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

Abstract

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 the MEFV gene. Among them, the most frequently-identified genes were NLRP3, NOD2, NLRP12, NLRC4, and PLCG2, 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 than MEFV were 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.

Keywords:

• Autoinflammatory syndrome
• familial Mediterranean fever
• MEFV
• next generation sequencing
• unexplained fever

Conflict of interest

None.

Additional information

Funding

This work was supported by ‘Research on Measures for Intractable Diseases’ grant from the Japanese Ministry of Health, Labor, and Welfare [H31-Nanchi-Ippan-020] for KM, OO, RN, HI, and JSPS KAKENHI [Grant Numbers 19K08899] for HI.