Objectives: Familial Mediterranean Fever (FMF) is an inflammatory disease characterised by periodic fever and concurrent episodes of serous membrane inflammation. FMF is considered to be inherited in autosomal recessive manner and biallelic mutations in the MEFV gene are associated with the disease. However, approximately 20-25% of patients only have a single mutation in MEFV gene, which creates confusion in differential diagnosis of many patients. This study aimed to reveal rare variants that may act in conjunction with the single pathogenic MEFV variant in the pathogenesis of FMF.
Methods: We performed whole exome sequencing in 17 individuals from 5 different families who were diagnosed according to the clinical criteria, responded positively to colchicine treatment, but had no biallelic MEFV mutation.
Results: A disease-causing variant or a common affected cellular pathway that was shared in all index cases was not detected. When cases were examined individually, two de novo variants were identified in the BIRC2 and BCL10 genes, both of which play a role in inflammatory pathways. Functional studies are needed to confirm the physiopathological relationship of these genes with FMF.
Conclusions: This study is one of the most extensive aetiological researches in FMF cases with monoallelic MEFV mutation. We have shown that genotype-phenotype correlation in these cases may not be established by rare genetic variants and discussed underlying causes. Clinical criteria with emphasis on colchicine response and family history should be the main tool and genetic results should only be used for support in FMF diagnosis.