Presence of rare potential pathogenic variants in subjects under 65 years old with very severe or fatal COVID‑19

Rare variants affecting host defense against pathogens could be involved in COVID‑19 severity and
may help explain fatal outcomes in young and middle‑aged patients. Our aim was to report the
presence of rare genetic variants in certain genes, by using whole exome sequencing, in a selected
group of COVID‑19 patients under 65 years who required intubation or resulting in death (n = 44).
To this end, different etiopathogenic mechanisms were explored using gene prioritization‑based
analysis in which genes involved in immune response, immunodeficiencies or blood coagulation
were studied. We detected 44 different variants of interest, in 29 different patients (66%). Some of
these variants were previously described as pathogenic and were located in genes mainly involved
in immune response. A network analysis, including the 42 genes with candidate variants, showed
three main components, consisting of 25 highly interconnected genes related to immune response
and two additional networks composed by genes enriched in carbohydrate metabolism and in DNA
metabolism and repair processes. In conclusion, we have detected candidate variants that may
potentially influence COVID‑19 outcome in our cohort of patients. Further studies are needed to
confirm the ultimate role of the genetic variants described in the present study on COVID‑19 severity.EGA study EGAS00001006372