The global impact of COVID-19 was staggering, with millions of cases and related mortality reported worldwide. Genetic variations play a significant role in determining an individual's susceptibility to SARS-CoV-2 infection and progress to severe disease. This pilot study provides an experimental approach using WES to identify certain rare and novel genetic variants that might affect an individual's susceptibility to the risk of SARS-CoV-2 infection, offering an initial exploration of these genetic variants. In the study cohort with 16 patients, the mortality rate was higher in male patients due to severe disease. There was a substantial burden of comorbidity, including hypertension, ischemic heart disease, and T2DM, conditions which independently increase the risk of adverse outcomes in COVID-19 patients. A total of 4478 variants were identified, distributed across 322 genes within the cohort. The majority of these variants were missense substitutions along with frameshift variants, inframe insertions/deletions (indels), and nonsense variants. The variants were further categorized by types to include single-nucleotide polymorphisms (SNPs), deletions (DEL), and insertions (INS). The gene with the highest number of variants was HLA-DRB1, followed by HLA-B, ABO, HPS4, and SP110 displaying both common polymorphisms and rare variants. Moreover, the HLA-B gene exhibited the highest number of rare candidate variants, followed by AK2, IRF7, KMT2D, TAP1, and HLA-DRB1. Several genes harbored multiple novel variants, including TAP1, AK2, G6PC3, HLA-B, IL12RB2, and ITGB2. The frequencies of the identified variants were found to be either zero or extremely low (below 1% threshold) in the Middle Eastern or in the overall combined population, suggesting that these are indeed rare and do not represent common indigenous polymorphisms. Functional enrichment analysis of the constructed protein-protein interaction network in our preliminary findings revealed that the identified genes are primarily enriched in pathways associated with immune deficiency and DNA repair. This initial exploration of genetic variants in COVID-19 susceptibility provides a foundation for future large-scale studies.

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (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 Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (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 defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit 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.

Coronavirus disease 2019 (COVID-19) has spread rapidly and become a pandemic. Caused by a novel human coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), severe COVID-19 is characterized by cytokine storm syndromes due to innate immune activation. Primary immunodeficiency (PID) cases represent a special patient population whose impaired immune system might make them susceptible to severe infections, posing a higher risk to COVID-19, but this could also lead to suppressed inflammatory responses and cytokine storm. It remains an open question as to whether the impaired immune system constitutes a predisposing or protective factor for PID patients when facing SARS-CoV-2 infection. After literature review, it was found that, similar to other patient populations with different comorbidities, PID patients may be susceptible to SARS-CoV-2 infection. Their varied immune status, however, may lead to different disease severity and outcomes after SARS-CoV-2 infection. PID patients with deficiency in antiviral innate immune signaling [eg, Toll-like receptor (TLR)3, TLR7, or interferon regulatory factor 7 (IRF7)] or interferon signaling (IFNAR2) may be linked to severe COVID-19. Because of its anti-infection, anti-inflammatory, and immunomodulatory effects, routine intravenous immunoglobulin therapy may provide some protective effects to the PID patients.

Influenza viruses infect millions of people around the globe annually, usually causing self-limited upper respiratory tract infections. However, a small but non-negligible proportion of patients suffer from life-threatening pulmonary disease. Those affected include otherwise healthy individuals, and children with primary infections in particular. Much effort has been devoted to virological studies of influenza and vaccine development. By contrast, the enormous interindividual variability in susceptibility to influenza has received very little attention. One interesting hypothesis is that interindividual variability is driven largely by the genetic makeup of the infected patients. Unbiased genomic approaches have been used to search for genetic lesions in children with life-threatening pulmonary influenza. Four monogenic causes of severe influenza pneumonitis-deficiencies of GATA2, IRF7, IRF9, and TLR3-have provided evidence that severe influenza pneumonitis can be genetic and often in patients with no other severe infections. These deficiencies highlight the importance of human type I and III IFN-mediated immunity for host defense against influenza. Clinical penetrance is incomplete, and the underlying mechanisms are not yet understood. However, human genetic studies have clearly revealed that seemingly sporadic and isolated life-threatening influenza pneumonitis in otherwise healthy individuals can be genetic.

In an Egyptian girl born to consanguineous parents, whole-exome sequencing (WES) identified a homozygous mutation in PHGDH, c.1273G>A (p.Val425Met), indicating 3-phosphoglycerate dehydrogenase deficiency. This diagnosis was compatible with the patient's microcephaly, severe psychomotor retardation, seizures and cataracts. However, she additionally suffered from recurrent (at least monthly) episodes of prolonged and severe chest infections requiring hospitalization, suggesting a secondary, predisposing and potentially Mendelian, condition. A local reactivation of an EBV infection in the respiratory tract was detected after a recent chest infection, likely representing an opportunistic infection based on a compromised immune system. Further inspection of WES data revealed a homozygous nonsense mutation, c.2665A>T (p.Lys889∗), in IFIH1, encoding MDA5. MDA5 detects long viral double-stranded RNA that is generated during replication of picorna viruses, and thereby activates the type I interferon signaling pathway. The results of Western blot analysis of protein from cultured fibroblasts of the patient indicates absence of wild type MDA5/IFIH1, compatible with NMD. We propose that, analogous to the severe course of primary influenza infection due to biallelic deficiency of a downstream effector, IRF7, homozygous loss of IFIH1 defines a novel Mendelian immunodeficiency disorder that increases susceptibility to severe viral infections. This is contrasted to heterozygous gain-of-function IFIH1 mutations in autoimmune diseases. Our findings highlight the potential of comprehensive genomic investigations in patients from consanguineous families to identify monogenic predispositions to severe infections.