Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.
Level 4 - case-series / case-control
Case-control genetic association study with in vitro functional validation
PubMed 32972995 · doi:10.1126/science.abd4570
What was done
Sequenced 13 human genetic loci governing TLR3- and IRF7-dependent type I interferon (IFN) immunity in 659 patients with life-threatening COVID-19 pneumonia compared to 534 individuals with asymptomatic or benign SARS-CoV-2 infection. Identified rare variants were experimentally tested to confirm loss-of-function (LOF) status, and human fibroblasts carrying pathway mutations were tested for susceptibility to SARS-CoV-2.
What was found
Patients with life-threatening COVID-19 had an enrichment of predicted LOF variants in the 13 type I IFN loci compared to controls. Experimentally validated autosomal-recessive or autosomal-dominant LOF variants were confirmed in 23 severe patients (3.5%), aged 17 to 77 years. In vitro, human fibroblasts with defects in this circuit demonstrated vulnerability to SARS-CoV-2 infection.
Why it matters
This study shows that monogenic inborn errors of type I IFN immunity explain a small but critical fraction of severe, life-threatening COVID-19 cases in patients without prior history of severe viral infections.
Limits
The identified inborn errors explain only ~3.5% of life-threatening cases, leaving the vast majority of severe outcomes unexplained by these 13 loci. The abstract does not provide exact odds ratios, confidence intervals, or statistical values for the enrichment analysis, nor details on the ancestry composition of cases versus controls.
Cited by
- supports Genetic mutations that abolish interferon secretion were identified exclusively in severe COVID-19 patients and explained a significant proportion of severe cases in a cohort published in Science.