Rare genetic variants and severe COVID-19 in previously healthy admixed Latin American adults

Rare genetic variants that affect host defense against SARS-CoV-2 may contribute to COVID-19 progression, helping to explain severe or fatal cases in young and middle-aged patients. This study aimed to identify rare genetic variants potentially implicated in life-threatening COVID-19 in a cohort of Brazilian patients aged 18 to 60, with no prior history of health issues, who required intensive care unit admission (n = 161). Whole genome sequencing was performed, followed by a prioritization approach for rare variants in loci previously associated with severe COVID-19. A total of 104 rare and potentially deleterious variants were identified in 79 genes. Ultra-rare variants in MUC5AC, IFNA10, ZNF778, and PTOV1 were the most frequently observed. We report 17 novel variants, including those likely pathogenic or indicating strong loss-of-function (LoF) intolerance. Patients carrying prioritized rare variants had a significantly higher incidence of acute respiratory distress syndrome (ARDS) (p = 0.027, OR = 2.59). Additionally, patients with variants in highly LoF-intolerant genes had a fourfold higher risk of death (p = 0.0084, OR = 4.04). To date, this is the first genomic analysis of previously healthy young and middle-aged Latin American patients with severe COVID-19. Our findings highlight the importance of identifying population-specific genetic risk factors.