TY - JOUR
T1 - Blood-based test for diagnosis and functional subtyping of familial Mediterranean fever
AU - Van Gorp, Hanne
AU - Huang, Linyan
AU - Saavedra, Pedro
AU - Vuylsteke, Marnik
AU - Asaoka, Tomoko
AU - Prencipe, Giusi
AU - Insalaco, Antonella
AU - Ogunjimi, Benson
AU - Jeyaratnam, Jerold
AU - Cataldo, Ilaria
AU - Jacques, Peggy
AU - Vermaelen, Karim
AU - Dullaers, Melissa
AU - Joos, Rik
AU - Sabato, Vito
AU - Stella, Alessandro
AU - Frenkel, Joost
AU - De Benedetti, Fabrizio
AU - Dehoorne, Joke
AU - Haerynck, Filomeen
AU - Calamita, Giuseppe
AU - Portincasa, Piero
AU - Lamkanfi, Mohamed
N1 - Funding Information:
Funding This work was supported by the research Foundation Flanders (grant 1861219n to Bo and TBM T006116n to JD, FH and Ml) and the european research council (grant 727674 and 683144 to Ml).
Publisher Copyright:
© 2020 Royal Society of Chemistry. All rights reserved.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/7/1
Y1 - 2020/7/1
N2 - BACKGROUND AND OBJECTIVE: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease (AID) worldwide. The disease is caused by mutations in the MEFV gene encoding the inflammasome sensor Pyrin. Clinical diagnosis of FMF is complicated by overlap in symptoms with other diseases, and interpretation of genetic testing is confounded by the lack of a clear genotype-phenotype association for most of the 340 reported MEFV variants. In this study, the authors designed a functional assay and evaluated its potential in supporting FMF diagnosis.METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from patients with Pyrin-associated autoinflammation with an FMF phenotype (n=43) or with autoinflammatory features not compatible with FMF (n=8), 10 asymptomatic carriers and 48 healthy donors. Sera were obtained from patients with distinct AIDs (n=10), and whole blood from a subset of patients and controls. The clinical, demographic, molecular genetic factors and other characteristics of the patient population were assessed for their impact on the diagnostic test read-out. Interleukin (IL)-1β and IL-18 levels were measured by Luminex assay.RESULTS: The ex vivo colchicine assay may be performed on whole blood or PBMC. The functional assay robustly segregated patients with FMF from healthy controls and patients with related clinical disorders. The diagnostic test distinguished patients with classical FMF mutations (M694V, M694I, M680I, R761H) from patients with other MEFV mutations and variants (K695R, P369S, R202Q, E148Q) that are considered benign or of uncertain clinical significance.CONCLUSION: The ex vivo colchicine assay may support diagnosis of FMF and functional subtyping of Pyrin-associated autoinflammation.
AB - BACKGROUND AND OBJECTIVE: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease (AID) worldwide. The disease is caused by mutations in the MEFV gene encoding the inflammasome sensor Pyrin. Clinical diagnosis of FMF is complicated by overlap in symptoms with other diseases, and interpretation of genetic testing is confounded by the lack of a clear genotype-phenotype association for most of the 340 reported MEFV variants. In this study, the authors designed a functional assay and evaluated its potential in supporting FMF diagnosis.METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from patients with Pyrin-associated autoinflammation with an FMF phenotype (n=43) or with autoinflammatory features not compatible with FMF (n=8), 10 asymptomatic carriers and 48 healthy donors. Sera were obtained from patients with distinct AIDs (n=10), and whole blood from a subset of patients and controls. The clinical, demographic, molecular genetic factors and other characteristics of the patient population were assessed for their impact on the diagnostic test read-out. Interleukin (IL)-1β and IL-18 levels were measured by Luminex assay.RESULTS: The ex vivo colchicine assay may be performed on whole blood or PBMC. The functional assay robustly segregated patients with FMF from healthy controls and patients with related clinical disorders. The diagnostic test distinguished patients with classical FMF mutations (M694V, M694I, M680I, R761H) from patients with other MEFV mutations and variants (K695R, P369S, R202Q, E148Q) that are considered benign or of uncertain clinical significance.CONCLUSION: The ex vivo colchicine assay may support diagnosis of FMF and functional subtyping of Pyrin-associated autoinflammation.
KW - familial mediterranean fever
KW - fever syndromes
KW - inflammation
UR - http://www.scopus.com/inward/record.url?scp=85083830314&partnerID=8YFLogxK
U2 - 10.1136/annrheumdis-2019-216701
DO - 10.1136/annrheumdis-2019-216701
M3 - Article
C2 - 32312770
SN - 0003-4967
VL - 79
SP - 960
EP - 968
JO - Annals of the Rheumatic Diseases
JF - Annals of the Rheumatic Diseases
IS - 7
ER -