Determining inborn errors of immunity associated with life-threatening SARS-CoV-2 infections in previously healthy young individuals.

There is stunning inter-individual variability among individuals infected with COVID-19, ranging from asymptomatic infection to severe lethal disease. Although patients with severe disease were mostly elderly or patients with comorbidities, a good proportion of otherwise healthy, young people developed severe symptoms. The reason behind that is not known. In this context, we hypothesize that life-threatening COVID-19 in young previously healthy individuals can be caused by monogenic inborn errors of immunity (IEIs). Whole exome sequences of young patients with severe COVID-19 will be analysed for candidate disease-causing variants using a cutting-edge strategy. We will then perform in-depth functional studies to decipher the molecular, cellular, and immunological mechanisms by which they actually predispose to severe disease. This is specifically important in countries with high consanguinity, like the gulf area including UAE, where the rate of inborn errors of immunity are expected to be higher. This information will guide the genetic diagnosis and counselling, while paving the way to design preventive and therapeutic strategies including anti-viral drugs and vaccines.