Clinical phenotypes and genetic analyses for diagnosis of systemic autoinflammatory diseases in adult patients with unexplained fever

Objective To make an accurate diagnosis of systemic autoinflammatory diseases (SAIDs), clinical and genetic analyses were performed in patients with unexplained fever. Methods The clinical phenotype and genomic variants of 11 genes responsible for SAIDs were analyzed in 179 Japanese patients with unexplained fever. Genetic analysis was performed by next generation sequencing (NGS) on exons including exon-intron boundaries. Results Three cases met the diagnostic criteria for SAIDs other than familial Mediterranean fever (FMF). Considering 176 patients with unexplained fever, 43 cases (24.0%) were clinically diagnosed as FMF. Gene variants were found in 53 cases (30.1%) when searching for variants in the 10 disease genes other than theMEFVgene. Among them, the most frequently-identified genes wereNLRP3,NOD2,NLRP12,NLRC4, andPLCG2, which accounted for 14, 7, 17, 7, and 6 cases, respectively. These variants were less than 1% of healthy individuals or novel variants, but not regarded as pathogenic since the patients did not meet the diagnostic criteria of SAIDs caused by their identified variants clinically. Conclusion Twenty four percent of Japanese patients with unexplained fever were clinically diagnosed as FMF in this study. Low frequency but not pathogenic variants in genes other thanMEFVwere identified in 30.1% of the cases. It is not clear how much these gene variants contribute to the inflammatory phenotypes; therefore, further analysis would uncover their autoinflammatory phenotypes that cause fever.

Automated summary

In this study, 24% of Japanese patients with unexplained fever were clinically diagnosed as FMF, and genetic variants were identified in 30.1% of cases in genes other than MEFV, with these variants not considered pathogenic. Further analysis is needed to uncover the contribution of these gene variants to the inflammatory phenotypes causing fever.