There are several innate immune pathways which can drive the production of type I IFN production and antiviral defence, which are also important for tumor surveillance and immunotherapy. Unfortunately, de novo or inherited mutations can also arise in genes of these pathways to cause interferonopathies, a class of diseases due to overactivation of type I IFN. Here we present several new mutations, all unpublished, that cause different interferonopathies. One of these is a new mutation in the pathway controlling linear ubiquitination (LUBAC), for which proteins such as HOIL, HOIP and in this case OTULIN are all implicated in different syndromes. Another is a novel gene that regulates mitochondrial RNA, mutation of which leads to type I IFN activation via the innate immune sensor of dsRNA MDA5. Finally we document the first variants in human UNC93B1, which regulate TLR signalling, and drive childhood-onset lupus. Characterising these diseases and understanding the underlying pathways provides answers for the affected families and facilitates successful therapeutic intervention. Evidence in humans regarding these targets can also be harnessed to boost immunity and anti-cancer responses.