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Mediterranean fever gene variants modify clinical phenotypes of idiopathic multi-centric Castleman disease
Yushiro Endo1, Tomohiro Koga1, Yoshihumi Ubara2
1Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Medical Sciences, Nagasaki, Japan.
Abstract:
Four cases of idiopathic multi-centric Castleman disease (iMCD) reportedly have variants in hereditary autoinflammatory disease-related genes; however, the frequency and role of these variants in iMCD is still unknown. We therefore investigated such gene variants among patients with iMCD and aimed to reveal the relationship between iMCD and autoinflammatory disease-related genes. We reviewed 14 Japanese iMCD patients who were recruited between January 2015 and September 2019. All patients met both the Japanese tentative diagnostic criteria for Castleman disease and the international consensus diagnostic criteria for iMCD. We performed genetic analyses for 31 autoinflammatory disease-related genes by targeted next-generation sequencing. The MEFV gene variants were observed in 10 of 14 patients with iMCD. Although iMCD had a high percentage of exons 2 or 3 variants of MEFV, comparison of data from healthy Japanese subjects indicated that there was no significant difference in the percentage between healthy Japanese subjects and patients with iMCD. Variants of uncertain significance (VUS) in the TNFRSF1A and CECR1 genes were observed in two of the patients, respectively. We divided patients into two groups-those with MEFV variants (excluding E148Q variants) and those without MEFV variants-and compared the clinical characteristics between these two groups. Patients with MEFV variants, excluding E148Q variants, exhibited a significantly higher likelihood of fever and significantly lower levels of hemoglobin than those lacking MEFV variants. Our results indicated that patients with iMCD tended to have a high frequency of MEFV gene variants and the presence of such variants can affect iMCD clinical phenotypes.
Insights
Genetic variants in hereditary autoinflammatory disease genes, particularly MEFV, are frequent in idiopathic multicentric Castleman disease (iMCD). These MEFV variants influence iMCD clinical presentation, including fever and hemoglobin levels.
Area of Science:
- Genetics
- Immunology
- Hematology
Background:
- Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder.
- Previous reports suggest a link between iMCD and hereditary autoinflammatory diseases, but the frequency and role of associated gene variants remain unclear.
Purpose of the Study:
- To investigate the frequency and impact of autoinflammatory disease-related gene variants in Japanese iMCD patients.
- To explore the relationship between iMCD and genes associated with hereditary autoinflammatory conditions.
Main Methods:
- Reviewed 14 Japanese iMCD patients meeting established diagnostic criteria.
- Conducted targeted next-generation sequencing for 31 autoinflammatory disease-related genes.
- Compared genetic data with healthy Japanese subjects and analyzed clinical characteristics based on gene variants.
Main Results:
- MEFV gene variants were found in 10 out of 14 iMCD patients.
- No significant difference in MEFV exon 2 or 3 variant frequency was observed between iMCD patients and healthy controls.
- Patients with MEFV variants (excluding E148Q) showed increased fever and lower hemoglobin levels compared to those without.
Conclusions:
- A high frequency of MEFV gene variants is observed in iMCD patients.
- Specific MEFV variants are associated with distinct clinical phenotypes in iMCD, suggesting a role in disease presentation.
- Further research is warranted to elucidate the precise role of these genetic variants in iMCD pathogenesis.
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