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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 v1.31 | IL18BP | Sarah Leigh Publications for gene: IL18BP were set to 32086639; 32048120; 31213488; 32285199 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v1.11 | IL18BP | Alison Coffey reviewed gene: IL18BP: Rating: AMBER; Mode of pathogenicity: ; Publications: 31213488, 28900426; Phenotypes: ; Mode of inheritance: Unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v1.10 | IL18BP | Sarah Leigh commented on gene: IL18BP | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.171 | IL18BP | Sophie Hambleton reviewed gene: IL18BP: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.165 | IL18BP | Rebecca Foulger commented on gene: IL18BP | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.165 | IL18BP | Rebecca Foulger Publications for gene: IL18BP were set to 32086639; 32048120; PubMed: 31213488 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 v0.102 | 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 v0.81 | IL18BP |
Abdelazeem Elhabyan gene: IL18BP was added gene: IL18BP was added to Viral susceptibility. Sources: Literature Mode of inheritance for gene: IL18BP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: IL18BP were set to PubMed: 31213488 Mode of pathogenicity for gene: IL18BP was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Added comment: Inherited IL-18BP deficiency in human fulminant viral hepatitis Fulminant viral hepatitis (FVH) is a devastating and unexplained condition that strikes otherwise healthy individuals during primary infection with common liver-tropic viruses. We report a child who died of FVH upon infection with hepatitis A virus (HAV) at age 11 yr and who was homozygous for a private 40-nucleotide deletion in IL18BP, which encodes the IL-18 binding protein (IL-18BP). This mutation is loss-of-function, unlike the variants found in a homozygous state in public databases. We show that human IL-18 and IL-18BP are both secreted mostly by hepatocytes and macrophages in the liver. Moreover, in the absence of IL-18BP, excessive NK cell activation by IL-18 results in the uncontrolled killing of human hepatocytes in vitro. Inherited human IL-18BP deficiency thus underlies fulminant HAV hepatitis by unleashing IL-18. These findings provide proof-of-principle that FVH can be caused by single-gene inborn errors that selectively disrupt liver-specific immunity. They also show that human IL-18 is toxic to the liver and that IL-18BP is its antidote. Sources: Literature |
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