Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

Research output: Contribution to journalResearch articleContributedpeer-review


  • Université Paris Cité
  • Rockefeller University
  • National Institutes of Health (NIH)
  • Helix
  • Vita-Salute San Raffaele University
  • Karolinska Institutet
  • Tehran University of Medical Sciences
  • Al Jalila Children’s Specialty Hospital
  • Mohammed Bin Rashid University of Medicine and Health Sciences
  • Fondazione Telethon
  • Shahid Beheshti University of Medical Sciences
  • Complutense University
  • University of Oviedo
  • Universidad de Antioquia
  • Konya City Hospital
  • Division of Clinical Immunology
  • Universidad de la Sabana
  • Universidad Autónoma de Madrid
  • Hospital Universitario Reina Sofía
  • Hôpital Avicenne
  • Sorbonne Université
  • Vall d'Hebron Research Institute (VHIR)
  • Autonomous University of Barcelona
  • Universidade de São Paulo
  • Lebanese University
  • Institute of Technology and Renewable Energies
  • CIBER - Center for Biomedical Research Network
  • Hospital Universitario Nuestra Senora de Candelaria
  • University of Fernando Pessoa Canarias
  • Northwell Health System
  • CRG - Centre for Genomic Regulation
  • Jeffrey Modell Diagnosis and Research Centre
  • University of Sharjah
  • Istanbul University
  • University of Health Sciences
  • Dr. Cemil Tascioglu City Hospital
  • Necmettin Erbakan University
  • Université Paris-Saclay
  • Imagine Institute
  • Necker–Enfants Malades Hospital


Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No 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 × 10−4) for 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 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/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 × 10−5). Conclusions: Rare 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.


Original languageEnglish
Article number22
Pages (from-to)1-25
Number of pages25
JournalGenome medicine
Issue number2023
Publication statusPublished - Dec 2023

External IDs

ORCID /0009-0003-6519-0482/work/146644426
WOS 001022167700001
PubMed 37020259



  • COVID-19, Immunity, Rare variants, Type I interferon, Covid-19, Autoantibodies, Humans, Middle Aged, Interferon Type I, Toll-Like Receptor 7, Young Adult, SARS-CoV-2, Adult, Toll-Like Receptor 3/genetics

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