Recurrent severe viral infection in a child with inherited complete TBK1 deficiency

TANK-binding kinase 1 (TBK1) acts at the crossroads of various host immune pathways. Autosomal dominant (AD) and recessive (AR) TBK1 deficiencies have been reported in human patients with herpes simplex encephalitis and SARS-CoV-2 pneumonia (AD deficiency) or systemic inflammation (AR deficiency). We describe here a Turkish boy, born to consanguineous parents and homozygous for a loss-of-function mutation of TBK1, who had experienced recurrent vesicular skin eruptions presumably triggered by herpesviral infection and five episodes of viral pneumonia since the age of 2 mo. Whole-exome sequencing identified a biallelic mutation of the TBK1 gene (NM_013254.4: c.922C>T, p.Arg308Ter). The induction of IFNB, IFNL1, IFIT1, and IL6 was abolished or severely impaired in SV40-fibroblasts from the patient following stimulation of the TLR3 or RIG-I/MDA5-RIG-I pathways. The patient underwent stem-cell transplantation, but unfortunately succumbed to suspected post-viral acute disseminated encephalomyelitis at the age of 2.5 years. AD or AR TBK1 deficiency should be considered in patients with severe viral infections.