In summary, we have identified 8 variants in 18 MIS-C patients with impaired BTNL8 expression and/or function among a total of 835 MIS-C patients (2.2%) This evidence suggests that in these patients, there is likely to be an impaired capacity of BTNL8/BTNL3 heterodimer to engage γδ T cells, potentially creating homeostatic imbalance in the gut, a major site of MIS-C pathology. Here, BTNL8 is linked to COVID-19–associated multisystem inflammatory syndrome in children.