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DDI joined the global COVID Human Genetic Effort consortium to study rare cases of COVID-19

Dr. Fahd Al-Mulla recently joined CGGE collaboration which aims to discover causative genetic variations underlying resistance to viral infection or predisposition to severe disease.

Young patients admitted to an ICU with no known underlying medical conditions and presenting severe symptoms of COVID-19 are enrolled worldwide. Their genome is sequenced and their genetic variations are tested biochemically and immunologically in the goal of detecting inborn errors blunting the immune system’s normal defenses against the virus.

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Amid this collaboration ; Zhang et al. 1, reported, in Science, the analyses of exome or genome sequences from 659 patients with severe COVID-19 from >15 countries (including Kuwait). The authors found deleterious variants of 13 candidate genes of the type I interferon (IFN) pathway in 3.5% (23/659) of cases. These patients had defects in type I IFN gene expression and protein levels and higher SARS-CoV-2 viral loads than controls, demonstrating an inability to properly clear the virus. This highlights the importance of type I IFN signaling pathway in the defense against SARS-CoV-2 infection and suggests the implication of inherited variants in a subset of severe COVID-19.

Bastard et al 2. identified neutralizing autoantibodies against type I IFNs (which block the activation of the pathway in vitro) were found in up to 13.7% (135/987) of patients with life-threatening COVID. However, these autoantibodies were not found in patients with mild or asymptomatic COVID-19 and were only found in 0.33% (4/1227) of healthy individuals not exposed to SARS-CoV-2. The presence of neutralizing autoantibodies correlated with low serum IFN-α concentrations. Remarkably, 94% of the patients with autoantibodies were males suggesting a cause of the higher male-specific disease mortalities.

By analyzing patients with severe COVID-19, these two studies provide evidence that type I IFNs are protective against COVID-19 and that limiting this response through either gene mutations or autoantibodies leads to severe disease. Findings from these studies have paved the way for precision medicine and personalized treatment strategies for COVID-19.