Genetic mosaicism in Systemic Auto-Inflammatory Diseases: A review of the literature

Systemic auto-inflammatory diseases (SAIDs) are disorders associated with deregulation of innate immunity in which patients present classically with systemic inflammatory manifestations, in particular fever, skin-mucosal rashes, arthromyalgia and abdominal pain, with an increase in blood biomarkers of inflammation. At the time of their discovery, these diseases were associated with constitutional mutations in genes encoding proteins involved in innate immunity, and it was then considered that they had to begin in childhood. This dogma of constitutional mutations in SAIDs is no longer so unquestionable, since 2005 several cases of mosaicism have been reported in the literature, initially in cryopyrinopathies, but also in other SAIDs in patients with obvious clinical phenotypes and late onset of disease expression, in particular in the VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic Syndrome) and very recently in MEVF gene. Next-generation sequencing techniques are more sensitive than Sanger for detecting mosaicisms. So, when a clinical diagnosis seems obvious but no constitutional mutation is found by low-depth genetic analysis, it is useful to discuss with expert geneticists whether to consider another genetic approach in a child or an adult. This modifies the situations in which clinicians can evoke these diseases. This review provides an update on mosaicism in SAIDs.