DOI: 10.5061/dryad.8pk0p2nkk
title: Genotype count for all coding variants in type I IFN genes investigated in 659 life-threatening COVID-19 patients and 534 asymptomatic/mild infected controls

description: Clinical outcome upon infection with SARS-CoV-2 ranges from silent
 infection to lethal COVID-19. We have found an enrichment in rare variants
 predicted to be loss-of-function (LOF) at the 13 human loci known to
 govern TLR3- and IRF7-dependent type I interferon (IFN) immunity to
 influenza virus, in 659 patients with life-threatening COVID-19 pneumonia,
 relative to 534 subjects with asymptomatic or benign infection. By testing
 these and other rare variants at these 13 loci, we experimentally define
 LOF variants in 23 patients (3.5%), aged 17 to 77 years, underlying
 autosomal recessive or dominant deficiencies. We show that human
 fibroblasts with mutations affecting this pathway are vulnerable to
 SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity
 can underlie life-threatening COVID-19 pneumonia in patients with no prior
 severe infection.
description: Epidemiological studies have identified three risk factors for
 severe disease: being male, elderly, and having other medical conditions.
 However, interindividual clinical variability remains huge in each
 demographic category. Discovering the root cause and detailed molecular,
 cellular, tissue- and body-level mechanisms underlying life-threatening
 COVID-19 is of the utmost biological and medical importance. We included
 in this study 659 patients with life-threatening COVID-19 pneumonia
 defined as patients with pneumonia who developed critical disease, whether
 pulmonary with mechanical ventilation (CPAP, BIPAP, intubation, hi-flow
 oxygen), septic shock, or with any other organ damage requiring admission
 to the ICU. Patients who developed Kawasaki-like syndrome were excluded.
 As controls, we enrolled 534 individuals infected with SARS-CoV-2 (based
 on a positive PCR and/or serological test and/or the presence of typical
 symptoms such as anosmia/ageusia after exposure to a confirmed COVID-19
 case) who remained asymptomatic or developed mild, self-healing,
 ambulatory disease. <strong>Next-generation
 sequencing</strong> Genomic DNA was extracted
 from whole blood. For the 1193 patients and controls included, the whole
 exome (N=687) or whole genome (N=506) was sequenced at several sequencing
 centers, including the Genomics Core Facility of the Imagine Institute
 (Paris, France), the Yale Center for Genome Analysis (USA), the New-York
 Genome Center (NY, USA), and the American Genome Center (TAGC, USUHS,
 Bethesda, USA). For WES, libraries were generated with the Twist
 Bioscience kit (Twist Human Core Exome Kit), the xGen Exome Research Panel
 from Integrated DNA Technologies (IDT xGen), the Agilent SureSelect V7 kit
 or the SeqCap EZ MedExome kit from Roche. Massively parallel sequencing
 was performed on a NovaSeq6000 system (Illumina). We
 used the Genome Analysis Software Kit (GATK) (version 3.4-46 or 4)
 best-practice pipeline to analyze our WES data (30). We aligned the reads
 obtained with the human<br> reference genome (hg19), using the
 maximum exact matches algorithm in the Burrowsâ€“ Wheeler Aligner (BWA).
 PCR duplicates were removed with Picard tools (picard.sourceforge.net).
 The GATK base quality score recalibrator was applied to correct sequencing
 artifacts.  Annotation was performed using Ensembl
 Variant Effect Predictor on the canonical transcript. All the variants
 were manually curated using IGV and confirmed to affect the main
 functional protein isoform by checking the protein sequence before
 inclusion in further analyzes.  The analysis of IKBKG was customized to
 differentiate the duplicated region in IKBKG using a special pipeline
 previously described.
description: This dataset includes detailed genotype counts for all coding
 variants in the 13 genes investigated in the manuscript "Inborn
 errors of type I IFN immunity in patients with life-threatening
 COVID-19" by Zhang Q et al., Science 2020, in press.