Table 3 Rare monogenic variants identified in patients with severe/critical COVID-19 or MIS-C
From: Clinical implications of host genetic variation and susceptibility to severe or critical COVID-19
Affected gene | Inheritance pattern | Mutational mechanism | Functional defect | Severe/critical COVID-19 population(s) studied | Prevalence of proven defect(s) |
|---|---|---|---|---|---|
Severe COVID-19 | |||||
 TLR7 | XLR | LoF (complete or hypomorph) | Impaired viral clearance due to disrupted TLR7 signaling with a defective production of type I/II interferons | Adult male brother pairs <35 years without predisposing comorbidities, who developed respiratory insufficiency requiring mechanical ventilation in ICU [8] | - |
Adult men aged <60 years with respiratory insufficiency requiring mechanical ventilation in ICU | 2.2% (3/135) | ||||
Adult men aged <50 years without predisposing comorbidities, who developed respiratory insufficiency requiring high-flow oxygen devices or mechanical ventilation [52] | 14.3% (2/14) | ||||
Individuals (n = 1304) with respiratory insufficiency requiring mechanical ventilation or resulting in death [50] | 0.55% (7/1267) | ||||
Men with life-threatening pneumonia requiring high-flow oxygen devices or mechanical ventilation, septic shock or another type of organ damage requiring ICU admission [53] | 1.3% (16/1202) | ||||
 IRF7 | AD, AR | LoF (complete or hypomorph) | Impaired viral clearance due to defective type I interferon signaling and production | Men with life-threatening pneumonia requiring high-flow oxygen devices or mechanical ventilation, septic shock or another type of organ damage requiring ICU admission [51] | 3.5% (24/659) |
 TLR3 | AD | ||||
 TICAM1 | AD | ||||
 IRF3 | AD | ||||
 TBK1 | AD | ||||
 IFNAR1 | AD, AR | ||||
 IFNAR2 | AD | ||||
 UNC93B1 | AD | ||||
MIS-C | |||||
 SOCS1 | AD | LoF | Hyperinflammation due to decreased negative regulation of type I/II interferon signaling (increased STAT1 phosphorylation and expression of type I/II IFN-stimulated and proaptotic genes) | Children meeting the criteria for multisystem inflammatory syndrome (MIS-C), defined as fever, elevated inflammatory marker levels, multisystem organ involvement, and SARS-CoV-2 infection or exposure within 4 weeks of symptoms without an alternative diagnosis [54, 94] | 17% (3/18) |
 XIAP | XLR | LoF | Hyperinflammation due to decreased negative regulation of the NLRP3 inflammasome with basally elevated levels of IL-6, IL-18, IL-10 and CXCL9 (and IL-1β after stimulation) | ||
 CYBB | XLR | LoF | Hyperinflammation due a decreased phagocytic oxidative burst (impaired function of NADPH oxidase) and decreased inhibition of type I interferon signaling | ||