Abstract
Familial Mediterranean fever is an auto inflammatory genetic disease involving especially Turks, Armenians, Arabs and non-Ashkenazi Jews and caused by variants in the MEFV gene. In this study, we aimed to evaluate the distribution and frequency of clinical, MEFV gene variants in FMF patients and the relationship between mutations in different exons and phenotype-genotype and clinical findings. 1028 patients diagnosed as FMF were included. The most common genotypes were M694V / R202Q heterozygous (10.4%), M694V homozygous (7.5%), M694V / E148Q / R202Q heterozygous (4.6%), V726A heterozygous (4.5%), M680I heterozygous (4.2%). c.1611–1 G > C, G152R, S104C, R116S, E336K, R461Q mutations were detected in the literature for the first time in FMF patients. We also divided the patients into 4 groups according to whether the MEFV mutations were exon 10 or non-exon 10. The first group consisted of non-exon 10 homozygous or compound heterozygous (n = 180) patients, Group 2 consisted of exon 10- non-exon 10 compound heterozygous (n = 318) patients, Group 3 consisted of exon 10 homozygous or compound heterozygous (n = 256) patients, while Group 4 consisted of heterozygous (n = 227) patients at any exon. There was no significant difference between the groups in terms of abdominal pain, arthritis, arthralgia, vomiting diarrhea, erysipelas like rash, amyloidosis, renal failure family history. There was no difference in fever between Group 1 (55.6%) and 2 (62.3%); however, these two groups were different from Group 3 (75.8%) and 4 (76.7%). Group 3 (18.8%) had the highest rate of appendectomy. In addition, allele frequencies of all mutations detected in the analyses were compared with allele frequencies of healthy people in the gnomad database. It is useful to analyse all exons in the MEFV gene with the next generation sequence analysis in the detection of FMF disease. S104C, R116S, G152R, E336K, R461Q, L508Q and c.1611–1 G > C mutations are also new variants in literature. c.1611–1 G > C is a possible pathogenic variant.
Similar content being viewed by others
References
Touitou I (2001) The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet 9(7):473–483. https://doi.org/10.1038/sj.ejhg.5200658
Booth DR, Gillmore JD, Lachmann HJ, Booth SE, Bybee A, Soyturk M, Akar S, Pepys MB, Tunca M, Hawkins PN (2000) The genetic basis of autosomal dominant familial Mediterranean fever. QJM 93(4):217–221
Moradian MM, Sarkisian T, Ajrapetyan H, Avanesian N (2010) Genotype-phenotype studies in a large cohort of Armenian patients with familial Mediterranean fever suggest clinical disease with heterozygous MEFV mutations. J Hum Genet 55(6):389–393. https://doi.org/10.1038/jhg.2010.52
Tunca M, Akar S, Onen F, Ozdogan H, Kasapcopur O, Yalcinkaya F, Tutar E, Ozen S, Topaloglu R, Yilmaz E, Arici M, Bakkaloglu A, Besbas N, Akpolat T, Dinc A, Erken E, Turkish FMFSG (2005) Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore) 84(1):1–11
French FMFC (1997) A candidate gene for familial Mediterranean fever. Nat Genet 17(1):25–31. https://doi.org/10.1038/ng0997-25
Dogan HO, Omma A, Turhan T, Bogdaycioglu N, Karaaslan Y, Yavuz H, Demirpence O, Aydin H, Bakir S (2016) Decreased chitotriosidase activity and levels in Familial Mediterranean Fever. J Korean Med Sci 31(12):1902–1906. https://doi.org/10.3346/jkms.2016.31.12.1902
Stella A, Cortellessa F, Scaccianoce G, Pivetta B, Settimo E, Portincasa P (2018) Familial Mediterranean fever: breaking all the (genetic) rules. Rheumatology (Oxford). https://doi.org/10.1093/rheumatology/key328
Dundar M, Kiraz A, Emirogullari EF, Saatci CE, Taheri S, Baskol M, Polat S, Ozkul Y (2012) A molecular analysis of familial Mediterranean fever disease in a cohort of Turkish patients. Ann Saudi Med 32(4):343–348
Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, Migdal A, Padeh S, Pras M (1997) Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 40(10):1879–1885. https://doi.org/10.1002/art.1780401023
Coskun S, Kurtgoz S, Keskin E, Sonmez F, Bozkurt G (2015) Frequency of mutations in Mediterranean fever gene, with gender and genotype-phenotype correlations in a Turkish population. J Genet 94(4):629–635
Dusunsel R, Dursun I, Gunduz Z, Poyrazoglu MH, Gurgoze MK, Dundar M (2008) Genotype-phenotype correlation in children with familial Mediterranean fever in a Turkish population. Pediatr Int 50(2):208–212. https://doi.org/10.1111/j.1442-200X.2008.02554.x
Giancane G, Ter Haar NM, Wulffraat N, Vastert SJ, Barron K, Hentgen V, Kallinich T, Ozdogan H, Anton J, Brogan P, Cantarini L, Frenkel J, Galeotti C, Gattorno M, Grateau G, Hofer M, Kone-Paut I, Kuemmerle-Deschner J, Lachmann HJ, Simon A, Demirkaya E, Feldman B, Uziel Y, Ozen S (2015) Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever. Ann Rheum Dis 74(4):635–641. https://doi.org/10.1136/annrheumdis-2014-206844
Ece A, Cakmak E, Uluca U, Kelekci S, Yolbas I, Gunes A, Yel S, Tan I, Sen V (2014) The MEFV mutations and their clinical correlations in children with familial Mediterranean fever in southeast Turkey. Rheumatol Int 34(2):207–212. https://doi.org/10.1007/s00296-013-2858-1
Ben-Chetrit E (2003) Familial Mediterranean fever (FMF) and renal AA amyloidosis–phenotype-genotype correlation, treatment and prognosis. J Nephrol 16(3):431–434
Ben-Chetrit E, Backenroth R (2001) Amyloidosis induced, end stage renal disease in patients with familial Mediterranean fever is highly associated with point mutations in the MEFV gene. Ann Rheum Dis 60(2):146–149. https://doi.org/10.1136/ard.60.2.146
Dundar M, Emirogullari EF, Kiraz A, Taheri S, Baskol M (2011) Common Familial Mediterranean Fever gene mutations in a Turkish cohort. Mol Biol Rep 38(8):5065–5069. https://doi.org/10.1007/s11033-010-0652-7
Barut K, Sahin S, Adrovic A, Sinoplu AB, Yucel G, Pamuk G, Aydin AK, Dasdemir S, Turanli ET, Buyru N, Kasapcopur O (2018) Familial Mediterranean fever in childhood: a single-center experience. Rheumatol Int 38(1):67–74. https://doi.org/10.1007/s00296-017-3796-0
Lachmann HJ, Sengul B, Yavuzsen TU, Booth DR, Booth SE, Bybee A, Gallimore JR, Soyturk M, Akar S, Tunca M, Hawkins PN (2006) Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations. Rheumatology (Oxford) 45(6):746–750. https://doi.org/10.1093/rheumatology/kei279
Balta B, Erdogan M, Alisik M, Kiraz A, Akalin T, Bastug F, Erel O (2018) Does thiol-disulphide balance show oxidative stress in different MEFV mutations? Rheumatol Int 38(1):97–104. https://doi.org/10.1007/s00296-017-3914-z
Kilinc M, Ganiyusufoglu E, Sager H, Celik A, Olgar S, Cetin GY, Davutoglu M, Altunoren O (2016) The report of sequence analysis on familial Mediterranean fever gene (MEFV) in South-eastern Mediterranean region (Kahramanmaras) of Turkey. Rheumatol Int 36(1):25–31. https://doi.org/10.1007/s00296-015-3329-7
Sayin Kocakap DB, Gunel-Ozcan A, Cabuk F, Ensari C (2014) The frequency of Familial Mediterranean fever gene mutations and genotypes at Kirikkale and comparison with the mean of regional MEFV mutation frequency of Turkey. Mol Biol Rep 41(3):1419–1426. https://doi.org/10.1007/s11033-013-2986-4
Comak E, Akman S, Koyun M, Dogan CS, Gokceoglu AU, Arikan Y, Keser I (2014) Clinical evaluation of R202Q alteration of MEFV genes in Turkish children. Clin Rheumatol 33(12):1765–1771. https://doi.org/10.1007/s10067-014-2602-6
Author information
Authors and Affiliations
Ethics declarations
Conflict of interest
The authors of this paper have no conflicts of interest, including specific financial interests, relationships, and/or affiliations relevant to the subject matter or materials included.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Balta, B., Erdogan, M., Kiraz, A. et al. A comprehensive molecular analysis and genotype–phenotype correlation in patients with familial mediterranean fever. Mol Biol Rep 47, 1835–1843 (2020). https://doi.org/10.1007/s11033-020-05277-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11033-020-05277-x