: HLA-DRB1 were set to PMID: 19445991,26456283,19597844,10823757, Penetrance for gene: HLA-DRB1 were set to unknown Mode of pathogenicity for gene: HLA-DRB1 was set to Other Review for gene: HLA-DRB1 was set to GREEN Added comment: Association of human leukocyte antigen class II alleles with severe acute respiratory syndrome in the Vietnamese population PMID: 19445991, HLA-DRB1*12 was more frequently shown in SARS patients than in controls (corrected p = 0.042). HLA-DRB1*1202, the predominant allele in the Vietnamese population showed the strongest association with SARS in a dominant model (corrected p = 0.0065 and 0.0052, depending on the controls to be compared). Our results and accumulated data on HLA in the Asian populations would help in the understanding of associations with emerging infectious diseases. Amino Acid Variation in HLA Class II Proteins Is a Major Determinant of Humoral Response to Common Viruses PMID: 26456283 The magnitude of the human antibody response to viral antigens is highly variable. To explore the human genetic contribution to this variability, we performed genome-wide association studies of the immunoglobulin G response to 14 pathogenic viruses in 2,363 immunocompetent adults. Significant associations were observed in the major histocompatibility complex region on chromosome 6 for influenza A virus, Epstein-Barr virus, JC polyomavirus, and Merkel cell polyomavirus. Using local imputation and fine mapping, we identified specific amino acid residues in human leucocyte antigen (HLA) class II proteins as the most probable causal variants underlying these association signals. Common HLA-DRβ1 haplotypes showed virus-specific patterns of humoral-response regulation Clear and Independent Associations of Several HLA-DRB1 Alleles With Differential Antibody Responses to Hepatitis B Vaccination in Youth PMID: 19597844 To confirm and refine associations of human leukocyte antigen (HLA) genotypes with variable antibody (Ab) responses to hepatitis B vaccination, we have analyzed 255 HIV-1 seropositive (HIV(+)) youth and 80 HIV-1 seronegatives (HIV(-)) enrolled into prospective studies. In univariate analyses that focused on HLA-DRB1, -DQA1, and -DQB1 alleles and haplotypes, the DRB1*03 allele group and DRB1*0701 were negatively associated with the responder phenotype (serum Ab concentration > or = 10 mIU/mL) (P = 0.026 and 0.043, respectively). Collectively, DRB1*03 and DRB1*0701 were found in 42 (53.8%) out of 78 non-responders (serum Ab <10 mIU/mL), 65 (40.6%) out of 160 medium responders (serum Ab 10-1,000 mIU/mL), and 27 (27.8%) out of 97 high responders (serum Ab >1,000 mIU/mL) (P < 0.001 for trend). Meanwhile, DRB1*08 was positively associated with the responder phenotype (P = 0.010), mostly due to DRB1*0804 (P = 0.008). Influence of HLA Supertypes on Susceptibility and Resistance to Human Immunodeficiency Virus Type 1 Infection PMID: 10823757 To determine whether HLA polymorphism influences HIV-1 susceptibility, a longitudinal cohort of highly HIV-1-exposed female sex workers based in Nairobi, Kenya, was prospectively analyzed. Decreased HIV-1 infection risk was strongly associated with possession of a cluster of closely related HLA alleles (A2/6802 supertype; incidence rate ratio [IRR], 0.45; 95% confidence interval [CI], 0.27-0.72; P=.0003). The alleles in this supertype are known in some cases to present the same peptide epitopes for T cell recognition. In addition, resistance to HIV-1 infection was independently associated with HLA DRB1*01 (IRR, 0.22; 95% CI, 0.06-0.60; P=.0003), which suggests that anti-HIV-1 class II restricted CD4 effector mechanisms may play an important role in protecting against viral challenge Sources: Literature |
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| COVID-19 research v0.81 | POLR3A |
Abdelazeem Elhabyan changed review comment from: This gene is responsible for A subunit of Polymerase which sense DNA in viral infection eg Varicella Zoster. SARS-CoV-2 is an RNA virus. Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections(PMID: 28783042) We report 4 cases of acute severe VZV infection affecting the central nervous system or the lungs in unrelated, otherwise healthy children who are heterozygous for rare missense mutations in POLR3A (one patient), POLR3C (one patient), or both (two patients). POLR3A and POLR3C encode subunits of RNA polymerase III. Leukocytes from all 4 patients tested exhibited poor IFN induction in response to synthetic or VZV-derived DNA. Moreover, leukocytes from 3 of the patients displayed defective IFN production upon VZV infection and reduced control of VZV replication. These phenotypes were rescued by transduction with relevant WT alleles. This work demonstrates that monogenic or digenic POLR3A and POLR3C deficiencies confer increased susceptibility to severe VZV disease in otherwise healthy children, providing evidence for an essential role of a DNA sensor in human immunity Different classes of PRRs are involved in recognition of virus infections, including membrane-associated TLRs; cytosolic retinoic acid–inducible gene 1–like (RIG-I–like) receptors, which sense RNA; and DNA sensors (24). Each of these classes of PRRs stimulates production of IFNs, which exhibit antiviral activity through their ability to induce IFN-stimulated genes (ISGs). With respect to DNA sensors, TLR9 detects unmethylated DNA, RNA polymerase III (POL III) recognizes AT-rich DNA, while gamma-interferon-inducible protein 16 (IFI16) and cyclic GMP-AMP synthase (cGAS) sense double-stranded DNA in a sequence-independent manner (25–29). Mutations in RNA Polymerase III genes and defective DNA sensing in adults with varicella-zoster virus CNS infection PMID: 29728610 Recently, deficiency in the cytosolic DNA sensor RNA Polymerase III was described in children with severe primary varicella-zoster virus (VZV) infection in the CNS and lungs. In the present study we examined adult patients with VZV CNS infection caused by viral reactivation. By whole exome sequencing we identified mutations in POL III genes in two of eight patients. These mutations were located in the coding regions of the subunits POLR3A and POLR3E. In functional assays, we found impaired expression of antiviral and inflammatory cytokines in response to the POL III agonist Poly(dA:dT) as well as increased viral replication in patient cells compared to controls. Altogether, this study provides significant extension on the current knowledge on susceptibility to VZV infection by demonstrating mutations in POL III genes associated with impaired immunological sensing of AT-rich DNA in adult patients with VZV CNS infection.; to: This gene is responsible for A subunit of Polymerase which senses DNA viruses especially AT-rich regions eg Varicella Zoster. SARS-CoV-2 is an RNA virus. Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections(PMID: 28783042) We report 4 cases of acute severe VZV infection affecting the central nervous system or the lungs in unrelated, otherwise healthy children who are heterozygous for rare missense mutations in POLR3A (one patient), POLR3C (one patient), or both (two patients). POLR3A and POLR3C encode subunits of RNA polymerase III. Leukocytes from all 4 patients tested exhibited poor IFN induction in response to synthetic or VZV-derived DNA. Moreover, leukocytes from 3 of the patients displayed defective IFN production upon VZV infection and reduced control of VZV replication. These phenotypes were rescued by transduction with relevant WT alleles. This work demonstrates that monogenic or digenic POLR3A and POLR3C deficiencies confer increased susceptibility to severe VZV disease in otherwise healthy children, providing evidence for an essential role of a DNA sensor in human immunity Different classes of PRRs are involved in recognition of virus infections, including membrane-associated TLRs; cytosolic retinoic acid–inducible gene 1–like (RIG-I–like) receptors, which sense RNA; and DNA sensors (24). Each of these classes of PRRs stimulates production of IFNs, which exhibit antiviral activity through their ability to induce IFN-stimulated genes (ISGs). With respect to DNA sensors, TLR9 detects unmethylated DNA, RNA polymerase III (POL III) recognizes AT-rich DNA, while gamma-interferon-inducible protein 16 (IFI16) and cyclic GMP-AMP synthase (cGAS) sense double-stranded DNA in a sequence-independent manner (25–29). Mutations in RNA Polymerase III genes and defective DNA sensing in adults with varicella-zoster virus CNS infection PMID: 29728610 Recently, deficiency in the cytosolic DNA sensor RNA Polymerase III was described in children with severe primary varicella-zoster virus (VZV) infection in the CNS and lungs. In the present study we examined adult patients with VZV CNS infection caused by viral reactivation. By whole exome sequencing we identified mutations in POL III genes in two of eight patients. These mutations were located in the coding regions of the subunits POLR3A and POLR3E. In functional assays, we found impaired expression of antiviral and inflammatory cytokines in response to the POL III agonist Poly(dA:dT) as well as increased viral replication in patient cells compared to controls. Altogether, this study provides significant extension on the current knowledge on susceptibility to VZV infection by demonstrating mutations in POL III genes associated with impaired immunological sensing of AT-rich DNA in adult patients with VZV CNS infection. |
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| COVID-19 research v0.75 | DBR1 |
Abdelazeem Elhabyan changed review comment from: I found that it has been promoted from the Australling susceptibility to viral infections on this link https://panelapp.agha.umccr.org/panels/237/gene/DBR1/ This is based on this notion : Seven individuals from three unrelated families with viral brainstem encephalitis and bi-allelic hypomorphic variants. When I reviewed the paper, I found a notion of influenza viral encephalitis among other viruses(eg HSV-1) and a suggestion that this predisposition to the disease is due to involvement of DBR1 in intrinsic resistance of brainstem cells to those viruses via the enzyme encoded by DBR1.; to: I found that it has been promoted from the Australling susceptibility to viral infections on this link https://panelapp.agha.umccr.org/panels/237/gene/DBR1/ This is based on this notion in this paper : https://pubmed.ncbi.nlm.nih.gov/29474921/ Seven individuals from three unrelated families with viral brainstem encephalitis and bi-allelic hypomorphic variants. When I reviewed the paper, I found a notion of influenza viral encephalitis among other viruses(eg HSV-1) and a suggestion that this predisposition to the disease is due to the involvement of DBR1 in intrinsic resistance of brainstem cells to those viruses via the enzyme encoded by DBR1. |
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| COVID-19 research v0.75 | DBR1 |
Abdelazeem Elhabyan commented on gene: DBR1: I found that it has been promoted from the Australling susceptibility to viral infections on this link https://panelapp.agha.umccr.org/panels/237/gene/DBR1/ This is based on this notion : Seven individuals from three unrelated families with viral brainstem encephalitis and bi-allelic hypomorphic variants. When I reviewed the paper, I found a notion of influenza viral encephalitis among other viruses(eg HSV-1) and a suggestion that this predisposition to the disease is due to involvement of DBR1 in intrinsic resistance of brainstem cells to those viruses via the enzyme encoded by DBR1. |
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| COVID-19 research v0.74 | FPR2 |
Catherine Snow changed review comment from: FPR2 is a seven transmembrane G protein-coupled receptor, which plays an important role in sensing of bacteria and modulation of immune responses Mouse model PMID: 31908042 Fpr2/3 knockout (KO) mice and wild‐type (WT) controls were infected intranasally with S pneumoniae. AnxA1 and Fpr2/3 KO mice were highly susceptible to infection, displaying uncontrolled inflammation, increased bacterial dissemination, and pulmonary dysfunction compared to WT animals PMID: 28928730 The review gives an overview on the pathogenesis of influenza with a focus on the role of FPR2 and discusses the advantages of using FPR2 antagonists to treat the flu. Preclinical studies have proven that FPR2 antagonists efficiently protect mice against IAV infections, by inhibiting viral replication and deleterious inflammation of the lungs; to: FPR2 is a seven transmembrane G protein-coupled receptor, which plays an important role in sensing of bacteria and modulation of immune responses Mouse model PMID: 31908042 Fpr2/3 knockout (KO) mice and wild‐type (WT) controls were infected intranasally with S pneumoniae. AnxA1 and Fpr2/3 KO mice were highly susceptible to infection, displaying uncontrolled inflammation, increased bacterial dissemination, and pulmonary dysfunction compared to WT animals PMID: 28928730 The review gives an overview on the pathogenesis of influenza with a focus on the role of FPR2 and discusses the advantages of using FPR2 antagonists to treat the flu. Preclinical studies have proven that FPR2 antagonists efficiently protect mice against IAV infections, by inhibiting viral replication and deleterious inflammation of the lungs |
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| COVID-19 research v0.74 | FPR2 |
Catherine Snow changed review comment from: FPR2 is a seven transmembrane G protein-coupled receptor, which plays an important role in sensing of bacteria and modulation of immune responses Mouse model PMID: 31908042 Fpr2/3 knockout (KO) mice and wild‐type (WT) controls were infected intranasally with S pneumoniae. AnxA1 and Fpr2/3 KO mice were highly susceptible to infection, displaying uncontrolled inflammation, increased bacterial dissemination, and pulmonary dysfunction compared to WT animals PMID: 28928730 The review gives an overview on the pathogenesis of influenza with a focus on the role of FPR2 and discusses the advantages of using FPR2 antagonists to treat the flu. Preclinical studies have proven that FPR2 antagonists efficiently protect mice against IAV infections, by inhibiting viral replication and deleterious inflammation of the lungs; to: FPR2 is a seven transmembrane G protein-coupled receptor, which plays an important role in sensing of bacteria and modulation of immune responses Mouse model PMID: 31908042 Fpr2/3 knockout (KO) mice and wild‐type (WT) controls were infected intranasally with S pneumoniae. AnxA1 and Fpr2/3 KO mice were highly susceptible to infection, displaying uncontrolled inflammation, increased bacterial dissemination, and pulmonary dysfunction compared to WT animals PMID: 28928730 The review gives an overview on the pathogenesis of influenza with a focus on the role of FPR2 and discusses the advantages of using FPR2 antagonists to treat the flu. Preclinical studies have proven that FPR2 antagonists efficiently protect mice against IAV infections, by inhibiting viral replication and deleterious inflammation of the lungs |
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| COVID-19 research v0.60 | MPO |
Sarah Leigh Added comment: Comment on list classification: PMID 3208230 outlines the role of neutrophil extracellular traps (NETs) in the control of some pathogens including viruses, by virus capture and neutralization. In vivo treatment of the mice with DNase resulted in the enhanced susceptibility of IFNAR-/- mice to the CHIKV virus. Furthermore, the levels of MPO-DNA complex in acutely CHIKV-infected patients, were correlated with the levels of NETs and the viral load in the blood, suggesting that NETs are also released in natural human infection cases. Therefore, variants that result in myeloperoxidase deficiency, may well contribute to an increased susceptiblity to viral infection. At least 9 variants have been reported in Myeloperoxidase deficiency 254600 and these could well be contributing to increased viral susceptibily. |
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| COVID-19 research v0.54 | GAD1 | Catherine Snow Added comment: Comment on list classification: GAD1 has no relationship to virus susceptibility. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.52 | IFNAR1 | Sarah Leigh Added comment: Comment on list classification: Not associated with phenotype in OMIM or in Gen2Phen. However, the publications listed below give evidence that the three LOF variants in two unrelated cases are associated with an adverse reaction to attenuated virus vaccines, which are rescued by wt IFNAR1 protein in vitro. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.49 | STAT5A |
Eleanor Williams edited their review of gene: STAT5A: Added comment: April 2020 - no association with any human disease phenotype in OMIM (page last updated Feb 2020). - no associations in Gene2Phenotype. - PubMed search - no publications describing reports of variants in STAT5 and PID/viral susceptibility but : PMID: 26541527- Leahy et al 2016 - mention that STAT5 mRNA (which is in the IL-15 pathway) is differentially expressed in children with severe bronchiolitis compared with those with moderate severity bronchiolitis. PMID: 23593005- Hong et al 2013 - in human papillomavirus (HPV) infections STAT-5 is activated as part of the process to regulate genome amplification in suprabasal cells. PMID: 22520852 - Li et al - show in mouse studies that tetramerization of STAT5 is critical for cytokine responses and normal immune function; Changed publications: 16418296, 26541527, 23593005, 22520852 |
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| COVID-19 research v0.49 | IRF9 | Catherine Snow Added comment: Comment on list classification: Rating Green on this panel following feedback with Genomics England clinical team, as this is a research panel and IRF9 has two unrelated cases and an animal model. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.47 | CCL2 | Rebecca Foulger commented on gene: CCL2: PMID:27260136 (Kim et al., 2016) report that CCL2 ablation highly increased susceptibility to Japanese encephalitis, indicating that CCL2 plays an essential role in conferring protection against JE caused by JE virus (JEV) infection. They also note a surprising opposite effect for ablation of the CCR2 (the corresponding receptor). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.40 | KDM6A |
Ellen McDonagh Source Expert Review Green was added to KDM6A. Added phenotypes Combined immunodeficiencies with associated or syndromic features; Kabuki Syndrome 2 due to KDM6A deficiency; Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present for gene: KDM6A Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | IRAK1 |
Ellen McDonagh Source Expert Review Green was added to IRAK1. Added phenotypes Bacterial infections, X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1; Defects in Intrinsic and Innate Immunity for gene: IRAK1 Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | NFAT5 |
Ellen McDonagh Source Expert Review Green was added to NFAT5. Added phenotypes NFAT5 haploinsufficieny; IBD, recurrent sinopulmonary infections; Diseases of Immune Dysregulation for gene: NFAT5 Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | KMT2D |
Ellen McDonagh Source Expert Review Green was added to KMT2D. Added phenotypes Kabuki syndrome 1, 147920; Combined immunodeficiencies with associated or syndromic features; Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present for gene: KMT2D Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | JAK1 |
Ellen McDonagh Source Expert Review Green was added to JAK1. Added phenotypes Hypereosinophilic syndrome; HSM, eosinophilia, eosinophilic enteritis, thyroid disease, poor growth, viral infections; Diseases of Immune Dysregulation; Susceptibility to mycobacteria and viruses, urothelial carcinoma; Defects in Intrinsic and Innate Immunity; HSM, eosinophilic enteritis, thyroid disease, poor growth, viral infections for gene: JAK1 Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | ERBIN |
Ellen McDonagh Source Expert Review Green was added to ERBIN. Added phenotypes ERBIN deficiency; Combined immunodeficiencies with associated or syndromic features; Recurrent respiratory infections, susceptibility to S. aureus, eczema, hyperextensible joints, scoliosis, arterial dilatation in some for gene: ERBIN Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | TNFRSF13B |
Ellen McDonagh Source Expert Review Green was added to TNFRSF13B. Added phenotypes IgA with IgG subclass deficiency; Immunodeficiency, common variable, 2; Immunodeficiency, common variable, 2, 240500; Variable clinical expression; Isolated IgG subclass deficiency; IGAD; Selective IgA deficiency; Common variable immunodeficiency disorders (CVID); Predominantly Antibody Deficiencies; Immunoglobulin A deficiency 2, 609529; CVID for gene: TNFRSF13B Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | CFHR2 |
Ellen McDonagh Source Expert Review Green was added to CFHR2. Added phenotypes Complement Deficiencies; Age related macular degeneration; Atypical hemolytic uremic syndrome susceptibility; Older onset atypical hemolytic-uremic syndrome, disseminated neisserial infections for gene: CFHR2 Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | WRAP53 |
Ellen McDonagh Source Expert Review Green was added to WRAP53. Added phenotypes Bone marrow failure; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; Combined immunodeficiencies with associated or syndromic features; Intrauterine growth retardation, microcephaly, nail dystrophy, sparse scalp hair and eyelashes, hyperpigmentation of skin, palmar hyperkeratosis, premalignant oral leukoplakia, pancytopenia, myelodysplasia, +/- recurrent infections. A severe phenotype with developmental delay and cerebellar hypoplasia known as Hoyeraal-Hreidarsson Syndrome (HHS) may occur in some DKC patients; microcephaly, neurodevelopmental delay for gene: WRAP53 Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | TRIM22 |
Ellen McDonagh Source Expert Review Green was added to TRIM22. Added phenotypes TRIM22; Granulomatous colitis; Autoinflammatory Disorders; Diseases of Immune Dysregulation for gene: TRIM22 Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | TGFB1 |
Ellen McDonagh Source Expert Review Green was added to TGFB1. Added phenotypes Inflammatory bowel disease, immunodeficiency, and encephalopathy, 618213; IBD, immunodeficiency, recurrent viral infections, microcephaly, and encephalopathy; TGFB1 deficiency; Diseases of Immune Dysregulation for gene: TGFB1 Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | IL6R |
Ellen McDonagh Source Expert Review Green was added to IL6R. Added phenotypes Eczema; Recurrent infections; Recurrent pyogenic infections, cold abscesses, high circulating IL-6 levels; Hyper-IgE; Combined immunodeficiencies with associated or syndromic features for gene: IL6R Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | FERMT1 |
Ellen McDonagh Source Expert Review Green was added to FERMT1. Added phenotypes FERMT1 deficiency (Kindler syndrome); Diseases of Immune Dysregulation; Kindler syndrome, 173650; Dermatosis characterized by congenital blistering, skin atrophy, photosensitivity, skin fragility, and scaling for gene: FERMT1 Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | FCHO1 |
Ellen McDonagh Source Expert Review Green was added to FCHO1. Added phenotypes Recurrent infections, lymphoproliferation, increased activation-induced T-cell death, defective clathrin-mediated endocytosis; FCHO1 deficiency; Immunodeficiencies affecting cellular and humoral immunity for gene: FCHO1 Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | FAAP24 |
Ellen McDonagh Source Expert Review Green was added to FAAP24. Added phenotypes EBV infection-driven lymphoproliferative disease; Diseases of Immune Dysregulation for gene: FAAP24 Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | DEF6 |
Ellen McDonagh Source Expert Review Green was added to DEF6. Added phenotypes DEF6 deficiency; Diseases of Immune Dysregulation; Enteropathy, hepatosplenomegaly, cardiomyopathy, recurrent infections for gene: DEF6 Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | AP3D1 |
Ellen McDonagh Source Expert Review Green was added to AP3D1. Added phenotypes neutropenia; Immunodeficient HPS; seizures; Diseases of Immune Dysregulation; Hermansky-Pudlak syndrome with neutropenia; neuordevelopmental delay; albinism; ?Hermansky-Pudlak syndrome 10, 617050; Hermansky-Pudlak syndrome; Oculocutaneous albinism, recurrent infections, seizures, hearing loss and neurodevelopmental delay; Oculocutaneous albinism, severe neutropenia, recurrent infections, seizures, hearing loss and neurodevelopmental delay; HSP10 for gene: AP3D1 Rating Changed from Red List (low evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | TINF2 |
Ellen McDonagh Source Expert Review Green was added to TINF2. Added phenotypes microcephaly, neurodevelopmental delay exudative retinopathy; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay for gene: TINF2 Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | TERC |
Ellen McDonagh Source Expert Review Green was added to TERC. Added phenotypes Dyskeratosis congenita; Bone marrow failure; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; Dyskeratosis congenita 1; Intrauterine growth retardation, microcephaly, nail dystrophy, sparse scalp hair and eyelashes, hyperpigmentation of skin, palmar hyperkeratosis, premalignant oral leukoplakia, pancytopenia, myelodysplasia, +/- recurrent infections. A severe phenotype with developmental delay and cerebellar hypoplasia known as Hoyeraal-Hreidarsson Syndrome (HHS) may occur in some DKC patients; Combined immunodeficiencies with associated or syndromic features; Hoyeraal-Hreidarsson syndrome; microcephaly, neurodevelopmental delay for gene: TERC Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | TBX1 |
Ellen McDonagh Source Expert Review Green was added to TBX1. Added phenotypes Hypoparathyroidism, conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability; DiGeorge syndrome 188400; Di George syndrome; T-B+ SCID; Severe combined immunodeficiency (SCID); Combined immunodeficiencies with associated or syndromic features for gene: TBX1 Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | TERT |
Ellen McDonagh Source Expert Review Green was added to TERT. Added phenotypes Bone marrow failure; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay for gene: TERT Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | RAC2 |
Ellen McDonagh Source Expert Review Green was added to RAC2. Added phenotypes Reticular dysgenesis; poststreptococcal glomerulonephritis; Congenital defects of phagocyte number or function; Neutrophil immunodeficiency syndrome; RAS-related C3 Bolutinum toxin substrate 2 deficiency (RAC2); T-B+ SCID; Neutrophil immunodeficiency syndrome 608203; Recurrent sinopulmonary infections, selective IgA defiency; urticaria; T-B- SCID; Poor wound healing, leukocytosis for gene: RAC2 Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | CFHR4 |
Ellen McDonagh Source Expert Review Green was added to CFHR4. Added phenotypes Complement Deficiencies; Age related macular degeneration; Atypical hemolytic uremic syndrome susceptibility; Older onset atypical hemolytic-uremic syndrome, disseminated neisserial infections for gene: CFHR4 Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | CFHR3 |
Ellen McDonagh Source Expert Review Green was added to CFHR3. Added phenotypes Complement Deficiencies; Age related macular degeneration; Atypical hemolytic uremic syndrome susceptibility; Older onset atypical hemolytic-uremic syndrome, disseminated neisserial infections for gene: CFHR3 Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | CFHR1 |
Ellen McDonagh Source Expert Review Green was added to CFHR1. Added phenotypes Complement Deficiencies; Age related macular degeneration; Atypical hemolytic uremic syndrome susceptibility; Older onset atypical hemolytic-uremic syndrome, disseminated neisserial infections for gene: CFHR1 Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | CFB |
Ellen McDonagh Source Expert Review Green was added to CFB. Added phenotypes Infections with encapsulated organisms; Complement Deficiencies; complement factor B deficiency (AR); Atypical Hemolytic-uremic syndrome; Complement factor B deficiency, 615561; Susceptibility to atypical haemolytic uraemic syndrome 4 (AD) for gene: CFB Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | TNFRSF13C |
Ellen McDonagh Source Expert Review Green was added to TNFRSF13C. Added phenotypes Immunodeficiency, common variable, 4; Variable clinical expression; Isolated IgG subclass deficiency; Common variable immunodeficiency disorders (CVID); Predominantly Antibody Deficiencies for gene: TNFRSF13C Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | DNASE1L3 |
Ellen McDonagh Source Expert Review Green was added to DNASE1L3. Added phenotypes Systemic lupus erythematosus 16, 614420; Autoinflammatory Disorders; Diseases of Immune Dysregulation; familial early-onset SLE; Systemic lupus erythematosus, lupus nephritis, hypocomplementemic urticarial vasculitis for gene: DNASE1L3 Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | CR2 |
Ellen McDonagh Source Expert Review Green was added to CR2. Added phenotypes Recurrent infections; Lupus; Isolated IgG subclass deficiency; Immunodeficiency, common variable, 7; Common variable immunodeficiency disorders (CVID); hypogammaglobulinaemia; Predominantly Antibody Deficiencies; Immunodeficiency, common variable, 7, 614699 for gene: CR2 Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| COVID-19 research v0.40 | CD81 |
Ellen McDonagh Source Expert Review Green was added to CD81. Added phenotypes CD81 deficiency; Isolated IgG subclass deficiency; Recurrent infections, may have glomerulonephritis; Common variable immunodeficiency disorders (CVID); hypogammaglobulinaemia; Predominantly Antibody Deficiencies; Immunodeficiency, common variable 6, 613496 for gene: CD81 Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| COVID-19 research v0.39 | IFNAR1 |
Sarah Leigh gene: IFNAR1 was added gene: IFNAR1 was added to Viral susceptibility. Sources: Literature Mode of inheritance for gene: IFNAR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IFNAR1 were set to 31270247; 26676772; 20020050 Phenotypes for gene: IFNAR1 were set to IFNAR1 associated adverse reactions to certain live attenuated viral vaccines Review for gene: IFNAR1 was set to AMBER Added comment: Hypothesis from Abdelazeem Elhabyan (Tanta University Hospitals): this gene is involved in the interferon-mediated immune response to viruses of those is SARS Coronavirus (2003) which down-regulates the IFNAR1 receptors through its 3a protein. Additionally, Influenzavirus A suppress immune response by downregulation of this gene. It has been also linked to adverse reactions to measles and yellow fever vaccines in healthy individuals. Sources: Literature |
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| COVID-19 research v0.36 | KDM6A |
Ellen McDonagh gene: KDM6A was added gene: KDM6A was added to Viral susceptibility. Sources: Expert Review Red,IUIS Classification February 2018,IUIS Classification December 2019 Mode of inheritance for gene: KDM6A was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: KDM6A were set to 25142838; 25546742; 26411453; 32086639; 15887282; 15523604; 32048120 Phenotypes for gene: KDM6A were set to Combined immunodeficiencies with associated or syndromic features; Kabuki Syndrome 2 due to KDM6A deficiency; Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present |
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| COVID-19 research v0.36 | XIAP |
Ellen McDonagh gene: XIAP was added gene: XIAP was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: XIAP was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: XIAP were set to 25943627; 21119115; 17080092; 21173700; 22228567 Phenotypes for gene: XIAP were set to Lymphoproliferative syndrome, X-linked, 2 (XLP2); inflammatory bowel disease; 300635; splenomegaly; Diseases of Immune Dysregulation; X-linked lymphoproliferative syndrome (XLP); haemophagocytic lymphohistiocytosis; Lymphoproliferative syndrome, X-linked, 2; EBV infection, Splenomegaly, lymphoproliferation, HLH, Colitis, IBD, hepatitis, Low iNKT cells, hypogammaglobulinemia |
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| COVID-19 research v0.36 | CYBB |
Ellen McDonagh gene: CYBB was added gene: CYBB was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: CYBB was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: CYBB were set to 1710153; 2556453; 17293536 Phenotypes for gene: CYBB were set to Chronic granulomatous disease, X-linked, 306400; Defects with susceptibility to mycobacterial infection (MSMD); Congenital defects of phagocyte number or function; Immunodeficiency 34, mycobacteriosis, X-linked, 300645; Chronic granulomatous disease (CGD); Isolated susceptibility to mycobacteria; Infections, autoinflammatory phenotype, IBD, McLeod phenotype in patients with deletions extending into the contiguous Kell locus; Defects in Intrinsic and Innate Immunity |
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| COVID-19 research v0.36 | IRAK1 |
Ellen McDonagh gene: IRAK1 was added gene: IRAK1 was added to Viral susceptibility. Sources: Expert Review Red,IUIS Classification February 2018,IUIS Classification December 2019 Mode of inheritance for gene: IRAK1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: IRAK1 were set to 32086639; 32048120; 28069966 Phenotypes for gene: IRAK1 were set to Bacterial infections, X-linked MECP2 deficiency-related syndrome due to a large de novo Xq28 chromosomal deletion encompassing both MECP2 and IRAK1; Defects in Intrinsic and Innate Immunity |
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| COVID-19 research v0.36 | WAS |
Ellen McDonagh gene: WAS was added gene: WAS was added to Viral susceptibility. Sources: Expert Review Green,Combined B and T cell defect v1.12,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,Congenital neutropaenia v1.22,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: WAS was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: WAS were set to 11242115; 16804117 Phenotypes for gene: WAS were set to Wiskott-Aldrich syndrome (WAS); Combined immunodeficiencies with associated or syndromic features; Neutropenia, myeloid maturation arrest, monocytopenia, variable lymphoid anomalies; Congenital neutropenia; X-linked thrombocytopenia; Congenital defects of phagocyte number or function; X-linked thrombocytopenia with mutations in WASP; Thrombocytopenia with small platelets, recurrent bacterial and viral infections, bloody diarrhea, eczema, lymphoma, autoimmune disease, IgA nephropathy, vasculitis; Neutropenia, severe congenital, X-linked, 300299; XL thrombocytopenia is a mild form of WAS, and XL neutropenia is caused by missense mutations in the GTPase binding domain of WASp; Wiskott-Aldrich syndrome Mode of pathogenicity for gene: WAS was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments |
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| COVID-19 research v0.36 | SH2D1A |
Ellen McDonagh gene: SH2D1A was added gene: SH2D1A was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: SH2D1A was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: SH2D1A were set to 10598819; 29670631; 10556288; 11049992; 9774102; 10694488; 9771704 Phenotypes for gene: SH2D1A were set to EBV, HLH, Lymphoproliferation, Aplastic anaemia, Lymphoma. Hypogammaglobulinemia, Absent iNKT cells; Lymphoproliferative syndrome, X-linked, 1 308240; Diseases of Immune Dysregulation; X-linked lymphoproliferative syndrome (XLP); Lymphoproliferative syndrome, X-linked, 1 (XLP1) |
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| COVID-19 research v0.36 | POLA1 |
Ellen McDonagh gene: POLA1 was added gene: POLA1 was added to Viral susceptibility. Sources: Expert Review Green,North West GLH,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: POLA1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: POLA1 were set to 27019227 Phenotypes for gene: POLA1 were set to Hyperpigmentation, characteristic facies, lung and GI involvement; Autoinflammatory Disorders; Pigmentary disorder, reticulate, with systemic manifestations, X-linked 301220; X-linked reticulate pigmentary disorder; x-linked cutaneous amyloidosis with systemic features |
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| COVID-19 research v0.36 | MAGT1 |
Ellen McDonagh gene: MAGT1 was added gene: MAGT1 was added to Viral susceptibility. Sources: Expert Review Green,Combined B and T cell defect v1.12,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: MAGT1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: MAGT1 were set to 21796205; 25504528; 25205404; 24550228; 23846901; 27095930; 23871722; 21983175; 25956530 Phenotypes for gene: MAGT1 were set to Chronic active EBV, lymphoproliferation, combined immunodeficiency, impaired t cell function; Combined immunodeficiency; Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasia; Immunodeficiency, X-linked, with magnesium defect; Diseases of Immune Dysregulation; Epstein-Barr virus infection and neoplasia (XMEN); EBV infection, lymphoma, viral infections, respiratory and GI infections; XMEN syndrome |
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| COVID-19 research v0.36 | IKBKG |
Ellen McDonagh gene: IKBKG was added gene: IKBKG was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: IKBKG was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: IKBKG were set to 11047757 Phenotypes for gene: IKBKG were set to Ectodermal, dysplasia, anhidrotic, lymphedema and immunodeficiency, 300301; Immunodeficiency 33, 300636; 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; Ectodermal dysplasia, hypohidrotic, with immune deficiency 300291; Combined immunodeficiencies with associated or syndromic features; Immunodeficiency, isolated, 300584 |
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| COVID-19 research v0.36 | GATA1 |
Ellen McDonagh gene: GATA1 was added gene: GATA1 was added to Viral susceptibility. Sources: Expert Review Green,North West GLH,Congenital neutropaenia v1.22,NHS GMS,London North GLH Mode of inheritance for gene: GATA1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: GATA1 were set to 16783379; 22706301 Phenotypes for gene: GATA1 were set to neutropenia; dyserythropoietic anaemia; thrombocytopenia; Anemia, X-linked, with/without neutropenia and/or platelet abnormalities, 300835 |
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| COVID-19 research v0.36 | G6PD |
Ellen McDonagh Mode of inheritance for gene G6PD was changed from X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) to X-LINKED: hemizygous mutation in males, biallelic mutations in females Added phenotypes Infections; haemolytic anaemia; Congenital defects of phagocyte number or function; chronic granulomatous disease-like susceptibility to infection; Glucose-6-phosphate dehydrogenase deficiency (G6PD) for gene: G6PD Publications for gene G6PD were updated from 26694452; 18269318; 27458052; 27914961 to 18269318; 3681550; 26694452; 12130518; 27914961; 27458052 |
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| COVID-19 research v0.36 | FOXP3 |
Ellen McDonagh gene: FOXP3 was added gene: FOXP3 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: FOXP3 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: FOXP3 were set to 17635943; 11120765; 11295725; 16741580; 14671208 Phenotypes for gene: FOXP3 were set to FOXP3 deficiency (IPEX); Immune dysregulation polyendocrinopathy enteropathy X-linked syndrome; Diseases of Immune Dysregulation; Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked, 304790; IPEX; Autoimmune enteropathy, early onset diabetes, hyroiditis hemolytic anemia, thrombocytopenia, eczema, elevated IgE, IgA |
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| COVID-19 research v0.36 | BTK |
Ellen McDonagh gene: BTK was added gene: BTK was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,A- or hypo-gammaglobulinaemia v1.25,IUIS Classification February 2018 Mode of inheritance for gene: BTK was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: BTK were set to 20301626 Phenotypes for gene: BTK were set to Agammaglobulinemia, X-linked 1, 300755; Agammaglobulinemia, X-linked; Agammaglobulinemia, X-linked 1 (XLA); Agammaglobulinemia; Severe bacterial infections, normal numbers of pro-B cells; agammaglobulinaemia; Agammaglobulinemia and isolated hormone deficiency, 307200; Agammaglobulinemia and isolated hormone deficiency; Predominantly Antibody Deficiencies; CVID |
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| COVID-19 research v0.36 | ELF4 |
Ellen McDonagh gene: ELF4 was added gene: ELF4 was added to Viral susceptibility. Sources: Expert Review Red,A- or hypo-gammaglobulinaemia v1.25 Mode of inheritance for gene: ELF4 was set to Unknown Publications for gene: ELF4 were set to 16264330 Phenotypes for gene: ELF4 were set to X-linked hypogammaglobulinemia with isolated growth hormone deficiency |
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| COVID-19 research v0.36 | STAT3 |
Ellen McDonagh gene: STAT3 was added gene: STAT3 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: STAT3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: STAT3 were set to 17676033; 17881745; 25038750; 25359994 Phenotypes for gene: STAT3 were set to Hyper-IgE recurrent infection syndrome 147060; Hyper IgE syndrome (HIES); Diseases of Immune Dysregulation; Early-onset multi-organ autoimmune disease; Autoimmune disease, multisystem, infantile-onset, 1 615952; Combined immunodeficiencies with associated or syndromic features; Autoimmune disease, multisystem, infantile-onset Mode of pathogenicity for gene: STAT3 was set to Other - please provide details in the comments |
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| COVID-19 research v0.36 | CTLA4 |
Ellen McDonagh gene: CTLA4 was added gene: CTLA4 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,A- or hypo-gammaglobulinaemia v1.25,IUIS Classification February 2018 Mode of inheritance for gene: CTLA4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CTLA4 were set to 25213377; 25329329 Phenotypes for gene: CTLA4 were set to Autoimmune lymphoproliferative syndrome, type V; interstitual lung disease; autoimmunity; lymphadenopathy; T cell lymphopenia; Combined immunodeficiency; Immune dysregulation; a broad range of autoimmune phenomena have been described along with polyclonal lymphocytic infiltrates. Susceptibility to infection and hypogammaglobulinaemia are not usually present in isolation; Diseases of Immune Dysregulation; Early-onset multi-organ autoimmune disease; Autoimmune lymphoproliferative syndrome, type V 616100; hypogammaglobulinaemia; enteropathy; Autoimmune cytopenias, enteropathy, interstitial lung disease, extra-lymphoid lymphocytic infiltration recurrent infections; CVID |
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| COVID-19 research v0.36 | CARD14 |
Ellen McDonagh gene: CARD14 was added gene: CARD14 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: CARD14 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CARD14 were set to 23648549; 23067081; 22703878; 29689250; 29980436; 29704870; 23711932; 22521418; 30248356 Phenotypes for gene: CARD14 were set to Other autoinflammatory diseases with known genetic defect; Psoriasis 2, 602723; Autoinflammatory Disorders; Pityriasis rubra pilaris,173200; immune dysregulation; CARD14 mediated psoriasis; Psoriasis |
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| COVID-19 research v0.36 | ISCA-37433-Loss |
Ellen McDonagh Region: ISCA-37433-Loss was added Region: ISCA-37433-Loss was added to Viral susceptibility. Sources: Expert Review Green,ClinGen Mode of inheritance for Region: ISCA-37433-Loss was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for Region: ISCA-37433-Loss were set to 20301696; 15889418; 15545748 Phenotypes for Region: ISCA-37433-Loss were set to diaphragmatic hernia; facial dysmorphic features, high frequency of cardiac defects, including conotruncal defects, prematurity, growth restriction, microcephaly, and mild developmental delay; 192430; 188400; 22q11.2 deletion syndrome; renal anomalies; cleft palate, polydactyly; congenital heart disease; Learning difficulties; Velocardiofacial syndrome; polyhydramnios; DiGeorge syndrome; immune deficiency |
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| COVID-19 research v0.36 | RET |
Ellen McDonagh gene: RET was added gene: RET was added to Viral susceptibility. Sources: North West GLH,NHS GMS,GOSH PID v.8.0,London North GLH,Expert Review Red Mode of inheritance for gene: RET was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RET were set to 12086152; 9497256 Phenotypes for gene: RET were set to Central hypoventilation syndrome, congenital 209880 |
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| COVID-19 research v0.36 | NFAT5 |
Ellen McDonagh gene: NFAT5 was added gene: NFAT5 was added to Viral susceptibility. Sources: Victorian Clinical Genetics Services,GRID V2.0,IUIS Classification December 2019,Expert Review Red,IUIS Classification February 2018 Mode of inheritance for gene: NFAT5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: NFAT5 were set to 32086639; 32048120 Phenotypes for gene: NFAT5 were set to NFAT5 haploinsufficieny; IBD, recurrent sinopulmonary infections; Diseases of Immune Dysregulation |
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| COVID-19 research v0.36 | KMT2D |
Ellen McDonagh gene: KMT2D was added gene: KMT2D was added to Viral susceptibility. Sources: Expert Review Red,IUIS Classification February 2018,IUIS Classification December 2019 Mode of inheritance for gene: KMT2D was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: KMT2D were set to 25142838; 26411453; 32086639; 15887282; 15523604; 32048120 Phenotypes for gene: KMT2D were set to Kabuki syndrome 1, 147920; Combined immunodeficiencies with associated or syndromic features; Typical facial abnormalities, cleft or high arched palate, skeletal abnormalities, short stature, intellectual disability, congenital heart defects, recurrent infections (otitis media, pneumonia) in 50% of patients. Autoimmunity may be present |
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| COVID-19 research v0.36 | JAK1 |
Ellen McDonagh gene: JAK1 was added gene: JAK1 was added to Viral susceptibility. Sources: Expert Review Red,IUIS Classification February 2018,IUIS Classification December 2019 Mode of inheritance for gene: JAK1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: JAK1 were set to 28111307; 32086639; 32048120 Phenotypes for gene: JAK1 were set to Hypereosinophilic syndrome; HSM, eosinophilia, eosinophilic enteritis, thyroid disease, poor growth, viral infections; Diseases of Immune Dysregulation; Susceptibility to mycobacteria and viruses, urothelial carcinoma; Defects in Intrinsic and Innate Immunity; HSM, eosinophilic enteritis, thyroid disease, poor growth, viral infections Mode of pathogenicity for gene: JAK1 was set to Other - please provide details in the comments |
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| COVID-19 research v0.36 | ERBIN |
Ellen McDonagh gene: ERBIN was added gene: ERBIN was added to Viral susceptibility. Sources: IUIS Classification December 2019 Mode of inheritance for gene: ERBIN was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ERBIN were set to 28126831; 32086639; 32048120 Phenotypes for gene: ERBIN were set to ERBIN deficiency; Combined immunodeficiencies with associated or syndromic features; Recurrent respiratory infections, susceptibility to S. aureus, eczema, hyperextensible joints, scoliosis, arterial dilatation in some |
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| COVID-19 research v0.36 | TINF2 |
Ellen McDonagh gene: TINF2 was added gene: TINF2 was added to Viral susceptibility. Sources: ESID Registry 20171117,Victorian Clinical Genetics Services,GRID V2.0,IUIS Classification February 2018,Expert Review Amber Mode of inheritance for gene: TINF2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TINF2 were set to 18252230; 21199492; 21477109; 18979121; 27033759; 18669893; 29742735 Phenotypes for gene: TINF2 were set to microcephaly, neurodevelopmental delay exudative retinopathy; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay |
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| COVID-19 research v0.36 | TERC |
Ellen McDonagh gene: TERC was added gene: TERC was added to Viral susceptibility. Sources: ESID Registry 20171117,Victorian Clinical Genetics Services,GRID V2.0,IUIS Classification December 2019,IUIS Classification February 2018,Expert Review Amber Mode of inheritance for gene: TERC was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TERC were set to 16332973; 32086639; 12525685; 32048120; 11574891 Phenotypes for gene: TERC were set to Dyskeratosis congenita; Bone marrow failure; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; Dyskeratosis congenita 1; Intrauterine growth retardation, microcephaly, nail dystrophy, sparse scalp hair and eyelashes, hyperpigmentation of skin, palmar hyperkeratosis, premalignant oral leukoplakia, pancytopenia, myelodysplasia, +/- recurrent infections. A severe phenotype with developmental delay and cerebellar hypoplasia known as Hoyeraal-Hreidarsson Syndrome (HHS) may occur in some DKC patients; Combined immunodeficiencies with associated or syndromic features; Hoyeraal-Hreidarsson syndrome; microcephaly, neurodevelopmental delay |
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| COVID-19 research v0.36 | TBX1 |
Ellen McDonagh gene: TBX1 was added gene: TBX1 was added to Viral susceptibility. Sources: ESID Registry 20171117,Victorian Clinical Genetics Services,GRID V2.0,IUIS Classification December 2019,SCID v1.6,IUIS Classification February 2018,Expert Review Amber Mode of inheritance for gene: TBX1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: TBX1 were set to 11242110; 24198816; 14585638; 32086639; 32048120 Phenotypes for gene: TBX1 were set to Hypoparathyroidism, conotruncal cardiac malformation, velopalatal insufficiency, abnormal facies, intellectual disability; DiGeorge syndrome 188400; Di George syndrome; T-B+ SCID; Severe combined immunodeficiency (SCID); Combined immunodeficiencies with associated or syndromic features |
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| COVID-19 research v0.36 | RPSA |
Ellen McDonagh gene: RPSA was added gene: RPSA was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: RPSA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: RPSA were set to 22560297; 23579497 Phenotypes for gene: RPSA were set to Isolated congential asplenia 271400; Bacteremia (encapsulated bacteria); Defects in Intrinsic and Innate Immunity |
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| COVID-19 research v0.36 | PLCG2 |
Ellen McDonagh gene: PLCG2 was added gene: PLCG2 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,A- or hypo-gammaglobulinaemia v1.25,IUIS Classification February 2018 Mode of inheritance for gene: PLCG2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: PLCG2 were set to 29538758; 23000145; 22236196 Phenotypes for gene: PLCG2 were set to Other autoinflammatory diseases with known genetic defect; Cold urticaria hypogammaglobulinemia, autoinflammation; Familial cold autoinflammatory syndrome 3 614468; Familial cold autoinflammatory syndrome 3; Autoinflammatory Disorders; Hypogammaglobulinaemia, cold induced urticaria, autoinflammatory; Autoinflammation, antibody deficiency, and immune dysregulation syndrome 614878 Mode of pathogenicity for gene: PLCG2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments |
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| COVID-19 research v0.36 | NFKB2 |
Ellen McDonagh gene: NFKB2 was added gene: NFKB2 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,A- or hypo-gammaglobulinaemia v1.25,IUIS Classification February 2018 Mode of inheritance for gene: NFKB2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: NFKB2 were set to 25237204; 24140114; 25524009; 24888602 Phenotypes for gene: NFKB2 were set to Recurrent sinopulmonary infections, alopecia and endorinopathies; Immunodeficiency, common variable, 10 615577; Unclassified antibody deficiency; Hypogammaglobuliaemia; central adrenal insufficiency; immune dysregulation; Common variable immunodeficiency disorders (CVID); Predominantly Antibody Deficiencies |
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| COVID-19 research v0.36 | CXCR4 |
Ellen McDonagh Mode of inheritance for gene CXCR4 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Mode of pathogenicity for gene CXCR4 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Added phenotypes Myelokathexis, isolated; Warts hypogammaglobulinemia infections and myelokathexis (WHIM); WHIM syndrome, 193670; WHIM syndrome; Warts (HPV) infection, neutropenia, low B cell number, hypogammaglobulinemia; Defects in Intrinsic and Innate Immunity for gene: CXCR4 Publications for gene CXCR4 were updated from to 12692554; 15536153 |
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| COVID-19 research v0.36 | COPA |
Ellen McDonagh gene: COPA was added gene: COPA was added to Viral susceptibility. Sources: Expert Review Green,Victorian Clinical Genetics Services,North West GLH,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: COPA was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: COPA were set to 28956095; 25894502; 29137621 Phenotypes for gene: COPA were set to Autoimmune interstitial lung disease-arthritis syndrome; Autoimmune inflammatory arthritis and interstitial lung disease with Th17 dysregulation and autoantibody production; Autoinflammatory Disorders; Autoimmune inflammatoy arthritis and interstial lung disease, 616414; COPA syndrome |
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| COVID-19 research v0.36 | CASP10 |
Ellen McDonagh gene: CASP10 was added gene: CASP10 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: CASP10 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CASP10 were set to 16446975; 9028957; 10412980; 25663566; 16611303; 21447005 Phenotypes for gene: CASP10 were set to Adenopathies, splenomegaly, autoimmunity; Autoimmune lymphoproliferative syndrome, type II, 603909; Autoimmune lymphoproliferative syndrome (ALPS); Diseases of Immune Dysregulation |
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| COVID-19 research v0.36 | BACH2 |
Ellen McDonagh gene: BACH2 was added gene: BACH2 was added to Viral susceptibility. Sources: Expert Review Green,North West GLH,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: BACH2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: BACH2 were set to 27807919; 28530713; 27680876 Phenotypes for gene: BACH2 were set to Diseases of Immune Dysregulation; BACH2-related immunodeficiency and autoimmunity (BRIDA); hypogammaglobulinaemia; infantile onset enterocolitis; Lymphocytic colitis, sinopulmonary infections |
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| COVID-19 research v0.36 | TNFRSF13B |
Ellen McDonagh gene: TNFRSF13B was added gene: TNFRSF13B was added to Viral susceptibility. Sources: ESID Registry 20171117,Victorian Clinical Genetics Services,IUIS Classification December 2019,GRID V2.0,GOSH PID v.8.0,A- or hypo-gammaglobulinaemia v1.25,Expert Review Red,IUIS Classification February 2018 Mode of inheritance for gene: TNFRSF13B was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: TNFRSF13B were set to 29114388; 28834165; 16007086; 16007087; 32086639; 18981294; 32048120 Phenotypes for gene: TNFRSF13B were set to IgA with IgG subclass deficiency; Immunodeficiency, common variable, 2; Immunodeficiency, common variable, 2, 240500; Variable clinical expression; Isolated IgG subclass deficiency; IGAD; Selective IgA deficiency; Common variable immunodeficiency disorders (CVID); Predominantly Antibody Deficiencies; Immunoglobulin A deficiency 2, 609529; CVID |
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| COVID-19 research v0.36 | CFHR2 |
Ellen McDonagh gene: CFHR2 was added gene: CFHR2 was added to Viral susceptibility. Sources: Victorian Clinical Genetics Services,GRID V2.0,IUIS Classification December 2019,Expert Review Red,IUIS Classification February 2018 Mode of inheritance for gene: CFHR2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CFHR2 were set to 32086639; 32048120 Phenotypes for gene: CFHR2 were set to Complement Deficiencies; Age related macular degeneration; Atypical hemolytic uremic syndrome susceptibility; Older onset atypical hemolytic-uremic syndrome, disseminated neisserial infections |
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| COVID-19 research v0.36 | TERT |
Ellen McDonagh gene: TERT was added gene: TERT was added to Viral susceptibility. Sources: ESID Registry 20171117,Victorian Clinical Genetics Services,GRID V2.0,IUIS Classification February 2018,Expert Review Amber Mode of inheritance for gene: TERT was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: TERT were set to 16247010; 18460650; 15885610; 17785587 Phenotypes for gene: TERT were set to Bone marrow failure; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; microcephaly, neurodevelopmental delay |
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| COVID-19 research v0.36 | RAC2 |
Ellen McDonagh gene: RAC2 was added gene: RAC2 was added to Viral susceptibility. Sources: Combined B and T cell defect v1.12,ESID Registry 20171117,Victorian Clinical Genetics Services,Congenital neutropaenia v1.22,GRID V2.0,SCID v1.6,IUIS Classification February 2018,Expert Review Amber Mode of inheritance for gene: RAC2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: RAC2 were set to 21167572; 30654050; 30723080; 31071452; 25512081; 10758162; 31382036; 10961859 Phenotypes for gene: RAC2 were set to Reticular dysgenesis; poststreptococcal glomerulonephritis; Congenital defects of phagocyte number or function; Neutrophil immunodeficiency syndrome; RAS-related C3 Bolutinum toxin substrate 2 deficiency (RAC2); T-B+ SCID; Neutrophil immunodeficiency syndrome 608203; Recurrent sinopulmonary infections, selective IgA defiency; urticaria; T-B- SCID; Poor wound healing, leukocytosis |
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| COVID-19 research v0.36 | CFHR4 |
Ellen McDonagh gene: CFHR4 was added gene: CFHR4 was added to Viral susceptibility. Sources: Victorian Clinical Genetics Services,GRID V2.0,IUIS Classification December 2019,IUIS Classification February 2018,Expert Review Amber Mode of inheritance for gene: CFHR4 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CFHR4 were set to 32086639; 32048120 Phenotypes for gene: CFHR4 were set to Complement Deficiencies; Age related macular degeneration; Atypical hemolytic uremic syndrome susceptibility; Older onset atypical hemolytic-uremic syndrome, disseminated neisserial infections |
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| COVID-19 research v0.36 | CFHR3 |
Ellen McDonagh gene: CFHR3 was added gene: CFHR3 was added to Viral susceptibility. Sources: Victorian Clinical Genetics Services,GRID V2.0,IUIS Classification December 2019,IUIS Classification February 2018,Expert Review Amber Mode of inheritance for gene: CFHR3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CFHR3 were set to 32086639; 32048120 Phenotypes for gene: CFHR3 were set to Complement Deficiencies; Age related macular degeneration; Atypical hemolytic uremic syndrome susceptibility; Older onset atypical hemolytic-uremic syndrome, disseminated neisserial infections |
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| COVID-19 research v0.36 | CFHR1 |
Ellen McDonagh gene: CFHR1 was added gene: CFHR1 was added to Viral susceptibility. Sources: Victorian Clinical Genetics Services,GRID V2.0,IUIS Classification December 2019,IUIS Classification February 2018,Expert Review Amber Mode of inheritance for gene: CFHR1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CFHR1 were set to 32086639; 32048120 Phenotypes for gene: CFHR1 were set to Complement Deficiencies; Age related macular degeneration; Atypical hemolytic uremic syndrome susceptibility; Older onset atypical hemolytic-uremic syndrome, disseminated neisserial infections |
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| COVID-19 research v0.36 | CFB |
Ellen McDonagh gene: CFB was added gene: CFB was added to Viral susceptibility. Sources: ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018,Expert Review Amber Mode of inheritance for gene: CFB was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CFB were set to 4109808; 24152280 Phenotypes for gene: CFB were set to Infections with encapsulated organisms; Complement Deficiencies; complement factor B deficiency (AR); Atypical Hemolytic-uremic syndrome; Complement factor B deficiency, 615561; Susceptibility to atypical haemolytic uraemic syndrome 4 (AD) |
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| COVID-19 research v0.36 | PARN |
Ellen McDonagh gene: PARN was added gene: PARN was added to Viral susceptibility. Sources: Expert Review Green,Victorian Clinical Genetics Services,North West GLH,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: PARN was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: PARN were set to 25848748; 26342108; 25893599 Phenotypes for gene: PARN were set to Pulmonary fibrosis and/or bone marrow failure,telomere-related, 4 616371; Dyskeratosis congenita, autosomal recessive 6 616353; Intrauterine growth retardation, microcephaly, nail dystrophy, sparse scalp hair and eyelashes, hyperpigmentation of skin, palmar hyperkeratosis, premalignant oral leukoplakia, pancytopenia, myelodysplasia, +/- recurrent infections. A severe phenotype with developmental delay and cerebellar hypoplasia known as Hoyeraal-Hreidarsson Syndrome (HHS) may occur in some DKC patients; Combined immunodeficiencies with associated or syndromic features |
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| COVID-19 research v0.36 | FAS |
Ellen McDonagh gene: FAS was added gene: FAS was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: FAS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: FAS were set to 10709732; 15459302; 26258116; 8929361; 9927496; 7540117; 28668589; 9028321; 9821419 Phenotypes for gene: FAS were set to Splenomegaly, adenopathies, autoimmune cytopenias, increased lymphoma risk, IgG and A normal or increased, elevated serum FasL and IL-10, vitamin B12; Diseases of Immune Dysregulation; Autoimmune lymphoproliferative syndrome, type IA (ALPS-FAS); Autoimmune lymphoproliferative syndrome type IA, 601859; Autoimmune lymphoproliferative syndrome (ALPS) |
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| COVID-19 research v0.36 | AIRE |
Ellen McDonagh gene: AIRE was added gene: AIRE was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: AIRE was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: AIRE were set to 9888391; 19807739; 11600535; 11836330; 10677297; 29437776; 29108822; 19758376; 9398839; 9837820; 28911151 Phenotypes for gene: AIRE were set to Autoimmune polyendocrinopathy syndrome, type I, with or without reversible metaphyseal dysplasia, 240300; Multiple endocrine deficiency Addison disease candidiasis syndrome; Autoimmune hypoparathyroidism chronic candidiasis Addison disease syndrome; Diseases of Immune Dysregulation; Chronic mucocutaneous candidiasis (CMC); Autoimmunity: hypoparathyroidism hypothyroidism, adrenal insufficiency, diabetes, gonadal dysfunction and other endocrine abnormalities, chronic mucocutaneous candidiasis, dental enamel hypoplasia, alopecia areata enteropathy, pernicious anemia; Hypoparathyroidism Addison disease mucocutaneous candidiasis syndrome; Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) |
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| COVID-19 research v0.36 | WRAP53 |
Ellen McDonagh gene: WRAP53 was added gene: WRAP53 was added to Viral susceptibility. Sources: IUIS Classification February 2018,IUIS Classification December 2019 Mode of inheritance for gene: WRAP53 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WRAP53 were set to 32086639; 32048120 Phenotypes for gene: WRAP53 were set to Bone marrow failure; Bone marrow failure, pulmonary and hepatic fibrosis, nail dystrophy, leukoplakia, reticulate skin pigmentation; Combined immunodeficiencies with associated or syndromic features; Intrauterine growth retardation, microcephaly, nail dystrophy, sparse scalp hair and eyelashes, hyperpigmentation of skin, palmar hyperkeratosis, premalignant oral leukoplakia, pancytopenia, myelodysplasia, +/- recurrent infections. A severe phenotype with developmental delay and cerebellar hypoplasia known as Hoyeraal-Hreidarsson Syndrome (HHS) may occur in some DKC patients; microcephaly, neurodevelopmental delay |
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| COVID-19 research v0.36 | TRIM22 |
Ellen McDonagh gene: TRIM22 was added gene: TRIM22 was added to Viral susceptibility. Sources: IUIS Classification December 2019 Mode of inheritance for gene: TRIM22 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRIM22 were set to 26836588; 32086639; 32048120 Phenotypes for gene: TRIM22 were set to TRIM22; Granulomatous colitis; Autoinflammatory Disorders; Diseases of Immune Dysregulation |
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| COVID-19 research v0.36 | TGFB1 |
Ellen McDonagh gene: TGFB1 was added gene: TGFB1 was added to Viral susceptibility. Sources: IUIS Classification December 2019 Mode of inheritance for gene: TGFB1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TGFB1 were set to 32086639; 32048120; 29483653 Phenotypes for gene: TGFB1 were set to Inflammatory bowel disease, immunodeficiency, and encephalopathy, 618213; IBD, immunodeficiency, recurrent viral infections, microcephaly, and encephalopathy; TGFB1 deficiency; Diseases of Immune Dysregulation |
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| COVID-19 research v0.36 | IL6R |
Ellen McDonagh gene: IL6R was added gene: IL6R was added to Viral susceptibility. Sources: Expert Review Red,Literature,IUIS Classification December 2019 Mode of inheritance for gene: IL6R was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IL6R were set to 31235509; 32086639; 32048120; 31778705 Phenotypes for gene: IL6R were set to Eczema; Recurrent infections; Recurrent pyogenic infections, cold abscesses, high circulating IL-6 levels; Hyper-IgE; Combined immunodeficiencies with associated or syndromic features |
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| COVID-19 research v0.36 | FERMT1 |
Ellen McDonagh gene: FERMT1 was added gene: FERMT1 was added to Viral susceptibility. Sources: IUIS Classification December 2019 Mode of inheritance for gene: FERMT1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FERMT1 were set to 32086639; 32048120; 21936020 Phenotypes for gene: FERMT1 were set to FERMT1 deficiency (Kindler syndrome); Diseases of Immune Dysregulation; Kindler syndrome, 173650; Dermatosis characterized by congenital blistering, skin atrophy, photosensitivity, skin fragility, and scaling |
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| COVID-19 research v0.36 | FCHO1 |
Ellen McDonagh gene: FCHO1 was added gene: FCHO1 was added to Viral susceptibility. Sources: IUIS Classification December 2019 Mode of inheritance for gene: FCHO1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FCHO1 were set to 32086639; 30822429; 32048120 Phenotypes for gene: FCHO1 were set to Recurrent infections, lymphoproliferation, increased activation-induced T-cell death, defective clathrin-mediated endocytosis; FCHO1 deficiency; Immunodeficiencies affecting cellular and humoral immunity |
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| COVID-19 research v0.36 | FAAP24 |
Ellen McDonagh gene: FAAP24 was added gene: FAAP24 was added to Viral susceptibility. Sources: Expert Review Red,IUIS Classification February 2018,IUIS Classification December 2019 Mode of inheritance for gene: FAAP24 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FAAP24 were set to 32086639; 27473539; 32048120 Phenotypes for gene: FAAP24 were set to EBV infection-driven lymphoproliferative disease; Diseases of Immune Dysregulation |
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| COVID-19 research v0.36 | DEF6 |
Ellen McDonagh gene: DEF6 was added gene: DEF6 was added to Viral susceptibility. Sources: IUIS Classification December 2019 Mode of inheritance for gene: DEF6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DEF6 were set to 32086639; 31308374; 32048120 Phenotypes for gene: DEF6 were set to DEF6 deficiency; Diseases of Immune Dysregulation; Enteropathy, hepatosplenomegaly, cardiomyopathy, recurrent infections |
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| COVID-19 research v0.36 | BLOC1S6 |
Ellen McDonagh gene: BLOC1S6 was added gene: BLOC1S6 was added to Viral susceptibility. Sources: Victorian Clinical Genetics Services, London North GLH,GRID V2.0,NHS GMS,GRID V2.0North West GLH,Expert Review Red Mode of inheritance for gene: BLOC1S6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BLOC1S6 were set to 224,614,752,030,146,000,000,000 Phenotypes for gene: BLOC1S6 were set to Immune Dysregulation; Hermansky-pudlak syndrome 9, 614171; HPS9, palladin deficiency (NK cell defect) |
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| COVID-19 research v0.36 | AP3D1 |
Ellen McDonagh gene: AP3D1 was added gene: AP3D1 was added to Viral susceptibility. Sources: Expert Review Red,Literature,IUIS Classification February 2018,IUIS Classification December 2019 Mode of inheritance for gene: AP3D1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AP3D1 were set to 26744459; 32086639; 32048120 Phenotypes for gene: AP3D1 were set to neutropenia; Immunodeficient HPS; seizures; Diseases of Immune Dysregulation; Hermansky-Pudlak syndrome with neutropenia; neuordevelopmental delay; albinism; ?Hermansky-Pudlak syndrome 10, 617050; Hermansky-Pudlak syndrome; Oculocutaneous albinism, recurrent infections, seizures, hearing loss and neurodevelopmental delay; Oculocutaneous albinism, severe neutropenia, recurrent infections, seizures, hearing loss and neurodevelopmental delay; HSP10 |
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| COVID-19 research v0.36 | TNFRSF13C |
Ellen McDonagh gene: TNFRSF13C was added gene: TNFRSF13C was added to Viral susceptibility. Sources: ESID Registry 20171117,Victorian Clinical Genetics Services,GRID V2.0,IUIS Classification December 2019,IUIS Classification February 2018,Expert Review Amber Mode of inheritance for gene: TNFRSF13C was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TNFRSF13C were set to 32086639; 32048120 Phenotypes for gene: TNFRSF13C were set to Immunodeficiency, common variable, 4; Variable clinical expression; Isolated IgG subclass deficiency; Common variable immunodeficiency disorders (CVID); Predominantly Antibody Deficiencies |
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| COVID-19 research v0.36 | DNASE1L3 |
Ellen McDonagh gene: DNASE1L3 was added gene: DNASE1L3 was added to Viral susceptibility. Sources: North West GLH,NHS GMS,London North GLH,IUIS Classification December 2019,IUIS Classification February 2018,Expert Review Amber Mode of inheritance for gene: DNASE1L3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: DNASE1L3 were set to 27821515; 23666765; 22019780; 32086639; 32048120 Phenotypes for gene: DNASE1L3 were set to Systemic lupus erythematosus 16, 614420; Autoinflammatory Disorders; Diseases of Immune Dysregulation; familial early-onset SLE; Systemic lupus erythematosus, lupus nephritis, hypocomplementemic urticarial vasculitis |
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| COVID-19 research v0.36 | CR2 |
Ellen McDonagh gene: CR2 was added gene: CR2 was added to Viral susceptibility. Sources: ESID Registry 20171117,Victorian Clinical Genetics Services,GRID V2.0,A- or hypo-gammaglobulinaemia v1.25,IUIS Classification February 2018,Expert Review Amber Mode of inheritance for gene: CR2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CR2 were set to 22035880; 26325596 Phenotypes for gene: CR2 were set to Recurrent infections; Lupus; Isolated IgG subclass deficiency; Immunodeficiency, common variable, 7; Common variable immunodeficiency disorders (CVID); hypogammaglobulinaemia; Predominantly Antibody Deficiencies; Immunodeficiency, common variable, 7, 614699 |
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| COVID-19 research v0.36 | CD81 |
Ellen McDonagh gene: CD81 was added gene: CD81 was added to Viral susceptibility. Sources: ESID Registry 20171117,Victorian Clinical Genetics Services,GRID V2.0,IUIS Classification December 2019,IUIS Classification February 2018,Expert Review Amber Mode of inheritance for gene: CD81 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CD81 were set to 27250108; 32086639; 14530327; 32048120; 20237408 Phenotypes for gene: CD81 were set to CD81 deficiency; Isolated IgG subclass deficiency; Recurrent infections, may have glomerulonephritis; Common variable immunodeficiency disorders (CVID); hypogammaglobulinaemia; Predominantly Antibody Deficiencies; Immunodeficiency, common variable 6, 613496 |
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| COVID-19 research v0.36 | ZAP70 |
Ellen McDonagh gene: ZAP70 was added gene: ZAP70 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,SCID v1.6,IUIS Classification February 2018 Mode of inheritance for gene: ZAP70 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ZAP70 were set to Selective T-cell defect; Combined immunodeficiency; Autoimmune disease, multisystem, infantile-onset, 2; Immunodeficiency 48; Severe Combined Immune Deficiency; Diseases of Immune Dysregulation; Immunodeficiencies affecting cellular and humoral immunity; Severe autoimmunity; Zap-70 deficiency; May have immune dysregulation, autoimmunity; Severe combined immunodeficiency (SCID) |
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| COVID-19 research v0.36 | WIPF1 |
Ellen McDonagh gene: WIPF1 was added gene: WIPF1 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: WIPF1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: WIPF1 were set to 11869681; 22231303; 9405671; 14757742; 27742395 Phenotypes for gene: WIPF1 were set to WIP deficiency; ?Wiskott-Aldrich syndrome 2 614493; Wiskott-Aldrich syndrome like, WIP deficiency; Combined immunodeficiencies with associated or syndromic features; Thrombocytopenia with or without small platelets, recurrent bacterial and viral infections, eczema, bloody diarrhea, WAS protein absent |
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| COVID-19 research v0.36 | UNC13D |
Ellen McDonagh gene: UNC13D was added gene: UNC13D was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: UNC13D was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: UNC13D were set to 15632205; 14622600; 16278825; 15703195; 17993578 Phenotypes for gene: UNC13D were set to Hemophagocytic lymphohistiocytosis, familial 3, 608898; Diseases of Immune Dysregulation; Familial hemophagocytic lymphohistiocytosis syndromes (FHLH); HPLH3; HLH3; FHL3; Fever, HSM, HLH, cytopenias, |
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| COVID-19 research v0.36 | TRAC |
Ellen McDonagh gene: TRAC was added gene: TRAC was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: TRAC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRAC were set to 3464003; 21206088 Phenotypes for gene: TRAC were set to Immunodeficiencies affecting cellular and humoral immunity; Recurrent viral, bacterial, fungal infections, immune dysregulation and autoimmunity, diarrhea; Immunodeficiency 7, TCR-alpha/beta deficient, 615387; Combined immunodeficiency |
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| COVID-19 research v0.36 | TPP2 |
Ellen McDonagh gene: TPP2 was added gene: TPP2 was added to Viral susceptibility. Sources: Expert Review Green,Victorian Clinical Genetics Services,North West GLH,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: TPP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TPP2 were set to 25525876; 25414442 Phenotypes for gene: TPP2 were set to immune thrombocytopenia and autoimmune hemolytic anemia; Autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome; TPP2 deficiency; Tripeptidyl-Peptidase II Deficiency; Diseases of Immune Dysregulation; Evans syndrome; Variable lymphoproliferation, severe autoimmune cytopenias, hypergammaglobulinemia, recurrent infections |
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| COVID-19 research v0.36 | TCN2 |
Ellen McDonagh gene: TCN2 was added gene: TCN2 was added to Viral susceptibility. Sources: Expert Review Green,Agranulocytosis v1.3,Combined B and T cell defect v1.12,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,Congenital neutropaenia v1.22,GRID V2.0,NHS GMS,London North GLH,A- or hypo-gammaglobulinaemia v1.25,SCID v1.6,IUIS Classification February 2018 Mode of inheritance for gene: TCN2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TCN2 were set to 20352340; 24305960; 7849710; 7980584; 18956254 Phenotypes for gene: TCN2 were set to Transcobalamin-2 precursor; Transcobalamin II deficiency; Agammaglobulinemia; Megaloblastic anemia, pancytopenia, if untreated for prolonged periods results in intellectual disability; pancytopenia; Transcobalamin II deficiency, 275350; neutropenic colitis; Defects of Vitamin B12 and Folate metabolism; megaloblastic bone; can have a presentation similar to severe combined immunodeficiency; Combined immunodeficiencies with associated or syndromic features |
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| COVID-19 research v0.36 | STXBP2 |
Ellen McDonagh gene: STXBP2 was added gene: STXBP2 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: STXBP2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: STXBP2 were set to 19804848; 19884660; 20301617; 20798128 Phenotypes for gene: STXBP2 were set to Hemophagocytic lymphohistiocytosis, familial 5, 613101; Diseases of Immune Dysregulation; Fever, HSM, cHLH, cytopenias, enteropathy; FHL5; Familial hemophagocytic lymphohistiocytosis syndromes (FHLH) |
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| COVID-19 research v0.36 | STX11 |
Ellen McDonagh gene: STX11 was added gene: STX11 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: STX11 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: STX11 were set to 20301617; 24459464; 16582076; 16278825; 15703195 Phenotypes for gene: STX11 were set to HLH4; Hemophagocytic lymphohistiocytosis, familial 4, 603552; Diseases of Immune Dysregulation; Familial hemophagocytic lymphohistiocytosis syndromes (FHLH); FHL4; HPLH4; Fever, HSM, cHLH, cytopenias, |
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| COVID-19 research v0.36 | SLC46A1 |
Ellen McDonagh gene: SLC46A1 was added gene: SLC46A1 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: SLC46A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC46A1 were set to 17446347; 17129779; 27664775 Phenotypes for gene: SLC46A1 were set to Folate malabsorption, hereditary 229050; Congenital defect of folate absorption; Megaloblastic anemia, failure to thrive, if untreated for prolonged periods results in intellectual disability; Defects of Vitamin B12 and Folate metabolism; Combined immunodeficiencies with associated or syndromic features |
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| COVID-19 research v0.36 | SLC35C1 |
Ellen McDonagh gene: SLC35C1 was added gene: SLC35C1 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: SLC35C1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC35C1 were set to 11326279; 24403049; 11213799; 12116250; 11326280; 1279426 Phenotypes for gene: SLC35C1 were set to Mild LAD type 1 features with hh-blood group, growth retardation, developmental delay; Congenital defects of phagocyte number or function; Leukocyte adhesion deficiency (LAD); Congenital disorder of glycosylation, type IIc 266265 |
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| COVID-19 research v0.36 | RASGRP1 |
Ellen McDonagh gene: RASGRP1 was added gene: RASGRP1 was added to Viral susceptibility. Sources: Expert Review Green,North West GLH,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: RASGRP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RASGRP1 were set to 27776107; 28822832; 30030704; 29282224; 29155103 Phenotypes for gene: RASGRP1 were set to Recurrent pneumonia, herpesvirus infections, EBV associated lymphoma; Immunodeficiency 64, 618534; Diseases of Immune Dysregulation; Immunodeficiency; EBV-induced lymphoma; immunde dysregulation |
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| COVID-19 research v0.36 | RAB27A |
Ellen McDonagh gene: RAB27A was added gene: RAB27A was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: RAB27A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: RAB27A were set to 12058346; 12531900; 12522785; 15163896 Phenotypes for gene: RAB27A were set to Diseases of Immune Dysregulation; Partial albinism, fever, HSM, HLH, cytopenias; Griscelli syndrome, type 2 607624 |
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| COVID-19 research v0.36 | PRKCD |
Ellen McDonagh gene: PRKCD was added gene: PRKCD was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: PRKCD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRKCD were set to 23430113; 23319571; 23666743 Phenotypes for gene: PRKCD were set to Recurrent infections, EBV chronic infection, lymphoproliferation, SLE-like autoimmunity (nephrotic and antiphospholipid syndromes), low IgG; Autoimmune lymphoproliferative syndrome, type III 615559; Diseases of Immune Dysregulation; Unclassified antibody deficiency; Immunodeficiency, common variable, 9; Autoimmune lymphoproliferative syndrome (ALPS) |
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| COVID-19 research v0.36 | PRF1 |
Ellen McDonagh gene: PRF1 was added gene: PRF1 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: PRF1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PRF1 were set to 15365097; 11179007; 15632205; 20301617; 10583959; 14757862; 12229880; 16860143 Phenotypes for gene: PRF1 were set to Fever, HSM, Hemophagocytic lymphohistiocytosis (HLH), cytopenias; FHL2; HPLH2; Familial hemophagocytic lymphohistiocytosis syndromes (FHLH); Diseases of Immune Dysregulation; Hemophagocytic lymphohistiocytosis, familial 2, 603553; HLH2 |
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| COVID-19 research v0.36 | PEPD |
Ellen McDonagh gene: PEPD was added gene: PEPD was added to Viral susceptibility. Sources: Expert Review Green,North West GLH,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: PEPD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PEPD were set to 6637477; 19308961; 15309682; 17142620; 8900231; 1972707; 2365824; 16470701 Phenotypes for gene: PEPD were set to Prolidase deficiency, 170100; Autoantibodies common, chronic skin ulcers, eczema, infections; Diseases of Immune Dysregulation |
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| COVID-19 research v0.36 | MTHFD1 |
Ellen McDonagh gene: MTHFD1 was added gene: MTHFD1 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: MTHFD1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MTHFD1 were set to 25633902; 27707659 Phenotypes for gene: MTHFD1 were set to Recurrent bacterial infection, Pneumocystis jirovecii, megaloblastic anemia, failure to thrive, neutropenia, seizures, intellectual disability, folate-responsive; Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia 617780; Combined immunodeficiencies with associated or syndromic features; Defects of Vitamin B12 and Folate metabolism |
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| COVID-19 research v0.36 | MOGS |
Ellen McDonagh gene: MOGS was added gene: MOGS was added to Viral susceptibility. Sources: Expert Review Green,Victorian Clinical Genetics Services,North West GLH,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: MOGS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MOGS were set to 24716661; 29235540; 10788335 Phenotypes for gene: MOGS were set to Bacterial and viral infections, severe neurologic disease, also known as congenital disorder of glycosylation type IIb (CDG-IIb); Congenital disorder of glycosylation, type IIb 606056; Predominantly Antibody Deficiencies |
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| COVID-19 research v0.36 | LYST |
Ellen McDonagh gene: LYST was added gene: LYST was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: LYST was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LYST were set to 9215679; 9215680; 10482950; 8896560 Phenotypes for gene: LYST were set to Chediak-Higashi syndrome 214500; Chediak Higashi syndrome; Partial albinism, recurrent infections, fever, HSM, HLH, giant lysosomes, neutropenia, cytopenias, bleeding tendency, progressive neurological dysfunction; Diseases of Immune Dysregulation |
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| COVID-19 research v0.36 | LRBA |
Ellen McDonagh gene: LRBA was added gene: LRBA was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: LRBA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LRBA were set to 25468195; 22608502; 22721650 Phenotypes for gene: LRBA were set to Unclassified antibody deficiency; Recurrent infections, inflammatory bowel disease, autoimmunity, EBV infections; Diseases of Immune Dysregulation; Immunodeficiency, common variable, 8, with autoimmunity, 614700 |
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| COVID-19 research v0.36 | LCK |
Ellen McDonagh gene: LCK was added gene: LCK was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: LCK was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LCK were set to 11351273; 9664084; 22985903 Phenotypes for gene: LCK were set to Severe combined immunodeficiency due to LCK deficiency; Recurrent infections, immune dysregulation, autoimmunity; Combined immunodeficiency; Immunodeficiency 22, 615758; Immunodeficiencies affecting cellular and humoral immunity; LCK deficiency |
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| COVID-19 research v0.36 | LAT |
Ellen McDonagh gene: LAT was added gene: LAT was added to Viral susceptibility. Sources: Expert Review Green,Combined B and T cell defect v1.12,North West GLH,NHS GMS,London North GLH,A- or hypo-gammaglobulinaemia v1.25,SCID v1.6,IUIS Classification February 2018 Mode of inheritance for gene: LAT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: LAT were set to 27522155; 27242165 Phenotypes for gene: LAT were set to Immunodeficiencies affecting cellular and humoral immunity; Immunodeficiency 52, 617514; Adenopathy, splenomegaly, recurrent infections, autoimmunity |
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| COVID-19 research v0.36 | ITK |
Ellen McDonagh gene: ITK was added gene: ITK was added to Viral susceptibility. Sources: Expert Review Green,Combined B and T cell defect v1.12,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: ITK was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ITK were set to 21109689; 19425169; 22289921 Phenotypes for gene: ITK were set to EBV associated B cell lymphoproliferation, lymphoma, Nl or low IgG; Combined immunodeficiency; Diseases of Immune Dysregulation; ITK deficiency (HLH phenotype); EBV viraemia, HLH; Lymphoproliferative syndrome 1 |
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| COVID-19 research v0.36 | ITCH |
Ellen McDonagh gene: ITCH was added gene: ITCH was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: ITCH was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ITCH were set to 26854353; 27322655; 20962770; 19592251; 20170897 Phenotypes for gene: ITCH were set to Early-onset chronic lung disease (interstitial pneumonitis), autoimmunity (thyroiditis, type I diabetes, chronic diarrhea/enteropathy, and hepatitis), failure to thrive, developmental delay, dysmorphic facial features; Diseases of Immune Dysregulation; Autoimmune disease, multisystem, with facial dysmorphism, 613385; Syndromic multisystem autoimmune disease due to Itch deficiency; Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) |
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| COVID-19 research v0.36 | IRAK4 |
Ellen McDonagh gene: IRAK4 was added gene: IRAK4 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: IRAK4 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IRAK4 were set to 17878374; 17114497; 12637671; 16950813 Phenotypes for gene: IRAK4 were set to Defects with susceptibility to mycobacterial infection (MSMD); Defects of TLR/NFkappa-B signalling; Invasive pneumococcal disease, recurrent isolated, 1, 6107; IRAK4 deficiency, 610799; Defects in Intrinsic and Innate Immunity; Bacterial infections (pyogens) |
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| COVID-19 research v0.36 | IL2RA |
Ellen McDonagh gene: IL2RA was added gene: IL2RA was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: IL2RA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IL2RA were set to 23416241; 9096364; 17196245; 24116927 Phenotypes for gene: IL2RA were set to Combined immunodeficiency; Immunodeficiency 41 with lymphoproliferation and autoimmunity, 606367; Interleukin 2 receptor alpha deficiency (CD25) (IPEX phenotype); Diseases of Immune Dysregulation; Interleukin-2 receptor, alpha chain, deficiency of; Omenn syndrome; Lymphoproliferation, autoimmunity, impaired T cell proliferation |
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| COVID-19 research v0.36 | IL21R |
Ellen McDonagh gene: IL21R was added gene: IL21R was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: IL21R was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IL21R were set to 23440042; 12700598 Phenotypes for gene: IL21R were set to Combined immunodeficiency; Atypical Severe Combined Immunodeficiency (Atypical SCID); Immunodeficiency 56, 615207; Immunodeficiencies affecting cellular and humoral immunity; Omenn syndrome; Immunodeficiency, primary, autosomal recessive, IL21R-related; IL-21R deficiency; Severe combined immunodeficiency (SCID); Recurrent infections, Pneumocystis jiroveci, Cryptosporidium infections and liver disease |
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| COVID-19 research v0.36 | IL10RB |
Ellen McDonagh gene: IL10RB was added gene: IL10RB was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: IL10RB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IL10RB were set to 21519361; 19890111; 27350736; 27302973; 28785144 Phenotypes for gene: IL10RB were set to Inflammatory bowel disease 25, early onset, autosomal recessive,612567; Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections syndrome; Diseases of Immune Dysregulation; IBD, folliculitis, recurrent respiratory diseases, arthritis, lymphoma |
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| COVID-19 research v0.36 | IL10RA |
Ellen McDonagh gene: IL10RA was added gene: IL10RA was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: IL10RA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IL10RA were set to 22476154; 21519361; 29059189; 28864178; 19890111; 29788474; 29248579; 29140941 Phenotypes for gene: IL10RA were set to IBD, Folliculitis, recurrent respiratory diseases, arthritis, lymphoma; Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections syndrome; Diseases of Immune Dysregulation; Inflammatory bowel disease 28, early onset, autosomal recessive, 613148 |
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| COVID-19 research v0.36 | IL10 |
Ellen McDonagh gene: IL10 was added gene: IL10 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: IL10 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IL10 were set to 19890111; 20951137 Phenotypes for gene: IL10 were set to Early-onset inflammatory bowel disease; Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections syndrome; Inflammatory bowel disease (IBD) Folliculitis, recurrent respiratory diseases, arthritis,; Diseases of Immune Dysregulation |
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| COVID-19 research v0.36 | ICOS |
Ellen McDonagh gene: ICOS was added gene: ICOS was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,A- or hypo-gammaglobulinaemia v1.25,IUIS Classification February 2018 Mode of inheritance for gene: ICOS was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ICOS were set to 15507387; 12577056; 29867948; 29226302; 24795713; 26399252; 25678089; 19380800; 28861081; 10413651; 29226301 Phenotypes for gene: ICOS were set to combined immunodeficiency; Isolated IgG subclass deficiency; gammaglobulinaemia; Immunodeficiency, common variable, 1, 607594; Immunodeficiencies affecting cellular and humoral immunity; Common variable immunodeficiency disorders (CVID); hypogammaglobulinaemia; Immunodeficiency, common variable, 1; Recurrent infections, autoimmunity, gastroenteritis, granulomas |
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| COVID-19 research v0.36 | FASLG |
Ellen McDonagh gene: FASLG was added gene: FASLG was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: FASLG was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FASLG were set to 17605793; 8787672; 20301287; 27848183 Phenotypes for gene: FASLG were set to Autoimmune lymphoproliferative syndrome, type IB, 601859; Diseases of Immune Dysregulation; Autoimmune lymphoproliferative syndrome, type IB (ALPS-FASG); Splenomegaly, adenopathies, autoimmune cytopenias, SLE, soluble FasL is not elevated; Autoimmune lymphoproliferative syndrome (ALPS) |
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| COVID-19 research v0.36 | FADD |
Ellen McDonagh gene: FADD was added gene: FADD was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: FADD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: FADD were set to 21109225; 17656375; 25794656 Phenotypes for gene: FADD were set to para-infectious encephalopathy and hepatopathy; Functional hyposplenism, bacterial and viral infections, recurrent episodes of encephalopathy and liver dysfunction; Diseases of Immune Dysregulation; invasive pneumococcal disease; cardiovascular malformations; Infections, recurrent, with encephalopathy, hepatic dysfunction, and cardiovasuclar malformations, 613759; functional hyposplenism; ALPS-like disease |
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| COVID-19 research v0.36 | EXTL3 |
Ellen McDonagh gene: EXTL3 was added gene: EXTL3 was added to Viral susceptibility. Sources: Expert Review Green,North West GLH,NHS GMS,London North GLH,A- or hypo-gammaglobulinaemia v1.25,IUIS Classification February 2018 Mode of inheritance for gene: EXTL3 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EXTL3 were set to 28132690; 28148688 Phenotypes for gene: EXTL3 were set to Combined immunodeficiencies with associated or syndromic features; EXTL3 deficiency; Platyspondyly, kyphosis, variable skeletal dysplasias, developmental delay; Immunoskeletal dysplasia with neurodevelopmental abnormalities, 617425 |
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| COVID-19 research v0.36 | EPG5 |
Ellen McDonagh gene: EPG5 was added gene: EPG5 was added to Viral susceptibility. Sources: Expert Review Green,Combined B and T cell defect v1.12,Victorian Clinical Genetics Services,North West GLH,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: EPG5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: EPG5 were set to 23222957; 23838600; 25331754; 26395118; 23674064; 26917586; 28624465 Phenotypes for gene: EPG5 were set to Vici syndrome; Vici syndrome due to EPG5 deficiency; Vici syndrome, 242840; Agenesis of the corpus callosum, cataracts, cardiomyopathy, skin hypopigmentation, intellectual disability, microcephaly, recurrent infections, chronic mucocutaneous candidiasis; Immunodeficiency with cleft lip/palate, cataract, hypopigmentation, and absent corpus callosum; syndromic phenotype (immunodeficiency variable); Combined immunodeficiencies with associated or syndromic features |
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| COVID-19 research v0.36 | CTPS1 |
Ellen McDonagh gene: CTPS1 was added gene: CTPS1 was added to Viral susceptibility. Sources: Expert Review Green,Victorian Clinical Genetics Services,North West GLH,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: CTPS1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CTPS1 were set to 9536098; 24870241; 27638562; 26424649; 17576681 Phenotypes for gene: CTPS1 were set to Recurrent/chronic bacterial and viral infections (EBV, VZV), EBV lymphoproliferation, B-cell non-Hodgkin lymphoma; Severe combined immunodeficiency due to CTPS1 deficiency; Immunodeficiency 24, 615897; Patients develop Epstein-Barr Virus (EBV) driven Hemophagocytic Lymphohistiocytosis (HLH ); Diseases of Immune Dysregulation |
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| COVID-19 research v0.36 | CFI |
Ellen McDonagh gene: CFI was added gene: CFI was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,Inherited complement deficiency v0.11,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: CFI was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CFI were set to 18374984; 24142231; 22710145; 19065647; 8613545; 12562389; 27091480; 3897024; 21316765; 25988862 Phenotypes for gene: CFI were set to {Macular degeneration, age-related, 13, susceptibility to}, 615439; Complement factor I deficiency; Factor I deficiency; {Hemolytic uremic syndrome, atypical, susceptibility to, 3}, 612923; Infections, disseminated neisserial infections, atypical Hemolytic-uremic syndrome, preeclampsia; Complement Deficiencies; Immunodeficiency with factor I anomaly; C3b inactivator deficiency; Complement factor I deficiency, 610984 |
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| COVID-19 research v0.36 | CD70 |
Ellen McDonagh gene: CD70 was added gene: CD70 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: CD70 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CD70 were set to 28011864; 28011863; 29434583 Phenotypes for gene: CD70 were set to Combined immunodeficiency; CD70-deficiency; Diseases of Immune Dysregulation; EBV-related malignancy; EBV susceptibility, Hodgkin lymphoma |
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| COVID-19 research v0.36 | CD27 |
Ellen McDonagh gene: CD27 was added gene: CD27 was added to Viral susceptibility. Sources: Expert Review Green,Combined B and T cell defect v1.12,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: CD27 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CD27 were set to 22197273; 25843314; 22801960 Phenotypes for gene: CD27 were set to Lymphoproliferative syndrome 2; Combined immunodeficiency; Diseases of Immune Dysregulation; Features triggered by EBV infection, HLH, aplastic anemia, low iNKT cells, lymphoma; Combined immunodeficiency with EBV-associated lymphoproliferation; CD27 deficiency |
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| COVID-19 research v0.36 | CD19 |
Ellen McDonagh gene: CD19 was added gene: CD19 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,A- or hypo-gammaglobulinaemia v1.25,IUIS Classification February 2018 Mode of inheritance for gene: CD19 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CD19 were set to 16672701; 21159371; 21330302 Phenotypes for gene: CD19 were set to Immunodeficiency, common variable, 3; Isolated IgG subclass deficiency; Recurrent infections, may have glomerulonephritis; Immunodeficiency, common variable, 3 613493; Common variable immunodeficiency disorders (CVID); Predominantly Antibody Deficiencies; hypogammaglobulinemia |
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| COVID-19 research v0.36 | CASP8 |
Ellen McDonagh gene: CASP8 was added gene: CASP8 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: CASP8 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CASP8 were set to 24240292; 16157684; 12353035; 20301287 Phenotypes for gene: CASP8 were set to Caspase-8 deficiency state; Immunodeficiency due to CASP8 deficiency; CEDS; ?Autoimmune lymphoproliferative syndrome, type IIB, 607271; Diseases of Immune Dysregulation; Caspase 8 deficiency; Autoimmune lymphoproliferative syndrome (ALPS); Adenopathies, splenomegaly, bacterial and viral infections, hypogammaglobulinemia |
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| COVID-19 research v0.36 | CARMIL2 |
Ellen McDonagh gene: CARMIL2 was added gene: CARMIL2 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: CARMIL2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CARMIL2 were set to 27647349; 27896283; 28112205 Phenotypes for gene: CARMIL2 were set to warts, molluscum contagiosum, and T cell dysfunction; Combined immunodeficiency; Recurrent bacterial, fungal and mycobacterial infections, viral warts, molluscum and EBV lymphoproliferative and other malignancy, atopy; Diseases of Immune Dysregulation; EBV+ disseminated smooth muscle tumours |
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| COVID-19 research v0.36 | C4B |
Ellen McDonagh gene: C4B was added gene: C4B was added to Viral susceptibility. Sources: Expert Review Green,Victorian Clinical Genetics Services,North West GLH,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C4B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C4B were set to 12626442; 2355198; 19062096; 1569346; 2788199 Phenotypes for gene: C4B were set to C4B deficiency, 614379; SLE, infections with encapsulated organisms , partial deficiency is common (either C4A or C4B) and appears to have a modest effect on host defense; Complement Deficiencies; SLE predisposition |
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| COVID-19 research v0.36 | C4A |
Ellen McDonagh gene: C4A was added gene: C4A was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C4A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C4A were set to 15294999; 2295875; 22482068 Phenotypes for gene: C4A were set to C4a deficiency, 614380; Complement Deficiencies; SLE, infections with encapsulated organisms , partial deficiency is common (either C4A or C4B) and appears to have a modest effect on host defense; Complement component 4 deficiency; SLE predisposition; Immunodeficiency due to a classical component pathway complement deficiency; infections with encapsulated organisms |
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| COVID-19 research v0.36 | C2 |
Ellen McDonagh gene: C2 was added gene: C2 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,Inherited complement deficiency v0.11,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C2 were set to 1577763; 15643297; 11079100; 8621452; 7901282 Phenotypes for gene: C2 were set to Complement Component C2 Deficiency; Lupus; Complement Deficiencies; SLE, infections with encapsulated organisms, atherosclerosis; C2 deficiency, 217000; Immunodeficiency due to C1, C4, or C2 component complement deficiency |
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| COVID-19 research v0.36 | C1S |
Ellen McDonagh gene: C1S was added gene: C1S was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C1S was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C1S were set to 27745832; 11390518; 20727163; 9856483 Phenotypes for gene: C1S were set to SLE; pyogenic infections; Complement component 1 deficiency; SLE, infections with encapsulated organisms, Ehlers Danlos phenotype; Complement Deficiencies; C1s deficiency, 613783; C1s deficiency, Lupus |
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| COVID-19 research v0.36 | C1R |
Ellen McDonagh gene: C1R was added gene: C1R was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C1R was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C1R were set to 28544690; 21784777; 27745832; 29795138; 28711143 Phenotypes for gene: C1R were set to SLE; pyogenic infections; Complement component 1 deficiency; SLE, infections with encapsulated organisms, Ehlers Danlos phenotype; Complement Deficiencies; C1r/C1s deficiency, combined, Lupus; Immunodeficiency due to a classical component pathway complement deficiency |
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| COVID-19 research v0.36 | C1QC |
Ellen McDonagh gene: C1QC was added gene: C1QC was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C1QC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C1QC were set to 24157463; 8630118; 7900940; 21654842 Phenotypes for gene: C1QC were set to SLE, infections with encapsulated organisms; Complement component 1 deficiency; C1q deficiency, 613652; Complement Deficiencies; Immunodeficiency due to a classical component pathway complement deficiency |
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| COVID-19 research v0.36 | C1QB |
Ellen McDonagh gene: C1QB was added gene: C1QB was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,Inherited complement deficiency v0.11,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C1QB was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C1QB were set to 9476130; 2894352; 24160257; 12133956; 25454803; 23651859; 17513176 Phenotypes for gene: C1QB were set to SLE, infections with encapsulated organisms; SLE; lupus-like disease; Complement component 1 deficiency; Immunodeficiency due to an early component of complement deficiency, 613652; C1q deficiency; susceptibility to invasive bacterial infection; Complement Deficiencies |
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| COVID-19 research v0.36 | C1QA |
Ellen McDonagh gene: C1QA was added gene: C1QA was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: C1QA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: C1QA were set to 7594474; 28601358; 25133636; 8840296; 26032012; 21654842 Phenotypes for gene: C1QA were set to SLE, infections with encapsulated organisms; Complement component 1 deficiency; C1q deficiency, 613652; Complement Deficiencies; Immunodeficiency due to a classical component pathway complement deficiency |
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| COVID-19 research v0.36 | ARPC1B |
Ellen McDonagh gene: ARPC1B was added gene: ARPC1B was added to Viral susceptibility. Sources: Expert Review Green,North West GLH,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: ARPC1B was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ARPC1B were set to 29127144; 28368018; 27965109 Phenotypes for gene: ARPC1B were set to inflammatory predisposition; Platelet abnormalities with eosinophilia and immune-mediated inflammatory disease, 617718; Mild thrombocytopenia with normal sized platelets, recurrent invasive infections, colitis, vasculitis, autoantibodies (ANA, ANCA), eosinophilia, defective Arp2/3, filament branching; Immunodeficiency with thrombocytopenia; Combined immunodeficiencies with associated or syndromic features; Thrombocytopenia & Immune Deficiency |
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| COVID-19 research v0.36 | AP3B1 |
Ellen McDonagh gene: AP3B1 was added gene: AP3B1 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: AP3B1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: AP3B1 were set to 28585318; 16537806; 11809908; 16507770; 19679886; 14566336; 8042664; 23403622; 10024875 Phenotypes for gene: AP3B1 were set to Partial albinism, recurrent infections, pulmonary fibrosis, increased bleeding, neutropenia, HLH; Immunodeficient HPS; Hermansky-Pudlak syndrome 2; Diseases of Immune Dysregulation; Hermansky-Pudlak syndrome with neutropenia; Hermansky-Pudlak syndrome, 608233; HPS2 |
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| COVID-19 research v0.36 | ADAR |
Ellen McDonagh gene: ADAR was added gene: ADAR was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: ADAR was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADAR were set to 25604658; 24183309; 23001123; 24262145; 27643693; 25769924 Phenotypes for gene: ADAR were set to Fever Syndromes and Related Diseases, Aicardi-Goutieres syndrome 6, 615010; Type 1 interferonopathies; Autoinflammatory Disorders; AGS6; Classical AGS, BSN, SP |
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| COVID-19 research v0.36 | ACP5 |
Ellen McDonagh gene: ACP5 was added gene: ACP5 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: ACP5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ACP5 were set to 21217752; 26789720; 21217755; 26951490; 18924170; 26346816 Phenotypes for gene: ACP5 were set to Spondyloenchondrodysplasia with immune dysregulation Type 1 interferonopathies; Short stature, SP, ICC, SLE, thrombocytopenia and autoimmune hemolytic anemia, possibly recurrent bacterial and viral infections; Spondyloenchondrodysplasia with immune dysregulation, 607944; Type 1 interferonopathies; Autoinflammatory Disorders |
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| COVID-19 research v0.34 | TMEM173 |
Ellen McDonagh commented on gene: TMEM173: 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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| COVID-19 research v0.20 | ACE |
Ellen McDonagh gene: ACE was added gene: ACE was added to Viral susceptibility. Sources: Literature Mode of inheritance for gene: ACE was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: ACE were set to 15819995 Phenotypes for gene: ACE were set to Not associated with susceptibility to SARS-coronavirus infection and disease outcomes Added comment: PMID: A case-control study found no association with the I/D polymorphism in this gene and increased susceptibility to SARS-coronavirus infection nor with poor outcomes after SARS-coronavirus infection (140 genetically unrelated Chinese SARS cases and 326 healthy volunteers were recruited). Sources: Literature |
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| COVID-19 research v0.19 | CCL2 |
Ellen McDonagh gene: CCL2 was added gene: CCL2 was added to Viral susceptibility. Sources: Literature Mode of inheritance for gene: CCL2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CCL2 were set to 25818534 Phenotypes for gene: CCL2 were set to Susceptibility to Severe Acute Respiratory Syndrome Coronavirus Infection; Susceptibility to SARS-CoV Added comment: PMID: 25818534 reports that the CCL2 G-2518A and MBL codon 54 variants have a significantly cumulative effect on increased risk of SARS-CoV infection. Sources: Literature |
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| COVID-19 research v0.18 | G6PD |
Ellen McDonagh gene: G6PD was added gene: G6PD was added to Viral susceptibility. Sources: Literature Mode of inheritance for gene: G6PD was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: G6PD were set to 26694452 Phenotypes for gene: G6PD were set to Susceptible to viral infection Added comment: PMID: 26694452 - a study that investigated the underlying mehanism of why glucose-6-phosphate dehydrogenase (G6PD)-deficient cells are highly susceptible to viral infection. Sources: Literature |
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| COVID-19 research v0.14 | MBL2 | Ellen McDonagh commented on gene: MBL2: PMID: 25818534 reports that the CCL2 G-2518A and MBL codon 54 variants have a significantly cumulative effect on increased risk of SARS-CoV infection. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.9 |
Ellen McDonagh List of related panels changed from to Panel status changed from public to internal |
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