TBK1 and TNFRSF13B mutations and an autoinflammatory disease in a child with lethal COVID-19

Schmidt, Axel; Peters, Sophia; Knaus, Alexej; Sabir, Hemmen; Hamsen, Frauke; Maj, Carlo; Fazaal, Julia; Sivalingam, Sugirthan; Savchenko, Oleksandr; Mantri, Aakash; Holzinger, Dirk; Neudorf, Ulrich; Müller, Andreas; Ludwig, Kerstin U.; Krawitz, Peter M.; Engels, Hartmut; Nöthen, Markus M.; Bagci, Soyhan

Among children, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are typically mild. Here, we describe the case of a 3.5-year-old girl with an unusually severe presentation of coronavirus disease (COVID-19). The child had an autoinflammatory disorder of unknown etiology, which had been treated using prednisolone and methotrexate, and her parents were half cousins of Turkish descent. After 5 days of nonspecific viral infection symptoms, tonic-clonic seizures occurred followed by acute cardiac insufficiency, multi-organ insufficiency, and ultimate death. Trio exome sequencing identified a homozygous splice-variant in the gene TBK1, and a homozygous missense variant in the gene TNFRSF13B. Heterozygous deleterious variants in the TBK1 gene have been associated with severe COVID-19, and the variant in the TNFRSF13B gene has been associated with common variable immunodeficiency (CVID). We suggest that the identified variants, the autoinflammatory disorder and its treatment, or a combination of these factors probably predisposed to lethal COVID-19 in the present case.