This study aimed to explore the presence of genetic variants associated with primary immunodeficiencies in young COVID-19 patients. Two pairs of brothers (four men total) from separate families were included in a case series. All four patients were under the age of 35 with no chronic medical history. Each patient required mechanical ventilation in the ICU, and one patient died. Rapid clinical whole-exome sequencing revealed loss-of-function variants of X-chromosomal TLR7 that were associated with impaired type I and type II interferon responses. The data suggest that functional immunological errors in type I and type II interferons may be associated with the presence of rare loss-of-function TLR7 variants in severe COVID-19 patients.