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"A"}, {"family": "Quaresima", "given": "Virginia", "initials": "V"}, {"family": "Quiros-Roldan", "given": "Eugenia", "initials": "E"}, {"family": "Rossi", "given": "Camillo", "initials": "C"}, {"family": "Meyts", "given": "Isabelle", "initials": "I", "orcid": "0000-0003-1214-0302", "researcher": {"href": "https://publications.scilifelab.se/researcher/dfde01a48b334b2a896597ac69be80c8.json"}}, {"family": "Zhang", "given": "Shen Ying", "initials": "SY"}, {"family": "Puel", "given": "Anne", "initials": "A", "orcid": "0000-0003-2603-0323", "researcher": {"href": "https://publications.scilifelab.se/researcher/3bcef4c205904e5db9e36f3aadaa13bb.json"}}, {"family": "Notarangelo", "given": "Luigi D", "initials": "LD", "orcid": "0000-0002-8335-0262", "researcher": {"href": "https://publications.scilifelab.se/researcher/d8d346e44c2d443ba3da3fcf2725b96c.json"}}, {"family": "Boisson-Dupuis", "given": "Stephanie", "initials": "S", "orcid": "0000-0002-7115-116X", "researcher": {"href": "https://publications.scilifelab.se/researcher/5584eef132004c55a120c70d9a9f9eee.json"}}, {"family": "Su", "given": "Helen C", "initials": "HC", "orcid": "0000-0002-5582-9110", "researcher": {"href": "https://publications.scilifelab.se/researcher/5f3b00f2707541b39b2205d70fd2d6f7.json"}}, {"family": "Boisson", "given": "Bertrand", "initials": "B", "orcid": "0000-0001-5240-3555", "researcher": {"href": "https://publications.scilifelab.se/researcher/e7c47acbcc3346bcb65102b534b25cc8.json"}}, {"family": "Jouanguy", "given": "Emmanuelle", "initials": "E", "orcid": "0000-0002-7358-9157", "researcher": {"href": "https://publications.scilifelab.se/researcher/2667361dc2e7417bb94bfc89bf425cc6.json"}}, {"family": "Casanova", "given": "Jean Laurent", "initials": "JL"}, {"family": "Zhang", "given": "Qian", "initials": "Q"}, {"family": "Abel", "given": "Laurent", "initials": "L", "orcid": "0000-0001-7016-6493", "researcher": {"href": "https://publications.scilifelab.se/researcher/24ef4ca1eb3a4b1bbee73f07cd64fe92.json"}}, {"family": "Cobat", "given": "Aur\u00e9lie", "initials": "A", "orcid": "0000-0001-7209-6257", "researcher": {"href": "https://publications.scilifelab.se/researcher/eaba2f9452294eec89161b589d96ff29.json"}}], "type": "journal-article", "published": "2023-04-05", "journal": {"title": "Genome Med", "issn": "1756-994X", "issn-l": "1756-994X", "volume": "15", "issue": "1", "pages": null}, "abstract": "We previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and auto-antibodies against type I IFN in another 15-20% of cases.\r\n\r\nWe report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis.\r\n\r\nNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7 , with an OR of 27.68 (95%CI:1.5-528.7, P= 1.1\u00d710 -4 ), in analyses restricted to biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70 [95%CI:1.3-8.2], P= 2.1\u00d710 -4 ). Adding the recently reported TYK2 COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4]; P= 3.4\u00d710 -3 ). When these 14 loci and TLR7 were considered, all individuals hemizygous ( n =20) or homozygous ( n =5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0], P =4.7\u00d710 -7 ), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9], P =0.02). Finally, the patients with pLOF or bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P= 1.68\u00d710 -5 ).\r\n\r\nRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.", "doi": "10.1186/s13073-023-01173-8", "pmid": "36324795", "labels": {"Clinical Genomics Stockholm": "Service", "Clinical Genomics": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC9628204"}, {"db": "pii", "key": "2022.10.22.22281221"}], "notes": [], "created": "2022-11-30T05:59:39.705Z", "modified": "2024-01-19T11:56:54.797Z"}, {"entity": "publication", "iuid": "bce3eb78ee8e4437bf9e297ccb44a8f7", "links": {"self": {"href": "https://publications.scilifelab.se/publication/bce3eb78ee8e4437bf9e297ccb44a8f7.json"}, "display": {"href": "https://publications.scilifelab.se/publication/bce3eb78ee8e4437bf9e297ccb44a8f7"}}, "title": "X-linked recessive TLR7 deficiency in ~1% of men under 60 years old with life-threatening COVID-19.", "authors": [{"family": "Asano", "given": "Takaki", "initials": "T", "orcid": "0000-0003-1424-2433", "researcher": {"href": "https://publications.scilifelab.se/researcher/ac5194017554453e88b16a4db83ff29a.json"}}, {"family": "Boisson", "given": "Bertrand", "initials": "B", "orcid": "0000-0001-5240-3555", "researcher": {"href": "https://publications.scilifelab.se/researcher/e7c47acbcc3346bcb65102b534b25cc8.json"}}, {"family": "Onodi", "given": "Fanny", "initials": "F", "orcid": "0000-0002-8429-4821", "researcher": {"href": "https://publications.scilifelab.se/researcher/734764c2e1a24c1c88b6de07fee9c1d2.json"}}, {"family": "Matuozzo", "given": "Daniela", "initials": "D", "orcid": "0000-0001-9514-3837", "researcher": {"href": "https://publications.scilifelab.se/researcher/3a74128c36fa425981d8f14b0dc7e90e.json"}}, {"family": "Moncada-Velez", "given": "Marcela", "initials": "M", "orcid": "0000-0002-3073-5345", "researcher": {"href": "https://publications.scilifelab.se/researcher/2bf242c5e03d4aec82e164cc56a45bc8.json"}}, {"family": "Maglorius Renkilaraj", "given": "Majistor Raj Luxman", "initials": "MRL", "orcid": "0000-0002-8385-2860", "researcher": {"href": "https://publications.scilifelab.se/researcher/fa2732242a264ef88ddb2340bb1a447e.json"}}, {"family": "Zhang", "given": "Peng", "initials": "P", "orcid": "0000-0002-6129-567X", "researcher": {"href": "https://publications.scilifelab.se/researcher/20fcd31c47a940e8b72a8eb8d6e2a63b.json"}}, {"family": "Meertens", "given": "Laurent", "initials": "L", "orcid": "0000-0003-2811-3675", "researcher": {"href": "https://publications.scilifelab.se/researcher/171bf268e49840758cd60ad009f5fd2f.json"}}, {"family": "Bolze", "given": "Alexandre", "initials": "A", "orcid": "0000-0001-7399-2766", "researcher": {"href": "https://publications.scilifelab.se/researcher/99d7674f36d44b05b224d486d987521d.json"}}, {"family": "Materna", "given": "Marie", "initials": "M"}, {"family": "Korniotis", "given": "Sarantis", "initials": "S"}, {"family": "Gervais", "given": "Adrian", "initials": "A", "orcid": "0000-0002-1083-5787", "researcher": {"href": "https://publications.scilifelab.se/researcher/f4d47775a4da4ee6ac0ff7da16c0155c.json"}}, {"family": "Talouarn", "given": "Estelle", "initials": "E", "orcid": "0000-0002-5016-0446", "researcher": {"href": "https://publications.scilifelab.se/researcher/780c4505b98642c586f622dd83f60d6c.json"}}, {"family": "Bigio", "given": "Benedetta", "initials": "B", "orcid": "0000-0001-7291-5638", "researcher": {"href": "https://publications.scilifelab.se/researcher/8032507cc7734657a92612f39b6a0117.json"}}, {"family": "Seeleuthner", "given": "Yoann", "initials": "Y"}, {"family": "Bilguvar", "given": "Kaya", "initials": "K", "orcid": 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"initials": "A", "orcid": "0000-0001-7209-6257", "researcher": {"href": "https://publications.scilifelab.se/researcher/eaba2f9452294eec89161b589d96ff29.json"}}, {"family": "Zhang", "given": "Qian", "initials": "Q", "orcid": "0000-0002-9040-3289", "researcher": {"href": "https://publications.scilifelab.se/researcher/5bee352280384ad99b180f4f4bac42f5.json"}}, {"family": "Casanova", "given": "Jean-Laurent", "initials": "JL", "orcid": "0000-0002-7782-4169", "researcher": {"href": "https://publications.scilifelab.se/researcher/009e2306468648c08fb1eea319f0c488.json"}}], "type": "journal article", "published": "2021-08-19", "journal": {"title": "Sci Immunol", "issn": "2470-9468", "volume": "6", "issue": "62", "issn-l": null}, "abstract": "Autosomal inborn errors of type I IFN immunity and autoantibodies against these cytokines underlie at least 10% of critical COVID-19 pneumonia cases. We report very rare, biochemically deleterious X-linked TLR7 variants in 16 unrelated male individuals aged 7 to 71 years (mean: 36.7 years) from a cohort of 1,202 male patients aged 0.5 to 99 years (mean: 52.9 years) with unexplained critical COVID-19 pneumonia. None of the 331 asymptomatically or mildly infected male individuals aged 1.3 to 102 years (mean: 38.7 years) tested carry such TLR7 variants (p = 3.5 \u00d7 10-5). The phenotypes of five hemizygous relatives of index cases infected with SARS-CoV-2 include asymptomatic or mild infection (n=2, 5 and 38 years), or moderate (n=1, 5 years), severe (n=1, 27 years), or critical (n=1, 29 years) pneumonia. Two boys (aged 7 and 12 years) from a cohort of 262 male patients with severe COVID-19 pneumonia (mean: 51.0 years) are hemizygous for a deleterious TLR7 variant. The cumulative allele frequency for deleterious TLR7 variants in the male general population is < 6.5x10-4 We also show that blood B cell lines and myeloid cell subsets from the patients do not respond to TLR7 stimulation, a phenotype rescued by wild-type TLR7 The patients' blood plasmacytoid dendritic cells (pDCs) produce low levels of type I IFNs in response to SARS-CoV-2. Overall, X-linked recessive TLR7 deficiency is a highly penetrant genetic etiology of critical COVID-19 pneumonia, in about 1.8% of male patients below the age of 60 years. Human TLR7 and pDCs are essential for protective type I IFN immunity against SARS-CoV-2 in the respiratory tract.", "doi": "10.1126/sciimmunol.abl4348", "pmid": "34413140", "labels": {"Clinical Genomics Stockholm": "Service", "Clinical Genomics": "Service"}, "xrefs": [{"db": "mid", "key": "NIHMS1744435"}, {"db": "pmc", "key": "PMC8532080"}, {"db": "pii", "key": "6/62/eabl4348"}], "notes": [], "created": "2022-11-30T05:59:36.974Z", "modified": "2023-06-19T09:15:18.018Z"}]}