A rare likely pathogenic HLA-DRB1 variant with compromised immunity in severe COVID-19 patient and in-hospital mortality

The severity of COVID-19 disease can vary greatly, influenced by genetic factors and comorbid conditions that may increase mortality. This study has examined potential genetic influences on the disease for a young adult aged 36 years with T2DM-CAD multi-morbidity with severe COVID-19 disease and in-hospital mortality using whole-exome sequencing. The patient exhibited a constellation of severe symptoms and abnormality in several biochemical markers associated with COVID-19 disease and comorbid conditions. A total of 756 variants were discovered in the patient, including several rare and novel variants associated with immune pathways. A set of 10 unique candidate variants in 10 distinct genes were identified with nine variants located within genes associated with the COVID-19 panel (HLA-DRB1, IL23R, PRKDC, RNF31, SLC37A4, TAP2, TCIRG1, TCN2, and TPP2), while one variant was found in a gene (PAX6) from Diabetes panel. Enrichment analysis showed that the top three enriched GO biological processes were a response to stimulus (<i>n</i> = 23, <i>p</i> = 6.8E-3), immune system process (<i>n</i> = 22, <i>p</i> = 3.6E-12), and regulation of immune system process (<i>n</i> = 19, <i>p</i> = 1.57E-11). The Maximal Clique Centrality algorithm identified HLA-DRB1 as a prominent hub gene and potential loss-of-function mutation in HLA-DRB1, suggests a compromised antigen presentation mechanism within this patient.