Genome sequencing unveils mutational landscape of the familial Mediterranean fever: Potential implications of IL33/ST2 signalling

Familial Mediterranean fever (FMF) is the most common auto‐inflammatory disease. It is transmitted as autosomal recessive trait with mutations in MEditerranean FeVer (MEFV) gene. Despite a typical clinical expression, many patients have either a single or no mutation in MEFV. The current work is aimed to revisit the genetic landscape of FMF disease using high‐coverage whole genome sequencing. In atypical patients (carrying a single or no mutation in MEFV), we revealed many rare variants in genes associated with auto‐inflammatory disorders, and more interestingly, we discovered a novel variant ( a 2.1‐Kb deletion) in exon 11 of IL1RL1 gene, present only in patients. To validate and screen this patient‐specific variant, a tandem of allele‐specific PCR and quantitative real‐time PCR was performed in 184 FMF patients and 218 healthy controls and we demonstrated that the novel deletion was absent in controls and was present in more than 19% of patients. This study sheds more light on the mutational landscape of FMF. Our discovery of a disease‐specific variant in IL1RL1 gene may constitute a novel genetic marker for FMF. This finding suggesting a potential role of the IL33/ST2 signalling in the disease pathogenicity highlights a new paradigm in FMF pathophysiology.